TREATING AUTOIMMUNE DISEASES

TECHNICAL FIELD The present invention relates to novel compounds that are modulators of RORgamma and the pharmaceutical use of such compounds.

BACKGROUND The retinoic acid-related orphan receptor γ (RORy) is a member of the ROR subfamily of nuclear receptors which includes three genes; RORA, RORB and RORC (also known as RORy). rory gene encodes two isoforms RORyl and RORy2 (also termed RORyt). RORyl is preferentially expressed in skeletal muscle and several other tissues, including pancreas, thymus, prostate, liver and testis (Hirose et al, 1994; Ortiz et al, 1995). RORyt is restricted to several distinct immune cell types (He et al, 1998). This immune system-specific isoform (RORyt) is the key lineage-defining transcription factor for the differentiation program of T helper type 17 (Th17) cells, a subset of CD4+ T-helper and the most prominent cells in producing a number of inflammatory cytokines, such as IL-17A, IL-17F, IL-22, and IL-23 considered as important pathogenic factors for many immune and inflammatory diseases. During the disease process Th17 cells are activated and are responsible for recruiting other inflammatory cell types, such as neutrophils, to mediate pathology in the target tissues (Korn et al, 2009). RORyt is also able to induce IL-17A and IL-17F in naive CD4+ T-helper, NKT and iNKT cells (Rachitskaya et al, 2008), γδΤ cells (Murdoch & Lloyd, 2010), CD8+ Tcells (Liu et al, 2007) and CD4-CD8+TCRab+T cells (Crispin et al, 2008). RORyt is also expressed in and is required for the generation of LTi cells (Eberl et al, 2004), which are central to the development of lymphoid organs such as lymph node and Peyer's patch (Lipp & Muller, 2004).

Overexpression of RORyt in naive CD4+ T cells was demonstrated to drive the induction and development of Th17 cells. In contrast, RORyt deficiency in mice completely impairs Th17 cell differentiation and induces resistance to the development of autoimmune diseases, such as experimental autoimmune encephalomyelitis (EAE) a model of multiple sclerosis (Dang et al, 201 1 ; Yang et al, 2008) or experimental autoimmune myocarditis (EAM) (Yamashita et al, 201 1 ). In the same manner, mice lacking IL-17 are resistant to development of EAE, and collagen-induced arthritis (CIA), a model of rheumatoid arthritis. IL- 17 neutralization with a targeted antibody suppresses autoimmune inflammation, joint damage, and bone destruction (Furuzawa-Carballeda et al, 2007; Lubberts et al, 2004; Stockinger et al, 2007). Moreover, blocking Th17 pathway demonstrated good efficacy in patients with some chronic inflammatory diseases. For example, the anti-p40 monoclonal antibody Ustekinumab (Stelara) that targets Th17 and Th1 through IL-23 and IL-12 respectively, has been approved for the treatment of moderate to severe plaque psoriasis in adult patients and showed a clinical (phase lib) efficacy in refractory Crohn diseased patients (Tuskey & Behm, 2014).

Small molecule RORvt modulators have therapeutic effects in preclinical disease models. In particular, compounds TMP778 and SR1001 were efficacious in psoriasis and multiple sclerosis models, respectively, when administered by injection (Skepner et al, 2014; Solt et al, 201 1 ). Recently, Vitae Pharma has announced that a small molecule RORgt inverse agonist VTP-43742 reduced the Psoriasis Area Severity Index (PASI) score and plasma IL-17 levels, relative to placebo, in patients with moderate to severe psoriasis.

To summarise, RORvt activity modulation results in the modulation of IL-17 dependent immune and inflammatory responses.

Currently, there is considerable evidence suggesting that RORvt/IL-17 component is closely associated with a range of chronic inflammatory diseases such as multiple sclerosis (MS), psoriasis, inflammatory bowel diseases (IBD), rheumatoid arthritis (RA), uveitis and lung diseases. Compounds able to modulate RORvt activity are also expected to provide a therapeutic benefit in the treatment of numerous medical disorders, including autoimmune, inflammatory, fibrotic and cholestatic disorders, such as asthma, ankylosing spondylitis, autoimmune cardiomyopathy, autoimmune hepatitis, Crohn's disease, chronic obstructive proliferative disease (COPD), diabetes mellitus type 1 , lupus erythematosus, lupus nephritis, multiple sclerosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, ulcerative colitis, myocarditis, pulmonary fibrosis (idiopathic pulmonary, interstitial lung, cystic and progressive massive fibrosis), Non Alcoholic Fatty Liver Disease (NAFLD), NonAlcoholic SteatoHepatitis (NASH) and Alcoholic SteatoHepatitis (ASH), cardiac fibrosis and heart myocardial and endomyocardial fibrosis, arterial fibrosis, atherosclerosis/restenosis, intestinal fibrosis (occurs for example in Crohn's disease and collagenous colitis), kidney fibrosis, scleroderma and systemic sclerosis Primary Biliary Cholangitis (PBC), primary sclerosisng cholangitis (PSC), billiary artesia, Progressive familial intrahepatic cholestasis (PFIC), Hepatitis (hepatitis A, hepatitis B, hepatitis C).

The present invention describes novel RORvt modulators, their preparation and their use in therapy, in particular in the treatment of immune, inflammatory, metabolic, fibrotic and cholestatic diseases. SUMMARY OF INVENTION

RORy inverse agonists were proposed in Skepner et al., 2014 who allegedly showed that compound T was efficacious in psoriasis model when administered by injection.

Recently, data from a Phase 2a proof -of-concept clinical trial with RORgt inverse agonist (VTP-43742) were reported (Vitae Pharma press release)..

VTP-43742 demonstrated a clear signal of efficacy, with patients in the 350 mg dose group achieving a 24 percent reduction in the Psoriasis Area Severity Index (PASI) score relative to placebo. In the 700 mg dose group, patients achieved a 30 percent placebo- adjusted PASI score reduction.

The present invention provides novel compounds that are modulators of RORy and have the following formula (I):

In a particular embodiment, the novel compounds have the following formula (la):

The present invention also provides pharmaceutical compositions comprising the compounds of formula (I) or (la), since they modulate RORy in vitro and in cellular models, indicating that these compounds have properties of pharmaceutical interest. Accordingly, further objects of the invention include methods of treatment comprising the administration of said pharmaceutical composition for the treatment of RORy-related diseases such as autoimmune, inflammatory diseases, metabolic, fibrotic and cholestatic diseases.

The present invention also provides a compound of formula (I) or (la), for use as a medicament. The present invention also provides a compound of formula (I) or (la), for use in a method for the treatment of RORv-related diseases.

Further objects of the present invention, including preferred compounds of formula (I) or (la), methods of preparing compounds of formula (I) or (la) and preferred medical uses or methods, in combination or not with other compounds, are provided in the Detailed Description.

DESCRIPTION OF THE FIGURES Abbreviations used in the figures and in the text:

- ACLF acute-on-chronic liver failure

- ADME absorption, distribution, metabolism, and excretion

- ALF acute liver failure

- ASH Alcoholic SteatoHepatitis

- AUC area under the curve

- BINAP 2,2'-Bis(diphenylphosphino)-1 ,1 '-binaphthalene

- BOC tButylOxyCarbonyl

- CD Cluster of Differentiation

- CDCI3 deuterated chloroform

- CFA Complete Freund's Adjuvant

- CHCI3 chloroform

- CH2CI2 Dichloromethane

- CIA collagen-induced arthritis

- CMC CarboxyMethyl Cellulose

- CNS Conserved non coding sequence

- COPD chronic obstructive proliferative disease

- Cpd: Compound

- Cs2C03 Cesium Carbonate

- di-tert-butyl X-Phos 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl

- DMAP 4-(DiMethylAmino)Pyridine

- DMEM Dulbecco's modified Eagle's medium

- DMF DiMethylFormamide

- DMSO DiMethyl Sulfoxide

- EAE Experimental Autoimmune Encephalomyelitis

- EAM Experimental Autoimmune Myocarditis

- EDCI.HCI N-Ethyl-N'-(3-Dimethylaminopropyl)Carbodilmide Hydrochloride - EDTA ethylene-diamine tetra-acetic acid

- equiv equivalent

- Et20 Diethyl ether

- Et3N Triethylamine

- EtOAc Ethyl acetate

- EtOH Ethanol

- H20 water

- H2S04 sulfuric acid

- HCI Hydrochloric acid

- HN03 nitric acid

- HPLC High Performance Liquid Chromatography

- HTAB hexadecyltrimethyl ammonium bromide

- IBD inflammatory bowel disease

- ICP intrahepatic cholestasis of pregnancy

- IC50 Half maximal inhibitory concentration

- IL-12 interleukin 12

- IL-17 interleukin 17

- IL-22 interleukin 22

- IL-23 interleukin 23

- iPrOH isopropanol

- lUPAC International Union of Pure and Applied Chemistry

- K2C03 potassium carbonate

- LCMS Liquid Chromatography-Mass Spectrometry

- Me3SiCI Trimethylsilyl chloride

- MeOH Methanol

- mg miligramme

- MgS04 Magnesium sulphate

- min minute

- ml_ mililiter

- ML microliter

- MOG Myelin Oligodendrocyte Glycoprotein

- mp melting point

- MS multiple sclerosis

- NAFLD non-alcoholic fatty liver disease

- NaHC03 Sodium bicarbonate

- NaN3 sodium azide - NaOH sodium hydroxide

- NASH NonAlcoholic SteatoHepatitis

- NH4CI ammonium chloride

- NMR nuclear magnetic resonance

- NR Nuclear Receptor

- PAS I psoriasis area and severity index

- PBC primary biliary cholangitis

- PBS phosphate-buffered saline

- PCR Polymerase Chain Reaction

- Pd2(dba)3 Tris(dibenzylideneacetone)dipalladium(0)

- Pd/C palladium on carbon

- Pd(OAc)2 Palladium(ll) acetate

- PdCI2(dppf)2 1 ,1 '-Bis(diphenylphosphino)ferrocene]dichloropalladium(ll)

- PFIC progressive familial intrahepatic cholestasis

- PMA Phorbol 12-Myristate 13-Acetate

- ppm parts-per-million

- PSC primary sclerosing cholangitis

- PTX pertussis toxin

- PyBOP (benzotriazol-l -yloxy)tripyrrolidinophosphonium hexafluorophosphate

- RA rheumatoid arthritis

- RPMI Roswell Park Memorial Institute medium

- ROR Retinoic Acid-Related Orphan Receptor

- rt room temperature

- sat. saturated

- SIRS systemic inflammatory response syndrome

- SPF Specific Pathogen Free

- TFA trifluoroacetic acid

- Th1 T helper 1

- Th17 T helper 17

- THF TetraHydroFuran

- TLC Thin-Layer Chromatography

- UV ultra-violet

- XPhos Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl

- W Microwave Fig. 1 and 2-I intermediate compounds for the synthesis of the Compounds of formula (I) or m

Intermediates are independently generated for the synthesis of compounds of formula (I) or (la): for example 2-(3-oxo-3,4-dihydro-2H-1 ,4-benzoxazin-7-yl)acetic acid Ex.2 (Figure 1AA), 2-(2 _! 3-dioxo-1 ,2 _! 3,4-tetrahydroquinoxalin-6-yl)acetic acid Ex.11 (Figure 1AB), 2-(3- oxo-3,4-dihydro-2H-1 ,4-benzoxazin-6-yl)acetic acid Ex.12 (Figure 1AC), 2-(2,2-difluoro-3- oxo-3,4-dihydro-2H-1 ,4-benzoxazin-7-yl)acetic acid Ex.13 (Figure 1AD), 2-(2-oxo-2,3- dihydro-1 H-indol-5-yl)acetic acid Ex.14 (Figure 1AE), 2-(2,2-dimethyl-3-oxo-3,4-dihydro-2H- 1 ,4-benzoxazin-7-yl)acetic acid Ex.15 (Figure 1AF), 2-(2,2-dioxo-1 ,3-dihydro-2,1 - benzothiazol-5-yl)acetic acid hydrochloride Ex.17 (Figure 1AG), 2-(2-oxo-1 ,2,3,4- tetrahydroquinolin-6-yl)acetic acid Ex.23 (Figure 1AH), 2-(1 -methyl-2-oxo-2,3-dihydro-1 H- indol-5-yl)acetic acid Ex.24 (Figure 1AI), 2-(3-hydroxy-1 ,3-dimethyl-2-oxo-2,3-dihydro-1 H- indol-5-yl)acetic acid Ex.25 (Figure 1AI), 2-(1 ,3,3-trimethyl-2-oxo-2,3-dihydro-1 H-indol-5- yl)acetic acid Ex.26 (Figure 1AI), 2-(2-methanesulfonyl-2,3-dihydro-1 H-isoindol-5-yl)acetic acid Ex.27 (Figure 1AJ), 2-(2-methanesulfonyl-2,3-dihydro-1 H-isoindol-4-yl)acetic acid Ex.28 (Figure 1AK), 2-(1 -oxo-2,3-dihydro-1 H-inden-5-yl)acetic acid Ex.29 (Figure 1AL), 2-(7- methyl-2-oxo-2,3-dihydro-1 H-indol-5-yl)acetic acid Ex.30 (Figure 1AM), 2-[2-oxo-3-(propan- 2-ylidene)-2,3-dihydro-1 H-indol-5-yl]acetic acid Ex.31 (Figure 1AN), 1 -(2-methanesulfonyl- 2,3-dihydro-1 H-isoindol-5-yl)cyclopropane-1 -carboxylic acid Ex.33 (Figure 1AO), 2-[3-(2- hydroxyethyl)-1 H-indol-5-yl]acetic acid Ex.34 (Figure 1AP)1 -(3-oxo-3,4-dihydro-2H-1 ,4- benzoxazin-7-yl)cyclopropane-1 -carboxylic acid Ex.35 (Figure 1AQ), 1 -[3-(2-hydroxyethyl)- 1 H-indol-5-yl]cyclopropane-1 -carboxylic acid Ex.36 (Figure 1AR), 1 -(2-oxo-2,3-dihydro-1 H- indol-5-yl)cyclopropane-1 -carboxylic acid Ex.37 (Figure 1AS), 1 -(2,2-dioxo-1 ,3-dihydro-2,1 - benzothiazol-5-yl)cyclopropane-1 -carboxylic acid Ex.38 (Figure 1AT), 2-(3-methyl-1 H-indol- 5-yl)acetic acid Ex.39 (Figure 1AU), 1 -(1 -methyl-2,2-dioxo-1 ,3-dihydro-2-benzothiazol-5- yl)cyclopropane-1 -carboxylic acid Ex.40 (Figure 1AV), 1 -{1 -[2-(benzyloxy)ethyl]-2,3-dihydro- 1 H-indol-5-yl}cyclopropane-1 -carboxylic acid Ex.41 (Figure 1 AW), 1 -(2,2-dioxo-1 ,3-dihydro- 2-benzothiophen-5-yl)cyclopropane-1 -carboxylic acid Ex.43 (Figure 1AY), 2-(2,2-dioxo-1 ,3- dihydro-2-benzothiophen-5-yl)acetic acid Ex.46 (Figure 1 BB), 2-(3-oxo-2,3-dihydro-1 H- inden-5-yl)acetic acid Ex.51 (Figure 1 BG), 2-(2-ethoxy-1 H-1 ,3-benzodiazol-5-yl)acetic acid Ex.52 (Figure 1 BH), 2-[6-(methylsulfanyl)naphthalen-2-yl]acetic acid Ex.53 (Figure 1 BI), 2-[2- (ethylsulfanyl)-l H-1 ,3-benzodiazol-5-yl]acetic acid Ex.54 (Figure 1 BJ), 2-[2-(morpholin-4-yl)- 1 H-1 ,3-benzodiazol-5-yl]acetic acid Ex.55 (Figure 1 BK), 1 -(1 -cyclopropanecarbonyl-2,3- dihydro-1 H-indol-5-yl)cyclopropane-1 -carboxylic acid Ex.56 (Figure 1 BL), 2-{1 -[3-(tert- butoxy)-3-oxopropyl]-1 H-indol-5-yl}acetic acid Ex.57 (Figure 1 BM), 2-[3-(2- methanesulfonylethyl)-1 H-indol-5-yl]acetic acid Ex.58 (Figure 1 BN), 2-[3-(2- methanesulfonylacetyl)-1 H-indol-5-yl]acetic acid Ex.59 (Figure 1B0), 1-(1 H-indol-5- yl)cyclopropane-1-carboxylic acid Ex.61 (Figure 1BQ), 2-[3-(methylsulfamoyl)-1 H-indol-5- yl]acetic acid Ex.64 (Figure 1BT), 2-[3-(morpholine-4-carbonyl)-1 H-indol-5-yl]acetic acid Ex.65 (Figure 1BU), 1-[2-(2-methoxyacetyl)-2,3-dihydro-1 H-isoindol-5-yl]cyclopropane-1- carboxylic acid Ex.67 (Figure 1BW), 2-(1-cyclopropanecarbonyl-2,3-dihydro-1 H-indol-5- yl)acetic acid Ex.68 (Figure 1BX), 1-(2,2-dioxo-1,3-dihydro-4,2,1-benzoxathiazin-6- yl)cyclopropane-1 -carboxylic acid Ex.69 (Figure 1BY), 1-(2,3-dioxo-2,3-dihydro-1 H-indol-5- yl)cyclopropane-1 -carboxylic acid Ex.70 (Figure 1BZ), 1 -(1 -acetylindolin-5- yl)cyclopropanecarboxylic acid = 1-(1-acetyl-2,3-dihydro-1 H-indol-5-yl)cyclopropane-1- carboxylic acid Ex.71 (Figure 1CA), 1-(2-acetylisoindolin-5-yl)cyclopropanecarboxylic acid = 1-(2-acetyl-2,3-dihydro-1 H-isoindol-5-yl)cyclopropane-1 -carboxylic acid Ex.72 (Figure 1CB), 1-(1-methyl-2-oxo-2,3-dihydro-1 H-indol-5-yl)cyclopropane-1 -carboxylic acid Ex.75 (Figure 1 CE), 1 -(1 -ethyl-2,2-dioxo-1 ,3-dihydro-2, 1 -benzothiazol-5-yl)cyclopropane-1 -carboxylic acid Ex.76 (Figure 1CF), 1-(1-oxo-2,3-dihydro-1 H-inden-5-yl)cyclopropane-1 -carboxylic acid Ex.82 (Figure 1CL), 1-{2-oxo-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-6-yl}cyclopropane -1- carboxylic acid Ex.84 (Figure 1CN), 1-(3,3-dimethyl-2-oxo-2,3-dihydro-1 H-indol-5- yl)cyclopropane-1 -carboxylic acid Ex.85 (Figure 1CO), 2-(2,2-dioxo-1,3-dihydro-4,2,1- benzoxathiazin-6-yl)acetic acid Ex.86 (Figure 1CP), 1-(2H-1,3-benzodioxol-5- yl)cyclopropane-1 -carboxylic acid Ex.88 (Figure 1CR), 1-[1-(oxan-4-ylmethyl)-2,2-dioxo-1,3- dihydro-2,1-benzothiazol-5-yl]cyclopropane-1 -carboxylic acid Ex.91 (Figure 1CU), 1-(7- fluoro-2-oxo-2,3-dihydro-1 H-indol-5-yl)cyclopropane-1 -carboxylic acid Ex.92 (Figure 1CV), 1- (3, 3-difluoro-2-oxo-2, 3-dihydro-1 H-indol-5-yl)cyclopropane-1 -carboxylic acid Ex.93 (Figure 1CW), 1-[1-(hydroxyimino)-2,3-dihydro-1 H-inden-5-yl]cyclopropane-1 -carboxylic acid Ex.94 (Figure 1CX), 2-[1-(oxan-4-ylmethyl)-2,2-dioxo-1,3-dihydro-2,1-benzothiazo l-5-yl]acetic acid Ex.95 (Figure 1CY), 1-(2,2-dimethyl-2,4-dihydro-1 ,3-benzodioxin-7-yl)cyclopropane-1- carboxylic acid Ex.96 (Figure 1CZ), 1-(2,2-dimethyl-2,4-dihydro-1,3-benzodioxin-6- yl)cyclopropane-1 -carboxylic acid Ex.97 (Figure 1DA), 1-[3-(1-hydroxy-2-methylpropan-2-yl)- 1 H-indol-5-yl]cyclopropane-1 -carboxylic acid Ex.98 (Figure 1DB), 1-(1-methyl-2,2-dioxo-1,3- dihydro-4,2,1-benzoxathiazin-6-yl)cyclopropane-1 -carboxylic acid (Figure 1DD) and 1-(2,2- dimethyl-2H-1,3-benzodioxol-5-yl)cyclopropane-1 -carboxylic acid (Figure 1DF).

In a same manner were synthetised (2-bromo-4-methylphenyl)(5-methylfuran-2- yl)methanamine hydrochloride Ex.18 (Figure 2A), (2,4-dimethylphenyl)(5-methylfuran-2- yl)methanamine Ex.19 (Figure 2B), [4-methoxy-2-(morpholin-4-yl)phenyl](5-methylfuran-2- yl)methanamine hydrochloride Ex.20 (Figure 2C), (2,4-dimethylphenyl)(5-ethylfuran-2- yl)methanamine hydrochloride Ex.21 (Figure 2D), (2-bromo-4-methoxyphenyl)(5- methylfuran-2-yl)methanamine Ex.22 (Figure 2E), (5-chlorofuran-2-yl)(2,4- dimethylphenyl)methanamine Ex.32 (Figure 2F), 2-[amino(5-methylfuran-2-yl)methyl]-N,N,5- trimethylaniline hydrochloride Ex.42 (Figure 2G), [4-methyl-2-(pyrrolidin-1 -yl)phenyl](5- methylfuran-2-yl)methanamine hydrochloride Ex.44 (Figure 2H), (5-chlorofuran-2-yl)[4- methyl-2-(piperidin-1 -yl)phenyl]methanamine Ex.47 (Figure 2I), (5-chlorofuran-2-yl)[4-methyl- 2-(pyrrolidin-1 -yl)phenyl]methanamine hydrochloride Ex.48 (Figure 2J), [2-(azepan-1 -yl)-4- methoxyphenyl](5-methylfuran-2-yl)methanamine Ex.63 (Figure 2K), (2,4-dimethylphenyl)(6- methylpyridin-2-yl)methanamine dihydrochloride Ex.77 (Figure 2L), (2,4- dimethylphenyl)(furan-2-yl)methanamine Ex.80 (Figure 2N), (3-chlorophenyl)(2,4- dimethylphenyl)methanamine hydrochloride Ex.83 (Figure 20), (3,5-dimethylpyridin-2-yl)(5- methylfuran-2-yl)methanamine dihydrochloride Ex.87 (Figure 2P), [4-methyl-2- (trifluoromethyl)phenyl](5-methylfuran-2-yl)methanamine hydrochloride Ex.99 (Figure 2Q) and (2-methoxy-4-methylphenyl)(5-methylfuran-2-yl)methanamine Ex.101 (Figure 2R).

Fig. 3-General synthesis scheme of Compounds of formula (I) or (la)

Compounds of formula (I) or (la) are generated using the Protocol A summarized in

Figure 3.

Fig. 4- Effect of compounds according to the invention on clinical score.

Clinical score from MOG-induced EAE mice determined daily by a visual inspection of behavior. Fig. 4A shows the mean of EAE disease course in mice treated with vehicle or Cpd. 24 at 30 and 60 mpk. Fig. 4B shows the AUC of clinical disease curves for all mice treated with vehicle or Cpd.24 at 30 and 60 mpk; horizontal line: median value. Error bars: SEM; P =0.005 by 2-Way ANOVA. ^** P<0.01 . Fig. 5- Effect of compounds according to the invention on psoriasis model.

Fig. 5A shows the effect of Cpd. 24 oral administrations (30 mpk) on cumulative clinical score evolution during the course of the experiment. Fig. 5B shows the effect of Cpd. 24 oral administrations (30 mpk) on MPO activity. Statistical evaluation of differences between the experimental groups was determined by using two-way Anova followed by a Bonferroni post test. ^*** p<0.001 , IMQ- Vehicle compared withlMQ-Cpd. 24 at 30 mpk.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides novel compounds that are modulators of RORgamma. These compounds, and pharmaceutical compositions comprising the same, are suitable for treating any disease wherein the RORgamma activity is involved, for instance in multiple autoimmune, inflammatory, metabolic, fibrotic and cholestatic disorders. Compounds of formula (I)

According to a first aspect, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof:

in which, A is a C-R1 e group or a nitrogen atom;

R1 a is a halogen atom, a nitrile group, a nitro group (N02), a (C1 -C6) alkyl group, a (C1 -C6) alkyloxy group, a (C1 -C6) alkylthio group, a -NH2 group, a (C1 -C6) alkylamino group, a (C1 -C6)dialkylamino group or a heterocyclic group;

R1 b is a hydrogen atom, a (C1 -C6)alkyloxy group, a (C1 -C6)alkyl group or a heterocyclic group;

R1 c is a hydrogen atom, a halogen atom, a (C1 -C6)alkyl group, a (C1 -C6)alkyloxy group, a (C1 -C6)alkylthio group, a heterocyclic group, a cyano group, an amido group or a hydroxyl group;

R1 d and R1 e are, independently, a hydrogen atom, a halogen atom, a (C1 -C6)alkyloxy group or an (C1 -C6)alkyl group;

R2 is an unsubstituted, branched (C3-C6)alkyl group; an (C2-C6)alkynyl group; a (C3- C14)cycloalkyl group; an (C6-C14)aryl group optionally substituted by a (C1 -C6)alkyl group or a halogen; a 5-membered hetoaryl group containing an oxygen or a nitrogen atom optionally substituted by a (C1 -C6)alkyl group or a halogen; or a 6-membered heteroaryl group containing at least one nitrogen atom optionally substituted by a (C1 -C6)alkyl group or a halogen;

R'2 is a hydrogen atom; an (C1 -C6)alkyl group; an (C2-C6)alkynyl group; a (C3- C14)cycloalkyl group; a (C6-C14)aryl group optionally substituted by a (Ci-Ce)alkyl group or a halogen; or a heterocyclic group optionally substituted by a (Ci-Ce)alkyl group or a halogen; or R2 and R2' can form, together with the carbon atom to which they are attached, cycloalkyl group or a heterocycloalkyl group;

L1 is a -NH-CO- or -CO-NH- group;

L2 represents a CR4R'4 group;

R4 and R'4 are independently, a hydrogen atom or a (C1 -C6)alkylgroup;

or R4 and R'4 can form, together with the carbon atom to which they are attached, cycloalkyl group; ") or (II"'):

which:

A1 is a nitrogen atom or a CX3 group;

A2 is a nitrogen atom or a CX3' group;

A3 is a nitrogen atom or a CX3" group;

wherein one and only one of A1 , A2 and A3 is a nitrogen atom;

X1 and X2 form together, with the carbons of the ring to which they are attached:

• an unsaturated 5- to 8-membered ring optionally interrupted by at least one group selected from N-R8; an oxygen atom; a sulfur atom; a S02 group; a CO group; and a -N-S02-R7- group with R7 being a (C1 -C4)alkyl group; or · a saturated 5- to 8-membered ring interrupted by at least one group selected in the group consisting of a nitrogen atom; an oxygen atom; a sulfur atom; a S02 group; a CHOH; a CO group; and a -N-S02-R7- group with R7 being a (C1 -C4)alkyl group;

R8 is a hydrogen atom; a (C1 -C6) alkyl group optionally substituted by a COOH group, a COO(C1 -C6)alkyl or a heterocycloalkyle group; a COR9 group or a S02R9 group;

R9 is a (C1 -C6)alkyl or a heterocycloalkyle,

said 5- to 8-membered saturated or unsaturated rings are optionally substituted by at least one radical selected in the group consisting of: - a (C1 -C6)alkyl group optionally substituted by at least one hydroxyl, morpholino, tetrahydropyran, S02R5, or NH-S02-R5 group, R5 being a hydrogen or a (C1 -C6)alkyl group; with the proviso that two hydroxyl groups cannot be attached to the same carbon atom;

- a (C2-C6)alkenyl group optionally substituted by at least one hydroxyl, or a heterocyclic group;

- a fluorine atom;

- a =N-NRR' group with R and R' being independently a hydrogen or a (C1 -C6)alkyl group;

- a =NR" group with R" being a hydrogen, a (C1 -C6)alkyl group or a hydroxy;

- a OR6 group or a SR6 group, R6 being a hydrogen atom or a (C1 -C6)alkyl group ;

- a COR10 group, R10 being a morpholino group or a tetrahydopyran group, or R10 being an alkyl optionally substituted, by a S02R1 1 group, or a N-S02-R1 1 group, R1 1 being a (C1 -C6)alkyl ; and

- a =CH-R"' with R'" being a heteroaryl optionally substituted by at least one substituent selected from a (C1 -C6)alkyl and a NRR' with R and R' are such as above defined; and

X3, X3' and X3" are, independently, a hydrogen, a halogen atom, or a (C1 -C6)alkyl group.

In particular embodiments, in the compound of formula (I) of the present invention: a (C1 -C6)alkyl group may be a substituted or unsubstituted (C1 -C6)alkyl group, in particular a substituted or unsubstituted (C1 -C4)alkyl group;

a (C1 -C6)alkyloxy group may be a substituted or unsubstituted (C1 -C6)alkyloxy group, in particular a substituted or unsubstituted (C1 -C4)alkyloxy group;

a (C6-C14)aryl group may be a substituted or unsubstituted (C6-C14)aryl group;

a heterocyclic group may be a substituted or unsubstituted heterocycloalkyl or heteroaryl group.

The present invention also includes stereoisomers (diastereoisomers, enantiomers), pure or mixed, as well as racemic mixtures and geometric isomers, or tautomers of compounds of formula (I). The invention further includes salts, solvates (in particular hydrates) and polymorphs or crystalline forms of the compounds of formula (I). In a particular embodiment, A is a C-R1 e group.

In a further particular embodiment, R1 a is a halogen atom, a nitrile group, a nitro group (N02), a (C1 -C6)alkyl group, a (C1 -C6)alkyloxy group, a (C1 -C6)alkylthio group, an amino group, a (C1 -C6)alkylamino group, a (C1 -C6)dialkylamino group, a piperidinyl group, a pyrrolidinyl group, an azepanyl group, a piperazinyl group, or a morpholinyl group, wherein said piperidinyl, pyrrolidinyl, azepanyl, piperazinyl or morpholinyl group can be optionally substituted by at least one (C1 -C6)alkyl groups. In a further particular embodiment, R1 a is a halogen atom, a nitrile group, a nitro group (N02), a (C1 -C6)alkyl group, a (C1 -C6)alkyloxy group, a (C1 -C6)alkylthio group, an amino group, a (C1 -C6)alkylamino group, a (C1 - C6)dialkylamino group, a piperidinyl group, a pyrrolidinyl group or an azepanyl group, wherein said piperidinyl, pyrrolidinyl or azepanyl group can be optionally substituted by at least one (C1 -C6)alkyl groups. In another particular embodiment, R1 a is selected in the group consisting of a halogen atom (such as a bromine atom), a (C1 -C6)alkyl group (such as a methyl or a CF3 group), a (C1 -C6)dialkylamino group (such as dimethylamino group, a piperidinyl group (such as a piperidin-1 -yl group), a piperazinyl group (such as a piperazin-1 - yl) and an azepanyl group (such as an azepan-1 -yl). In a further particular embodiment, R1 a is selected in the group consisting of a halogen atom (such as a bromine atom), a (C1 - C6)alkyl group (such as a methyl group), a piperidinyl group (such as a piperidin-1 -yl group) or a piperazinyl group (such as a piperazin-1 -yl). In another particular embodiment, R1 a is a halogen, group, a (C1 -C6)alkyl group, a piperidinyl group (such as a piperidin-1 -yl group), a morpholinyl group (such as morpholin-4-yl group), a pyrrolidinyl group (such as a pyrrolidin- 1 -yl group), a piperazinyl group (such as a piperazin-1 -yl), or an azepanyl group (such as an azepan-1 -yl). In a particular embodiment, R1 a is a halogen atom, a (C1 -C6)alkyl group, a piperidinyl group (such as a piperidin-1 -yl group), a morpholinyl group (such as morpholin-4- yl group) or a pyrrolidinyl group (such as a pyrrolidin-1 -yl group).

In a particular embodiment, R1 b is a hydrogen atom.

In a particular embodiment, R1 c is a hydrogen atom, an (C1 -C6)alkyl group, or an (C1 - C6)alkyloxy group. In another particular embodiment, R1 c is a (C1 -C6)alkyl group (such as a methyl group), or a (C1 -C6)alkyloxy group (such as a methoxy group).

In a particular embodiment, R1 d is a hydrogen atom.

In a particular embodiment, R1 e is a hydrogen atom.

In a further particular embodiment, R1 b, R1 d and R1 e are hydrogen atoms. In a further variant, R1 b, R1 d and R1 e are hydrogen atoms and R1 c is a (C1 -C6)alkyl group (such as a methyl group) or a (C1 -C6)alkyloxy group (such as a methoxy group). In another embodiment, R2 is a (C3-C6)alkyl group, a (C3-C14)aryl group, or a heteroaryl group.

In a further embodiment, R2 is a (C6-C14)aryl group or a heteroaryl group. In a particular variant, R2 is selected in the group consisting of a phenyl group, a furanyl group and a pyridinyl group, wherein the substituents of said phenyl, furanyl and pyridinyl group may be unsubstituted or substituted, such as by at least one group selected in the group consisting of (C1 -C6)alkyl groups (e.g. at least one methyl group, such as one or two methyl groups) and halogen atoms (e.g. chlorine, such as one or two chlorine atoms). Illustratively, R2 may be a phenyl group, a methylphenyl group, a dimethylphenyl group (such as a 2,4- dimethylphenyl group), a chlorophenyl group (such as a 3-chlorophenyl group), a furanyl group (such as a furan-2-yl group), a methylfuranyl group (such as a 5-methylfuran-2-yl group), a chlorofuranyl group (such as a 5-chlorofuranyl group), a pyridinyl group (such as a pyridine-2-yl group) or a methylpyridinyl group (such as a 6-methylpyridin-2-yl group). In a particular embodiment, R2 is selected in the group consisting of a dimethylphenyl group (such as a 2,4-dimethylphenyl group), a chlorophenyl group (such as a 3-chlorophenyl group), a furanyl group (such as a furan-2-yl group), a methylfuranyl group (such as a 5- methylfuran-2-yl group), a chlorofuranyl group (such as a 5-chlorofuranyl group) and a methylpyridinyl group (such as a 6-methylpyridin-2-yl group). In a particular embodiment, R2 is a furanyl group, such as a furan-2-yl group, which is unsubstituted, or substituted with a least one (C1 -C6)alkyl group, in particular at least one methyl group, such as a 5- methylfuran-2-yl group.

In another embodiment, R'2 is a hydrogen atom.

In another particular embodiment, R2 is an (C3-C6)alkyl group, an (C6-C14)aryl group, or a heteroaryl group, and R'2 is a hydrogen atom.

In a further particular embodiment, the invention relates to a compound of formula (I) wherein:

R1 a is a halogen atom, a nitrile group, a nitro group (N02), a (C1 -C6)alkyl group, a (C1 -C6)alkyloxy group, a (C1 -C6)alkylthio group, an amino group, a (C1 -C6)alkylamino group, a (C1 -C6)dialkylamino group, a piperidinyl group, a morpholinyl group, a pyrrolidinyl group, a piperazinyl group, or an azepanyl group, wherein said piperidinyl, morpholinyl, pyrrolidinyl, piperazinyl, or azepanyl group can be optionally substituted by at least one (C1 - C6)alkyl groups;

R1 b is a hydrogen atom;

R1 c is a hydrogen atom, a (C1 -C6)alkyl group, or a (C1 -C6)alkyloxy group; R2 is a (C3-C6)alkyl group, an (C6-C14)aryl group, or a heteroaryl group, and R'2 is a hydrogen atom.

In a further particular embodiment, the invention relates to a compound of formula (I) wherein:

R1 a is a halogen atom, a nitrile group, a nitro group (N02), a (C1 -C6)alkyl group, a (C1 -C6)alkyloxy group, a (C1 -C6)alkylthio group, an amino group, a (C1 -C6)alkylamino group, a (C1 -C6)dialkylamino group, a piperidinyl group, a morpholinyl group or a pyrrolidinyl group, wherein said piperidinyl or pyrrolidinyl, can be optionally substituted by at least one (C1 -C6)alkyl groups;

R1 b is a hydrogen atom;

R1 c is a hydrogen atom, a (C1 -C6)alkyl group, or a (C1 -C6)alkyloxy group;

R2 is a (C3-C6)alkyl group, an (C6-C14)aryl group, or a heteroaryl group, and R'2 is a hydrogen atom.

In a particular embodiment, HET is a group selected in the following list:

In a particular embodiment, HET is selected in the group consisting of HET1 , HET6, HET8, HET9, HET1 1 , HET12, HET15, HET21 , HET23, HET26, HET27, HET28, HET31 , HET32, HET33, HET34, HET35, HET36, HET37, HET39, HET40, HET41 , HET42, HET43, HET48, HET49, HET51 , HET52, HET54, HET55, HET56, HET57, HET58, HET59, HET60, HET61 , HET64, HET65, HET66, HET69, HET70, HET71 , HET72, HET73, HET78, HET80 and HET83. In a further particular embodiment, HET is selected in the group consisting of HET1 , HET6, HET30, HET38, HET44, HET47 and HET77. In a particular embodiment, L1 is a NH-CO group.

In a particular embodiment, L2 is a a CR4R'4 group (such as a cyclopropyl group of formula (III) or cyclobutyl of formula (IV)

In a particular embodiment, L2 is a cyclopropyl group of formula (III). In a further particular embodiment, L1 is a NH-CO group, and L2 is a (C1 -C6)alkyl group or a (C3-C14)cycloalkylgroup. In a particular embodiment, L1 is a NH-CO group and L2 is a CH2 group or a cyclopropyl group of formula (III). In a particular embodiment, the invention relates to a compound of formula (I), in which:

A is a CR1 e group;

R1 a is a halogen atom (such as bromine), a (C1-C6)alkyl group (such as a methyl or ethyl group, in particular a methyl group), a piperidinyl group (such as a piperidin-1 -yl group), a morpholinyl group (such as a morpholin-4-yl), a pyrrolidinyl group (such as a pyrrolidin-1 -yl group), or a piperazinyl group (such as a piperazin-1 -yl), or an azepanyl group (such as an azepan-1 -yl), wherein said piperidinyl, morpholinyl, or pyrrolidinyl group can be optionally substituted by at least one (C1 -C6)alkyl groups;

R1 b is a hydrogen atom;

R1 c is a hydrogen, a (C1 -C6)alkyl group (such as a methyl or ethyl group, in particular a methyl group), or a (C1 -C6)alkoxy group (such as a methoxy or a an ethoxy group, in particular a methoxy group);

R1 d and R1 e are hydrogen atoms;

R2 is a (C3-C6)alkyl group (such as an isobutyl group), a phenyl group or a heterocyclic group (such as a substituted or unsubstituted furanyl group, in particular a 5- methylfuranyl group or a 5-ethylfuranyl group, more particularly a 5-methylfuran-2-yl group);

L1 represents a NH-CO group,

L2 is a CH2 group or a cyclopropyl group of formula (III);

HET is selected in the group consisting of:

In a particular embodiment, the invention relates to a compound of formula (I), in which: A is a CR1 e group;

R1 a is a halogen atom (such as bromine), a (C1-C6)alkyl group (such as a methyl or ethyl group, in particular a methyl group), a piperidinyl group (such as a piperidin-1 -yl group), a morpholinyl group (such as a morpholin-4-yl) or a pyrrolidinyl group (such as a pyrrolidin-1 -yl group), wherein said piperidinyl, morpholinyl, or pyrrolidinyl group can be optionally substituted by at least one (C1 -C6)alkyl groups;

R1 b is a hydrogen atom;

R1 c is a hydrogen, a (C1 -C6)alkyl group (such as a methyl or ethyl group, in particular a methyl group), or a (C1 -C6)alkoxy group (such as a methoxy or a an ethoxy group, in particular a methoxy group);

R1 d and R1 e are hydrogen atoms;

R2 is a (C3-C6)alkyl group (such as an isobutyl group), a phenyl group or a heterocyclic group (such as a substituted or unsubstituted furanyl group, in particular a 5- methylfuranyl group or a 5-ethylfuranyl group, more particularly a 5-methylfuran-2-yl group);

L1 represents a NH-CO group,

L2 is a CH2 group or a cyclopropyl group of formula (III); and

HET is selected in the group consisting of HET1 , HET2, HET6, HET7, HET8 and

HET9.

In a particular embodiment, the invention relates to a compound of formula (I), in which: R1 a is a heterocyclic group (in particular a piperidinyl group (such as a piperidin-1 -yl group)); R1 c is a (C1 -C6)alkyl group (such as a methyl or ethyl group, in particular a methyl group);

R2 is a heterocyclic group (such as a substituted or unsubstituted furanyl group, in particular a 5-methylfuranyl group or a 5-ethylfuranyl group, more particularly a 5- methylfuran-2-yl group);

L1 represents a NH-CO group,

L2 is a CH2 group or a cyclopropyl group of formula (III);

HET is selected in the group consisting of:

HET being in particular selected in the group consisting of HET1 , HET2, HET6, HET7, HET8 and HET9.

In a particular embodiment, the invention relates to a compound of formula (I), in which: R1 a is a heterocyclic group (in particular a piperidinyl group (such as a piperidin-1 -yl group)) or a (C1 -C6)alkyl group (such as a methyl or ethyl group, in particular a methyl group);

R1 c is a (C1 -C6)alkyl group (such as a methyl or ethyl group, in particular a methyl group);

R2 is a heterocyclic group (such as a substituted or unsubstituted furanyl group, in particular a 5-methylfuranyl group or a 5-ethylfuranyl group or a 5-chlorofuranyl, more particularly a 5-chlorofuran-2-yl group);

L1 represents a NH-CO group; and

L2 is a CR4R'4 group (such as a cyclopropyl group of formula (III) or cyclobutyl of formul

In a particular embodiment, the invention relates to a compound of formula (I), in which:

R1 a is a heterocyclic group (in particular a piperidinyl group (such as a piperidin-1 -yl group)) or a (C1 -C6)alkyl group (such as a methyl or ethyl group, in particular a methyl group);

R1 c is a (C1 -C6)alkyl group (such as a methyl or ethyl group, in particular a methyl group);

R2 is a heterocyclic group (such as a substituted or unsubstituted furanyl group, in particular a 5-methylfuranyl group or a 5-ethylfuranyl group or a 5-chlorofuranyl, more particularly a 5-chlorofuran-2-yl group);

L1 represents a NH-CO group;

L2 is a CR4R'4 group (such as a cyclopropyl group of formula (III) or cyclobutyl of formul

HET is selected in the group consisting of the following HET groups:

In a particular embodiment of the compound of formula (I):

R1 a represents a halogen, in particular a bromine atom ; a (C1 -C6)alkyl group, in particular a methyl group ; a heterocyclic group, in particular a piperadin-1 -yl group, a piperazin-1 -yl group, or an azepan-1 -yl group; a di(C1 -C6)alkylamaino group, in particular a N(CH3)2 group;

R1 b, R1 d and R1 e represent hydrogen atoms;

R1 c is a (C1 -C6)alkyl group, in particular a methyl group, or a (C1 -C6)alkyloxy group, in particular a methoxy group;

R2 represents a 5 membered heteroaryl group containing an oxygen or a nitrogen atom optionally substituted by a (Ci-Ce)alkyl group or a halogen, in particular a furan-1 -yl group, a 5-methylfuran-2-yl group or a 5-chlorofuran-2-yl group; a (C6-C14)aryl group optionally substituted by a (Ci-Ce)alkyl group, in particular a phenyl group optionally substituted by one or more methyl group or by a chlorine atom ; or a heterocyclic group optionally substituted by a (Ci-Ce)alkyl group, in particular a 6-methylpyridin-2-yl; R'2 is a hydrogen atom;

L1 represents a NH-CO group; and

L2 represents a (C1 -C6)alkyl group, in particular a -CH2- group, or a a CR4R'4 group, in particular a cyclopropyl group of formula (III) (III).

In a particular embodiment of the compound of formula (I):

R1 a represents a halogen, in particular a bromine atom; a (C1 -C6)alkyl group, in particular a methyl group ; a heterocyclic group, in particular a piperadin-1 -yl group, or a piperazin-1 -yl group;

R1 b, R1 d and R1 e represent a hydrogen atom;

R1 c is a (C1 -C6)alkyl group, in particular a methyl group;

R2 represents a 5 membered heteroaryl group containing an oxygen or a nitrogen atom optionally substituted by a (Ci-Ce)alkyl group or a halogen, in particular a 5- methylfuran-2-yl group or a 5-chlorofuran-2-yl group;

R'2 is a hydrogen atom;

L1 represents a NH-CO group;

L2 represents a (C1 -C6)alkyl group, in particular a -CH2- group, or a a CR4R'4 group, in particular a cyclopropyl group of formula (III) (III) ; and

HET is HET1 , HET6, HET30, HET38, HET44, HET47, HET67 or HET77.

Compounds of formula (la)

In a second aspect, the present invention relates to a compound of formula (la), or a pharmaceutically acceptable salt thereof: R1 e R

R1d

R1 c

R1 a is a hydrogen atom, a halogen atom, a nitrile group, a nitro group (N02), a (C1 - C6) alkyl group, a (C1 -C6) alkyloxy group, a (C1-C6) alkylthio group, a -NH2 group, a (C1 - C6) alkylamino group, a (C1 -C6)dialkylamino group, or a heterocyclic group;

R1 b is a hydrogen atom, a (C1 -C6)alkyloxy group, a (C1 -C6)alkyl group or a heterocyclic group;

R1 c is a hydrogen atom, a halogen atom, a (C1 -C6)alkyl group, a (C1 -C6)alkyloxy group, a (C1 -C6)alkylthio group, a heterocyclic group, a cyano group, an amido group or a hydroxyl group;

R1 d and R1 e are, independently, a hydrogen atom, a halogen atom, a (C1 -C6)alkyloxy group or an (C1 -C6)alkyl group;

R2 is a (C1 -C6)alkyl group, a (C2-C6)alkynyl group, a (C3-C14)cycloalkyl group, a (C6- C14)aryl group or a heterocyclic group optionally substituted by a (Ci-Ce)alkyl group or a halogen;

R'2 is a hydrogen atom, a (C1 -C6)alkyl group, a (C2-C6)alkynyl group, a (C3-

C14)cycloalkyl group, a (C6-C14)aryl group or a heterocyclic group optionally substituted by a (Ci-C6)alkyl group or a halogen;

or R2 and R2' can form, together with the carbon atom to which they are attached, a cycloalkyl group or a heterocycloalkyl group;

L1 is a NR3-CO-CH2, NR3-CO-, NR3-CO-C(CH3)2, CO-NH-CH2, CO-NH or CO-NH-

C(CH3)2 group;

R3 represents a hydrogen atom or a (C1 -C6)alkyl group;

L2 represents a bond, a (C1 -C6)alkyl group, a (C3-C14)cycloalkylgroup, or a CR4R'4 group;

R4 and R'4 are independently, a hydrogen atom, or a (C1 -C6)alkyl group;

R4 and R'4 can form, together with the carbon atom to which they are attached, a cycloalkyl group;

HET is a bicyclic group of formula (ΙΓ) or (II"):

in which:

X1 and X2 form together, with the carbons of the phenyl ring where they are attached, a saturated or unsaturated 5- to 8-membered ring optionally interrupted by at least one group selected in the group consisting of a nitrogen atom, an oxygen atom, a sulfur atom, a N-S02-R7 group, with R7 being a (C1 -C6)alkyl group, a S02 group, or a CO group; said 5- to 8-membered ring is optionally substituted by at least one radical selected in the group consisting of:

- a (C1 -C6)alkyl group optionally substituted by at least one hydroxy; or a (C2-C6)alkenyl group optionally substituted by at least one hydroxy,

- a halogen atom,

- a =N-NRR' group, with R and R' being independently a hydrogen or a (C1 -C6)alkyl group,

- a =NR" group, with R" being a hydrogen, a (C1 -C6)alkyl group or a hydroxy;

- a hydroxyl group, and

- a =CH-R"' group, with R'" being a heteroaryl optionally substituted by at least one substituent selected from a (C1 -C6)alkyl and a NRR' group with R and R' are such as above defined; and

X3, X3' and X3" are, independently, a hydrogen or a (C1 -C6)alkyl group.

In particular embodiments, in the compound of formula (la) of the present invention: a (C1 -C6)alkyl group may be a substituted or unsubstituted (C1 -C6)alkyl group, in particular a substituted or unsubstituted (C1 -C4)alkyl group;

a (C1 -C6)alkyloxy group may be a substituted or unsubstituted (C1 -C6)alkyloxy group, in particular a substituted or unsubstituted (C1 -C4)alkyloxy group;

a (C6-C14)aryl group may be a substituted or unsubstituted (C6-C14)aryl group; a heterocyclic group may be a substituted or unsubstituted heterocycloalkyl or heteroaryl group.

The present invention also includes stereoisomers (diastereoisomers, enantiomers), pure or mixed, as well as racemic mixtures and geometric isomers, or tautomers of compounds of formula (la). The invention further includes salts, solvates (in particular hydrates) and polymorphs or crystalline forms of the compounds of formula (la).

According to a particular embodiment, the invention relates to a compound of formula (la) wherein

R1 a is a hydrogen atom, a halogen atom, a nitrile group, a nitro group (N02), a (C1 - C6)alkyl group, a (C1 -C6)alkyloxy group, a (C1 -C6)alkylthio group, an amino group, a (C1 - C6)alkylamino group, a (C1 -C6)dialkylamino group, a piperidinyl group, a pyrrolidinyl group, an azepanyl group, a piperazinyl group, or a morpholinyl group, wherein said piperidinyl, pyrrolidinyl, azepanyl, piperazinyl or morpholinyl group can be optionally substituted by at least one (C1 -C6)alkyl groups. In a further particular embodiment, R1 a is a hydrogen atom, a halogen atom, a nitrile group, a nitro group (N02), a (C1 -C6)alkyl group, a (C1 -C6)alkyloxy group, a (C1 -C6)alkylthio group, an amino group, a (C1 -C6)alkylamino group, a (C1 - C6)dialkylamino group, a piperidinyl group, a pyrrolidinyl group or an azepanyl group, wherein said piperidinyl, pyrrolidinyl or azepanyl group can be optionally substituted by at least one (C1 -C6)alkyl groups. In another particular embodiment, R1 a is selected in the group consisting of a halogen atom (such as a bromine atom), a (C1 -C6)alkyl group (such as a methyl or a CF3 group), a (C1 -C6)dialkylamino group (such as dimethylamino group, a piperidinyl group (such as a piperidin-1 -yl group), a piperazinyl group (such as a piperazin-1 - yl) and an azepanyl group (such as an azepan-1 -yl). In a further particular embodiment, R1 a is selected in the group consisting of a halogen atom (such as a bromine atom), a (C1 - C6)alkyl group (such as a methyl group), a piperidinyl group (such as a piperidin-1 -yl group) or a piperazinyl group (such as a piperazin-1 -yl). In another particular embodiment, R1 a is a hydrogen atom, a halogen, group, a (C1 -

C6)alkyl group, a piperidinyl group (such as a piperidin-1 -yl group), a morpholinyl group (such as morpholin-4-yl group), a pyrrolidinyl group (such as a pyrrolidin-1 -yl group), a piperazinyl group (such as a piperazin-1 -yl), or an azepanyl group (such as an azepan-1 -yl). In a particular embodiment, R1 a is a hydrogen atom, a halogen, group, a (C1 -C6)alkyl group), a piperidinyl group (such as a piperidin-1 -yl group), a morpholinyl group (such as morpholin-4-yl group) or a pyrrolidinyl group (such as a pyrrolidin-1 -yl group). In a particular embodiment, R1 b is a hydrogen atom.

In a particular embodiment, R1 c is a hydrogen atom, an (C1 -C6)alkyl group, or an (C1 - C6)alkyloxy group. In another particular embodiment, R1 c is a (C1 -C6)alkyl group (such as a methyl group), or a (C1 -C6)alkyloxy group (such as a methoxy group).

In a particular embodiment, R1 d is a hydrogen atom.

In a particular embodiment, R1 e is a hydrogen atom.

In a further particular embodiment, R1 b, R1 d and Rl e are hydrogen atoms. In a further variant, R1 b, R1 d and R1 e are hydrogen atoms and R1 c is a (C1 -C6)alkyl group (such as a methyl group) or a (C1 -C6)alkyloxy group (such as a methoxy group).

In another embodiment, R2 is a (C1 -C6)alkyl group, a (C6-C14)aryl group, or a heteroaryl group.

In a further embodiment, R2 is a (C6-C14)aryl group or a heteroaryl group. In a particular variant, R2 is selected in the group consisting of a phenyl group, a furanyl group and a pyridinyl group, wherein the substituents of said phenyl, furanyl and pyridinyl group may be unsubstituted or substituted, such as by at least one group selected in the group consisting of (C1 -C6)alkyl groups (e.g. at least one methyl group, such as one or two methyl groups) and halogen atoms (e.g. chlorine, such as one or two chlorine atoms). Illustratively, R2 may be a phenyl group, a methylphenyl group, a dimethylphenyl group (such as a 2,4- dimethylphenyl group), a chlorophenyl group (such as a 3-chlorophenyl group), a furanyl group (such as a furan-2-yl group), a methylfuranyl group (such as a 5-methylfuran-2-yl group), a chlorofuranyl group (such as a 5-chlorofuranyl group), a pyridinyl group (such as a pyridine-2-yl group) or a methylpyridinyl group (such as a 6-methylpyridin-2-yl group). In a particular embodiment, R2 is selected in the group consisting of a dimethylphenyl group (such as a 2,4-dimethylphenyl group), a chlorophenyl group (such as a 3-chlorophenyl group), a furanyl group (such as a furan-2-yl group), a methylfuranyl group (such as a 5- methylfuran-2-yl group), a chlorofuranyl group (such as a 5-chlorofuranyl group) and a methylpyridinyl group (such as a 6-methylpyridin-2-yl group). In a particular embodiment, R2 is a furanyl group, such as a furan-2-yl group, which is unsubstituted, or substituted with a least one (C1 -C6)alkyl group, in particular at least one methyl group, such as a 5- methylfuran-2-yl group.

In another embodiment, R'2 is a hydrogen atom.

In another particular embodiment, R2 is a (C1 -C6)alkyl group, a (C6-C14)aryl group, or a heteroaryl group, and R'2 is a hydrogen atom. In a further particular embodiment, the invention relates to a compound of formula (la) wherein: R1 a is a hydrogen atom, a halogen atom, a nitrile group, a nitro group (N02), a (C1 - C6)alkyl group, a (C1 -C6)alkyloxy group, a (C1 -C6)alkylthio group, an amino group, a (C1 - C6)alkylamino group, a (C1 -C6)dialkylamino group, a piperidinyl group, a morpholinyl group, a pyrrolidinyl group, a piperazinyl group, or an azepanyl group,

wherein said piperidinyl, morpholinyl, pyrrolidinyl, piperazinyl, or azepanyl group can be optionally substituted by at least one (C1 -C6)alkyl groups;

R1 b is a hydrogen atom;

R1 c is a hydrogen atom, a (C1 -C6)alkyl group, or a (C1 -C6)alkyloxy group;

R2 is a (C1 -C6)alkyl group, an (C6-C14)aryl group, or a heteroaryl group, and R'2 is a hydrogen atom.

In a further particular embodiment, the invention relates to a compound of formula (la) wherein:

R1 a is a hydrogen atom, a halogen atom, a nitrile group, a nitro group (N02), a (C1 - C6)alkyl group, a (C1 -C6)alkyloxy group, a (C1 -C6)alkylthio group, an amino group, a (C1 - C6)alkylamino group, a (C1 -C6)dialkylamino group, a piperidinyl group, a morpholinyl group or a pyrrolidinyl group,

wherein said piperidinyl or pyrrolidinyl, can be optionally substituted by at least one (C1 -C6)alkyl groups;

R1 b is a hydrogen atom;

R1 c is a hydrogen atom, a (C1 -C6)alkyl group, or a (C1 -C6)alkyloxy group;

R2 is a (C1 -C6)alkyl group, an (C6-C14)aryl group, or a heteroaryl group, and R'2 is a hydrogen atom. In a particular embodiment, HET is a group selected in the following list:

In a particular embodiment, HET is a group selected in group consisting of HET1 to HET44. In a particular embodiment, HET is selected in the group consisting of HET1 , HET6, HET8, HET9, HET1 1 , HET12, HET15, HET21 , HET23, HET26, HET27, HET28, HET31 , HET32, HET33, HET34, HET35, HET36, HET37, HET39, HET40, HET41 , HET42, HET43, HET48, HET49, HET51 , HET52, HET54, HET55, HET56, HET57, HET58, HET59, HET60, HET61 , HET64, HET65, HET66, HET69, HET70, HET71 , HET72, HET73, HET78, HET80 and HET83. In a further particular embodiment, HET is selected in the group consisting of HET1 , HET6, HET30, HET38, HET44, HET47 and HET77.

In a particular embodiment, L1 is a NR3-CO-CH2, NR3-CO-C(CH3)2, CO-NH-CH2, or CO-NH-C(CH3)2 group. In a further particular embodiment, L1 is a NR3-CO-CH2 group. In another particular embodiment, R3 is a hydrogen atom.

In another embodiment, L1 is a NH-CO group.

In a particular embodiment, L2 is a a CR4R'4 group (such as a cyclopropyl group of formula (III) or cyclobutyl of formula (IV)

In a particular embodiment, L2 is a cyclopropyl group of formula (III).

In a further particular embodiment, L1 is NR3-CO group or CO-NH group, in particular a NH-CO group, and L2 is a (C1 -C6)alkyl group or a (C3-C14)cycloalkylgroup. In a particular embodiment, L1 is a NH-CO group and L2 is a CH2 group or a cyclopropyl group of formula (III).

In a particular embodiment, the invention relates to a compound of formula (la), in which:

R1 a is a halogen atom (such as bromine), a (C1-C6)alkyl group (such as a methyl or ethyl group, in particular a methyl group), a piperidinyl group (such as a piperidin-1 -yl group), a morpholinyl group (such as a morpholin-4-yl), a pyrrolidinyl group (such as a pyrrolidin-1 -yl group), or a piperazinyl group (such as a piperazin-1 -yl), or an azepanyl group (such as an azepan-1 -yl), wherein said piperidinyl, morpholinyl, piperazinyl, azepanyl or pyrrolidinyl group can be optionally substituted by at least one (C1 -C6)alkyl group;

R1 b is a hydrogen atom;

R1 c is a hydrogen, a (C1 -C6)alkyl group (such as a methyl or ethyl group, in particular a methyl group), or a (C1 -C6)alkoxy group (such as a methoxy or a an ethoxy group, in particular a methoxy group); R1 d and R1 e are hydrogen atoms;

R2 is a (C1 -C6)alkyl group (such as an isobutyl group), a phenyl group or a heterocyclic group (such as a substituted or unsubstituted furanyl group, in particular a 5- methylfuranyl group or a 5-ethylfuranyl group, more particularly a 5-methylfuran-2-yl group);

L1 represents a NH-CO-CH2 group, L2 is a bond;

HET is choosen in the list:

In a particular embodiment, the invention relates to a compound of formula (la), in which:

A is a CR1 e group;

R1 a is a halogen atom (such as bromine), a (C1-C6)alkyl group (such as a methyl or ethyl group, in particular a methyl group), a piperidinyl group (such as a piperidin-1 -yl group), a morpholinyl group (such as a morpholin-4-yl) or a pyrrolidinyl group (such as a pyrrolidin-1 -yl group), wherein said piperidinyl, morpholinyl, or pyrrolidinyl group can be optionally substituted by at least one (C1 -C6)alkyl groups;

R1 b is a hydrogen atom;

R1 c is a hydrogen, a (C1 -C6)alkyl group (such as a methyl or ethyl group, in particular a methyl group), or a (C1 -C6)alkoxy group (such as a methoxy or a an ethoxy group, in particular a methoxy group);

R1 d and R1 e are hydrogen atoms;

R2 is a (C1 -C6)alkyl group (such as an isobutyl group), a phenyl group or a heterocyclic group (such as a substituted or unsubstituted furanyl group, in particular a 5- methylfuranyl group or a 5-ethylfuranyl group, more particularly a 5-methylfuran-2-yl group);

L1 represents a NH-CO-CH2 group, L2 is a bond;

HET is selected in the group consisting of HET1 , HET2, HET6, HET7, HET8 and HET9. In a particular embodiment, the invention relates to a compound of formula (la), in which:

R1 a is a heterocyclic group (in particular a piperidinyl group (such as a piperidin-1 -yl group));

R1 c is a (C1 -C6)alkyl group (such as a methyl or ethyl group, in particular a methyl group);

R2 is a heterocyclic group (such as a substituted or unsubstituted furanyl group, in particular a 5-methylfuranyl group or a 5-ethylfuranyl group, more particularly a 5- methylfuran-2-yl group);

L represents a NH-CO-CH2 group, L2 is a bond;

HET is choosen in the list:

HET being in particular selected in the group consisting of HET1 , HET2, HET6, HET7, HET8 and HET9.

In a particular embodiment, the invention relates to a compound of formula (la), in which:

R1 a is a heterocyclic group (in particular a piperidinyl group (such as a piperidin-1 -yl group)) or a (C1 -C6)alkyl group (such as a methyl or ethyl group, in particular a methyl group);

R1 c is a (C1 -C6)alkyl group (such as a methyl or ethyl group, in particular a methyl group);

R2 is a heterocyclic group (such as a substituted or unsubstituted furanyl group, in particular a 5-methylfuranyl group or a 5-ethylfuranyl group or a 5-chlorofuranyl, more particularly a 5-chlorofuran-2-yl group);

L1 represents a NH-CO- group, L2 is a CR4R'4 group (such as a cyclopropyl group of formula (III) or cyclobutyl of formula (IV)

In a particular embodiment, the invention relates to a compound of formula (la), in which:

R1 a is a heterocyclic group (in particular a piperidinyl group (such as a piperidin-1 -yl group)) or a (C1 -C6)alkyl group (such as a methyl or ethyl group, in particular a methyl group); R1 c is a (C1 -C6)alkyl group (such as a methyl or ethyl group, in particular a methyl group);

R2 is a heterocyclic group (such as a substituted or unsubstituted furanyl group, in particular a 5-methylfuranyl group or a 5-ethylfuranyl group or a 5-chlorofuranyl, more particularly a 5-chlorofuran-2-yl group);

L1 represents a NH-CO group;

L2 is a CR4R'4 group (such as a cyclopropyl group of formula (III) or cyclobutyl group of formula (IV)

HET is selected in the group consisting of the following HET groups:

In a particular embodiment of the compound of formula (la) R1 a represents a halogen, in particular a bromine atom; a (C1 -C6)alkyl group, in particular a methyl group ; a heterocyclic group, in particular a piperadin-1 -yl group, a piperazin-1 -yl group, or an azepan-1 -yl group; a di(C1 -C6)alkylamaino group, in particular a N(CH3)2 group;

R1 b, R1 d and R1 e represent a hydrogen atom;

R1 c is a (C1 -C6)alkyl group, in particular a methyl group, or a (C1 -C6)alkyloxy group, in particular a methoxy group

R2 represents a 5 membered hetoaryl group containing an oxygen or a nitrogen atom optionally substituted by a (Ci-Ce)alkyl group or a halogen, in particular a furan-1 -yl group, a 5-methylfuran-2-yl group or a 5-chlorofuran-2-yl group; a (C6-C14)aryl group optionally substituted by a (Ci-Ce)alkyl group, in particular a phenyl group optionally substituted by one or more methyl group or by a chlorine atom ; or a heterocyclic group optionally substituted by a (Ci-C6)alkyl group, in particular a 6-methylpyridin-2-yl;

R'2 is a hydrogen atom;

L1 represents a NH-CO group; and

L2 represents a (C1 -C6)alkyl group, in particular a -CH2- group, or a a CR4R'4 group, in particular a cyclopropyl group of formula (III) (III).

In a particular embodiment of the compound of formula (la):

R1 a represents a halogen, in particular a bromine atom; a (C1 -C6)alkyl group, in particular a methyl group ; a heterocyclic group, in particular a piperadin-1 -yl group, or a piperazin-1 -yl group;

R1 b, R1 d and R1 e represent a hydrogen atom;

R1 c is a (C1 -C6)alkyl group, in particular a methyl group;

R2 represents a 5 membered hetoaryl group containing an oxygen or a nitrogen atom optionally substituted by a (Ci-Ce)alkyl group or a halogen, in particular a 5-methylfuran-2-yl group or a 5-chlorofuran-2-yl group;

R'2 is a hydrogen atom;

L1 represents a NH-CO group;

L2 represents a (C1 -C6)alkyl group, in particular a -CH2- group, or a a CR4R'4 group, in particular a cyclopropyl group of formula (III)

HET is HET1 , HET6, HET30, HET38, HET44, HET47, HET67 or HET77.

Particular embodiments and aspects of the invention

The term "alkyl" refers to a saturated hydrocarbon radical that is linear or branched, substituted or not, having preferably from one to six, and even more preferably from one to four carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, or sec-butyl. The alkyl group can be optionally substituted by one or more halogen atoms, by an (C6-C14)aryl group or by a (C3-C14)cycloalkyl group. Further possible substituents of an alkyl group also include one or more substituents selected from a -Nhb group, a (C1 - C6)alkylamino group, a (C1 -C6)dialkylamino group, and a (C2-C6)alkynyl group.

The term alkynyl denotes linear or branched hydrocarbon groups containing from 2 to 6 carbon atoms and containing at least one triple bond. Examples of alkynyl containing from 3 to 6 carbon atoms are 1 -propynyl, 2-propynyl, 1 -butynyl, 2-butynyl, 3-butynyl, 1 -pentynyl, 2- pentynyl, 3-pentynyl, 4-pentynyl, 1 -hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl and the isomeric forms thereof.

The terms "alkyloxy" and "alkylthio" refer to an alkyl group as defined above that is linked to the remainder of the compound by an oxygen or sulfur atom, respectively.

The term "(C1 -C6)alkylamino" refers to a -NH-(C1 -C6)alkyl group. In a particular embodiment, the alkyl group of the alkylamino group may be substituted or not with a (C3- C14)cycloalkyl group, a (C6-C14)aryl group, a heterocyclic group, or an (C1 - C6)alkyloxycarbonyl group.

The term "(C1 -C6)dialkylamino" refers to a -NRR' group where R and R' independently represent a (C1 -C6)alkyl group as defined above. In a particular embodiment, the alkyl groups of the dialkylamino group may independently be substituted or not with a (C3- C14)cycloalkyl group, a (C6-C14)aryl group, a heterocyclic group, or a (C1 - C6)alkyloxycarbonyl group.

The term "cycloalkyi" designates a substituted or unsubstituted alkyl group that forms one cycle having preferably from three to fourteen carbon atoms, and more preferably five to six carbon atoms, such as cyclopropyl, cyclopentyl and cyclohexyl. The cycloalkyi group of the present invention may be unsubstituted, or substituted, for example with a (C1 -C6)alkyl group, in particular with a (C1 -C6)alkyl group substituted with one or more halogen atoms, such as the CF3 group. The term "cycloalkylamino" refers to a -NH-(C3-C14)cycloalkyl group or a -N((C1 - C6)alkyl)(C3-C14)cycloalkyl group.

The term "amino group" designates a -IMH2 group.

The term "hydroxyl group" refers to a -OH group.

The term "carbonyl" designates a CO group.

The term "carbonyl(C1 -C6)alkyl" designates a CO-(C1 -C6)alkyl group.

The term "amido" designates a CO-NH2 group.

The term "alkylamido" designates a CO-NH-(C1 -C6)alkyl group.

The term "(C1 -C6)dialkylamido" designates a CO-NRR' group, R and R' representing a (C1 -C6)alkyl group as defined above.

A sulfone group designates a S02 group;

The term "aryl" designates an aromatic group, substituted or not, having preferably from six to fourteen carbon atoms such as phenyl, a-naphtyl, b-naphtyl, or biphenyl.

The term "heterocyclic" refers to a heterocycloalkyi group or a heteroaryl group. The term "heterocycloalkyi" group refers to a cycloalkyi as indicated above that further comprises one or several heteroatoms selected among nitrogen, oxygen or sulfur. They generally comprise from four to fourteen carbon atoms, such as morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, tetrahydropyranyl, dithiolanyl and azepanyl groups. In a particular embodiment, the heterocycloalkyi group is a 5-, 6- or 7-membered cycle. The term "heteroaryl" refers to an aryl group as indicated above, substituted or not, that further comprises one or several heteroatoms selected among nitrogen, oxygen or sulfur. They generally comprise from four to fourteen carbon atoms. In a particular embodiment, the heteroaryl group is a 5-, 6- or 10- membered heteroaryl group. Representative heteroaryl groups include a pyridinyl, pyrimidinyl, furanyl, thiophenyl, quinoleinyl, and isoquinoleinyl group.

The aryl group or the heterocyclic group can be optionally substituted by one or more halogen atom(s), (C1 -C6)alkyl group(s), or (C1 -C6)alkyloxy group(s).By halogen atom, an atom of bromine, chlorine, fluorine or iodine is understood, in particular an atom of bromine, chlorine or fluorine. Specific compounds according to the invention include:

Cpd.1 N-{[4-methyl-2-(piperidin-1 -yl)phenyl](phenyl)methyl}-2-(3-oxo-3,4-dihydro-2H-

1 ,4-benzoxazin-7-yl)acetamide;

Cpd.2 N-{[4-methyl-2-(morpholin-4-yl)phenyl](phenyl)methyl}-2-(3-o xo-3,4-dihydro- 2H-1 ,4-benzoxazin-7-yl)acetamide;

Cpd.3 2-(3-oxo-3,4-dihydro-2H-1 ,4-benzoxazin-7-yl)-N-{phenyl[2-(piperidin-1 - yl)phenyl]methyl}acetamide; Cpd.4 N-{[4-methoxy-2-(piperidin-1 -yl)phenyl](phenyl)methyl}-2-(3-oxo-3,4-dihydro-2H-

1 ,4-benzoxazin-7-yl)acetamide;

Cpd.5 2-(3-oxo-3,4-dihydro-2H-1 ,4-benzoxazin-7-yl)-N-{phenyl[2-(pyrrolidin-1 - yl)phenyl]methyl}acetamide;

Cpd.6 N-{3-methyl-1 -[2-(piperidin-1 -yl)phenyl]butyl}-2-(3-oxo-3,4-dihydro-2H-1 ,4- benzoxazin-7-yl)acetamide;

Cpd.7 N-{[2-(morpholin-4-yl)phenyl](phenyl)methyl}-2-(3-oxo-3,4-di hydro-2H-1 ,4- benzoxazin-7-yl)acetamide;

Cpd.8 N-{[4-methyl-2-(morpholin-4-yl)phenyl](phenyl)methyl}-2-(4-m ethyl-2-oxo-1 ,2- dihydroquinolin-6-yl)acetamide;

Cpd.9 N-[(2,4-dimethylphenyl)(phenyl)methyl]-2-(4-methyl-2-oxo-1 ,2-dihydroquinolin-

6-yl)acetamide;

Cpd.10 N-{[4-methoxy-2-(piperidin-1 -yl)phenyl](phenyl)methyl}-2-(4-methyl-2-oxo-1 ,2- dihydroquinolin-6-yl)acetamide;

Cpd.1 1 N-{[4-methyl-2-(piperidin-1 -yl)phenyl](phenyl)methyl}-2-(4-methyl-2-oxo-1 ,2- dihydroquinolin-6-yl)acetamide;

Cpd.12 2-(2,3-dioxo-1 _! 2 _! 3,4-tetrahydroquinoxalin-6-yl)-N-{phenyl[2-(piperidin- 1 - yl)phenyl]methyl}acetamide;

Cpd.13 2-(3-oxo-3,4-dihydro-2H-1 ,4-benzoxazin-6-yl)-N-{phenyl[2-(piperidin-1 - yl)phenyl]methyl}acetamide;

Cpd.14 2-(2,2-difluoro-3-oxo-3 _! 4-dihydro-2H-1 ,4-benzoxazin-7-yl)-N-{phenyl[2-

(piperidin-1 -yl)phenyl]methyl}acetamide;

Cpd.15 2-(2-oxo-2,3-dihydro-1 H-indol-5-yl)-N-{phenyl[2-(piperidin-1 - yl)phenyl]methyl}acetamide;

Cpd.16 N-{[4-methyl-2-(piperidin-1 -yl)phenyl](phenyl)methyl}-2-(2-oxo-2,3-dihydro-1 H- indol-5-yl)acetamide;

Cpd.17 N-{[2-(morpholin-4-yl)phenyl](phenyl)methyl}-2-(2-oxo-2,3-di hydro-1 H-indol-5- yl)acetamide;

Cpd.18 N-{[4-methyl-2-(morpholin-4-yl)phenyl](phenyl)methyl}-2-(2-o xo-2,3-dihydro-1 H- indol-5-yl)acetamide;

Cpd.19 2-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-1 ,4-benzoxazin-7-yl)-N-{phenyl[2-

(piperidin-1 -yl)phenyl]methyl}acetamide;

Cpd.20 2-(2,3-dioxo-2,3-dihydro-1 H-indol-5-yl)-N-{phenyl[2-(piperidin-1 - yl)phenyl]methyl}acetamide;

Cpd.21 2-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-1 ,4-benzoxazin-7-yl)-N-{[4-methyl-2- (morpholin-4-yl)phenyl](phenyl)methyl}acetamide; 2-(2 _! 3-dioxo-2 _! 3-dihydro-1 H-indol-5-yl)-N-{[4-methoxy-2-(piperidin-1 - yl)phenyl](phenyl)methyl}acetamide;

2-(2 _! 3-dioxo-2,3-dihydro-1 H-indol-5-yl)-N-{[4-methyl-2-(piperidin-1 -yl)phenyl](5- methylfuran-2-yl)methyl}acetamide;

N-{[4-methyl-2-(piperidin-1 -yl)phenyl](5-methylfuran-2-yl)methyl}-2-(2-oxo-2,3- dihydro-1 H-indol-5-yl)acetamide;

2-(2 _! 2-dimethyl-3-oxo-3 _! 4-dihydro-2H-1 ,4-benzoxazin-7-yl)-N-{[4-methyl-2- (piperidin-1 -yl)phenyl](5-methylfuran-2-yl)methyl}acetamide;

2-(2,2-dioxo-1 _! 3-dihydro-2,1 -benzothiazol-5-yl)-N-{phenyl[2-(piperidin-1 - yl)phenyl]methyl}acetamide;

2-(2 _! 2-dioxo-1 _! 3-dihydro-2,1 -benzothiazol-5-yl)-N-{[4-methyl-2-(piperidin-1 - yl)phenyl](5-methylfuran-2-yl)methyl}acetamide;

N-[(2-bromo-4-methylphenyl)(5-methylfuran-2-yl)methyl]-2-(2 _! 2-dioxo-1 ,3- dihydro-2,1 -benzothiazol-5-yl)acetamide;

N-[(2 _! 4-dimethylphenyl)(5-methylfuran-2-yl)methyl]-2-(2-oxo- 2,3-dihydro-1 H- indol-5-yl)acetamide;

2-(2 _! 2-dimethyl-3-oxo-3 _! 4-dihydro-2H-1 ,4-benzoxazin-7-yl)-N-{[4-methoxy-2- (morpholin-4-yl)phenyl](5-methylfuran-2-yl)methyl}acetamide;

N-[(2-bromo-4-methylphenyl)(5-methylfuran-2-yl)methyl]-2- (3-oxo-3,4-dihydro- 2H-1 ,4-benzoxazin-7-yl)acetamide;

N-[(2 _! 4-dimethylphenyl)(5-ethylfuran-2-yl)methyl]-2-(3-oxo-3 _! 4-dihydro-2H-1 ,4- benzoxazin-7-yl)acetamide;

N-[(2 _! 4-dimethylphenyl)(5-methylfuran-2-yl)methyl]-2-(3-oxo- 3 _! 4-dihydro-2H-1 ,4- benzoxazin-7-yl)acetamide;

N-[(2-bromo-4-methoxyphenyl)(5-methylfuran-2-yl)methyl]-2-(3 -oxo-3,4-dihydro- 2H-1 ,4-benzoxazin-7-yl)acetamide;

N-{[4-methyl-2-(piperidin-1 -yl)phenyl](5-methylfuran-2-yl)methyl}-2-(3-oxo-3,4- dihydro-2H-1 ,4-benzoxazin-7-yl)acetamide;

N-[(2-bromo-4-methylphenyl)(5-methylfuran-2-yl)methyl]-2-(2- oxo-1 ,2,3,4- tetrahydroquinolin-6-yl)acetamide;

2-(3-hydrazinylidene-2-oxo-2,3-dihydro-1 H-indol-5-yl)-N-{[4-methyl-2-(piperidin-

1 - yl)phenyl](5-methylfuran-2-yl)methyl}acetamide;

N-{[4-methyl-2-(piperidin-1 -yl)phenyl](5-methylfuran-2-yl)methyl}-2-(1 -methyl-2- oxo-2,3-dihydro-1 H-indol-5-yl)acetamide;

2- (3-hydroxy-1 ,3-dimethyl-2-oxo-2,3-dihydro-1 H-indol-5-yl)-N-{[4-methyl-2- (piperidin-1 -yl)phenyl](5-methylfuran-2-yl)methyl}acetamide; N-{[4-methyl-2-(piperidin-1 -yl)phenyl](5-methylfuran-2-yl)methyl}-2-(1 ,3,3- trimethyl-2-oxo-2,3-dihydro-1 H-indol-5-yl)acetamide;

2-(2-methanesulfonyl-2,3-dihydro-1 H-isoindol-5-yl)-N-{[4-methyl-2-(piperidin-1 - yl)phenyl](5-methylfuran-2-yl)methyl}acetamide;

2-[3-(hydroxyimino)-2-oxo-2,3-dihydro-1 H-indol-5-yl]-N-{[4-methyl-2-(piperidin-

1 - yl)phenyl](5-methylfuran-2-yl)methyl}acetamide;

2- {3-[(dimethyl-1 _! 2-oxazol-4-yl)methylidene]-2-oxo-2,3-dihydro-1 H-indol-5-yl}-N- {[4-methyl-2-(piperidin-1 -yl)phenyl](5-methylfuran-2-yl)methyl}acetamide;

2-{3-[(2-amino-1 _! 3-thiazol-5-yl)methylidene]-2-oxo-2,3-dihydro-1 H-indol-5-yl}-N- {[4-methyl-2-(piperidin-1 -yl)phenyl](5-methylfuran-2-yl)methyl}acetamide;

2-(1 -methyl-2,3-dioxo-2,3-dihydro-1 H-indol-5-yl)-N-{[4-methyl-2-(piperidin-1 - yl)phenyl](5-methylfuran-2-yl)methyl}acetamide;

2-(3-hydroxy-2-oxo-2,3-dihydro-1 H-indol-5-yl)-N-{[4-methyl-2-(piperidin-1 - yl)phenyl](5-methylfuran-2-yl)methyl}acetamide;

2-(3-hydroxy-3-methyl-2-oxo-2,3-dihydro-1 H-indol-5-yl)-N-{[4-methyl-2- (piperidin-1 -yl)phenyl](5-methylfuran-2-yl)methyl}acetamide;

N-{[4-methyl-2-(piperidin-1 -yl)phenyl](5-methylfuran-2-yl)methyl}-2-[(3E)-3-(2- methylpropylidene)-2-oxo-2,3-dihydro-1 H-indol-5-yl]acetamide;

N-{[4-methyl-2-(piperidin-1 -yl)phenyl](5-methylfuran-2-yl)methyl}-2-(3-methyl-2- oxo-2,3-dihydro-1 H-indol-5-yl)acetamide;

2-(2-methanesulfonyl-2,3-dihydro-1 H-isoindol-4-yl)-N-{[4-methyl-2-(piperidin-1 - yl)phenyl](5-methylfuran-2-yl)methyl}acetamide;

N-{[4-methyl-2-(piperidin-1 -yl)phenyl](5-methylfuran-2-yl)methyl}-2-(1 -oxo-2,3- dihydro-1 H-inden-5-yl)acetamide;

2-(1 -hydroxy-2,3-dihydro-1 H-inden-5-yl)-N-{[4-methyl-2-(piperidin-1 - yl)phenyl](5-methylfuran-2-yl)methyl}acetamide;

2-(3-hydroxy-1 -methyl-2-oxo-2,3-dihydro-1 H-indol-5-yl)-N-{[4-methyl-2-

(piperidin-1 -yl)phenyl](5-methylfuran-2-yl)methyl}acetamide;

N-{[4-methyl-2-(piperidin-1 -yl)phenyl](5-methylfuran-2-yl)methyl}-2-(7-methyl-2- oxo-2,3-dihydro-1 H-indol-5-yl)acetamide;

N-{[4-methyl-2-(piperidin-1 -yl)phenyl](5-methylfuran-2-yl)methyl}-2-[2-oxo-3- (propan-2-ylidene)-2,3-dihydro-1 H-indol-5-yl]acetamide;

N-[(5-chlorofuran-2-yl)(2,4-dimethylphenyl)methyl]-1 -(2-methanesulfonyl-2,3- dihydro-1 H-isoindol-5-yl)cyclopropane-1 -carboxamide;

2-[3-(2-hydroxyethyl)-1 H-indol-5-yl]-N-{[4-methyl-2-(piperidin-1 -yl)phenyl](5- methylfuran-2-yl)methyl}acetamide; 2-[3-(hydroxymethyl)-1 H-indol-5-yl]-N-{[4-methyl-2-(piperidin-1 -yl)phenyl](5- methylfuran-2-yl)methyl}acetamide;

N-[(2 _! 4-dimethylphenyl)(5-methylfuran-2-yl)methyl]-1 -(3-oxo-3 _! 4-dihydro-2H-1 ,4 benzoxazin-7-yl)cyclopropane-1 -carboxamide;

N-[(2 _! 4-dimethylphenyl)(5-methylfuran-2-yl)methyl]-1 -[3-(2-hydroxyethyl)-1 H- indol-5-yl]cyclopropane-1 -carboxamide;

N-[(2 _! 4-dimethylphenyl)(5-methylfuran-2-yl)methyl]-1 -(2-oxo-2,3-dihydro-1 H- indol-5-yl)cyclopropane-1 -carboxamide;

N-[(5-chlorofuran-2-yl)(2,4-dimethylphenyl)methyl]-1 -[3-(2-hydroxyethyl)-1 H- indol-5-yl]cyclopropane-1 -carboxamide;

N-[(2 _! 4-dimethylphenyl)(5-methylfuran-2-yl)methyl]-1 -(2 _! 2-dioxo-1 _! 3-dihydro-2,1 benzothiazol-5-yl)cyclopropane-1 -carboxamide;

2-(3-methyl-1 H-indol-5-yl)-N-{[4-methyl-2-(piperidin-1 -yl)phenyl](5-methylfuran- 2-yl)methyl}acetamide;

N-[(2,4-dimethylphenyl)(5-methylfuran-2-yl)methyl]-1 -(2-methanesulfonyl-2,3- dihydro-1 H-isoindol-5-yl)cyclopropane-1 -carboxamide;

1 -[3-(2-hydroxyethyl)-1 H-indol-5-yl]-N-{[4-methyl-2-(piperidin-1 -yl)phenyl](5- methylfuran-2-yl)methyl}cyclopropane-1 -carboxamide;

N-{[4-methyl-2-(piperidin-1 -yl)phenyl](5-methylfuran-2-yl)methyl}-2-(3-oxo-2,3- dihydro-1 H-inden-5-yl)acetamide;

N-[(2-bromo-4-methylphenyl)(5-methylfuran-2-yl)methyl]-2-[1 -(oxan-4-ylmethyl)-

2.2- dioxo-1 ,3-dihydro-2,1 -benzothiazol-5-yl]acetamide;

N-[(2,4-dimethylphenyl)(5-methylfuran-2-yl)methyl]-1 -[1 -(2-hydroxyethyl)-1 H- indol-5-yl]cyclopropane-1 -carboxamide;

N-[(2,4-dimethylphenyl)(5-methylfuran-2-yl)methyl]-1 -(1 -methyl-2,2-dioxo-1 ,3- dihydro-2,1 -benzothiazol-5-yl)cyclopropane-1 -carboxamide;

N-{[2-(dimethylamino)-4-methylphenyl](5-methylfuran-2-yl) methyl}-1 -(2,2-dioxo-

1 .3- dihydro-2,1 -benzothiazol-5-yl)cyclopropane-1 -carboxamide;

N-[(5-chlorofuran-2-yl)(2 _! 4-dimethylphenyl)methyl]-1 -(2,2-dioxo-1 ,3-dihydro-2- benzothiophen-5-yl)cyclopropane-1 -carboxamide;

1 -(2-methanesulfonyl-2,3-dihydro-1 H-isoindol-5-yl)-N-{[4-methyl-2-(pyrrolidin-1 - yl)phenyl](5-methylfuran-2-yl)methyl}cyclopropane-1 -carboxamide;

N-[(2 _! 4-dimethylphenyl)(5-methylfuran-2-yl)methyl]-1 -(2,2-dioxo-1 ,3-dihydro-2- benzothiophen-5-yl)cyclopropane-1 -carboxamide;

2-(2-methyl-1 H-1 ,3-benzodiazol-5-yl)-N-{[4-methyl-2-(piperidin-1 - yl)phenyl](phenyl)methyl}acetamide; N-{[2-(dimethylamino)-4-methylphenyl](5-methylfuran-2-yl)met hyl}-1 -(2- methanesulfonyl-2,3-dihydro-1 H-isoindol-5-yl)cyclopropane-1 -carboxamide; N-[(2-bromo-4-methylphenyl)(5-methylfuran-2-yl)methyl]-2-(2- methyl-1 H-1 ,3- benzodiazol-5-yl)acetamide;

2-(2,2-dioxo-1 ,3-dihydro-2-benzothiophen-5-yl)-N-{[4-methyl-2-(piperidin-1 - yl)phenyl](5-methylfuran-2-yl)methyl}acetamide;

N-[(5-chlorofuran-2-yl)[4-methyl-2-(piperidin-1 -yl)phenyl]methyl]-2-(2- methanesulfonyl-2,3-dihydro-1 H-isoindol-5-yl)acetamide;

N-[(5-chlorofuran-2-yl)[4-methyl-2-(pyrrolidin-1 -yl)phenyl]methyl]-1 -(2- methanesulfonyl-2,3-dihydro-1 H-isoindol-5-yl)cyclopropane-1 -carboxamide; N-[(2-bromo-4-methylphenyl)(phenyl)methyl]-2-(2-methyl-1 H-1 ,3-benzodiazol-5 yl)acetamide;

2-(2-methyl-1 H-1 ,3-benzodiazol-5-yl)-N-{[4-methyl-2-(pyrrolidin-1 - yl)phenyl](phenyl)methyl}acetamide;

N-[(5-chlorofuran-2-yl)[4-methyl-2-(piperidin-1 -yl)phenyl]methyl]-2-(2-oxo-2,3- dihydro-1 H-indol-5-yl)acetamide;

2-[(3Z)-3-hydrazinylidene-2-oxo-2,3-dihydro-1 H-indol-5-yl]-N-{[4-methyl-2- (piperidin-1 -yl)phenyl](5-methylfuran-2-yl)methyl}acetamide;

2-(3-hydroxy-2,3-dihydro-1 H-inden-5-yl)-N-{[4-methyl-2-(piperidin-1 - yl)phenyl](5-methylfuran-2-yl)methyl}acetamide;

N-[(5-chlorofuran-2-yl)(2 _! 4-dimethylphenyl)methyl]-1 -(2-oxo-2,3-dihydro-1 H- indol-5-yl)cyclopropane-1 -carboxamide;

N-[(5-chlorofuran-2-yl)(2,4-dimethylphenyl)methyl]-1 -(2 _! 2-dioxo-1 _! 3-dihydro-2,1 benzothiazol-5-yl)cyclopropane-1 -carboxamide;

2-(1 H-indol-6-yl)-N-((4-methyl-2-(piperidin-1 -yl)phenyl)(5-methylfuran-2- yl)methyl)acetamide;

2-[3-(hydroxymethyl)-1 H-indol-6-yl]-N-{[4-methyl-2-(piperidin-1 -yl)phenyl](5- methylfuran-2-yl)methyl}acetamide;

1 -(1 H-indol-5-yl)-N-((4-methyl-2-(piperidin-1 -yl)phenyl)(5-methylfuran-2- yl)methyl)cyclopropanecarboxamide;

1 -[3-(hydroxymethyl)-1 H-indol-5-yl]-N-{[4-methyl-2-(piperidin-1 -yl)phenyl](5- methylfuran-2-yl)methyl}cyclopropane-1 -carboxamide;

N-[(2-bromo-4-methylphenyl)(phenyl)methyl]-2-(2-ethoxy-1 H-1 ,3-benzodiazol-5 yl)acetamide;

N-{[4-methyl-2-(piperidin-1 -yl)phenyl](5-methylfuran-2-yl)methyl}-2-[6- (methylsulfanyl)naphthalen-2-yl]acetamide; N-[(2-bromo-4-methylphenyl)(phenyl)methyl]-2-[2-(ethylsulfan yl)-1 H-1 ,3- benzodiazol-5-yl]acetamide;

N-{[4-methyl-2-(piperidin-1 -yl)phenyl](5-methylfuran-2-yl)methyl}-2-[2-

(morpholin-4-yl)-1 H-1 ,3-benzodiazol-5-yl]acetamide;

N-{[4-methyl-2-(piperidin-1 -yl)phenyl](5-methylfuran-2-yl)methyl}-2-[3-

(morpholin-4-ylmethyl)-1 H-indol-5-yl]acetamide;

1 -(1 -cyclopropanecarbonyl-2,3-dihydro-1 H-indol-5-yl)-N-[(2,4- dimethylphenyl)(5-methylfuran-2-yl)methyl]cyclopropane-1 -carboxamide;

tert-butyl 3-{5-[({[4-methyl-2-(piperidin-1 -yl)phenyl](5-methylfuran-2- yl)methyl}carbamoyl)methyl]-1 H-indol-1 -yl}propanoate;

3-{5-[({[4-methyl-2-(piperidin-1 -yl)phenyl](5-methylfuran-2- yl)methyl}carbamoyl)methyl]-1 H-indol-1 -yl}propanoic acid;

2- [3-(2-methanesulfonylethyl)-1 H-indol-5-yl]-N-{[4-methyl-2-(piperidin-1 - yl)phenyl](5-methylfuran-2-yl)methyl}acetamide;

tert-butyl 3-[5-({[(2,4-dimethylphenyl)(5-methylfuran-2- yl)methyl]carbamoyl}methyl)-1 H-indol-1 -yl]propanoate;

tert-butyl 3-[5-({[(2-bromo-4-methylphenyl)(5-methylfuran-2- yl)methyl]carbamoyl}methyl)-1 H-indol-1 -yl]propanoate;

3- [5-({[(2,4-dimethylphenyl)(5-methylfuran-2-yl)methyl]carbamo yl}methyl)-1 H- indol-1 -yl]propanoic acid;

3-[5-({[(2-bromo-4-methylphenyl)(5-methylfuran-2-yl)methyl]c arbamoyl}methyl)- 1 H-indol-1 -yl]propanoic acid;

2-[3-(2-methanesulfonylacetyl)-1 H-indol-5-yl]-N-{[4-methyl-2-(piperidin-1 - yl)phenyl](5-methylfuran-2-yl)methyl}acetamide;

N-[(2-bromo-4-methylphenyl)(5-methylfuran-2-yl)methyl]-2-[3- (2- methanesulfonylacetyl)-1 H-indol-5-yl]acetamide;

2-(1 H-indol-5-yl)-N-{[4-methyl-2-(piperidin-1 -yl)phenyl](5-methylfuran-2- yl)methyl}acetamide;

2-(1 -methanesulfonyl-1 H-indol-5-yl)-N-{[4-methyl-2-(piperidin-1 -yl)phenyl](5- methylfuran-2-yl)methyl}acetamide;

N-[(2,4-dimethylphenyl)(5-methylfuran-2-yl)methyl]-2-[3-( 2- methanesulfonylacetyl)-1 H-indol-5-yl]acetamide;

N-[(2,4-dimethylphenyl)(5-methylfuran-2-yl)methyl]-1 -(1 H-indol-5- yl)cyclopropane-1 -carboxamide;

tert-butyl 3-{5-[({[2-(azepan-1 -yl)-4-methoxyphenyl](5-methylfuran-2- yl)methyl}carbamoyl)methyl]-1 H-indol-1 -yl}propanoate; 3-{5-[({[2-(azepan-1 -yl)-4-methoxyphenyl](5-methylfuran-2- yl)methyl}carbamoyl)methyl]-1 H-indol-1 -yl}propanoic acid;

N-[(5-chlorofuran-2-yl)[4-methyl-2-(pyrrolidin-1 -yl)phenyl]methyl]-2-[3-(2- methanesulfonylethyl)-1 H-indol-5-yl]acetamide;

N-{[4-methyl-2-(piperidin-1 -yl)phenyl](5-methylfuran-2-yl)methyl}-2-[1 -(oxan-4- ylmethyl)-1 H-indol-5-yl]acetamide;

N-{[4-methyl-2-(piperidin-1 -yl)phenyl](5-methylfuran-2-yl)methyl}-2-[1 - (morpholine-4-carbonyl)-1 H-indol-6-yl]acetamide;

N-{[4-methyl-2-(piperidin-1 -yl)phenyl](5-methylfuran-2-yl)methyl}-2-[3- (methylsulfamoyl)-l H-indol-5-yl]acetamide;

N-{[4-methyl-2-(piperidin-1 -yl)phenyl](5-methylfuran-2-yl)methyl}-2-[1 - (morpholine-4-carbonyl)-1 H-indol-5-yl]acetamide;

2-[3-(2-methanesulfonylacetyl)-1 H-indol-6-yl]-N-{[4-methyl-2-(piperidin-1 - yl)phenyl](5-methylfuran-2-yl)methyl}acetamide;

N-{[4-methyl-2-(piperidin-1 -yl)phenyl](5-methylfuran-2-yl)methyl}-2-[1 -(oxane-4- carbonyl)-1 H-indol-5-yl]acetamide;

1 -[3-(methanesulfonamidomethyl)-1 H-indol-5-yl]-N-{[4-methyl-2-(piperidin-1 - yl)phenyl](5-methylfuran-2-yl)methyl}cyclopropane-1 -carboxamide;

N-{[4-methyl-2-(piperidin-1 -yl)phenyl](5-methylfuran-2-yl)methyl}-2-[3- (morpholine-4-carbonyl)-1 H-indol-5-yl]acetamide;

N-[(2 _! 4-dimethylphenyl)(5-methylfuran-2-yl)methyl]-1 -[2-(2-methoxyacetyl)-2,3- dihydro-1 H-isoindol-5-yl]cyclopropane-1 -carboxamide;

2-(1 -cyclopropanecarbonyl-2,3-dihydro-1 H-indol-5-yl)-N-{[4-methyl-2-(piperidin- 1 -yl)phenyl](5-methylfuran-2-yl)methyl}acetamide;

N-[(2 _! 4-dimethylphenyl)(5-methylfuran-2-yl)methyl]-1 -(2 _! 2-dioxo-1 ,3-dihydro- 4,2, 1 -benzoxathiazin-6-yl)cyclopropane-1 -carboxamide

N-[(2,4-dimethylphenyl)(5-methylfuran-2-yl)methyl]-1 -(2,3-dioxo-2,3-dihydro-1 H- indol-5-yl)cyclopropane-1 -carboxamide;

1 -(1 -acetyl-2,3-dihydro-1 H-indol-5-yl)-N-[(2,4-dimethylphenyl)(5-methylfuran-2- yl)methyl]cyclopropane-1 -carboxamide

1 - (2-acetyl-2,3-dihydro-1 H-isoindol-5-yl)-N-[(2,4-dimethylphenyl)(5-methylfuran-

2- yl)methyl]cyclopropane-1 -carboxamide;

N-[(2,4-dimethylphenyl)(5-methylfuran-2-yl)methyl]-1 -(1 -methyl-2-oxo-2,3- dihydro-1 H-indol-5-yl)cyclopropane-1 -carboxamide;

N-[(2-bromo-4-methylphenyl)(5-methylfuran-2-yl)methyl]-1 -(2,2-dioxo-1 ,3- dihydro-4,2,1 -benzoxathiazin-6-yl)cyclopropane-1 -carboxamide; N-[(2,4-dimethylphenyl)(5-methylfuran-2-yl)methyl]-1 -(1 -ethyl-2,2-dioxo-1 ,3- dihydro-2,1 -benzothiazol-5-yl)cyclopropane-1 -carboxamide;

N-{[2-(dimethylamino)-4-methylphenyl](5-methylfuran-2-yl)met hyl}-1 -(1 -methyl-

2.2- dioxo-1 ,3-dihydro-2,1 -benzothiazol-5-yl)cyclopropane-1 -carboxamide; N-[(5-chlorofuran-2-yl)(2 _! 4-dimethylphenyl)methyl]-1 -(3-oxo-3 _! 4-dihydro-2H-1 ,4 benzoxazin-7-yl)cyclopropane-1 -carboxamide;

N-[(2-bromo-4-methylphenyl)(5-methylfuran-2-yl)methyl]-1 -(3-0X0-3, 4-dihydro- 2H-1 ,4-benzoxazin-7-yl)cyclopropane-1 -carboxamide;

N-[(2 _! 4-dimethylphenyl)(6-methylpyridin-2-yl)methyl]-1 -(3-oxo-3,4-dihydro-2H- 1 ,4-benzoxazin-7-yl)cyclopropane-1 -carboxamide;

1 -(2H-1 _! 3-benzodioxol-5-yl)-N-[(2,4-dimethylphenyl)(5-methylfu ran-2- yl)methyl]cyclopropane-1 -carboxamide;

N-[(2,4-dimethylphenyl)(furan-2-yl)methyl]-1 -(3-oxo-3 _! 4-dihydro-2H-1 ,4- benzoxazin-7-yl)cyclopropane-1 -carboxamide;

N-[(4-chlorophenyl)(2,4-dimethylphenyl)methyl]-1 -(3-oxo-3 _! 4-dihydro-2H-1 ,4- benzoxazin-7-yl)cyclopropane-1 -carboxamide;

N-[(2,4-dimethylphenyl)(5-methylfuran-2-yl)methyl]-1 -(1 -oxo-2,3-dihydro-1 H- inden-5-yl)cyclopropane-1 -carboxamide;

1 -(2,3-dihydro-1 H-indol-5-yl)-N-[(2,4-dimethylphenyl)(5-methylfuran-2- yl)methyl]cyclopropane-1 -carboxamide;

N-[(3-chlorophenyl)(2,4-dimethylphenyl)methyl]-1 -(3-oxo-3 _! 4-dihydro-2H-1 ,4- benzoxazin-7-yl)cyclopropane-1 -carboxamide;

N-[(2,4-dimethylphenyl)(5-methylfuran-2-yl)methyl]-1 -{2-oxo-1 H,2H,3H- pyrido[2,3-b][1 ,4]oxazin-6-yl}cyclopropane-1 -carboxamide;

N-[(5-chlorofuran-2-yl)[4-methyl-2-(piperidin-1 -yl)phenyl]methyl]-1 -(3-0X0-3, 4- dihydro-2H-1 ,4-benzoxazin-7-yl)cyclopropane-1 -carboxamide;

1 -(3,3-dimethyl-2-oxo-2 _! 3-dihydro-1 H-indol-5-yl)-N-[(2,4-dimethylphenyl)(5- methylfuran-2-yl)methyl]cyclopropane-1 -carboxamide;

N-[(2-bromo-4-methoxyphenyl)(5-methylfuran-2-yl)methyl]-1 -(2,2-dioxo-1 ,3- dihydro-4,2,1 -benzoxathiazin-6-yl)cyclopropane-1 -carboxamide;

N-{[2-(dimethylamino)-4-methylphenyl](5-methylfuran-2-yl) methyl}-1 -(2,2-dioxo-

1 .3- dihydro-4,2,1 -benzoxathiazin-6-yl)cyclopropane-1 -carboxamide;

N-[(5-chlorofuran-2-yl)(2 _! 4-dimethylphenyl)methyl]-1 -(2,2-dioxo-1 ,3-dihydro- 4,2, 1 -benzoxathiazin-6-yl)cyclopropane-1 -carboxamide;

N-[ (2-bromo-4-methylphenyl)(5-methylfuran-2-yl)methyl]-2-(2,2-d ioxo-1 ,3- dihydro-4,2,1 -benzoxathiazin-6-yl)acetamide; 3-[5-(1 -{[(2,4-dimethylphenyl)(5-methylfuran-2- yl)methyl]carbamoyl}cyclopropyl)-1 H-indol-1 -yl]propanoic acid;

N-[(3 _! 5-dimethylpyridin-2-yl)(5-methylfuran-2-yl)methyl]-1 -(2 _! 2-dioxo-1 ,3- dihydro-4,2,1 -benzoxathiazin-6-yl)cyclopropane-1 -carboxamide;

3-{5-[1 -({[4-methyl-2-(piperidin-1 -yl)phenyl](5-methylfuran-2- yl)methyl}carbamoyl)cyclopropyl]-1 H-indol-1 -yl}propanoic acid;

N-[(2,4-dimethylphenyl)(5-methylfuran-2-yl)methyl]-1 -(1 -hydroxy-2,3-dihydro- 1 H-inden-5-yl)cyclopropane-1 -carboxamide;

N-{[2-(dimethylamino)-4-methylphenyl](5-methylfuran-2-yl)met hyl}-1 -(3-0X0-3, 4- dihydro-2H-1 ,4-benzoxazin-7-yl)cyclopropane-1 -carboxamide;

N-[(2,4-dimethylphenyl)(5-methylfuran-2-yl)methyl]-1 -[1 -(oxan-4-ylmethyl)-2,2- dioxo-1 ,3-dihydro-2,1 -benzothiazol-5-yl]cyclopropane-1 -carboxamide;

N-[(2,4-dimethylphenyl)(5-methylfuran-2-yl)methyl]-1 -(7-fluoro-2-oxo-2,3- dihydro-1 H-indol-5-yl)cyclopropane-1 -carboxamide;

1 -(3,3-difluoro-2-oxo-2 _! 3-dihydro-1 H-indol-5-yl)-N-[(2,4-dimethylphenyl)(5- methylfuran-2-yl)methyl]cyclopropane-1 -carboxamide;

N-[(5-chlorofuran-2-yl)(2,4-dimethylphenyl)methyl]-1 -(1 -methyl-2,2-dioxo-1 ,3- dihydro-2,1 -benzothiazol-5-yl)cyclopropane-1 -carboxamide;

1 -(2H-1 ,3-benzodioxol-5-yl)-N-[(2-bromo-4-methylphenyl)(5-methylfur an-2- yl)methyl]cyclopropane-1 -carboxamide;

N-{[4-methyl-2-(piperidin-1 -yl)phenyl](5-methylfuran-2-yl)methyl}-1 -[1 -(oxan-4- ylmethyl)-2,2-dioxo-1 ,3-dihydro-2,1 -benzothiazol-5-yl]cyclopropane-1 - carboxamide;

N-[(2-bromo-4-methylphenyl)(5-methylfuran-2-yl)methyl]-1 -[1 -(oxan-4-ylmethyl)- 2,2-dioxo-1 ,3-dihydro-2,1 -benzothiazol-5-yl]cyclopropane-1 -carboxamide; 1 -(2H-1 ,3-benzodioxol-5-yl)-N-{[4-methyl-2-(piperidin-1 -yl)phenyl](5- methylfuran-2-yl)methyl}cyclopropane-1 -carboxamide;

N-[(2,4-dimethylphenyl)(5-methylfuran-2-yl)methyl]-1 -[1 -(hydroxyimino)-2,3- dihydro-1 H-inden-5-yl]cyclopropane-1 -carboxamide;

N-[(2,4-dimethylphenyl)(5-methylfuran-2-yl)methyl]-2-[1 -(oxan-4-ylmethyl)-2,2- dioxo-1 ,3-dihydro-2,1 -benzothiazol-5-yl]acetamide;

N-{[4-methyl-2-(piperidin-1 -yl)phenyl](5-methylfuran-2-yl)methyl}-2-[1 -(oxan-4- ylmethyl)-2,2-dioxo-1 ,3-dihydro-2,1 -benzothiazol-5-yl]acetamide;

1 -(2,2 limethyl-2,4 lihydro-1 ,3-benzodioxin-7-yl)-N-[(2,4-dimethylphenyl)(5- methylfuran-2-yl)methyl]cyclopropane-1 -carboxamide; Cpd.169 1 -(2,2 limethyl-2,4 lihydro-1 ,3-benzodioxin-6-yl)-N-[(2,4-dimethylphenyl)(5- methylfuran-2-yl)methyl]cyclopropane-1 -carboxamide;

Cpd.170 N-[(2 _! 4-dimethylphenyl)(5-methylfuran-2-yl)methyl]-1 -[3-(1 -hydroxy-2- methylpropan-2-yl)-1 H-indol-5-yl]cyclopropane-1 -carboxamide;

Cpd.171 1 -(2,2-dioxo-1 ,3-dihydro-4,2,1 -benzoxathiazin-6-yl)-N-{[4-methyl-2-

(trifluoromethyl)phenyl](5-methylfuran-2-yl)methyl}cyclop ropane-1 -carboxami Cpd.172 N-[(2,4-dimethylphenyl)(5-methylfuran-2-yl)methyl]-1 -(1 -methyl-2,2-d

dihydro-4,2,1 -benzoxathiazin-6-yl)cyclopropane-1 -carboxamide;

Cpd.173 N-[(2-bromo-4-methylphenyl)(5-methylfuran-2-yl)methyl]-1 -(1 -methyl-2,2-dioxo- 1 ,3-dihydro-4,2,1 -benzoxathiazin-6-yl)cyclopropane-1 -carboxamide;

Cpd.174 1 -(2,2-dioxo-1 ,3-dihydro-4,2,1 -benzoxathiazin-6-yl)-N-[(2-methoxy-4- methylphenyl)(5-methylfuran-2-yl)methyl]cyclopropane-1 -carboxamide; and Cpd.175 1 -(2 _! 2-dimethyl-2H-1 ,3-benzodioxol-5-yl)-N-[(2,4-dimethylphenyl)(5- methylfuran-2-yl)methyl]cyclopropane-1 -carboxamide.

In the present invention, the terms "RORgamma", "RORy" and "RORg" are used interchangeably.

"RORy modulator" refers to a chemical compound that modulates, either directly or indirectly, the activity of RORy. In particular, the RORy modulator modulates, in particular inhibits or activates, more particularly inhibits, either directly or indirectly, the activity of RORy. RORy modulators include antagonists, inverse agonists and agonists of RORy, in particular antagonists and inverse agonists.

RORgamma modulators can be used as medicinal products. Consequently, the present invention provides a compound of formula (I) or (la) for use as a medicament.

The present invention further provides a pharmaceutical composition comprising a compound of formula (I) or (la) and a pharmaceutically acceptable carrier. A compound of formula (I) or (la), optionally in combination with one or more other therapeutically active substances, may be used in methods for treating diseases for which the modulation of RORgamma has positive effects in a subject in need thereof.

The present invention further provides a compound of formula (I) or (la) for use in the treatment of a RORy related-disease. The invention also provides a method for treating a RORy related-disease comprising the administration of a therapeutically effective amount of a compound of formula (I) or (la) to a subject in need thereof. The invention further provides the use of a compound of formula (I) or (la), in the manufacture of a medicament for use in the treatment of a RORy related-disease. The compounds of the invention may in particular be used in the treatment of a RORy related-disease such as an autoimmune or autoimmune-related disease, inflammation- related disease, metabolic disease and/or fibrotic disease, cholestatic, cholestasis-related disease or a cancer. In a particular embodiment, the compound of formula (I) or (la) is used in the treamtent of an autoimmune or autoimmune-related disease, an inflammation-related disease, a metabolic disease, a fibrotic disease, a cholestatic disease or a cholestasis- related disease.

The term "autoimmune disease" is used to designate a condition that arises from an abnormal immune response of the body against substances and tissues normally present in the body. The disease may be restricted to certain organs (e.g pancreas, in type I diabetes or thyroid gland in autoimmune thyroiditis) or involve a particular tissue in different places (e.g. in Goodpasture's disease, affection of the basement membrane in the lung and the kidney).

The term "inflammation" is used to designate a condition that arise from a protective response involving host cells, blood vessels, and proteins and other mediators which may serve to eliminate the cause of cell/tissue injury, as well as the necrotic cells/tissues resulting from the original insult, and to initiate the process of repair. The inflammatory reaction may be manifested by pain, heat, redness, swelling, blood vessels dilatation, blood flow increase and loss of function.

Fibrosis is a pathologic process, which includes scar formation and over production of extracellular matrix, by the connective tissue, as a response to tissue damage. Damage to tissue can result from a variety of stimuli including autoimmune reactions and mechanical injury. This can be a reactive, benign, or pathological state that occurs in an organ or tissue. In response to injury this is called scarring and if fibrosis arises from a single cell line this is called a fibroma. Physiologically the deposit of connective tissue can obliterate the architecture and function of the underlying organ or tissue.

Cholestasis is defined as a decrease in bile flow due to impaired secretion by hepatocytes (hepato-cellular cholestasis) or to obstruction of bile flow through intra-or extrahepatic bile ducts (obstructive cholestasis). In clinical practice, cholestasis is any condition in which the flow of bile from the liver is slowed or blocked.

Cancers are a large family of diseases that involve abnormal cell growth with the potential to invade or spread to other parts of the body. IL-17, which is produced by several types of cells, including immune cells, where IL-17 expression relies on RORgt, is known to contribute to malignant transformation and metastasis of several cancers.

Examples of autoimmune diseases, autoimmune-related diseases, inflammatory diseases, metabolic diseases, fibrotic diseases, cholestatic diseases and cancers include arthritis, asthma, severe, glucocorticoid-nonresponsive asthma, asthma exacerbations due to ongoing and/or past pulmonary infection, Addison's disease, allergy, agammaglobulinemia, alopecia areata, ankylosing spondylitis, atherosclerosis, atopic allergy, atopic dermatitis, autoimmune cardiomyopathy, autoimmune enteropathy, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune lymphoproliferative syndrome, autoimmune pancreatitis, autoimmune peripheral neuropathy, Crohn's disease, Celiac disease, colitis, chronic inflammatory demyelinating polyneuropathy, chronic obstructive pulmonary disease (COPD), dermatomyositis, diabetes mellitus type 1 , diffuse cutaneous systemic sclerosis, eczema, gastrointestinal disorder, Goodpasture's syndrome, Graves' disease, Guillain-Barre syndrome, Hashimoto's encephalopathy, Hashimoto's thyroiditis, idiopathic thrombocytopenic purpura, inflammatory bowel disease (IBD), irritable bowel syndrome, lupus, lupus erythematosus, lupus nephritis, mixed connective tissue disease, Kawasaki disease, multiple sclerosis, neuromyelitis optica, myasthenia gravis, narcolepsy, optic neuritis, osteorathritis, pemphigus vulgaris, pernicious anaemia, polymyositis, psoriasis, psoriatic arthritis, reactive arthritis, relapsing polychondritis, respiratory disorder, rheumatoid arthritis, rheumatic fever, Sjorgen's syndrome, systemic lupus erythematosus, transverse myelitis, undifferentiated connective tissue disease, ulcerative colitis, uveitis, vasculitis, Wegener's granulomatosis, systemic inflammatory response syndrome (SIRS), sepsis, Behcets disease, allergic contact dermatitis, cutaneous lupus erythematosus, dry eye and glomerulonephritis, myocarditis, acute liver failure (ALF), including acute-on-chronic liver failure (ACLF), pulmonary fibrosis (idiopathic pulmonary, interstitial lung, cystic and progressive massive fibrosis), liver fibrosis and cirrhosis of diverse etiologies (congenital, of autoimmune origin, induced by cardiometabolic diseases, alcohol consumption, cholestasis, drugs, infectious agents, trauma, radiation), metabolic syndrome, non-alcoholic fatty liver disease (NAFLD), NonAlcoholic SteatoHepatitis (NASH) and Alcoholic SteatoHepatitis (ASH), cardiac fibrosis and heart myocardial and endomyocardial fibrosis, arterial fibrosis, atherosclerosis/restenosis, mediastinal fibrosis (soft tissue of the mediastinum), macular degeneration, retinal and vitreal retinopathy, ocular scarring, cataract, Alzheimer's disease, cancer, local, disseminated or metastatic cancer, scleroderma, glioblastoma, myelofibrosis (bone marrow), retroperitoneal fibrosis (soft tissue of the retroperitoneum), nephrogenic systemic fibrosis (skin, joints, eyes, and internal organs), keloid (skin), intestinal fibrosis (occurs for example in Crohn's disease and collagenous colitis), kidney fibrosis, scleroderma and systemic sclerosis (skin, lungs, kidneys, heart, and gastrointestinal tract), arthrofibrosis (knee, shoulder, other joints), Peyronie's disease (penis), Dupuytren's contracture (hands and fingers), some forms of adhesive capsulitis (shoulder), obesity, Primary Biliary Cholangitis (PBC), Primary Sclerosing Cholangitis (PSC), Intarhepatic Cholestasis of Pregnancy (ICP), Progressive Familial Intrahepatic Cholestasis (PFIC), Biliary atresia, Cholelithiasis, Infectious cholangitis, Cholangitis associated with Langerhans cell histiocytosis, Alagille syndrome, Nonsyndromic ductal paucity, Hepatitis (hepatitis A, hepatitis B, hepatitis C), Alphal -antitrypsin deficiency, Inborn errors of bile acid synthesis, Drug- induced cholestasis, Total parenteral nutrition (TPN)-associated cholestasis, breast cancer and breast cancer metastasis, pancreatic cancer and pancreatic cancer metastasis, pancreatic ductal adenocarcinoma, liver cancer and liver cancer metastasis, hepatocellular carcinoma, lung cancer and lung cancer metastasis, non-small-cell lung cancer, colorectal cancer and colorectal cancer metastasis, colorectal carcinoma, prostate cancer and prostate cancer metastasis, gallbladder cancer and gallbladder cancer metastasis.

In particular, RORg modulators may be used in the treatment of asthma, ankylosing spondylitis, autoimmune cardiomyopathy, autoimmune hepatitis, Crohn's disease, chronic obstructive proliferative disease (COPD), diabetes mellitus type 1 , lupus erythematosus, lupus nephritis, multiple sclerosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, ulcerative colitis, myocarditis, pulmonary fibrosis (idiopathic pulmonary, interstitial lung, cystic and progressive massive fibrosis), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steato-hepatitis (NASH) and alcoholic steatoHepatitis (ASH), cardiac fibrosis and heart myocardial and endomyocardial fibrosis, arterial fibrosis, atherosclerosis/restenosis, intestinal fibrosis (occurs for example in Crohn's disease and collagenous colitis), kidney fibrosis, scleroderma, systemic sclerosis, primary biliary cholangitis (PBC), hepatitis (hepatitis A, hepatitis B, hepatitis C), colon cancer, small-cell lung cancer, non-small cell lung cancer, prostate cancer, renal cancer, ovarian cancer, bladder cancer, stomach cancer, liver cancer, testis cancer, uterus cancer, leukemia, adenocarcinoma, melanoma and cancer of central nervous system tissue.

The term "treatment" or "treating" refers to therapy, prevention, or prophylaxis of a disorder in a subject in need thereof. The treatment involves the administration of a pharmaceutical composition to subjects (e.g. patients) having a declared disorder to prevent, cure, delay, reverse, or slow down the progression of the disorder, improving thereby the condition of patients. A treatment may also be administered to subjects that are either healthy or at risk of developing a disorder such as an autoimmune, inflammatory, fibrotic or cholestatic disorder.

The term "subject" refers to a mammal and more particularly a human. The subjects to be treated according to the invention can be appropriately selected on the basis of several criteria associated with autoimmune, inflammatory, fibrotic and cholestatic pathological processes such as previous and/or present drug treatments, associated pathologies, genotype, exposure to risk factors, as well as any other relevant biomarker that can be evaluated by means of any suitable immunological, biochemical, or enzymatic method.

The Examples show how Compounds of formula (I) or (la) can be produced and tested. The details of the general methods of synthesis and purification of intermediate products for Compounds of formula (I) or (la) are provided in Example 1 .

Specific reaction intermediates can be synthesized and purified from compounds that may be already available commercially or that can be readily synthesized.

The details of the general methods of synthesis and purification of Compounds of formula (I) or (la) are provided in Example 2.

General schemes of synthesis of the compounds of formula (I) or (la) are presented in Figure 3A.

The functional groups optionally present in the reaction intermediates that are generated for obtaining the desired compounds of formula (I) or (la) can be protected, either permanently, or temporarily, by protective groups, which ensure unequivocal synthesis of the desired compounds. The reactions of protection and deprotection are carried out according to techniques well known by a person skilled in the art or such as those described in the literature, as in the book "Greene's Protective Groups in Organic Synthesis" (Wuts & Greene, 2007).

The compounds according to the invention may contain one or more asymmetric centers. The present invention includes stereoisomers (diastereoisomers, enantiomers), pure or mixed, as well as racemic mixtures and geometric isomers, or tautomers of compounds of formula (I) or (la). When an enantiomerically pure (or enriched) mixture is desired, it can be obtained either by purification of the final product or of chiral intermediates, or by asymmetric synthesis according to methods known by a person skilled in the art (using for example chiral reactants and catalysts). Certain compounds according to the invention can have various stable tautomeric forms and all these forms and mixtures thereof are included in the invention. The techniques for obtaining and characterizing the stereoisomers, pure or mixed, as well as racemic mixtures and geometric isomers, or tautomers are described in the literature, such as in the book "Chirality in Drug Design and Development" (Reddy & Mehvar, 2004).

The compounds of formula (I) or (la) can be purified by precipitation or solid/liquid extraction after evaporation of the reaction medium. Further or other purification step can be performed by chromatography over silica gel or by crystallization, when the compound is stable as a solid form, by applying techniques well known in the literature or, more in general, for chemicals (Armarego & Chai, 2009).

Moreover, the required purification and/or (re-)crystallization steps that are appropriate for isolating compounds of formula (I) or (la) from the reaction mixture, can be used for obtaining amorphous, polymorphous, mono- or poly-crystalline forms. Such polymorphisms may present distinct pharmacological and/or chemical properties, for example in terms of solubility, intrinsic dissolution rate, melting temperature, bioavailability, and/or possible transition from a polymorphic state to another one in pharmaceutical compositions and/or biological fluids.

The (re-)crystallisation assays can be performed in panels of different solvents (such as isopropanol, acetone, methanol, diisopropyl ether or water) or mixture thereof, and by applying different conditions, such as reaction volumes or temperatures. The resulting samples can be analyzed by different techniques such as microscopy, calorimetry, and/or spectroscopy that allow establishing the features of a particular crystalline form, such as structure, solubility, stability or conversion to other forms (Bauer, 2004; Erdemir et al, 2007; Morissette et al, 2004; Yin & Grosso, 2008).

Such a polymorphism study allows characterizing the crystalline form of a compound that is pharmaceutically acceptable for both pharmacological and manufacturing points of view.

Certain compounds of formula (I) or (la) can be isolated in the form of zwitterions and each of these forms is included in the invention, as well as mixtures thereof.

Compounds of formula (I) or (la) and their salts can be stable in liquid or solid forms. The present invention includes all solid and liquid forms of formula (I) or (la), which includes the amorphous, polymorphic, mono- and poly-crystalline forms. In particular, the compounds of formula (I) or (la) can exist in the free form or in the solvated form, i.e. in the form of associations or combinations with one or more molecules of a solvent, for example with pharmaceutically acceptable solvents such as water (hydrates) or ethanol. The present invention also includes the prodrugs of the compounds according to the invention which, after administration to a subject, are converted to the compounds as described in the invention or to their metabolites having therapeutic activities comparable to the compounds according to the invention.

Specific compounds of formula (I) or (la) can comprise at least one atom of the structure that is replaced by an isotope (radioactive or not). Examples of isotopes that can be included in the structure of the compounds according to the invention can be selected from hydrogen, carbon, nitrogen, oxygen, sulphur such as ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ 0, ¹⁷ 0, ³⁵ S respectively. When non-radioactive, the stable isotope can be selectively incorporated in the structure in place of hydrogen (in the case of deuterium) or carbon (in the case of ¹³ C) not only as means of performing absorption, distribution, metabolism, and excretion (ADME) studies but also as means for obtaining compounds that may retain the desired biochemical potency and selectivity of the original compound while the metabolic fate is substantially altered. In some favourable cases, this modification has the potential to have a positive impact effect on safety, efficacy and/or tolerability of the original compound (Mutlib, 2008). Otherwise radioactive isotopes ³ H and ¹⁴ C are particularly preferred as they are easy to prepare and detect in studies of the bioavailability in vivo of the substances. The heavy isotopes (such as ² H) are particularly preferred as they are used as internal standards in analytical studies and as possible variants of pharmaceutical interest.

Compounds of formula (I) or (la) can be obtained as specific salts, hydrates, and polymorphs that can be obtained during the final purification step of the compound or, in the case of salts, by incorporating the salt into the previously purified compound. The selection of a compound of formula (I) or (la) that is produced according to the methods of the Invention as an optimal candidate for drug development can be automated for a comprehensive biopharmaceutical characterization at the scale-up stage and for the solid or liquid formulation that is appropriate for the desired route of administration and therapeutic indication (Kumar et al, 2007; Mahato & Narang, 201 1 ; Stahl & Wermuth, 2002).

In view of their use as medicinal products, the compounds of formula (I) or (la) can be formulated as pharmaceutically acceptable salts obtained from organic or inorganic bases or acids of such compounds. Alternatively, the compounds of formula (I) or (la) can be formulated as pharmaceutically acceptable hydrates or polymorphs of such compounds. These salts, hydrates, and polymorphs can be obtained during the final purification step of the compound or, in the case of salts, by incorporating the salt into the previously purified compound (Stahl & Wermuth, 2002).

These salts can be prepared with pharmaceutically acceptable acids but the salts of other acids useful for purifying or isolating the compounds of formula (I) or (la) also form part of the invention. In particular, when the compounds according to the invention are in the form of a salt, it is a salt of an alkali metal, in particular a salt of sodium or of potassium, or a salt of an alkaline-earth metal, in particular magnesium or calcium, or a salt with an organic amine, more particularly with an amino acid such as arginine or lysine.

The present invention further provides pharmaceutical compositions comprising a compound of formula (I) or (la), or a pharmaceutically acceptable salt thereof, and optionally at least one pharmaceutically acceptable carrier or diluent. The pharmaceutical compositions comprising a compound of formula (I) or (la) may comprise one or several excipients or vehicles acceptable within a pharmaceutical context (e.g., for liquid formulations, saline solutions, physiological solutions, isotonic solutions).

A further object of the invention are methods of preparing such pharmaceutical compositions, comprising admixing a compound of formula (I) or (la), with at least one pharmaceutically acceptable carrier, vehicle, or diluent. These methods involve, for example, conventional mixing, dissolving, granulation, dragee-making, levigating, emulsifying, encapsulating, entrapping, lyophilizing processes or spray drying (Gennaro, 2000; Rowe et al, 2003).

The phrase "pharmaceutically acceptable" refers to those properties and/or substances that are acceptable to the patient from a pharmacological/toxicological point of view and to the manufacturing pharmaceutical chemist from a physical/chemical point of view regarding composition, formulation, stability, patient acceptance and bioavailability.

The term "carrier", "vehicle", or "excipient" refers to any substance, not itself a therapeutic agent, that is added to a pharmaceutical composition to be used as a carrier, vehicle, and/or diluent for the delivery of a therapeutic agent to a subject in order to improve its handling or storage properties or to permit or facilitate formation of a dosage unit of the composition into a discrete article. The pharmaceutical compositions of the invention, either individually or in combination, can comprise one or several agents or vehicles chosen among dispersants, solubilisers, stabilisers, preservatives, etc. Agents or vehicles useful for these formulations (liquid and/or injectable and/or solid) are particularly methylcellulose, hydroxymethylcellulose, polysorbate 80, mannitol, gelatin, lactose, vegetable oils, liposomes, etc. Acceptable excipients can be chosen among disintegrants, binding agents, adhesives, wetting agents, lubricants, glidants, flavors, dyes, fragrances, stearic acid, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, magnesium carbonate, talc, gelatin, lactose, sucrose, starches, polymers, such as polyvinyl alcohol and polyethylene glycols, and other pharmaceutically acceptable materials added to improve taste, odor or appearance of the composition.

The compounds can be made up in solid or liquid form, such as tablets, capsules, powders, syrups, elixirs and the like, aerosols, sterile solutions, suspensions or emulsions, and the like. The composition may be presented in a solid preformulation composition wherein the active ingredients are dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective dosage forms such as tablets, pills and capsules. Additionally, the combined compositions may be delivered using sustained-release formulations.

The compositions can be formulated as injectable suspensions, gels, oils, pills, suppositories, powders, gel caps, capsules, aerosols, etc., eventually by means of galenic forms or devices assuring a prolonged and/or slow release. For this kind of formulation, agents such as cellulose, carbonates or starches can advantageously be used. The compositions of the present invention can also be formulated in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of lipids, including but not limited to amphipathic lipids such as phosphatidylcholines, sphingomyelins, phophatidylcholines, cardiolipins, phosphatidylethanolamines, phosphatidylserines, phosphatidylglycerols, phosphatidic acids, phosphatidylinositols, diacyl trimethylammonium propanes, diacyl dimethylammonium propanes, and stearylamine, neutral lipids such as triglycerides, and combinations thereof.

The pharmaceutical combination of the invention can be administered in a systematic or parenteral way, by using oral, topical, perlingual, nasal, rectal, transmucosal, transdermal, intestinal, intramuscular, intravenously, subcutaneous, intraarterial, intraperitoneal, intrapulmonary or intraocular route, by using methods known in the art.

Formulations for oral administration may be in the form of aqueous solutions and suspensions, in addition to solid tablets and capsule formulations. The aqueous solutions and suspensions may be prepared from sterile powders or granules. The compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers.

For administration by inhalation, the pharmaceutical compositions comprising a compound of formula (I) or (la) are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, 1 ,1 ,1 ,2- tetrafluoroethane, 1 ,1 ,1 ,2,3,3,3-heptafluoropropane, carbon dioxide or other suitable gas, alone or in combination. Pressurized aerosols may be formulated as suspensions or solutions, and include an appropriate propellant formulation, and various excipients, such as surfactants, co-solvents, etc. In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of e.g. gelatin for use in an inhaler or insufflators may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

The tablets or pills of the composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of material can be used for such enteric layers or coatings, such materials including a number of polymeric acids with such as shellac and cellulose acetate.

The liquid forms in which the pharmaceutical compositions can be incorporated for oral administration or by injection include, aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions, include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin. The liquid forms in suitably flavored suspending or dispersing agents may also include the synthetic and natural gums, for example, tragacanth, acacia, methyl-cellulose and the like. For parenteral administration, sterile suspensions and solutions are desired. A person skilled in the art will take care to select the possible compound or compounds to be added to these compositions in such a way that the advantageous properties intrinsically attaching to the present invention are not or substantially not altered by the addition envisaged, as is also explained in the literature, for example in the book "Pharmaceutical Dosage Forms and Drug Delivery" (2007; edited by Mahato R; published by CRC Press).

A pharmaceutical composition as disclosed herein is understood to be useful for treating a RORy related-disease, that is, the active ingredients are contained in an amount to achieve their intended purpose. At this scope, a compound of formula (I) or (la) should be administered in an effective amount by using a pharmaceutical composition as above- defined. Administration can be performed daily or even several times per day, if necessary, and in an amount that can be optimal or suboptimal, if they are compared with dosages that are normally used for such compounds.

The term "effective amount" refers to an amount of the compound sufficient to produce the desired therapeutic result. In particular the compounds of formula (I) or (la) are administered in amounts that are sufficient to display a desired effect.

Optimal dosages of compounds of formula (I) or (la) to be administered may be readily determined by those skilled in the art, and will vary with the particular compound used, the strength of the preparation, the mode of administration, and the severity of the condition to be treated. In addition, factors associated with the particular patient being treated, including patient age, weight, diet and time of administration, will result in the need to adjust dosages and interval. The frequency and/or dose relative to the simultaneous or separate administrations can be adapted by one of ordinary skill in the art, in function of the patient, the pathology, the form of administration, etc. For instance, a compound of formula (I) or (la) should be provided in a dosage that allows its administration in the amount 0.01 mg/day to 1000 mg/day, preferably from 0.1 mg/day to 10 mg/day.

The compounds of formula (I) or (la) can advantageously be formulated and/or administered in combination with one or more other therapeutically active substances, marketed or under development, that are selected according to a specific autoimmune, inflammatory, fibrotic or cholestatic disorder or any other disorders that may be found associated to said disorder in medical settings and that should be also treated. Such a combined administration includes two possibilities: the two agents are administered to a subject at substantially similar times; or the two agents are administered to a subject at different times, at independent intervals that may or may not overlap or coincide. As such, the invention also relates to a kit-of-parts, comprising a compound of the invention, in association with another therapeutically active agent, for their simultaneous, separate or sequential use in the therapy, in particular in the treatment of an autoimmune, inflammatory, fibrotic or cholestatic disorder.

The invention also relates to a pharmaceutical composition comprising a compound of formula (I) or (la) and at least one other therapeutically active agent.

A non-exhaustive list of active agents that may be advantageously formulated and/or administered with compounds of formula (I) or (la) includes:

anti-inflammatory;

- anti-oxidant agents;

immunosuppressor agents;

agents used in the treatment of asthma;

agents used in the treatment of psoriasis;

agents used in the treatment of respiratory diseases;

- hepatoprotective agents;

agents used in the treatment of heart failure or coronary insufficiency Antihypertensive and hypotensive agents;

anti-coagulant, vasodilators,

anti-ischemic agents;

- agents used in the treatment of metabolic diseases, such as anti-diabetic, hypolipidemic, hypocholesterolemic, anti-atherosclerotic and anti-obesity agents, anti-viral agents;

anti-cancer agents and cancer prevention agents;

anti-cholestatic agents;

- anti-fibrotic agents;

anti-NAFLD agents; anti-NASH agents.

In a particular embodiment, the invention relates to the use of a compound of formula (I) or (la) in combination with an anti-fibrotic, anti-NAFLD or anti-NASH agent. Therefore, the invention relates to a first combination product comprising:

a) a RORgamma modulator, such as a compound of formula (I) or (la) or a pharmaceutically acceptable salt thereof; and

b) another therapeutically active agent.

In a particular embodiment, the other therapeutically active agent is an anti-fibrotic, anti-NAFLD or anti-NASH agent. In another particular embodiment, the other therapeutically active agent is a PPAR activator as defined below.

In a particular embodiment, the combination product is a composition comprising the RORgamma modulator and the other therapeutically active agent, and a pharmaceutically acceptable carrier.

In another embodiment, the combination product is a kit of parts comprising components a) and b) of the combination product. The kit of parts of the invention is for sequential, separate or simultaneous use in the treatment of any of the diseases mentioned above.

In another aspect, the invention relates to a combination of a RORy modulator and a PPAR activator. In a particular embodiment, the invention relates to a composition comprising a RORy modulator and a PPAR activator. In another embodiment, the invention relates to a kit-of-parts comprising a RORy modulator and a PPAR activator, for simultanate, separate or sequential use.

The PPARs (α, β/δ (herein after δ), γ) belong to the hormone-activated nuclear receptor family. The PPARs, or "Peroxisome Proliferator Activated Receptors", are nuclear receptors from the superfamily of transcription factors activated by the following ligands: steroids/thyroid hormones/retinoids. To date, three PPAR isotypes have been identified in mice and humans: PPARa, PPAR5 and PPARy. While PPAR β/δ expression in humans appears to be ubiquitous, PPARa and γ exhibit a differential tissue distribution (Braissant O and Wahli W, 1998). PPARa is expressed in cells with high fatty acid catabolic activity and in cells with high peroxisomal activity (hepatocytes, cardiomyocytes, renal proximal tubules, intestinal mucosa). PPAR β/δ is expressed ubiquitously and abundantly in most tissues. As far as PPARy expression is concerned, it is limited mainly to adipose tissue, certain immune system cells and retina and is present in only trace amounts in other organs (Braissant O and Wahli W, 1998).

Taking the example of PPARa, its action is mediated by a class of compounds such as the fibrates which have a lipid-lowering effect. Natural ligands have also been identified such as for example fatty acids, eicosanoids (leukotriene B4) and 8(S)-hydroxyeicosatetraenoic acid (Kliewer SA et al., 1997). The PPARs have been associated primarily with lipid and glucose metabolism. PPAR activators, such as fibrates, enable a regulation of plasma cholesterol and triglyceride concentrations via activation of PPARa (Hourton D et al., 2001 ). Fibrate therapy leads to an increase in fatty acid oxidation in liver. Fibrates also decrease the synthesis of triglycerides (Staels B and Auwerx J, 1998). PPARa activators are also capable of correcting hyperglycemia and insulin level. Fibrates also reduce adipose tissue mass through a mechanism which is independent of food intake and leptin gene expression (Guerre-Millo M et al., 2000). The therapeutic interest of PPARy agonists has been widely investigated in the treatment of type 2 diabetes (Spiegelman BM, 1998). It has been shown that PPARy agonists restore insulin sensitivity in target tissues and reduce plasma glucose, lipid and insulin levels both in animal models of type 2 diabetes and in humans (Ram VJ, 2003). PPAR activation by ligands also plays a role in regulating the expression of genes that participate in processes such as inflammation, angiogenesis, cell proliferation and differentiation, apoptosis and the activities of iNOS, MMPase and TIMPs. Activation of PPARa in keratinocytes results in a cessation of their proliferation and expression of genes involved in differentiation (Komuves LG et al., 2000). The PPARs have anti-inflammatory properties because they negatively interfere with transcription mechanisms involving other transcription factors like NF-κΒ or transcriptional activators like STAT and AP-1 (Desvergne B and Wahli W, 1999). Said anti-inflammatory and anti-proliferative properties make the PPARS (and particularly PPARa) interesting therapeutic targets for the treatment of diseases such as vascular occlusive diseases (atherosclerosis, etc.), hypertension, diseases related to neovascularization (diabetic retinopathy, etc.), inflammatory diseases (inflammatory bowel disease, psoriasis, etc.) and neoplastic diseases (carcinogenesis, etc.).

The combination of the invention may be used as a medicament. In a particular embodiment, the combination is used for the treatment of one of the diseases mentioned above. The RORy modulator and the PPAR activator are each administered to a subject in need thereof in a therapeutically effective amount.

In a particular embodiment, the ROR modulator in the combination is a compound of formula (I) or (la).

In a particular embodiment, the PPAR activator in the combination is a PPARa, PPAR5, PPARy, PPARa/δ (or dual PPARa/δ), PPARa/γ (or dual PPARa/γ), PPARy/δ (or dual PPARy/δ), or PPARa/γ/δ (or pan-PPAR) activator. In a particular embodiment, the PPAR alpha agonist is a fibrate such as fenofibrate, ciprofibrate, pemafibrate, gemfibrozil, clofibrate, binifibrate, clinofibrate, clofibric acid, nicofibrate, pirifibrate, plafibride, ronifibrate, theofibrate, tocofibrate or SR10171 .

In a particular embodiment, the PPAR gamma agonist is a glitazone (or thiazolidinedione) such as Rosiglitazone, Pioglitazone, deuterated pioglitazone, efatutazone, ΑΤχΟβ-001 , OMS-405 , CHS-131 , THR-0921 , SER-150-DN, KDT-501 , GED-0507-34-Levo, CLC-3001 or ALL-4.

In a particular embodiment, the PPAR delta agonist is GW501516 (Endurabol or ({4- [({4-methyl-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5-yl}methyl)sulfanyl]-2- methylphenoxy}acetic acid)), MBX8025 (Seladelpar or {2-methyl-4-[5-methyl-2-(4- trifluoromethyl- phenyl)-2H-[l,2,3]triazol-4-ylmethylsylfanyl]-phenoxy}-aceti c acid), GW0742 ([4-[[[2-[3-fluoro-4- (trifluoromethyl)phenyl]-4-methyl-5-thiazolyl]methyl]thio]-2 -methyl phenoxy]acetic acid), L165041 , HPP-593 or NCP-1046.

In a particular embodiment, the PPAR alpha/gamma dual agonist is a glitazar such as Saroglitazar, Aleglitazar, Muraglitazar, Tesaglitazar or DSP-8658.

In a particular embodiment, the PPAR alpha/delta dual agonist is Elafibranor (GFT505) or T913659.

In a particular embodiment, the PPAR gamma/delta dual agonist is a conjugated linoleic acid (CLA) or T3D-959.

In a particular embodiment, the PPAR alpha/gamma/delta pan agonist is IVA337, TTA

(tetradecylthioacetic acid), Bavachinin, GW4148, GW9135, Bezafibrate, Lobeglitazone or CS038.

In a more particular embodiment, the PPAR activator is a compound of formula (II), or a pharmaceutically acceptable salt thereof:

in which:

Y1 represents a halogen, a Ra, or Ga-Ra group;

A represents a CH=CH or a CH2-CH2 group;

Y2 represents a Gb-Rb group;

Ga and Gb, identical or different, represent an atom of oxygen or sulfur; Ra represents a hydrogen atom, an unsubstituted (C1 -C6)alkyl group, a (C6-C14)aryl group or a (C1 -C6)alkyl group that is substituted by one or more halogen atoms, a (C1 - C6)alkoxy or a (C1 -C6)alkylthio group, (C3-C14)cycloalkyl groups, (C3- C14)cycloalkylthio groups or heterocyclic groups;

Rb represents a (C1 -C6)alkyl group substituted by at least a -COORc group, wherein Rc represents a hydrogen atom, or a (C1 -C6)alkyl group that is substituted or not by one or more halogen atoms, (C3-C14)cycloalkyl groups, or heterocyclic groups; and Y4 and Y5, identical or different, representing a (C1 -C6)alkyl group that is substituted or not by one or more halogen atoms, (C3-C14)cycloalkyl groups or heterocyclic groups.

In a particular embodiment of the compound of formula (II):

Y1 represents a halogen, a Ra, or a Ga-Ra group;

A represents a CH=CH group;

Y2 represents a Gb-Rb group;

Ga and Gb, identical or different, represent an atom of oxygen or sulfur;

Ra represents a (C1 -C6)alkyl or (C3-C14)cycloalkyl group, in particular a (C1 -C7)alkyl or (C3-C14)cycloalkyl group substituted or not by one or more halogen atoms;

Rb represents a (C1 -C6)alkyl group substituted by a -COOR3 group, wherein Rc represents a hydrogen atom or an alkyl group having from one to four carbon atoms; and

Y4 and Y5 independently represent a (C1 -C4)alkyl group.

In a particular embodiment of the compound of formula (II):

Y1 represents a Ra or Ga-Ra group;

A represents a CH2-CH2 group;

Y2 represents a Gb-Rb group;

Ga represents an atom of oxygen or sulfur and Gb represents an atom of oxygen; Ra represents a (C1 -C6)alkyl or (C3-C7)cycloalkyl group;

Rb represents a (C1 -C6)alkyl group substituted by at least a -COORc group, wherein Rc represents a hydrogen atom or (C1 -C4)alkyl group; and

Y4 and Y5 independently represent a (C1 -C4)alkyl group.

In a particular embodiment of the compound of formula (II):

Y1 represents a halogen atom or a Ra or Ga-Ra group;

A represents a CH2-CH2 group;

Y2 represents a Gb-Rb group;

Ga represents an atom of oxygen or sulfur and Gb represents an atom of oxygen; Ra represents a (C1 -C6)alkyl or (C3-C14)cycloalkyl group that is substituted by one or more halogen atoms;

Rb represents a (C1 -C6)alkyl group substituted or not by one or more halogen atoms and substituted by at least a -COORc group, wherein Rc represents a hydrogen atom or a (C1 -C4)alkyl group; and

Y4 and Y5 represent a (C1 -C4)alkyl group.

In a particular embodiment of the compound of formula (II), Gb is an oxygen atom and Rb is (C1 -C6)alkyl group substituted by a -COORc group, wherein Rc represents a hydrogen atom or an unsubstituted linear or branched (C1 -C4)alkyl group.

In a particular embodiment of the compound of formula (II), Y1 is a (C1 -C6)alkylthio group that comprises a (C1 -C6)alkyl group that is linear or branched that is substituted or not by one or more halogen atoms.

In a particular embodiment, the compound of formula (II) is selected in the group consisting of 1 -[4-methylthiophenyl]-3-[3,5-dimethyl-4-carboxydimethylmethy loxy phenyl]prop-2-en-1 -one (Elafibranor or GFT505), 1 -[4-methylthiophenyl]-3-[3,5-dimethyl-4- isopropyloxy carbonyldimethylmethyloxyphenyl]prop-2-en-1 -one, 1 -[4-methylthiophenyl]-3- [3,5-dimethyl-4-tertbutyloxycarbonyldimethylmethyloxyphenyl] prop-2-en-1 -one, 1 -[4- trifluoromethylphenyl]-3-[3,5-dimethyl-4-tertbutyloxycarbony l dimethylmethyloxyphenyl]prop- 2-en-1 -one, 1-[4-trifluoromethylphenyl]-3-[3,5-dimethyl-4- carboxydimethylmethyloxyphenyl]prop-2-en-1 -one, 1 -[4-trifluoromethyl oxyphenyl]-3-[3,5- dimethyl-4-tertbutyloxycarbonyldimethylmethyloxy phenyl] prop-2-en-1 -one, 1 -[4- trifluoromethyloxyphenyl]-3-[3,5-dimethyl-4-carboxydimethylm ethyl oxyphenyl]prop-2-en-1 - one, 2-[2,6-dimethyl-4-[3-[4-(methylthio)phenyl]-3-oxo-propyl] phenoxy]-2-methylpropanoic acid, and 2-[2,6-dimethyl-4-[3-[4-(methylthio) phenyl]-3-oxo-propyl]phenoxy]-2-methyl- propanoic acid isopropyl ester. In a more particular embodiment, the PPAR activator is 1 -[4-methylthiophenyl]-3-[3,5- dimethyl-4-carboxydimethylmethyloxy phenyl]prop-2-en-1 -one (or Elafibranor - GFT505), or a pharmaceutically acceptable salt thereof.

In a particular aspect, the invention relates to a combination product comprising:

i) a RORgamma modulator, in particular a compound of formula (I) or (la) or a pharmaceutically acceptable salt thereof; ii) a PPAR activator, in particular a compound of formula (II) or a pharmaceutically acceptable salt thereof, in particular Elafibranor or a pharmaceutically acceptable salt thereof.

In a particular embodiment, the combination product is a composition comprising:

i) a RORgamma modulator, in particular a compound of formula (I) or (la) or a pharmaceutically acceptable salt thereof; and

ii) a PPAR activator, in particular a compound of formula (II) or a pharmaceutically acceptable salt thereof, in particular Elafibranor or a pharmaceutically acceptable salt thereof; and

iii) a pharmaceutically acceptable carrier.

In a particular embodiment, the combination product is a kit of parts comprising:

i) a RORgamma modulator, in particular a compound of formula (I) or (la) or a pharmaceutically acceptable salt thereof; and

ii) a PPAR activator, in particular a compound of formula (II) or a pharmaceutically acceptable salt thereof, in particular Elafibranor or a pharmaceutically acceptable salt thereof;

for sequential, separate or simultaneous use in the treatment of any of the diseases mentioned above. Several other advantages of the invention will rise in the reading of the following examples; they should be considered as illustrative data and not as limitative ones.

EXAMPLES

Chemical names follow lUPAC nomenclature. Starting materials and solvents were purchased from commercial suppliers (Acros Organic, Sigma Aldrich, Combi-Blocks, Fluorochem, Fluka, Alfa Aesar or Lancaster) and were used as received without further purification. Some starting materials can be readily synthesized by a person skilled in the art. Air and moisture sensitive reactions were carried out under an inert atmosphere of nitrogen, and glassware was oven-dried. No attempts were made to optimize reaction yields. Thin- layer chromatography (TLC) was done on Merck silica gel 60 UV254 (250 μηη) plates. Visualization was accomplished with UV light. Column chromatography was performed on Geduran silica gel 60 (40 - 63 μηη) from Merck. Melting points (mp) were recorded with a Buchi Melting Point B-545 and are uncorrected. All microwave irradiation experiments were carried out in a Biotage Initiator microwave apparatus. ¹ H spectra were recorded on Bruker Advance I spectrometer at 300MHz. Chemical shifts (δ) are reported in ppm (parts per million), by reference to the hydrogenated residues of deuterated solvent as internal standard: 2.50 ppm for DMSO-d6, 7.26 ppm for CDCI3, and 3.31 , and 4.78 for Methanol-d4. The spectral splitting patterns are designated as follows: s, singlet; d, doublet; dd, doublet of doublets; ddd, doublet of doublet of doublets; t, triplet; dt, doublet of triplets; q, quartet; m, multiplet; br s, broad singlet. Coupling constants (J) are quoted to the nearest 0.1 Hz. All tested compounds exhibited≥ 95% chemical purity assessed by HPLC on a Merck HITACHI Lachrom L-7000 series and Merck HITACHI diode array detector L-7455 with a Waters column Symmetry C18 (3.5 μηη, 4.6 ^* 75 mm) and using a gradient of MeOH / Millipore water containing 0.1 % of formic acid. Chromatograms were analyzed with Lachrom software version 890-8800-09. Mass spectrometry measurements were performed on Alliance 2695 and DAD detector 2998 equiped with an Acquity QDa detector from Waters using a Waters column Symmetry C18 (3.5 μηη, 4.6 ^* 75 mm) and using a gradient of MeOH / Millipore water containing 0.1 % of formic acid (chromatograms were analyzed with Empower 3 software) or they were performed on apparatus equipped with Waters 2545 binary gradient module, Waters 2489 UVA isible detector and Acquity QDa detector using a Waters column Symmetry C18 (3.5 μηη, 4.6 ^* 75 mm) and using a gradient of MeOH / Millipore water containing 0.1 % of formic acid (chromatograms were analyzed with MassLynx 4.1 ). Preparative HPLC were performed on apparatus equipped with Waters 2545 binary gradient module, Waters 2489 UVA isible detector, Acquity QDa detector and Waters 2767 sample manager using a Waters column SymmetryPrep C18 (7 μηη, 19 ^* 150 mm) and using a gradient of MeOH / Millipore water containing 0.1 % of formic acid (chromatograms were analyzed with MassLynx 4.1 ). All solvents are HPLC grade. The compounds of the invention are prepared according to the general methods and general protocols of synthesis given below. Representative procedures suitable for the preparation of compounds of formula (I) or (la) are outlined in the Reaction Schemes for intermediate (Fig.1 and Fig. 2) and final (Fig. 3) compounds. Reagents and conditions may be adapted and additional steps employed to produce further compounds encompassed in the present invention having alternative substituent groups, or for achieving such compounds at higher yield and/or of higher purity.

Example 1 : Synthesis of intermediates for the synthesis of compounds according to the invention

In the following, compounds termed Έχ. X" are intermediate compounds used for the synthesis of compounds of the present invention. The general treatments and purification steps are carried out according to techniques well known by a person skilled in the art or such as those described in the literature: the reaction was quenched either with water, brine or sat. NH4CI. Excess or solvent used for the reaction was removed under reduced pressure. The aqueous layer was extracted three times with a non-water miscible solvent (e.g. Et20, EtOAc, CH2CI2). The organic layer was dried over MgS04, filtered and the solution was concentrated under reduced pressure. Purification of the crude material was realized either by double extraction using cone. HCI and/or NaOH 2N, by hydrochloride formation or by purification on silica gel column chromatography using standard mixture systems (cyclohexane/EtOAc, CH2CI2/MeOH and CH2CI2/EtOAc).

Example 1 a: Synthesis of acid intermediates for the synthesis of compounds according to the invention Intermediate Ex.2 : 2-(3-oxo-3,4-dihvdro-2H-1 ,4-benzoxazin-7-yl)acetic acid (Figure 1AA) Table 1.1

Starting compounds, Reaction conditions and purification,

Cpd.

Yield, Appearance ¹ H NMR (solvent) data

methyl 2-(3-hydroxy-4-nitrophenyl)acetate

- Step 1 : methyl 2-(3-hydroxyphenyl)acetate (9.0 g, 54.18 mmol) was dissolved in CH2CI2 (180 mL) and glacial acetic acid (70 ml_). The mixture was cooled to - 30°C and a solution of nitric acid 65% (3.78 mL, 54.18 mmol) in glacial acetic acid (75 mL) was added dropwise over 30 min. maintaining the temperature below - 25°C. When the addition was complete the mixture was allowed to warm up to rt and stirred at rt for 1 h. The mixture was quenched into a stirred mixture of CH2CI2/H20 (400 mL/ 400 mL). The phases were separated, the organic layer

Ex.2a

was washed with sat. NaHC03 and brine, was dried over MgS04, filtered and the solution was concentrated to dryness. The crude material was purified by silica gel column chromatography eluting with heptane and a gradient of

heptane/EtOAc from [100:0] to [60:40]. The product fractions were concentrated to dryness to afford methyl 2-(3-hydroxy-4-nitrophenyl)acetate (2.64 g, 23%) as yellow oil which solidified upon standing at rt.

- 1 H NMR (300 MHz, DMSO-d6, d in ppm): 3.63 (s, 3H), 3.76 (S, 2H), 6.89 (d, 1 H, J=9.0Hz), 7.05 (s, 1 H), 7.86 (d, 1 H, J=9.0Hz), 10.93 (s, 1 H).

ethyl 2-[5-(2-methoxy-2-oxoethyl)-2-nitrophenoxy]acetate

- Step 2: methyl 2-(3-hydroxy-4-nitrophenyl)acetate Ex.2a (2.50 g, 1 1.80 mmol) was dissolved in DMSO (25 mL), ethyl bromoacetate (1 .44 mL, 12.8 mmol) and K2C03 (1.77 g, 12.8 mmol) were added and the mixture was stirred at rt for 16 h.

Ex.2b The mixture was quenched with water and the aqueous layer was extracted with

EtOAc. The organic layer was dried over MgS04, filtered and the solution was concentrated to dryness. The crude material was purified by silica gel column chromatography eluting with heptane and a gradient of heptane/EtOAc from

[100:0] to [80:20]. The product fractions were concentrated to dryness to afford ethyl 2-[5-(2-methoxy-2-oxoethyl)-2-nitrophenoxy]acetate (3.29 g, 94%) as yellow oil which solidified upon standing at rt.

- 1 H NMR (300 MHz, CDCI3, d in ppm): 1.31 (t, 3H, J=6.0Hz), 3.67 (s, 2H), 3.73 (s, 3H), 4.29 (q, 2H, J=6.0Hz), 4.79 (s, 2H), 6.96 (s, 1 H), 7.03 (d, 1 H, J=9.0Hz), 7.86 (d, 1 H, J=9.0Hz).

methyl 2-(3-oxo-3,4-dihydro-2H-1 ,4-benzoxazin-7-yl)acetate

- Step 3: ethyl 2-[5-(2-methoxy-2-oxoethyl)-2-nitrophenoxy]acetate Ex.2b (3.20 g, 10.8 mmol) was dissolved in glacial acetic acid (50 mL) and iron powder (1.81 g, 32.4 mmol) was added. The mixture was heated to 70-80°C for 2 h. The mixture was concentrated to approx. half its volume. Water was added and the resulting suspension was stirred at rt for 30 min. The solid was collected by filtration and

Ex.2c washed with water until it was white. The solid was dried under vacuum to

constant weight and adsorbed onto silica gel for purification by column chromatography eluting with EtOAc (100%). The product fractions were combined and concentrated to dryness to afford methyl 2-(3-oxo-3,4-dihydro-2H-1 ,4- benzoxazin-7-yl)acetate (1 .69 g, 71 %) as white solid.

- 1 H NMR (300 MHz, DMSO-d6, d in ppm): 3.58-3.60 (m, 5H), 4.55 (s, 2H), 6.83- 6.85 (m, 3H), 10.67 (s, 1 H).

2-(3-oxo-3,4-dihydro-2H-1 ,4-benzoxazin-7-yl)acetic acid

- Step 4: methyl 2-(3-oxo-3,4-dihydro-2H-1 ,4-benzoxazin-7-yl)acetate Ex.2c (1 .68 g, 7.59 mmol) was dissolved in a mixture of methanol (20 mL), THF (20 mL) and water (10 mL) to afford a clean yellow solution and lithium hydroxide

monohydrate (640 mg, 15.2 mmol) was added to the mixture. The solution was

Ex.2 stirred at rt for 60 h. The organic solvents were removed under vaccum and 2 M

HCI was added dropwise to the residues until pH 3 was reached. A white precipitate was formed, collected by filtration, washed with water and dried under vacuum to constant weight to afford 2-(3-oxo-3,4-dihydro-2H-1 ,4-benzoxazin-7- yl)acetic acid (1 .30 g, 83%) as white solid.

- 1 H NMR (300 MHz, DMSO-d6, d in ppm): 3.47 (s, 2H), 4.55 (s, 2H), 6.82-6.85 (m, 3H), 10.65 (s, 1 H), 12.29 (br(s), 1 H).

Intermediate Ex.11 : 2-(2,3-dioxo-1 ,2,3,4-tetrahydroquinoxalin-6-yl)acetic acid (Figure 1AB)

Table 1.2

Starting compounds, Reaction conditions and purification,

Cpd.

Yield, appearance, ¹ H NMR (solvent) data

methyl 2-(4-amino-3-nitrophenyl)acetate

- Step 1 : methyl 2-(4-aminophenyl)acetate (17.70 g, 107.0 mmol) was dissolved in TFA (red dark solution) and cooled to -10°C. Then fuming HN03 (4.76 mL,

1 12.0 mmol) was added dropwise. The reaction mixture was warmed to rt and stirred for 18 h. TFA was evaporated and the residue was neutralized with sat.

Ex.11 a NaHC03 and solid NaHC03. The aqueous layer was extracted with EtOAc. The organic layer was dried over MgS04, filtered and the solution was concentrated to dryness. The crude material was purified by silica gel column chromatography eluting with heptane and a gradient of heptane/EtOAc from [100:0] to [80:20] to afford the desired product (12.30 g, 55%) as yellow solid.

- 1 H NMR (300 MHz, CDCI3, d in ppm): 3.55 (s, 2H), 3.71 (s, 3H), 6.04 (s, 2H), 6.79 (d, 1 H, J=8.6Hz), 7.31 (dd, 1 H, J=8.5Hz, J=1.8Hz), 8.02 (s, 1 H).

methyl 2-(4-(ethyl carbamoylformyl)-3-nitrophenyl)acetate

- Step 2: to a solution of methyl 2-(4-amino-3-nitrophenyl)acetate Ex.11 a (1 .50 g, 7.14 mmol) in CH2CI2 (28 mL) and triethylamine (2.25 mL, 10.71 mmol) was added dropwise ethyl oxalylchloride (1 .47 mL, 12.84 mmol) at 0°C. The reaction mixture was stirred at rt for 18 h. The reaction was quenched with brine. The aqueous layer was extracted with EtOAc. The organic layer was dried over

Ex.11 b MgS04, filtered and the solution was concentrated to dryness. The crude

material was purified by silica gel column chromatography eluting with heptane and a gradient of heptane/EtOAc from [100:0] to [70:30] to give methyl 2-(4- (ethyl carbamoylformyl)-3-nitrophenyl)acetate (1.55 g, 70%).

- 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .33 (t, 3H, J=7.1 Hz), 3.61 (s, 3H), 3.65 (s, 2H), 4.34 (d, 2H, J=7.1 Hz), 7.70 (d, 1 H, J=8.6Hz), 8.01 (d, 1 H, J=8.4Hz), 8.08 (s, 1 H), 1 1 .35 (s, 1 H).

methyl 2-(1 ,2,3,4-tetrahydro-2,3-dioxoquinoxalin-7-yl)acetate

- Step 3: to a solution of methyl 2-(4-(ethyl carbamoylformyl)-3- nitrophenyl)acetate Ex.11 b (1 .55 g, 4.99 mmol) in AcOH (23 mL) was added at rt iron powder (975 mg, 17.45 mmol). The reaction mixture was warmed to 78°C for 4 h. The reaction mixture was filtered and quenched with sat. NaHC03. The aqueous layer was extracted with iPrOH/CHCI3 [1 :1]. The organic layer was

Ex.11 c dried over MgS04, filtered and the solution was concentrated to dryness. The crude material was purified by silica gel column chromatography eluting with heptane and a gradient of heptane/EtOAc from [100:0] to [0:100], then a gradient of EtOAc/MeOH from [100:0] to [30:70] to afford the title compound (669 mg, 57%).

- 1 H NMR (300 MHz, DMSO-d6, d in ppm): 3.60 (s, 3H), 3.65 (s, 2H), 6.97 (d, 1 H, J=9.0Hz), 7.02 (s, 1 H), 7.07 (d, 1 H, J=9.0Hz).

2-(2,3-dioxo-1 ,2,3,4-tetrahydroquinoxalin-6-yl)acetic acid

- Step 4: to a solution of methyl 2-(1 ,2,3,4-tetrahydro-2,3-dioxoquinoxalin-7- yl)acetate Ex.11 c (669 mg, 2.86 mmol) in THF (28 mL) and water (14 mL) was added lithium hydroxide monohydrate (367 mg, 8.57 mmol) at 0°C. The reaction mixture was stirred for 5 h. The organic solvent was evaporated under vacuum and the aqueous layer was treated with 2 M HCI until pH 5 was reached. The

Ex.11

precipitate formed was filtered-off, washed with water and dried under vacuum at 60°C for 24 h to afford 2-(2,3-dioxo-1 ,2,3,4-tetrahydroquinoxalin-6-yl)acetic acid (549 mg, 87%) as pale yellow solid.

- 1 H NMR (300 MHz, DMSO-d6, d in ppm): 3.53 (s, 2H), 6.97 (d, 1 H, J=8.0Hz), 7.02 (s, 1 H), 7.05 (d, 1 H, J=8.1 Hz), 1 1 .89 (d, 2H, J=4.1 Hz), 12.14-12.55 (m, 1 H).

Intermediate Ex.12 : 2-(3-oxo-3,4-dihydro-2H-1 ,4-benzoxazin-6-yl)acetic acid (Figure 1AC) Table 1.3

Starting compounds, Reaction conditions and purification,

Cpd.

Yield, appearance, ¹ H NMR (solvent) data

Ex.12a ethyl 2-[4-(2-methoxy-2-oxoethyl)-2-nitrophenoxy]acetate - Step 1 : to a suspension of methyl 2-(4-hydroxy-3-nitrophenyl)acetate (2.5 g, 1 1.84 mmol) and K2C03 (1 .97 g, 14.21 mmol) in DMF (36 mL) was added methyl bromoacetate (1 .62 mL, 14.21 mmol). Then the reaction mixture was stirred at rt over the weekend. Water and EtOAc were added. The two layers were partitionated. The organic layer was dried over MgS04, filtered and the solution was concentrated to dryness. The crude material was purified by silica gel column chromatography eluting with heptane and a gradient of heptane/EtOAc to from [100:0] to [80:20]. The product fractions were combined and concentrated to dryness to afford the desired product (6.05 g, 80 %) as brown solid.

2-(3,4-dihydro-3-oxo-2H-benzo[b][1 ,4]oxazin-6-yl)acetate

- Step 2: iron powder (1.82 g, 32.67 mmol) was added to the mixture of ethyl 2-[4- (2-methoxy-2-oxoethyl)-2-nitrophenoxy]acetate Ex.12a (3.09 g, 10.89 mmol) acid in glacial acetic acid (35 mL). The reaction mixture was heated at 80°C for

Ex.12b 3 h. The mixture was concentrated to approx. half its volume. Water and EtOAc were added. The organic layer was separated, concentrated and purified by silica gel column chromatography eluting with heptane and a gradient of heptane/EtOAc from [100:1 ] to [1 :1]. The product fractions were combined and concentrated to dryness to afford methyl 2-(3,4-dihydro-3-oxo-2H- benzo[b][1 ,4]oxazin-6-yl)acetate (2.30 g, 96%) as white solid.

2-(3,4-dihydro-3-oxo-2H-benzo[b][1 ,4]oxazin-6-yl)acetic acid

- Step 3: lithium hydroxide monohydrate (910 mg, 21.60 mmol) was added to the mixture of methyl 2-(3,4-dihydro-3-oxo-2H-benzo[b][1 ,4]oxazin-6-yl)acetate Ex.12b (2.30 g, 10.80 mmol) in THF (32 mL) and water (16 mL). The reaction mixture was stirred at rt for 16h. 1 N HCI was added to the reaction mixture until

Ex.12 pH=2 was reached. The solid formed was collected by filtration, washed with water and with Et20. The solid was dried under vacuum at 60°C to constant weight to afford 2-(3,4-dihydro-3-oxo-2H-benzo[b][1 ,4]oxazin-6-yl)acetic acid

(1 .53 g, 68%) as white solid.

- 1 H NMR (300 MHz, DMSO-d6, d in ppm): 3.47 (s, 2H), 4.54 (s, 2H), 6.78-6.80 (m, 2H), 6.87 (d, 1 H, J=8.5Hz), 10.69 (s, 1 H), 12.30 (br(s), 1 H).

Intermediate Ex.13 : 2-(2,2-difluoro-3-oxo-3,4-dihydro-2H-1 ,4-benzoxazin-7-yl)acetic acid (Figure 1AD)

Table 1 .4

Starting compounds, Reaction conditions and purification,

Cpd.

Yield, appearance, ¹ H NMR (solvent) data

methyl 2-(3-amino-4-hydroxyphenyl)acetate

- Step 1 : methyl 2-(4-hydroxy-3-nitrophenyl)acetate (1.2 g, 5.68 mmol) was dissolved in EtOH (17 mL). The mixture was stirring at rt under nitrogen

Ex.13a atmosphere. Then Pd/C 10 % (568 mg) was added and the nitrogen

atmosphere was replaced by hydrogen. The reaction mixture was stirred at rt for 16 h (hydrogen balloon). The suspension was filtered through a pad of Celite and concentrated to dryness to afford the desired product (1.00 g, 97%) as white solid. methyl 2-[3-(2-bromo-2,2-difluoroacetamido)-4-hydroxyphenyl]acetate

- Step 2: to a suspension of methyl 2-(3-amino-4-hydroxyphenyl)acetate Ex.13a (840 mg, 4.64 mmol) and triethylamine (71 1 μΙ_, 5.10 mmol) in EtOAc (7 mL) was added ethyl bromodifluoroacetate (660 μΙ_, 5.10 mmol) under nitrogen atmosphere. The reaction mixture was heated at 90°C for 2 h. EtOAc and water

Ex.13b were added to the mixture to quench the reaction. The two phases were

partitionated. The organic layer was dried over MgS04, filtered and the solution was concentrated under reduced pressure. The crude material was purified by silica gel column chromatography eluting with heptane and a gradient of heptane/EtOAc from [100:0] to [8:2]. The product fractions were combined and concentrated to dryness to afford methyl 2-[3-(2-bromo-2,2-difluoroacetamido)- 4-hydroxyphenyl]acetate (1.14 g, 72%) as white solid.

methyl 2-(2,2-difluoro-3-oxo-3,4-dihydro-2H-1 ,4-benzoxazin-6-yl)acetate

- Step 3: to a mixture of methyl 2-[3-(2-bromo-2,2-difluoroacetamido)-4- hydroxyphenyl]acetate Ex.13b (1 .14 g, 3.37 mmol) in DMF (10 mL) was added K2C03 (560 mg, 4.04 mmol). The reaction mixture was heated at 50°C for 3h.

Ex.13c EtOAc and water were added to quench the reaction. The organic layer was separated, concentrated and purified by silica gel column chromatography eluting with heptane and a gradient of heptane/EtOAc from [100:0] to [8:2]. The product fractions were combined and concentrated to dryness to afford methyl 2-(2,2-difluoro-3-oxo-3,4-dihydro-2H-1 ,4-benzoxazin-6-yl)acetate (850 mg, 98%) as yellow solid.

2-(2,2-difluoro-3-oxo-3,4-dihydro-2H-1 ,4-benzoxazin-7-yl)acetic acid

- Step 4: methyl 2-(2,2-difluoro-3-oxo-3,4-dihydro-2H-1 ,4-benzoxazin-6-yl)acetate Ex.13c (850 mg, 3.30 mmol) was added to the mixture of lithium hydroxide monohydrate (280 mg, 6.60 mmol) in THF (10 mL) and water (5 mL). The reaction mixture was stirred at rt for 16 h. TLC showed still starting material. A further 1 equiv of lithium hydroxide monohydrate was added to the reaction mixture. The suspension was stirred at rt for additional 16 h. 1 M HCI was added to quench the reaction and until pH=2 was reached, a brown oil was formed

Ex.13 which was separated from the aqueous layer. The crude material was purified by silica gel column chromatography eluting with CH2CI2 and a gradient of CH2CI2/MeOH from [100:0] to [9:1]. The product fractions were combined and concentrated to dryness. The resulting solid was triturated with water, filtered, washed with Et20 and dried under vacuum at 60°C to constant weight yielding 2-(2,2-difluoro-3-oxo-3,4-dihydro-2H-1 ,4-benzoxazin-7-yl)acetic acid (805 mg, quantitative).

- 1 H NMR (300 MHz, DMSO-d6, d in ppm): 3.57 (s, 2H), 7.10 (br(s), 1 H), 7.17- 7.19 (m, 2H), 7.95 (s, 1 H), 12.22 (br(s), 1 H).

Intermediate Ex.14 : 2-(2-oxo-2,3-dihvdro-1 H-indol-5-yl)acetic acid (Figure 1AE)

Table 1.5

c . Starting compounds, Reaction conditions and purification,

p ^' Yield, appearance, ¹ H NMR (solvent) data

Intermediate Ex.15 : 2-(2,2-dimethyl-3-oxo-3,4-dihvdro-2H-1 ,4-benzoxazin-7-yl)acetic acid (Figure 1AF)

Table 1.6

Starting compounds, Reaction conditions and purification,

Cpd.

Yield, appearance, ¹ H NMR (solvent) data

-ethyl 2-[5-(2-methoxy-2-oxoethyl)-2-nitrophenoxy]-2-methylpropanoa te

Ex.15a - Step 1 : the previously synthesized methyl 2-(4-hydroxy-3-nitrophenyl)acetate

(4.50 g, 21.31 mmol) was dissolved in acetonitrile (65 mL). Ethyl 2- bromoisobutyrate (3.75 mL, 25.57 mmol) and Cs2C03 (8.33 g, 25.57 mmol)

Intermediate Ex.17 : 2-(2,2-dioxo-1 ,3-dihvdro-2,1 -benzothiazol-5-yl)acetic acid hydrochloride (Figure 1AG)

Table 1 .7

Starting compounds, Reaction conditions and purification,

Cpd.

Yield, appearance, ¹ H NMR (solvent) data

tert-butyl 2-(bromozincio)acetate

- Step 1 : to a solution of zinc dust (3.0 g, 30.26 mmol) in dry THF (30 mL) was added at rt 1 ,2-dibromoethane (434 μΙ_, 5.04 mmol) under nitrogen atmosphere. The reaction mixture was stirred at 70°C for 1 min and cooled down to rt. This

Ex.17a procedure was repeated 5 times. Me3SiCI (256 μΙ_, 2.02 mmol) was added and the resulting suspension was stirred at rt for 15 min. It was then heated to 65°C and a few drops of tert-butyl 2-bromoacetate were added. Then a solution of tert-butyl 2-bromoacetate (4.92 g, 25.22 mmol) in dry THF (5 mL) was added at such a rate that reflux was maintained. Upon completion of addition, the reaction mixture was refluxed for an additional 20 min and allowed to cool down to rt. The zinc was allowed to settle and the supernatant was used further without any analysis. Complete conversion was assumed.

1 -benzyl -5-bromo-1 ,3-dihydro-2,1 -benzothiazole-2,2-dione

- Step 2: K2C03 (1 1 1 mg, 0.80 mmol) was added to the mixture of 5-bromo-1 ,3- dihydro-2,1 -benzothiazole-2,2-dione (100 mg, 0.40 mmol) in DMF (10 mL) at 0°C. Then, benzyl bromide (50 μΙ_, 0.42 mmol) was added to the reaction mixture. The suspension was stirred at rt for 16h. The reaction mixture was

Ex.17b diluted with EtOAc and water. After phase separation, the organic layer was washed with brine, dried over MgS04, filtered and the solution was concentrated to dryness. The crude material was purified by flash column chromatography on silica gel eluting with heptane and a gradient of heptane/EtOAc from [100:0] to [50:50]. The desired fractions were combined and concentrated to obtain 1 -benzyl-5-bromo-1 ,3-dihydro-2,1 -benzothiazole-2,2- dione (170 mg, quantitative) as white solid.

tert-butyl 2-(1 -benzyl-2,2-dioxo-1 ,3-dihydro-2,1 -benzothiazol-5-yl)acetate

- Step 3: 1 -benzyl-5-bromo-1 ,3-dihydro-2,1 -benzothiazole-2,2-dione Ex.17b (980 mg, 2.90 mmol), tert-butyl 2-(bromozincio)acetate Ex.17a (10 mL, 8.70 mmol) and dry THF (9 mL) were charged to a flask and the mixture was degassed by bubbling nitrogen through it for 5 min. Then Pd2(dba)3 (266 mg, 0.29 mmol) and XPhos (277 mg, 0.58 mmol) were added and the solution was stirred at 75°C for

Ex.17c 16h. The reaction mixture was concentrated to dryness and the residue was diluted with EtOAC and water. After phase separation, the combined organic layer was washed with brine, dried over MgS04, filtered and the solution was concentrated under reduced pressure. The crude material was purified by flash column chromatography on silica gel eluting with heptane and a gradient of heptane/EtOAc from [100:0] to [50:50]. The desired fractions were combined and concentrated to obtain tert-butyl 2-(1 -benzyl-2,2-dioxo-1 ,3-dihydro-2,1 - benzothiazol-5-yl)acetate (1 .00 g, 92%) as pale yellow oil.

tert-butyl 2-(2,2-dioxo-1 ,3-dihydro-2,1 -benzothiazol-5-yl)acetate

- Step 4: tert-butyl 2-(1 -benzyl-2,2-dioxo-1 ,3-dihydro-2,1 -benzothiazol-5- yl)acetate Ex.17c (1 .00 g, 2.68 mmol) was dissolved in EtOH (10 mL). Pd/C 10% (268 mg) was added and the mixture was purged with hydrogen. The reaction mixture was stirred under hydrogen atmosphere at 45°C for 36 h.

Ex.17d Further Pd/C (100 mg) was added to the reaction mixture and the solution was stirred at 45°C for additional 20 h. The suspension was filtered through a pad of Celite and the solution was concentrated to dryness. The crude material was purified by flash column chromatography on silica gel eluting with heptane and a gradient of heptane/EtOAc from [100:0] to [50:50]. The desired fractions were combined and concentrated to afford tert-butyl 2-(2,2-dioxo-1 ,3-dihydro-2,1 - benzothiazol-5-yl)acetate (623 mg, 47%) as white solid.

2-(2,2-dioxo-1 ,3-dihydro-2,1 -benzothiazol-5-yl)acetic acid hydrochloride

- Step 5: 4 N HCI in dioxane (1.10 mL, 4.40 mmol) was added to tert-butyl 2-(2,2- dioxo-1 ,3-dihydro-2,1 -benzothiazol-5-yl)acetate Ex.17d (623 mg, 2.20 mmol) dissolved in CH2CI2 (2 mL). The reaction mixture was stirred at rt for 16h. The

Ex.17 precipitate was collected by filtration, washed with Et20 and dried under

vacuum until constant weight to afford 2-(2,2-dioxo-1 ,3-dihydro-2,1 - benzothiazol-5-yl)acetic acid hydrochloride (415 mg, 83%).

- 1 H NMR (300 MHz, DMSO-d6, d in ppm): 2.47 (s, 2H), 3.44 (s, 2H), 4.44 (s, 2H) 6.70 (d, 1 H), 7.06 (d, 1 H), 7.10 (s, 1 H), 10.33 (s, 1 H). Intermediate Ex.23 : 2-(2-oxo-1 ,2,3,4-tetrahydroquinolin-6-yl)acetic acid (Figure 1AH)

Table 1.8

Starting compounds, Reaction conditions and purification,

Cpd.

Yield, appearance, ¹ H NMR (solvent) data

tert-butyl 6-bromo-3,4-dihydro-2-oxoquinoline-1(2H)-carboxylate

- Step 1 : 6-bromo-1 ,2,3,4-tetra-hydro-2-quinolinone (5.0 g, 22.12 mmol) was dissolved in CH2CI2 (100 mL) and triethylamine (3.39 mL, 24.33 mmol) was added followed by 4-(dimethylamino)-pyridine (260 mg, 2.21 mmol) and the portionwise addition of di-tert-butyl dicarbonate(5.07 g, 23.23 mmol), upon which gas evolution was observed. The mixture was stirred at rt for 16 h. The reaction was quenched with water and the two phases were separated. The organic

Ex.23a layer was dried over MgS04, filtered and the solution was concentrated to

dryness. The crude material was purified by silica gel column chromatography eluting with heptane and a gradient of heptane/EtOAc from [100:0] to [85:15]. The product fractions were combined and concentrated to dryness to afford tert- butyl 6-bromo-3,4-dihydro-2-oxoquinoline-1 (2H)-carboxylate (6.00 g, 83%) as off-white solid.

- 1 H NMR (300 MHz, CDCI3, d in ppm): 1 .53 (s, 9H), 2.56-2.61 (m, 2H), 2.84- 2.89 (m, 2H), 6.79 (d, 1 H, J=9.0Hz), 7.25-7.27 (m, 2H).

tert-butyl 2-oxo-6-(tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 ,2,3,4- tetrahydroquinoline-1 -carboxylate

- Step 2: tert-butyl 6-bromo-3,4-dihydro-2-oxoquinoline-1 (2H)-carboxylate Ex.23a (6.00 g, 18.40 mmol) was dissolved in DMF (60 mL). Bis(pinacolato)diboron (5.60 g, 22.10 mmol) and potassium acetate (5.05 g, 51 .50 mmol) were added and the resulting suspension was purged with N2. PdCI2(dppf)2 (450 mg, 0.55 mmol) was added and the mixture was heated at 90°C for 16 h. After cooling to rt, the reaction was quenched with water. The aqueous layer was extracted with

Ex.23b EtOAc. The organic layer was washed with brine, dried over MgS04, filtered and the solution was concentrated to dryness. The crude material was purified by flash column chromatography on silica gel eluting with heptane and a gradient of heptane/EtOAc from [100:0] to [80:20]. The product fractions were combined and concentrated to dryness to afford tert-butyl 2-oxo-6-(tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-1 ,2,3,4-tetrahydroquinoline-1 -carboxylate (4.61 g, 67%) as pale green oil, which solidified upon standing at rt.

- 1 H NMR (300 MHz, CDCI3, d in ppm): 1.27 (s, 12H), 1 .53 (s, 9H), 2.56-2.61 (m, 2H), 2.87-2.91 (m, 2H), 6.85 (d, 1 H, J=9.0Hz), 7.56-7.60 (m, 2H).

tert-butyl 2-(2-oxo-1 ,2,3,4-tetrahydroquinolin-6-yl)acetate

- Step 3: tert-butyl 2-oxo-6-(tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 ,2,3,4- tetrahydroquinoline-1 -carboxylate Ex.23b (3.60 g, 9.64 mmol) was dissolved in DMF (30 mL), water (8 mL) was added followed by sodium carbonate (2.04 g, 19.28 mmol) and tert-butylbromo-acetate (5.62 g, 28.90 mmol). The mixture was

Ex.23c purged with nitrogen. PdCI2(dppf)2 (400 mg, 0.47 mmol) was added and the resulting suspension was heated under nitrogen atmosphere at 85°C for 24 h. After cooling to rt, water and EtOAc were added to quench the reaction. The two phases were separated. The organic layer was washed with brine, dried over MgS04, filtered and the solution was concentrated to dryness. The crude material was purified by silica gel column chromatography eluting with heptane

Intermediate Ex.24 : 2-(1 -methyl-2-oxo-2,3-dihvdro-1 H-indol-5-yl)acetic acid (Figure 1AI)

Table 1.9

Starting compounds, Reaction conditions and purification,

Cpd.

Yield, appearance, ¹ H NMR (solvent) data

methyl 2-(1 -methyl-2-oxo-2,3-dihydro-1 H-indol-5-yl)acetate

and

methyl 2-(1 ,3-dimethyl-2-oxo-2,3-dihydro-1 H-indol-5-yl)acetate

and

methyl 2-(1 ,3,3-trimethyl-2-oxo-2,3-dihydro-1 H-indol-5-yl)acetate

- Step 1 : to a solution of 2-(2-oxo-2,3-dihydro-1 H-indol-5-yl)acetic acid Ex.14 (1 g, 5.23 mmol) in acetonitrile (40 mL) and DMF (10 mL) was added K2C03 (2.89 g, 20.92 mmol) followed by iodomethane (1.30 mL, 20.92 mmol). The reaction mixture was heated at 70°C for 3 h. Additional K2C03 (2 equiv) and iodomethane (1 equiv) were added and the solution was stirred for additional 1 h30 at 70°C. Water was added to quench the reaction. The aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgS04,

Ex.24a

filtered and the solution was concentrated under reduced pressure. The crude Ex.24b

material was diluted in acetonitrile (12 mL) in microwave srew cap vial and

Ex.24c

K2C03 (3 equiv) followed by iodomethane (3 equiv) were added. The reaction was heated under microwave irradiation at 100°C for 30 min. The suspension was filtered through pad of Celite, the filtrate was concentrated to dryness. The residue was purified by silica gel column chromatography eluting with cyclohexane/EtOAc (7:3) affording:

- Ex.24a : methyl 2-(1 -methyl-2-oxo-2,3-dihydro-1 H-indol-5-yl)acetate (360 mg, 31 %), 1 H NMR (300 MHz, CDCI3, d in ppm): 3.21 (s, 3H), 3.53 (s, 2H), 3.61 (s, 2H), 3.71 (s, 3H), 6.78 (d, 1 H, J=8.4Hz), 7.17-7.21 (m, 2H);

- Ex.24b: methyl 2-(1 ,3-dimethyl-2-oxo-2,3-dihydro-1 H-indol-5-yl)acetate (52 mg, 4%), 1 H NMR (300 MHz, CDCI3, d in ppm): 1.48 (d, 3H, J=7.7Hz), 3.20 (s, 3H), 3.45 (q, 1 H, J=7.6Hz), 3.62 (s, 2H), 3.71 (s, 3H), 6.78 (d, 1 H, J=8.2Hz), 7.17- 7.21 (m, 2H); - Ex.24c : methyl 2-(1 _! 3 _! 3-trimethyl-2-oxo-2,3-dihydro-1 H-indol-5-yl)acetate (80 mg, 6%), 1 H NMR (300 MHz, CDCI3, d in ppm): 1 .38 (s, 6H), 3.21 (s, 3H), 3.62 (s, 2H), 3.71 (s, 3H), 6.81 (d, 1 H, J=8.0Hz), 7.13 (d, 1 H, J=1 .7Hz), 7.20 (dd, 1 H, J=7.9Hz, J=1.8Hz).

2-(1 -methyl-2-oxo-2,3-dihydro-1 H-indol-5-yl)acetic acid

- Step 2: methyl 2-(1 -methyl-2-oxo-2,3-dihydro-1 H-indol-5-yl)acetate Ex.24a (75 mg, 0.34 mmol) was dissolved in MeOH/THF (2 mL, 1 :1 ) and NaOH 2N (257 μΙ_, 0.51 mmol) was added. The reaction mixture was heated at 50°C for 1 h. The solvents were removed under reduced pressure. Water was added followed by

Ex.24 1 N citric acid until pH=5 was reached. The aqueous solution was extracted with

EtOAc. The organic layer was dried over MgS04, filtered and the solution was concentrated under reduced pressure to afford 2-(1 -methyl-2-oxo-2,3-dihydro- 1 H-indol-5-yl)acetic acid (60 mg, 86%) as white solid.

- 1 H NMR (300 MHz, DMSO-d6, d in ppm): 3.09 (s, 3H), 3.51 (s, 2H), 3.52 (s, 2H), 6.89 (d, 1 H, J=8.5Hz), 7.13-7.15 (m, 2H), 12.24 (br(s), 1 H).

Intermediate Ex.25 : 2-(3-hvdroxy-1 ,3-dimethyl-2-oxo-2,3-dihvdro-1 H-indol-5-yl)acetic acid (Figure 1AI)

Table 1 .10

Intermediate Ex.26 : 2-(1 ,3,3-trimethyl-2-oxo-2,3-dihvdro-1 H-indol-5-yl)acetic acid (Figure Table 1 .1 1

Starting compounds, Reaction conditions and purification,

Cpd.

Yield, appearance, ¹ H NMR (solvent) data

2-(1 ,3,3-trimethyl-2-oxo-2,3-dihydro-1 H-indol-5-yl)acetic acid

- The previously synthesized methyl 2-(1 ,3,3-trimethyl-2-oxo-2,3-dihydro-1 H-

Ex.26 indol-5-yl)acetate Ex.24c (75 mg, 0.30 mmol) was dissolved in MeOH/THF (2 mL, 1 :1 ) and NaOH 2N (227 μί, 0.46 mmol) was added. The reaction mixture was heated at 50°C for 1 h. The solvents were removed under reduced

Intermediate Ex.27 : 2-(2-methanesulfonyl-2,3-dihvdro-1 H-isoindol-5-yl)acetic acid (Figure 1AJ)

Table 1 .12

Starting compounds, Reaction conditions and purification,

Cpd.

Yield, appearance, ¹ H NMR (solvent) data

5-bromo-2-methanesulfonyl-2,3-dihydro-1 H-isoindole

- Step 1 : Et3N (4.22 ml_, 30.30 mmol) was added to the mixture of 5- bromoisoindoline hydrochloride (2 g, 10.10 mmol) in CH2CI2 (35 mL) at 0°C. Then, methanesulfonyl chloride (860 μΙ_, 1 1 .1 1 mmol) was added to the reaction

Ex.27a mixture. The mixture reaction was stirred at rt for 16h. The solution was diluted with EtOAc and water. After phase separation, the combined organic layers were washed with brine, dried over MgS04, filtered and the solution was concentrated to dryness. The solid was triturated with diethyl ether and filtered- off to afford the desired product as pale brown solid (2.10 g, 75%).

methyl 2-(2-methanesulfonyl-2,3-dihydro-1 H-isoindol-5-yl)acetate

- Step 2: 5-bromo-2-methanesulfonyl-2,3-dihydro-1 H-isoindole Ex.27a (1 .95 g, 7.06 mmol), methyl acetoacetate (2.28 mL, 21.18 mmol) and potassium phosphate (6.00 g, 28.24 mmol) were charged to a screw cap tube, toluene (30 mL) was added and the mixture was purged with nitrogen for 5 min. Then Pd(OAc)2 (79 mg, 0.35 mmol) followed by di-tert-butyl X-Phos (302 mg, 0.71 mmol) were added and the tube was closed under nitrogen atmosphere. The

Ex.27b reaction mixture was stirred at 80°C for 3 h, then at 120°C for 16 h. The residue was diluted with EtOAc and water. After phase separation, the combined organic layers were washed with brine, dried over MgS04, filtered and the solution was concentrated to dryness. The crude material was purified by flash chromatography on silica gel eluting with heptane and a gradient of heptane/EtOAc from [100:0] to [50:50]. The desired fractions were combined and concentrated to obtain methyl 2-(2-methanesulfonyl-2,3-dihydro-1 H- isoindol-5-yl)acetate (1.6 g, 84%) as yellow solid.

2-(2-methanesulfonyl-2,3-dihydro-1 H-isoindol-5-yl)acetic acid

- Step 3: lithium hydroxide monohydrate (250 mg, 5.94 mmol) was added to the mixture of methyl 2-(2-methanesulfonyl-2,3-dihydro-1 H-isoindol-5-yl)acetate Ex.27b (1 .6 g, 5.94 mmol) in THF (18 mL) and water (9 mL) at 0°C. Then, the reaction mixture was stirred at rt for 18 h. EtOAc and water were added to

Ex.27

quench the reaction. The two phases were partitionated. 1 M HCI was added to the aqueous layer under vigorous stirring until pH=4 was reached. The aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgS04, filtered and the solution was concentrated to dryness. The crude material was purified by silica gel column chromatography eluting with heptane and a gradient of heptane/EtOAc from [100:0] to [0:100]. The product fractions were combined and concentrated to dryness. The solid was triturated with diethyl ether and filtered-off. Final drying to constant weight was carried out under vacuum at 65°C to give 2-(2-methanesulfonyl-2,3-dihydro-1 H-isoindol-5- yl)acetic acid (455 mg, 30%).

- 1 H NMR (300 MHz, DMSO-d6, d in ppm): 2.97 (s, 3H), 3.58 (s, 2H), 4.61 (s, 4H), 7.18-7.28 (m, 3H), 12.4 (br(s), 1 H).

Intermediate Ex.28 : 2-(2-methanesulfonyl-2,3-dihvdro-1 H-isoindol-4-yl)acetic acid (Figure 1AK)

Table 1 .13

Starting compounds, Reaction conditions and purification,

Cpd.

Yield, appearance, ¹ H NMR (solvent) data

4-bromo-2-methanesulfonyl-2,3-dihydro-1 H-isoindole

- Step 1 : Et3N (2.51 mL, 18.00 mmol) was added to a solution of 4-bromo- isoindoline hydrochloride (1.41 g, 6.00 mmol) in CH2CI2 (30 mL) at 0°C. Then, methanesulfonyl chloride (510 μί, 6.60 mmol) was added to the reaction mixture. The solution was stirred at rt for 16 h. The solvent was removed under

Ex.28a reduced pressure. The solid was dissolved with EtOAc and water. After phase separation, the combined organic layers were washed with brine, dried over MgS04, filtered and the solution was concentrated to dryness. The solid was purified by silica gel column chromatography eluting with a gradient of heptane/EtOAc from [100:0] to [50:50]. The product fractions were combined and concentrated to dryness to afford the desired product (918 mg, 55%).

tert-butyl 2-(2-methanesulfonyl-2,3-dihydro-1 H-isoindol-4-yl)acetate

- Step 2: 4-bromo-2-methanesulfonyl-2,3-dihydro-1 H-isoindole Ex.28a (550 mg, 1 .99 mmol), the previously synthesized tert-butyl 2-(bromozincio)acetate (7 mL, 5.98 mmol) and dry THF (5 mL) were placed in flask, the mixture was degassed by nitrogen bubbling for 5 min. Then Pd2(dba)3 (182 mg, 0.20 mmol) and XPhos (190 mg, 0.40 mmol) were incorporated and the reaction mixture was

Ex.28b stirred at 75°C for 16 h. The reaction mixture was concentrated to dryness. The residue was diluted with EtOAc and water. The two phases were separated. The organic layer was dried over MgS04, filtered and the solution was concentrated under reduced pressure. The crude material was purified twice by flash chromatography on silica gel eluting with heptane and a gradient of heptane/EtOAc from [100:0] to [70:30]. The desired fractions were combined and concentrated to obtain tert-butyl 2-(2-methanesulfonyl-2,3-dihydro-1 H- isoindol-4-yl)acetate (560 mg, 90%) as yellow solid.

2-(2-methanesulfonyl-2,3-dihydro-1 H-isoindol-4-yl)acetic acid

- Step 3: tert-butyl 2-(2-methanesulfonyl-2,3-dihydro-1 H-isoindol-4-yl)acetate Ex.28b (560 mg, 1 .80 mmol) was dissolved in CH2CI2 (5 mL) and then was added 4M HCI in dioxane (1.8 mL, 7.20 mmol). The reaction mixture was stirring for 20 h at rt. The solid formed was collected by filtration, washed with diethyl

Ex.28

ether and dried under vacuum until constant weight to afford 2-(2- methanesulfonyl-2,3-dihydro-1 H-isoindol-4-yl)acetic acid (312 mg, 60%) as off- white solid.

- 1 H NMR (300 MHz, DMSO-d6, d in ppm): 2.96 (s, 3H), 3.60 (s, 2H), 4.62 (m, 2H), 4.66 (m, 2H), 7.16-7.31 (m, 3H), 12.47 (br(s), 1 H). Intermediate Ex.29 : 2-(1 -oxo-2,3-dihvdro-1 H-inden-5-yl)acetic acid (Figure 1AL)

Table 1 .14

Intermediate Ex.30 : 2-(7-methyl-2-oxo-2,3-dihvdro-1 H-indol-5-yl)acetic acid (Figure 1AM)

Table 1 .15

Starting compounds, Reaction conditions and purification,

Cpd.

Yield, appearance, ¹ H NMR (solvent) data

2-{4-[2-(N-hydroxyimino)acetamido]-3-methylphenyl}acetic acid

- Step 1 : sodium sulfate (992 mg, 6.99 mmol) was added to 2,2,2- trichloroacetaldehyde (755 mg, 5.12 mmol) dissolved in water (5 mL). IThe

Ex.30a reaction mixture was stirred at rt for 15 min. Ethyl 2-(4-amino-3- methylphenyl)acetate (900 mg, 4.66 mmol) dissolved in 1 N HCI (5 mL) was added dropwise followed by hydroxylamine hydrochloride (809 mg, 1 1 .64 mmol) dissolved in water (5 mL). The resulting solution was heated at 80°C for 2 h. After cooling to rt, water was added to quench the reaction and the aqueous layer was extracted with EtOAc. The combined organic layer was dried over MgS04, filtered and the solution was concentrated under reduced pressure. The compound was used as such in the next step.

2-(7-methyl-2,3-dioxo-2,3-dihydro-1 H-indol-5-yl)acetic acid

- Step 2: 2-{4-[2-(N-hydroxyimino)acetamido]-3-methylphenyl}acetic acid Ex.30a was dissolved in cone. H2S04 (3 mL) and the solution was heated at 50°C for 2 h. The reaction mixture was poured onto ice. Brine was added and the aqueous solution was extracted with EtOAc. The combined organic layers were dried

Ex.30b over MgS04, filtered and the solution was concentrated under reduced pressure to afford 2-(7-methyl-2,3-dioxo-2,3-dihydro-1 H-indol-5-yl)acetic acid (505 mg, 50% over two steps) as orange solid. The compound was used in the next step without further purification.

- 1 H NMR (300 MHz, DMSO-d6, d in ppm): 2.17 (s, 3H), 3.52 (s, 2H), 7.23 (s, 1 H), 7.30 (s, 1 H), 1 1 .05 (s, 1 H).

2-(7-methyl-2-oxo-2,3-dihydro-1 H-indol-5-yl)acetic acid

- Step 3: to a solution of 2-(7-methyl-2,3-dioxo-2,3-dihydro-1 H-indol-5-yl)acetic acid Ex.30b (505 mg, 2.30 mmol) in MeOH was added hydrazine 50% in water (162 mg, 2.53 mmol). The reaction mixture was heated at 80°C overnight. After cooling to rt, Et3N (1 .921 mL, 13.82 mmol) was added. The solution was heated under microwave irradiation at 140°C for 1 h30. Solvent was removed under

Ex.30

reduced pressure. The residue was triturated in 1 N citric acid. The solid formed was filtered, washed with water and dried under vacuum until constant weight to afford 2-(7-methyl-2-oxo-2,3-dihydro-1 H-indol-5-yl)acetic acid (305 mg, 65% over two steps) as pale brown solid.

- 1 H NMR (300 MHz, DMSO-d6, d in ppm): 2.16 (s, 3H), 3.43 (s, 2H), 3.44 (s, 2H), 6.85 (s, 1 H), 6.90 (s, 1 H), 10.36 (s, 1 H), 12.12 (br(s), 1 H).

Intermediate Ex.31 : 2-[2-oxo-3-(propan-2-ylidene)-2,3-dihvdro-1 H-indol-5-yllacetic acid (Figure 1AN)

Table 1 .16

Starting compounds, Reaction conditions and purification,

Cpd.

Yield, appearance, ¹ H NMR (solvent) data

tert-butyl 2-{5-[2-(tert-butoxy)-2-oxoethyl]-2-nitrophenyl}acetate

- Step 1 : 2, 4-dibromo-1 -nitrobenzene (3.0 g, 10.68 mmol), the previously synthesized tert-butyl 2-(bromozincio)acetate (65 mL, 53.39 mmol) and dry THF (10 mL) were placed in flask, the mixture was degassed by nitrogen bubbling for 5 min. Then XPhos (1.01 g, 2.14 mmol) and Pd2(dba)3 (978 mg, 1.07 mmol) were incorporated and the reaction mixture was stirred at 75°C for 16 h.The

Ex.31 a solution was concentrated and the residue was diluted with EtOAc/H20 and the phases were separated. The organic layer was dried over MgS04, filtered and the solution was concentrated to dryness. The crude material was purified by flash chromatography on silica gel eluting with heptane and a gradient of heptane/EtOAc from [100:0] to [50:50]. The desired fractions were combined and concentrated to obtain tert-butyl 2-{5-[2-(tert-butoxy)-2-oxoethyl]-2- nitrophenyl}acetate (2.16 g, 58%) as yellow oil.

tert-butyl 2-{2-amino-5-[2-(tert-butoxy)-2-oxoethyl]phenyl}acetate

- Step 2: tert-butyl 2-{5-[2-(tert-butoxy)-2-oxoethyl]-2-nitrophenyl}acetate Ex.31 a

Ex.31 b

(2.16 g, 6.15 mmol) was dissolved in MeOH (120 mL). Then Pd/C 10% (720 mg) was added and the reaction mixture was strirred at rt for 20 h under hydrogen. The solution was filtered over a pad of Celite, washed with EtOAc and concentrated to afford tert-butyl 2-{2-amino-5-[2-(tert-butoxy)-2- oxoethyl]phenyl}acetate (1 .90 g, 96%) as orange solid.

tert-butyl 2-(2-oxo-2,3-dihydro-1 H-indol-5-yl)acetate

- Step 3: tert-butyl 2-{2-amino-5-[2-(tert-butoxy)-2-oxoethyl]phenyl}acetate Ex.31 b (1 .90 g, 5.97 mmol) was dissolved in 2-propanol (15 ml_). Then glacial acetic acid (3.42 ml_, 59.70 mmol) was added, the reaction mixture was heated in a sealed tube at 95°C for 16 h. Excess of acetic acid was neutralized with

NaHC03 and the solution was concentrated under reduced pressure. The

Ex.31 c

residue was dissolved in EtOAc and washed with sat. NaHC03. The organic layer was dried over MgS04, filtered and the solution was concentrated to dryness. The crude material was purified by flash column chromatography on silica gel eluting with heptane/EtOAc [40:60]. Column fractions were combined and concentrated to afford tert-butyl 2-(2-oxo-2,3-dihydro-1 H-indol-5-yl)acetate (1 .40 g, 95%) as red solid.

tert-butyl 2-[2-oxo-3-(propan-2-ylidene)-2,3-dihydro-1 H-indol-5-yl]acetate

- Step 4: tert-butyl 2-(2-oxo-2,3-dihydro-1 H-indol-5-yl)acetate Ex.31 c (250 mg, 1 .01 mmol) was dissolved in acetone (2.5 mL) and absolute EtOH (2.5 ml_). Then, piperidine (400 μΙ_, 4.04 mmol) was added, the reaction mixture was stirred at rt for 5 h. The solvents were removed under reduced pressure. EtOAc

Ex.31 d and water was added to the residue. The organic layer was separated, dried over MgS04, filtered and the solution was concentrated to dryness. The crude material was purified by silica gel column chromatography eluting with heptane/EtOAc using a gradient from [100:0] to [50:50]. The product fractions were concentrated to dryness to afford tert-butyl 2-[2-oxo-3-(propan-2-ylidene)- 2,3-dihydro-1 H-indol-5-yl]acetate (223 mg, 77%) as brown oil.

2-[2-oxo-3-(propan-2-ylidene)-2,3-dihydro-1 H-indol-5-yl]acetic acid

- Step 5: tert-butyl 2-[2-oxo-3-(propan-2-ylidene)-2,3-dihydro-1 H-indol-5-yl]acetate Ex.31 d (270 mg, 1.01 mmol) was dissolved in CH2CI2 (4 mL). Then, 4M HCI in dioxane (1.5 mL, 6 mmol) was added dropwise. The mixture of reaction was

Ex.31 stirred at rt overnight. Solvent was removed under reduced pressure. The solid was triturated in diethyl ether and filtered to give 2-[2-oxo-3-(propan-2-ylidene)- 2,3-dihydro-1 H-indol-5-yl]acetic acid (126 mg, 50%) as yellow solid.

- 1 H NMR (300 MHz, DMSO-d6, d in ppm): 2.32 (s, 3H), 3.54 (s, 2H), 6.75 (d, 1 H), 7.05 (d, 1 H), 7.44 (s, 1 H), 10.38 (s, 1 H), 12.24 (s, 1 H).

Intermediate Ex.33 : 1 -(2-methanesulfonyl-2,3-dihvdro-1 H-isoindol-5-yl)cvclopropane-1 - carboxylic acid (Figure 1AO)

Table 1 .17

Starting compounds, Reaction conditions and purification,

Cpd.

Yield, appearance, ¹ H NMR (solvent) data

bromo[1 -(methoxycarbonyl)cyclopropyl]zinc

- Step 1 : to a solution of zinc dust (2.0 g, 30.26 mmol) in dry THF (25 mL) at rt was added 1 ,2-dibromoethane (434 μί, 5.04 mmol) under N2 atmosphere. The reaction mixture was stirred at 70°C for 1 min and cooled down to rt. This

Ex.33a procedure was repeated 5 times. Chlorotrimethylsilane (256 μί, 2.02 mmol) was added and the resulting suspension was stirred at rt for 15 min. It was the heated to 65°C and a few drops of methyl 1 -bromocyclopropane-1 -carboxylate were added. Methyl 1 -bromocyclopropane-1 -carboxylate (2.61 mL, 25.22 mmol) dissolved in dry THF (5 mL) was added at such a rate that reflux was maintained. Upon completion of addition, the reaction mixture was refluxed for an additional 20 min and allowed to cool down to rt. The zinc was allowed to settle and the supernatant was used further. Complete conversion was assumed.

5-bromo-2-methanesulfonyl-2,3-dihydro-1 H-isoindole

- Step 2: to a solution of 5-bromo-isoindoline hydrochloride (450 mg, 1.92 mmol) in CH2CI2 (8 mL) was added Et3N (801 μΙ_, 5.76 mmol). The reaction mixture was stirred until all material was totally dissolved and then cooled down to 0°C. Methanesulfonyl chloride (161 μί, 2.1 1 mmol) was added dropwise to the solution and the reaction mixture was stirred at rt for 16 h. The solvent was

Ex.33b

removed under reduced pressure. The residue was re-dissolved in EtOAc and washed with H20. The organic layer was dried over MgS04, filtered and the solution was concentrated to dryness. The crude material was purified by flash silica gel column chromatography eluting with a gradient of CH2CI2/MeOH from [100:0] to [90:10] to afford 5-bromo-2-methanesulfonyl-2,3-dihydro-1 H-isoindole (480 mg, 91 %) as white solid.

methyl 1 -(2-methanesulfonyl-2,3-dihydro-1 H-isoindol-5-yl)cyclopropane-1 - carboxylate

- Step 3: 5-bromo-2-methanesulfonyl-2,3-dihydro-1 H-isoindole Ex.33b (480 mg, 1 .74 mmol) and bromo[1 -(methoxycarbonyl)cyclopropyl]zinc Ex.33a (6.5 mL, 5.21 mmol) were dissolved in dry THF (5 mL) and the solution was degassed by nitrogen bubbling for 5 min. Then, XPhos (166 mg, 0.35 mmol) and Pd2(dba)3 (159 mg, 0.17 mmol) were incorporated and the reaction mixture was stirred at

Ex.33c 75°C for 16 h. The reaction mixture was concentrated to dryness and the

residue was diluted with EtOAc/H20. The two layers were partitionated and the organic layer was dried over MgS04, filtered and the solution was concentrated under reduced pressure. The crude material was purified by flash silica gel column chromatography eluting with a gradient of heptane/EtOAc from [100:0] to [50:50]. The desired fractions were combined and concentrate to obtain methyl 1 -(2-methanesulfonyl-2,3-dihydro-1 H-isoindol-5-yl)cyclopropane-1 - carboxylate (285 mg, 56%) as white solid.

1 -(2-methanesulfonyl-2,3-dihydro-1 H-isoindol-5-yl)cyclopropane-1 - carboxylic acid

- Step 4: methyl 1 -(2-methanesulfonyl-2,3-dihydro-1 H-isoindol-5-yl)cyclopropane- 1 -carboxylate Ex.33c (285 mg, 0.96 mmol) was dissolved in THF/H20 (20 mL/ 5 mL). Lithium hydroxide monohydrate (81 mg, 1.93 mmol) was added to the solution and the reaction mixture was stirred overnigth at rt. The solvent was removed under reduced pressure. Water was added and pH was adjusted to pH

Ex.33

4 with cone. HCI. The aqueous solution was extracted with EtOAc. The combined organic layers were dried over MgS04, filtered and the solution was concentrated to dryness. The residue was triturated with tert-butyl methyl ester and then filtered-off to give 1 -(2-methanesulfonyl-2,3-dihydro-1 H-isoindol-5- yl)cyclopropane-1 -carboxylic acid (217 mg, 80%) as white solid.

- 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .12 (d, 2H, J=2.4Hz), 1.45 (d, 2H, J =2.4Hz), 2.97 (s, 3H), 4.60 (s, 4H), 7.27 (m, 3H).

Intermediate Ex.34 : 2-[3-(2-hvdroxyethyl)-1 H-indol-5-yllacetic acid (Figure 1AP)

Table 1 .18

I Cpd. Starting compounds, Reaction conditions and purification, Yield, appearance, ¹ H NMR (solvent) data

5-bromo-3-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-1 H-indole

- Step 1 : t-butyldimethylsilyl chloride (3.01 g, 20 mmol) was added to a solution of 5-bromotryptophol (4.00 g, 16.65 mmol) and triethylamine (3.23 mL, 23.31 mmol) in CH2CI2 (45 mL) at 0°C under N2 atmosphere. The mixture was allowed to reach rt and stirred for 15 h. The reaction was quenched by addition

Ex.34a of sat. NH4CI and the product was extracted with EtOAc. The organic layer was washed with water and brine, dried over MgS04, filtered and the solution was concentrated to dryness. The residue was purified by flash silica gel column chromatography eluting with heptane and EtOAc. The desired fractions were combined and concentrated to obtain 5-bromo-3-{2-[(tert- butyldimethylsilyl)oxy]ethyl}-1 H-indole (5.29 g, 89%).

5-bromo-3-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-1 -(4- methylbenzenesulfonyl)-1 H-indole

- Step 2 : 5-bromo-3-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-1 H-indole Ex.34a (5.29 g, 14.92 mmol) was dissolved in DMF (45 mL). The mixture was cooled to 0°C and p-toluenesulfonyl chloride (3.41 g, 17.90 mmol) was added. The mixture was stirred at 0°C for 20 min, then sodium hydride (60% in mineral oil), (660 mg, 16.41 mmol) was added in one portion and the mixture was allowed to warm up

Ex.34b

to rt and stirred for 2 h. The reaction was quenched by addition of water and the crude was diluted with EtOAc. The organic layer was washed with water and brine, dried over MgS04, filtered and the solution was concentrated to dryness. The residue was purified by flash silica gel column chromatography with heptane and EtOAc. The desired fractions were combined and concentrated to obtain 5-bromo-3-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-1 -(4- methylbenzenesulfonyl)-1 H-indole (4.81 g, 63%).

methyl 2-(3-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-1 -(4- methylbenzenesulfonyl)-1 H-indol-5-yl)acetate

- Step 3 : 5-bromo-3-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-1 -(4- methylbenzenesulfonyl)-1 H-indole Ex.34b (4.81 g, 9.45 mmol), methyl acetoacetate (3.1 mL, 28.35 mmol) and potassium phosphate (8.10 g, 37.80 mmol) were charged to a screw cap tube, toluene (100 mL) was added and the mixture was purged with nitrogen for 5 min. Then, Pd(OAc)2 (1 10 mg, 0.47 mmol) and di-tert-butyl X-Phos (400 mg, 0.94 mmol) were added and the tube

Ex.34c

was closed under N2 atmosphere. The reaction mixture was stirred at 120°C for 15 h. After cooling EtOAc and water were added to the reaction mixture. The two phases were separated, washed with brine, dried over MgS04, filtered and the solution was concentrated to dryness. The resulting oil was purified by flash silica gel column chromatography eluting with heptane and EtOAc. The desired fractions were combined and concentrated to obtain methyl 2-(3-{2-[(tert- butyldimethylsilyl)oxy]ethyl}-1 -(4-methylbenzenesulfonyl)-1 H-indol-5-yl)acetate (2.02 g, 42%).

methyl 2-[3-(2-hydroxyethyl)-1 -(4-methylbenzenesulfonyl)-1 H-indol-5- yl]acetate

- Step 4 : tetrabutylammonium fluoride (1 M in THF), (6.03 mL, 6.03 mmol) was added to a solution of methyl 2-(3-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-1 -(4- methylbenzenesulfonyl)-1 H-indol-5-yl)acetate Ex.34c (2.02 g, 4.02 mmol)

Ex.34d dissolved in THF (12 mL). The mixture was stirred at rt for 3 h. The reaction was diluted with EtOAc and washed with water and then brine. The organic layer was dried over MgS04, filtered and the solution was concentrated to dryness. The residue was purified by flash silica gel column chromatography eluting with heptane and EtOAc. The desired fractions were combined and concentrated to obtain methyl 2-[3-(2-hydroxyethyl)-1 -(4-methylbenzenesulfonyl)-1 H-indol-5- yl]acetate (1.18 g, 75%).

methyl 2-[3-(2-hydroxyethyl)-1 H-indol-5-yl]acetate

- Step 5 : methyl 2-[3-(2-hydroxyethyl)-1 -(4-methylbenzenesulfonyl)-1 H-indol-5- yl]acetate Ex.34d (1 .18 g, 3.05 mmol) was added to a solution of magnesium (370 mg, 15.20 mmol) in dry MeOH (20 ml_). The suspension was stirred at rt overnight. The reaction was diluted with CH2CI2 and washed with 0.5 N HCI,

Ex.34e

sat. NaHC03 and brine. The organic layer was dried over MgS04, filtered and the solution was concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography eluting with heptane and EtOAc. The concentration of the appropriate fractions afforded pure methyl 2-[3-(2- hydroxyethyl)-1 H-indol-5-yl]acetate (570 mg, 80%).

2-[3-(2-hydroxyethyl)-1 H-indol-5-yl]acetic acid

- Step 6 : methyl 2-[3-(2-hydroxyethyl)-1 H-indol-5-yl]acetate Ex.34e (570 mg, 2.44 mmol) was dissolved in THF/H20 (8 mL/ 2 mL) and lithium hydroxide monohydrate (310 mg, 7.32 mmol) was added at 0°C. Then, the reaction mixture was allowed to warm up and stirred at rt for 3 h. The reaction was acidified by addition of 1 N HCI and the product was extracted with CH2CI2. The organic layer was dried over MgS04, filtered and the solution was concentrated

Ex.34

to dryness. The residue was purified by flash silica gel column chromatography eluting with CH2CI2 and MeOH. After evaporation of the appropriate fractions, the resulting solid was triturated in CH2CI2 and then filtered to afford 2-[3-(2- hydroxyethyl)-1 H-indol-5-yl]acetic acid as a white solid (320 g, 60%).

- 1 H NMR (300 MHz, DMSO-d6, d in ppm): 2.81 (t, 2H), 3.57 (s, 2H), 3.63 (t, 2H), 4.61 (br(s), 1 H), 6.95 (d, 1 H), 7.1 1 (s, 1 H), 7.25 (d, 1 H), 7.37 (s, 1 H), 10.73 (s, 1 H), 12.12 (br(s), 1 H).

Intermediate Ex.35 : 1 -(3-oxo-3,4-dihydro-2H-1 ,4-benzoxazin-7-yl)cvclopropane-1 - carboxylic acid (Figure 1AQ)

Table 1.19

was dissolved in dry THF (10 ml_). The solution was purged with nitrogen and Pd2(dba)3 (278 mg, 0.30 mmol) and XPhos (289 mg, 0.61 mmol) were added to afford a deep red suspension. The freshly prepared bromo[1 - (methoxycarbonyl)cyclopropyl]zinc (10.1 1 ml_, 8.09 mmol) was added to the solution. The resulting deep red mixture was heated at 70°C for 1 h. The reaction mixture was cooled to rt and quenched with water and extracted with EtOAc. The combined organic layers were dried over MgS04, filtered and the solution was concentrated to dryness. The crude material was adsorbed onto silica gel and purified by column chromatography eluting with a gradient of Cyclohexane/EtOAc from [100:0] to [85:15]. The product fractions were combined and concentrated to dryness to afford methyl 1 -(3- ((ethoxycarbonyl)methoxy)-4-nitrophenyl)cyclopropanecarboxyl ate Ex.35b (1 .00 g, 77%) as yellow viscous oil. 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1.18 (t, 3H, J=7.1 Hz), 1 .25-1 .29 (m, 2H), 1 .49-1 .53 (m, 2H), 3.56 (s, 3H), 4.15 (q, 2H, J=4.2Hz), 5.03 (s, 2H), 7.12 (dd, 1 H, J=8.4Hz, J=1.8Hz), 7.26 (d, 1 H, J=1 .5Hz), 7.81 (d, 1 H, J=8.1 Hz).

methyl 1 -(3,4-dihydro-3-oxo-2H-benzo[b][1 ,4]oxazin-7- yl)cyclopropanecarboxylate

- Step 3: methyl 1 -(3-((ethoxycarbonyl)methoxy)-4- nitrophenyl)cyclopropanecarboxylate Ex.35b (1 .00 g, 3.09 mmol) was dissolved in glacial acetic acid (10 mL) at rt. Iron powder (1 .73 g, 3.09 mmol) was added and the resulting brown suspension was heated at 60°C for 3h. Water was added followed by 10% aq. potassium carbonate solution until pH = 6-7 was reached. The aqueous layer was extracted with EtOAc. The organic layer was

Ex.35c

dried over MgS04, filtered and the solution was concentrated under vacuum. The crude material was purified by silica gel column chromatography eluting with a gradient of cyclohexane/EtOAc from [100:0] to [1 :1]. The product fractions were combined and concentrated to dryness to afford methyl 1 -(3,4-dihydro-3- oxo-2H-benzo[b][1 ,4]oxazin-7-yl)cyclopropanecarboxylate Ex.35c (631 mg, 83%) as white solid. 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .12-1 .15 (m, 2H), 1 .40-1 .44 (m, 2H), 3.53 (s, 3H), 4.55 (s, 2H), 6.78-6.81 (m, 1 H), 6.89-6.91 (m, 2H), 10.68 (br(s), 1 H).

1 -(3-oxo-3,4-dihydro-2H-1 ,4-benzoxazin-7-yl)cyclopropane-1 -carboxylic acid

- Step 4: methyl 1 -(3,4-dihydro-3-oxo-2H-benzo[b][1 ,4]oxazin-7- yl)cyclopropanecarboxylate Ex.35c (630 mg, 2.55 mmol) was dissolved in THF/H20 [4:1] (15 mL). Lithium hydroxide monohydrate (321 mg, 7.64 mmol) was added and the mixture was stirred overnight at rt. The organic solvent was removed under reduced pressure and the remaining aqueous layer was acidifed

Ex.35

to pH = 3-4 by addition of 3 M HCI. The solid formed was collected by filtration, washed with water and dried under vacuum at 40°C to constant weight to afford 1 -(3-0X0-3, 4-dihydro-2H-1 ,4-benzoxazin-7-yl)cyclopropane-1 -carboxylic acid Ex.35 (601 mg, quantitative) as white solid. 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .06-1 .09 (m, 2H), 1 .37-1 .40 (m, 2H), 4.54 (s, 2H), 6.77 (d, 1 H, J=7.5Hz), 6.87-6.90 (m, 2H), 10.66 (s, 1 H), 12.26 (s, 1 H).

Intermediate Ex.36 : 1 -[3-(2-hvdroxyethyl)-1 H-indol-5-yl1cyclopropane-1 -carboxylic acid (Figure 1AR)

Table 1 .20

I Cpd. Starting compounds, Reaction conditions and purification, Yield, appearance, ¹ H NMR (solvent) data

5-bromo-3-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-1 H-indole

- Step 1 : imidazole (31 1 mg, 4.57 mmol) was added to a solution of 2-(5-bromo- 1 H-dindol-3-yl) ethanol dissolved in DMF (5 ml_). The mixture was cooled at 0°C then tert-butyl dimethyl silyl chloride (485 mg, 3.12 mmol) was added portionwise. The mixture was stirred at rt for 20h. EtOAc/H20 were added to

Ex.36a quench the reaction. After phases separation, the organic layer was dried over

MgS04, filtered and the solution was concentrated under reduced pressure. The crude material was purified by flash column chromatography on silica gel eluting with Heptane/EtOAc [20:80]. Column fractions were combined and concentrated to afford 5-bromo-3-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-1 H-indole Ex.36a (664 mg, 90%) as orange oil.

methyl 1 -(3-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-1 H-indol-5- yl)cyclopropane-1 -carboxylate

- Step 2: 5-bromo-3-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-1 H-indole Ex.36a (660 mg, 1 .86 mmol) and freshly prepared bromo[1 -

(methoxycarbonyl)cyclopropyl]zinc (6.5 ml_, 5.59 mmol) were dissolved in dry THF (5 mL) and the solution was degassed by nitrogen bubbling for 5 min. Then, XPhos (177 mg, 0.37 mmol) and Pd2(dba)3 (170 mg, 0.19 mmol) were incorporated and the reaction mixture was stirred at 75°C for 16h. The reaction

Ex.36b mixture was concentrated to dryness and the residue was diluted with

EtOAc/H20. The two layers were partitionated and the organic layer was dried over MgS04, filtered and the solution was concentrated under reduced pressure. The crude material was purified by flash column chromatography on silica gel eluting with a gradient of Heptane/EtOAc from [100:0] to [50:50]. The desired fractions were combined and concentrated to obtain methyl 1 -(3-{2- [(tert-butyldimethylsilyl)oxy]ethyl}-1 H-indol-5-yl)cyclopropane-1 -carboxylate Ex.36b (660 mg, crude) . The desired compound could not be isolated appropriately and it was used as such for the next synthetic step.

methyl 1 -[3-(2-hydroxyethyl)-1 H-indol-5-yl]cyclopropane-1 -carboxylate

- Step 3: tetrabutylammonium fluoride solution 1 M in THF (3.53 mL, 3.53 mmol) was slowly added to a solution of methyl 1 -(3-{2-[(tert- butyldimethylsilyl)oxy]ethyl}-1 H-indol-5-yl)cyclopropane-1 -carboxylate Ex.36b (660 mg, 1.76 mmol) diluted in THF (5 mL). The reaction mixture was stirred at rt for 72h. EtOAc and water were added to quench the reaction. The organic

Ex.36c layer was washed with water several times and the aqueous layer was washed with EtOAc. The organic layers were combined, dried over MgS04, filtered and the solution was concentrated to dryness. The crude material was purified by flash column chromatography on silica gel eluting with a gradient of Heptane/EtOAc [100:0] to [50:50]. Column fractions were combined to afford methyl 1 -[3-(2-hydroxyethyl)-1 H-indol-5-yl]cyclopropane-1 -carboxylate Ex.36c (268 mg, 59%) as orange solid.

1 -[3-(2-hydroxyethyl)-1 H-indol-5-yl]cyclopropane-1 -carboxylic acid

- Step 4: methyl 1 -[3-(2-hydroxyethyl)-1 H-indol-5-yl]cyclopropane-1 -carboxylate Ex.36c (268 mg, 1.03 mmol) was dissolved in THF/H20 (8 mL/ 2 mL). Lithium hydroxide monohydrate (42 mg, 1.03 mmol) was added to the solution and the reaction mixture was stirred overnigth at rt. Additional lithium hydroxide

Ex.36 monohydrate (84 mg, 2.06 mmol) was added and the reaction mixture was heated at 50°C overnight. The solvent was removed under reduced pressure. Water was added and pH was adjusted to pH 4 with cone. HCI. The aqueous solution was extracted with EtOAc. The combined organic layers were dried over MgS04, filtered and the solution was concentrated to dryness. The residue was purified by flash column chromatography on silica gel eluting with a long gradient of CH2CI2/MeOH to afford 1 -[3-(2-hydroxyethyl)-1 H-indol-5- yl]cyclopropane-1 -carboxylic acid Ex.36 (1 1 1 mg, 44%) as white solid. 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .18(s, 2H), 1.48(s, 2H), 2.86 (t, 2H, J=7.3Hz), 3.63-3.70 (m, 2H), 4.64 (t, 1 H, J=5.3Hz), 7.06 (d, 1 H, J=8.4Hz), 7.14 (s, 1 H), 7.26 (d, 1 H, J=8.3Hz), 7.44 (s, 1 H), 10.75 (s, 1 H), 12.10 (br(s), 1 H).

Intermediate Ex.37 : 1 -(2-oxo-2,3-dihydro-1 H-indol-5-yl)cvclopropane-1 -carboxylic acid (Figure 1AS)

Table 1 .21

Starting compounds, Reaction conditions and purification,

Cpd.

Yield, appearance, ¹ H NMR (solvent) data

methyl 1 -(2-oxoindolin-5-yl)cyclopropanecarboxylate

- Step 1 : 5-bromoindolin-2-one (250 mg, 1.18 mmol) and freshly prepared bromo[1 -(methoxycarbonyl)cyclopropyl]zinc (4.42 mL, 3.54 mmol) were dissolved in dry THF (5 mL) and the solution was degassed by nitrogen bubbling for 5 min. Then, XPhos (1 12 mg, 0.24 mmol) and Pd2(dba)3 (108 mg, 0.12 mmol) were incorporated and the reaction mixture was stirred at 85°C for 1 h. The reaction mixture was concentrated to dryness. The crude material was

Ex.37a

purified by column chromatography on silica gel eluting with

Cyclohexane/EtOAc (60:40). The desired fractions were combined and concentrated to obtain methyl 1 -(2-oxoindolin-5-yl)cyclopropanecarboxylate Ex.37a (1 10 mg, 40%) as pale yellow solid. 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .09-1 .15 (m, 2H), 1 .41 -1 .47 (m, 2H), 3.43 (s, 2H), 3.52 (s, 3H), 6.72 (d, 1 H, J=7.9Hz), 7.10 (dd, 1 H, J=8.0Hz, J=1.9Hz), 7.14-7.17 (m, 1 H), 10.33 (s, 1 H).

1 -(2-oxo-2,3-dihydro-1 H-indol-5-yl)cyclopropane-1 -carboxylic acid

- Step 2: methyl 1 -(2-oxoindolin-5-yl)cyclopropanecarboxylate Ex.37a (60 mg, 0.26 mmol) was dissolved in THF/MeOH (2 mL/ 3 mL). 5 M NaOH (259 μί, 1.30 mmol) was added to the solution and the reaction mixture was stirred at rt for 5h. The solvent was removed under reduced pressure. Water and EtOAc were added to the solution and the two phases were separated. The pH of the

Ex.37 aqueous layer was adjusted to pH = 3 - 4 with 1 M citric acid. The aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgS04, filtered and the solution was concentrated under reduced pressure to afford 1 -(2-0X0-2, 3-dihydro-1 H-indol-5-yl)cyclopropane-1 -carboxylic acid Ex.37 (56 mg, 99%) as off-white solid. 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1.12 (q, 2H, J=3.1 Hz), 1 .35-1 .45 (m, 2H), 3.43 (s, 2H), 6.71 (d, 1 H, J=7.9Hz), 7.10 (dd, 1 H, J=8.0Hz, J=1.8Hz), 7.16 (s, 1 H), 10.31 (s, 1 H), 12.22 (br(s), 1 H).

Intermediate Ex.38 : 1 -(2,2-dioxo-1 ,3-dihydro-2,1-benzothiazol-5-yl)cyclopropane-1 - carboxylic acid (Figure 1AT)

Table 1 .22

Starting compounds, Reaction conditions and purification,

Cpd.

Yield, appearance, ¹ H NMR (solvent) data

methyl 1 -(2,2-dioxo-1 ,3-dihydro-2,1 -benzothiazol-5-yl)cyclopropane-1 -

Ex.38a carboxylate

- Step 1 : 5-bromo-1 ,3-dihydro-2,1 -benzothiazole-2,2-dione (500 mg, 2.01 mmol) and freshly prepared bromo[1 -(methoxycarbonyl)cyclopropyl]zinc (7 ml_, 6.05 mmol) were dissolved in dry THF (5 mil) and the solution was degassed by nitrogen bubbling for 5 min. Then, XPhos (191 mg, 0.40 mmol) and Pd2(dba)3 (184 mg, 0.20 mmol) were incorporated and the reaction mixture was stirred at 75°C for 16h. The reaction mixture was concentrated to dryness and the residue was diluted with EtOAc/H20. The two layers were partitionated and the organic layer was dried over MgS04, filtered and the solution was concentrated under reduced pressure. The crude material was purified by flash column chromatography on silica gel eluting with a gradient of Heptane/EtOAc from

[100:0] to [50:50]. The desired fractions were combined and concentrated to obtain methyl 1 -(2,2-dioxo-1 ,3-dihydro-2,1 -benzothiazol-5-yl)cyclopropane-1 - carboxylate Ex.38a (198 mg, 37%) as yellow solid.

1 -(2,2-dioxo-1 ,3-dihydro-2,1 -benzothiazol-5-yl)cyclopropane-1 -carboxylic acid

- Step 2: methyl 1 -(2,2-dioxo-1 ,3-dihydro-2,1 -benzothiazol-5-yl)cyclopropane-1 - carboxylate Ex.38a (198 mg, 0.74 mmol) was dissolved in THF/H20 (8 mL/ 3 ml_). Lithium hydroxide monohydrate (62 mg, 1.48 mmol) was added to the solution and the reaction mixture was stirred overnigth at rt. Further lithium hydroxide monohydrate (31 mg, 0.74 mmol) was added and the reaction mixture

Ex.38 was heated at 50°C for 8h. The solvent was removed under reduced pressure.

Water was added and pH was adjusted to pH 4 with 1 M HCI. The solid was collected by filtration, triturated in Et20, filtered-off and dried until constant weight to afford 1 -(2,2-dioxo-1 ,3-dihydro-2,1 -benzothiazol-5-yl)cyclopropane-1 - carboxylic acid Ex.38 (157 mg, 84%) as yellow solid. 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .08 (br(s), 2H), 1 .41 (br(s), 2H), 4.48 (s, 2H), 6.73 (d, 1 H, J=8.1 Hz), 7.18 (d, 1 H), 7.23 (s, 1 H). Acidic and sulfonamide protons exchanged with the deuterated solvent.

Intermediate Ex.39 : 2-(3-methyl-1 H-indol-5-yl)acetic acid (Figure 1AU)

Table 1 .23

Starting compounds, Reaction conditions and purification,

Cpd.

Yield, appearance, ¹ H NMR (solvent) data

5-bromo-3-methyl-1 -tosyl-1 H-indole

- Step 1 : 5-bromo-3-methyl-1 H-indole (3.50 g, 16.66 mmol) was dissolved in dimethylacetamide (50 mL). The mixture was purged with N2 and cooled to 0- 5°C. Sodium hydride (60% in mineral oil) (800 mg, 19.99 mmol) was added portionwise over 30 min under a flow of N2. Gas evolution was observed upon addition. When the addition was completed the mixture was stirred for 30 min at 0-5°C. p-Toluenesulfonyl chloride (3.80 g, 19.99 mmol) was added in one portion and the mixture was allowed to warm up to rt and stirred overnight. The

Ex.39a

reaction was quenched with water to form a suspension. EtOAc was added and the phases were separated. The combined organic layers were washed with brine, dried over MgS04, filtered and the solution was concentrated to dryness. The crude material was purified by column chromatography on silica gel eluting with a gradient of Heptane/EtOAc from [100:0] to [70:30]. The product fractions were combined and concentrated to dryness to afford a pale yellow oil, which solidified upon standing at rt affording 5-bromo-3-methyl-1 -tosyl-1 H-indole (5.32 g, 88%) as pale yellow solid.

methyl 2-(3-methyl-1 -tosyl-1 H-indol-5-yl)acetate

Ex.39b

- Step 2: 5-bromo-3-methyl-1 -tosyl-1 H-indole Ex.39a (2.78 g, 8.24 mmol), methyl acetoacetate (2.66 mL, 24.72 mmol) and K3P04 (7.00 g, 32.96 mmol) were charged to a round bottom flask and suspended in dry toluene (100 mL). The mixture was purged with N2 and tBuXPhos (348 mg, 0.82 mmol) was added followed by Pd(OAc)2 (92 mg, 0.41 mmol). The obtained suspension was heated to 120°C for 16h. The mixture was cooled to rt, filtered through a pad of Celite, poured into water and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgS04, filtered and the solution was concentrated to dryness. The crude material was purified by column chromatography on silica gel eluting with a gradient of Heptane/EtOAc from

[100:0] to [70:30]. The product fractions were combined and concentrated to dryness to afford methyl 2-(3-methyl-1 -tosyl-1 H-indol-5-yl)acetate Ex.39b (2.16 g, 73%) as pale yellow oil.

methyl 2-(3-methyl-1 H-indol-5-yl)acetate

- Step 3: methyl 2-(3-methyl-1 -tosyl-1 H-indol-5-yl)acetate Ex.39b (1 .90 g, 5.32 mmol) was dissolved in dry MeOH (95 mL). Magnesium (700 mg, 26.60 mmol) was added and the mixture was stirred overnight at rt. The reaction mixture was concentrated in vacuo. The residues were suspended in EtOAc and a 10% aq. solution of EDTA (disodium salt) was added. The phases were mixed vigorously

Ex.39c and the organic layer was separated. The aqueous phase was washed with further EtOAc. The combined organic layers were dried over MgS04, filtered and the solution was concentrated to dryness. The crude material was purified by column chromatography on silica gel eluting with a gradient of

Heptane/EtOAc form [100:0] to [75:25]. The product fractions were combined and concentrated to dryness to afford methyl 2-(3-methyl-1 H-indol-5-yl)acetate Ex.39c (618 mg, 57%) as pale yellow oil.

2-(3-methyl-1 H-indol-5-yl)acetic acid

- Step 4: lithium hydroxide monohydrate (150 mg, 3.68 mmol) was added to the mixture of methyl 2-(3-methyl-1 H-indol-5-yl)acetate Ex.39c (618 mg, 3.04 mmol) diluted in THF/H20 (10 mL/ 5 mL) at 0°C. Then, the reaction mixture was stirred at rt for 16h. The mixture was diluted with EtOAc and 1 M HCI was added under vigorous stirring until pH = 4 was reached. The organic layer was separated, dried over MgS04, filtered and the solution was concentrated to dryness. The

Ex.39

crude material was purified by column chromatography on silica gel eluting with a gradient of CH2CI2/MeOH from [100:0] to [9:1 ]. The product fractions were combined and concentrated to dryness. The residue was triturated with diethyl ether and the solid was collected by filtration to give 2-(3-methyl-1 H-indol-5- yl)acetic acid Ex.39 (121 mg, 20%) as white solid. 1 H NMR (300 MHz, DMSO- d6, d in ppm): 2.23 (s, 3H), 3.58 (s, 2H), 6.96 (m, 1 H), 7.08 (s, 1 H), 7.25 (m, 1 H), 7.33 (s, 1 H), 10.66 (s, 1 H), 12.13 (br(s), 1 H).

Intermediate Ex.40 : 1 -(1 -methyl-2,2-dioxo-1 ,3-dihvdro-2,1 -benzothiazol-5-yl)cvclopropane- 1 -carboxylic acid (Figure 1AV)

Table 1 .24

Starting compounds, Reaction conditions and purification,

Cpd.

Yield, appearance, ¹ H NMR (solvent) data

methyl 1 -(1 -methyl-2,2-dioxo-1 ,3-dihydro-2,1 -benzothiazol-5- yl)cyclopropane-1 -carboxylate

Ex.40a - Step 1 : to a solution of previously synthesized methyl 1 -(2,2-dioxo-1 ,3-dihydro- 2, 1 -benzothiazol-5-yl)cyclopropane-1 -carboxylate (100 mg, 0.37 mmol) dissolved in dry DMF (2 mL) was added K2C03 (155 mg, 1.12 mmol) followed by iodomethane (35μΙ_, 0.56 mmol). The reaction mixture was stirred at rt for 1 h. The reaction mixture was poured onto brine. The aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgS04, filtered and the solution was concentrated under reduced pressure. The residue was triturated in small amount of cold MeOH and the precipitate was filtered-off to afford methyl 1 -(1 -methyl-2,2-dioxo-1 ,3-dihydro-2, 1 -benzothiazol-5- yl)cyclopropane-1 -carboxylate Ex.40a (56 mg, 53%) as white solid. 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .15 (q, 2H, J=4.2Hz), 1 .47 (q, 2H, J=3.7Hz), 3.02 (s, 3H), 3.53 (s, 3H), 4.61 (s, 2H), 6.87 (d, 1 H, J=8.8Hz), 7.25-7.35 (m, 2H).

1 -(1 -methyl-2,2-dioxo-1 ,3-dihydro-2,1 -benzothiazol-5-yl)cyclopropane-1 - carboxylic acid

- Step 2: methyl 1 -(1 -methyl-2,2-dioxo-1 ,3-dihydro-2,1 -benzothiazol-5- yl)cyclopropane-1 -carboxylate Ex.40a (56 mg, 0.20 mmol) was dissolved in THF/MeOH (1 mL/ 0.5 mL). 5 M NaOH (408 μΙ_, 2.04 mmol) was added and the mixture was stirred overnight at rt. The reaction mixture was diluted with sat. NH4CI and EtOAc. The two phases were separated. The aqueous layer was

Ex.40

acidified to pH = 3-4 by addition of 10% citric acid. The aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgS04, filtered and the solution was concentrated under reduced pressure to afford 1 - (1 -methyl-2,2-dioxo-1 ,3-dihydro-2,1 -benzothiazol-5-yl)cyclopropane-1 -carboxylic acid Ex.40 (30 mg, 56%) as white solid. 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .10 (q, 2H, J=4.1 Hz), 1 .47 (q, 2H, J=3.6Hz), 3.01 (s, 3H), 4.61 (s, 2H), 6.85 (d, 1 H, J=8.7Hz), 7.25-7.35 (m, 2H), 12.28 (s, 1 H).

Intermediate Ex.41 1 -{1 -r2-(benzyloxy)ethyll-2,3-dihydro-1 H-indol-5-yl}cyclopropane-1 - carboxylic acid (Figure 1AW)

Table 1 .25

Starting compounds, Reaction conditions and purification,

Cpd.

Yield, appearance, ¹ H NMR (solvent) data

1 -[2-(benzyloxy)ethyl]-5-bromo-2,3-dihydro-1 H-indole

- Step 1 : 5-bromo-2,3-dihydro-1 H-indole (700 mg, 3.53 mmol) was dissolved in dry acetonitrile (10 mL). K2C03 (1.47 g, 10.60 mmol) was added to the solution followed by [(2-bromoethoxy)methyl]benzene (616 μΙ_, 3.89 mmol). The microwave vial was sealed and the reaction was heated at 100°C for 15 min under microwave irradiation. After TLC, no conversion was observed. The reaction was heated for additional 1 h at 120°C under microwave irradiation. The TLC showed only starting material. Dry DMF (1 mL) was added and the reaction was heated at 120°C for 1 h under microwave irradiation. After TLC, small conversion was observed. A catalytic amount of tetrabutylammonium bromide

Ex.41 a was added and the reaction was heated at 120°C for 1 h under microwave

irradiation. The TLC showed complete conversion. The solution was decomposed into water. The aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgS04, filtered and the solution was concentrated under reduced pressure. The crude material was purified by silica gel column chromatography eluting with cyclohexane/EtOAc (90:10). The desired fractions were combined and concentrated to dryness to afford 1 -[2- (benzyloxy)ethyl]-5-bromo-2,3-dihydro-1 H-indole Ex.41 a (620 mg, 53%) as colourless oil. 1 H NMR (300 MHz, DMSO-d6, d in ppm): 2.85 (t, 2H, J=8.5Hz), 3.25 (t, 2H, J=5.6Hz), 3.41 (t, 2H, J=8.5Hz), 3.62 (t, 2H, J=5.6Hz), 4.50 (s, 2H), 6.43 (d, 1 H, J=8.3Hz), 7.07 (dd, 1 H, J=8.3Hz, J=2.1 Hz), 7.13 (m, 1 H), 7.22-7.35

Intermediate Ex.43 : 1 -(2,2-dioxo-1 ,3-dihvdro-2-benzothiophen-5-yl)cvclopropane-1 - carboxylic acid (Figure 1AY)

Table 1 .26

Starting compounds, Reaction conditions and purification,

Cpd.

Yield, appearance, ¹ H NMR (solvent) data

methyl 1 -(2,2-dioxo-1 ,3-dihydro-2-benzothiophen-5-yl)cyclopropane-1 - carboxylate

- Step 1 : 5-bromo-1 ,3-dihydro-2-benzothiophene-2,2-dione (475 mg, 1.92 mmol)

Ex.43a and freshly prepared bromo[1 -(methoxycarbonyl)cyclopropyl]zinc (4.81 mL, 3.84 mmol) were dissolved in dry THF (5 mil) and the solution was degassed by nitrogen bubbling for 5 min. Then, XPhos (183 mg, 0.38 mmol) and Pd2(dba)3 (176 mg, 0.19 mmol) were incorporated and the reaction mixture was stirred at

Intermediate Ex.46 : 2-(2,2-dioxo-1 ,3-dihvdro-2-benzothiophen-5-yl)acetic acid (Figure 1 BB)

Table 1 .27

Starting compounds, Reaction conditions and purification,

Cpd.

Yield, appearance, ¹ H NMR (solvent) data

tert-butyl 2-(2,2-dioxo-1 ,3-dihydro-2-benzothiophen-5-yl)acetate

- Step 1 : 5-Bromo-1 ,3-dihydro-benzo(c)thiophene 2,2-dioxide (500 mg, 2.02 mmol), the previously synthesized tert-butyl 2-(bromozincio)acetate (7.60 mL, 6.07 mmol) and dry THF (5 mL) were placed in flask, the mixture was degassed by nitrogen bubbling for 5 min. Then Pd2(dba)3 (185 mg, 0.20 mmol) and XPhos (193 mg, 0.41 mmol) were incorporated and the reaction mixture was stirred at 75°C for 1 h. The mixture was cooled to rt, EtOAc and water was added and the two-phase mixture was filtered through a pad of Celite. The phases

Ex.46a were separated, the organic layer was dried over MgS04, filtered and the

solution was concentrated to dryness. The crude material was purified by column chromatography eluting with a gradient of Cyclohexane/EtOAc from

[100:0] to [70:30]. The product fractions were combined and concentrated to dryness. The residue was triturated with Cyclohexane/Et20 [1 :1], filtered and dried under vacuum at 40°C. The product tert-butyl 2-(2,2-dioxo-1 ,3-dihydro-2- benzothiophen-5-yl)acetate Ex.46a (421 mg, 74%) was isolated as a white fluffy solid. 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .39 (s, 9H), 3.58 (s, 2H), 4.46 (s, 2H), 4.48 (s, 2H), 7.22-7.25 (m, 2H), 7.32 (d, 1 H, J=7.5Hz).

2-(2,2-dioxo-1 ,3-dihydro-2-benzothiophen-5-yl)acetic acid

Ex.46 - Step 2: tert-butyl 2-(2,2-dioxo-1 ,3-dihydro-2-benzothiophen-5-yl)acetate Ex.46a

(200 mg, 0.71 mmol) was dissolved in CH2CI2 (2 mL) and then was added 4M HCI in dioxane (2 mL, 8 mmol). The reaction mixture was stirring for 6h at rt. Slow conversion was observed. The reaction mixture was heated at 40°C for 18h. The solution was concentrated to dryness to afford a colourless oil. A mixture of Et20/Cyclohexane was added to the residue and a white precipitate formed. The solid was collected by filtration and dried under vacuum at 40°C until constant weight to afford 2-(2,2-dioxo-1 ,3-dihydro-2-benzothiophen-5- yl)acetic acid Ex.46 (109 mg, 68%) as white solid. 1 H NMR (300 MHz, DMSO- d6, d in ppm): 3.59 (s, 2H), 4.45 (s, 2H), 4.47 (s, 2H), 7.26-7.33 (m, 3H), 12.38 (s, 1 H).

Intermediate Ex.51 : 2-(3-oxo-2,3-dihvdro-1 H-inden-5-yl)acetic acid (Figure 1 BG)

Table 1 .28

Intermediate Ex.52 : 2-(2-ethoxy-1 H-1 ,3-benzodiazol-5-yl)acetic acid (Figure 1 BH)

Table 1 .29

Starting compounds, Reaction conditions and purification,

Cpd.

Yield, appearance, ¹ H NMR (solvent) data

Ex.52a

- Step 1 : a solution of methyl 2-(3,4-diaminophenyl)acetate (synthesized following the procedure described in WO2013019682A1 ) (330 mg, 1 .83 mmol) and tetraethyl orthocarbonate (536 μΙ_, 2.56 mmol) was heated overnight at 70°C. After cooling to rt, the crude material was purified by silica gel column chromatography using CH2CI2/MeOH (90:10) as eluent affording methyl 2-(2- ethoxy-1 H-1 ,3-benzodiazol-5-yl)acetate Ex.52a (300 mg, 70%) as pale brown solid. 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .37 (t, 3H, J=7.1 Hz), 3.60 (s, 3H), 3.68 (s, 2H), 4.45 (q, 2H, J=7.1 Hz), 6.92 (dd, 1 H, J=8.2Hz, J=1.6Hz), 7.10- 7.30 (m, 2H), 1 1.80 (s, 1 H).

2-(2-ethoxy-1 H-1 ,3-benzodiazol-5-yl)acetic acid

- Step 2: methyl 2-(2-ethoxy-1 H-1 ,3-benzodiazol-5-yl)acetate Ex.52a (300 mg,

I .28 mmol) was dissolved in MeOH (3 ml_). 2M NaOH (1.28 ml_, 2.56 mmol) was added to the solution. The reaction mixture was stirred at rt for 5h. The solvent was removed under reduced pressure. 1 M citric acid was added up pH

Ex.52

= 6 was reached. The solid formed was collected by filtration to give 2-(2- ethoxy-1 H-1 ,3-benzodiazol-5-yl)acetic acid Ex.52 (230 mg, 82%) as off-white solid. 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .37 (t, 3H, J=8.7Hz), 3.56 (s, 2H), 4.46 (q, 2H, J=7.0Hz), 6.92 (dd, 1 H, J=8.2Hz, J=1.6Hz), 7.17-7.22 (m, 2H),

I I .76 (s, 1 H).

Intermediate Ex.53 : 2-[6-(methylsulfanyl)naphthalen-2-yllacetic acid (Figure 1 BI)

Table 1 .30

Starting compounds, Reaction conditions and purification,

Cpd.

Yield, appearance, ¹ H NMR (solvent) data

methyl 2-(2-methoxynaphthalen-6-yl)acetate

- Step 1 : 2-bromo-6-methoxynaphthalene (500 mg, 2.1 1 mmol) was weighted into a reaction vial. Potassium phosphate (1 .79 g, 8.44 mmol) and toluene (15 mL) were added followed by di-tert-butyl Xphos (90 mg, 0.21 mmol) and methyl acetoacetate (807 μΙ_, 6.33 mmol). The mixture was purged with N2 an Pd(OAc)2 (24 mg, 0.1 1 mmol) was added. The reaction vial was sealed under

Ex.53a N2 atmosphere and heated under vigorous stirring at 100°C for 16h. Water was added to quench the reaction. The solution was diluted with EtOAc and filtered through a plug of Celite. The phases were separated. The organic layer was dried over MgS04, filtered and the solution was concentrated to dryness. The crude material was purified by silica gel column chromatography eluting with Cyclohexane/EtOAc (90:10) to afford methyl 2-(2-methoxynaphthalen-6- yl)acetate Ex.53a (332 mg, 68%) as white solid.

2-(2-methoxynaphthalen-6-yl)acetic acid

- Step 2: methyl 2-(2-methoxynaphthalen-6-yl)acetate Ex.53a (330 mg, 1.43 mmol) was dissolved in a mixture of MeOH (2 mL), THF (2 mL) and water (2 mL) and introduced in a sealed tube. 5N NaOH (2.90 mL, 14.33 mmol) was added to the solution and the reaction mixture was heated at 100°C for 40 min

Ex.53b under microwave irradiation. The solvent was evaporated under reduced

pressure and the residue was washed with water. The solution was acidified with 1 N HCI until pH = 1 was reached. The solid was collected by filtration and dried until constant weight to give 2-(2-methoxynaphthalen-6-yl)acetic acid

Ex.53b (270 mg, 87%) as white solid. 1 H NMR (300 MHz, DMSO-d6, d in ppm): 3.62 (s, 2H), 3.86 (s, 3H), 7.12 (dd, 1 H, J=2.6Hz, J=8.9Hz), 7.27 (d, 1 H, J=2.6Hz), 7.35 (dd, 1 H, J=1.8Hz, J=8.4Hz), 7.65 (s, 1 H), 7.73 (d, 1 H, J=8.4Hz), 7.74 (d, 1 H, J=8.9Hz).

2-[6-(methylsulfanyl)naphthalen-2-yl]acetic acid

- Step 3: to a solution of 2-(2-methoxynaphthalen-6-yl)acetic acid Ex.53b (270 g, 1 .25 mmol) dissolved in CH2CI2 (3 mL) was added boron trifluoride methyl sulfide complex (1 .31 mL, 12.45 mmol). The reaction was stirred at rt over the weekend. The solvent was removed under reduced pressure and the residue was diluted with EtOAc. The combined organic layers were washed with brine

Ex.53

and water. The organic layer was dried over MgS04, filtered and the solution was concentrated under reduced pressure. The crude material was purified by silica gel column chromatography eluting with CH2CI2/MeOH (95:5) to afford 2- [6-(methylsulfanyl)naphthalen-2-yl]acetic acid Ex.53 (140 g, 47%) as pale green solid. 1 H NMR (300 MHz, DMSO-d6, d in ppm): 2.56 (s, 3H), 3.70 (s, 2H), 7.34- 7.43 (m, 2H), 7.65-7.73 (m, 2H), 7.73-7.82 (m, 2H), 12.35 (br(s), 1 H).

Intermediate Ex.54 : 2-r2-(ethvlsulfanvD-1 H-1 ,3-benzodiazol-5-vHacetic acid (Figure 1 BJ)

Table 1 .31

Starting compounds, Reaction conditions and purification,

Cpd.

Yield, appearance, ¹ H NMR (solvent) data

methyl 2-(2-sulfanylidene-2,3-dihydro-1 H-1 ,3-benzodiazol-5-yl)acetate

- Step 1 : methyl 2-(3,4-diaminophenyl)acetate (synthesized following the procedure described in WO2013019682A1 ) (300 mg, 1 .66 mmol) was dissolved in dry THF (5 mL) and 1 , 1 '-thiocarbonyldiimidazole (356 mg, 2.00 mmol) was added to the solution. The reaction mixture was stirred at rt for 2h. The solvent

Ex.54a was removed under reduced pressure. The crude material was purified by silica gel column chromatography using CH2CI2/MeOH (96:4) as eluent affording methyl 2-(2-sulfanylidene-2,3-dihydro-1 H-1 ,3-benzodiazol-5-yl)acetate Ex.54a (280 mg, 76%) as pale brown solid. 1 H NMR (300 MHz, DMSO-d6, d in ppm): 3.62 (s, 3H), 3.72 (s, 2H), 7.01 (dd, 1 H, J=8.0Hz, J=1 .6Hz), 7.06 (d, 1 H, J=8.0Hz), 7.09 (d, 1 H , J=1 .6Hz), 12.51 (s, 2H).

methyl 2-[2-(ethylsulfanyl)-1 H-1 ,3-benzodiazol-5-yl]acetate

- Step 2: methyl 2-(2-sulfanylidene-2,3-dihydro-1 H-1 ,3-benzodiazol-5-yl)acetate Ex.54a (181 mg, 0.81 mmol) was dissolved in a mixture of DMF/THF (2 mL/ 2 mL) and K2C03 (340 mg, 2.44 mmol) was added followed by iodoethane (66 L, 0.82 mmol). The reaction mixture was stirred at rt for 1 h. Water was added to quench the reaction. The aqueous layer was extracted with EtOAc. The

Ex.54b

combined organic layers were dried over MgS04, filtered and the solution was concentrated to dryness yielding methyl 2-[2-(ethylsulfanyl)-1 H-1 ,3-benzodiazol- 5-yl]acetate Ex.54b (204 mg, quantitative). The title compound was used at the next step without further purification. 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .36 (t, 3H, J=7.3Hz), 3.26 (q, 2H, J=7.3Hz), 3.61 (s, 3H); 3.73 (s, 2H), 6.98- 7.03 (m, 1 H), 7.26-7.30 (m, 1 H), 7.40-7.45 (m, 1 H), 12.46 (s, 1 H).

2-[2-(ethylsulfanyl)-1 H-1 ,3-benzodiazol-5-yl]acetic acid

- Step 3: methyl 2-[2-(ethylsulfanyl)-1 H-1 ,3-benzodiazol-5-yl]acetate Ex.54b (202

Ex.54 mg, 0.81 mmol) was dissolved in MeOH (4 mL). 2M NaOH (807 μΙ_, 1 .61 mmol) was added to the solution. The reaction mixture was stirred at rt for 1 h. The solvent was removed under reduced pressure. 1 M citric acid was added up pH = 4-5 was reached. The solid formed was collected by filtration to give 2-[2- (ethylsulfanyl)-1 H-1 ,3-benzodiazol-5-yl]acetic acid Ex.54 (180 mg, 94%) as off- white solid. 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .36 (t, 3H, J=7.3Hz), 3.25 (q, 2H, J=7.4Hz), 3.59 (s, 2H), 7.00 (dd, 1 H, J=8.2Hz, J=1.2Hz), 7.31 (d, 1 H, J=1.2Hz), 7.65 (d, 1 H, J=8.2Hz). The acidic proton exchanged with the deuterated solvent.

Intermediate Ex.55 : 2-[2-(morpholin-4-yl)-1 H-1 ,3-benzodiazol-5-yllacetic acid (Figure 1 BK)

Table 1 .32

Starting compounds, Reaction conditions and purification,

Cpd.

Yield, appearance, ¹ H NMR (solvent) data

methyl 2-(2,3-dihydro-2-oxo-1 H-benzo[d]imidazol-5-yl)acetate

- Step 1 : to a solution of methyl 2-(3,4-diaminophenyl)acetate (synthesized following the procedure described in WO2013019682A1 ) (2.00 g, 1 1 .10 mmol) in THF (30 mL) was added dropwise a solution of 1 ,1 '-carbonyldiimidazole (2.16

Ex.55a g, 13.32 mmol) dissolved in CH2CI2 (30 mL). The reaction was stirred at rt for

16h. Tert-butylmethylether (30 mL) wad added to the reaction mixture. The resulting precipitate was collected by filtration and washed with tert- butylmethylether and dried under vacuum to afford methyl 2-(2,3-dihydro-2-oxo- 1 H-benzo[d]imidazol-5-yl)acetate Ex.55a (1 .42 g, 62%) as pale brown solid.

methyl 2-(2-chloro-1 H-benzo[d]imidazol-5-yl)acetate

- Step 2: phosphorus oxychloride (1 mL) was added to methyl 2-(2,3-dihydro-2- oxo-1 H-benzo[d]imidazol-5-yl)acetate Ex.55a (100 mg, 0.49 mmol). The reaction mixture was stirred at 90°C for 4h. The reaction was quenched by dropwise addition of sat. NaHC03 solution. CH2CI2 was added and the phases

Ex.55b were separated. The organic layer was dried over MgS04, filtered and the

solution was concentrated under reduced pressure. The crude material was purified by column chromatography eluting with a gradient of Heptane/EtOAc from [100:0] to [50:50]. The product fractions were combined and concentrated to dryness to afford methyl 2-(2-chloro-1 H-benzo[d]imidazol-5-yl)acetate Ex.55b (40 mg, 37%) as white solid.

methyl 2-(2-morpholino-1 H-benzo[d]imidazol-5-yl)acetate

- Step 3: methyl 2-(2-chloro-1 H-benzo[d]imidazol-5-yl)acetate Ex.55b (380 mg, 1 .69 mmol) was dissolved in tert-butanol (12 mL) and then morpholine (580 μί, 6.77 mmol) was added. The reaction mixture was stirred at rt for 72h. LC-MS did not show conversion. Additional morpholine (290 μί, 3.39 mmol) was added and reaction was stirred at 50°C for 1 week. LC-MS still did not show conversion. Then 1 ,8-diazabicyclo[5.4.0]undec-7-ene (250 μί, 1 .69 mmol) was added in addition of additional morpholine (290 μί, 3.39 mmol), the mixture reaction was stirred at rt for 72h. LCMS showed a peak with [M+H]+ = 276.1

Ex.55c

(10% of conversion). Morpholine (290 μΙ_, 3.39 mmol) and 1 ,8- diazabicyclo[5.4.0]undec-7-ene (250 μί, 1 .69 mmol) were added and reaction was stirred at rt for 2 weeks. LCMS showed 30% of conversion. The reaction mixture was diluted with EtOAc and water. The organic layer was dried over MgS04, filtered and the solution was concentrated to dryness. The crude material was purified by column chromatography eluting with a gradient of Heptane/EtOAc from [100:0] to [0:100]. The product fractions were combined and concentrated to afford methyl 2-(2-morpholino-1 H-benzo[d]imidazol-5- yl)acetate Ex.55c (78 mg, 17%) as light yellow oil. 2-[2-(morpholin-4-yl)-1 H-1 ,3-benzodiazol-5-yl]acetic acid

Step 4: methyl 2-(2-morpholino-1 H-benzo[d]imidazol-5-yl)acetate Ex.55c (78 mg, 0.28 mmol) was dissolved in THF (8 mL). Water (2 mL) was added followed by lithium hydroxide monohydrate (24 mg, 0.57 mmol) and the reaction mixture was stirred overnight at rt. The solvent was removed under reduced pressure. Water was added to the residue and the pH was adjusted to pH = 4 with 1 N HCI. The aqueous layer was evaporated to dryness. The crude of the reaction was absorbed onto silica gel and purified by column chromatography eluting a gradient of CH2CI2/MeOH from [100:0] to [75:25]. The product fractions were combined and concentrated to dryness to afford 2-[2-(morpholin-4-yl)-1 H-1 ,3- benzodiazol-5-yl]acetic acid Ex.55 (36 mg, 48%) as yellow oil. 1 H NMR (300 MHz, DMSO-d6, d in ppm): 3.16 (s, 2H), 3.38-3.45 (m, 4H), 3.69-3.72 (m, 4H), 6.82 (d, 1 H), 7.08-7.1 1 (m, 2H), 8.45 (s, 1 H).

Intermediate Ex.56 : 1 -(1 -cvclopropanecarbonyl-2,3-dihydro-1 H-indol-5-yl)cvclopropane-1 - carboxylic acid (Figure 1 BL)

Table 1 .33

Starting compounds, Reaction conditions and purification,

Cpd.

Yield, appearance, ¹ H NMR (solvent) data

methyl 1 -(1 -cyclopropanecarbonyl-2,3-dihydro-1 H-indol-5-yl)cyclopropane-

1 -carboxylate

- Step 1 : 5-bromoindoline (500 mg, 2.52 mmol) and freshly prepared bromo[1 - (methoxycarbonyl)cyclopropyl]zinc (12.62 mL, 10.10 mmol) were dissolved in dry THF (5 mL) and the solution was degassed by nitrogen bubbling for 5 min. Then, XPhos (60 mg, 0.13 mmol) and Pd2(dba)3 (58 mg, 0.06 mmol) were incorporated and the reaction mixture was stirred at 75°C for 2h. The reaction mixture was cooled to rt. Water and ice was added to the residue and the

Ex.56a aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgS04, filtered and the solution was concentrated to reduced pressure. The crude material was triturated with a mixture of Et20/petroleum ether and the solid was collected by filtration. The filtrate was concentrated to dryness to afford methyl 1 -(1 -cyclopropanecarbonyl-2,3-dihydro-1 H-indol-5- yl)cyclopropane-1 -carboxylate Ex.56a (540 mg, 75%). 1 H NMR (300 MHz, DMSO-d6, d in ppm): 0.80-0.90 (m, 4H), 1.13 (q, 2H, J=3.0Hz), 1.44 (q, 2H, J=4.1 Hz), 1 .85-2.00 (m, 1 H), 3.14 (t, 2H, J=8.1 Hz), 3.52 (s, 3H), 4.27 (t, 2H, J=7.4Hz), 7.07 (dd, 1 H, J=8.2Hz), 7.18 (s, 1 H), 7.91 (d, 1 H, J=7.0Hz).

1 -(1 -cyclopropanecarbonyl-2,3-dihydro-1 H-indol-5-yl)cyclopropane-1 - carboxylic acid

- Step 2: methyl 1 -(1 -cyclopropanecarbonyl-2,3-dihydro-1 H-indol-5- yl)cyclopropane-1 -carboxylate Ex.56a (500 mg, 1.75 mmol) was dissolved in MeOH (3 mL) and THF (2 mL). 5 M NaOH (1 .75 mL, 8.76 mmol) was added and

Ex.56 the solution was stirred at rt for 5h. The reaction was quenched with brine and was extracted with EtOAc. The aqueous layer was acidified with 1 M citric acid up pH = 3 - 4 and the precipitate formed was collected by filtration and washed with water to afford 1 -(1 -cyclopropanecarbonyl-2,3-dihydro-1 H-indol-5- yl)cyclopropane-1 -carboxylic acid Ex.56 (405 mg, 85%) as pale pink solid. 1 H NMR (300 MHz, DMSO-d6, d in ppm): 0.80-0.90 (m, 4H), 1.07 (q, 2H, J=4.0Hz), 1 .40 (q, 2H, J=3.5Hz), 1 .85-2.00 (m, 1 H), 3.14 (t, 2H, J=8.0Hz), 4.27 (m, 2H), 7.06 (d, 1 H, J=7.9Hz), 7.17 (s, 1 H), 7.89 (d, 1 H, J=8.4Hz), 12.20 (br(s), 1 H).

Intermediate Ex.57 : 2-{1 -[3-(tert-butoxy)-3-oxopropyll-1 H-indol-5-yl)acetic acid (Figure 1 BM)

Table 1 .34

Starting compounds, Reaction conditions and purification,

Cpd.

Yield, appearance, ¹ H NMR (solvent) data

tert-butyl 3-[5-(2-methoxy-2-oxoethyl)-1 H-indol-1 -yl]prop-2-enoate

- Step 1 : methyl 2-(1 H-indol-5-yl)acetate (5.60 g, 29.60 mmol) was dissolved in acetonitrile (30 mL) and triethylamine (4.54 ml_, 32.55 mmol) was added to the solution followed by tert-butyl propiolate (4.46 mL, 32.55 mmol). The solution was stirred at rt for 90 min. The mixture was concentrated to dryness. The residue was dissolved in EtOAc/H20 and, after phases separation, the

Ex.57a combined organic layer were washed with brine, dried over MgS04, filtered and the solution was concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel eluting with a gradient of Heptane/EtOAc from [100:0] to [65:35]. The fractions of the main product were concentrated to dryness to afford a pale yellow solid. This solid was triturated with heptane to obtain tert-butyl 3-[5-(2-methoxy-2-oxoethyl)-1 H-indol-1 -yl]prop- 2-enoate Ex.57a (6.40 g, 69%) as white solid.

tert-butyl 3-[5-(2-methoxy-2-oxoethyl)-1 H-indol-1 -yl]propanoate

- Step 2: tert-butyl 3-[5-(2-methoxy-2-oxoethyl)-1 H-indol-1 -yl]prop-2-enoate Ex.57a (1 .15 g, 3.65 mmol) was dissolved in dry MeOH (10 mL) and dry THF (3 mL) and the mixture was purged with N2. Pd/C 5% (58 mg) was added and the N2 atmosphere was replaced by hydrogen and the mixture was stirred at 40°C for 5h. TLC showed starting material. The reaction mixture was stirred at rt for additional 72h. TLC showed still starting material. Additional Pd/C 5% (58 mg) was added and the reaction mixture was stirred at rt for 18h. LCMS showed total consumption of starting material but 50% of product, [M+H]+ = 318, and 50% of reduced indol ring (indoline), [M+H]+ = 320. The reaction mixture was filtered

Ex.57b

through a pad of Celite and washed with EtOAc. The filtrate was concentrated to dryness and EtOAc/H20 were added. After phases separation, the product was extracted with EtOAc and the combined organic layer were washed with brine, dried over MgS04, filtered and the solution was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with heptane and a gradient of CH2CI2 and CH2CI2/EtOAc from [100:0] to [80:20]. The product fractions were combined and concentrated to dryness to afford tert-butyl 3-[5-(2-methoxy-2-oxoethyl)-1 H-indol-1 -yl]propanoate Ex.57b (346 mg, 30%) as yellow oil. During the purification process also 180 mg of indoline derivative was isolated as a yellow oil.

2-{1 -[3-(tert-butoxy)-3-oxopropyl]-1 H-indol-5-yl}acetic acid

- Step 3: tert-butyl 3-[5-(2-methoxy-2-oxoethyl)-1 H-indol-1 -yl]propanoate Ex.57b (346 mg, 1.09 mmol) was dissolved in THF:H20 (9 mL/ 3 mL) and lithium

Ex.57 hydroxide monohydrate (55 mg, 1.31 mmol) was added at 0°C. Then, the

reaction mixture was allowed to warm up to rt and stirred at this temperature for 18h. The reaction mixture was concentrated to dryness and 2 M HCI was added at 0°C until pH = 4 was reached. EtOAc/H20 were added and, after phases separation, the combined organic layer were washed with brine, dried over MgS04, filtered and the solution was concentrated under reduced pressure. The crude material was purified by flash column chromatography on silica gel eluting with a gradient of CH2CI2/MeOH from [100:0] to [60:40]. The product fractions were combined and concentrated to dryness affording 2-{1 -[3-(tert-butoxy)-3- oxopropyl]-1 H-indol-5-yl}acetic acid Ex.57 (144 mg, 44%) as white solid. 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1.36 (s, 9H), 2.73-2.77 (m, 2H), 3.62 (s, 2H), 4.38-4.42 (m, 2H), 6.40 (d, 1 H, J=1.9Hz), 7.06 (d, 1 H, J=8.3Hz), 7.34 (d, 1 H, J=2.0Hz), 7.44 (m, 2H), 12.24 (s, 1 H).

Intermediate Ex.58 : 2-[3-(2-methanesulfonylethyl)-1 H-indol-5-yllacetic acid (Figure 1 BN)

Table 1 .35

Starting compounds, Reaction conditions and purification,

Cpd.

Yield, appearance, ¹ H NMR (solvent) data

methyl 2-(3-(2-(methylsulfonyl)vinyl)-1 H-indol-5-yl)acetate

- Step 1 : methyl 2-(3-formyl-1 H-indol-5-yl)acetate (synthesized following the procedure described in WO2016102633) (708 mg, 3.26 mmol) and diethyl(methylsulfonylmethyl) phosphonate (900 mg, 3.91 mmol) were dissolved in acetonitrile (6 mL) and Et3N (6 ml_). Lithium bromide (340 mg, 3.91 mmol) was added and the reaction mixture was stirred at rt for 16h. The reaction mixture was concentrated to dryness and the residue was partitioned between

Ex.58a

EtOAc and water. After phase separation, the organic layer was washed with brine, dried over MgS04, filtered and the solution was concentrated under reduced pressure. The crude material was purified by flash column chromatography on silica gel eluting with a gradient of Heptane/EtOAc from [100:0] to [80:20]. The product fractions were combined and concentrated to dryness to afford methyl 2-(3-(2-(methylsulfonyl)vinyl)-1 H-indol-5-yl)acetate Ex.58a (800 mg, 84%) as white solid.

methyl 2-(3-(2-(methylsulfonyl)ethyl)-1 H-indol-5-yl)acetate

- Step 2: methyl 2-(3-(2-(methylsulfonyl)vinyl)-1 H-indol-5-yl)acetate Ex.58a (800 mg, 2.73 mmol) was dissolved in MeOH (30 mL) and the mixture was purged with N2. Then, Pd/C 10% (80 mg) was added and the N2 atmosphere was replaced by hydrogen and the mixture was stirred at rt for 1 h. The reaction

Ex.58b mixture was filtered through a pad of Celite and washed with EtOAc. The

solution was concentrated to dryness and the residue was purified by flash column chromatography on silica gel eluting with a gradient of Heptane/EtOAc from [100:0] to [30:70]. The product fractions were combined and concentrated under reduced pressure to afford methyl 2-(3-(2-(methylsulfonyl)ethyl)-1 H-indol- 5-yl)acetate Ex.58b (713 mg, 89%) as pale brown oil.

2-[3-(2-methanesulfonylethyl)-1 H-indol-5-yl]acetic acid

- Step 3: lithium hydroxide monohydrate (122 mg, 2.90 mmol) was added to the mixture of methyl 2-(3-(2-(methylsulfonyl)ethyl)-1 H-indol-5-yl)acetate Ex.58b (713 mg, 2.41 mmol) diluted in THF/H20 (19 mL/ 6 mL) at 0°C. Then, the

Ex.58 reaction mixture was stirred overnight at rt. The reaction mixture was

concentrated to dryness and 2 M HCI was added at 0°C and under vigorous stirring until pH = 4 was reached. The solid formed was collected by filtration and wash with water to afford 2-[3-(2-methanesulfonylethyl)-1 H-indol-5-yl]acetic acid Ex.58 (393 mg, 58%) as pink solid. 1 H NMR (300 MHz, DMSO-d6, d in ppm): 3.05 (s, 3H), 3.1 1 -3.17 (m, 2H), 3.45-3.50 (m, 2H), 3.64 (s, 2H), 7.03 (d, 1 H, J=8.3Hz), 7.27 (s, 1 H), 7.32 (d, 1 H, J=8.3Hz), 7.46 (s, 1 H), 10.90 (s, 1 H), 12.19 (s, 1 H).

Intermediate Ex.59 : 2-[3-(2-methanesulfonylacetyl)-1 H-indol-5-yllacetic acid (Figure 1 BO)

Table 1 .36

Intermediate Ex.61 : 1 -(1 H-indol-5-yl)cvclopropane-1 -carboxylic acid (Figure 1 BQ)

Table 1.37

Starting compounds, Reaction conditions and purification,

Cpd.

Yield, appearance, ¹ H NMR (solvent) data

methyl 1 -phenylcyclopropanecarboxylate

- Step 1 : 1 -phenylcyclopropanecarboxylic acid (10.00 g, 61 .66 mmol) was dissolved in MeOH (150 mL). HCI 4M in dioxane (10 mL) was added and the mixture was heated at 50°C for 16h. The solvent was removed under reduced

Ex.61a pressure. The residue was partitioned between EtOAc and sat. NaHC03

solution. The organic layer was dried over MgS04, filtered and the solution was concentrated to dryness to afford methyl 1 -phenylcyclopropanecarboxylate

Ex.61 a (10.40 g, 96%) as colorless oil. 1 H NMR (300 MHz, CDCI3, d in ppm): 1 .22-1 .24 (m, 2H), 1 .61 -1.64 (m, 2H), 3.65 (s, 3H), 7.28-7.39 (m, 5H).

methyl 1 -(4-nitrophenyl)cyclopropanecarboxylate

Ex.61 b - Step 2: methyl 1 -phenylcyclopropanecarboxylate Ex.61 a (9.50 g, 53.90 mmol) was dissolved in a mixture of concentrated H2S04 (25 mL) and CH2CI2 (25 mL) and cooled at 0°C. Sodium nitrate (4.58 g, 53.90 mmol) was added in portionwise and the mixture was stirred at 0°C for 2h and then allowed to warm up to rt. After 36h, the reaction mixture was quenched with EtOAc and water. The phases were separated, the organic layer was washed with sat. NaHC03 solution, dried over MgS04, filtered and the solution was concentrated to dryness. The crude material was purified by column chromatography on silica gel eluting with a gradient of Heptane/EtOAc from [100:0] to [30:70]. The product fractions were combined and concentrated to dryness to afford a colourless oil, which solidified upon standing at rt to give methyl 1 -(4- nitrophenyl)cyclopropanecarboxylate Ex.61 b (5.20 g, 44% (uncorrected for impurities)). The product was considered to be suitable for the next synthetic step. 1 H NMR (300 MHz, CDCI3, d in ppm): 1 .15-1 .18 (m, 2H), 1 .62-1.66 (m, 2H), 3.57 (s, 3H), 7.44 (d, 2H, J=8.8Hz), 8.1 1 (d, 2H, J=8.8Hz).

methyl 1 -(4-aminophenyl)cyclopropanecarboxylate

- Step 3: methyl 1 -(4-nitrophenyl)cyclopropanecarboxylate Ex.61 b (5.20 g, 23.5 mmol) was dissolved in MeOH (100 mL). The solution was purged with N2 and Pd/C 10% (520 mg) was added under N2 atmosphere. The N2 atmosphere was replaced by hydrogen (balloon) and the mixture was stirred at rt for 16h. The catalyst was removed by filtration through a pad of Celite, the filtrate was

Ex.61 c

concentrated to dryness and purified by column chromatography on silica gel eluting with a gradient of Heptane/EtOAc from [100:0] to [50:50]. The product fractions were combined and concentrated to dryness to afford methyl 1 -(4- aminophenyl)cyclopropanecarboxylate Ex.61 c (3.59 g, 80%) as an off-white solid. 1 H NMR (300 MHz, CDCI3, d in ppm): 1 .03-1 .07 (m, 2H), 1 .45-1.49 (m, 2H), 3.54-3.55 (m, 5H), 6.56 (d, 2H, J=8.4Hz), 7.05 (d, 2H, J=8.4Hz).

methyl 1 -(4-amino-3-bromophenyl)cyclopropanecarboxylate

- Step 4: methyl 1 -(4-aminophenyl)cyclopropanecarboxylate Ex.61 c (3.59 g, 18.77 mmol) was dissolved in acetonitrile (100 mL). N-bromosuccinimide (3.34 g, 18.77 mmol) was added and the mixture was stirred at rt for 16h. The mixture was concentrated to dryness. The residue was partitioned between water and EtOAc. The organic layer was separated, dried over MgS04, filtered and the solution was concentrated to dryness. The residue was purified by column

Ex.61 d

chromatography on silica gel eluting with a gradient of Heptane/EtOAc from [100:0] to [70:30]. The product fractions were combined and concentrated to dryness to afford a pale brown sticky oil which solidified upon standing at rt to give methyl 1 -(4-amino-3-bromophenyl)cyclopropanecarboxylate Ex.61 d (4.17 g, 82%) as pale brown solid. 1 H NMR (300 MHz, CDCI3, d in ppm): 1 .03-1.07 (m, 2H), 1 .46-1 .49 (m, 2H), 3.55 (s, 3H), 3.99 (br(s), 2H), 6.62 (d, 1 H, J=8.2Hz), 7.01 (dd, 1 H, J=8.2Hz, J=1 .8Hz), 7.31 (d, 1 H, J=1.8Hz).

methyl 1 -(4-amino-3-(2- (trimethylsilyl)ethynyl)phenyl)cyclopropanecarboxylate

- Step 5: methyl 1 -(4-amino-3-bromophenyl)cyclopropanecarboxylate Ex.61 d (3.90 g, 13.57 mmol) was dissolved in Et3N (50 mL). Ethynyltrimethylsilane (19.18 mL, 135.7 mmol) was added followed by DMAP (33 mg, 0.27 mmol). The

Ex.61 e mixture was purged with N2 and PdCI2(PPh3)2 (190 mg, 0.27 mmol) was added to the solution. The mixture was heated at 90°C for 16h. The reaction was cooled to rt, the solids were removed by filtration through a pad of Celite and washed with EtOAc. The filtrate was concentrated to dryness. The crude material was purified by column chromatography on silica gel eluting with a gradient of Heptane/EtOAc from [100:0] to [75:25]. The product fractions were combined and concentrated to dryness to afford a dark yellow sticky oil, which solidified upon standing at rt to give methyl 1 -(4-amino-3-(2- (trimethylsilyl)ethynyl)phenyl)cyclopropanecarboxylate Ex.61e (1 .38 g, 35%) as yellow solid. 1 H NMR (300 MHz, CDCI3, d in ppm): 0.27 (s, 9H), 1 .1 1 -1.14 (m, 2H), 1 .53-1 .55 (m, 2H), 3.62 (s, 3H), 4.23 (s, 2H), 6.65 (d, 1 H, J=8.3Hz), 7.1 1 (dd, 1 H, J=8.3Hz, J=1.9Hz), 7.28 (s, 1 H).

methyl 1 -(1 H-indol-5-yl)cyclopropanecarboxylate

- Step 6: methyl 1 -(4-amino-3-(2- (trimethylsilyl)ethynyl)phenyl)cyclopropanecarboxylate Ex.61e (470 mg, 1.64 mmol) was dissolved in a pressure tube in dry DMF (10 ml_). The solution was purged with N2 and Cul (155 mg, 0.82 mmol) was added. The tube was sealed under N2 and heated at 80°C for 36h. The mixture was cooled to rt, water and EtOAc were added. The phases were separated and the aqueous layer was

Ex.61f washed with EtOAc. The combined organic phases were dried over MgS04, filtered and the solution was concentrated to dryness. The crude oil was purified by column chromatography on silica gel eluting with a gradient of

Heptane/EtOAc from [100:0] to [75:25]. The product fractions were combined and concentrated to dryness to afford methyl 1 -(1 H-indol-5- yl)cyclopropanecarboxylate Ex.61f (235 mg, 67%) as yellow oil. 1 H NMR (300 MHz, CDCI3, d in ppm): 1.17-1 .20 (m, 2H), 1 .54-1.57 (m, 2H), 3.54 (s, 3H), 6.45 (s, 1 H), 7.12-7.15 (m, 2H), 7.27 (d, 1 H, J=8.4Hz), 7.53 (s, 1 H), 8.08 (br(s), 1 H).

1 -(1 H-indol-5-yl)cyclopropane-1 -carboxylic acid

- Step 7: methyl 1 -(1 H-indol-5-yl)cyclopropanecarboxylate Ex.61 f (355 mg, 1.65 mmol) was dissolved in THF (10 ml_). Lithium hydroxide monohydrate (138 mg, 3.30 mmol) dissolved in water (2 mL) was added and the reaction mixture was stirred at rt for 16h. Further lithium hydroxide monohydrate (2.0 equiv) was added and the reaction mixture was stirred at rt for 60 h. The reaction was quenched with EtOAc. 1 M HCI was added until pH = 3-4 was reached. The phases were separated and the organic layer was dried over MgS04, filtered

Ex.61 and the solution was concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel eluting with a gradient of CH2CI2/MeOH from [100:0] to [95:5]. The product fractions were combined and concentrated to dryness to afford a yellow solid. The solid was triturated with CH2CI2/MeOH [95:5], filtered and dried under vacuum at 50°C until constant weight. The product 1 -(1 H-indol-5-yl)cyclopropane-1 -carboxylic acid Ex.61 (1 10 mg, 33%) was isolated as a yellow solid. 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .13-1 .14 (m, 2H), 1.44-1 .45 (m, 2H), 6.36 (s, 1 H), 7.06 (dd, 1 H, J=1 .3Hz, J=8.4Hz), 7.28-7.32 (m, 2H), 7.45 (s, 1 H), 1 1 .00 (s, 1 H), 12.07 (br(s), 1 H).

Intermediate Ex.64 : 2-[3-(methylsulfamoyl)-1 H-indol-5-yllacetic acid (Figure 1 BT)

Table 1.38

Starting compounds, Reaction conditions and purification,

Cpd.

Yield, appearance, ¹ H NMR (solvent) data

5-((methoxycarbonyl)methyl)-1 H-indole-3-sulfonic acid

- Step 1 : methyl 2-(1 H-indol-5-yl)acetate (550 mg, 2.91 mmol) was dissolved in

Ex.64a pyridine (8 mL). Sulfur trioxide pyridine complex (460 mg, 2.91 mmol) was

added and the mixture was heated at 120°C for 2h. Water and EtOAc were added to quench the reaction. The aqueous layer was separated and concentrated under reduced pressure. The crude was dried under vacuum to afford 5-((methoxycarbonyl)methyl)-1 H-indole-3-sulfonic acid Ex.64a (crude) as an oil. No purification was carried out and the crude was used in the next synthetic step.

methyl 2-[3-(chlorosulfonyl)-1 H-indol-5-yl]acetate

- Step 2: 5-((methoxycarbonyl)methyl)-1 H-indole-3-sulfonic acid Ex.64a (crude, 2.91 mmol, complete conversion estimated) was dissolved in a mixture of sulfolane/acetonitrile (6 mL/ 6 mL). The mixture was cooled to 0°C and

Ex.64b phosphorus oxychloride (972 μί, 3.78 mmol) was added dropwise under

stirring. Then the mixture was heated at 80°C for 1 h. The mixture was concentrated to dryness to afford methyl 2-[3-(chlorosulfonyl)-1 H-indol-5- yl]acetate Ex.64b (crude) as an oil. The crude was used in the next synthetic step without any purification.

methyl 2-[3-(methylsulfamoyl)-1 H-indol-5-yl]acetate

- Step 3: methyl 2-[3-(chlorosulfonyl)-1 H-indol-5-yl]acetate Ex.64b (crude, 2.91 mmol, complete conversion estimated) was dissolved in dry THF (18 mL). The mixture was cooled to 0°C and pyridine (285 μί, 3.49 mmol) was added. Then, methylamine (2M in THF) (4.36 mL, 8.73 mmol) was added dropwise under stirring. The reaction mixture was stirred overnight at rt. Further methylamine (2M in THF) (4.36 mL, 8.73 mmol) was added to the reaction mixture at 0°C and

Ex.64c the solution was stirred overnight at rt. Water and EtOAc were added to quench the reaction. The organic layer was separated, dried over MgS04, filtered and the solution was concentrated to dryness. The crude material was purified by column chromatography on silica gel eluting with a gradient of Heptane/EtOAc from [100:0] to [90:10]. The product fractions were combined and concentrated to dryness to afford methyl 2-[3-(methylsulfamoyl)-1 H-indol-5-yl]acetate Ex.64c (crude) as an oil. Residual sulfolane could not be removed at this point and the mixture was used as such in the next synthetic step.

2-[3-(methylsulfamoyl)-1 H-indol-5-yl]acetic acid

- Step 4: lithium hydroxide monohydrate (160 mg, 3.90 mmol) was added to a mixture of methyl 2-[3-(methylsulfamoyl)-1 H-indol-5-yl]acetate Ex.64c (1 .10 g) diluted in THF/H20 (8 mL/ 4 mL) at 0°C. The reaction mixture was stirred at rt over the weekend. Water and EtOAc were added to the reaction mixture and the organic layer was separated. 1 M HCI was added under vigorous stirring to the aqueous layer until pH = 4 was reached. The aqueous layer was extracted with EtOAc. The organic layer was separated, dried over MgS04, filtered and the

Ex.64

solution was concentrated to dryness. The crude material was purified by column chromatography on silica gel eluting with a gradient of CH2CI2/MeOH from [100:0] to [90:10]. The product fractions were combined and concentrated to dryness to afford 2-[3-(methylsulfamoyl)-1 H-indol-5-yl]acetic acid Ex.64 (95 mg, 13% over 4 steps) as white solid. 1 H NMR (300 MHz, DMSO-d6, d in ppm): 2.32 (d, 3H, J=5.0Hz), 3.56 (s, 2H), 7.03 (d, 1 H, J=5.1 Hz), 7.08 (d, 1 H, J=8.5Hz), 7.37 (d, 1 H, J=8.4Hz), 7.63 (s, 1 H), 7.79 (d, 1 H), 1 1 .84 (s, 1 H), 12.19 (br(s), 1 H).

Intermediate Ex.65 : 2-[3-(morpholine-4-carbonyl)-1 H-indol-5-yllacetic acid (Figure 1 BU) Table 1 .39 Starting compounds, Reaction conditions and purification,

Cpd.

Yield, appearance, ¹ H NMR (solvent) data

5-bromo-1 -tosyl-1 H-indole-3-carboxylic acid

- Step 1 : 5-bromo-1 H-indole-3-carboxylic acid (3.26 g, 13.6 mmol) was dissolved in dioxane (30 ml_). The mixture was purged with nitrogen and cooled to 0-5°C. Sodium Hydride (60% in mineral oil) (1 .63 g, 40.8 mmol) was added portionwise over approx. 30 min under a flow of N2. Gas evolution was observed upon addition. When the addition was completed the mixture was stirred for 30 min at 0-5°C. p-Toluenesulfonyl chloride (5.17 g, 27.1 mmol) was dissolved in dioxane (10 mL) and added dropwise over 1 h to the suspension. The reaction mixture

Ex.65a was allowed to warm up to rt and stirred at temperature overnight. A white

insoluble solid was formed. 1 M HCI was added up to pH = 6. The reaction mixture was filtered and washed with CH2CI2. The combined organic layer were washed with brine, dried over MgS04, filtered and the solution was concentrated under reduced pressure. The crude material was purified by flash column chromatography on silica gel with a gradient of CH2CI2/CH2CI2:MeOH (9:1 ) from [100:0] to [0:100]. The column fractions were concentrated to dryness to afford 5-bromo-1 -tosyl-1 H-indole-3-carboxylic acid Ex.65a (1 .47 g, 27%) as pale orange solid.

(5-bromo-1 -tosyl-1 H-indol-3-yl)(morpholino)methanone

- Step 2: 5-bromo-1 -tosyl-1 H-indole-3-carboxylic acid Ex.65a (1 .47 g, 3.73 mmol) was dissolved in DMF (30 mL) and (1 -cyano-2-ethoxy-2- oxoethylidenaminooxy)dimethylamino-morpholino-carbenium

hexafluorophosphate (1 .91 g, 4.48 mmol) was added followed by Et3N (1.26

Ex.65b mL, 4.48 mmol) and morpholine (376 μί, 4.48 mmol). The reaction mixture was stirred at 50°C for 20h. The reaction mixture was concentrated to dryness. The crude material was purified by flash column chromatography on silica gel using a gradient of Heptane/EtOAc from [100:0] to [20:80]. The desired fractions were concentrated to dryness to afford (5-bromo-1 -tosyl-1 H-indol-3- yl)(morpholino)methanone Ex.65b (1 .45 g, 84%) as yellow oil.

methyl 2-[1 -(4-methylbenzenesulfonyl)-3-(morpholine-4-carbonyl)-1 H-indol-

5-yl]acetate

- Step 3: (5-bromo-1 -tosyl-1 H-indol-3-yl)(morpholino)methanone Ex.65b (1 .45 g, 3.13 mmol), methyl acetoacetate (1 mL, 9.39 mmol) and potassium phosphate (2.65 g, 12.52 mmol) were placed in a screw cap tube, toluene (15 mL) was added and the mixture was degassed by N2 bubbling for 5 min. Then, Pd(OAc)2 (26 mg, 0.16 mmol) and di-tert-butyl XPhos (131 mg, 0.31 mmol) were

Ex.65c

incorporated and the tube was closed under N2 atmosphere. The reaction mixture was stirred overnight at 120°C. After cooling to rt, the mixture was diluted with water. The aqueous layer was extracted with EtOAc, dried over MgS04, filtered and the solution was concentrated to dryness. The crude material methyl 2-[1 -(4-methylbenzenesulfonyl)-3-(morpholine-4-carbonyl)-1 H- indol-5-yl]acetate Ex.65c (1 .54 g, crude) was used as such in the next synthetic step.

methyl 2-[3-(morpholine-4-carbonyl)-1 H-indol-5-yl]acetate

- Step 4: magnesium (409 mg, 16.80 mmol) was added portionwise to a solution

Ex.65d of methyl 2-[1 -(4-methylbenzenesulfonyl)-3-(morpholine-4-carbonyl)-1 H-indol-5- yl]acetate Ex.65c (1 .54 g, crude) in dry methanol (25 mL). The suspension was stirred at rt for 20h. Gas formation was observed. The reaction mixture was concentrated and EtOAc/H20 were added. The residu was filtered through a pad of Celite. The two phases were separated. The organic layer was dried over MgS04, filtered and the solution was concentrated to dryness. The crude material was purified by flash column chromatography on silica gel using a gradient of Heptane/EtOAc from [100:0] to [0: 100]. The desired fractions were combined and concentrated to dryness to afford methyl 2-[3-(morpholine-4- carbonyl)-1 H-indol-5-yl]acetate Ex.65d (568 mg, 56%) as white solid.

2-[3-(morpholine-4-carbonyl)-1 H-indol-5-yl]acetic acid

- Step 5: methyl 2-[3-(morpholine-4-carbonyl)-1 H-indol-5-yl]acetate Ex.65d (568 mg, 1 .88 mmol) was dissolved in THF (5 mL). Water (1 .5 mL) was added followed by lithium hydroxide monohydrate (158 mg, 3.76 mmol). The reaction mixture was stirred at rt for 16h. The solvent was removed under reduced pressure. EtOAc and water were added followed by 1 M HCI under vigorous stirring until pH = 4 was reached. The phases were separated. The organic layer

Ex.65

was dried over MgS04, filtered and the solution was concentrated to dryness. The crude material was purified by flash column chromatography on silica gel using a gradient of CH2CI2/CH2CI2:MeOH (9: 1 ) from [100:0] to [0: 100]. The desired fractions were combined and concentrated to afford 2-[3-(morpholine-4- carbonyl)-1 H-indol-5-yl]acetic acid Ex.65 (1 12 mg, 21 %) as white solid. 1 H NMR (300 MHz, DMSO-d6, d in ppm): 3.63 (s, 10H), 7.07-7.10 (d, 1 H), 7.38- 7.41 (d, 1 H), 7.61 (s, 1 H), 7.71 (s, 1 H), 1 1 .59 (s, 1 H), 12.20 (br(s), 1 H).

Intermediate Ex.67 : 1 -[2-(2-methoxyacetyl)-2,3-dihvdro-1 H-isoindol-5-yl1cyclopropane-1 - carboxylic acid (Figure 1 BW)

Table 1 .40

Starting compounds, Reaction conditions and purification,

Cpd.

Yield, appearance, ¹ H NMR (solvent) data

1 -(5-bromoisoindolin-2-yl)-2-methoxyethanone

- Step 1 : to a solution of 5-bromoisoindoline (300 mg, 1 .51 mmol) and Et3N (633 L, 4.54 mmol) in CH2CI2 (2 mL) was added dropwise 2-methoxyacetyl chloride (208 μί, 2.27 mmol). The reaction mixture was stirred at rt for 1 h. The solution was poured onto a mixture of cold water and CH2CI2. The phases were separated and the aqueous layer was extracted twice with CH2CI2. The combined organic layers were dried over MgS04, filtered and the solution was

Ex.67a

concentrated to dryness. The residue was triturated in Et20 and filtered-off. The filtrate was concentrated under reduced pressure and triturated with a mixture of Et20 (3 mL) and petroleum ether (3 mL). The solid formed was collected by filtration to afford 1 -(5-bromoisoindolin-2-yl)-2-methoxyethanone Ex.67a (205 mg, 50%) as pale brown solid. 1 H NMR (300 MHz, DMSO-d6, d in ppm): 3.33 (s, 3H), 4.12 (s, 2H), 4.63 (d, 2H, J=13.4Hz), 4.75 (d, 2H, J=12.8Hz), 7.32 (t, 1 H, J=8.1 Hz), 7.48 (dd, 1 H, J=8.1 Hz, J=1 .9Hz), 7.58 (d, 1 H, J=8.3Hz).

methyl 1 -(2-(2-methoxyacetyl)isoindolin-5-yl)cyclopropanecarboxylate

- Step 2: 1 -(5-bromoisoindolin-2-yl)-2-methoxyethanone Ex.67a (205 mg, 0.76 mmol) and freshly prepared bromo[1 -(methoxycarbonyl)cyclopropyl]zinc (1 .89

Ex.67b mL, 1 .52 mmol) were dissolved in dry THF (2 mL) and the solution was

degassed by nitrogen bubbling for 5 min. Then, XPhos (36 mg, 0.08 mmol) and Pd2(dba)3 (35 mg, 0.04 mmol) were incorporated and the reaction mixture was stirred at 75°C for 16h. The mixture was cooled to rt and quenched with water and extracted with EtOAc. The combined organic layers were dried over MgS04, filtered and the solution was concentrated to dryness. The crude was adsorbed onto silica gel and purified by column chromatography eluting with a gradient of Cyclohexane/EtOAc from [20:80] to [0:100]. The product fractions were combined and concentrated to dryness to afford methyl 1 -(2-(2- methoxyacetyl)isoindolin-5-yl)cyclopropanecarboxylate Ex.67b (120 mg, 55%) as white solid. 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .15-1.20 (m, 2H), 1 .45-1 .50 (m, 2H), 3.33 (s, 3H), 3.53 (s, 3H), 4.12 (s, 2H), 4.63 (s, 2H), 4.74 (s, 2H), 7.20-7.35 (m, 3H).

1 -[2-(2-methoxyacetyl)-2,3-dihydro-1 H-isoindol-5-yl]cyclopropane-1 - car boxy lie acid

- Step 3: methyl 1 -(2-(2-methoxyacetyl)isoindolin-5-yl)cyclopropanecarboxylate Ex.67b (120 mg, 0.42 mmol) was dissolved in THF/MeOH (1 mL/ 1 ml_). 5 M NaOH (415 μΙ_, 2.07 mmol) was added and the reaction mixture was heated at 100°C for 5 min under microwave irradiation. Brine was added to quench the reaction. The aqueous layer was acidified with 1 M citric acid up pH = 3 - 4 and

Ex.67

was extracted twice with EtOAc. The combined organic layers were dried over MgS04, filtered and the solution was concentrated under reduced pressure. The residue was triturated with Et20, filtered, washed with Et20 and dried until constant weight to afford 1 -[2-(2-methoxyacetyl)-2,3-dihydro-1 H-isoindol-5- yl]cyclopropane-1 -carboxylic acid Ex.67 (40 mg, 35%) as white solid. 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .05-1 .15 (m, 2H), 1 .40-1 .60 (m, 2H), 3.38 (s, 3H), 4.12 (s, 3H), 4.62 (s, 2H), 4.74 (s, 2H), 7.20-7.35 (m, 2H), 12.26 (br(s), 1 H).

Intermediate Ex.68 : 2-(1 -cvclopropanecarbonvl-2,3-dihvdro-1 H-indol-5-vl)acetic acid

(Fiqure 1 BX)

Table 1.41

Starting compounds, Reaction conditions and purification,

Cpd.

Yield, appearance, ¹ H NMR (solvent) data

(5-bromoindolin-1 -yl)(cyclopropyl)methanone

- Step 1 : cyclopropanecarboxylic acid (452 μΙ_, 5.68 mmol) and 5-bromoindoline (750 mg, 3.79 mmol) were dissolved in DMF (7 mL). DMAP (555 mg, 4.54 mmol) and EDCI.HCI (1 .60 g, 8.33 mmol) were added to the solution and the reaction mixture was stirred at rt for 12h. Water was added to quench the reaction. The aqueous layer was extracted with EtOAc. The combined organic

Ex.68a

layers were washed with 0.25 M HCI, water, 5% NaHC03 and water, dried over MgS04, filtered and the solution was concentrated to reduced pressure to afford (5-bromoindolin-1 -yl)(cyclopropyl)methanone Ex.68a (998 mg, 99%) as white solid. 1 H NMR (300 MHz, DMSO-d6, d in ppm): 0.80-0.90 (m, 4H), 1.94 (m, 1 H), 3.18 (t, 2H, J=8.4Hz), 4.29 (t, 2H, J=8.6Hz), 7.25-7.30 (m, 1 H), 7.42 (m, 1 H), 7.93 (d, 1 H, J=8.0Hz).

tert-butyl 2-(1 -cyclopropanecarbonyl-2,3-dihydro-1 H-indol-5-yl)acetate

- Step 2: (5-bromoindolin-1 -yl)(cyclopropyl)methanone Ex.68a (820 mg, 3.08

Ex.68b mmol), the previously synthesized tert-butyl 2-(bromozincio)acetate (5.60 mL,

6.16 mmol) and dry THF (4 mL) were placed in flask, the mixture was degassed by nitrogen bubbling for 5 min. Then Pd2(dba)3 (28 mg, 0.03 mmol) and XPhos (29 mg, 0.06 mmol) were incorporated and the reaction mixture was refluxed for 3h. The mixture was cooled to rt, EtOAc and water was added and the two- phase mixture was filtered through a pad of Celite. The phases were separated, the organic layer was dried over MgS04, filtered and the solution was concentrated to dryness. The crude material was purified by column chromatography eluting with Cyclohexane/EtOAc (90:10). The product fractions were combined and concentrated to dryness to give tert-butyl 2-(1 - cyclopropanecarbonyl-2,3-dihydro-1 H-indol-5-yl)acetate Ex.68b (900 mg, 97%) as white solid. 1 H NMR (300 MHz, DMSO-d6, d in ppm): 0.8-0.9 (m, 4H), 1.38 (s, 9H), 1 .85-2.00 (m, 1 H), 3.15 (t, 2H, J=8.0Hz), 3.46 (s, 2H), 4.27 (t, 2H, J=7.4Hz), 6.98 (d, 1 H, J=8.1 Hz), 7.09 (s, 1 H), 7.92 (d, 1 H, J=7.3Hz).

2-(1 -cyclopropanecarbonyl-2,3-dihydro-1 H-indol-5-yl)acetic acid

- Step 3: tert-butyl 2-(1 -cyclopropanecarbonyl-2,3-dihydro-1 H-indol-5-yl)acetate Ex.68b (900 mg, 2.99 mmol) was dissolved in dry CH2CI2 (5 mL) and 4 M HCI in dioxane (3.73 mL, 14.93 mmol) was added to the solution. The reaction mixture was stirred overnight at rt. Et20 was added and the precipitate formed

Ex.68 was collected by filtration and dried at 40°C under vacuum until constant weight to give 2-(1 -cyclopropanecarbonyl-2,3-dihydro-1 H-indol-5-yl)acetic acid Ex.68 (470 mg, 64%) as pale pink solid. 1 H NMR (300 MHz, DMSO-d6, d in ppm): 0.75-0.90 (m, 4H), 1 .85-2.00 (m, 1 H), 3.15 (t, 2H, J=8.6Hz), 3.48 (s, 2H), 4.27 (t, 2H, J=7.8Hz), 6.98 (d, 1 H, J=8.5Hz), 7.1 1 (s, 1 H), 7.92 (d, 1 H, J=7.1 Hz), 12.22 (br(s), 1 H).

Intermediate Ex.69 : 1 -(2,2-dioxo-1 ,3-dihvdro-4,2,1 -benzoxathiazin-6-yl)cvclopropane-1 - carboxylic acid (Figure 1 BY)

Table 1.42

Starting compounds, Reaction conditions and purification,

Cpd.

Yield, appearance, ¹ H NMR (solvent) data

1 -chloro-N-(2-methoxyphenyl)methanesulfonamide

- Step 1 : 2-methoxyaniline(6.5 g, 52.78 mmol) was dissolved in CH2CI2 (150 mL) and Et3N (1 1.00 mL, 79.17 mmol) was added. The solution was cooled to 0°C and chloromethanesulfonyl chloride (9.61 g, 58.10 mmol) was added dropwise. The reaction was then warmed to rt and stirred at this temperature overnight. Water was added to quench the reaction. The phases were separated. The aqueous layer was extracted twice with CH2CI2. The combined organic layers

Ex.69a

were dried over MgS04, filtered and the solution was concentrated under reduced pressure. The crude material was purified by silica gel column chromatography eluting with Cyclohexane/EtOAc (80:20). The desired fractions were concentrated to dryness to afford 1 -chloro-N-(2- methoxyphenyl)methanesulfonamide Ex.69a (10.25 g, 72%) as pale brown solid. 1 H NMR (300 MHz, DMSO-d6, d in ppm): 3.82 (s, 3H), 4.88 (s, 2H), 6.88- 6.95 (m, 1 H), 7.03-7.10 (m, 1 H), 7.20-7.27 (m, 2H), 9.50 (br(s), 1 H).

1 -chloro-N-(2-hydroxyphenyl)methanesulfonamide

- Step 2: 1 -chloro-N-(2-methoxyphenyl)methanesulfonamide Ex.69a (10.25 g, 37.84 mmol) was dissolved in CH2CI2 (200 mL, stabilized with amylene) and

Ex.69b

the solution was cooled to 0°C. 1 M tribromoborane (1 13.5 mL, 1 13.5 mmol) was added dropwise over approx. 50 min.

- The stirring was kept at 0°C for 1 h30 and then poured into ice under good stirring. The two phases were separated. The aqueous phase was extracted twice with CH2CI2. The combined organic layers were washed three times with water, dried over MgS04, filtered and the solution was concentrated to dryness. The crude material was purified by silica gel column chromatography eluting with Cyclohexane/EtOAc (80:20). The desired fractions were concentrated to dryness to afford 1 -chloro-N-(2-hydroxyphenyl)methanesulfonamide Ex.69b (4.10 g, 49%) as pale brown solid. 1 H NMR (300 MHz, DMSO-d6, d in ppm): 4.90 (s, 2H), 6.72-6.80 (m, 1 H), 6.87 (dd, 1 H, J=8.1 Hz, J=1 .4Hz), 7.03-7.10 (m, 1 H), 7.16 (dd, 1 H, J=7.8Hz, J=1.6Hz), 9.33 (s, 1 H), 9.91 (br(s), 1 H).

1 ,3-dihydro-4,2,1 -benzoxathiazine-2,2-dione

- Step 3: 1 -chloro-N-(2-hydroxyphenyl)methanesulfonamide Ex.69b (3.50 g, 14.35 mmol) was dissolved in MeOH (52.5 mL) and K2C03 (5.95 g, 43.05 mmol) wa added. The solution was distributed in 4 microwave vials. Each vial was heated at 100°C for 15 min under microwave irradiation. The combined reaction mixture were concentrated under reduced pressure. Water and EtOAc were added to the residue and pH was adjusted with 1 N citric acid. After

Ex.69c phases separation, the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgS04, filtered and the solution was concentrated under reduced pressure. The crude material was purified by silica gel column chromatography eluting with Cyclohexane/EtOAc (80:20). The desired fractions were concentrated to dryness to afford 1 ,3-dihydro-4,2,1 - benzoxathiazine-2,2-dione Ex.69c (1 .38 g, 52%) as pale brown solid. 1 H NMR (300 MHz, DMSO-d6, d in ppm): 5.19 (s, 2H), 6.80-6.86 (m, 1 H), 6.96-7.09 (m, 3H), 10.56 (br(s), 1 H).

6-bromo-1 ,3-dihydro-4,2,1 -benzoxathiazine-2,2-dione

- Step 4: 1 ,3-dihydro-4,2,1 -benzoxathiazine-2,2-dione Ex.69c (1 .66 g, 8.94 mmol) was dissolved in CH2CI2 (30 mL) and the solution was cooled to 0°C. Bromine (503 μί, 9.83 mmol) was added dropwise and the solution was slowly warmed to rt and stirred at this temperature overnight. The precipitate formed was collected by filtration, washed with CH2CI2 and dried under vacuum to afford a

Ex.69d first batch (1.34 g). The filtrate was concentrated under reduced pressure and the precipitate formed was collected by filtration to give a second batch of the title compound (630 mg). This two batches were joined to afford 6-bromo-1 ,3- dihydro-4,2,1 -benzoxathiazine-2,2-dione Ex.69d (1 .97 g, 83%) as pale orange solid. 1 H NMR (300 MHz, DMSO-d6, d in ppm): 5.24 (s, 2H), 6.78 (d, 1 H, J=8.6Hz), 7.22 (dd, 1 H, J=8.6Hz, J=2.2Hz), 7.32 (d, 1 H, J=2.2Hz), 10.77 (s, 1 H).

methyl 1 -(2,2-dioxo-1 ,3-dihydro-4,2,1 -benzoxathiazin-6-yl)cyclopropane-1 - carboxylate

- Step 5: 6-bromo-1 ,3-dihydro-4,2,1 -benzoxathiazine-2,2-dione Ex.69d (1 .97 g, 6.44 mmol) was dissolved in dry THF (10 mL). The solution was purged with N2 and Pd2(dba)3 (589 mg, 0.64 mmol) and XPhos (614 mg, 1.29 mmol) were added . The freshly prepared bromo[1 -(methoxycarbonyl)cyclopropyl]zinc (24.14

Ex.69e mL, 19.31 mmol) was added to the solution. The reaction mixture was heated overnight at 85°C. The solution was cooled to rt and quenched with water and extracted with EtOAc. The combined organic layers were dried over MgS04, filtered and the solution was concentrated to dryness. The crude material was adsorbed onto silica gel and purified by column chromatography eluting with Cyclohexane/EtOAc (70:30). The product fractions were combined and concentrated to dryness to afford methyl 1 -(2,2-dioxo-1 ,3-dihydro-4,2,1 - benzoxathiazin-6-yl)cyclopropane-1 -carboxylate Ex.69e (1 .17 g, 64%) as pale yellow solid. 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .1 1 -1 .20 (m, 2H), 1 .39- 1 .49 (m, 2H), 3.54 (s, 3H), 5.18 (s, 2H), 6.75 (d, 1 H, J=8.8Hz), 6.97-7.04 (m, 2H), 10.54 (br(s), 1 H).

1 -(2,2-dioxo-1 ,3-dihydro-4,2,1 -benzoxathiazin-6-yl)cyclopropane-1 - carboxylic acid

- Step 6: methyl 1 -(2,2-dioxo-1 ,3-dihydro-4,2,1 -benzoxathiazin-6-yl)cyclopropane- 1 -carboxylate Ex.69e (1 .17 g, 4.13 mmol) was dissolved in a mixture of

THF/MeOH (10 mL/ 10 ml_). 5 M NaOH (4.13 ml_, 8.26 mmol) was added and the solution was stirred overnight at rt. The solvents were removed under reduced pressure. Water was added to the residue and the solution was

Ex.69 extracted with Et20. The resulting aqueous layer was acidified with 1 N citric acid to pH = 3-4 and then extracted with EtOAc. The combined organic layers were dried over MgS04, filtered and the solution was concentrated under reduced pressure to afford 1 -(2,2-dioxo-1 ,3-dihydro-4,2,1 -benzoxathiazin-6- yl)cyclopropane-1 -carboxylic acid Ex.69 (1 .10 g, 99%) as white solide. 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .06-1 .13 (m, 2H), 1 .36-1 .44 (m, 2H), 5.15 (s, 2H), 6.73 (d, 1 H, J=8.7Hz), 6.93-7.03 (m, 2H), 10.51 (br(s), 1 H), 12.25 (br(s), 1 H).

Intermediate Ex.70 : 1 -(2,3-dioxo-2,3-dihydro-1 H-indol-5-vl)cvclopropane-1 -carboxvlic acid

(Fiqure 1 BZ)

Table 1.43

Starting compounds, Reaction conditions and purification,

Cpd.

Yield, appearance, ¹ H NMR (solvent) data

5'-bromo-1 ',2'-dihydrospiro[1 ,3-dioxolane-2,3'-indole]-2'-one

- Step 1 : 5-bromo-2,3-dihydro-1 H-indole-2,3-dione (5.00 g, 22.10 mmol) was suspended in toluene (150 mL). Ethane-1 ,2-diol (12.34 mL, 221 mmol) was added followed by p-toluenesulfonic acid monohydrate (210 mg, 1 .1 1 mmol). The mixture was heated to reflux in a Dean-Stark apparatus for 24h. The reaction mixture was cooled to rt and concentrated to dryness. The oil was taken up in EtOAc and washed with water. The organic layer was dried over

Ex.70a

MgS04, filtered and the solution was concentrated until precipitation started. Diethyl ether was added to the slurry, the mixture was stirred at rt for 1 h and the solid was collected by filtration and washed with a small amount of diethyl ether. The solid was dried under vacuum at 40°C until constant weight to afford 5'- bromo-1 ',2'-dihydrospiro[1 ,3-dioxolane-2,3'-indole]-2'-one Ex.70a (3.88 g, 65%) as pale yellow solid. 1 H NMR (300 MHz, DMSO-d6, d in ppm): 4.23-4.34 (m, 4H), 6.80 (dd, 1 H, J=7.8Hz, J=1.2Hz), 7.49-7.53 (m, 2H), 10.59 (s, 1 H).

methyl 1 -{2'-oxo-1 ',2'-dihydrospiro[1 ,3-dioxolane-2,3'-indole]-5'- yl}cyclopropane-1 -carboxylate

- Step 2: 5'-bromo-1 ',2'-dihydrospiro[1 ,3-dioxolane-2,3'-indole]-2'-one Ex.70a (500

Ex.70b mg, 1 .85 mmol) was dissolved in dry THF (5 mL). The solution was purged with

N2 and Pd2(dba)3 (127 mg, 0.14 mmol) and XPhos (132 mg, 0..28 mmol) were added. The freshly prepared bromo[1 -(methoxycarbonyl)cyclopropyl]zinc (6.94 mL, 5.55 mmol) was added slowly as a solution in THF (approx. 0.8 M, 1.85 mL, 3 eq.). The resulting deep red mixture was heated at 70°C for 1 h30. TLC (cyclohexane ethyl acetate [8:2]) showed partial conversion. Heating was continued for 16h, no change in profile was observed by TLC (still residual starting material present). The mixture was cooled to rt and was quenched with water and EtOAc. The mixture was filtered through a pad of Celite. The aqueous phase was separated from the filtrate. The remaining organic layer was dried over MgS04, filtered and the solution was concentrated to dryness. The crude material was adsorbed onto silica gel and purified by column chromatography eluting with a gradient of Cyclohexane/EtOAc from [100:0] to [85:15]. The product fractions were combined and concentrated to dryness to afford methyl 1 -{2'-oxo-1 ',2'-dihydrospiro[1 ,3-dioxolane-2,3'-indole]-5'-yl}cyclopropane-1 - carboxylate Ex.70b (190 mg, 36%) as white solid. 1 H NMR (300 MHz, DMSO- d6, d in ppm): 1 .13-1 .17 (m, 2H), 1 .44-1 .47 (m, 2H), 3.53 (s, 3H), 4.22-4.35 (m, 4H), 6.77 (dd, 1 H, J=7.8Hz, J=0.3Hz), 7.26-7.30 (m, 2H), 10.43 (s, 1 H).

methyl 1 -(2,3-dioxo-2,3-dihydro-1 H-indol-5-yl)cyclopropane-1 -carboxylate

- Step 3: methyl 1 -{2'-oxo-1 ',2'-dihydrospiro[1 ,3-dioxolane-2,3'-indole]-5'- yl}cyclopropane-1 -carboxylate Ex.70b (500 mg, 1 .73 mmol) was dissolved in methanol (10 ml_). 1 M HCI (2.0 mL) was added and the reaction mixture was heated at 70°C for 16h. LCMS showed complete conversion. The mixture was cooled to rt and water was added to quench the reaction. The solid formed was

Ex.70c

collected by filtration, washed with water and dried under vacuum at 40°C until constant weight to give methyl 1 -(2,3-dioxo-2,3-dihydro-1 H-indol-5- yl)cyclopropane-1 -carboxylate Ex.70c (345 mg, 81 %) as orange solid. 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .16-1 .20 (m, 2H), 1 .45-1 .49 (m, 2H), 3.54 (s, 3H), 6.85 (dd, 1 H, J=8.1 Hz, J=0.3Hz), 7.44 (d, 1 H, J=2.1 Hz), 7.56 (dd, 1 H, J=8.1 Hz, J=2.1 Hz), 1 1.03 (s, 1 H).

1 -(2,3-dioxo-2,3-dihydro-1 H-indol-5-yl)cyclopropane-1 -carboxylic acid

- Step 4: methyl 1 -(2,3-dioxo-2,3-dihydro-1 H-indol-5-yl)cyclopropane-1 - carboxylate Ex.70c (340 mg, 1.39 mmol) was suspended in THF/H20 [4:1] (10 mL). Lithiumhydroxide monohydrate (175 mg, 4.16 mmol) was added and the reaction mixture was stirred at rt for 24h. LCMS showed complete consumption of the starting material. The organic solvent was removed under reduced pressure and the remaining aqueous solution was acidified to pH = 2-3 by

Ex.70

addition of 1 M HCI. The mixture was stirred overnight at rt. The solid formed was collected by filtration, washed with water and dried under vacuum at 40°C until constant weight to afford 1 -(2,3-dioxo-2,3-dihydro-1 H-indol-5- yl)cyclopropane-1 -carboxylic acid (278 mg, 87%) as orange solid. 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .10-1 .14 (m, 2H), 1 .42-1 .45 (m, 2H), 6.84 (d, 1 H, J=8.1 Hz), 7.41 (d, 1 H, J=1 .8Hz), 7.54 (dd, 1 H, J=8.1 Hz, J=1 .8Hz), 1 1 .01 (s, 1 H), 12.38 (br(s), 1 H).

Intermediate Ex.71 : 1 -(1 -acetylindolin-5-yl)cvclopropanecarboxylic acid = 1 -(1 -acetyl-2,3- dihydro-1 H-indol-5-yl)cvclopropane-1 -carboxylic acid (Figure 1 CA, 1 CB)

Table 1.44

Starting compounds, Reaction conditions and purification,

Cpd.

Yield, appearance, ¹ H NMR (solvent) data

1 -(5-bromoindolin-1 -yl)ethanone

Ex.71a

- Step 1 : to a solution of 5-bromoindoline (600 mg, 3.03 mmol) dissolved in dry CH2CI2 (2 mL) was added sodium hydrogencarbonate (1.27 g, 15.15 mmol). After few min of stirring, acetyl chloride (248 μί, 3.64 mmol) was slowly added at rt to the solution. The reaction mixture was stirred at rt for 1 h. The solution was poured onto brine. The aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgS04, filtered and the solution was dried under reduced pressure to afford 1 -(5-bromoindolin-1 -yl)ethanone Ex.71 a (551 mg, 76%) as white solid. The product was pure enough and used as such in the next synthetic step.l H NMR (300 MHz, DMSO-d6, d in ppm): 2.13 (s, 3H), 3.13 (t, 2H, J=8.5Hz), 4.09 (t, 2H, J=8.8Hz), 7.30 (dd, 1 H, J=8.6Hz, J=2.1 Hz), 7.40 (d, 1 H, J=0.8Hz), 7.95 (d, 1 H, J=8.6Hz).

methyl 1 -(1 -acetylindolin-5-yl)cyclopropanecarboxylate

- Step 2: 1 -(5-bromoindolin-1 -yl)ethanone Ex.71 a (550 mg, 2.29 mmol) was dissolved in dry THF (4 mL). The solution was purged with N2 and Pd2(dba)3 (21 mg, 0.02 mmol) and XPhos (22 mg, 0.04 mmol) were added to the solution. The freshly prepared bromo[1 -(methoxycarbonyl)cyclopropyl]zinc (4.17 mL, 4.58 mmol) was added to the solution. The resulting mixture was heated at reflux for 5h. The reaction mixture was cooled to rt and quenched with sat. NH4CI and extracted with EtOAc. The combined organic layers were dried over MgS04,

Ex.71 b filtered and the solution was concentrated to dryness. The crude material was purified by silica gel column chromatography eluting with Cyclohexane/EtOAc from [90:10]. The product fractions were combined and concentrated to dryness and the residue was triturated in Et20. The solid was collected by filtration to afford methyl 1 -(1 -acetylindolin-5-yl)cyclopropanecarboxylate Ex.71 b (524 mg, 88%) as pale brown solid. 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .13 (q, 2H, J=4.2Hz), 1 .44 (q, 2H, J=3.0Hz), 2.13 (s, 3H), 3.10 (t, 2H, J=8.4Hz), 3.52 (s, 3H), 4.07 (t, 2H, J=8.7Hz), 7.08 (d, 1 H, J=8.3Hz), 7.16 (s, 1 H), 7.92 (d, 1 H, J=8.3Hz).

1 -(1 -acetylindolin-5-yl)cyclopropanecarboxylic acid = 1 -(1 -acetyl -2,3- dihydro-1 H-indol-5-yl)cyclopropane-1 -carboxylic acid

- Step 3: to a solution of methyl 1 -(1 -acetylindolin-5-yl)cyclopropanecarboxylate Ex.71 b (475 mg, 1.83 mmol) dissolved in MeOH/THF (3 mL/ 2 mL) was added 5 M NaOH (1.83 mL, 9.16 mmol). The solution was stirred at rt for 8h. The solution was poured onto brine and the aqueous solution was extracted with

Ex.71 Et20 twice. The pH of the aqueous layer was then adjusted to pH = 2-3 with 1 M citric acid. The solid formed was collected by filtration and dried until constant weight to afford 1 -(1 -acetylindolin-5-yl)cyclopropanecarboxylic acid Ex.71 (308 mg, 69%) as pale pink solid. 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .07 (q, 2H, J=4.8Hz), 1 .40 (q, 2H, J=3.8Hz), 2.13 (s, 3H), 3.10 (t, 2H, J=9.4Hz), 4.06 (t, 2H, J=8.8Hz), 7.06 (d, 1 H, J=7.6Hz), 7.15 (s, 1 H), 7.91 (d, 1 H, J=8.4Hz), 12.20 (br(s), 1 H).

Intermediate Ex.72 : 1 -(2-acetylisoindolin-5-yl)cvclopropanecarboxylic acid = 1 -(2-acetyl- 2, 3-dihydro-1 H-isoindol-5-yl)cvclopropane-1 -carboxylic acid (Figure 1 CA, 1 CB)

Table 1.45

Starting compounds, Reaction conditions and purification,

Cpd.

Yield, appearance, ¹ H NMR (solvent) data

Ex.72a 1 -(6-bromoindolin-1 -yl)ethanone - Step 1 : to a solution of 6-bromoindoline (600 mg, 3.03 mmol) dissolved in dry CH2CI2 (2 ml.) was added sodium hydrogencarbonate (1.27 g, 15.15 mmol). After few min of stirring, acetyl chloride (248 μΙ_, 3.64 mmol) was slowly added at rt to the solution. The reaction mixture was stirred at rt for 1 h. The solution was poured onto brine. The aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgS04, filtered and the solution was dried under reduced pressure to afford 1 -(6-bromoindolin-1 -yl)ethanone Ex.72a (400 mg, 55%) as white solid. The product was pure enough and used as such in the next synthetic step. 1 H NMR (300 MHz, DMSO-d6, d in ppm): 2.03 (s, 3H), 4.57 (d, 2H, J=13.6Hz), 4.80 (d, 2H, J=1 1.9Hz), 7.25-7.35 (m, 1 H), 7.47 (dd, 1 H, J=8.0Hz, J=1 .9Hz), 7.57 (d, 1 H, J=7.7Hz).

methyl 1 -(1 -acetylindolin-6-yl)cyclopropanecarboxylate

- Step 2: 1 -(6-bromoindolin-1 -yl)ethanone Ex.72a (400 mg, 1.67 mmol) was dissolved in dry THF (4 mL). The solution was purged with N2 and Pd2(dba)3 (15 mg, 0.02 mmol) and XPhos (16 mg, 0.03 mmol) were added to the solution. The freshly prepared bromo[1 -(methoxycarbonyl)cyclopropyl]zinc (3.03 mL, 3.33 mmol) was added to the solution. The resulting mixture was heated at reflux for 5h. The reaction mixture was cooled to rt and quenched with sat. NH4CI and

Ex.72b extracted with EtOAc. The combined organic layers were dried over MgS04, filtered and the solution was concentrated to dryness. The crude material was purified by silica gel column chromatography eluting with Cyclohexane/EtOAc from [70:30]. The product fractions were combined and concentrated to dryness to afford methyl 1 -(1 -acetylindolin-6-yl)cyclopropanecarboxylate Ex.72b (150 mg, 35%) as white solid. 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .15-1 .20 (m, 2H), 1 .45-1 .50 (m, 2H), 2.04 (s, 3H), 3.53 (s, 3H), 4.57 (s, 2H), 4.79 (s, 2H), 7.25-7.27 (m, 2H), 7.30 (d, 1 H, J=6.4Hz).

1 -(2-acetylisoindolin-5-yl)cyclopropanecarboxylic acid = 1 -(2 -acetyl -2,3- dihydro-1 H-isoindol-5-yl)cyclopropane-1 -carboxylic acid

- Step 3: to a solution of methyl 1 -(1 -acetylindolin-6-yl)cyclopropanecarboxylate Ex.72b (150 mg, 0.58 mmol) dissolved in MeOH/THF (1.5 mL/ 0.5 mL) was added 5 M NaOH (578 μί, 2.89 mmol). The solution was stirred at rt for 8h. The solution was poured onto brine and the aqueous solution was extracted with

Ex.72 Et20 twice. The pH of the aqueous layer was then adjusted to pH = 3-4 with 1 M citric acid and extracted with EtOAc. The combined organic layers were dried over MgS04, filtered and the solution was concentrated under reduced pressure to afford 1 -(1 -acetylindolin-6-yl)cyclopropanecarboxylic acid Ex.72 (138 mg, 97%) as yellow oil. 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .1 1 (q, 2H, J=4.2Hz), 1 .40 (m, 2H), 2.04 (s, 3H), 4.57 (s, 2H), 4.78 (s, 2H), 7.23-7.25 (m, 2H), 7.28 (d, 1 H, J=6.8Hz), 12.25 (br(s), 1 H).

Intermediate Ex.75 : 1 -(1 -methyl-2-oxo-2,3-dihvdro-1 H-indol-5-yl)cvclopropane-1 -carboxylic acid (Figure 1 CE)

Table 1 .46

Starting compounds, Reaction conditions and purification,

Cpd.

Yield, appearance, ¹ H NMR (solvent) data

Ex.75a methyl 1 -(1 -methyl-2-oxo-2,3-dihydro-1 H-indol-5-yl)cyclopropane-1 - carboxylate

- Step 1 : 5-bromo-1 -methylindolin-2-one (500 mg, 2.21 mmol) was dissolved in dry THF (5 mL). The solution was purged with N2 and Pd2(dba)3 (127 mg, 0.14 mmol) and XPhos (132 mg, 0.28 mmol) were added to the solution. The freshly prepared bromo[1 -(methoxycarbonyl)cyclopropyl]zinc (6.94 mL, 5.55 mmol) was added slowly as a solution in THF (approx. 0.8 M). The resulting mixture was heated at 70°C for 1 h30. Partial conversion was obersved by LCMS. The mixture was heated at 70°C overnight, no change in profile. Further Pd2(dba)3 (127 mg, 0.14 mmol) and XPhos (132 mg, 0.28 mmol) were added followed by bromo[1 -(methoxycarbonyl)cyclopropyl]zinc (6.94 mL, 5.55 mmol). Heating to 70°C was continued until almost complete conversion was observed (1 h30).The mixture was cooled to rt and was quenched with water and EtOAc. The mixture was filtered through a pad of Celite. After phases separation, the remaining organic layer was dried over MgS04, filtered and the solution was concentrated to dryness. The crude material was purified by column chromatography eluting with a gradient of Cyclohexane/EtOAc from [100:0] to [65:35]. The product fractions were combined and concentrated to dryness to afford methyl 1 -(1 - methyl-2-oxo-2,3-dihydro-1 H-indol-5-yl)cyclopropane-1 -carboxylate Ex.75a (99 mg, 18%) as pale orange solid. 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .12- 1 .16 (m, 2H), 1 .44-1 .48 (m, 2H), 3.09 (s, 3H), 3.51 (s, 2H), 3.52 (s, 3H), 6.88 (d, 1 H, J=8.7Hz), 7.21 (d, 1 H, J=1.8Hz), 7.23 (d, 1 H, J=1 .8Hz).

1 -(1 -methyl-2-oxo-2,3-dihydro-1 H-indol-5-yl)cyclopropane-1 -carboxylic acid

- Step 2: methyl 1 -(1 -methyl-2-oxo-2,3-dihydro-1 H-indol-5-yl)cyclopropane-1 - carboxylate Ex.75a (40 mg, 0.16 mmol) was taken up in concentrated H2S04 (1 mL) and the mixture was stirred overnight at 50°C. The solution was cooled to rt and poured onto ice and water. The pH was adjusted up to pH = 4 - 5 with 5 M NaOH solution. The aqueous layer was extracted with EtOAc. The combined

Ex.75

organic layers were dried over MgS04, filtered and the solution was concentrated under reduced pressure to afford 1 -(1 -methyl-2-oxo-2,3-dihydro- 1 H-indol-5-yl)cyclopropane-1 -carboxylic acid Ex.75 (35 mg, 93%) as pale brown solid. 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .05-1 .12 (m, 2H), 1 .39-1 .46 (m, 2H), 3.09 (s, 3H), 3.51 (s, 2H), 6.86 (d, 1 H, J=8.5Hz), 7.15-7.26 (m, 2H), 12.27 (br(s), 1 H).

Intermediate Ex.76 : 1 -(1 -ethyl-2,2-dioxo-1 ,3-dihvdro-2,1 -benzothiazol-5-yl)cvclopropane-1 - carboxylic acid (Figure 1 CF)

Table 1 .47

Starting compounds, Reaction conditions and purification,

Cpd.

Yield, appearance, ¹ H NMR (solvent) data

methyl 1 -(1 -ethyl-2,2-dioxo-1 ,3-dihydro-2,1 -benzothiazol-5-yl)cyclopropane-

1 -carboxylate

- Step 1 : to a previously synthesized methyl 1 -(2,2-dioxo-1 ,3-dihydro-2,1 - benzothiazol-5-yl)cyclopropane-1 -carboxylate (120 mg, 0.45 mmol) dissolved in

Ex.76a dry DMF (I O mL) were added K2C03 (186 mg, 1.35 mmol) followed by

iodoethane (54 μί, 0.67 mmol). After 1 h at rt, TLC showed not total consumption of the starting material. Additional iodoethane (54 μί, 0.67 mmol) and K2C03 (186 mg, 1 .35 mmol) were added to the reaction mixture and the solution was stirred for 5h. The reaction mixture was quenched with brine. The aqueous solution was extracted with EtOAc, dried over MgS04, filtered and the solution was concentrated under reduced pressure to afford methyl 1 -(1 -ethyl- 2,2-dioxo-1 ,3-dihydro-2,1 -benzothiazol-5-yl)cyclopropane-1 -carboxylate Ex.76 (70 mg, 53%). 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1.15 (q, 2H, J=4.2Hz), 1 .25 (t, 3H, J=7.1 Hz), 1.47 (q, 2H, J=3.7Hz), 3.53 (s, 3H), 3.61 (q, 2H, J=7.1 Hz), 4.59 (s, 2H), 6.90 (d, 1 H, J=8.8Hz), 7.25-7.35 (m, 2H).

1 -(1 -ethyl-2,2-dioxo-1 ,3-dihydro-2,1 -benzothiazol-5-yl)cyclopropane-1 - carboxylic acid

- Step 2: to a solution of methyl 1 -(1 -ethyl-2,2-dioxo-1 ,3-dihydro-2,1 -benzothiazol- 5-yl)cyclopropane-1 -carboxylate Ex.76a (70 mg, 0.24 mmol) dissolved in MeOH/THF (800 L/ 200 L) was added 5 M NaOH (237 μΙ_, 1 .19 mmol). The solution was stirred overnight at rt. The solution was poured onto sat. NH4CI and the aqueous solution was extracted with EtOAc twice. The pH of the

Ex.76

aqueous layer was then adjusted to pH = 3-4 with 1 M citric acid and extracted with EtOAc. The combined organic layers were dried over MgS04, filtered and the solution was concentrated under reduced pressure to afford 1 -(1 -ethyl-2,2- dioxo-1 ,3-dihydro-2,1 -benzothiazol-5-yl)cyclopropane-1 -carboxylic acid Ex.76 (54 mg, 81 %) as pale brown solid. 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .10 (q, 2H, J=3.0Hz), 1.25 (t, 3H, J=7.1 Hz), 1.43 (q, 2H, J=3.6Hz), 3.60 (q, 2H, J=7.1 Hz), 4.58 (s, 2H), 6.87 (d, 1 H, J=5.9Hz), 7.25-7.35 (m, 2H), 12.22 (s, 1 H).

Intermediate Ex.82 : 1 -(1 -oxo-2,3-dihydro-1 H-inden-5-vl)cvclopropane-1 -carboxvlic acid

(Fiqure 1 CL)

Table 1 .48

Starting compounds, Reaction conditions and purification,

Cpd.

Yield, appearance, ¹ H NMR (solvent) data

methyl 1 -(1 -oxo-2,3-dihydro-1 H-inden-5-yl)cyclopropane-1 -carboxylate

- Step 1 : 5-bromo-1 -indanone (200 mg, 9.48 mmol) was dissolved in dry THF (5 ml_). The solution was purged with N2 and Pd2(dba)3 (87 mg, 0.09 mmol) and XPhos (90 mg, 0.19 mmol) were added to the solution. The freshly prepared bromo[1 -(methoxycarbonyl)cyclopropyl]zinc (3.55 ml_, 2.84 mmol) was added slowly as a solution in THF (approx. 0.8 M). The resulting mixture was heated at 70°C for 1 h30. TLC showed complete conversion. After cooling to rt, the reaction mixture was quenched with water and EtOAc and filtered through a pad of Celite. After phases separation, the remaining organic layer was dried over

Ex.82a

MgS04, filtered and the solution was concentrated to dryness. The crude material was adsorbed onto silica gel and purified by column chromatography eluting with a gradient of Cyclohexane/EtOAc from [100:0] to [75:25]. The product fractions were combined and concentrated to dryness. The solid was triturated with a small amount of Et20, filtered and dried until constant weight to afford methyl 1 -(1 -oxo-2,3-dihydro-1 H-inden-5-yl)cyclopropane-1 -carboxylate Ex.82a (129 mg, 59%) as pale yellow solid. 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .24-1 .28 (m, 2H), 1 .51 -1 .55 (m, 2H), 2.60-2.64 (m, 2H), 3.05-3.09 (m, 2H), 3.55 (s, 3H), 7.37-7.40 (m, 1 H), 7.53-7.58 (m, 2H).

1 -(1 -oxo-2,3-dihydro-1 H-inden-5-yl)cyclopropane-1 -carboxylic acid

Ex.82 - Step 2: methyl 1 -(1 -oxo-2,3-dihydro-1 H-inden-5-yl)cyclopropane-1 -carboxylate

Ex.82a (100 mg, 0.43 mmol) was taken up in a mixture of THF and water [4:1] (5 ml_). Lithium hydroxide monohydrate (36 mg, 0.87 mmol) was added and the mixture was stirred at rt for 2h. LCMS showed complete conversion. The organic solvent was removed in vacuo and the remaining aqueous mixture was acidified to pH = 2-3 by addition of 3 M HCI. The solid formed was collected by filtration and washed with water. The product contained some impurities and was adsorbed onto silica gel and purified by column chromatography eluting with a gradient of CH2CI2/MeOH from [100:0] to [95:5]. The product fractions were combined and concentrated to dryness to afford 1-(1 -oxo-2,3-dihydro-1 H-inden- 5-yl)cyclopropane-1 -carboxylic acid Ex.82 (68 mg, 72%) as an off-white solid. 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .18-1 .22 (m, 2H), 1 .48-1.51 (m, 2H), 2.59-2.63 (m, 2H), 3.05-3.09 (m, 2H), 7.37 (dd, 1 H, J=1 .5Hz, J=7.8Hz), 7.51 - 7.56 (m, 2H), 12.45 (s, 1 H)

Intermediate Ex.84 : 1 -{2-oxo-1 H,2H,3H-pyridor2,3-biri ,41oxazin-6-yl)cvclopropane-1 - carboxylic acid (Figure 1 CN)

Table 1 .49

Starting compounds, Reaction conditions and purification,

Cpd.

Yield, appearance, ¹ H NMR (solvent) data

methyl 1 -{2-oxo-1 H,2H,3H-pyrido[2,3-b][1 ,4]oxazin-6-yl}cyclopropane-1 - carboxylate

- Step 1 : 6-bromo-1 h-pyrido[2,3-b][1 ,4]oxazin-2(3h)-one (970 mg, 4.24 mmol) was dissolved in dry THF (12 mL). The solution was purged with N2 and Pd2(dba)3 (388 mg, 0.42 mmol) and XPhos (404 mg, 0.85 mmol) were added to the solution. The freshly prepared bromo[1 -(methoxycarbonyl)cyclopropyl]zinc (3.1 1 g, 12.71 mmol) was added slowly as a solution in THF (approx. 0.8 M). The resulting mixture was heated at 75°C for 16h. TLC showed complete conversion. After cooling to rt, the reaction mixture was quenched with water and EtOAc and filtered through a pad of Celite. After phases separation, the

Ex.84a

remaining organic layer was dried over MgS04, filtered and the solution was concentrated to dryness. The crude material was adsorbed onto silica gel and purified by column chromatography eluting with a gradient of Hexanes/EtOAc from [50:50] to [30:70]. The product fractions were combined and concentrated to dryness. The solid was triturated with a small amount of Et20, filtered and dried until constant weight to afford methyl 1 -{2-oxo-1 H,2H,3H-pyrido[2,3- b][1 ,4]oxazin-6-yl}cyclopropane-1 -carboxylate Ex.84a (500 mg, 34%) as yellowish solid. 1 H NMR (400 MHz, DMSO-d6, d in ppm): 1 .28 (q, 2H, J=4.0Hz), 1 .44 (q, 2H, J=3.9Hz), 3.58 (s, 3H), 4.75 (s, 2H), 7.10-7.19 (m, 2H), 10.81 (s, 1 H).

1 -{2-OXO-1 H,2H,3H-pyrido[2,3-b][1 ,4]oxazin-6-yl}cyclopropane-1 -carboxylic acid

- Step 2: methyl 1 -{2-oxo-1 H,2H,3H-pyrido[2,3-b][1 ,4]oxazin-6-yl}cyclopropane-1 - carboxylate Ex.84a (500 mg, 2.01 mmol) was taken up in a mixture of

Ex.84 THF/H20 (15 mL/ 7.5 mL). Lithium hydroxide monohydrate (254 mg, 6.04

mmol) was added and the mixture was stirred at rt for 7 days. Water and EtOAc were added to quench the reaction. The mixture was acidified to pH = 2-3 by addition of 3 M HCI. After phases separation, the organic layer was dried over MgS04, filtered and the solution was concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel eluting with a gradient of CH2CI2/MeOH. The product fractions were combined and concentrated to dryness to afford 1 -{2-oxo-1 H,2H,3H-pyrido[2,3-b][1 ,4]oxazin-6- yl}cyclopropane-1 -carboxylic acid Ex.84 (132 mg, 28%) as pale brown solid. 1 H NMR (400 MHz, DMSO-d6, d in ppm): 1 .24 (q, 2H, J=3.7Hz), 1 .41 (q, 2H, J=3.8Hz), 4.74 (s, 2H), 7.16 (d, 2H, J=1 .7Hz), 10.79 (s, 1 H), 12.42 (s, 1 H).

Intermediate Ex.85 : 1 -(3,3-dimethyl-2-oxo-2,3-dihvdro-1 H-indol-5-yl)cvclopropane-1 - carboxylic acid (Figure 1 CO)

Table 1 .50

Starting compounds, Reaction conditions and purification,

Cpd.

Yield, appearance, ¹ H NMR (solvent) data

5-bromo-3,3-dimethyl-2,3-dihydro-1 H-indol-2-one

- Step 1 : 3,3-dimethyl-2,3-dihydro-1 H-indol-2-one (500 mg, 3.10 mmol) was dissolved in dry CH2CI2 (25 ml_). Tetrabutylammonium tribromide (3.74 g, 7.75 mmol) was added portion wise to the solution. The reaction mixture was stirred at rt overnight. Water was added to quench the reaction. After phases separation, the organic layer was dried over MgS04, filtered and the solution

Ex.85a was concentrated under reduced pressure. The crude material was purified by silica gel column chromatography eluting with Cyclohexane/EtOAc (70:30). Product fractions were collected and evaporated to dryness to afford 5-bromo- 3,3-dimethyl-2,3-dihydro-1 H-indol-2-one Ex.85a (730 mg, 3.04 mmol) as yellow solid. 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .24 (s, 6H), 6.79 (d, 1 H, J=8.2Hz), 7.32 (dd, 1 H, J=8.0Hz, J=2.1 Hz), 7.52 (d, 1 H, J=2.1 Hz), 10.44 (s, 1 H).

methyl 1 -(3,3-dimethyl-2-oxo-2,3-dihydro-1 H-indol-5-yl)cyclopropane-1 - carboxylate

- Step 2: 5-bromo-3,3-dimethyl-2,3-dihydro-1 H-indol-2-one Ex.85a (300 mg, 1.25 mmol) was dissolved in dry THF (5 ml_). The solution was purged with N2 and Pd2(dba)3 (1 14 mg, 0.13 mmol) and XPhos (1 19 mg, 0.25 mmol) were added to the solution. The freshly prepared bromo[1 -(methoxycarbonyl)cyclopropyl]zinc (4.69 ml_, 3.75 mmol) was added slowly as a solution in THF (approx. 0.8 M). The resulting mixture was heated at 85°C for 1 h. TLC showed not complete conversion. Additional Pd2(dba)3 (228 mg, 0.26 mmol) and XPhos (238 mg, 0.50 mmol) were added to the solution followed by bromo[1 - (methoxycarbonyl)cyclopropyl]zinc (9.37 ml_, 7.50 mmol). The reaction mixture

Ex.85b was stirred at 80°C for 18h. After cooling to rt, the reaction was quenched with water and EtOAc and filtered through a pad of Celite. After phases separation, the remaining organic layer was dried over MgS04, filtered and the solution was concentrated to dryness. The crude material was adsorbed onto silica gel and purified by column chromatography eluting with Cyclohexane/EtOAc (70:30). The product fractions were combined and concentrated to dryness. The solid was triturated with Et20, filtered and dried until constant weight to afford methyl 1 -(3,3-dimethyl-2-oxo-2,3-dihydro-1 H-indol-5-yl)cyclopropane-1 -carboxylate Ex.85b (178 mg, 52%) as pale brown solid. 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .1 1 -1 .18 (m, 2H), 1 .22 (s, 6H), 1 .42-1 .48 (m, 2H), 3.53 (s, 3H), 6.75 (d, 1 H, J=7.9Hz), 7.10 (dd, 1 H, J=8.0Hz, J=1 .8Hz), 7.23 (d, 1 H, J=1.8Hz), 10.29 (br(s), 1 H).

Ex.85 1 -(3,3-dimethyl-2-oxo-2,3-dihydro-1 H-indol-5-yl)cyclopropane-1 -carboxylic acid

- Step 3: methyl 1 -(3,3-dimethyl-2-oxo-2,3-dihydro-1 H-indol-5-yl)cyclopropane-1 - carboxylate Ex.85b (170 mg, 0.66 mmol) was taken up in a mixture of THF and water [4: 1 ] (5 ml_). Lithium hydroxide monohydrate (55 mg, 1 .31 mmol) was added and the mixture was stirred at rt overnight. TLC showed not total consumption of the starting material. Additional lithium hydroxide monohydrate (55 mg, 1 .31 mmol) was added and the solution was heated at 45°C for 2h. The organic solvent was removed in vacuo. Water was added to the residue and the aqueous layer was extracted with Et20. After phases separation, the remaining aqueous mixture was acidified to pH = 2-3 by addition of 1 M citric acid and extracted with EtOAc. The combined organic layers were dried over MgS04, filtered and the solution was concentrated under reduced pressure to afford 1 - (3,3-dimethyl-2-oxo-2,3-dihydro-1 H-indol-5-yl)cyclopropane-1 -carboxylic acid Ex.85 (147 mg, 91 %) as white solid. 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .05-1 .12 (m, 2H), 1 .22 (m, 6H), 1 .37-1 .45 (m, 2H), 6.74 (d, 1 H, J=8.0Hz), 7.09 (dd, 1 H, J=8.0Hz, J=1 .8Hz), 7.22 (d, 1 H, J=1 .7Hz), 10.26 (s, 1 H), 12.18 (br(s), 1 H).

Intermediate Ex.86 : 2-(2,2-dioxo-1 ,3-dihvdro-4,2, 1 -benzoxathiazin-6-yl)acetic acid (Figure 1 CP)

Table 1 .51

Starting compounds, Reaction conditions and purification,

Cpd.

Yield, appearance, ¹ H NMR (solvent) data

tert-butyl 2-(2,2-dioxo-1 ,3-dihydro-4,2,1 -benzoxathiazin-6-yl)acetate

- Step 1 : the previously synthesized 6-bromo-1 ,3-dihydro-4,2, 1 -benzoxathiazine- 2,2-dione (300 mg, 1 .14 mmol) and tert-butyl 2-(bromozincio)acetate (3.10 ml_, 3.41 mmol) were dissolved in dry THF (7 mL) and placed in flask, the mixture was degassed by N2 bubbling for 5 min. Then Pd2(dba)3 (104 mg, 0.1 1 mmol) and XPhos (108 mg, 0.23 mmol) were incorporated and the reaction mixture was stirred at 85°C for 2h. The mixture was cooled to rt and solvent was

Ex.86a

removed under reduced pressure. The crude material was purified by column chromatography eluting with Cyclohexane/EtOAc (60:40). The product fractions were combined and concentrated to dryness to afford tert-butyl 2-(2,2-dioxo-1 ,3- dihydro-4,2, 1 -benzoxathiazin-6-yl)acetate Ex.86a (251 mg, 74%) as pale brown solid. 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .39 (s, 9H), 3.49 (s, 2H), 5.18 (s, 2H), 6.77 (d, 1 H, J=8.1 Hz), 6.92 (dd, 1 H, J=8.2Hz, J=1 .9Hz), 6.95 (d, 1 H, J=1 .6Hz), 10.49 (s, 1 H).

2-(2,2-dioxo-1 ,3-dihydro-4,2,1 -benzoxathiazin-6-yl)acetic acid

- Step 2: tert-butyl 2-(2,2-dioxo-1 ,3-dihydro-4,2, 1 -benzoxathiazin-6-yl)acetate Ex.86a (250 mg, 0.84 mmol) was dissolved in MeOH (5 mL). 5 M NaOH (835 L, 4.18 mmol) was added and the reaction mixture was heated at 1 10°C for 30

Ex.86 min under microwave irradiation. The solvent was removed under reduced

pressure. Water was added to the residue and the aqueous layer was extracted with Et20. After phases separation, the remaining aqueous layer was acidified up to pH = 2-3 with 1 M citric acid and extracted with EtOAc. The combined organic layers were dried over MgS04, filtered and the solution was concentrated to dryness. The crude material was triturated with Et20. The solid formed was collected by filtration and dried under vacuum to afford 2-(2,2-dioxo- 1,3-dihydro-4,2,1-benzoxathiazin-6-yl)acetic acid Ex.86 (120 mg, 59%) as pale brown solid.1H NMR (300 MHz, DMSO-d6, d in ppm): 3.50 (s, 2H), 5.17 (s, 2H), 6.76 (d, 1H, J=8.1Hz), 6.92 (dd, 1H, J=8.1Hz, J=1.9Hz), 6.96 (d, 1H, J=1.7Hz), 10.48 (br(s), 1H), 12.29 (br(s), 1H).

Intermediate Ex.88 : 1-(2H-1,3-benzodioxol-5-yl)cvclopropane-1 -carboxylic acid (Figure 1CR)

Table 1.52

Intermediate Ex.91 : 1-[1-(oxan-4-ylmethyl)-2,2-dioxo-1,3-dihvdro-2,1-benzothiazo l-5- yllcyclopropane-1 -carboxylic acid (Figure 1CU)

Table 1.53 1 -[1 -(oxan-4-ylmethyl)-2,2-dioxo-1 ,3-dihydro-2,1 -benzothiazol-5- yl]cyclopropane-1 -carboxylate

- Step 1 : to a previously synthesized methyl 1 -(2,2-dioxo-1 ,3-dihydro-2,1 - benzothiazol-5-yl)cyclopropane-1 -carboxylate (100 mg, 0.37 mmol) dissolved in dry DMF (2 mL) were added K2C03 (155 mg, 1.12 mmol) followed by 4- bromomethyltetrahydropyran (63 μΙ_, 0.49 mmol). After 4h at rt, TLC showed not total consumption of the starting material. The reaction was heated at 60°C for 5 min under microwave irradiation. TLC showed almost total consumption of the starting material. The reaction was heated for additional 5 min at 100°C under microwave irradiation. TLC showed complete reaction. The mixture was diluted

Ex.91a

with water. The aqueous solution was extracted with EtOAc, dried over MgS04, filtered and the solution was concentrated under reduced pressure. The crude material was purified by silica gel column chromatography eluting with Cyclohexane/EtOAc (70:30). The desired fractions were collected and evaporated to dryness to afford methyl 1 -[1 -(oxan-4-ylmethyl)-2,2-dioxo-1 ,3- dihydro-2,1 -benzothiazol-5-yl]cyclopropane-1 -carboxylate Ex.91 a (80 mg, 59%) as colorless oil. 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .15 (q, 2H, J=4.1 Hz), 1 .20-1 .35 (m, 2H), 1 .47 (q, 2H, J=3.0Hz), 1.67 (d, 2H, J=10.6Hz), 1 .90-2.00 (m, 1 H), 3.20-3.25 (m, 2H), 3.35-3.45 (m, 2H), 3.53 (s, 3H), 3.84 (dd, 2H, J=1 1 .7Hz, J=2.9Hz), 4.62 (s, 2H), 6.91 (d, 1 H, J=8.8Hz), 7.25-7.35 (m, 2H).

1 -[1 -(oxan-4-ylmethyl)-2,2-dioxo-1 ,3-dihydro-2,1 -benzothiazol-5- yl]cyclopropane-1 -carboxylic acid

- Step 2: to a solution of methyl 1 -[1 -(oxan-4-ylmethyl)-2,2-dioxo-1 ,3-dihydro-2,1 - benzothiazol-5-yl]cyclopropane-1 -carboxylate Ex.91a (78 mg, 0.21 mmol) dissolved in MeOH/THF (800 μί/ 200μί) was added 5 M NaOH (213 μί, 1.07 mmol). The solution was stirred overnight at rt. The solution was poured onto sat. NH4CI and the aqueous solution was extracted with EtOAc twice. The pH of the aqueous layer was then adjusted to pH = 3-4 with 1 M citric acid and

Ex.91

extracted with EtOAc. The combined organic layers were dried over MgS04, filtered and the solution was concentrated under reduced pressure to afford 1 - [1 -(oxan-4-ylmethyl)-2,2-dioxo-1 ,3-dihydro-2,1 -benzothiazol-5-yl]cyclopropane- 1 -carboxylic acid Ex.91 (65 mg, 87%) as yellow oil. 1 H NMR (300 MHz, DMSO- d6, d in ppm): 1.09 (q, 2H, J=3.0Hz), 1 .20-1 .35 (m, 2H), 1 .42 (q, 2H, J=2.9Hz), 1 .67 (d, 2H, J=10.9Hz), 1 .85-1 .95 (m, 1 H), 3.20-3.25 (m, 2H), 3.35-3.45 (m, 2H), 3.84 (dd, 2H, J=1 1.1 Hz, J=2.6Hz), 4.61 (s, 2H), 6.91 (d, 1 H, J=8.9Hz), 7.25-7.30 (m, 2H), 12.29 (br(s), 1 H).

Intermediate Ex.92 : 1 -(7-fluoro-2-oxo-2,3-dihvdro-1 H-indol-5-yl)cvclopropane-1 -carboxylic acid (Figure 1 CV)

Table 1 .54

Starting compounds, Reaction conditions and purification,

Cpd.

Yield, appearance, ¹ H NMR (solvent) data

methyl 1 -(7-fluoro-2-oxo-2,3-dihydro-1 H-indol-5-yl)cyclopropane-1 - carboxylate

Ex.92a - Step 1 : 5-bromo-7-fluorooxindole (250 mg, 1 .09 mmol) was dissolved in dry THF

(10 mL). The solution was purged with N2 and Pd2(dba)3 (100 mg, 0.1 1 mmol) and XPhos (104 mg, 0.22 mmol) were added to the solution. The freshly prepared bromo[1 -(methoxycarbonyl)cyclopropyl]zinc (4.08 mL, 3.26 mmol) was added slowly as a solution in THF (approx. 0.8 M). The resulting mixture was heated at 85°C for 1 h. After cooling to rt, the solvent was removed under reduced pressure. The crude material was purified by column chromatography on silica gel eluting with Cyclohexane/EtOAc (60:40). The product fractions were combined and concentrated to dryness to afford methyl 1 -(7-fluoro-2-oxo-2,3- dihydro-1 H-indol-5-yl)cyclopropane-1 -carboxylate Ex.92a (1 12 mg, 41 %) as pale yellow solid. 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .14-1 .20 (m, 2H), 1 .40-1 .48 (m, 2H), 3.48-3.58 (m, 5H), 7.10-7.1 1 (m, 2H), 10.81 (br(s), 1 H).

1 -(7-fluoro-2-oxo-2,3-dihydro-1 H-indol-5-yl)cyclopropane-1 -carboxylic acid

- Step 2: methyl 1 -(7-fluoro-2-oxo-2,3-dihydro-1 H-indol-5-yl)cyclopropane-1 - carboxylate Ex.92a (100 mg, 0.40 mmol) was dissolced in concentrated sulfuric acid (1 .5 ml_). The solution was heated at 80°C for 15 min under microwave irradiations. After cooling to rt, the solution was poured onto a mixture of ice and water. The aqueous layer was extracted with EtOAc. The combined organic

Ex.92

layers were washed several times with water, dried over MgS04, filtered and the solution was concentrated under reduced pressure to afford 1 -(7-fluoro-2- oxo-2,3-dihydro-1 H-indol-5-yl)cyclopropane-1 -carboxylic acid Ex.92 (75 mg, 79%) as pale brown solid. 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .06-1 .14 (m, 2H), 1 .37-1 .44 (m, 2H), 3.53 (s, 2H), 6.98-7.07 (m, 2H), 10.79 (s, 1 H), 12.25 (br(s), 1 H).

Intermediate Ex.93 : 1 -(3,3-difluoro-2-oxo-2,3-dihvdro-1 H-indol-5-yl)cvclopropane-1 - carboxylic acid (Figure 1 CW)

Table 1 .55

Starting compounds, Reaction conditions and purification,

Cpd.

Yield, appearance, ¹ H NMR (solvent) data

5-bromo-3,3-difluoro-2,3-dihydro-1 H-indol-2-one

- Step 1 : 5-bromoisatin (500 mg, 2.21 mmol) was dissolved in CH2CI2 (15 ml_). (Diethylamino)sulfur trifluoride (731 μΙ_, 5.53 mL) was added and the reaction mixture was stirred at rt for 16h. The solution was cooled to 0°C and MeOH was added to quench the reaction. The stirring was kept at 0°C for 30 min. The

Ex.93a solvent was removed under reduced. The residue was purified by silica gel column chromatography eluting with Cyclohexane/EtOAc (70:30). The desired fractions were combined and concentrated to dryness to afford 5-bromo-3,3- difluoro-2,3-dihydro-1 H-indol-2-one Ex.93a (385 mg, 70%) as yellow solid. 1 H NMR (300 MHz, DMSO-d6, d in ppm): 6.91 -7.00 (m, 1 H), 7.66-7.76 (m, 1 H), 7.91 -7.97 (m, 1 H), 1 1.29 (br(s), 1 H).

methyl 1 -(3,3-difluoro-2-oxo-2,3-dihydro-1 H-indol-5-yl)cyclopropane-1 - carboxylate

- Step 2: 5-bromo-3,3-difluoro-2,3-dihydro-1 H-indol-2-one Ex.93a (375 mg, 1.51 mmol) was dissolved in dry THF (10 mL). The solution was purged with N2 and

Ex.93b Pd2(dba)3 (138 mg, 0.15 mmol) and XPhos (144 mg, 0.30 mmol) were added to the solution. The freshly prepared bromo[1 -(methoxycarbonyl)cyclopropyl]zinc (5.67 mL, 4.54 mmol) was added slowly as a solution in THF (approx. 0.8 M). The resulting mixture was heated overnight at 85°C. After cooling to rt, the solvent was removed under reduced pressure. The crude material was purified by column chromatography on silica gel eluting with Cyclohexane/EtOAc (70:30). The product fractions were combined and concentrated to dryness to afford methyl 1 -(3,3-difluoro-2-oxo-2,3-dihydro-1 H-indol-5-yl)cyclopropane-1 - carboxylate Ex.93b (454 mg, 99%) as pale brown oil. 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .19-1.24 (m, 2H), 1 .48-1.52 (m, 2H), 3.54 (s, 3H), 6.90- 6.96 (m, 1 H), 7.44-7.52 (m, 1 H), 7.58-7.64 (m, 1 H), 1 1.18 (s, 1 H).

1 -(3,3-difluoro-2-oxo-2,3-dihydro-1 H-indol-5-yl)cyclopropane-1 -carboxylic acid

- Step 3: methyl 1 -(3,3-difluoro-2-oxo-2,3-dihydro-1 H-indol-5-yl)cyclopropane-1 - carboxylate Ex.93b (400 mg, 1.50 mmol) was dissolced in concentrated sulfuric acid (4 ml_). The solution was heated at 80°C for 15 min under microwave irradiations. After cooling to rt, the solution was poured onto a mixture of ice and water. The aqueous layer was extracted with EtOAc. The combined organic

Ex.93 layers were washed several times with water, dried over MgS04, filtered and the solution was concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel eluting with CH2CI2/MeOH (95:5). The product fractions were combined and concentrated to dryness to afford 1 -(3,3-difluoro-2-oxo-2,3-dihydro-1 H-indol-5-yl)cyclopropane-1 -carboxylic acid Ex.93 (70 mg, 17%) as orange solid. 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .1 1 -1 .18 (m, 2H), 1 .40-1 .48 (m, 2H), 6.91 (d, 1 H, J=8.1 Hz), 7.46 (dd, 1 H, J=8.2Hz, J=1.8Hz), 7.58 (d, 1 H, J=1 .7Hz), 1 1 .16 (s, 1 H), 12.36 (br(s), 1 H).

Intermediate Ex.94 : 1 -[1 -(hvdroxyimino)-2,3-dihvdro-1 H-inden-5-yllcyclopropane-1 - carboxylic acid (Figure 1 CX)

Table 1 .56

Starting compounds, Reaction conditions and purification,

Cpd.

Yield, appearance, ¹ H NMR (solvent) data

methyl 1 -[1 -(hydroxyimino)-2,3-dihydro-1 H-inden-5-yl]cyclopropane-1 - carboxylate

- Step 1 : methyl 1 -(1 -oxo-2,3-dihydro-1 H-inden-5-yl)cyclopropane-1 -carboxylate (mixed fractions, 1 .7 g containing an estimated 1 .0 g, 4.34 mmol of starting material) was dissolved in MeOH (35 ml_). Hydroxylamine hydrochloride (604 mg, 8.68 mmol) and potassium acetate (891 mg, 10.9 mmol) were added to the solution. The reaction mixture was heated at 60°C for 1 h. The solution was cooled to rt and was concentrated to dryness. The residue was partitioned

Ex.94a between water and EtOAc. The organic layer was dried over MgS04, filtered and concentrated under reduced pressure. The crude oil was purified by column chromatography on silica gel eluting with a gradient of Cyclohexane/EtOAc from [100:0] to [60:40]. The product fractions were combined and concentrated to dryness to afford methyl 1 -[1 -(hydroxyimino)-2,3-dihydro-1 H-inden-5- yl]cyclopropane-1 -carboxylate Ex.94a (769 mg, 72%) as yellow foam. The product was found to be stable under chromatographic conditions on silica gel. The product contained some unknown impurity ([M+H]+ = 462) but was considered to be suitable for the next synthetic step.

1 -[1 -(hydroxyimino)-2,3-dihydro-1 H-inden-5-yl]cyclopropane-1 -carboxylic

Ex.94 acid

- Step 2: methyl 1 -[1 -(hydroxyimino)-2,3-dihydro-1 H-inden-5-yl]cyclopropane-1 - carboxylate Ex.94a (150 mg, 0.62 mmol) was dissolved in dry THF (10 ml_). Potassium trimethylsilanolate (157 mg, 1 .22 mmol) was added and the mixture was heated at 65°C for 1 h. Upon heating a pale brown solid precipitated from the reaction mixture. The reaction was monitored by TLC. Full consumption of the starting material was observed after 1 h. The mixture was acidified to pH = 2- 3 by addition of 1 M HCI. The mixture was concentrated to dryness, adsorbed onto silica gel and purified by column chromatography eluting with a gradient of CH2CI2/MeOH from [100:0] to [95:5]. The product fractions were combined and concentrated to dryness to afford 1 -[1 -(hydroxyimino)-2,3-dihydro-1 H-inden-5- yl]cyclopropane-1 -carboxylic acid Ex.94 (67 mg, 47%) as pale yellow solid. 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .19-1.22 (m, 2H), 1 .57-1 .61 (m, 2H), 2.89-2.94 (m, 2H), 3.01 -3.06 (m, 2H), 7.25 (dd, 1 H, J=0.9Hz, J=8.1 Hz), 7.34 (d, 1 H, J=0.9Hz), 7.57 (d, 1 H, J=8.1 Hz). The two polar protons exchanged with the deuterated solvent.

Intermediate Ex.95 : 2-[1 -(oxan-4-ylmethyl)-2,2-dioxo-1 ,3-dihvdro-2,1 -benzothiazol-5- yllacetic acid (Figure 1 CY)

Table 1 .57

Starting compounds, Reaction conditions and purification,

Cpd.

Yield, appearance, ¹ H NMR (solvent) data

5-bromo-1 -(oxan-4-ylmethyl)-1 ,3-dihydro-2,1 -benzothiazole-2,2-dione

- Step 1 : to a solution of 5-bromo-1 ,3-dihydro-2,1 -benzothiazole-2,2-dione (200 mg, 0.81 mmol) dissolved in dry DMF (2 mL) were added potassium carbonate (334 mg, 2.42 mmol) and 4-bromomethyltetrahydropyran (135 μΙ_, 1 .05 mmol). The reaction mixture was heated at 60°C overnight. After cooling to rt, the solution was poured onto water and EtOAc. After phases separation, the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgS04, filtered and the solution was concentrated under reduced

Ex.95a

pressure. The crude material was purified by column chromatography on silica gel eluting with Cyclohexane/EtOAc (70:30). The desired fractions were collected and concentrated to dryness to afford 5-bromo-1 -(oxan-4-ylmethyl)- 1 ,3-dihydro-2,1 -benzothiazole-2,2-dione Ex.95a (157 mg, 56%) as colourless oil, which solidified to a white solid upon standing at rt. 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .25-1.45 (m, 2H), 1.64 (d, 2H, J=1 1 .1 Hz), 1 .85-2.00 (m, 1 H), 3.15-3.30 (m, 2H), 3.40 (d, 2H, J=7.3Hz), 3.84 (dd, 2H, J=1 1 .3Hz,

J=2.7Hz), 4.68 (s, 2H), 6.98 (d, 1 H, J=9.2Hz), 7.45-7.55 (m, 2H).

tert-butyl 2-[1 -(oxan-4-ylmethyl)-2,2-dioxo-1 ,3-dihydro-2,1 -benzothiazol-5- yl]acetate

- Step 2: 5-bromo-1 -(oxan-4-ylmethyl)-1 ,3-dihydro-2,1 -benzothiazole-2,2-dione Ex.95a (300 mg, 0.87 mmol), the previously synthesized tert-butyl 2- (bromozincio)acetate (2.36 mL, 2.60 mmol) and dry THF (4 mL) were placed in flask, the mixture was degassed by nitrogen bubbling for 5 min. Then Pd2(dba)3

Ex.95b (8 mg, 0.01 mmol) and XPhos (8 mg, 0.02 mmol) were incorporated and the reaction mixture was heated at 80°C for 5h. The mixture was cooled to rt, EtOAc and water was added and the two-phase mixture was filtered through a pad of Celite. The phases were separated, the organic layer was dried over MgS04, filtered and the solution was concentrated to dryness. The crude material was purified by column chromatography eluting with Cyclohexane/EtOAc (80:20). The product fractions were combined and concentrated to dryness to give tert- butyl 2-[1 -(oxan-4-ylmethyl)-2,2-dioxo-1 ,3-dihydro-2,1 -benzothiazol-5-yl]acetate Ex.95b (316 mg, 96%) as yellow solid. 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .20-1 .35 (m, 2H), 1 .37 (s, 9H), 1 .66 (d, 2H, J=1 1.1 Hz), 1.85-2.00 (m, 1 H), 3.20-3.30 (m, 2H), 3.37 (d, 2H, J=7.2Hz), 3.51 (s, 2H), 3.85 (dd, 2H, J=1 1 .1 Hz, J=2.7Hz), 4.64 (s, 2H), 6.94 (d, 1 H, J=8.7Hz), 7.15-7.25 (m, 2H).

2-[1 -(oxan-4-ylmethyl)-2,2-dioxo-1 ,3-dihydro-2,1 -benzothiazol-5-yl]acetic acid

- Step 3: to a solution of tert-butyl 2-[1 -(oxan-4-ylmethyl)-2,2-dioxo-1 ,3-dihydro- 2,1 -benzothiazol-5-yl]acetate Ex.95b (316 mg, 0.83 mmol) dissolved in MeOH/THF (2 mL/ 3 mL) was added 5 M NaOH (1 .65 ml_, 8.28 mmol). The reaction mixture was heated at 100°C for 10 min under microwave irradiations. After cooling to rt, the solution was poured onto water. The pH was then

Ex.95 adjusted to pH = 3-4 with 1 M citric acid and the solution was extracted with

EtOAc. The combined organic layers were dried over MgS04, filtered and the solution was concentrated under reduced pressure to afford 2-[1 -(oxan-4- ylmethyl)-2,2-dioxo-1 ,3-dihydro-2,1 -benzothiazol-5-yl]acetic acid Ex.95 (200 mg, 74%) as yellow foam. 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .15-1.35 (m, 2H), 1 .66 (d, 2H, J=12.6Hz), 1 .85-2.00 (m, 1 H), 3.15-3.30 (m, 2H), 3.37 (d, 2H, J=7.1 Hz), 3.52 (s, 2H), 3.85 (dd, 2H, J=1 1.9Hz, J=2.8Hz), 4.63 (s, 2H), 6.93 (d, 1 H, J=8.8Hz), 7.15-7.25 (m, 2H), 12.28 (br(s), 1 H).

Intermediate Ex.96 : 1 -(2,2-dimethyl-2,4-dihvdro-1 ,3-benzodioxin-7-yl)cvclopropane-1 - carboxylic acid (Figure 1 CZ, 1 DA)

Table 1 .58

Starting compounds, Reaction conditions and purification,

Cpd.

Yield, appearance, ¹ H NMR (solvent) data

7-bromo-2,2-dimethyl-2,4-dihydro-1 ,3-benzodioxine

- Step 1 : 5-bromo-2-(hydroxymethyl)phenol (500 mg, 2.46 mmol) was dissolved in acetone (10 mL). p-Toluenesulfonic acid (42 mg, 0.25 mmol) was added followed by 2,2-dimethoxypropane (1 .51 mL, 1 .23 mmol) and sodium sulfate (944 mg, 6.65 mmol). The resulting mixture was heated under vigorous stirring at 50°C for 1 h. After cooling to rt, the mixture was concentrated under reduced pressure and the residue was partitioned between water and EtOAc. The

Ex.96a organic layer was dried over MgS04, filtered and the solution was concentrated to dryness. The crude material was purified by column chromatography on silica gel eluting with a gradient of Cyclohexane/EtOAc from [100:0] to [90:10]. The product fractions were combined and concentrated to dryness to afford 7- bromo-2,2-dimethyl-2,4-dihydro-1 ,3-benzodioxine Ex.96a (456 mg, 76%) as colourless oil, which solidified to a white solid upon standing at rt. 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .46 (s, 6H), 4.78 (s, 2H), 7.00 (d, 1 H, J=1 .8Hz), 7.05 (d, 1 H, J=8.1 Hz), 7.08 (dd, 1 H, J=8.1 Hz, J=1.8Hz).

methyl 1 -(2,2-dimethyl-2,4-dihydro-1 ,3-benzodioxin-7-yl)cyclopropane-1 - carboxylate

Ex.96b - Step 2: 7-bromo-2,2-dimethyl-2,4-dihydro-1 ,3-benzodioxine Ex.96a (450 mg,

1 .85 mmol) was dissolved in dry THF (5 mL). The solution was purged with N2 and Pd2(dba)3 (127 mg, 0.14 mmol) and XPhos (132 mg, 0.28 mmol) were added. The freshly prepared bromo[1 -(methoxycarbonyl)cyclopropyl]zinc (4.63 ml_, 3.70 mmol) was added slowly as a solution in THF (approx. 0.8 M). The resulting mixture was heated at 70°C for 2h. TLC (visualisation with molybdate stain) showed complete conversion. The reaction was then quenched with water and EtOAc and filtered through a pad of Celite. After phases separation, the remaining organic layer was dried over MgS04, filtered and the solution was concentrated to dryness. The crude material was adsorbed onto silica gel and purified by column chromatography eluting with a gradient of

Cyclohexane/EtOAc from [100:0] to [80:20]. The product fractions were combined and concentrated to dryness to afford methyl 1 -(2,2-dimethyl-2,4- dihydro-1 ,3-benzodioxin-7-yl)cyclopropane-1 -carboxylate Ex.96b (293 mg, 60%) as yellow oil. 1 H NMR (300 MHz, CDCI3, d in ppm): 1 .14-1.17 (m, 2H), 1 .41 - 1 .45 (m, 8H), 3.53 (s, 3H), 4.78 (s, 2H), 6.72 (d, 1 H, J=1.5Hz), 6.84 (dd, 1 H, J=7.8Hz, J=1.5Hz), 6.98 (d, 1 H, J=7.8Hz).

1 -(2,2-dimethyl-2,4-dihydro-1 ,3-benzodioxin-7-yl)cyclopropane-1 -carboxylic acid

- Step 3: methyl 1 -(2,2-dimethyl-2,4-dihydro-1 ,3-benzodioxin-7-yl)cyclopropane-1 - carboxylate Ex.96b (375 mg, 1 .43 mmol) was taken up in a mixture of THF and water [4:1] (15 ml_). Lithium hydroxide monohydrate (150 mg, 3.57 mmol) was added and the mixture was stirred at rt for 16h. The organic solvent was removed in vacuo and the residual aqueous layer was acidified to pH = 3-4 by

Ex.96

dropwise addition of 3 M HCI. The solid formed was collected by filtration, washed with water and dried under vacuum at 40°C to constant weight to afford 1 -(2,2-dimethyl-2,4-dihydro-1 ,3-benzodioxin-7-yl)cyclopropane-1 -carboxylic acid Ex.96 (230 mg, 84%) as an off-white solid. 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .07-1 .1 1 (m, 2H), 1 .37-1 .41 (m, 2H), 1 .45 (s, 6H), 4.78 (s, 2H), 6.70 (d, 1 H, J=1.5Hz), 6.84 (dd, 1 H, J=7.8Hz, J=1.5Hz), 6.96 (d, 1 H, J=7.8Hz), 12.25 (s, 1 H).

Intermediate Ex.97 : 1 -(2,2-dimethyl-2,4-dihvdro-1 ,3-benzodioxin-6-yl)cvclopropane-1 - carboxylic acid (Figure 1 CZ, 1 DA)

Table 1 .59

Starting compounds, Reaction conditions and purification,

Cpd.

Yield, appearance, ¹ H NMR (solvent) data

6-bromo-2,2-dimethyl-2,4-dihydro-1 ,3-benzodioxine

- Step 1 : 4-bromo-2-(hydroxymethyl)phenol (500 mg, 2.46 mmol) was dissolved in acetone (10 ml_). p-Toluenesulfonic acid (42 mg, 0.25 mmol) was added followed by 2,2-dimethoxypropane (1 .51 ml_, 1 .23 mmol) and sodium sulfate (944 mg, 6.65 mmol). The resulting mixture was heated under vigorous stirring overnight at 50°C. After cooling to rt, the mixture was concentrated under reduced pressure and the residue was partitioned between water and EtOAc.

Ex.97a

The organic layer was dried over MgS04, filtered and the solution was concentrated to dryness. The crude material was purified by column chromatography on silica gel eluting with a gradient of Cyclohexane/EtOAc from [100:0] to [90:10]. The product fractions were combined and concentrated to dryness to afford 6-bromo-2,2-dimethyl-2,4-dihydro-1 ,3-benzodioxine Ex.97a (529 mg, 88%) as colourless oil. 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1.45 (s, 6H), 4.80 (s, 2H), 6.74-6.77 (m, 1 H), 7.29-7.32 (m, 2H).

Ex.97b methyl 1 -(2,2-dimethyl-2,4-dihydro-1 ,3-benzodioxin-6-yl)cyclopropane-1 - carboxylate

- Step 2: 6-bromo-2,2-dimethyl-2,4-dihydro-1 ,3-benzodioxine Ex.97a (500 mg, 2.06 mmol) was dissolved in dry THF (5 ml_). The solution was purged with N2 and Pd2(dba)3 (141 mg, 0.15 mmol) and XPhos (147 mg, 0.31 mmol) were added. The freshly prepared bromo[1 -(methoxycarbonyl)cyclopropyl]zinc (5.14 ml_, 4.1 1 mmol) was added slowly as a solution in THF (approx. 0.8 M). The resulting mixture was heated at 70°C for 2h. TLC (visualisation with molybdate stain) showed complete conversion. The reaction was then quenched with water and EtOAc and filtered through a pad of Celite. After phases separation, the remaining organic layer was dried over MgS04, filtered and the solution was concentrated to dryness. The crude material was adsorbed onto silica gel and purified by column chromatography eluting with a gradient of

Cyclohexane/EtOAc from [100:0] to [80:20]. The product fractions were combined and concentrated to dryness to afford methyl 1 -(2,2-dimethyl-2,4- dihydro-1 ,3-benzodioxin-6-yl)cyclopropane-1 -carboxylate Ex.97b (381 mg, 71 %) as yellow oil, which solidified upon standing at rt. 1 H NMR (300 MHz, CDCI3, d in ppm): 1 .1 1 -1 .15 (m, 2H), 1 .41 -1 .45 (m, 8H), 3.53 (s, 3H), 4.77 (s, 2H), 6.70 (d, 1 H, J=8.4Hz), 7.01 (d, 1 H, J=2.1 Hz), 7.10 (dd, 1 H, J=8.4Hz, J=2.1 Hz).

1 -(2,2-dimethyl-2,4-dihydro-1 ,3-benzodioxin-6-yl)cyclopropane-1 -carboxylic acid

- Step 3: methyl 1 -(2,2-dimethyl-2,4-dihydro-1 ,3-benzodioxin-6-yl)cyclopropane-1 - carboxylate Ex.97b (375 mg, 1 .43 mmol) was taken up in a mixture of THF and water [4:1] (15 ml_). Lithium hydroxide monohydrate (150 mg, 3.57 mmol) was added and the mixture was stirred at rt for 16h. LCMS showed approx 50% conversion. Further lithium hydroxide monohydrate (150 mg, 3.57 mmol) was added and the solution was stirred overnight at rt.The organic solvent was

Ex.97

removed in vacuo and the residual aqueous layer was acidified to pH = 3-4 by dropwise addition of 3 M HCI. The solid formed was collected by filtration, washed with water and dried under vacuum at 40°C to constant weight to afford 1 -(2,2-dimethyl-2,4-dihydro-1 ,3-benzodioxin-6-yl)cyclopropane-1 -carboxylic acid Ex.97 (276 mg, 78%) as an off-white solid. 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .04-1.07 (m, 2H), 1.37-1 .40 (m, 2H), 1 .44 (s, 6H), 4.77 (s, 2H), 6.68 (d, 1 H, J=8.4Hz), 7.00 (d, 1 H, J=2.1 Hz), 7.09 (dd, 1 H, J=8.4Hz, J=2.1 Hz), 12.23 (br(s), 1 H).

Intermediate Ex.98 : 1 -[3-(1 -hvdroxy-2-methylpropan-2-yl)-1 H-indol-5-yl1cyclopropane-1 - carboxylic acid (Figure 1 DB)

Table 1 .60

Starting compounds, Reaction conditions and purification,

Cpd.

Yield, appearance, ¹ H NMR (solvent) data

ethyl 2-(5-bromo-1 H-indol-3-yl)-2-methylpropanoate

- Step 1 (following the protocol described by Leitch Jamie A. et al. in ACS Catalysis, 2017, 7, 2616-2623): in a microwave vial were introduced 5-bromo-

Ex.98a 1 H-indole (500 mg, 2.55 mmol) and dry dioxane (8 ml_). The solution was

purged with N2. Potassium acetate (500 mg, 5.10 mmol), dichloro(p- cymene)ruthenium(ii) dimer (78 mg, 0.13 mmol) and ethyl 2-bromo-2- methylpropanoate (1.1 1 ml_, 7.65 mmol) were added to the solution under N2. The vial was sealed and heated at 120°C for 18h. The reaction was quenched with sat. NH4CI and the remaining mixture was extracted with EtOAc. The combined organic layers were washed with sat. NH4CI. After phases separation, the organic layer was dried over MgS04, filtered and the solution was concentrated under reduced pressure. The crude material was purified by silica gel column chromatography eluting with Cyclohexane/EtOAc (70:30). The desired fractions were combined and evaporated to dryness to afford ethyl 2-(5- bromo-1 H-indol-3-yl)-2-methylpropanoate Ex.98a (650 mg, 82%) as colourless oil, which solidified to a white solid upon standing at rt. 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .08 (t, 3H, J=7.1 Hz), 1 .56 (s, 6H), 4.02 (q, 2H, J=7.1 Hz), 7.16 (dd, 1 H, J=8.6Hz, J=1.9Hz), 7.29 (d, 1 H, J=2.6Hz), 7.32 (dd, 1 H, J=8.6Hz, J=0.5Hz), 7.61 (d, 1 H, J=2.0Hz), 1 1.18 (s, 1 H).

2-(5-bromo-1 H-indol-3-yl)-2-methylpropan-1 -ol

- Step 2: ethyl 2-(5-bromo-1 H-indol-3-yl)-2-methylpropanoate Ex.98a (650 mg, 2.10 mmol) was dissolved in dry THF (10 ml_). Lithium aluminum hydride (1 19 mg, 3.14 mmol) was added and the reaction mixture was stirred at rt for 1 h. TLC showed no conversion. The solution was heated at 80°C overnight. TLC showed still starting material. The solution was cooled to rt and additional lithium aluminum hydride (1 19 mg, 3.14 mmol) was added. After 2h of stirring at rt, the mixture was quenched with 220 μΙ_ of water followed by 15% NaOH (220 μΙ_) and 660 μΙ_ of water under vigorous stirring. The white precipitate was filtered-

Ex.98b off. The remaining solution was extracted with EtOAc. The combined organic layers were washed with sat. NH4CI and then partitionated. The organic layer was dried over MgS04, filtered and the solution was concentrated under reduced pressure. The crude material was purified by silica gel column chromatography eluting with Cyclohexane/EtOAc (70:30). The product fractions were combined and concentrated to dryness to give 2-(5-bromo-1 H-indol-3-yl)- 2-methylpropan-1 -ol Ex.98b (425 mg, 76%) as colourless oil, which solidified to a white solid upon standing at rt. 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1.30 (s, 6H), 3.51 (d, 2H, J=5.6Hz), 4.60 (t, 1 H, J=5.6Hz), 7.06-7.18 (m, 2H), 7.30 (d, 1 H, J=8.6Hz), 7.80 (d, 1 H, J=1 .8Hz), 1 1 .01 (s, 1 H).

5-bromo-3-{1 -[(tert-butyldimethylsilyl)oxy]-2-methylpropan-2-yl}-1 H-indole

- Step 3: 2-(5-bromo-1 H-indol-3-yl)-2-methylpropan-1 -ol Ex.98b (420 mg, 1.57 mmol) was dissolved in dry DMF (10 ml_). Imidazole (0.235 g, 3.446 mmol) was added and the solution was cooled to 0°C. tert-Butyldimethylsilyl chloride (307 mg, 2.04 mmol) was added portion wise and the reaction mixture was warmed up to rt. After 3h, the reaction was quenched by addition of sat. NH4CI. The solution was extracted with EtOAc. The combined organic layers were dried

Ex.98c over MgS04, filtered and the solution was concentrated under reduced

pressure. The crude material was purified by silica gel column chromatography eluting with Cyclohexane/EtOAc (90:10). The product fractions were combined and concentrated to dryness to give 5-bromo-3-{1 -[(tert-butyldimethylsilyl)oxy]-2- methylpropan-2-yl}-1 H-indole Ex.98c (590 mg, 98%) as yellow oil. 1 H NMR (300 MHz, DMSO-d6, d in ppm): -0.07 (s, 6H), 0.81 (s, 9H), 1.32 (s, 6H), 3.64 (s, 2H), 7.10-7.17 (m, 2H), 7.29 (dd, 1 H, J=8.6Hz, J=0.4Hz), 7.80 (d, 1 H, J=1 .9Hz), 1 1.03 (s, 1 H).

methyl 1 -(3-{1 -[(tert-butyldimethylsilyl)oxy]-2-methylpropan-2-yl}-1 H-indol-5- yl)cyclopropane-1 -carboxylate

Ex.98d - Step 4: 5-bromo-3-{1 -[(tert-butyldimethylsilyl)oxy]-2-methylpropan-2-yl}-1 H- indole Ex.98c (295 mg, 0.77 mmol) was dissolved in dry THF (8 ml_). The solution was purged with N2 and Pd2(dba)3 (71 mg, 0.08 mmol) and XPhos (74 mg, 0.15 mmol) were added to the solution. The freshly prepared bromo[1 - (methoxycarbonyl)cyclopropyl]zinc (2.89 mL, 2.31 mmol) was added slowly as a solution in THF (approx. 0.8 M). The resulting mixture was heated at 80°C for 1 h. After cooling to rt, the solvent was removed under reduced pressure. The crude material was purified by column chromatography on silica gel eluting with Cyclohexane/EtOAc (90:10). The product fractions were combined and concentrated to dryness to afford methyl 1 -(3-{1 -[(tert-butyldimethylsilyl)oxy]-2- methylpropan-2-yl}-1 H-indol-5-yl)cyclopropane-1 -carboxylate Ex.98d (252 mg, 81 %) as yellow oil, which solidified to a yellow solid upon standing at rt. 1 H NMR (300 MHz, DMSO-d6, d in ppm): -0.06 (s, 6H), 0.82 (s, 9H), 1 .14-1.20 (m, 2H), 1 .33 (s, 6H), 1 .45-1 .51 (m, 2H), 3.50 (s, 3H), 3.67 (s, 2H), 7.00 (dd, 1 H, J=8.4Hz, J=1.6Hz), 7.04 (d, 1 H, J=2.5Hz), 7.24 (d, 1 H, J=8.3Hz), 7.55 (s, 1 H), 10.78 (s, 1 H).

1 -[3-(1 -hydroxy-2-methylpropan-2-yl)-1 H-indol-5-yl]cyclopropane-1 - carboxylic acid

- Step 5: to a solution of methyl 1 -(3-{1 -[(tert-butyldimethylsilyl)oxy]-2- methylpropan-2-yl}-1 H-indol-5-yl)cyclopropane-1 -carboxylate Ex.98d (250 mg, 0.62 mmol) dissolved in MeOH/THF (2 mL/ 2 mL) was added 5 M NaOH (1.25 mL, 6.23 mmol). The reaction mixture was heated at 1 10°C for 1 h under microwave irradiations. TLC showed still starting material. The reaction mixture was heated by classical heating at 1 10°C for 16h. The solvent was removed under reduced pressure. Water was added and the solution was extracted twice

Ex.98

with EtOAc. The pH of the remaining aqueous phase was then adjusted to pH = 3-4 with 1 M citric acid and the solution was extracted with EtOAc. The combined organic layers were washed with water. After phases separation, the organic layer was dried over MgS04, filtered and the solution was concentrated under reduced pressure to afford 1 -[3-(1 -hydroxy-2-methylpropan-2-yl)-1 H-indol-5- yl]cyclopropane-1 -carboxylic acid Ex.98 (155 mg, 84%) as white solid. 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .09-1 .16 (m, 2H), 1 .31 (s, 6H), 1 .42-1.47 (m, 2H), 3.53 (d, 2H, J=5.6Hz), 4.55 (t, 1 H, J=5.6Hz), 6.97-7.04 (m, 2H), 7.22 (d, 1 H, J=8.3Hz), 7.55 (s, 1 H), 10.71 (s, 1 H), 12.04 (br(s), 1 H).

Intermediate Ex.100 : 1 -(1 -methvl-2,2-dioxo-1 ,3-dihvdro-4,2,1 -benzoxathiazin-6- vl)cvclopropane-1 -carboxvlic acid (Figure 1 DD)

Table 1 .61

Starting compounds, Reaction conditions and purification,

Cpd.

Yield, appearance, ¹ H NMR (solvent) data

- Step 1 : the previously synthesized 1 -(2,2-dioxo-1 ,3-dihydro-4,2,1 - benzoxathiazin-6-yl)cyclopropane-1 -carboxylic acid (150 mg, 0.56 mmol) was dissolved in dry DMF (3 mL) and potassium carbonate (231 mg, 1.67 mmol) followed by iodomethane (104 μί, 1.67 mmol) were added to the solution. The

Ex.100a reaction mixture was heated at 50°C for 1 h. The reaction was quenched by the addition of sat. NH4CI. The resulting mixture was extracted with EtOAc. The combined organic layers were dried over MgS04, filtered and the solution was concentrated under reduced pressure to afford methyl 1 -(1 -methyl-2,2-dioxo- 1 ,3-dihydro-4,2,1 -benzoxathiazin-6-yl)cyclopropane-1 -carboxylate Ex.100a (160 mg, 96%) as white solid. The compound was pure enough and used for the next step without further purification. 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .15-1 .22 (m, 2H), 1 .42-1 .49 (m, 2H), 3.21 (s, 3H), 3.55 (s, 3H), 5.38 (s, 2H), 7.02 (d, 1 H, J=1 .6Hz), 7.08 (dd, 1 H, J=8.4Hz, J=1 .8Hz), 7.13 (d, 1 H, J=8.4Hz).

1 -(1 -methyl-2,2-dioxo-1 ,3-dihydro-4,2,1 -benzoxathiazin-6-yl)cyclopropane-

1 -carboxylic acid

- Step 2: o a solution of methyl 1 -(1 -methyl-2,2-dioxo-1 ,3-dihydro-4,2,1 - benzoxathiazin-6-yl)cyclopropane-1 -carboxylate Ex.100a (160 mg, 0.54 mmol) dissolved in MeOH/THF (1.5 mL/ 1.5 mL) was added 2 M NaOH (538 μΙ_, 1.08 mmol). The reaction mixture was heated at 1 10°C for 20 min under microwave irradiations. After cooling to rt, the solution was concentrated under reduced pressure. Water was added and the solution was extracted twice with Et20.

Ex.100

The pH of the aqueous layer was then adjusted to pH = 3-4 with 1 M citric acid and the solution was extracted with EtOAc. The combined organic layers were dried over MgS04, filtered and the solution was concentrated under reduced pressure to afford 1 -(1 -methyl-2,2-dioxo-1 ,3-dihydro-4,2,1 -benzoxathiazin-6- yl)cyclopropane-1 -carboxylic acid Ex.100 (140 mg, 92%) as white solid. 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .07-1.14 (m, 2H), 1 .38-1 .46 (m, 2H), 3.20 (s, 3H), 5.36 (s, 2H), 6.99 (d, 1 H, J=1 .7Hz), 7.06 (dd, 1 H, J=8.4Hz, J=1.9Hz), 7.1 1 (d, 1 H, J=8.4Hz), 12.35 (br(s), 1 H).

Intermediate Ex.102 : 1 -(2,2-dimethvl-2H-1 ,3-benzodioxol-5-vl)cvcloDroDane-1 -carboxvlic acid (Figure 1 DF)

Table 1 .62

Starting compounds, Reaction conditions and purification,

Cpd.

Yield, appearance, ¹ H NMR (solvent) data

2,2-dimethyl-2H-1 ,3-benzodioxole

- Step 1 : benzene-1 ,2-diol (5.00 g, 45.40 mmol) was dissolved in a mixture of toluene (10 mL) and acetone (4.20 mL, 56.80 mmol). Phosphorus trichloride (1 .58 mL, 18.20 mmol) was added dropwise over approx. 10 min (gas evolution was observed). After addition, the stirring was continued for 15 min to afford a two phase mixture. Et3N (7 mL) was added slowly followed by water and EtOAc. The two phases were separated, the organic layer was

Ex.102a washed with 10% K2C03 solution and brine. The organic layer was then dried over MgS04, filtered and the solution was carefully concentrated under reduced pressure (caution the product has a bp of 50-51 °C at 2-3 mbar). The crude material was purified by silica gel column chromatography eluting with Petroleum ether/EtOAc [90:10]. The product fractions were combined and conentrated to dryness to afford 2,2-dimethyl-2H-1 ,3-benzodioxole Ex.102a (3.47 g, 51 %) as colourless oil. 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1.62 (s, 6H), 6.75-6.83 (m, 4H).

5-bromo-2,2-dimethyl-2H-1 ,3-benzodioxole

- Step 2: 2,2-dimethyl-2H-1 ,3-benzodioxole Ex.102a (1 .00 g, 6.66 mmol) was

Ex.102b dissolved in dry DMF (20 mL). N-bromosuccinimide (1 .19 g, 6.66 mmol) was added portionwise at rt. The mixture was then stirred overnight at this temperature. LCMS showed almost complete consumption of the starting material. The reaction was found to be difficult to monitor by TLC as starting material and product showed the same Rf. The mixture was diluted with water, some brine was added followed by EtOAc. The two phases were separated, the organic layer was dried over MgS04, filtered and the solution was conentrated to dryness. The crude oil was purified by silica gel column chromatography eluting with Cyclohexane/EtOAc [95:5]. The product fractions were combined and concentrated to dryness to afford 5-bromo-2,2-dimethyl- 2H-1 ,3-benzodioxole Ex.102b (1 .32 g, 86%) as colourless oil. 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .63 (s, 6H), 6.79 (d, 1 H, J=8.1 Hz), 6.95 (dd, 1 H, J=8.1 Hz, J=2.1 Hz), 7.06 (d, 1 H, J=2.1 Hz)

methyl 1 -(2,2-dimethyl-2H-1 ,3-benzodioxol-5-yl)cyclopropane-1 -carboxylate

- Step 3: 5-bromo-2,2-dimethyl-2H-1 ,3-benzodioxole Ex.102b (600 mg, 2.62 mmol) was dissolved in dry THF (5 ml_). The solution was purged with N2 and Pd2(dba)3 (180 mg, 0.20 mmol) and XPhos (187 mg, 0.39 mmol) were added. The freshly prepared bromo[1 -(methoxycarbonyl)cyclopropyl]zinc (6.55 ml_, 5.24 mmol) was added slowly as a solution in THF (approx. 0.8 M). The resulting mixture was heated at 70°C for 1 h. The solvent was removed under reduced pressure. Water and EtOAc were added to the residue and the

Ex.102c resulting mixture was filtered through a pad of Celite. After phases separation, the organic layer was dried over MgS04, filtered and the solution was concentrated to dryness. The crude material was purified by silica gel column chromatography eluting with a gradient of Cyclohexane/EtOAc from [100:0] to [90:10]. The product fractions were combined and concentrated to dryness to afford methyl 1 -(2,2-dimethyl-2H-1 ,3-benzodioxol-5-yl)cyclopropane-1 - carboxylate Ex.102c (303 mg, 47%) as orange viscous oil. 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .1 1 -1.15 (m, 2H), 1 .39-1.43 (m, 2H), 1.62 (s, 6H), 3.53 (s, 3H), 6.71 -6.72 (m, 2H), 6.79 (dd, 1 H, J=2.1 Hz, J=0.6Hz).

1 -(2,2-dimethyl-2H-1 ,3-benzodioxol-5-yl)cyclopropane-1 -carboxylic acid

- Step 4: methyl 1 -(2,2-dimethyl-2H-1 ,3-benzodioxol-5-yl)cyclopropane-1 - carboxylate Ex.102c (300 mg, 1 .21 mmol) was taken up in a mixture of THF and water [4:1] (10 ml_). Lithium hydroxide monohydrate (152 mg, 3.63 mmol) was added and the mixture was stirred at rt over the weekend. LCMS showed full conversion. The organic solvent was removed in vacuo and the residual aqueous layer was acidified to pH = 3-4 by dropwise addition of 3 M HCI. A cloudy solution was formed and the aqueous phase was extracted with EtOAc.

Ex.102

The combined organic layers were dried over MgS04, filtered and the solution was concentrated to dryness. The crude product was purified by silica gel column chromatography eluting with a gradient of Cyclohexane/EtOAc from [100:0] to [70:30]. The product fractions were combined and concentrated to dryness to afford 1 -(2,2-dimethyl-2H-1 ,3-benzodioxol-5-yl)cyclopropane-1 - carboxylic acid Ex.102 (242 mg, 86%) as pale yellow solid. 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .05-1 .09 (m, 2H), 1 .36-1 .39 (m, 2H), 1.61 (s, 6H), 6.69-6.70 (m, 2H), 6.76-6.77 (m, 1 H), 12.20 (s, 1 H).

The following acids are commercially available

Table 1 .63

Ex.9 2-(4-methyl-2-oxo-1 ,2-dihydroquinolin-6-yl)acetic acid (supplier Fluorochem) Ex.45 2-(2-methyl-1 H-1 ,3-benzodiazol-5-yl)acetic acid

Ex.89 2-(1 H-indol-6-yl)acetic acid

Ex.90 2-(1 H-indol-5-yl)acetic acid

Example 1 b: Synthesis of amine intermediates for the synthesis of compounds according to the invention

The following amines were obtained following the procedure described in WO2006035157 Table 1 .64

Ex.7 3-methyl-1 -[2-(piperidin-1 -yl)phenyl]butan-1 -amine

The following amines were obtained following the procedure described in WO2016102633 Table 1 .65

Ex.1 [4-methyl-2-(piperidin-1 -yl)phenyl](phenyl)methanamine

Ex.3 [4-methyl-2-(morpholin-4-yl)phenyl](phenyl)methanamine hydrochloride

Ex.4 phenyl[2-(piperidin-1 -yl)phenyl]methanamine hydrochloride

Ex.5 [4-methoxy-2-(piperidin-1 -yl)phenyl](phenyl)methanamine

Ex.6 phenyl[2-(pyrrolidin-1 -yl)phenyl]methanamine hydrochloride

Ex.8 [2-(morpholin-4-yl)phenyl](phenyl)methanamine hydrochloride

Ex.10 (2,4-dimethylphenyl)(phenyl)methanamine hydrochloride

Ex.16 [4-methyl-2-(piperidin-1 -yl)phenyl](5-methylfuran-2-yl)methanamine

Ex.49 (2-bromo-4-methylphenyl)(phenyl)methanamine

Ex.50 [4-methyl-2-(pyrrolidin-1 -yl)phenyl](phenyl)methanamine

The following amines were obtained following the procedure described in WO2013019635 Table 1 .66

I Ex.81 (4-chlorophenyl)(2,4-dimethylphenyl)methanamine hydrochloride | Intermediate Ex.18 : (2-bromo-4-methylphenyl)(5-methylfuran-2-yl)methanamine hydrochloride (Figure 2A)

Table 1 .67

Intermediate Ex.19 : (2,4-dimethylphenyl)(5-methylfuran-2-yl)methanamine (Figure 2B)

Table 1 .68 Starting compounds,

Yield, Appearance, ¹ H NMR (solvent)

Cpd. Reaction conditions and

data

purification,

2-methyl-N-[(5-methylfuran-2-yl)methylidene]propane-2-sulfin amide

- Step 1 : 5-methylfuran-2-carbaldehyde (1 .0 g, 9.08 mmol) was dissolved in dry THF (5 ml_). Titanium ethoxide (7.62 ml_, 36.3 mmol) and 2-methyl-2-propane- sulfinamide (1.76 g, 14.5 mmol) were added to the reaction mixture. The solution was stirred at rt until completion of the reaction. Brine was added to

Ex.19a quench the reaction and the solution was stirred vigorously. EtOAc was added and the resulting mixture was filtered on Celite. The two layers were partitionated. The organic layer was dried over MgS04, filtered and the solution was concentrated under reduced pressure to afford 2-methyl-N-[(5-methylfuran- 2-yl)methylidene]propane-2-sulfinamide (1.70 g, 88 %) as orange oil . The compound was used as such for the next step.

N-[(2,4-dimethylphenyl)(5-methylfuran-2-yl)methyl]-2-methylp ropane-2- sulfinamide

- Step 2: to a suspension of magnesium powder (239 mg, 9.79 mmol) in dry THF (small amount) was added dropwise 1 -bromo-2,4-dimethylbenzene (1.64 g, 8.86 mmol) diluted in dry THF (20 mL) and the reaction was heated at 40°C. After completion of Grignard reagent, 2-methyl-N-[(5-methylfuran-2- yl)methylidene]propane-2-sulfinamide Ex.19a (995 mg, 4.66 mmol) diluted in

Ex.19b

THF (10 mL) was added to the solution. The reaction mixture was stirred at rt overnight. Water was added to quench the reaction. The two layers were partitionated and the organic layer was dried over MgS04, filtered and the solution was concentrated under reduced pressure. The crude material was purified by silica gel column chromatography using a gradient of hexanes/EtOAc ([5:1 ] to [4:1 ]) to afford N-[(2,4-dimethylphenyl)(5-methylfuran-2-yl)methyl]-2- methylpropane-2-sulfinamide (1 .27 g, 85%) as yellowish oil.

(2,4-dimethylphenyl)(5-methylfuran-2-yl)methanamine

- Step 3: to a solution of N-[(2,4-dimethylphenyl)(5-methylfuran-2-yl)methyl]-2- methylpropane-2-sulfinamide Ex.19b (683 mg, 2.14 mmol) dissolved in dry dioxane (5 mL) was added 4 N HCI in dioxane (2.4 mL) at 0°C. The reaction mixture was stirred at this temperature for 2h and then the solid was collected

Ex.19 by filtration. The solid was triturated with Et20 and dried until constant weight to afford (2,4-dimethylphenyl)(5-methylfuran-2-yl)methanamine (194 mg, 36%) as white solid.

- 1 H NMR (400 MHz, DMSO-d6, d in ppm): 2.24 (s, 3H); 2.29 (d, J = 4.7 Hz, 6H), 5.64 (s, 1 H), 6.02-6.19 (m, 1 H), 6.25 (d, 1 H, J=3.2Hz), 7.09-7.16 (m, 1 H), 7.44 (d, 1 H, J=8.0Hz), 8.96 (s, 3H).

Intermediate Ex.20 : [4-methoxy-2-(morpholin-4-yl)phenyl1(5-methylfuran-2-yl)meth anamine hydrochloride (Figure 2C)

Table 1 .69 purification,

4-methoxy-2-(morpholin-4-yl)benzaldehyde

- Step 1 : a solution of 2-bromo-4-methoxybenzaldehyde (2.0 g, 9.30 mmol), morpholine (1.21 mL, 13.95 mmol), BINAP (232 mg, 0.37 mmol), Pd2(dba)3

Ex.20a (170 mg, 0.19 mmol) and Cs2C03 (7.56 g, 23.25 mmol) in dry toluene (50 mL) was heated at 1 10°C for 3 days. The solution was filtered on Celite and the filtrate was concentrated to dryness. The crude material was purified by silica gel column chromatography using hexanes/EtOAc (4:1 ) as eluent to afford 4- methoxy-2-(morpholin-4-yl)benzaldehyde (1.29 g, 63%) as yellowish oil .

N-{[4-methoxy-2-(morpholin-4-yl)phenyl]methylidene}-2-methyl propane-2- sulfinamide

- Step 2: 4-methoxy-2-(morpholin-4-yl)benzaldehyde Ex.20a (1 .29 g, 5.83 mmol) was dissolved in dry THF (25 mL). Titanium ethoxide (2.44 mL, 1 1.66 mmol) and 2-methyl-2-propane-sulfinamide (707 mg, 5.83 mmol) were added to the reaction mixture. The solution was stirred at rt until completion of the reaction.

Ex.20b Brine was added to quench the reaction and the solution was stirred vigorously.

EtOAc was added and the resulting mixture was filtered on Celite. The two layers were partitionated. The organic layer was dried over MgS04, filtered and the solution was concentrated under reduced pressure to afford N-{[4-methoxy- 2-(morpholin-4-yl)phenyl]methylidene}-2-methylpropane-2-sulf inamide (1.96 g, quantitative) as yellowish oil . The compound was used as such for the next step.

N-{[4-methoxy-2-(morpholin-4-yl)phenyl](5-methylfuran-2-yl)m ethyl}-2- methylpropane-2-sulfinamide

- Step 3: to a suspension of magnesium powder (323 mg, 13.29 mmol) in dry THF (small amount) was added cat. iodine followed by a dropwise addition of 2- bromo-5-methylfuran (2.04 g, 12.67 mmol) diluted in dry THF (20 mL). The reaction was heated at 40°C. After completion of Grignard reagent, N-{[4- methoxy-2-(morpholin-4-yl)phenyl]methylidene}-2-methylpropan e-2-sulfinamide

Ex.20c Ex.20b (1 .96 g, 5.83 mmol) diluted in THF (10 mL) was added to the solution.

The reaction mixture was stirred at rt overnight. Water was added to quench the reaction. The two layers were partitionated and the organic layer was dried over MgS04, filtered and the solution was concentrated under reduced pressure. The crude material was purified by silica gel column chromatography using hexanes/EtOAc (1 :1 ) to afford N-{[4-methoxy-2-(morpholin-4-yl)phenyl](5- methylfuran-2-yl)methyl}-2-methylpropane-2-sulfinamide (1.08 g, 44%) as yellowish oil.

[4-methoxy-2-(morpholin-4-yl)phenyl](5-methylfuran-2-yl)meth anamine hydrochloride

- Step 4: to a solution of N-{[4-methoxy-2-(morpholin-4-yl)phenyl](5-methylfuran- 2-yl)methyl}-2-methylpropane-2-sulfinamide Ex.20c (1 .08 g, 2.66 mmol) dissolved in dry dioxane (15 mL) was added 4 N HCI in dioxane (1 .66 mL) at

Ex.20 0°C. The reaction mixture was stirred at this temperature for 2h and then the solid was collected by filtration. The solid was washed with Et20 and dried until constant weight to afford [4-methoxy-2-(morpholin-4-yl)phenyl](5-methylfuran-2- yl)methanamine hydrochloride (904 mg, 92%) as white solid.

- 1 H NMR (400 MHz, DMSO-d6, d in ppm): 2.24 (d, 3H, J=1.1 Hz), 2.66-2.83 (m, 4H), 3.67-3.77 (m, 4H), 3.79 (s, 3H), 5.90 (d, 1 H, J=5.7Hz), 6.05-6.1 1 (m, 1 H), 6.28 (d, 1 H, J=3.2Hz), 6.86-6.90 (m, 2H), 7.62 (d, 1 H, J=9.4Hz), 8.95 (s, 3H).

Intermediate Ex.21 : (2,4-dimethylphenyl)(5-ethylfuran-2-yl)methanamine hydrochloride (Figure 2D)

Table 1 .70

Starting compounds,

Yield, Appearance, ¹ H NMR (solvent)

Cpd. Reaction conditions and

data

purification,

N-[(5-ethylfuran-2-yl)methylidene]-2-methylpropane-2-sulfina mide

- Step 1 : 5-ethylfuran-2-carbaldehyde (762 μΙ_, 6.48 mmol) was diluted in dry THF (10 mL). Titanium ethoxide (4.07 mL, 19.43 mmol) and 2-methyl-2-propane- sulfinamide (1 .04 g, 8.58 mmol) were added to the reaction mixture. The solution was stirred at rt until completion of the reaction. Brine was added to

Ex.21 a quench the reaction and the solution was stirred vigorously. EtOAc was added and the resulting mixture was filtered on Celite. The two layers were partitionated. The organic layer was dried over MgS04, filtered and the solution was concentrated under reduced pressure to afford N-[(5-ethylfuran-2- yl)methylidene]-2-methylpropane-2-sulfinamide (1.46 g, quantitative) as colourless oil . The compound was used as such for the next step.

N-[(2,4-dimethylphenyl)(5-ethylfuran-2-yl)methyl]-2-methylpr opane-2- sulfinamide

- Step 2: to a suspension of magnesium powder (328 mg, 13.49 mmol) in dry THF (small amount) was added dropwise 2,4-dimethylbromobenzene (2.33 g, 12.59 mmol) dissolved in dry THF (20 mL). The reaction was heated at 40°C. After completion of Grignard reagent, N-[(5-ethylfuran-2-yl)methylidene]-2- methylpropane-2-sulfinamide Ex.21 a (1 .46 g, 6.42 mmol) diluted in THF (10 mL)

Ex.21 b

was added to the solution. The reaction mixture was stirred at rt overnight.

Water was added to quench the reaction. The two layers were partitionated and the organic layer was dried over MgS04, filtered and the solution was concentrated under reduced pressure. The crude material was purified by silica gel column chromatography using hexanes/EtOAc (5:1 ) to afford N-[(2,4- dimethylphenyl)(5-ethylfuran-2-yl)methyl]-2-methylpropane-2- sulfinamide (1.63 g, 76%) as yellowish oil.

(2,4-dimethylphenyl)(5-ethylfuran-2-yl)methanamine hydrochloride

- Step 3: to a solution of N-[(2,4-dimethylphenyl)(5-ethylfuran-2-yl)methyl]-2- methylpropane-2-sulfinamide Ex.21 b (1 .63 g, 4.89 mmol) dissolved in dry dioxane (10 mL) was added 4 N HCI in dioxane (4.9 mL) at 0°C. The reaction mixture was stirred at this temperature for 2h and then the solid was collected by filtration. The solid was washed with Et20 and dried until constant weight to

Ex.21

afford (2,4-dimethylphenyl)(5-ethylfuran-2-yl)methanamine hydrochloride (872 mg, 68%) as white solid.

- 1 H NMR (400 MHz, DMSO-d6, d in ppm): 1.15 (t, 3H, J=7.5Hz), 2.28 (s, 3H), 2.30 (s, 3H), 2.58 (q, 2H, J=7.5Hz), 5.64 (s, 1 H), 6.09 (d, 1 H, J=3.2Hz), 6.27 (d, 1 H, J=3.2Hz), 7.07 (s, 1 H), 7.12 (d, 1 H, J=8.0Hz), 7.46 (d, 1 H, J=7.9Hz), 9.01 (s, 3H). Intermediate Ex.22 : (2-bromo-4-methoxyphenyl)(5-methylfuran-2-yl)methanamine (Figure 2E)

Table 1 .71

Starting compounds,

Yield, Appearance, ¹ H NMR (solvent)

Cpd. Reaction conditions and

data

purification,

N-[(2-bromo-4-methoxyphenyl)methylidene]-2-methylpropane-2-s ulfinamide

- Step 1 : 2-bromo-4-methoxybenzaldehyde (1 g, 4.65 mmol) was diluted in dry THF (20 ml_). Titanium ethoxide (2.92 mL, 13.95 mmol) and 2-methyl-2- propane-sulfinamide (750 mg, 6.19 mmol) were added to the reaction mixture. The solution was stirred at rt until completion of the reaction. Brine was added to

Ex.22a quench the reaction and the solution was stirred vigorously. EtOAc was added and the resulting mixture was filtered on Celite. The two layers were partitionated. The organic layer was dried over MgS04, filtered and the solution was concentrated under reduced pressure to afford N-[(2-bromo-4- methoxyphenyl)methylidene]-2-methylpropane-2-sulfinamide (1.48 g, quantitative) as colourless oil. The compound was used as such for the next step.

N-[(2-bromo-4-methoxyphenyl)(5-methylfuran-2-yl)methyl]-2-me thylpropane-

2-sulfinamide

- Step 2: to a suspension of magnesium powder (73 mg, 3.00 mmol) in dry THF (small amount) was added dropwise 2-bromo-5-methylfuran (430 mg, 2.67 mmol) dissolved in dry THF (5 mL). The reaction was heated at 40°C. After completion of Grignard reagent, N-[(2-bromo-4-methoxyphenyl)methylidene]-2- methylpropane-2-sulfinamide (500 mg, 1.57 mmol) diluted in THF (5 mL) was

Ex.22b

added to the solution. The reaction mixture was stirred at rt overnight. Water was added to quench the reaction. The two layers were partitionated and the organic layer was dried over MgS04, filtered and the solution was concentrated under reduced pressure. The crude material was purified by silica gel column chromatography using hexanes/EtOAc (5:1 ) to afford N-[(2-bromo-4- methoxyphenyl)(5-methylfuran-2-yl)methyl]-2-methylpropane-2- sulfinamide (440 mg, 70%) as yellowish oil.

(2,4-dimethylphenyl)(5-ethylfuran-2-yl)methanamine hydrochloride

- Step 3: to a solution of N-[(2-bromo-4-methoxyphenyl)(5-methylfuran-2- yl)methyl]-2-methylpropane-2-sulfinamide (880 mg, 2.21 mmol) dissolved in dry dioxane (10 mL) was added 4 N HCI in dioxane (2.2 mL) at 0°C. The reaction mixture was stirred at this temperature for 2h and then the solid was collected

Ex.22 by filtration. The solid was washed with Et20 and dried until constant weight to afford (2,4-dimethylphenyl)(5-ethylfuran-2-yl)methanamine hydrochloride (632 mg, 89%) as white solid.

- 1 H NMR (400 MHz, DMSO-d6, d in ppm): 2.25 (s, 3H), 3.81 (s, 3H), 5.71 (s, 1 H), 6.10 (d, 1 H, J=2.8Hz), 6.25 (d, 1 H, J=3.2Hz), 7.14 (dd, 1 H, J=8.8Hz, J=2.6Hz), 7.29 (d, 1 H, J=2.6Hz), 7.70 (d, 1 H, J=8.8Hz), 9.13 (s, 3H). Intermediate Ex.32 : (5-chlorofuran-2-yl)(2,4-dimethylphenyl)methanamine (Figure 2F) Table 1 .72

Starting compounds,

Yield, Appearance, ¹ H NMR (solvent)

Cpd. Reaction conditions and

data

purification,

2-methyl-N-[(5-chlorofuran-2-yl)methylidene]propane-2-sulfin amide

- Step 1 : 5-chlorofuran-2-carbaldehyde (1 .0 g, 7.66 mmol) was dissolved in dry THF (10 ml_). Titanium ethoxide (3.21 ml_, 15.3 mmol) and 2-methyl-2-propane- sulfinamide (975 mg, 8.04 mmol) were added to the reaction mixture. The solution was stirred at rt until completion of the reaction. Brine was added to

Ex.32a quench the reaction and the solution was stirred vigorously. EtOAc was added and the resulting mixture was filtered on Celite. The two layers were partitionated. The organic layer was dried over MgS04, filtered and the solution was concentrated under reduced pressure. The crude material was purified by silica gel column chromatography using Cyclohexane/EtOAc [9:1] as eluent to afford 2-methyl-N-[(5-chlorofuran-2-yl)methylidene]propane-2-sulfin amide (1.51 g, 84 %) as white solid.

N-[(5-chlorofuran-2-yl)(2,4-dimethylphenyl)methyl]-2-methylp ropane-2- sulfinamide

- Step 2: to a solution of 1 -bromo-2,4-dimethylbenzene(653 mg, 3.53 mmol) in dry THF (5 mL) was added dropwise n-butyllithium 1.6M (2.21 ml_, 3.53 mmol) at - 78°C under N2 atmosphere. The reaction mixture was stirred at -78°C for 20 minutes. Then, 2-methyl-N-[(5-chlorofuran-2-yl)methylidene]propane-2- sulfinamide Ex.32a (750 mg, 3.21 mmol) dissolved in dry THF (5 mL) was

Ex.32b added dropwise to the solution. The reaction mixture was slowly warmed to rt and kept at this temperature for 2 h under stirring. Sat. NH4CI was added to quench the reaction. The two layers were partitionated and the organic layer was dried over MgS04, filtered and the solution was concentrated under reduced pressure. The crude material was purified by silica gel column chromatography using Cyclohexane/EtOAc [8:2] as eluent to afford N-[(5- chlorofuran-2-yl)(2,4-dimethylphenyl)methyl]-2-methylpropane -2-sulfinamide (235 mg, 22%) as yellowish oil.

(5-chlorofuran-2-yl)(2,4-dimethylphenyl)methanamine

- Step 3: to a solution of N-[(5-chlorofuran-2-yl)(2,4-dimethylphenyl)methyl]-2- methylpropane-2-sulfinamide Ex.32b (230 mg, 0.67 mmol) dissolved in MeOH (2.5 mL) was added 6 N HCI (545 μί) at rt. The reaction mixture was stirred overnight at rt. Water was added to quench the reaction. The aqueous layer was washed with Et20 and then basified with NaOH 5N until pH 9-10. The resulting

Ex.32 basic aqueous phase was extracted with EtOAc. The combined organic layers were dried over MgS04, filtered and the solution was concentrated under reduced pressure to afford (5-chlorofuran-2-yl)(2,4- dimethylphenyl)methanamine (130 mg, 82%) as yellow solid.

- 1 H NMR (400 MHz, DMSO-d6, d in ppm): 2.23 (s, 3H), 2.25 (s, 3H), 2.30 (br(s), 2H), 5.1 1 (s, 1 H), 6.21 (dd, 1 H, J=3.3Hz, J=0.9Hz), 6.33 (d, 1 H, J=3.3Hz), 6.95- 6.98 (m, 2H), 7.19 (d, 1 H, J=7.7Hz). Intermediate Ex.42 : 2-[amino(5-methylfuran-2-yl)methyll-N,N,5-trimethylaniline hydrochloride (Figure 2G)

Table 1 .73

Intermediate Ex.44 : [4-methyl-2-(pyrrolidin-1 -yl)phenyl1(5-methylfuran-2-yl)methanamine hydrochloride (Figure 2H)

Table 1 .74 Starting compounds,

Yield, Appearance, ¹ H NMR (solvent)

Cpd. Reaction conditions and

data

purification,

4-methyl-2-(pyrrolidin-1 -yl)benzaldehyde

- Step 1 : a solution of 2-bromo-4-methylbenzaldehyde (3.00 g, 15.07 mmol), pyrrolidine (1.87 mL, 22.61 mmol), BINAP (436 mg, 0.75 mmol), Pd2(dba)3 (276 mg, 0.30 mmol) and Cs2C03 (6.88 g, 21.10 mmol) in dry toluene (60 mL) was

Ex.44a heated at 90°C for two days. Water was added to quench the reaction. The two layers were partitionated and the organic layer was dried over MgS04, filtered and the solution was concentrated under reduced pressure. The crude material was purified by silica gel column chromatography using Hexanes/EtOAc as eluent (15:1 ) to afford 4-methyl-2-(pyrrolidin-1 -yl)benzaldehyde Ex.44a (2.08 g, 73%).

2-methyl-N-{[4-methyl-2-(pyrrolidin-1 -yl)phenyl]methylidene}propane-2- sulfinamide

- Step 2: a solution of 4-methyl-2-(pyrrolidin-1 -yl)benzaldehyde Ex.44a (1 .00 g, 5.28 mmol), titanium ethoxide (4.32 mL, 20.61 mmol), 2-methyl-propane- sulfinamide (1 .23 g, 10.14 mmol) dry THF (30 mL) overnight at rt. Water was

Ex.44b added to quench the reaction. The two layers were partitionated and the organic layer was dried over MgS04, filtered and the solution was concentrated under reduced pressure. The crude material was purified by silica gel column chromatography eluting with a gradient of Hexanes/EtOAc (from [90:10] to

[80:20] to [70:30]) to afford 2-methyl-N-{[4-methyl-2-(pyrrolidin-1 - yl)phenyl]methylidene}propane-2-sulfinamide Ex.44b (1 .16 g, 75%).

2-methyl-N-{[4-methyl-2-(pyrrolidin-1 -yl)phenyl](5-methylfuran-2- yl)methyl}propane-2-sulfinamide

- Step 3: to a suspension of magnesium powder (96 mg, 3.97 mmol) in dry THF (small amount) was added dropwise 2-bromo-5-methylfurane (614 mg, 3.81 mmol) diluted in dry THF (5 mL) and the reaction was heated at 40°C. After completion of Grignard reagent, the previously prepared 2-methyl-N-{[4-methyl- 2-(pyrrolidin-1 -yl)phenyl]methylidene}propane-2-sulfinamide Ex.44b (446 mg,

Ex.44c 1 .53 mmol) diluted in THF (5 mL) was added to the solution. The reaction

mixture was stirred at rt overnight. Water was added to quench the reaction. The two layers were partitionated and the organic layer was dried over MgS04, filtered and the solution was concentrated under reduced pressure. The crude material was purified by silica gel column chromatography using a gradient of Hexanes/EtOAc (from [80:20] to [70:30]) to afford 2-methyl-N-{[4-methyl-2- (pyrrolidin-1 -yl)phenyl](5-methylfuran-2-yl)methyl}propane-2-sulfinamide Ex.44c (436 mg, 76%).

[4-methyl-2-(pyrrolidin-1 -yl)phenyl](5-methylfuran-2-yl)methanamine hydrochloride

- Step 4: to a solution of 2-methyl-N-{[4-methyl-2-(pyrrolidin-1 -yl)phenyl](5- methylfuran-2-yl)methyl}propane-2-sulfinamide Ex.44c (430 mg, 1.15 mmol) in

Ex.44 dry dioxane (17 mL) was added HCI 4 M in dioxane (1.06 mL, 4.24 mmol) at

0°C. The reaction mixture was stirred at this temperature for 2h. The solid formed was collected by filtration and washed with diethyl ether to afford [4- methyl-2-(pyrrolidin-1 -yl)phenyl](5-methylfuran-2-yl)methanamine hydrochloride Ex.44 (244 mg, 91 %) as pale orange solid. 1 H NMR (400 MHz, DMSO-d6, d in ppm): 2.00 (s, 4H), 2.25 (d, 3H, J=1.0Hz), 2.34 (s, 3H), 2.93-3.48 (m, 4H), 5.77 (s, 1 H), 6.10 (dd, 1 H, J=1 .2Hz, J=3.3Hz), 6.31 (s, 1 H), 7.13 (s, 1 H), 7.27 (s, 1 H), 7.57 (d, 1 H, J=7.9Hz), 9.00 (s, 3H). One proton hidden by the water peak.

Intermediate Ex.47 : (5-chlorofuran-2-yl)[4-methyl-2-(piperidin-1 -yl)phenyl]methanamine

(Figure 2I)

Table 1 .75

Starting compounds,

Yield, Appearance, ¹ H NMR (solvent)

Cpd. Reaction conditions and

data

purification,

2-methyl-N-[(5-chlorofuran-2-yl)methylidene]propane-2-sulfin amide

- Step 1 : 5-chlorofuran-2-carbaldehyde (1 .0 g, 7.66 mmol) was dissolved in dry THF (10 mL). Titanium ethoxide (3.21 mL, 15.3 mmol) and 2-methyl-2-propane- sulfinamide (975 mg, 8.04 mmol) were added to the reaction mixture. The solution was stirred at rt until completion of the reaction. Brine was added to

Ex.47a quench the reaction and the solution was stirred vigorously. EtOAc was added and the resulting mixture was filtered on Celite. The two layers were partitionated. The organic layer was dried over MgS04, filtered and the solution was concentrated under reduced pressure. The crude material was purified by silica gel column chromatography using Cyclohexane/EtOAc [9:1] as eluent to afford 2-methyl-N-[(5-chlorofuran-2-yl)methylidene]propane-2-sulfin amide

Ex.47a (1 .51 g, 84 %) as white solid.

N-[(5-chlorofuran-2-yl)[4-methyl-2-(piperidin-1 -yl)phenyl]methyl]-2- methylpropane-2-sulfinamide

- Step 2: to a solution of 1 -(2-bromo-5-methylphenyl)piperidine (synthesized following the procedure described in PCT Int. Appl. (2016), WO 2016102633) (897 mg, 3.53 mmol) diluted in dry THF (5 mL) was added dropwise nBuLi 1 .6 M in THF (2.21 mL, 3.53 mmol) at -78°C and under N2 atmosphere. The stirring was kept at -78°C for 20 min. 2-Methyl-N-[(5-chlorofuran-2- yl)methylidene]propane-2-sulfinamide Ex.47a (750 mg, 3.21 mmol) dissolved in

Ex.47b dry THF (5 mL) was added dropwise to the solution. The reaction mixture is

gently warmed to 0°C (takes approx. 2h). Sat. NH4CI was added to quench the reaction. After few min of stirring, the resulting mixture was extracted with EtOAc. The combined organic layers were dried over MgS04, filtered and the solution was concentrated under reduced pressure. The crude material was purified by silica gel column chromatography eluting with Cyclohexane/EtOAc (80:20) to afford N-[(5-chlorofuran-2-yl)[4-methyl-2-(piperidin-1 - yl)phenyl]methyl]-2-methylpropane-2-sulfinamide Ex.47b (717 mg, 55%) as white solid.

(5-chlorofuran-2-yl)[4-methyl-2-(piperidin-1 -yl)phenyl]methanamine

- Step 3: N-[(5-chlorofuran-2-yl)[4-methyl-2-(piperidin-1 -yl)phenyl]methyl]-2- methylpropane-2-sulfinamide Ex.47b (600 mg, 1.47 mmol) was dissolved in

Ex.47 MeOH (6 mL). 6N HCI (1 .22 mL, 7.34 mmol) was added to the solution. The reaction mixture was stirred overnight at rt. Water was added to quench the reaction and the aqueous layer was extracted with diethyl ether. After phases separation, the aqueous layer was basified with 5N NaOH up pH = 9-10 and extracted with EtOAc. The combined organic layers were dried over MgS04, filtered and the solution was concentrated to dryness to afford (5-chlorofuran-2- yl)[4-methyl-2-(piperidin-1 -yl)phenyl]methanamine Ex.47 (360 mg, 81 %) as yellowish oil.

Intermediate Ex.48 : (5-chlorofuran-2-yl)[4-methyl-2-(pyrrolidin-1 -yl)phenyllmethanamine hydrochloride (Figure 2J)

Table 1 .76

Starting compounds,

Yield, Appearance, ¹ H NMR (solvent)

Cpd. Reaction conditions and

data

purification,

2-methyl-N-[(5-chlorofuran-2-yl)methylidene]propane-2-sulfin amide

- Step 1 : 5-chlorofuran-2-carbaldehyde (1 .0 g, 7.66 mmol) was dissolved in dry THF (10 mL). Titanium ethoxide (3.21 mL, 15.3 mmol) and 2-methyl-2-propane- sulfinamide (975 mg, 8.04 mmol) were added to the reaction mixture. The solution was stirred at rt until completion of the reaction. Brine was added to

Ex.48a quench the reaction and the solution was stirred vigorously. EtOAc was added and the resulting mixture was filtered on Celite. The two layers were partitionated. The organic layer was dried over MgS04, filtered and the solution was concentrated under reduced pressure. The crude material was purified by silica gel column chromatography using Cyclohexane/EtOAc [9:1] as eluent to afford 2-methyl-N-[(5-chlorofuran-2-yl)methylidene]propane-2-sulfin amide

Ex.48a (1.51 g, 84 %) as white solid.

1 -(2-bromo-5-methylphenyl)pyrrolidine

- Step 2: a solution of 2-bromo-5-methylaniline (1.20 g, 6.45 mmol), 1 ,4- dibromobutane (1.54 mL, 12.90 mmol) and K2C03 (2.22 g, 16.12 mmol) dissolved in acetonitrile (50 mL) was refluxed for two days. The solvent was

Ex.48b removed under reduced pressure. Water was added to dissolve the inorganic salt. The aqueous layer was extracted with EtOAc. The combined organic layer was dried over MgS04, filtered and the solution was concentrated to dryness. The residue was purified by silica gel column chromatography using Hexanes (100%) as eluent affording 1 -(2-bromo-5-methylphenyl)pyrrolidine Ex.48b (1 .29 g, 83%).

2-methyl-N-{[4-methyl-2-(pyrrolidin-1 -yl)phenyl](5-methylfuran-2- yl)methyl}propane-2-sulfinamide

- Step 3: to a suspension of magnesium powder (151 mg, 6.21 mmol) in dry THF (small amount) was added dropwise 1 -(2-bromo-5-methylphenyl)pyrrolidine

Ex.48b (1 .29 g, 5.37 mmol) dissolved in dry THF. The reaction was heated at 40°C. After completion of Grignard reagent, 2-methyl-N-[(5-chlorofuran-2-

Ex.48c yl)methylidene]propane-2-sulfinamide Ex.48a (766 mg, 3.28 mmol) diluted in

THF (5 mL) was added to the solution. The reaction mixture was stirred at 45°C overnight. Water was added to quench the reaction. The two layers were partitionated and the organic layer was dried over MgS04, filtered and the solution was concentrated under reduced pressure. The crude material was purified by silica gel column chromatography using Hexanes/EtOAc (80:20) to afford 2-methyl-N-{[4-methyl-2-(pyrrolidin-1 -yl)phenyl](5-methylfuran-2- yl)methyl}propane-2-sulfinamide Ex.48c (972 mg, 75%) as yellowish oil.

(5-chlorofuran-2-yl)[4-methyl-2-(pyrrolidin-1 -yl)phenyl]methanamine hydrochloride

- Step 4: to a solution of 2-methyl-N-{[4-methyl-2-(pyrrolidin-1 -yl)phenyl](5- methylfuran-2-yl)methyl}propane-2-sulfinamide Ex.48c (972 mg, 2.46 mmol) dissolved in dry dioxane (5 mL) was added 4 N HCI in dioxane (600 μΙ_) at 0°C. The reaction mixture was stirred at this temperature for 2h and then the solid was collected by filtration. The solid was washed with Et20 and dried until constant weight to afford (5-chlorofuran-2-yl)[4-methyl-2-(pyrrolidin-1 - yl)phenyl]methanamine hydrochloride Ex.48 (667 mg, 83%) as pale pink solid. 1 H NMR (400 MHz, DMSO-d6, d in ppm): 1 .99 (s, 4H), 2.34 (s, 3H), 2.88-3.36 (m, 4H), 6.17 (s, 1 H), 6.52 (d, 1 H, J=3.4Hz), 6.55 (d, 1 H, J=3.6Hz), 7.13 (s, 1 H), 7.26 (s, 1 H), 7.58 (d, 1 H, J=7.9Hz), 9.14 (s, 3H).

Intermediate Ex.63 : [2-(azepan-1 -yl)-4-methoxyphenyll(5-methylfuran-2-yl)methanamine (Figure 2K)

Table 1 .77

Starting compounds,

Yield, Appearance, ¹ H NMR (solvent)

Cpd. Reaction conditions and

data

purification,

2-(azepan-1 -yl)-4-methoxybenzaldehyde

- Step 1 : a solution of 2-bromo-4-methoxybenzaldehyde (0.5 g, 2.33 mmol), hexamethyleneimine (262 μΙ_, 2.33 mmol), BINAP (58 mg, 0.10 mmol), Pd2(dba)3 (43 mg, 0.05 mmol) and Cs2C03 (1.134 g, 3.48 mmol) in dry toluene

Ex.63a (15 mL) was heated at 95°C for 17h. Water was added to quench the reaction.

The two layers were partitionated and the organic layer was dried over MgS04, filtered and the solution was concentrated under reduced pressure. The crude material was purified by silica gel column chromatography using

Hexanes/EtOAc as eluent ([100:1] to [20:1 ]) to afford 2-(azepan-1 -yl)-4- methoxybenzaldehyde Ex.63a (526 mg, 96%).

N-{[2-(azepan-1 -yl)-4-methoxyphenyl]methylidene}-2-methylpropane-2- sulfinamide

- Step 2: a solution of 2-(azepan-1 -yl)-4-methoxybenzaldehyde Ex.63a (526 mg, 2.25 mmol), titanium ethoxide (1.9 mL, 9.02 mmol), 2-methyl-propane-

Ex.63b sulfinamide (276 mg, 2.48 mmol) dry THF at rt. Water was added to quench the reaction. The two layers were partitionated and the organic layer was dried over MgS04, filtered and the solution was concentrated under reduced pressure. The crude material was pure enough and used in the next step without further purification.

N-{[2-(azepan-1 -yl)-4-methoxyphenyl](5-methylfuran-2-yl)methyl}-2- methylpropane-2-sulfinamide

- Step 3: to a suspension of magnesium powder (60 mg, 2.46 mmol) in dry THF

Ex.63c (small amount) was added dropwise 2-bromo-5-methylfurane (377 mg, 2.34 mmol) diluted in dry THF (5 mL) and the reaction was heated at 40°C. After completion of Grignard reagent, the previously prepared N-{[2-(azepan-1 -yl)-4- methoxyphenyl]methylidene}-2-methylpropane-2-sulfinamide Ex.63b (394 mg, 1 .17 mmol) diluted in THF (5 mL) was added to the solution. The reaction mixture was stirred at rt overnight. Water was added to quench the reaction. The two layers were partitionated and the organic layer was dried over MgS04, filtered and the solution was concentrated under reduced pressure. The crude material was purified by silica gel column chromatography using a gradient of Hexanes/EtOAc to afford N-{[2-(azepan-1 -yl)-4-methoxyphenyl](5-methylfuran- 2-yl)methyl}-2-methylpropane-2-sulfinamide Ex.63c (283 mg, 60%) as yellowish oil.

[2-(azepan-1 -yl)-4-methoxyphenyl](5-methylfuran-2-yl)methanamine

- Step 4: to a solution of N-{[2-(azepan-1 -yl)-4-methoxyphenyl](5-methylfuran-2- yl)methyl}-2-methylpropane-2-sulfinamide Ex.63c (283 mg, 0.70 mmol) in MeOH (5 mL) was added cone. HCI (3.1 mL) at 0°C. The reaction mixture was stirred at this temperature for 2h and then quench with sat. NaHC03 to reach ph 7-8. The aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgS04, filtered and the solution was concentrated under

Ex.63 reduced pressure. The residue was purified by silica gel column

chromatography using CH2CI2/EtOAc as eluent ([10:0] to [8:2]) followed by flash silica gel column chromatography using hexanes/EtOAc as eluent to afford [2-(azepan-1 -yl)-4-methoxyphenyl](5-methylfuran-2-yl)methanamine Ex.63 (62 mg, 28%) as yellowish oil. 1 H NMR (400 MHz, DMSO-d6, d in ppm): 1.66 (s, 8H), 2.17 (s, 3H), 2.91 -3.06 (m, 4H), 3.71 (s, 3H), 5.41 (s, 1 H), 5.92 (s, 2H), 6.62 (dd, 1 H, J=8.5Hz, J=2.6Hz), 6.66 (d, 1 H, J=2.6Hz), 7.23 (d, 1 H, J=8.5Hz) (NH2 exchange with deuterated solvent).

Intermediate Ex.77 : (2,4-dimethylphenyl)(6-methylpyridin-2-yl)methanamine dihvdrochloride (Figure 2L)

Table 1 .78

Starting compounds,

Yield, Appearance, ¹ H NMR (solvent)

Cpd. Reaction conditions and

data

purification,

(2,4-dimethylphenyl)(6-methylpyridin-2-yl)methanol

- Step 1 : in a three-neck round-bottom flask were placed 2-bromo-6- methylpyridine (2.82 g, 16.40 mmol) and dry THF (5.00 mL) under argon atmosphere. The solution was cooled down at -78°C. nBuLi 2.5 M in hexanes (6.56 mL, 16.40 mmol) was added dropwise to the solution. The reaction mixture was stirred at -78°C for 20 min and a solution of

2,4-dimethylbenzaldehyde (2.00 g, 14.91 mmol) dissolved in dry THF (0.5 mL) was added dropwise over 15 min. The reaction mixture was slowly warmed to rt

Ex.77a over 2h. TLC showed full conversion of starting material, and the reaction

mixture was poured onto cold brine solution, EtOAc was added and the two phases wereseparated. The organic layer was dried over MgS04, filtered and the solution was concentrated to dryness. The residue was triturated with a mixture of EtOAc/Hexanes to give (2,4-dimethylphenyl)(6-methylpyridin-2- yl)methanol Ex.77a (1 .65 g, 40%) as light orange solid. 1 H NMR (300 MHz, CDCI3, d in ppm): 2.30 (s, 3H), 2.31 (s, 3H), 2.60 (s, 3H), 5.47 (d, 1 H, J=3.3Hz), 5.87 (d, 1 H, J=3.0Hz), 6.77 (d, 1 H, J=7.8Hz), 6.93-7.02 (m, 2H), 7.04 (d, 1 H, J=7.6Hz), 7.10 (d, 1 H, J=7.7Hz), 7.47 (t, 1 H, J=7.7Hz). 2 -(2 ,4-d i methyl benzoyl ) -6-methy I py rid i ne

- Step 2: (2 _! 4-dimethylphenyl)(6-methylpyridin-2-yl)methanol Ex.77a (1 .65 g, 7.26 mmol) was dissolved in CH2CI2 (17 ml_), and manganese (IV) oxide (3.79 g, 43.55 mmol) was added. The solution was stirred at rt for 6h. The reaction

Ex.77b

mixture was filltered through a pad of celite, and the filtrate was evaporated to dryness to afford 2-(2,4-dimethylbenzoyl)-6-methylpyridine Ex.77b (1 .58 g, 97%) as yellow oil. 1 H NMR (300 MHz, CDCI3, d in ppm): 2.38 (s, 3H), 2.41 (s, 3H), 2.59 (s, 3H), 7.04 (d, 1 H, J=8.3Hz), 7.10 (s, 1 H), 7.30 (d, 1 H, J=4.0Hz), 7.40 (d, 1 H, J=7.8Hz), 7.69-7.77 (m, 2H).

N-[(2,4-dimethylphenyl)(6-methylpyridin-2-yl)methylidene]-2- methylpropane-

2-sulfinamide

- Step 3 : 2-(2,4-dimethylbenzoyl)-6-methylpyridine Ex.77b (1 .58 g, 7.01 mmol) was dissolved in THF (16 ml_). 2-methylpropane-2-sulfinamide (0.89 g, 7.36 mmol) was added to the solution followed by Ti(OEt)4 (2.94 ml_, 14.03 mmol). The reaction mixture was stirred overnight at 60°C. TLC showed not total consumption of the starting material. Additional Ti(OEt)4 (1.47 ml_, 7.01 mmol) was added and the stirring was kept at 60°C over the weekend. The reaction mixture was poured onto a mixture of EtOAc and sat. NH4CI under vigorous stirring. The inorganic salt was removed by filtration on Celite. The two layers were partitioned and the aqueous layer was washed with sat. NH4CI. The

Ex.77c

combined organic layers were dried over MgS04, filtered and the solution was concentrated under reduced pressure. The crude material was purified by silica gel column chromatography eluting with Hexanes/EtOAc (75:25). Pure fractions were combined and evaporated under reduced pressure. During the evaproration additional products were observed on TLC probably due to decomposition. The resulting oil was conserved at 4°C. The solid was triturated in pentane and filtered off to give N-[(2,4-dimethylphenyl)(6-methylpyridin-2- yl)methylidene]-2-methylpropane-2-sulfinamide Ex.77c (830 mg, 36%) as yellow solid. 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .19 (s, 9H), 2.00 (s, 3H), 2.33 (s, 3H), 2.37 (s, 3H), 6.92-7.15 (m, 3H), 7.40 (d, 1 H, J=7.6Hz), 7.86 (t, 1 H, J=7.6Hz), 7.95 (s, 1 H).

N-[(2,4-dimethylphenyl)(6-methylpyridin-2-yl)methyl]-2-methy lpropane-2-sulf inamide

- Step 4: N-[(2,4-dimethylphenyl)(6-methylpyridin-2-yl)methylidene]-2- methylpropane-2-sulfinamide Ex.77c (830 mg, 2.53 mmol) was solubilized in MeOH (8 mL) and NaBH4 (190 mg, 5.05 mmol) was added portion wise at 0°C. The reaction mixture was stirred at this temperature and monitored by TLC. The solution was poured onto cold brine and CH2CI2 was added. After phases separation, the organic layer was dried over MgS04, filtered and the solution was concentrated to dryness. The crude material was purified by silica gel

Ex.77d

column chromatography eluting with CH2CI2/EtOAc (80:20) containing 1 % of MeOH. Pure fractions were combined and evaporated to dryness to give N-[(2,4-dimethylphenyl)(6-methylpyridin-2-yl)methyl]-2-methy lpropane-2-sulfina mide Ex.77d (610 mg, 73%) as a pale yellow oil. 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1.12 (s, 9H), 1.14 (s, 8H), 2.22 (s, 3H), 2.23 (s, 3H), 2.28 (s, 3H), 2.36 (s, 3H), 2.41 (s, 3H), 2.46 (s, 3H), 5.63 (d, 1 H, J=4.3Hz), 5.67 (d, 1 H, J=5.2Hz), 5.82 (d, 1 H, J=5.3Hz), 6.02 (d, 1 H, J=4.4Hz), 6.91-7.01 (m, 4H), 7.04 (d, 1 H, J=7.8Hz), 7.07-7.13 (m, 2H), 7.15 (d, 1 H, J=3.3Hz), 7.19 (d, 1 H, J=8.5Hz), 7.30 (d, 1 H, J=7.8Hz), 7.65 (td, 2H, J=7.7Hz, J=4.2Hz). (2,4-dimethylphenyl)(6-methylpyridin-2-yl)methanamine dihydrochloride

- Step 5: to a solution of

N-[(2,4-dimethylphenyl)(6-methylpyridin-2-yl)methyl]-2-methy lpropane-2-sulfi mide Ex.77d (610 mg, 1 .85 mmol) dissolved in i-PrOH (6 mL) was added 6 N HCI in i-PrOH (1.08 mL, 6.46 mmol). The reaction mixture was stirred at rt for 2h. White precipitate was observed. Et20 was added to the suspension. The solid was collected by filtration, washed with Et20 and dried until constant weight to afford (2,4-dimethylphenyl)(6-methylpyridin-2-yl)methanamine 2xHCI salt Ex.77 (450 mg, 23%) as a white solid. 1 H NMR (300 MHz, DMSO-d6, d in ppm): 2.25 (s, 3H), 2.44 (s, 3H), 2.57 (s, 3H), 5.72 (q, 1 H, J=5.8Hz), 6.57 (s, 3H), 7.04 (dd, 1 H, J=7.9Hz, J=1.9Hz), 7.08 (s, 1 H), 7.16 (d, 1 H, J=7.8Hz), 7.27 (dd, 2H, J=12.3Hz, J=7.8Hz), 7.75 (t, 1 H, J=7.7Hz), 8.89 (s, 3H).

Intermediate Ex.80 : (2,4-dimethylphenyl)(furan-2-yl)methanamine (Figure 2N)

Table 1 .79

Starting compounds,

Yield, Appearance, ¹ H NMR (solvent)

Cpd. Reaction conditions and

data

purification,

N-[furan-2-ylmethylidene]-2-methylpropane-2-sulfinamide

- Step 1 : 2-furaldehyde (930 mg, 9.68 mmol) was dissolved in dry THF (9 mL). 2- methylpropane-2-sulfinamide(1.23 g, 10.16 mmol) was added to the solution followed by Ti(OEt)4 (4.06 mL, 19.36 mmol). The reaction mixture was stirred at rt for 2 days (over the weekend). The solution was poured onto a mixture of EtOAc and sat. NH4CI under vigorous stirring. The inorganic salt was removed

Ex.80a by filtration on Celite. The two layers were partitioned and the organic layer was washed with sat. NH4CI. The combined organic layers were dried over MgS04, filtered and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using Hexanes/EtOAc (50:50) as eluent to afford the N-[furan-2-ylmethylidene]-2-methylpropane-2- sulfinamide Ex.80a (1 .8 g, 87%) as yellowish solid. 1 H NMR (400 MHz, DMSO- d6, d in ppm): 1 .16 (s, 9H), 6.66-6.85 (m, 1 H), 7.31 -7.42 (m, 1 H), 7.95-8.13 (m, 1 H), 8.33 (d, 1 H, J=0.7Hz).

N-[(2,4-dimethylphenyl)(furan-2-yl)methyl]-2-methylpropane-2 -sulfinamide

- Step 2: in a three-neck round-bottom flask were placed 1 -bromo-2,4- dimethylbenzene (818 mg, 4.42 mmol) and dry THF (8 mL) under argon atmosphere. The solution was cooled down at -78°C. nBuLi 2.5 M in hexanes (1 .77 mL, 4.42 mmol) was added dropwise to the solution. The reaction mixture was stirred at -78°C for 20 min and a solution of N-[furan-2-ylmethylidene]-2-

Ex.80b methylpropane-2-sulfinamide Ex.80a (849 mg, 3.98 mmol) dissolved in dry THF

(8 mL) was added dropwise. The reaction mixture was slowly warmed to rt. After 18h, the reaction was finished. Sat. NH4CI was added to quench the reaction. The aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgS04, filtered and the solution was concentrated to dryness. The crude material was purified by silica gel flash column chromatography using a gradient of Hexanes/EtOAc to give N-[(2,4-dimethylphenyl)(furan-2-yl)methyl]- 2-methylpropane-2-sulfinamide Ex.80b (800 mg, 65%) as colorless oil. 1 H NMR (400 MHz, DMSO-d6, d in ppm): 1 .1 1 (s, 9H), 2.25 (s, 6H), 5.57-5.66 (m, 1 H), 5.87-5.96 (m, 1 H), 6.19-6.27 (m, 1 H), 6.35-6.42 (m, 1 H), 6.95-7.03 (m, 2H), 7.24-7.32 (m, 1 H), 7.50-7.61 (m, 1 H).

(2,4-dimethylphenyl)(furan-2-yl)methanamine

- Step 3: to a solution of N-[(2,4-dimethylphenyl)(furan-2-yl)methyl]-2- methylpropane-2-sulfinamide Ex.80b (750 g, 2.46 mmol) dissolved in i-PrOH (7.5 mL) was added 6M HCI in i-PrOH (1.02 ml_, 6.14 mmol) at 0°C. The reaction mixture was warmed and stirred overnight at rt. The solvent was removed under reduced pressure. The residue was triturated with Et20, filtered, washed with Et20 and dried under vacuo. The solid was dissolved in water,

Ex.80 K2C03 was added up to pH = 8-9, the emulsion was extracted with EtOAc, all organic layers were combined, dried over MgS04, filtered and the solution was concentrated under reduced pressure. The crude material was purified using by silica gel flash chromatography eluting with a gradient of Hexanes/EtOAc to give (2,4-dimethylphenyl)(furan-2-yl)methanamine Ex.80 (360 mg, 72%) as a yellowish oil. 1 H NMR (400 MHz, DMSO-d6, d in ppm): 2.15 (s, 2H), 2.23 (s, 3H), 2.26 (s, 3H), 5.16 (s, 1 H), 6.10-6.15 (m, 1 H), 6.31 -6.38 (m, 1 H), 6.95 (d, 2H, J=9.0Hz), 7.20 (d, 1 H, J=7.7Hz), 7.45-7.54 (m, 1 H).

Intermediate Ex.83 : (3-chlorophenyl)(2,4-dimethylphenyl)methanamine hydrochloride (Figure 20)

Table 1 .80

Starting compounds,

Yield, Appearance, ¹ H NMR (solvent)

Cpd. Reaction conditions and

data

purification,

N-[(3-chlorophenyl)methylidene]-2-methylpropane-2-sulfinamid e

- Step 1 : 3-chlorobenzaldehyde (2.00 g, 14.23 mmol) was dissolved in dry THF (25 mL). 2-methylpropane-2-sulfinamide (1.81 g ,14.94 mmol) was added to the solution followed by Ti(OEt)4 (6.49 g, 28.46 mmol). The reaction mixture was stirred at rt overnight. The reaction mixture was poured onto a mixture of EtOAc and sat. NH4CI under vigorous stirring. The inorganic salt was removed by

Ex.83a filtration on Celite. The two layers were partitionated and the aqueous layer was washed with sat. NH4CI. The corganic layer was dried over MgS04, filtered and the solution was concentrated under reduced pressure to afford N-[(3- chlorophenyl)methylidene]-2-methylpropane-2-sulfinamide Ex.83a (3.36 g, 97%). The crude material was used without further purification for the next step. 1 H NMR (400 MHz, DMSO-d6, d in ppm): 1 .20 (s, 9H), 7.58 (t, 1 H, J=7.8Hz), 7.67 (ddd, 1 H, J=8.1 Hz, J=2.2Hz, J=1.2Hz), 7.93 (dt, 1 H, J=7.7Hz, J=1 .3Hz), 8.00 (t, 1 H, J=1.8Hz), 8.58 (s, 1 H).

N-[(3-chlorophenyl)(2,4-dimethylphenyl)methyl]-2-methylpropa ne-2- sulfinamide

- Step 2: a dried round-bottom flask containing stir bar was charged with

Ex.83b magnesium (530 mg, 21.70 mmol), small piece of iodine and dry THF (73 mL) was added under argon. Solution of 1 -bromo-2,4-dimethylbenzene (3.65 g, 19.72 mmol) diluted in dry THF (3 mL) was added dropwise to the suspension and the solution was stirred at 50°C for 60 min. After the formation of Grignard reagent, the reaction mixture was cooled to 0°C, and then N-[(3- chlorophenyl)methylidene]-2-methylpropane-2-sulfinamide Ex.83a (3.37 g, 13.81 mmol) in dry THF (3 mL) was added dropwise. The resulting mixture was stirred at rt. After the completion of the reaction, the reaction mixture was quenched with sat. NH4CI and the solution was extracted with EtOAc. The combined organic layers were washed with brine. After phases separation, the organic layer was dried over MgS04, filtered and the solution was concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel eluting with a gradient of Hexanes/EtOAc from

[90:10] to [60:40] to afford N-[(3-chlorophenyl)(2,4-dimethylphenyl)methyl]-2- methylpropane-2-sulfinamide Ex.83b (2.30 g, 48%) as yellow oil. 1 H NMR (400 MHz, DMSO-d6, d in ppm): 1 .1 1 (s, 9H), 2.22 (s, 3H), 2.26 (s, 3H), 5.67 (d, 1 H, J=6.3Hz), 6.03 (d, 1 H, J=6.3Hz), 6.98 (s, 1 H), 7.04 (d, 1 H, J=8.0Hz), 7.19-7.27 (m, 1 H), 7.26-7.40 (m, 4H).

(3-chlorophenyl)(2,4-dimethylphenyl)methanamine hydrochloride

- Step 3: to a solution of N-[(3-chlorophenyl)(2,4-dimethylphenyl)methyl]-2- methylpropane-2-sulfinamide Ex.83b (2.30 g, 6.57 mmol) dissolved in iPrOH (23 mL) was added 6 N HCI in iPrOH (3.29 mL, 19.72 mmol). The reaction mixture

Ex.83 was stirred at rt overnight. Solvent was removed under reduced pressure, small amount of i-PrOH was left and Et20 was added. The solid formed was collected by filtration to give(3-chlorophenyl)(2,4-dimethylphenyl)methanamine hydrochloride Ex.83 (1 .39 g, 75%) as white powder. 1 H NMR (400 MHz, DMSO- d6, d in ppm): 2.22 (s, 3H), 2.27 (s, 3H), 5.70 (s, 1 H), 6.96-7.23 (m, 2H), 7.29- 7.63 (m, 5H), 9.14 (s, 3H).

Intermediate Ex.87 : (3,5-dimethylpyridin-2-yl)(5-methylfuran-2-yl)methanamine dihydrochloride (Figure 2P)

Table 1 .81

Starting compounds,

Yield, Appearance, ¹ H NMR (solvent)

Cpd. Reaction conditions and

data

purification,

(3,5-dimethylpyridin-2-yl)(5-methylfuran-2-yl)methanol

- Step 1 : in a three-neck round-bottom flask were placed 2-bromo-3,5- dimethylpyridine (5.00 g, 26.87 mmol) and dry THF (40 mL) under N2 atmosphere. The solution was cooled down at -78°C. nBuLi 2.5 M in hexanes (12.89 mL, 32.25 mmol) was added dropwise to the solution. The reaction mixture was stirred at -78°C for 20 min and 5-methylfuran-2-carbaldehyde (2.94 mL, 29.56 mmol) dissolved in dry THF (10 mL) was added dropwise to the solution. The reaction mixture was stirred at -78°C for 30 min and then was

Ex.87a

slowly warmed to rt and the stirring was kept at this temperature overnight. The reaction was quenched with sat. NH4CI. The aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgS04, filtered and the solution was concentrated to dryness. The crude material was purified by silica gel column chromatography eluting with a gradient of Hexanes/EtOAc from

[96:4] to [90:10]. The product fractions were collected and evaporated under redcued pressure to afford (3,5-dimethylpyridin-2-yl)(5-methylfuran-2- yl)methanol Ex.87a (3.29 g, 56%) as orange oil. 1 H NMR (400 MHz, CDCI3, d in ppm): 2.13 (s, 3H), 2.24 (d, 3H, J=0.8Hz), 2.33 (s, 3H), 5.71 (s, 1 H), 5.83-5.86 (m, 2H), 7.28-7.30 (m, 1 H), 8.26-8.28 (m, 1 H).

3,5-dimethyl-2-(5-methylfuran-2-carbonyl)pyridine

- Step 2: manganese (IV) oxide (15.80 g, 181 .71 mmol) was added to a solution of (3,5-dimethylpyridin-2-yl)(5-methylfuran-2-yl)methanol Ex.87a (3.29 g, 15.14 mmol) dissolved in CH2CI2 (40 ml_). The resulting mixture was stirred at rt for 16h. The solution was diluted by CH2CI2 and filtered through a pad of Celite.

Ex.87b

The filtrate was concentrated to dryness to afford 3,5-dimethyl-2-(5-methylfuran- 2-carbonyl)pyridine Ex.87b (3.09 g, 95%). The product was pure enough and used at the next synthetic step without further purification. 1 H NMR (400 MHz, DMSO-d6, d in ppm): 2.33 (s, 3H), 2.34 (s, 3H), 2.40 (s, 3H), 6.38 (dd, 1 H, J=3.4Hz, J=1 .0Hz), 7.19 (dd, 1 H, J=3.5Hz, J=0.7Hz), 7.58-7.64 (m, 1 H), 8.33 (dd, 1 H, J=1.4Hz, J=0.7Hz).

N-[(3,5-dimethylpyridin-2-yl)(5-methylfuran-2-yl)methylidene ]-2- methylpropane-2-sulfinamide

- Step 3: 3,5-dimethyl-2-(5-methylfuran-2-carbonyl)pyridine Ex.87b (3.09 g, 14.36 mmol) was dissolved in dry THF (30 ml_). 2-methylpropane-2-sulfinamide (1.83 g, 15.07 mmol) was added to the solution followed by Ti(OEt)4 (6.55 g, 28.71 mmol). The reaction mixture was heated at 60°C for 48h. The reaction mixture was poured onto a mixture of EtOAc and sat. NH4CI under vigorous stirring. The

Ex.87c inorganic salt was removed by filtration on Celite. After phases separation, the organic layer was washed with sat. NH4CI. The organic layers was dried over MgS04, filtered and the solution was concentrated under reduced pressure to afford N-[(3,5-dimethylpyridin-2-yl)(5-methylfuran-2-yl)methylidene ]-2- methylpropane-2-sulfinamide Ex.87c (4.5 g, 98%) as brown oil. The product was pure enough and used at the next synthetic step without further purification. 1 H NMR (400 MHz, DMSO-d6, d in ppm): 1 .14 (s, 9H), 2.32 (s, 3H), 2.37 (s, 3H), 6.30-6.35 (m, 1 H), 6.52 (s, 1 H), 7.53 (s, 1 H), 8.27 (s, 1 H).

N-[(3,5-dimethylpyridin-2-yl)(5-methylfuran-2-yl)methyl]-2-m ethylpropane-2- sulfinamide

- Step 4: sodium borohydride (4.50 g, 14.13 mmol) was added portion wise to a cooled (0°C) solution of the N-[(3,5-dimethylpyridin-2-yl)(5-methylfuran-2- yl)methylidene]-2-methylpropane-2-sulfinamide Ex.87c (5.35 g, 141 .31 mmol) in MeOH (45 ml_). After addition, the reaction was warmed to rt and stirred overnight at this temperature. The reaction was quenched with sat. NH4CI. The

Ex.87d

solution was extracted with EtOAc. After phases separation, the organic layer was dried over MgS04, filtered and the solution was concentrated under reduced pressure. The crude material was purified by silica gel column chromatography eluting with Hexanes/EtOAc (50:50). The desired fractions were collected and concentrated to dryness to afford N-[(3,5-dimethylpyridin-2- yl)(5-methylfuran-2-yl)methyl]-2-methylpropane-2-sulfinamide Ex.87d (3.80 g, 84%) as yellowish oil.

(3,5-dimethylpyridin-2-yl)(5-methylfuran-2-yl)methanamine dihydrochloride

- Step 5: to a solution of N-[(3,5-dimethylpyridin-2-yl)(5-methylfuran-2-yl)methyl]- 2-methylpropane-2-sulfinamide Ex.87d (3.80 g, 1 1.86 mmol) dissolved in iPrOH

Ex.87

(15 mL) was added 6 N HCI in iPrOH (5.93 ml_, 35.57 mmol). The reaction mixture was stirred at rt overnight. Solvent was removed under reduced pressure, small amount of iPrOH was left and Et20 was added. The solid formed was collected by filtration to give (3,5-dimethylpyridin-2-yl)(5- methylfuran-2-yl)methanamine dihydrochloride Ex.87 (3.19 g, 93%) as yellowish solid. 1 H NMR (400 MHz, DMSO-d6, d in ppm): 2.19 (d, 6H, J=8.6Hz), 2.30 (s, 3H), 5.79 (d, 1 H, J=5.4Hz), 6.08 (d, 1 H, J=3.0Hz), 6.25 (d, 1 H, J=3.0Hz), 7.52 (s, 1 H), 8.35 (s, 1 H), 8.86 (s, 1 H).

Intermediate Ex.99 : [4-methyl-2-(trifluoromethyl)phenyll(5-methylfuran-2-yl)meth anamine hydrochloride (Figure 2Q)

Table 1 .82

Starting compounds,

Yield, Appearance, ¹ H NMR (solvent)

Cpd. Reaction conditions and

data

purification,

2-methyl-N-{[4-methyl-2-(trifluoromethyl)phenyl](5-methylfur an-2- yl)methyl}propane-2 -sulfanamide

Step 1 : : to a suspension of magnesium powder (120 mg, 4.94 mmol) in dry THF (small amount) was added dropwise 1 -bromo-4-methyl-2- (trifluoromethyl)benzene (1 .12 g, 4.69 mmol) diluted in dry THF (4 mL) and the reaction was heated at 40°C. After completion of Grignard reagent, the previously prepared 2-methyl-N-[(5-methylfuran-2-yl)methylidene]propane-2- sulfinamide (500 mg, 2.34 mmol) diluted in THF (4 mL) was added to the

Ex.99a

solution. The reaction mixture was stirred at rt overnight. Water was added to quench the reaction. The two layers were partitionated and the organic layer was dried over MgS04, filtered and the solution was concentrated under reduced pressure. The crude material was purified by silica gel column chromatography using a gradient of Hexanes/EtOAc from [5:1 ] to [4:1 ]. The desired fractions were combined and concentrated to dryness to afford 2- methyl-N-{[4-methyl-2-(trifluoromethyl)phenyl](5-methylfuran -2- yl)methyl}propane-2-sulfinamide Ex.99a (534 mg, 61 %) as yellow oil.

[4-methyl-2-(trifluoromethyl)phenyl](5-methylfuran-2-yl)meth anamine hydrochloride

Step 2: to a solution of 2-methyl-N-{[4-methyl-2-(trifluoromethyl)phenyl](5- methylfuran-2-yl)methyl}propane-2-sulfinamide Ex.99a (534 mg, 1 .43 mmol) dissolved in dry dioxane (10 mL) was added HCI 4 M in dioxane (900 μί, 6.43 mmol) at 0°C. The reaction mixture was warmed to rt and stirred at rt for 4h.

Ex.99

Et20 was added to the reaction mixture. The solid formed was collected by filtration and washed with Et20 to afford [4-methyl-2-(trifluoromethyl)phenyl](5- methylfuran-2-yl)methanamine hydrochloride Ex.99 (232 mg, 55%) as yellowish solid. 1 H NMR (400 MHz, DMSO-d6, d in ppm): 2.24 (d, 3H, J=1 .0Hz), 2.43 (s, 3H), 5.59 (s, 1 H), 6.10 (dd, 1 H, J=3.2Hz, 1 .2Hz), 6.26 (d, 1 H, J=3.2Hz), 7.67 (d, 2H, J=6.9Hz), 7.90 (d, 1 H, J=8.5Hz), 9.25 (s, 3H).

Intermediate Ex.101 : (2-methoxy-4-methylphenyl)(5-methylfuran-2-yl)methanamine (Figure 2R)

Table 1 .83

Starting compounds, Yield, Appearance, ¹ H NMR (solvent) Reaction conditions and data

purification,

N-[(2-methoxy-4-methylphenyl)(5-methylfuran-2-yl)methyl]-2- methylpropane-2 -sulfanamide

- Step 1 : : to a solution of 1 -bromo-2-methoxy-4-methylbenzene (1.80 g, 8.95 mmol) dissolved in dry THF (12 mL) was added dropwise isopropylmagnesium chloride solution 2 M in THF (5.60 mL, 1 1.19 mmol) . The mixture was then heated at 70°C for 3h. After completion of Grignard reagent, the previously prepared 2-methyl-N-[(5-methylfuran-2-yl)methylidene]propane-2-sulfin amide (1 .91 g, 8.95 mmol) dissolved in dry THF. The mixture was then heated

Ex.101 a overnight at 70°C. After cooling to rt, sat. NH4CI was added followed by

EtOAc. The two phases were separated, the resulting organic layer was washed with brine and water. The combined organic layers were dried over MgS04, filtered and the solution was concentrated under reduced pressure. The crude material was purified by silica gel column chromatography using a gradient of Cyclohexane/EtOAc from [90:10] to [60:40]. The product fractions were combined and concentrated to dryness to afford N-[(2-methoxy-4- methylphenyl)(5-methylfuran-2-yl)methyl]-2-methylpropane-2-s ulfinamide

Ex.101 a (380 mg, 13%) as brownish oil.

(2-methoxy-4-methylphenyl)(5-methylfuran-2-yl)methanamine

- Step 2: to a solution of N-[(2-methoxy-4-methylphenyl)(5-methylfuran-2- yl)methyl]-2-methylpropane-2-sulfinamide Ex.101a (375 mg, 1.12 mmol) dissolved in dry dioxane (4 mL) was added HCI 4 M in dioxane (1 .26 mL, 5.03 mmol) at rt. The reaction mixture was stirred overnight at rt. The solvent was removed under reduced pressure. The residue was diluted with water, pH was

Ex.101 adjusted to pH = 8-9 with 1 N NaOH and the aqueous solution was extracted twice with EtOAc. The combined organic layers were dried over MgS04, filtered and the solution was concentrated under reduced pressure. The crude material was purified by silica gel column chromatography eluting with

CH2CI2/MeOH (95:5) to provide (2-methoxy-4-methylphenyl)(5-methylfuran-2- yl)methanamine Ex.101 (100 mg, 39%) as pale brown oil. 1 H NMR (300 MHz, DMSO-d6, d in ppm): 2.16 (s, 3H), 2.27 (s, 3H), 3.74 (s, 3H), 5.20 (s, 1 H), 5.87-5.90 (m, 2H), 6.71 (d, 1 H, J=7.8Hz), 6.78 (s, 1 H), 7.13 (d, 1 H, J=7.8Hz).

Example 2: Synthesis of the compounds according to the invention Protocol A: to a solution of the substituted acid in DMF (0.25 mmol/mL) were added DMAP (2 to 4 equiv), EDCI.HCI (1 to 1 .5 equiv) and the substituted amine (1 equiv). The reaction mixture was stirred at rt. After completion of the reaction (monitored by TLC), sat. NH4CI or HCI 0.5N was added and the solution was extracted with EtOAc. The organic layer was washed with sat. NH4CI, dried over MgS04, filtered and evaporated to dryness under reduced pressure (Figure 3AA).

Protocol B: to a solution of the substituted amine (1 equiv) and substituted acid (1 equiv) in DMF (0.30 mmol/mL) were added triethylamine (3 equiv) and PyBOP(1 equiv). The reaction mixture was heated at 100°C for 20 min underr microwave irradiation. After cooling to rt, the reaction mixture was quenched with sat. NH4CI. The solution was extracted with EtOAc. The combined organic layers were washed with sat. NH4CI, dried over MgS04, filtered and the solution was concentrated under reduced pressure (Figure 3AB). Table 2:

All the NMR were performed in DMSO-d6

(d, 1 H, J=8.5Hz), 6.76-6.84 (m, 3H), 8.81 (dt, 1 H, J=7.8Hz , J=1.6Hz), 7.04-7.18 (m, 5H), 7.19-7.29 (m, 3H), 8.75 (d, 1 H, J=8.6Hz), 10.63 (s, 1 H) ; m/z: 456 [M+H]+ (calc. mass: 455).

- From [4-methoxy-2-(piperidin-1 - yl)phenyl](phenyl)methanamine Ex.5 and 2-(3-oxo-3,4- dihydro-2H-1 ,4-benzoxazin-7-yl)acetic acid Ex.2 following

N-{[4-methoxy- protocol A, DMAP (2.2 equiv), EDCI.HCI (1.1 equiv), 18h at

2-(piperidin-1 - rt, purification by silica gel column chromatography

yl)phenyl](phen (Cyclohexane/EtOAc, 3:7), yield 61 %, mp: 162°C,

yl)methyl}-2-(3- appearance: white solid

oxo-3,4-dihydro-

2H-1 ,4- - 1 H NMR (300 MHz, d in ppm): 1 .44-1 .58 (m, 6H), 2.48-2.52 benzoxazin-7- (m, 2H), 2.83-2.88 (m, 2H), 3.42 (s, 2H), 3.70 (s, 3H), 4.51 yl)acetamide (s, 2H), 6.48 (d, 1 H, J=8.5Hz), 6.61 -6.65 (m, 2H), 6.76-6.84

(m, 3H), 7.08-7.18 (m, 4H), 7.23-7.28 (m, 2H), 8.67 (d, 1 H, J=8.6Hz), 10.62 (s, 1 H) ; m/z: 486 [M+H]+ (calc. mass: 485).

- From phenyl[2-(pyrrolidin-1 -yl)phenyl]methanamine

hydrochloride Ex.6 and 2-(3-oxo-3,4-dihydro-2H-1 ,4- benzoxazin-7-yl)acetic acid Ex.2 following protocol A,

2-(3-oxo-3,4- DMAP (2.2 equiv), EDCI.HCI (1.1 equiv), 18h at rt,

dihydro-2H-1 ,4- purification by silica gel column chromatography

benzoxazin-7- (Cyclohexane/EtOAc, 1 :1 ), yield 83%, mp: 207°C,

yl)-N-{phenyl[2- appearance: white solid

(pyrrolidin-1 - - 1 H NMR (300 MHz, d in ppm): 1 .76-1 .78 (m, 4H), 2.80-2.84 yl)phenyl]methy (m, 2H), 3.04-3.09 (m, 2H), 3.43 (s, 2H), 4.53 (s, 2H), 6.49 l}acetamide (d, 1 H, J=8.3Hz), 6.76-6.85 (m, 3H), 6.94 (dt, 1 H, J=7.8Hz ,

J=1.3Hz), 7.06-7.19 (m, 6H), 7.23-7.28 (m, 2H), 8.78 (d, 1 H, J=8.5Hz), 10.63 (s, 1 H) ; m/z: 442 [M+H]+ (calc. mass: 441 ).

- From 3-methyl-1 -[2-(piperidin-1 -yl)phenyl]butan-1 -amine Ex.7 and 2-(3-oxo-3,4-dihydro-2H-1 ,4-benzoxazin-7-

N-{3-methyl-1 - yl)acetic acid Ex.2 following protocol A, DMAP (2.2 equiv),

[2-(piperidin-1 - EDCI.HCI (1.1 equiv), 18h at rt, purification by silica gel yl)phenyl]butyl}- column chromatography (Cyclohexane/EtOAc, 1 :1 ), yield

2-(3-oxo-3,4- 48%, mp: 236°C, appearance: white solid

dihydro-2H-1 ,4- - 1 H NMR (300 MHz, d in ppm): 0.84-0.89 (m, 6H), 1 .22-1.65 benzoxazin-7- (m, 12H), 2.50-2.6 (m, 2H), 3.00-3.12 (m, 2H), 4.51 (s, 2H), yl)acetamide 6.75-6.81 (m, 3H), 7.00-7.17 (m, 3H), 7.26 (dd, 1 H, J=7.5Hz

, J=1 .5Hz), 8.33 (d, 1 H, J=8.4Hz), 10.61 (br(s), 1 H) ; m/z: 436 [M+H]+ (calc. mass: 435).

N-{[2-

- From [2-(morpholin-4-yl)phenyl](phenyl)methanamine

(morpholin-4- hydrochloride and 2-(3-oxo-3,4-dihydro-2H-1 ,4-benzoxazin- yl)phenyl](phen

7-yl)acetic acid Ex.2 following protocol A, DMAP (2.2 yl)methyl}-2-(3- equiv), EDCI.HCI (1 .1 equiv), 18h at rt, purification by silica oxo-3,4-dihydro- gel column chromatography (Cyclohexane/EtOAc, 4:6),

2H-1 ,4- yield 43%, mp: 216°C, appearance: white solid

benzoxazin-7- yl)acetamide - 1 H NMR (300 MHz, d in ppm): 2.50-2.54 (m, 2H), 2.88-2.93 (m, 2H), 3.42 (s, 2H), 3.53-3.62 (m, 4H), 4.51 (s, 2H), 6.63 (d, 1 H, J=8.6Hz), 6.58-6.83 (m, 3H), 7.08-7.13 (m, 1 H), 7.16-7.30 (m, 8H), 8.79 (d, 1 H, J=8.6Hz), 10.62 (s, 1 H) ; m/z: 458 [M+H]+ (calc. mass: 457).

- From [4-methyl-2-(morpholin-4- yl)phenyl](phenyl)methanamine hydrochloride Ex.3 and 2- (4-methyl-2-oxo-1 ,2-dihydroquinolin-6-yl)acetic acid Ex.9 following protocol A, DMAP (2.2 equiv), EDCI.HCI (1 .1 equiv), 18h at rt. After water addition, the precipitate was

N-{[4-methyl-2- collected by filtration. The solid was dissolved in CH2CI2

(morpholin-4- and the organic layer was washed with citric acid 1 M yl)phenyl](phen followed by water. The organic layer was dried over yl)methyl}-2-(4- MgS04, filtered and the solution was concentrated under methyl-2-oxo- reduced pressure, yield 61 %, mp: 158°C, appearance:

1 ,2- white solid

dihydroquinolin - 1 H NMR (300 MHz, d in ppm): 2.24 (s, 3H), 2.34 (d, 3H, -6-yl)acetamide J=0.9Hz), 2.45-2.55 (m, 2H), 2.84-2.89 (m, 2H), 3.48-3.64

(m, 6H), 6.37 (d, 1 H, J=1.0Hz), 6.60 (d, 1 H, J=8.6Hz), 6.90 (d, 1 H, J=8.0Hz), 6.99 (s, 1 H), 7.12-7.28 (m, 7H), 7.37 (dd, 1 H, J=8.4Hz , J=1.8Hz), 7.57 (d, 1 H, J=1.6Hz), 8.83 (d, 1 H, J=8.7Hz), 1 1.53 (br(s), 1 H) ; m/z: 482 [M+H]+ (calc. mass: 481 ).

- From (2,4-dimethylphenyl)(phenyl)methanamine

hydrochloride Ex.10 and 2-(4-methyl-2-oxo-1 ,2- dihydroquinolin-6-yl)acetic acid Ex.9 following protocol A,

N-[(2,4- DMAP (2.2 equiv), EDCI.HCI (1.1 equiv), 18h at rt. After dimethylphenyl) water addition, the precipitate was collected by filtration,

(phenyl)methyl]- triturated with cold MeOH and washed with Et20, yield

2-(4-methyl-2- 70%, mp: 259°C, appearance: white solid

oxo-1 ,2- - 1 H NMR (300 MHz, d in ppm): 2.14 (s, 3H), 2.22 (s, 3H), dihydroquinolin 2.36 (s, 3H), 3.57 (s, 2H), 6.18 (d, 1 H, J=8.4Hz), 6.37 (s,

-6-yl)acetamide 1 H), 6.93-7.01 (m, 3H), 7.15-7.25 (m, 4H), 7.27-7.32 (m,

2H), 7.37 (dd, 1 H, J=8.4Hz , J=1.8Hz), 7.57 (m, 1 H), 8.91 (d, 1 H, J=8.4Hz), 1 1 .53 (s, 1 H) ; m/z: 41 1 [M+H]+ (calc. mass: 410).

- From [4-methoxy-2-(piperidin-1 - yl)phenyl](phenyl)methanamine Ex.5 and 2-(4-methyl-2- oxo-1 ,2-dihydroquinolin-6-yl)acetic acid Ex.9 following

N-{[4-methoxy- protocol A, DMAP (2.2 equiv), EDCI.HCI (1.1 equiv), 18h at

2-(piperidin-1 - rt. After water addition, the precipitate was collected by yl)phenyl](phen filtration. The solid was dissolved in CH2CI2 and the yl)methyl}-2-(4- organic layer was washed with citric acid 1 M followed by methyl-2-oxo- water. The organic layer was dried over MgS04, filtered

1 ,2- and the solution was concentrated under reduced pressure, dihydroquinolin yield 65%, mp: 158°C, appearance: white solid

-6-yl)acetamide

- 1 H NMR (300 MHz, d in ppm): 1 .43-1 .56 (m, 6H), 2.35 (d, 3H, J=1.0Hz), 2.48-2.53 (m, 2H), 2.8-2.9 (m, 2H), 3.58 (s, 2H), 8.77 (s, 3H), 6.37 (d, 1 H, J=0.8Hz), 6.51 (d, 1 H, J=8.6Hz), 6.62-6.65 (m, 2H), 7.13-7.22 (m, 4H), 7.24-7.27 (m, 3H), 7.38 (dd, 1 H, J=8.4Hz , J=1.8Hz), 7.57 (d, 1 H, J=1.6Hz), 8.75 (d, 1 H, J=8.5Hz), 1 1 .52 (br(s), 1 H) ; m/z: 496 [M+H]+ (calc. mass: 495).

- From [4-methyl-2-(piperidin-1 - yl)phenyl](phenyl)methanamine Ex.1 and 2-(4-methyl-2- oxo-1 ,2-dihydroquinolin-6-yl)acetic acid Ex.9 following protocol A, DMAP (2.2 equiv), EDCI.HCI (1.1 equiv), 18h at rt. After water addition, the precipitate was collected by

N-{[4-methyl-2- filtration and washed with Et20. The solid was dissolved in

(piperidin-1 - CH2CI2 and the organic layer was washed with citric acid yl)phenyl](phen 1 M followed by water. The organic layer was dried over yl)methyl}-2-(4- MgS04, filtered and the solution was concentrated under methyl-2-oxo- reduced pressure, yield 30%, mp: 173°C, appearance:

1 ,2- white solid

dihydroquinolin - 1 H NMR (300 MHz, d in ppm): 1 .40-1 .56 (m, 6H), 2.22 (s, -6-yl)acetamide 3H), 2.35 (s, 3H), 2.48-2.52 (m, 2H), 2.81 -2.84 (m, 2H),

3.58 (s, 2H), 6.37 (s, 1 H), 6.55 (d, 1 H, J=8.6Hz), 6.86 (d, 1 H, J=8.0Hz), 6.93 (s, 1 H), 7.13-7.40 (m, 7H), 7.37 (dd, 1 H, J=8.4Hz , J=1.8Hz), 7.57 (d, 1 H, J=1.5Hz), 8.77 (d, 1 H, J=8.6Hz), 1 1.53 (s, 1 H) ; m/z: 480 [M+H]+ (calc. mass: 479).

- From phenyl[2-(piperidin-1 -yl)phenyl]methanamine

hydrochloride Ex.4 and 2-(2,3-dioxo-1 ,2,3,4- tetrahydroquinoxalin-6-yl)acetic acid Ex.11 following

2-(2,3-dioxo- protocol A, DMAP (2.2 equiv), EDCI.HCI (1 .1 equiv), 2h at 1 ,2,3,4- rt, purification by silica gel column chromatography

tetrahydroquino (CH2CI2/MeOH, 94:6), yield 37%, mp: 265°C, appearance: xalin-6-yl)-N- white solid

{phenyl[2-

(piperidin-1 - - 1 H NMR (300 MHz, d in ppm): 1 .45-1 ,57 (m, 6H), 2.47-2.52 yl)phenyl]methy (m, 2H), 2.84-2.89 (m, 2H), 3.49 (s, 2H), 6.58 (d, 1 H, l}acetamide J=8.6Hz), 6.96-7.03 (m, 2H), 7.04-7.06 (m, 2H), 7.10 (dd,

1 H, J=9.6Hz, J=1.4Hz), 7.14-7.28 (m, 7H), 8.79 (d, 1 H, J=8.5Hz), 1 1.88 (br(s), 2H) ; m/z: 469 [M+H]+ (calc. mass: 468).

- From phenyl[2-(piperidin-1 -yl)phenyl]methanamine

hydrochloride Ex.4 and 2-(3-oxo-3,4-dihydro-2H-1 ,4- benzoxazin-6-yl)acetic acid Ex.12 following protocol A,

2-(3-oxo-3,4- DMAP (2.2 equiv), EDCI.HCI (1.1 equiv), 2h at rt. After dihydro-2H-1 ,4- water addition, the precipitate was collected by filtration and benzoxazin-6- washed with Et20. The solid was triturated with CH2CI2 yl)-N-{phenyl[2- containing small amount of MeOH and filtered-off, yield

(piperidin-1 - 38%, mp: 209°C, appearance: white solid

yl)phenyl]methy 1 H NMR (300 MHz, d in ppm): 1 .46-1 .58 (m, 6H), 2.48- l}acetamide 2.52 (m, 2H), 2.85-2.89 (m, 2H), 3.42 (s, 2H), 4.50 (s, 2H),

6.58 (d, 1 H, J=8.5Hz), 6.78-6.85 (m, 3H), 7.06 (m, 1 H), 7.12-7.29 (m, 8H), 8.75 (d, 1 H, J=8.5Hz), 10.69 (br(s), 1 H) ; m/z: 456 [M+H]+ (calc. mass: 455).

2- (2,2-difluoro-

3- 0X0-3,4- - From phenyl[2-(piperidin-1 -yl)phenyl]methanamine dihydro-2H-1 ,4- hydrochloride Ex.4 and 2-(2,2-difluoro-3-oxo-3,4-dihydro- benzoxazin-7- 2H-1 ,4-benzoxazin-7-yl)acetic acid Ex.13 following protocol yl)-N-{phenyl[2- A, substituted amine (0.9 equiv), DMAP (2.2 equiv),

(piperidin-1 - EDCI.HCI (1.2 equiv), 15h at rt, purification by silica gel yl)phenyl]methy column chromatography (Cyclohexane/EtOAc, 1 :1 ), l}acetamide followed by a second purification by silica gel column

chromatography (Cyclohexane/EtOAc, 6:4), yield 2%, mp: 106°C, appearance: white solid

- 1 H NMR (300 MHz, d in ppm): 1 .40-1 .70 (m, 8H), 2.75-2.90 (m, 2H), 3.52 (s, 2H), 6.59 (d, 1 H, J=8.4Hz), 7.00 (d, 1 H, J=8.1 Hz), 7.01 -7.10 (m, 2H), 7.13-7.29 (m, 10H), 8.80 (d, 1 H, J=8.4Hz) ; m/z: 492 [M+H]+ (calc. mass: 491 ).

- From phenyl[2-(piperidin-1 -yl)phenyl]methanamine

hydrochloride Ex.4 and 2-(2-oxo-2,3-dihydro-1 H-indol-5- yl)acetic acid Ex.14 following protocol A, DMAP (2.2 equiv),

2-(2-oxo-2,3- EDCI.HCI (1.1 equiv), 18h at rt, purification by silica gel dihydro-1 H- column chromatography (Cyclohexane/EtOAc, 3:7), yield indol-5-yl)-N- 66%, mp: 208°C, appearance: white solid

{phenyl[2-

(piperidin-1 - - 1 H NMR (300 MHz, d in ppm): 1 .44-1 .58 (m, 6H), 2.48-2.52 yl)phenyl]methy (m, 2H), 2.85-2.89 (m, 2H), 3.41 (s, 2H), 3.45 (s, 2H), 6.59 l}acetamide (d, 1 H, J=8.5Hz), 6.70 (d, 1 H, J=7.9Hz), 7.03-7.09 (m, 3H),

7.12-7.21 (m, 5H), 7.24-7.29 (m, 3H), 8.73 (d, 1 H,

J=8.6Hz), 10.29 (s, 1 H) ; m/z: 440 [M+H]+ (calc. mass: 439).

- From [4-methyl-2-(piperidin-1 - yl)phenyl](phenyl)methanamine hydrochloride Ex.1 and 2- (2-0X0-2, 3-dihydro-1 H-indol-5-yl)acetic acid Ex.14 following protocol A, DMAP (2.2 equiv), EDCI.HCI (1.1 equiv), 18h at

N-{[4-methyl-2- rt, purification by silica gel column chromatography

(piperidin-1 - (Cyclohexane/EtOAc, 3:7), yield 67%, mp: 202°C,

yl)phenyl](phen appearance: white solid

yl)methyl}-2-(2- oxo-2,3-dihydro- - 1 H NMR (300 MHz, d in ppm): 1 .39-1 .58 (m, 6H), 2.23 (s,

1 H-indol-5- 3H), 2.48-2.52 (m, 2H), 2.83-2.86 (m, 2H), 3.41 (s, 2H), yl)acetamide 3.44 (s, 2H), 6.53 (d, 1 H, J=8.3Hz), 6.70 (d, 1 H, J=7.9Hz),

6.87 (dd, 1 H, J=7.7Hz, J=1.1 Hz), 6.94 (d, 1 H, J=1 .1 Hz), 7.04 (dd, 1 H, J=8.1 Hz, J=1.4Hz), 7.09-7.18 (m, 5H), 7.23- 7.28 (m, 2H), 8.67 (d, 1 H, J=8.6Hz), 10.28 (s, 1 H) ; m/z: 454 [M+H]+ (calc. mass: 453).

- From [2-(morpholin-4-yl)phenyl](phenyl)methanamine hydrochloride Ex.8 and 2-(2-oxo-2,3-dihydro-1 H-indol-5-

N-{[2- yl)acetic acid Ex.14 following protocol A, DMAP (2.2 equiv),

(morpholin-4- EDCI.HCI (1 .1 equiv), 2h at rt, purification by silica gel yl)phenyl](phen column chromatography (CH2CI2/MeOH, 96:4). The solid yl)methyl}-2-(2- was then triturated in Et20 containing small amount of oxo-2,3-dihydro- CH2CI2 and filtered-off, yield 45%, mp: 160°C, appearance:

1 H-indol-5- white solid

yl)acetamide

- 1 H NMR (300 MHz, d in ppm): 2.48-2.53 (m, 2H), 2.89-2.94 (m, 2H), 3.41 (s, 2H), 3.44 (s, 2H), 3.53-3.58 (m, 2H), 3.61 - 3.65 (m, 2H), 6.63 (d, 1 H, J=8.6Hz), 6.71 (d, 1 H, J=7.9Hz), 7.06 (dd, 1 H, J=8.0Hz, J=1.5Hz), 7.09 (d, 1 H, J=1 .6Hz), 7.12 (dd, 1 H, J=7.3Hz, J=1.6Hz), 7.16-7.30 (m, 8H), 8.78 (d, 1 H, J=8.6Hz), 10.29 (s, 1 H) ; m/z: 442 [M+H]+ (calc. mass: 441 ).

- From [4-methyl-2-(morpholin-4- yl)phenyl](phenyl)methanamine hydrochloride Ex.3 and 2- (2-0X0-2, 3-dihydro-1 H-indol-5-yl)acetic acid Ex.14 following protocol A, DMAP (2.2 equiv), EDCI.HCI (1.1 equiv), 2h at rt, purification by silica gel column chromatography

N-{[4-methyl-2- (CH2CI2/MeOH, 96:4). The solid was then triturated in Et20

(morpholin-4- containing small amount of CH2CI2 and filtered-off, yield yl)phenyl](phen 53%, mp: 226°C, appearance: white solid

yl)methyl}-2-(2- oxo-2,3-dihydro- - 1 H NMR (300 MHz, d in ppm): 2.25 (s, 3H), 2.48-2.52 (m,

1 H-indol-5- 2H), 2.87-2.92 (m, 2H), 3.41 (s, 2H), 3.43 (s, 2H), 3.50-3.56 yl)acetamide (m, 2H), 3.61 -3.67 (m, 2H), 6.58 (d, 1 H, J=8.6Hz), 6.70 (d,

1 H, J=7.9Hz), 6.91 (dd, 1 H, J=7.9Hz, J=1 .0Hz), 6.99 (d, 1 H, J=1.2Hz), 7.04 (dd, 1 H, J=7.9Hz, J=1 .7Hz), 7.08 (s, 1 H), 7.12 (d, 1 H, J=7.8Hz), 7.16-7.19 (m, 3H), 7.24-7.29 (m, 2H), 8.72 (d, 1 H, J=8.6Hz), 10.29 (s, 1 H) ; m/z: 456 [M+H]+ (calc. mass: 455).

- From phenyl[2-(piperidin-1 -yl)phenyl]methanamine

hydrochloride Ex.4 and 2-(2,2-dimethyl-3-oxo-3,4-dihydro-

2- (2,2-dimethyl- 2H-1 ,4-benzoxazin-7-yl)acetic acid Ex.15 following protocol

3- oxo-3,4- A, substituted amine (0.9 equiv), DMAP (2.2 equiv), dihydro-2H-1 ,4- EDCI.HCI (1 .2 equiv), 4h at rt, purification by silica gel benzoxazin-7- column chromatography (CH2CI2/MeOH, 95:5), yield 71 %, yl)-N-{phenyl[2- mp: 190°C, appearance: white solid

(piperidin-1 - - 1 H NMR (300 MHz, d in ppm): 1.36 (s, 6H), 1 .40-1 .65 (m, yl)phenyl]methy 6H), 2.50-2.54 (m, 2H), 2.80-2.91 (m, 2H), 3.43 (s, 2H), l}acetamide 6.59 (d, 1 H, J=8.4Hz), 6.73-6.87 (m, 3H), 7.01 -7.09 (m,

1 H), 7.1 1 -7.30 (m, 8H), 8.72 (d, 1 H, J=8.5Hz), 10.53 (br(s), 1 H) ; m/z: 484 [M+H]+ (calc. mass: 483).

- From phenyl[2-(piperidin-1 -yl)phenyl]methanamine

hydrochloride Ex.4 and 2-(2,3-dioxo-2,3-dihydro-1 H-indol-5- yl)acetic acid Ex.14b following protocol A, substituted amine (0.9 equiv), DMAP (2.2 equiv), EDCI.HCI (1 .2 equiv),

2-(2,3-dioxo-2,3- 18h at rt, purification by silica gel column chromatography dihydro-1 H- (Cyclohexane/EtOAc, 4:6). The solid was then triturated in indol-5-yl)-N- Et20 and filtered-off, yield 6%, mp: 227°C, appearance: red

{phenyl[2- solid

(piperidin-1 - yl)phenyl]methy - 1 H NMR (300 MHz, d in ppm): 1.36-1 .68 (m, 6H), 2.52-2.60 l}acetamide (m, 2H), 2.80-2.94 (m, 2H), 3.51 (s, 2H), 6.60 (d, 1 H,

J=8.5Hz), 6.83 (d, 1 H, J=8.0Hz), 7.02-7.1 1 (m, 1 H), 7.12- 7.30 (m, 8H), 7.39 (d, 1 H, J=1 .4Hz), 7.45 (dd, 1 H, J=8.1 Hz, J=1.8Hz), 8.80 (d, 1 H, J=8.6Hz), 10.97 (br(s), 1 H) ; m/z: 454 [M+H]+ (calc. mass: 453).

2- (2,2-dimethyl-

3- 0X0-3,4- - From [4-methyl-2-(morpholin-4- dihydro-2H-1 ,4- yl)phenyl](phenyl)methanamine hydrochloride Ex.3 and 2- benzoxazin-7- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-1 ,4-benzoxazin-7- yl)-N-{[4-methyl- yl)acetic acid Ex.15 following protocol A, substituted amine

2-(morpholin-4- (0.9 equiv), DMAP (2.2 equiv), EDCI.HCI (1 .2 equiv), 4h at yl)phenyl](phen rt, purification by silica gel column chromatography

yl)methyl}aceta (CH2CI2/MeOH, 95:5), yield 76%, mp: 127°C, appearance: mide white solid

- 1 H NMR (300 MHz, d in ppm): 1.36 (s, 6H), 2.25 (s, 3H), 2.50-2.58 (m, 2H), 2.82-2.92 (m, 2H), 3.38-3.44 (m, 2H), 3.49-3.58 (m, 2H), 3.60-3.68 (m, 2H), 6.58 (d, 1 H,

J=8.6Hz), 6.74-6.85 (m, 3H), 6.87-6.93 (m, 1 H), 6.99 (s, 1 H), 7.07 (d, 1 H, J=7.8Hz), 7.12-7.21 (m, 3H), 7.22-7.28 (m, 2H), 8.71 (d, 1 H, J=8.6Hz), 10.53 (br(s), 1 H) ; m/z: 500 [M+H]+ (calc. mass: 499).

- From [4-methoxy-2-(piperidin-1 - yl)phenyl](phenyl)methanamine Ex.5 and 2-(2,3-dioxo-2,3- dihydro-1 H-indol-5-yl)acetic acid Ex.14b following protocol

2-(2,3-dioxo-2,3- A, substituted amine (0.9 equiv), DMAP (2.2 equiv), dihydro-1 H- EDCI.HCI (1.2 equiv), 18h at rt, purification by silica gel indol-5-yl)-N-{[4- column chromatography (Cyclohexane/EtOAc, 4:6). The methoxy-2- solid was then triturated in Et20 and filtered-off, yield 13%,

(piperidin-1 - mp: 231 °C, appearance: red solid

yl)phenyl](phen - 1 H NMR (300 MHz, d in ppm): 1 .37-1 .67 (m, 6H), 2.53-2.60 yl)methyl}aceta (m, 2H), 2.77-2.92 (m, 2H), 3.49 (s, 2H), 3.70 (s, 3H), 6.49 mide (d, 1 H, J=8.5Hz), 6.60-6.68 (m, 2H), 6.83 (d, 1 H, J=8.0Hz),

7.05-7.20 (m, 4H), 7.21 -7.30 (m, 2H), 7.36-7.41 (m, 1 H), 7.45 (dd, 1 H, J=8.0Hz, J=1.8Hz), 8.72 (d, 1 H, J=8.4Hz), 10.97 (br(s), 1 H) ; m/z: 484 [M+H]+ (calc. mass: 483).

- From [4-methyl-2-(piperidin-1 -yl)phenyl](5-methylfuran-2- yl)methanamine Ex.16 and 2-(2,3-dioxo-2,3-dihydro-1 H- indol-5-yl)acetic acid Ex.14b following protocol A, DMAP

2-(2,3-dioxo-2,3- (2.2 equiv), EDCI.HCI (1.2 equiv), 18h at rt, purification by dihydro-1 H- silica gel column chromatography (Cyclohexane/EtOAc, indol-5-yl)-N-{[4- 3:7), yield 30%, mp: 215°C, appearance: orange solid methyl-2-

(piperidin-1 - - 1 H NMR (300 MHz, d in ppm): 1 .35-1 .65 (m, 6H), 2.17 (s, yl)phenyl](5- 3H), 2.24 (s, 3H), 2.50-2.60 (m, 2H), 2.70-2.85 (m, 2H), methylfuran-2- 3.43 (s, 2H), 5.80 (d, 1 H, J=3.0Hz), 5.90-5.95 (m, 1 H), 6.47 yl)methyl}aceta (d, 1 H, J=8.4Hz), 6.82 (d, 1 H, J=8.1 Hz), 6.89 (d, 1 H, mide J=8.0Hz), 6.94 (s, 1 H), 7.17 (d, 1 H, J=7.8Hz), 7.37 (d, 1 H,

J=1.5Hz), 7.43 (dd, 1 H, J=8.1 Hz, J=1.8Hz), 8.76 (d, 1 H, J=8.4Hz), 10.96 (br(s), 1 H) ; m/z: 472 [M+H]+ (calc. mass: 471 ).

N-{[4-methyl-2- - From [4-methyl-2-(piperidin-1 -yl)phenyl](5-methylfuran-2-

(piperidin-1 - yl)methanamine Ex.16 and 2-(2-oxo-2,3-dihydro-1 H-indol- yl)phenyl](5- 5-yl)acetic acid Ex.14 following protocol A, DMAP (2.2 methylfuran-2- equiv), EDCI.HCI (1 .2 equiv), 18h at rt, purification by silica yl)methyl}-2-(2- gel column chromatography (Cyclohexane/EtOAc, 4:6), oxo-2,3-dihydro- yield 80%, mp: 95°C, appearance: white solid

1 H-indol-5-

- 1 H NMR (300 MHz, d in ppm): 1 .40-1 .65 (m, 6H), 2.18 (s, yl)acetamide

3H), 2.26 (s, 3H), 2.50-2.60 (m, 2H), 2.70-2.85 (m, 2H), 3.39 (s, 2H), 3.42 (s, 2H), 5.80 (d, 1H, J=3.0Hz), 5.90-5.95 (m, 1H), 6.48 (d, 1H, J=8.3Hz), 6.70 (d, 1H, J=7.9Hz), 6.89 (d, 1H, J=7.7Hz), 6.94 (s, 1H), 7.03 (d, 1H, J=7.9Hz), 7.08 (s, 1H), 7.18 (dd, 1H, J=7.8Hz), 8.77 (d, 1H, J=8.5Hz), 10.29 (br(s), 1H) ; m/z: 458 [M+H]+ (calc. mass: 457).

- From [4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2- yl)methanamine Ex.16 and 2-(2,2-dimethyl-3-oxo-3,4-

2- (2,2-dimethyl- dihydro-2H-1,4-benzoxazin-7-yl)acetic acid Ex.15 following

3- oxo-3,4- protocol A, substituted amine (0.9 equiv), DMAP (3.2 dihydro-2H-1,4- equiv), EDCI.HCI (1.2 equiv), 18h at rt, purification by silica benzoxazin-7- gel column chromatography (Cyclohexane/EtOAc, 6:4), yl)-N-{[4-methyl- yield 43%, mp: 101°C, appearance: white solid

2-(piperidin-1- - 1H NMR (300 MHz, d in ppm): 1.37 (s, 6H), 1.42-1.62 (m, yl)phenyl](5- 6H), 2.18 (s, 3H), 2.26 (s, 3H), 2.53-2.62 (m, 2H), 2.73-2.82 methylfuran-2- (m, 2H), 3.37 (s, 2H), 5.80 (d, 1H, J=2.6Hz), 5.93 (dd, 1H, yl)methyl}aceta J=3.0Hz, J=1.1Hz), 6.48 (d, 1H, J=8.4Hz), 6.73-6.81 (m, mide 2H), 6.83 (s, 1H), 6.89 (d, 1H, J=7.9Hz), 6.95 (s, 1H), 7.16

(d, 1H, J=7.8Hz), 8.79 (d, 1H, J=8.5Hz), 10.53 (s, 1H) ; m/z: 502 [M+H]+ (calc. mass: 501).

- From phenyl[2-(piperidin-1-yl)phenyl]methanamine Ex.4 hydrochloride and 2-(2,2-dioxo-1 ,3-dihydro-2,1- benzothiazol-5-yl)acetic acid Ex.17 following protocol A,

2-(2,2-dioxo-1,3- DMAP (2.2 equiv), EDCI.HCI (1.1 equiv), 2h at rt,

dihydro-2,1- purification by silica gel column chromatography

benzothiazol-5- (CH2CI2/MeOH, 97:3), yield 56%, mp: 198°C, appearance: yl)-N-{phenyl[2- white solid

(piperidin-1- - 1H NMR (300 MHz, d in ppm): 1.36-1.58 (m, 6H), 2.48-2.5 yl)phenyl]methy (m, 2H), 2.84-2.89 (m, 2H), 3.47 (s, 2H), 4.46 (s, 2H), 6.59 l}acetamide (d, 1H, J=8.4Hz), 6.73 (d, 1H, J=8.0Hz), 7.04-7.10 (m, 1H),

7.13-7.21 (m, 7H), 7.24-7.29 (m, 3H), 8.75 (d, 1H,

J=8.6Hz), 10.35 (br(s), 1H) ; m/z: 476 [M+H]+ (calc. mass: 475).

- From [4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2- yl)methanamine Ex.16 and 2-(2,2-dioxo-1,3-dihydro-2,1- benzothiazol-5-yl)acetic acid Ex.17 following protocol A,

2-(2,2-dioxo-1,3- DMAP (3.2 equiv), EDCI.HCI (1.1 equiv), 18h at rt,

dihydro-2,1- purification by silica gel column chromatography

benzothiazol-5- (CH2CI2/EtOAc, 9:1), yield 59%, mp: 108°C, appearance: yl)-N-{[4-methyl- white solid

2-(piperidin-1- - 1H NMR (300 MHz, d in ppm): 1.40-1.60 (m, 6H), 2.17 (s, yl)phenyl](5- 3H), 2.25 (s, 3H), 2.52-2.57 (m, 2H), 2.69-2.83 (m, 2H), methylfuran-2- 3.40 (s, 2H), 4.46 (s, 2H), 5.81 (d, 1H, J=3.0Hz), 5.92 (dd, yl)methyl}aceta 1H, J=3.0Hz, J=1.0Hz), 6.47 (d, 1H, J=8.4Hz), 6.72 (d, 1H, mide J=7.8Hz), 6.89 (d, 1H, J=7.6Hz), 6.94 (s, 1H), 7.10 (d, 1H,

J=8.4Hz), 7.13 (s, 1H), 7.17 (d, 1H, J=7.8Hz), 8.71 (d, 1H, J=8.5Hz), 10.34 (br(s), 1H) ; m/z: 494 [M+H]+ (calc. mass: 493).

N-[(2-bromo-4- methylphenyl)(5 - From (2-bromo-4-methylphenyl)(5-methylfuran-2- -methylfuran-2- yl)methanamine hydrochloride Ex.18 and 2-(2,2-dioxo-1 ,3- yl)methyl]-2- dihydro-2,1 -benzothiazol-5-yl)acetic acid Ex.17 following

(2,2-dioxo-1 ,3- protocol A, DMAP (3.2 equiv), EDCI.HCI (1.1 equiv), 18h at dihydro-2,1 - rt, purification by silica gel column chromatography

benzothiazol-5- (CH2CI2/EtOAc, 6:4), yield 68%, mp: 102°C, appearance: yl)acetamide white solid

- 1 H NMR (300 MHz, d in ppm): 2.21 (s, 3H), 2.28 (s, 3H), 3.44 (s, 2H), 4.48 (s, 2H), 5.76 (d, 1 H, J=3.0Hz), 5.96 (dd, 1 H, J=3.0Hz, J=1.0Hz), 6.23 (d, 1 H, J=8.1 Hz), 6.74 (d, 1 H, J=8.0Hz), 7.12 (dd, 1 H, J=8.1 Hz, J=1 .7Hz), 7.15 (s, 1 H), 7.20 (dd, 1 H, J=8.0Hz, J=1.0Hz), 7.29 (d, 1 H, J=7.9Hz), 7.42 (d, 1 H, J=0.8Hz), 9.06 (d, 1 H, J=8.1 Hz), 10.36 (s, 1 H) ; m/z: 51 1 [M+Na]+, 513 [M+Na]+ (calc. mass: 488).

- From (2,4-dimethylphenyl)(5-methylfuran-2-yl)methanamine Ex.19 and 2-(2-oxo-2,3-dihydro-1 H-indol-5-yl)acetic acid

N-[(2,4- Ex.14 following protocol A, substituted amine (0.9 equiv), dimethylphenyl) DMAP (3.2 equiv), EDCI.HCI (1.2 equiv), 18h at rt,

(5-methylfuran- purification by preparative HPLC, yield 56%, mp: 176°C,

2-yl)methyl]-2- appearance: white solid

(2-oxo-2,3- - 1 H NMR (300 MHz, d in ppm): 2.17 (s, 3H), 2.20 (s, 3H), dihydro-1 H- 2.23 (s, 3H), 3.40 (s, 2H), 3.41 (s, 2H), 5.84 (d, 1 H,

indol-5- J=2.9Hz), 5.96 (dd, 1 H, J=3.0Hz, J=1 .0Hz), 6.09 (d, 1 H, yl)acetamide J=8.3Hz), 6.70 (d, 1 H, J=7.9Hz), 6.90-7.13 (m, 5H), 8.89 (d,

1 H, J=8.4Hz), 10.29 (br(s), 1 H) ; m/z: 389 [M+H]+ (calc. mass: 388).

- From [4-methoxy-2-(morpholin-4-yl)phenyl](5-methylfuran-

2- yl)methanamine hydrochloride Ex.20 and 2-(2,2-dimethyl-

2- (2,2-dimethyl- 3- 0X0-3, 4-dihydro-2H-1 ,4-benzoxazin-7-yl)acetic acid Ex.15

3- 0X0-3,4- following protocol A, substituted amine (0.9 equiv), DMAP dihydro-2H-1 ,4- (3.2 equiv), EDCI.HCI (1.2 equiv), 18h at rt, purification by benzoxazin-7- preparative HPLC, yield 51 %, mp: 99°C, appearance: white yl)-N-{[4- solid

methoxy-2- (morpholin-4- - 1 H NMR (300 MHz, d in ppm): 1.36 (s, 6H), 2.17 (s, 3H), yl)phenyl](5- 2.55-2.63 (m, 2H), 2.75-2.89 (m, 2H), 3.35 (s, 2H), 3.49- methylfuran-2- 3.58 (m, 2H), 3.59-3.67 (m, 2H), 3.73 (s, 3H), 5.84 (d, 1 H, yl)methyl}aceta J=3.0Hz), 5.93 (dd, 1 H, J=2.9Hz, J=1.0Hz), 6.45 (d, 1 H, mide J=8.4Hz), 6.66-6.84 (m, 5H), 7.18 (d, 1 H, J=9.1 Hz), 8.72 (d,

1 H, J=8.5Hz), 10.53 (br(s), 1 H) ; m/z: 520 [M+H]+ (calc. mass: 519).

- From (2-bromo-4-methylphenyl)(5-methylfuran-2-

N-[(2-bromo-4- yl)methanamine hydrochloride Ex.18 and 2-(3-oxo-3,4- methylphenyl)(5 dihydro-2H-1 ,4-benzoxazin-7-yl)acetic acid Ex.2 following

-methylfuran-2- protocol A, DMAP (3.2 equiv), EDCI.HCI (1 .1 equiv), 2h at yl)methyl]-2-(3- rt. After sat. NH4CI addition, the precipitate was collected oxo-3,4-dihydro- by filtration and washed with Et20, yield 65%, mp: 250°C,

2H-1 ,4- appearance: white solid

benzoxazin-7-

- 1 H NMR (300 MHz, d in ppm): 2.21 (s, 3H), 2.28 (s, 3H), yl)acetamide

3.40 (s, 2H), 4.52 (s, 2H), 5.76 (d, 1 H, J=2.9Hz), 5.96 (d, 1 H, J=2.2Hz), 6.24 (d, 1 H, J=7.9Hz), 6.76-6.84 (m, 3H), 7.20 (d, 1 H, J=7.7Hz), 7.29 (d, 1 H, J=7.9Hz), 7.43 (br(s), 1 H), 9.05 (d, 1 H, J=8.0Hz), 10.63 (s, 1 H) ; m/z: 491

[M+Na]+, 493 [M+Na]+ (calc. mass: 468).

- From (2,4-dimethylphenyl)(5-ethylfuran-2-yl)methanamine hydrochloride Ex.21 and 2-(3-oxo-3,4-dihydro-2H-1 ,4- benzoxazin-7-yl)acetic acid Ex.2 following protocol A,

N-[(2,4- DMAP (3.2 equiv), EDCI.HCI (1.1 equiv), 2h at rt. After sat. dimethylphenyl) NH4CI addition, the precipitate was collected by filtration

(5-ethylfuran-2- and washed with Et20, yield 73%, mp: 248°C, appearance: yl)methyl]-2-(3- white solid

oxo-3,4-dihydro-

2H-1 ,4- - 1 H NMR (300 MHz, d in ppm): 1.12 (t, 3H, J=7.6Hz), 2.17 benzoxazin-7- (s, 3H), 2.23 (s, 3H), 2.54 (q, 2H, J=7.5Hz), 3.38 (s, 2H), yl)acetamide 4.52 (s, 2H), 5.84 (d, 1 H, J=2.6Hz), 5.97 (d, 1 H, J=3.1 Hz),

6.10 (d, 1 H, J=8.2Hz), 6.75-6.84 (m, 3H), 6.96-6.98 (m, 2H), 7.07 (d, 1 H, J=8.2Hz), 8.90 (d, 1 H, J=8.4Hz), 10.62 (s, 1 H) ; m/z: 441 [M+Na]+ (calc. mass: 418).

- From (2,4-dimethylphenyl)(5-methylfuran-2-yl)methanamine Ex.19 and 2-(3-oxo-3,4-dihydro-2H-1 ,4-benzoxazin-7-

N-[(2,4- yl)acetic acid Ex.2 following protocol A, DMAP (3.2 equiv), dimethylphenyl) EDCI.HCI (1.1 equiv), 2h at rt. After sat. NH4CI addition, the

(5-methylfuran- precipitate was collected by filtration and washed with

2-yl)methyl]-2- Et20, yield 87%, mp: 250°C, appearance: white solid

(3-oxo-3,4- - 1 H NMR (300 MHz, d in ppm): 2.17 (s, 3H), 2.20 (s, 3H), dihydro-2H-1 ,4- 2.23 (s, 3H), 3.38 (s, 2H), 4.52 (s, 2H), 5.84 (d, 1 H,

benzoxazin-7- J=2.9Hz), 5.96 (d, 1 H, J=2.1 Hz), 6.09 (d, 1 H), 6.75-6.83 (m, yl)acetamide 3H), 6.96-6.98 (m, 2H), 7.08 (d, 1 H, J=8.4Hz), 8.91 (d, 1 H,

J=8.4Hz), 10.63 (s, 1 H) ; m/z: 427 [M+Na]+ (calc. mass: 404).

- From (2-bromo-4-methoxyphenyl)(5-methylfuran-2- yl)methanamine hydrochloride Ex.22 and 2-(3-oxo-3,4- dihydro-2H-1 ,4-benzoxazin-7-yl)acetic acid Ex.2 following

N-[(2-bromo-4- protocol A, DMAP (3.2 equiv), EDCI.HCI (1 .1 equiv), 2h at methoxyphenyl) rt. After sat. NH4CI addition, the precipitate was collected

(5-methylfuran- by filtration and washed with Et20, yield 79%, mp: 235°C,

2-yl)methyl]-2- appearance: white solid

(3-0X0-3,4- dihydro-2H-1 ,4- - 1 H NMR (300 MHz, d in ppm): 2.21 (s, 3H), 3.39 (s, 2H), benzoxazin-7- 3.76 (s, 3H), 4.52 (s, 2H), 5.77 (d, 1 H, J=2.8Hz), 5.96 (d, yl)acetamide 1 H, J=2.1 Hz), 6.22 (d, 1 H, J=8.1 Hz), 6.79-6.84 (m, 3H),

6.98 (dd, 1 H, J=8.6Hz, J=2.6Hz), 7.16 (d, 1 H, J=2.6Hz), 7.31 (d, 1 H, J=8.6Hz), 9.02 (d, 1 H, J=7.9Hz), 10.63 (s, 1 H) ; m/z: 507 [M+Na]+, 509 [M+Na]+ (calc. mass: 484).

N-{[4-methyl-2-

- From [4-methyl-2-(piperidin-1 -yl)phenyl](5-methylfuran-2-

(piperidin-1 - yl)methanamine Ex.16 and 2-(3-oxo-3,4-dihydro-2H-1 ,4- yl)phenyl](5- benzoxazin-7-yl)acetic acid Ex.2 following protocol A, methylfuran-2- DMAP (2.2 equiv), EDCI.HCI (1.1 equiv), 2h at rt. After sat. yl)methyl}-2-(3- NH4CI addition, the precipitate was collected by filtration oxo-3,4-dihydro- and washed with Et20, yield 37%, mp: 154°C, appearance:

2H-1.4- white solid

benzoxazin-7- yl)acetamide - 1 H NMR (300 MHz, d in ppm): 1 .44-1 .53 (m, 6H), 2.17 (s, 3H), 2.25 (s, 3H), 2.52-2.56 (m, 2H), 2.75-2.79 (m, 2H), 3.36 (s, 2H), 4.51 (s, 2H), 5.80 (d, 1 H, J=3.1 Hz), 5.92 (d, 1 H, J=3.1 Hz), 6.47 (d, 1 H, J=8.2Hz), 6.75-6.82 (m, 3H), 6.88 (d, 1 H, J=8.2Hz), 6.94 (br(s), 1 H), 7.17 (d, 1 H,

J=7.8Hz), 8.69 (d, 1 H, J=8.0Hz), 10.61 (s, 1 H) ; m/z: 474 [M+H]+ (calc. mass: 473).

- From (2-bromo-4-methylphenyl)(5-methylfuran-2- yl)methanamine hydrochloride Ex.18 and 2-(2-oxo-1 ,2,3,4- tetrahydroquinolin-6-yl)acetic acid Ex.23 following protocol

N-[(2-bromo-4- A, DMAP (3.2 equiv), EDCI.HCI (1 .1 equiv), 2h at rt. After methylphenyl)(5 sat. NH4CI addition, the precipitate was collected by

-methylfuran-2- filtration and washed with Et20, yield 77%, mp: 188°C, yl)methyl]-2-(2- appearance: white solid

oxo-1 ,2,3,4- - 1 H NMR (300 MHz, DMSO-d6, d in ppm): 2.21 (s, 3H), 2.28 tetrahydroquino (s, 3H), 2.40 (t, 2H, J=8.0Hz), 2.81 (t, 2H, J=7.3Hz), 3.40 (s, lin-6- 2H), 5.77 (d, 1 H, J=3.0Hz), 5.96 (d, 1 H, J=2.3Hz), 6.24 (d, yl)acetamide 1 H, J=8.1 Hz), 6.74 (d, 1 H, J=7.9Hz), 7.00 (dd, 1 H, J=8.1 Hz,

J=1.9Hz), 7.02 (s, 1 H), 7.20 (d, 1 H, J=8.2Hz), 7.31 (d, 1 H, J=8.0Hz), 7.42 (d, 1 H), 9.04 (d, 1 H, J=8.3Hz), 9.99 (s, 1 H) ; m/z: 489 [M+Na]+, 491 [M+Na]+ (calc. mass: 466).

- See Figure 3AC

- To a solution of previously synthesized 2-(2,3-dioxo-2,3- dihydro-1 H-indol-5-yl)-N-{[4-methyl-2-(piperidin-1 - yl)phenyl](5-methylfuran-2-yl)methyl}acetamide Cpd.23 (30

2-(3- mg, 0.064 mmol) in MeOH (2 mL) was added hydrazine hydrazinylidene

hydrate 50% (w/w) (4 mg, 0.07 mmol). The reaction was

-2-oxo-2,3- heated at 100°c overnight. The solvents were removed dihydro-1 H- under reduced pressure. The crude material was purified by indol-5-yl)-N-{[4- silica gel column chromatography using

methyl-2- Cyclohexane/EtOAc (1 :1 ) as eluent to afford Cpd.37 (5 mg,

(piperidin-1 - 16%) as white solid

yl)phenyl](5- methylfuran-2- - 1 H NMR (300 MHz, d in ppm): 1 .47-2.30 (m, 6H), 2.20 (s, yl)methyl}aceta 3H), 2.30 (s, 3H), 2.58-2.66 (m, 2H), 2.71 -2.82 (m, 2H), mide 3.53 (s, 0.8H), 3.56 (s, 1.2H), 5.82-5.83 (m, 1 H), 5.86-5.88

(m, 1 H), 6.60 (s, 0.4H), 6.63 (s, 0.6H), 6.81 -6.99 (m, 2H), 7.10 (s, 1 H), 7.10-7.21 (m, 2H), 7.41 (d, 0.4H, J=1 .2Hz), 7.73 (d, 0.6H, J=1 .1 Hz) ; m/z: 486 [M+H]+ (calc. mass: 485) ; mp: n.d.

- From [4-methyl-2-(piperidin-1 -yl)phenyl](5-methylfuran-2-

N-{[4-methyl-2- yl)methanamine Ex.16 and 2-(1 -methyl-2-oxo-2,3-dihydro-

(piperidin-1 - 1 H-indol-5-yl)acetic acid Ex.24 following protocol A, DMAP yl)phenyl](5- (3.2 equiv), EDCI.HCI (1 .1 equiv), 2h at rt, purification by methylfuran-2- silica gel column chromatography (Cyclohexane/EtOAc, yl)methyl}-2-(1 - 6:4), yield 30%, mp: 215°C, appearance: white solid

methyl-2-oxo-

2,3-dihydro-1 H- - 1 H NMR (300 MHz, d in ppm): 1 .39-1 .55 (m, 6H), 2.17 (s, indol-5- 3H), 2.25 (s, 3H), 2.52-2.59 (m, 2H), 2.77-2.81 (m, 2H), yl)acetamide 3.08 (s, 3H), 3.42 (s, 2H), 3.49 (s, 2H), 5.80 (d, 1 H,

J=3.1 Hz), 5.91 -5.93 (m, 1 H), 6.48 (d, 1 H, J=8.6Hz), 6.85- 6.91 (m, 2H), 6.94 (s, 1H), 7.12-7.13 (m, 2H), 7.19 (d, 1H, J=7.8Hz), 8.69 (d, 1H, J=8.4Hz) ; m/z: 472 [M+H]+ (calc. mass: 471).

- From [4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2- yl)methanamine Ex.16 and 2-(3-hydroxy-1 ,3-dimethyl-2- oxo-2,3-dihydro-1 H-indol-5-yl)acetic acid Ex.25 following

2-(3-hydroxy- protocol A, DMAP (3.2 equiv), EDCI.HCI (1.1 equiv), 2h at

1, 3 -dimethyl -2 - rt, purification by silica gel column chromatography

oxo-2,3-dihydro- (Cyclohexane/EtOAc, 6:4), yield 36%, mp: 103°C,

1H-indol-5-yl)-N- appearance: white solid

{[4-methyl-2-

(piperidin-1- - 1H NMR (300 MHz, d in ppm): 1.32 (s, 1.5H), 1.34 (s, yl)phenyl](5- 1.5H), 1.39-1.53 (m, 6H), 2.17 (s, 1.5H), 2.18 (s, 1.5H), 2.24 methylfuran-2- (s, 3H), 2.51-2.56 (m, 2H), 2.71-2.79 (m, 2H), 3.06 (d, 3H, yl)methyl}aceta J=0.9Hz), 3.43 (s, 2H), 5.81 (d, 1H, J=3.1Hz), 5.89 (s, 1H), mide 5.91-5.93 (m, 1H), 6.49 (d, 1H, J=8.7Hz), 6.85-6.91 (m,

2H), 6.94 (s, 1H), 7.14-7.17 (m, 1H), 7.19 (d, 1H, J=7.9Hz), 7.22-7.24 (m, 1H), 8.71 (d, 0.5H, J=8.5Hz), 8.73 (d, 0.5H, J=8.2Hz) ; m/z: 502 [M+H]+ (calc. mass: 501).

- From [4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2- yl)methanamine Ex.16 and 2-(1,3,3-trimethyl-2-oxo-2,3- dihydro-1 H-indol-5-yl)acetic acid Ex.26 following protocol A,

N-{[4-methyl-2- DMAP (3.2 equiv), EDCI.HCI (1.1 equiv), 2h at rt,

(piperidin-1- purification by silica gel column chromatography

yl)phenyl](5- (Cyclohexane/EtOAc, 6:4), yield 28%, mp: 75°C,

methylfuran-2- appearance: white solid

yl)methyl}-2-

(1,3,3-trimethyl- - 1H NMR (300 MHz, d in ppm): 1.21 (s, 3H), 1.22 (s, 3H),

2-0X0-2,3- 1.45-1.54 (m, 6H), 2.17 (s, 3H), 2.24 (s, 3H), 2.52-2.58 (m, dihydro-1H- 2H), 2.73-2.85 (m, 2H), 3.09 (s, 3H), 3.43 (s, 2H), 5.81 (d, indol-5- 1H, J=3.0Hz), 5.92 (dd, 1H, J=3.0Hz, J=1.1Hz), 6.49 (d, 1H, yl)acetamide J=8.4Hz), 6.87 (dd, 1H, J=7.7Hz, J=1.3Hz), 6.90 (d, 1H,

J=7.8Hz), 6.92 (d, 1H, J=0.9Hz), 7.12 (dd, 1H, J=8.0Hz, J=1.6Hz), 7.18 (d, 1H, J=2.1Hz), 7.20 (d, 1H, J=4.3Hz), 8.70 (d, 1H, J=8.6Hz) ; m/z: 500 [M+H]+ (calc. mass: 499).

- From [4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2- yl)methanamine Ex.16 and 2-(2-methanesulfonyl-2,3-

2-(2- dihydro-1 H-isoindol-5-yl)acetic acid Ex.27 following protocol methanesulfony A, DMAP (2.2 equiv), EDCI.HCI (1.2 equiv), 18h at rt,

1- 2,3-dihydro- purification by silica gel column chromatography

1H-isoindol-5- (Cyclohexane/EtOAc, 1:1), yield 83%, mp: 83°C,

yl)-N-{[4-methyl- appearance: white solid

2- (piperidin-1- - 1H NMR (300 MHz, d in ppm): 1.46-1.55 (m, 6H), 2.17 (s, yl)phenyl](5- 3H), 2.25 (s, 3H), 2.53-2.59 (m, 2H), 2.77-2.81 (m, 2H), methylfuran-2- 2.95 (s, 3H), 3.48 (s, 2H), 4.57 (s, 4H), 5.81 (d, 1H,

yl)methyl}aceta J=3.0Hz), 5.93 (dd, 1H, J=3.0Hz, J=1.1Hz), 6.48 (d, 1H, mide J=8.3Hz), 6.89 (d, 1H, J=7.9Hz), 6.94 (s, 1H), 7.16-7.24 (m,

4H), 8.76 (d, 1H, J=8.5Hz) ; m/z: 522 [M+H]+ (calc. mass: 521).

2-[3-

- See Figure 3AD

(hydroxyimino)- 2-oxo-2,3- - A solution of previously synthesized 2-(2,3-dioxo-2,3- dihydro-1 H- dihydro-1 H-indol-5-yl)-N-{[4-methyl-2-(piperidin-1 - indol-5-yl]-N-{[4- yl)phenyl](5-methylfuran-2-yl)methyl}acetamide Cpd.23 (16 methyl-2- mg, 0.034 mmol) and hydroxylamine hydrochloride (4 mg,

(piperidin-1 - 0.051 mmol) in EtOH (1 mL) was heated at 80°C overnight. yl)phenyl](5- The solvents were removed under reduced pressure. The methylfuran-2- crude material was purified by silica gel column

yl)methyl}aceta chromatography using CH2CI2/MeOH (95:5) as eluent to mide afford N-{[4-methyl-2-(piperidin-1 -yl)phenyl](5-methylfuran- 2-yl)methyl}-2-(2-oxo-2,3-dihydro-1 H-indol-6-yl)acetamide (1 1 mg, 67%) as pale yellow solid, mp: n.d.

- 1 H NMR (300 MHz, d in ppm): 1 .40-1 .58 (m, 6H), 2.16 (s, 3H), 2.24 (s, 3H), 2.50-2.58 (m, 2H), 2.72-2.8 (m, 2H), 3.41 (s, 2H), 5.82 (d, 1 H, J=2.9Hz), 5.92 (d, 1 H, J=2.0Hz), 6.45 (d, 1 H, J=8.3Hz), 6.77 (d, 1 H, J=8.0Hz), 6.88 (d, 1 H, J=8.2Hz), 6.93 (s, 1 H), 7.17 (d, 1 H, J=7.8Hz), 7.21 (dd, 1 H, J=8.0Hz, J=1.6Hz), 7.88 (s, 1 H), 8.74 (d, 1 H, J=8.3Hz), 10.61 (s, 1 H), 13.26 (s, 1 H) ; m/z: 487 [M+H]+ (calc. mass: 486).

- See Figure 3AE

- To a solution of previously synthesized N-{[4-methyl-2- (piperidin-1 -yl)phenyl](5-methylfuran-2-yl)methyl}-2-(2-oxo- 2,3-dihydro-1 H-indol-5-yl)acetamide Cpd.24 (75 mg, 0.16 mmol) and 3,5-dimethyl-1 ,2-oxazole-4-carbaldehyde (25 mg, 0.20 mmol) in EtOH (2 mL) was added few drops of catalytic piperidine. The reaction mixture was heated at

2-{3-[(dimethyl- 80°C overnight. The solvents were removed under reduced

1 ,2-oxazol-4- pressure. The crude material was purified by silica gel yl)methylidene]- column chromatography using CH2CI2/MeOH (95:5) as

2-0X0-2,3- eluent to afford 2-{3-[(dimethyl-1 ,2-oxazol-4- dihydro-1 H- yl)methylidene]-2-oxo-2,3-dihydro-1 H-indol-5-yl}-N-{[4- indol-5-yl}-N-{[4- methyl-2-(piperidin-1 -yl)phenyl](5-methylfuran-2- methyl-2- yl)methyl}acetamide (80 mg, 86%) as yellow solid, mp:

(piperidin-1 - 128°C

yl)phenyl](5- methylfuran-2- - 1 H NMR (300 MHz, d in ppm): 1 .40-1 .54 (m, 6H), 2.16 (s, yl)methyl}aceta 3H), 2.20 (s, 3H), 2.22 (s, 3H), 2.24 (s, 3H), 2.50-2.60 (m, mide 2H), 2.71 -2.81 (m, 2H), 3.34 (s, 1 .5H), 3.44 (s, 0.5H), 5.77

(d, 0.75H, J=3.0Hz), 5.82 (d, 0.25H, J=2.9Hz), 5.90-5.95 (m, 1 H), 6.44 (d, 0.75H, J=8.3Hz), 6.49 (d, 0.25H, J=8.1 Hz), 6.74 (d, 0.25H, J=7.8Hz), 6.78 (d, 0.75H, J=8.0Hz), 6.85- 6.93 (m, 2.75H), 7.1 1 -7.13 (m, 1.75H), 7.20 (s, 0.75H), 7.22 (s, 0.25H), 7.41 (s, 0.25H), 7.51 (s, 0.25H), 8.68 (d, 0.75H, J=8.5Hz), 8.72 (d, 0.25H, J=8.0Hz), 10.47 (s, 0.25H), 10.57 (s, 0.75H) ; m/z: 565 [M+H]+ (calc. mass: 564).

2-{3-[(2-amino-

- See Figure 3AE

1 ,3-thiazol-5- yl)methylidene]- - To a solution of previously synthesized N-{[4-methyl-2-

2-0X0-2,3- (piperidin-1 -yl)phenyl](5-methylfuran-2-yl)methyl}-2-(2-oxo- dihydro-1 H- 2,3-dihydro-1 H-indol-5-yl)acetamide Cpd.24 (75 mg, 0.16 indol-5-yl}-N-{[4- mmol) and 2-amino-1 ,3-thiazole-5-carbaldehyde (25 mg, methyl-2- 0.20 mmol) in EtOH (2 mL) was added few drops of (piperidin-1 - catalytic piperidine. The reaction mixture was heated at yl)phenyl](5- 80°C overnight. The precipitate formed was collected by methylfuran-2- filtration, triturated with small amount of EtOH and dried yl)methyl}aceta until constant weight to afford 2-{3-[(2-amino-1 ,3-thiazol-5- mide yl)methylidene]-2-oxo-2,3-dihydro-1 H-indol-5-yl}-N-{[4- methyl-2-(piperidin-1 -yl)phenyl](5-methylfuran-2- yl)methyl}acetamide (55 mg, 59%) as yellow solid, mp: 235°C

- 1 H NMR (300 MHz, d in ppm): 1 .40-1 .55 (m, 6H), 2.16 (s, 3H), 2.24 (s, 3H), 2.50-2.58 (m, 2H), 2.72-2.78 (m, 2H), 3.42 (s, 2H), 5.81 (d, 1 H, J=2.9Hz), 5.92 (dd, 1 H, J=2.9Hz, J=1.0Hz), 6.49 (d, 1 H, J=8.6Hz), 6.68 (d, 1 H, J=8.0Hz), 6.89 (d, 1 H, J=7.7Hz), 6.93 (s, 1 H), 6.97 (dd, 1 H, J=8.1 Hz, J=1.4Hz), 7.20 (d, 1 H, J=7.8Hz), 7.35 (s, 1 H), 7.71 (s, 1 H), 7.72 (s, 1 H), 7.84 (br(s), 2H), 8.68 (d, 1 H, J=8.5Hz), 10.32 (s, 1 H) ; m/z: 568 [M+H]+ (calc. mass: 567).

- See Figure 3AF

- 2-(2,3-dioxo-2,3-dihydro-1 H-indol-5-yl)-N-{[4-methyl-2- (piperidin-1 -yl)phenyl](5-methylfuran-2-yl)methyl}acetamide Cpd.23 (100 mg, 0.21 mmol) was dissolved in dry THF (5 ml_). The solution was cooled to 0°C and sodium hydride 60% in oil (17 mg, 0.42 mmol) was added followed by iodomethane (15 μΙ_, 0.23 mmol). The ice bath was removed and the mixture was stirred at rt overnight. The

2-(1 -methyl-2,3- reaction was stopped with water. The aqueous layer was dioxo-2,3- extracted with EtOAc. The organic layer was dried over dihydro-1 H- MgS04, filtered and the solution was concentrated under indol-5-yl)-N-{[4- reduced pressure. The crude material was purified by silica methyl-2- gel column chromatography using Cyclohexane/EtOAc

(piperidin-1 - (6:4) as eluent affording 2-(1 -methyl-2,3-dioxo-2,3-dihydro- yl)phenyl](5- 1 H-indol-5-yl)-N-{[4-methyl-2-(piperidin-1 -yl)phenyl](5- methylfuran-2- methylfuran-2-yl)methyl}acetamide (50 mg, 49%) as orange yl)methyl}aceta

solid, mp: 99°C

mide

- 1 H NMR (300 MHz, d in ppm): 1 .40-1 .60 (m, 6H), 2.17 (s, 3H), 2.25 (s, 3H), 2.50-2.62 (m, 2H), 2.72-2.84 (m, 2H), 3.1 1 (s, 3H), 3.47 (s, 2H), 5.80 (d, 1 H, J=3.0Hz), 5.92 (dd, 1 H, J=2.9Hz, J=1 .0Hz), 6.49 (d, 1 H, J=8.7Hz), 6.89 (d, 1 H, J=7.7Hz), 6.94 (s, 1 H), 7.06 (d, 1 H, J=8.0Hz), 7.18 (d, 1 H, J=7.8Hz), 7.40 (d, 1 H, J=1 .5Hz), 7.51 (dd, 1 H, J=8.1 Hz, J=1.8Hz), 8.78 (d, 1 H, J=8.3Hz) ; m/z: 486 [M+H]+ (calc. mass: 485).

2-(3-hydroxy-2- - See Figure 3AG

oxo-2,3-dihydro-

- 2-(2,3-dioxo-2,3-dihydro-1 H-indol-5-yl)-N-{[4-methyl-2-

1 H-indol-5-yl)-N- (piperidin-1 -yl)phenyl](5-methylfuran-2-yl)methyl}acetamide

{[4-methyl-2- Cpd.23 (100 mg, 0.21 mmol) was dissolved in EtOH (10

(piperidin-1 - ml_). The solution was cooled to 0°C and sodium

yl)phenyl](5- borohydride (9 mg, 0.23 mmol) was added. After 10 min at methylfuran-2- 0°C, the reaction was completed. The reaction was yl)methyl}aceta

quenched with citric acid 1 N. The solvent was removed mide

under reduced pressure. EtOAc was added and the solution was washed with water. The organic layer was dried over MgS04, filtered and the solution was concentrated under reduced pressure to afford 2-(3-hydroxy-2-oxo-2,3-dihydro- 1 H-indol-5-yl)-N-{[4-methyl-2-(piperidin-1 -yl)phenyl](5- methylfuran-2-yl)methyl}acetamide (75 mg, 75%) as pale brown solid, mp: 1 10°C

- 1 H NMR (300 MHz, d in ppm): 1 .40-1 .60 (m, 6H), 2.17 (s, 3H), 2.25 (s, 3H), 2.50-2.60 (m, 2H), 2.76-2.82 (m, 2H), 3.39 (s, 2H), 4.75-4.78 (m, 1 H), 5.79-5.81 (m, 1 H), 5.90- 5.92 (m, 1 H), 6.14 (d, 1 H, J=7.7Hz), 6.47 (d, 1 H, J=8.2Hz), 6.67 (d, 1 H, J=7.9Hz), 6.89 (d, 1 H, J=7.7Hz), 6.94 (s, 1 H), 7.06 (d, 1 H, J=7.8Hz), 7.17-7.20 (m, 2H), 8.71 (d, 1 H, J=8.5Hz), 10.15 (s, 1 H) ; m/z: 474 [M+H]+ (calc. mass: 473).

- See Figure 3AH

- To a solution of 2-(2,3-dioxo-2,3-dihydro-1 H-indol-5-yl)-N- {[4-methyl-2-(piperidin-1 -yl)phenyl](5-methylfuran-2- yl)methyl}acetamide Cpd.23 (150 mg, 0.32 mmol) dissolved in dry THF (10 mL) was added dropwise methylmagnesium bromide (265 μΙ_, 0.80 mmol) at 0°C. The solution was slowly warmed to rt and stirred at this temperature overnight. TLC show still starting material. The solution was cooled to 0°C and additionnal methylmagnesium bromide (7.5 equiv) was added dropwise to the mixture. After 2 h,

2-(3-hydroxy-3- the reaction was stopped with water and neutralized with a methyl-2-oxo- solution of citric acid 1 N. The aqueous layer was extracted

2,3-dihydro-1 H- with EtOAc. The combined organic layers were dried over indol-5-yl)-N-{[4- MgS04, filtered and the solution was concentrated under methyl-2- reduced pressure. The crude material was purified by silica

(piperidin-1 - gel column chromatography using Cyclohexane/EtOAc yl)phenyl](5-

(1 :1 ) as eluent yielding 2-(3-hydroxy-3-methyl-2-oxo-2,3- methylfuran-2- dihydro-1 H-indol-5-yl)-N-{[4-methyl-2-(piperidin-1 - yl)methyl}aceta

yl)phenyl](5-methylfuran-2-yl)methyl}acetamide (50 mg, mide

32%) as white solid, mp: 1 12°C

- 1 H NMR (300 MHz, d in ppm): 1 .33 (s, 1.5H), 1 .34 (s, 1 .5H), 1 .34-1.62 (m, 6H), 2.16 (s, 1 .5H), 2.17 (s, 1 .5H), 2.24 (s, 3H), 2.50-2.60 (m, 2H), 2.73-2.84 (m, 2H), 3.39 (s, 1 H), 3.40 (s, 1 H), 5.80-5.81 (m, 1 H), 5.82 (s, 1 H), 5.91 -5.93 (m, 1 H), 6.48 (d, 1 H, J=8.5Hz), 6.69 (d, 1 H, J=7.8Hz), 6.88 (d, 0.5H, J=7.9Hz), 6.89 (d, 0.5H, J=8.2Hz), 6.94 (s, 1 H), 7.05 (d, 1 H, J=7.8Hz), 7.18-7.20 (m, 2H), 8.70 (d, 0.5H, J=8.3Hz), 8.71 (d, 0.5H, J=8.5Hz), 10.13 (s, 1 H) ; m/z: 488 [M+H]+ (calc. mass: 487).

N-{[4-methyl-2-

- See Figure 3AE

(piperidin-1 - yl)phenyl](5- - To a solution of previously synthesized N-{[4-methyl-2- methylfuran-2- (piperidin-1 -yl)phenyl](5-methylfuran-2-yl)methyl}-2-(2-oxo- yl)methyl}-2- 2,3-dihydro-1 H-indol-5-yl)acetamide Cpd.24 (50 mg, 0.1 1

[(3E)-3-(2- mmol) and isobutyraldehyde (10 μΙ_, 0.1 1 mmol) in EtOH (1 methylpropylide mL) was added few drops of catalytic piperidine. The ne)-2-oxo-2,3- reaction mixture was heated at 90°C overnight. The solvent dihydro-1 H- was removed under reduced pressure and the crude indol-5- material was purified by preparative HPLC to give N-{[4- yl]acetamide methyl-2-(piperidin-1 -yl)phenyl](5-methylfuran-2-yl)methyl}- 2-[(3E)-3-(2-methylpropylidene)-2-oxo-2,3-dihydro-1 H-indol- 5-yl]acetamide (10 mg, 17%) as white solid, mp: 91 °C

- 1 H NMR (300 MHz, d in ppm): 1 .07-1 .15 (m, 3H), 1 .23 (s, 3H), 1 .36-1 .63 (m, 6H), 2.16 (s, 3H), 2.24 (s, 3H), 2.55-2.58 (m, 2H), 2.73-2.81 (m, 2H), 3.39-3.44 (m, 2H), 5.81 (d, 1 H, J=3.03Hz), 5.90-5.95 (m, 1 H), 6.47 (d, 1 H, J=8.55Hz), 6.52 (s, 0.3H), 6.57 (d, 0.7H, J=10.0Hz), 6.73 (d, 1 H, J=7.8Hz), 6.86 (d, 1 H, J=7.6Hz), 6.93 (s, 1 H), 7.07 (d, 1 H, J=9.1 Hz), 7.17 (d, 1 H, J=7.8Hz), 7.48 (s, 1 H), 8.72 (d, 1 H, J=8.3Hz), 10.37 (br(s), 1 H) (proton on central carbon of isopropyl group is under the pic of DMSO-d6) ; m/z: 512 [M+H]+ (calc. mass: 51 1 ).

- See Figure 3AI

- To a solution of previously synthesized N-{[4-methyl-2- (piperidin-1 -yl)phenyl](5-methylfuran-2-yl)methyl}-2-(2-oxo- 2,3-dihydro-1 H-indol-5-yl)acetamide Cpd.24 (150 mg, 0.33 mmol) in THF (4 mL) was added

(dimethoxymethyl)dimethylamine (78 mg, 0.66 mmol). The reaction mixture was stirred at rt for 3 h, then the solvent was removed under reduced pressure. EtOH (5 mL) was added to the crude and the solution was cooled at 0°C. Sodium borohydride (25 mg, 0.66 mmol) was added to the solution. The reaction mixture was stirred at rt overnight.

N-{[4-methyl-2- Citric acid 1 N was added to quench the reaction and the

(piperidin-1 - aqueous layer was extracted with EtOAc. The combined yl)phenyl](5- organic layer was dried over MgS04, filtered and the methylfuran-2- solution was concentrated under reduced pressure. The yl)methyl}-2-(3- crude material was purified by silica gel column

methyl-2-oxo- chromatography using CH2CI2/MeOH (97:3) as eluent to

2,3-dihydro-1 H- afford N-{[4-methyl-2-(piperidin-1 -yl)phenyl](5-methylfuran- indol-5- 2-yl)methyl}-2-(3-methyl-2-oxo-2,3-dihydro-1 H-indol-5- yl)acetamide

yl)acetamide (12 mg, 8%) as white solid, mp: 102°C

- 1 H NMR (300 MHz, d in ppm): 1 .24 (d, 1 .5H, J=7.7Hz), 1 .28 (d, 1 .5H, J=7.7Hz), 1.4-1.62 (m, 6H), 2.16 (s, 1 .5H), 2.17 (s, 1.5H), 2.24 (s, 3H), 2.50-2.60 (m, 2H), 2.70-2.82 (m, 2H), 3.29-3.36 (m, 1 H), 3.39 (s, 2H), 5.81 (d, 1 H, J=3.0Hz), 5.90-5.95 (m, 1 H), 6.47 (d, 1 H, J=8.6Hz), 6.70 (d, 1 H, J=7.7Hz), 6.85-6.89 (m, 0.5H), 6.91 -6.94 (m, 0.5H), 6.93 (s, 1 H), 7.02 (d, 1 H, J=7.9Hz), 7.1 1 (s, 1 H), 7.18 (d, 1 H, J=7.7Hz), 8.67 (d, 0.5H, J=8.5Hz), 8.69 (d, 0.5H, J=9.0Hz), 10.24 (br(s), 1 H); m/z: 472 [M+H]+ (calc. mass: 471 )

2-(2- methanesulfony - From [4-methyl-2-(piperidin-1 -yl)phenyl](5-methylfuran-2-

1- 2,3-dihydro- yl)methanamine Ex.16 and 2-(2-methanesulfonyl-2,3- 1 H-isoindol-4- dihydro-1 H-isoindol-4-yl)acetic acid Ex.28 following protocol yl)-N-{[4-methyl- A, DMAP (3.2 equiv), EDCI.HCI (1 .2 equiv), 18h at rt,

2- (piperidin-1 - purification by silica gel column chromatography yl)phenyl](5- (Cyclohexane/EtOAc, 6:4). The solid was then triturated in methylfuran-2- Et20 and filtered-off, yield 64%, mp: 155°C, appearance: yl)methyl}aceta white solid

mide

- 1 H NMR (300 MHz, d in ppm): 1 .45-1 .52 (m, 6H), 2.18 (s, 3H), 2.25 (s, 3H), 2.52-2.59 (m, 2H), 2.76-2.80 (m, 2H), 2.89 (s, 3H), 3.48 (s, 2H), 4.62 (s, 4H), 5.82 (d, 1 H, J=3.1 Hz), 5.93 (dd, 1 H, J=3.0Hz, J=1 .0Hz), 6.49 (d, 1 H, J=8.3Hz), 6.90 (d, 1 H, J=7.9Hz), 6.94 (s, 1 H), 7.15-7.26 (m, 4H), 8.81 (d, 1 H, J=8.4Hz) ; m/z: 522 [M+H]+ (calc. mass: 521 ).

- From [4-methyl-2-(piperidin-1 -yl)phenyl](5-methylfuran-2- yl)methanamine Ex.16 and 2-(1 -oxo-2,3-dihydro-1 H-inden- 5-yl)acetic acid Ex.29 following protocol A, DMAP (1 .0

N-{[4-methyl-2- equiv), EDCI.HCI (1 .1 equiv), 18h at rt, purification by silica

(piperidin-1 - gel column chromatography (Cyclohexane/EtOAc, 7:3), yl)phenyl](5- yield 50%, mp: 74°C, appearance: white solid

methylfuran-2- yl)methyl}-2-(1 - - 1 H NMR (300 MHz, d in ppm): 1 .40-1 .60 (m, 6H), 2.17 (s, oxo-2,3-dihydro- 3H), 2.25 (s, 3H), 2.50-2.60 (m, 4H), 2.76-2.81 (m, 2H),

1 H-inden-5- 3.02-3.06 (m, 2H), 3.59 (s, 2H), 5.82 (d, 1 H, J=2.9Hz), 5.93 yl)acetamide (dd, 1 H, J=3.0Hz, J=1.0Hz), 6.50 (d, 1 H, J=8.4Hz), 6.90 (d,

1 H, J=7.9Hz), 6.94 (s, 1 H), 7.19 (d, 1 H, J=7.8Hz), 7.28 (d, 1 H, J=8.0Hz), 7.41 (s, 1 H), 7.54 (d, 1 H, J=7.9Hz), 8.84 (d, 1 H, J=8.4Hz) ; m/z: 457 [M+H]+ (calc. mass: 456).

- See Figure 3AJ

- The previously synthesized N-{[4-methyl-2-(piperidin-1 - yl)phenyl](5-methylfuran-2-yl)methyl}-2-(1 -oxo-2,3-dihydro- 1 H-inden-5-yl)acetamide Cpd.51 (120 mg, 0.26 mmol) was dissolved in EtOH (10 ml_). The solution was cooled to 0°C and sodium borohydride (15 mg, 0.39 mmol) was added. The ice bath was removed and the solution was stirred at rt

2-(1 -hydroxy- for 2 h. The solvent was removed under reduced pressure

2,3-dihydro-1 H- and citric acid 1 N to neutralized the solution. The aqueous inden-5-yl)-N- layer was extracted with CH2CI2. The organic layer was

{[4-methyl-2- dried over MgS04, filtered and the solution was

(piperidin-1 - concentrated under reduced pressure to afford 2-(1 - yl)phenyl](5- hydroxy-2,3-dihydro-1 H-inden-5-yl)-N-{[4-methyl-2- methylfuran-2- (piperidin-1 -yl)phenyl](5-methylfuran-2-yl)methyl}acetamide yl)methyl}aceta (83 mg, 67%) as white solid, mp: 97°C,

mide

- 1 H NMR (300 MHz, d in ppm): 1 .35-1 .55 (m, 6H), 1 .67-1.82 (m, 1 H), 2.17 (s, 3H), 2.25 (s, 3H), 2.27-2.34 (m, 1 H), 2.50- 2.70 (m, 3H), 2.73-2.91 (m, 3H), 3.43 (s, 2H), 4.97 (q, 1 H, J=6.2Hz), 5.12 (d, 1 H, J=5.9Hz), 5.80 (d, 1 H, J=2.9Hz), 5.92 (dd, 1 H, J=2.9Hz, J=1.0Hz), 6.48 (d, 1 H, J=9.8Hz), 6.89 (d, 1 H, J=7.9Hz), 6.93 (s, 1 H), 7.02-7.06 (m, 2H), 7.19 (d, 2H, J=7.8Hz), 8.71 (d, 1 H, J=8.5Hz) ; m/z: 459 [M+H]+ (calc. mass: 458).

2-(3-hydroxy-1 -

- See Figure 3AK

methyl-2-oxo-

2,3-dihydro-1 H- - 2-(1 -methyl-2,3-dioxo-2,3-dihydro-1 H-indol-5-yl)-N-{[4- indol-5-yl)-N-{[4- methyl-2-(piperidin-1 -yl)phenyl](5-methylfuran-2- methyl-2- yl)methyl}acetamide Cpd.45 (15 mg, 0.03 mmol) was

(piperidin-1 - dissolved in EtOH (500 μΙ_). The solution was cooled to 0°C yl)phenyl](5- and sodium borohydride (1 mg, 0.04 mmol) was added. methylfuran-2- After 5 min at 0°C, the reaction was completed. The yl)methyl}aceta reaction was quenched with citric acid 1 N. The solvent was mide removed under reduced pressure. EtOAc was added and the solution was washed with water. The organic layer was dried over MgS04, filtered and the solution was

concentrated under reduced pressure to afford 2-(3- hydroxy-1 -methyl-2-oxo-2,3-dihydro-1 H-indol-5-yl)-N-{[4- methyl-2-(piperidin-1 -yl)phenyl](5-methylfuran-2- yl)methyl}acetamide (12 mg, 74%) as white solid, mp: 155°C,

- 1 H NMR (300 MHz, d in ppm): 1 .40-1 .6 (m, 6H), 2.17 (s, 3H), 2.25 (s, 3H), 2.50-2.62 (m, 2H), 2.72-2.80 (m, 2H), 3.05 (s, 3H), 3.43 (s, 2H), 4.82-4.88 (m, 1 H), 5.79-5.82 (m, 1 H), 5.90-5.93 (m, 1 H), 6.21 (dd, 1 H, J=7.6Hz, J=0.5Hz), 6.48 (d, 1 H, J=8.7Hz), 6.86 (d, 1 H, J=8.1 Hz), 6.87-6.92 (m, 1 H), 6.94 (s, 1 H), 7.14-7.21 (m, 2H), 7.23 (s, 1 H), 8.72 (d, 1 H, J=8.5Hz) ; m/z: 488 [M+H]+ (calc. mass: 487).

- From [4-methyl-2-(piperidin-1 -yl)phenyl](5-methylfuran-2- yl)methanamine Ex.16 and 2-(7-methyl-2-oxo-2,3-dihydro-

N-{[4-methyl-2- 1 H-indol-5-yl)acetic acid Ex.30 following protocol A, DMAP

(piperidin-1 - (1 .0 equiv), EDCI.HCI (1 .1 equiv), 2h at rt, purification by yl)phenyl](5- silica gel column chromatography (Cyclohexane/EtOAc, methylfuran-2- 3:7), yield 30%, mp: 237°C, appearance: white solid yl)methyl}-2-(7- - 1 H NMR (300 MHz, d in ppm): 1 .40-1 .60 (m, 6H), 2.13 (s, methyl-2-oxo- 3H), 2.17 (s, 3H), 2.25 (s, 3H), 2.50-2.60 (m, 2H), 2.72-2.82

2,3-dihydro-1 H- (m, 2H), 3.34 (s, 2H), 3.41 (s, 2H), 5.80 (d, 1 H, J=2.8Hz), indol-5- 5.92 (dd, 1 H, J=3.0Hz, J=1.0Hz), 6.47 (d, 1 H, J=8.4Hz), yl)acetamide 6.83 (s, 1 H), 6.85-6.92 (m, 2H), 6.93 (s, 1 H), 7.19 (d, 1 H,

J=7.8Hz), 8.66 (d, 1 H, J=8.5Hz), 10.33 (s, 1 H) ; m/z: 472 [M+H]+ (calc. mass: 471 ).

- From [4-methyl-2-(piperidin-1 -yl)phenyl](5-methylfuran-2- yl)methanamine Ex.16 and 2-[2-oxo-3-(propan-2-ylidene)- 2,3-dihydro-1 H-indol-5-yl]acetic acid Ex.31 following

N-{[4-methyl-2- protocol A, DMAP (2.2 equiv), EDCI.HCI (1.2 equiv), 18h at

(piperidin-1 - rt, purification by silica gel column chromatography

yl)phenyl](5- (CH2CI2/MeOH, 98:2). The solid was triturated in EtOAc methylfuran-2- and filtered-off, yield 45%, mp: 172°C, appearance: white yl)methyl}-2-[2- solid

oxo-3-(propan-

2-ylidene)-2,3- - 1 H NMR (300 MHz, d in ppm): 1 .44-1 .53 (m, 6H), 2.16 (s, dihydro-1 H- 3H), 2.24 (s, 3H), 2.25 (s, 3H), 2.55-2.57 (m, 2H), 2.76-2.79 indol-5- (m, 2H), 3.42 (s, 2H), 5.79 (d, 1 H, J=2.9Hz), 5.92 (dd, 1 H, yl]acetamide J=2.9Hz, J=1.0Hz), 6.47 (d, 1 H, J=8.4Hz), 6.70 (d, 1 H,

J=7.9Hz), 6.87 (d, 1 H, J=7.9Hz), 6.93 (s, 1 H), 7.03 (dd, 1 H, J=7.9Hz, J=1.2Hz), 7.19 (d, 1 H, J=7.8Hz), 7.44 (s, 1 H), 8.7

- 1 (d, 1 H, J=8.5Hz), 10.33 (s, 1 H) (one CH3 group under the pic of DMSO-d6) ; m/z: 498 [M+H]+ (calc. mass: 497).

- From (5-chlorofuran-2-yl)(2,4-dimethylphenyl)methanamine

N-[(5- Ex.23 and 1 -(2-methanesulfonyl-2,3-dihydro-1 H-isoindol-5- chlorofuran-2- yl)cyclopropane-1 -carboxylic acid Ex.33 following protocol yl)(2,4- A, DMAP (1.0 equiv), EDCI.HCI (1 .1 equiv), 18h at rt, dimethylphenyl) purification by silica gel column chromatography

methyl]-1 -(2- (Cyclohexane/EtOAc, 1 :1 ), yield 52%, mp: 68°C,

methanesulfony appearance: white solid

l-2,3-dihydro- - 1 H NMR (300 MHz, d in ppm): 0.98-1 .02 (m, 2H), 1 .31 -1.35

1 H-isoindol-5- (m, 2H), 2.17 (s, 3H), 2.23 (s, 3H), 2.95 (s, 3H), 4.86 (s, yl)cyclopropane 4H), 5.99 (dd, 1 H, J=3.3Hz, J=1 .1 Hz), 6.18 (d, 1 H,

-1 -carboxamide J=8.2Hz), 6.36 (d, 1 H, J=3.3Hz), 6.97 (m, 3H), 7.27 (m,

3H), 7.86 (d, 1 H) ; m/z: 499 [M+H]+ (calc. mass: 498)."

- From [4-methyl-2-(piperidin-1 -yl)phenyl](5-methylfuran-2- yl)methanamine Ex.16 and 2-[3-(2-hydroxyethyl)-1 H-indol- 5-yl]acetic acid Ex.34 following protocol A, DMAP (1 .0

2-[3-(2- equiv), EDCI.HCI (1 .1 equiv), 18h at rt, purification by silica hydroxyethyl)- gel column chromatography (CH2CI2/MeOH, 98:2), yield

1 H-indol-5-yl]-N- 79%, mp: 80°C, appearance: white solid

{[4-methyl-2- - 1 H NMR (300 MHz, d in ppm): 1 .34-1 .64 (m, 6H), 2.16 (s,

(piperidin-1 - 3H), 2.24 (s, 3H), 2.50-2.60 (m, 2H), 2.72-2.85 (m, 4H), yl)phenyl](5- 3.49 (s, 2H), 3.58-3.66 (m, 2H), 4.60 (t, 1 H, J=5.3Hz), 5.81 methylfuran-2- (dd, 1 H, J=3.0Hz), 5.91 (d, 1 H, J=3.0Hz, J=1 .0Hz), 6.48 (d, yl)methyl}aceta 1 H, J=8.6Hz), 6.88 (d, 1 H, J=7.9Hz), 6.92 (s, 1 H), 6.95 (dd, mide 1 H, J=8.4Hz, J=1.5Hz), 7.08 (d, 1 H, J=2.2Hz), 7.20 (d, 1 H,

J=8.2Hz), 7.21 (d, 1 H, J=7.8Hz), 7.36 (s, 1 H), 8.65 (d, 1 H, J=8.4Hz), 10.66 (s, 1 H) ; m/z: 486 [M+H]+ (calc. mass: 485).

- See Figure 3AL

- Step 1 : to a solution of 2-(3-formyl-1 H-indol-5-yl)acetic acid (200 mg, 0.98 mmol) in DMF (3 mL) were added DMAP (265 mg, 2.17 mmol), EDCI.HCI (208 mg, 1 .08 mmol) and the [4-methyl-2-(piperidin-1 -yl)phenyl](5-methylfuran-2- yl)methanamine Ex.16 (280 mg, 0.98 mmol). The reaction

2-[3- mixture was stirred at rt. After completion of the reaction

(hydroxy methyl)

(monitored by TLC), sat. NH4CI was added and the solution

-1 H-indol-5-yl]- was extracted with EtOAc. The combined organic layer

N-{[4-methyl-2- were washed with sat. NH4CI, dried over MgS04, filtered

(piperidin-1 - and the solution was concentrated under reduced pressure. yl)phenyl](5- The crude material was purified by silica gel column methylfuran-2- chromatography eluting with CH2CI2/MeOH (98:2) to give yl)methyl}aceta

2-(3-formyl-1 H-indol-5-yl)-N-((4-methyl-2-(piperidin-1 - mide

yl)phenyl)(5-methylfuran-2-yl)methyl)acetamide (377 mg, 82%) as pale yellow solid. 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .42-1 .53 (m, 6H), 2.15 (s, 3H), 2.24 (s, 3H), 2.49- 2.52 (m, 2H), 2.72-2.79 (m, 2H), 3.54 (s, 2H), 5.82 (d, 1 H, J=2.5Hz), 5.91 (dd, 1 H, J=2.9Hz, J=1.0Hz), 6.46 (d, 1 H, J=8.4Hz), 6.88 (d, 1 H, J=7.9Hz), 6.92 (s, 1 H), 7.16 (dd, 1 H, J=8.3Hz, J=1.7Hz), 7.20 (d, 1 H, J=7.8Hz), 7.38 (d, 1 H, J=8.3Hz), 8.00 (d, 1 H, J=1 .0Hz), 8.23 (s, 1 H), 8.75 (d, 1 H, J=8.5Hz), 9.89 (s, 1 H), 12.05 (br(s), 1 H).

- Step 2 : to a previously synthesized 2-(3-formyl-1 H-indol-5- yl)-N-((4-methyl-2-(piperidin-1 -yl)phenyl)(5-methylfuran-2- yl)methyl)acetamide (100 mg, 0.21 mmol) in anhydrous MeOH (2 mL) was added sodium borohydride (24 mg, 0.64 mmol). The reaction mixture was stirred at rt for 4h. The reaction was partitioned between water and EtOAc. The pH of the aqueous layer was ajusted to pH = 7-8 with a solution of 10% citric acid. The aqueous phase was extracted with EtOAc. The organic layer was dried over MgS04, filtered and the solution was concentrated to dryness. The crude material was purified by silica gel column chromatography eluting with CH2CI2/EtOAc (50:50), yield 50%, mp: 99°C, appearance: white solid

- 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .40-1 .65 (m, 6H), 2.16 (s, 3H), 2.24 (s, 3H), 2.5-2.6 (m, 2H), 2.75-2.85 (m, 2H), 3.50 (s, 2H), 4.58 (d, 2H, J=5.2Hz), 4.66 (t, 1 H, J=1.2Hz), 5.81 (d, 1 H, J=2.7Hz), 5.90-5.95 (m, 1 H), 6.47 (d, 1 H, J=8.4Hz), 6.88 (d, 1 H, J=7.9Hz), 6.92 (s, 1 H), 6.98 (dd, 1 H, J=8.3Hz, J=1.6Hz), 7.10-7.30 (m, 3H), 7.44 (s, 1 H), 8.65 (d, 1 H, J=8.5Hz), 10.74 (s, 1 H) ; m/z: 472 [M+H]+ (calc. mass: 471 ).

- From (2,4-dimethylphenyl)(5-methylfuran-2-yl)methanamine Ex.19 and 1 -(3-oxo-3,4-dihydro-2H-1 ,4-benzoxazin-7-

N-[(2,4- yl)cyclopropane-1 -carboxylic acid Ex.35 following protocol dimethylphenyl) A, DMAP (1 equiv), EDCI.HCI (1 .1 equiv), 2h at rt. Sat.

(5-methylfuran- NH4CI was added to quench the reaction. The solid formed

2-yl)methyl]-1 - was collected by filtration and dried until constant weight,

(3-oxo-3,4- yield 73%, mp: 89°C, appearance: white solid

dihydro-2H-1 ,4- - 1 H NMR (300 MHz, DMSO-d6, d in ppm): 0.92-0.99 (m, benzoxazin-7- 2H), 1 .21 -1 .33 (m, 2H), 2.16 (s, 3H), 2.17 (s, 3H), 2.22 (s, yl)cyclopropane 3H), 4.55 (s, 2H), 5.76 (d, 1 H, J=3.1 Hz), 5.94 (dd, 1 H,

-1 -carboxamide J=3.0Hz, J=1.1 Hz), 6.12 (d, 1 H, J=8.2Hz), 6.83 (d, 1 H,

J=8.6Hz), 6.90-6.96 (m, 5H), 7.45 (d, 1 H, J=8.2Hz), 10.71 (s, 1 H) ; m/z: 453 [M+Na]+ (calc. mass: 430).

- From (2,4-dimethylphenyl)(5-methylfuran-2-yl)methanamine Ex.19 and 1 -[3-(2-hydroxyethyl)-1 H-indol-5- yl]cyclopropane-1 -carboxylic acid Ex.36 following protocol

N-[(2,4- A, DMAP (1 equiv), EDCI.HCI (1.1 equiv), 2h at rt,

dimethylphenyl)

purification by silica gel column chromatography

(5-methylfuran- (CH2CI2/EtOAc, 80:20), yield 53%, mp: 77°C, appearance: 2-yl)methyl]-1 - white solid

[3-(2- hydroxyethyl)- - 1 H NMR (300 MHz, DMSO-d6, d in ppm): 0.99-1 .10 (m, 1 H-indol-5- 2H), 1 .29-1 .42 (m, 2H), 2.12 (s, 3H), 2.14 (s, 3H), 2.20 (s, yl]cyclopropane 3H), 2.82 (t, 2H, J=7.3Hz), 3.57-3.66 (m, 2H), 4.60 (t, 1 H, -1 -carboxamide J=5.4Hz), 5.74 (d, 1 H, J=3.4Hz), 5.89 (dd, 1 H, J=3.0Hz,

J=1.1 Hz), 6.08 (d, 1 H, J=8.3Hz), 6.65 (d, 1 H, J=8.5Hz), 6.77 (d, 1 H, J=7.8Hz), 6.90 (d, 1 H, J=8.0Hz), 6.94 (s, 1 H), 7.07 (dd, 1 H, J=8.3Hz, J=1.7Hz), 7.15 (d, 1 H, J=2.2Hz), 7.32 (d, 1H, J=8.3Hz), 7.53 (d, 1H, J=1.4Hz), 10.84 (d, 1H, J=1.5Hz) ; -m/z: 465 [M+Na]+ (calc. mass: 442).

- From (2,4-dimethylphenyl)(5-methylfuran-2-yl)methanamine Ex.19 and 1-(2-oxo-2,3-dihydro-1 H-indol-5-yl)cyclopropane-

N-[(2,4- 1-carboxylic acid Ex.37 following protocol A, DMAP (1.1 dimethylphenyl) equiv), EDCI.HCI (1.1 equiv), over the weekend at rt,

(5-methylfuran- purification by silica gel column chromatography

2-yl)methyl]-1- (CH2CI2/EtOAc, 70:30), yield 67%, mp: 85°C, appearance:

(2-oxo-2,3- pale brown solid

dihydro-1H- - 1 H NMR (300 MHz, DMSO-d6, d in ppm): 0.88-1.01 (m, indol-5- 2H), 1.21-1.36 (m, 2H), 2.15 (s, 3H), 2.16 (s, 3H), 2.22 (s, yl)cyclopropane 3H), 3.44 (s, 2H), 5.76 (d, 1H, J=2.9Hz), 5.93 (dd, 1H, -1-carboxamide J=3.0Hz, J=1.1Hz), 6.11 (d, 1H, J=8.4Hz), 6.77 (d, 1H,

J=7.9Hz), 6.88-7.00 (m, 3H), 7.12-7.23 (m, 3H), 10.39 (br(s), 1H) ; -m/z: 437 [M+Na]+ (calc. mass: 414).

- From (5-chlorofuran-2-yl)(2,4-dimethylphenyl)methanamine Ex.32 and 1-[3-(2-hydroxyethyl)-1 H-indol-5- yl]cyclopropane-1-carboxylic acid Ex.36 following protocol A, DMAP (1.1 equiv), EDCI.HCI (1.1 equiv), 2h at rt,

N-[(5- purification by silica gel column chromatography

chlorofuran-2- (CH2CI2/EtOAc, 80:20), yield 63%, mp: 70°C, appearance: yl)(2,4- white solid

dimethylphenyl)

methyl]-1-[3-(2- - 1 H NMR (300 MHz, DMSO-d6, d in ppm): 0.97-1.11 (m, hydroxyethyl)- 2H), 1.28-1.42 (m, 2H), 2.15 (s, 3H), 2.21 (s, 3H), 2.82 (t,

1H-indol-5- 2H, J=7.3Hz), 3.58-3.65 (m, 2H), 4.59 (t, 1H, J=5.4Hz), 6.00 yl]cyclopropane (dd, 1H, J=3.3Hz, J=1.1Hz), 6.14 (d, 1H, J=8.4Hz), 6.33 (d,

-1-carboxamide 1H, J=3.3Hz), 6.81 (d, 1H, J=7.8Hz), 6.92 (d, 1H, J=7.9Hz),

6.96 (s, 1H), 7.00 (d, 1H, J=8.3Hz), 7.06 (dd, 1H, J=8.3Hz, J=1.7Hz), 7.14 (d, 1H, J=2.3Hz), 7.30 (d, 1H, J=8.3Hz), 7.52 (s, 1H), 10.82 (s, 1H) ; m/z: 485 [M+Na]+, 487

[M+Na]+ (calc. mass: 462).

- From (2,4-dimethylphenyl)(5-methylfuran-2-yl)methanamine Ex.19 and 1-(2,2-dioxo-1,3-dihydro-2,1-benzothiazol-5- yl)cyclopropane-1-carboxylic acid Ex.38 following protocol

N-[(2,4- A, DMAP (1 equiv), EDCI.HCI (1.1 equiv), 2h at rt,

dimethylphenyl) purification by silica gel column chromatography

(5-methylfuran- (Cyclohexane/EtOAc, 70:30), yield 19%, mp: 97°C,

2-yl)methyl]-1- appearance: white solid

(2,2-dioxo-1,3- dihydro-2,1- - 1 H NMR (300 MHz, DMSO-d6, d in ppm): 0.92-1.02 (m, benzothiazol-5- 2H), 1.26-1.36 (m, 2H), 2.15 (s, 3H), 2.17 (s, 3H), 2.22 (s, yl)cyclopropane 3H), 4.47 (s, 2H), 5.75 (d, 1H, J=3.0Hz), 5.93 (dd, 1H,

-1-carboxamide J=3.0Hz, J=1.0Hz), 6.11 (d, 1H, J=8.2Hz), 6.77 (d, 1H,

J=8.0Hz), 6.91-6.98 (m, 3H), 7.22 (dd, 1H, J=8.2Hz, J=1.9Hz), 7.25 (s, 1H), 7.43 (d, 1H, J=8.6Hz), 10.28 (br(s), 1H) ; m/z: 473 [M+Na]+ (calc. mass: 450).

2-(3-methyl-1H- indol-5-yl)-N-{[4- - From [4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2- methyl-2- yl)methanamine Ex.16 and 2-(3-methyl-1 H-indol-5-yl)acetic (piperidin-1- acid Ex.39 following protocol A, DMAP (2.2 equiv), yl)phenyl](5- EDCI.HCI (1.2 equiv), overnight at rt, purification by silica methylfuran-2- gel column chromatography (Cyclohexane/EtOAc, 70:30), yl)methyl}aceta yield 53%, mp: 68°C, appearance: white solid

mide

- 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .39-1 .55 (m, 6H), 2.16 (s, 3H), 2.20 (d, 3H, J=1 .0Hz), 2.24 (s, 3H), 2.54- 2.57 (m, 2H), 2.77-2.80 (m, 2H), 3.50 (s, 2H), 5.81 (d, 1 H, J=2.7Hz), 5.91 (dd, 1 H, J=3.0Hz, J=1.0Hz), 6.49 (d, 1 H, J=8.5Hz), 6.88 (d, 1 H, J=7.8Hz), 6.93 (s, 1 H), 6.96 (dd, 1 H, J=8.3Hz, J=1.6Hz), 7.03-7.04 (m, 1 H), 7.19 (dd, 1 H, J=8.3Hz, J=0.5Hz), 7.21 (d, 1 H, J=7.8Hz), 7.31 (s, 1 H), 8.66 (d, 1 H, J=8.6Hz), 10.59 (br(s), 1 H) ; m/z: 456 [M+H]+ (calc. mass: 455).

- From (2,4-dimethylphenyl)(5-methylfuran-2-yl)methanamine

N-[(2,4- Ex.19 and 1 -(2-methanesulfonyl-2,3-dihydro-1 H-isoindol-5- dimethylphenyl) yl)cyclopropane-1 -carboxylic acid Ex.33 following protocol (5-methylfuran- A, DMAP (1 equiv), EDCI.HCI (1 .1 equiv), 2h at rt, no

2-yl)methyl]-1 - purification was needed, yield 66%, mp: 67°C, appearance: (2- off-white solid

methanesulfony - 1 H NMR (300 MHz, DMSO-d6, d in ppm): 0.95-1 .05 (m, l-2,3-dihydro- 2H), 1 .28-1 .39 (m, 2H), 2.16 (s, 3H), 2.17 (s, 3H), 2.22 (s,

1 H-isoindol-5- 3H), 2.95 (s, 3H), 4.59 (s, 4H), 5.76 (d, 1 H, J=2.8Hz), 5.94 yl)cyclopropane (dd, 1 H, J=3.0Hz, J=1.0Hz), 6.14 (d, 1 H, J=8.2Hz), 6.90-

-1 -carboxamide 6.99 (m, 3H), 7.25-7.33 (m, 3H), 7.53 (d, 1 H, J=8.3Hz) ;

m/z: 501 [M+Na]+ (calc. mass: 478).

- From [4-methyl-2-(piperidin-1 -yl)phenyl](5-methylfuran-2- yl)methanamine Ex.16 and 1 -[3-(2-hydroxyethyl)-1 H-indol- 5-yl]cyclopropane-1 -carboxylic acid Ex.36 following protocol A, DMAP (2.2 equiv), EDCI.HCI (1 .2 equiv), overnight at rt,

1 -[3-(2- purification by silica gel column chromatography

hydroxyethyl)- (CH2CI2/MeOH from [97:3] to [95:5]), yield 39%, mp: 95°C,

1 H-indol-5-yl]-N- appearance: white solid

{[4-methyl-2-

(piperidin-1 - - 1 H NMR (300 MHz, DMSO-d6, d in ppm): 0.95-1 .05 (m, yl)phenyl](5- 2H), 1 .05-1 .64 (m, 6H), 1 .29-1 .35 (m, 1 H), 1 .35-1 .45 (m, methylfuran-2- 1 H), 2.08 (s, 3H), 2.21 (s, 3H), 2.25-2.35 (m, 2H), 2.5-2.55 yl)methyl}cyclo (m, 2H), 2.81 (t, 2H, J=7.5Hz), 3.59 (q, 2H, J=5.3Hz), 4.60 propane-1 - (t, 1 H, J=5.2Hz), 5.81 (dd, 1 H, J=2.9Hz), 5.91 (d, 1 H, carboxamide J=3.1 Hz, J=1.1 Hz), 6.30 (d, 1 H, J=8.9Hz), 6.77 (d, 1 H,

J=8.5Hz), 6.83 (d, 1 H, J=8.0Hz), 6.90 (d, 1 H, J=7.7Hz), 6.94 (s, 1 H), 7.09 (dd, 1 H, J=9.9Hz, J=1 .5Hz), 7.15 (d, 1 H, J=2.3Hz), 7.31 (d, 1 H, J=8.3Hz), 7.51 (s, 1 H), 10.83 (br(s), 1 H) ; m/z: 512 [M+H]+ (calc. mass: 51 1 ).

N-{[4-methyl-2- - From [4-methyl-2-(piperidin-1 -yl)phenyl](5-methylfuran-2-

(piperidin-1 - yl)methanamine Ex.16 and 2-(3-oxo-2,3-dihydro-1 H-inden- yl)phenyl](5- 5-yl)acetic acid Ex.51 following protocol A, DMAP (1 equiv), methylfuran-2- EDCI.HCI (1.1 equiv), overnight at rt, purification by silica yl)methyl}-2-(3- gel column chromatography (Cyclohexane/EtOAc, 70:30), oxo-2,3-dihydro- yield 49%, mp: 71 °C, appearance: white solid

1 H-inden-5-

- 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .40-1 .63 (m, yl)acetamide

6H), 2.17 (s, 3H), 2.25 (s, 3H), 2.53-2.65 (m, 4H), 2.70-2.84 (m, 2H), 3.05 (t, 2H, J=5.7Hz), 3.55 (s, 2H), 5.81 (d, 1 H, J=3.4Hz), 5.92 (dd, 1 H, J=3.0Hz, J=1.0Hz), 6.48 (d, 1 H, J=8.3Hz), 6.88 (d, 1 H, J=8.0Hz), 6.93 (s, 1 H), 7.17 (d, 1 H, J=7.8Hz), 7.46-7.56 (m, 3H), 8.79 (d, 1 H, J=8.3Hz) ; m/z: 457 [M+H]+ (calc. mass: 456).

- From (2-bromo-4-methylphenyl)(5-methylfuran-2- yl)methanamine Ex.18 and 2-[1 -(oxan-4-ylmethyl)-2,2-

N-[(2-bromo-4- dioxo-1 ,3-dihydro-2,1 -benzothiazol-5-yl]acetic acid Ex.95 methylphenyl)(5 following protocol A, substituted amine (0.9 equiv), DMAP

-methylfuran-2- (1 .1 equiv), EDCI.HCI (2.2 equiv), 8h at rt, purification by yl)methyl]-2-[1 - silica gel column chromatography (Cyclohexane/EtOAc,

(oxan-4- 50:50), yield 69%, mp: 92°C, appearance: yellowish solid ylmethyl)-2,2- dioxo-1 ,3- - 1 H NMR (300 MHz, DMSO-d6, d in ppm): 2.15 (s, 3H), 2.18 dihydro-2,1 - (s, 3H), 2.22 (s, 3H), 3.41 (s, 2H), 3.63 (s, 2H), 4.85 (s, 2H), benzothiazol-5- 5.81 (d, 1 H, J=2.9Hz), 5.95 (q, 1 H, J=3.0Hz, J=1 .1 Hz), 6.08 yl]acetamide (d, 1 H, J=8.6Hz), 6.75 (d, 1 H, J=8.1 Hz), 6.85-6.95 (m, 2H),

7.15-7.25 (m, 2H), 8.93 (d, 1 H, J=8.3Hz) ; m/z: 609

[M+Na]+, 61 1 [M+Na]+ (calc. mass: 586).

- See Figure 3AM

- Step 1 : To a solution of 1 -{1 -[2-(benzyloxy)ethyl]-2,3- dihydro-1 H-indol-5-yl}cyclopropane-1 -carboxylic acid Ex.41 (150 mg, 0.45 mmol) in DMF (2 mL) were added DMAP (65 mg, 0.53 mmol), EDCI.HCI (102 mg, 0.53 mmol) and (2,4- dimethylphenyl)(5-methylfuran-2-yl)methanamine Ex.19

(1 12 mg, 0.45 mmol). The reaction mixture was stirred at rt for 4h. Brine was added and the solution was extracted with EtOAc. The organic layer was dried over MgS04, filtered and the solution was evaporated to dryness. The crude

N-[(2,4- material was purified by silica gel column chromatography dimethylphenyl) eluting with a gradient of cyclohexane/EtOAc from [90:10] (5-methylfuran- to [85:15]. The product fractions were collected and

2-yl)methyl]-1 - evaporated under reduced pressure affording 1 -{1-[2- [1 -(2- (benzyloxy)ethyl]-2,3-dihydro-1 H-indol-5-yl}-N-[(2,4- hydroxyethyl)- dimethylphenyl)(5-methylfuran-2-yl)methyl]cyclopropane-1 - 1 H-indol-5- carboxamide (180 mg, 76%) as white solid. 1 H NMR (300 yl]cyclopropane MHz, DMSO-d6, d in ppm): 0.85-0.95 (m, 2H), 1 .15-1 .35 -1 -carboxamide (m, 2H), 2.14 (s, 6H), 2.21 (s, 3H), 2.86 (t, 2H, J=7.8Hz),

3.24 (t, 2H, J=5.8Hz), 3.38 (t, 2H, J=9.2Hz), 3.62 (t, 2H, J=5.6Hz), 4.49 (s, 2H), 5.78 (d, 1 H, J=3.2Hz), 5.92 (dd, 1 H, J=3.1 Hz, J=1.1 Hz), 6.05 (d, 1 H, J=8.4Hz), 6.45 (d, 1 H, J=8.1 Hz), 6.75-6.80 (m, 2H), 6.80-7.05 (m, 4H), 7.20-7.40 (m, 5H).

- Step 2 : 1 -{1 -[2-(benzyloxy)ethyl]-2,3-dihydro-1 H-indol-5-yl}- N-[(2,4-dimethylphenyl)(5-methylfuran-2- yl)methyl]cyclopropane-1 -carboxamide (180 mg, 0.34 mmol) was dissolved in MeOH (10 mL). A few amount of 5% Pd/C was added to the solution and the reaction was stirred under H2 atmosphere at rt for 4h. TLC showed small evolution of the reaction. The reaction mixture was heated at 50°C. After 1 h, LCMS showed two products (starting material and the expected molecule). The heating was kept overnight. LCMS showed no change. The catalyst was removed by filtration. The solvent was evaporated to dryness. The residue was diluted with THF (10 mL) and few amount of 5% Pd/C was added to the solution. The reaction mixture was stirred at rt over the weekend. LCMS showed formation of by-products and the expected molecule. The catalyst was removed by filtration and the solvent was concentrated under reduced pressure. After analysis by LCMS, the expected molecule was found in few amount (444 [M+H]+) and a new compound appeared with a mass of 465 [M+Na]+ which correspond to the oxidation of the indoline moiety to the corresponding indole. This compound was isolated by preparative HPLC and characterized by NMR to afford N-[(2,4-dimethylphenyl)(5-methylfuran-2- yl)methyl]-1 -[1 -(2-hydroxyethyl)-1 H-indol-5-yl]cyclopropane- 1 -carboxamide (4 mg, 3%) as white solid., yield 0,%, mp: 74°C, appearance: white solid

- 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1.02 (d, 2H, J=3.2Hz), 1 .23 (m, 2H), 2.12 (s, 3H), 2.14 (s, 3H), 2.20 (s, 3H), 3.68 (q, 2H, J=5.6Hz), 4.19 (t, 2H, J=5.7Hz), 4.85 (t, 1 H, J=5.3Hz), 5.76 (d, 1 H, J=2.8Hz), 5.90 (q, 1 H, J=3.1 Hz, J=1.1 Hz), 6.09 (d, 1 H, J=8.4Hz), 6.39 (d, 1 H, J=3.1 Hz), 6.74 (d, 1 H, J=8.6Hz), 6.79 (d, 1 H, J=7.7Hz), 6.85-6.95 (m, 2H), 7.14 (dd, 1 H, J=8.5Hz, J=1 .7Hz), 7.36 (d, 1 H,

J=3.1 Hz), 7.47 (d, 1 H, J=8.6Hz), 7.55 (d, 1 H, J=1.3Hz) ; m/z: (calc. mass: 442).

- From (2,4-dimethylphenyl)(5-methylfuran-2-yl)methanamine Ex.19 and 1 -(1 -methyl-2,2-dioxo-1 ,3-dihydro-2,1 - benzothiazol-5-yl)cyclopropane-1 -carboxylic acid Ex.40

N-[(2,4- following protocol A, DMAP (1.2 equiv), EDCI.HCI (2.2 dimethylphenyl) equiv), 8h at rt, purification by silica gel column

(5-methylfuran- chromatography (Cyclohexane/EtOAc, 80:20) followed by a

2-yl)methyl]-1 - second purification by silica gel column chromatography

(1 -methyl-2,2- (CH2CI2/MeOH, 98:2), yield 58%, mp: 70°C, appearance: dioxo-1 ,3- white solid

dihydro-2,1 - benzothiazol-5- - 1 H NMR (300 MHz, DMSO-d6, d in ppm): 0.98 (d, 2H, yl)cyclopropane J=2.8Hz), 1 .25-1 .35 (m, 2H), 2.16 (s, 3H), 2.17 (s, 3H), 2.22

-1 -carboxamide (s, 3H), 3.02 (s, 3H), 4.60 (s, 2H), 5.76 (d, 1 H, J=3.2Hz),

5.93 (q, 1 H, J=3.3Hz, J=1 .3Hz), 6.12 (d, 1 H, J=8.3Hz), 6.91 (d, 1 H, J=8.3Hz), 6.95 (s, 3H), 7.25-7.35 (m, 2H), 7.51 (d, 1 H, J=8.4Hz) ; m/z: 465 [M+H]+ (calc. mass: 464).

N-{[2-

- From 2-[amino(5-methylfuran-2-yl)methyl]-N,N,5-

(dimethylamino)

trimethylaniline Ex.42 and 1 -(2,2-dioxo-1 ,3-dihydro-2,1 - -4- benzothiazol-5-yl)cyclopropane-1 -carboxylic acid Ex.38 methylphenyl](5

following protocol A, DMAP (1 equiv), EDCI.HCI (1 .1 equiv),

-methylfuran-2- 2h at rt, purification by silica gel column chromatography yl)methyl}-1 - (Cyclohexane/EtOAc, 70:30), yield 31 %, mp: 107°C,

(2,2-dioxo-1 ,3- appearance: white solid

dihydro-2,1 - benzothiazol-5- - 1 H NMR (300 MHz, DMSO-d6, d in ppm): 0.88-1 .04 (m, yl)cyclopropane 2H), 1 .27-1 .39 (m, 2H), 2.13 (s, 3H), 2.18 (s, 6H), 2.23 (s, -1 -carboxamide 3H), 4.49 (s, 2H), 5.79 (dd, 1 H, J=2.9Hz, J=0.8Hz), 5.92

(dd, 1 H, J=3.0Hz, J=1.0Hz), 6.19 (d, 1 H, J=8.5Hz), 6.82 (d, 1 H, J=8.3Hz), 6.88 (dd, 1 H, J=7.7Hz, J=1.0Hz), 7.00 (d, 1 H, J=0.6Hz), 7.12 (d, 1 H, J=7.8Hz), 7.27-7.34 (m, 2H), 7.97 (d, 1 H, J=8.7Hz), 10.55 (br(s), 1 H) ; m/z: 480 [M+H]+ (calc. mass: 479).

- From (5-chlorofuran-2-yl)(2,4-dimethylphenyl)methanamine

N-[(5- Ex.32 and 1 -(2,2-dioxo-1 ,3-dihydro-2-benzothiophen-5- chlorofuran-2- yl)cyclopropane-1 -carboxylic acid Ex.43 following protocol yl)(2,4- A, DMAP (1 equiv), EDCI.HCI (1.1 equiv), overnight at rt, dimethylphenyl) purification by silica gel column chromatography

methyl]-1 -(2,2- (Cyclohexane/EtOAc, 70:30), yield 57%, mp: 80°C,

dioxo-1 ,3- appearance: white solid

dihydro-2- - 1 H NMR (300 MHz, DMSO-d6, d in ppm): 0.97-1 .1 1 (m, benzothiophen- 2H), 1 .30-1 .38 (m, 2H), 2.17 (s, 3H), 2.23 (s, 3H), 4.44 (s,

5- 2H), 4.46 (s, 2H), 6.00 (dd, 1 H, J=3.3Hz, J=0.9Hz), 6.18 (d, yl)cyclopropane 1 H, J=8.3Hz), 6.35 (d, 1 H, J=3.3Hz), 6.93-7.02 (m, 3H), -1 -carboxamide 7.26-7.36 (m, 3H), 8.06 (d, 1 H, J=8.3Hz) ; m/z: 492

[M+Na]+, 494 [M+Na]+ (calc. mass: 469).

- From [4-methyl-2-(pyrrolidin-1 -yl)phenyl](5-methylfuran-2- yl)methanamine Ex.44 and 1 -(2-methanesulfonyl-2,3-

1 -(2- dihydro-1 H-isoindol-5-yl)cyclopropane-1 -carboxylic acid methanesulfony Ex.33 following protocol A, DMAP (1 equiv), EDCI.HCI (1 .1

1- 2,3-dihydro- equiv), 2h at rt, purification by silica gel column

1 H-isoindol-5- chromatography (Cyclohexane/EtOAc, 70:30), yield 43%, yl)-N-{[4-methyl- mp: 84°C, appearance: pale brown solid

2- (pyrrolidin-1 - - 1 H NMR (300 MHz, DMSO-d6, d in ppm): 0.94-1 .04 (m, yl)phenyl](5- 2H), 1 .27-1 .38 (m, 2H), 1 .54-1.72 (m, 4H), 2.14 (s, 3H), methylfuran-2- 2.22 (s, 3H), 2.54-2.64 (m, 2H), 2.70-2.84 (m, 2H), 2.96 (s, yl)methyl}cyclo 3H), 4.46-4.71 (m, 4H), 5.78 (dd, 1 H, J=3.0Hz, J=0.8Hz), propane-1 - 5.93 (dd, 1 H, J=3.0Hz, J=1.0Hz), 6.23 (d, 1 H, J=8.3Hz), carboxamide 6.78 (d, 1 H, J=7.9Hz), 6.91 (s, 1 H), 7.04 (d, 1 H, J=7.8Hz),

7.30-7.35 (m, 3H), 7.47 (d, 1 H, J=8.6Hz) ; m/z: 534 [M+H]+ (calc. mass: 533).

- From (2,4-dimethylphenyl)(5-methylfuran-2-yl)methanamine Ex.19 and 1 -(2,2-dioxo-1 ,3-dihydro-2-benzothiophen-5-

N-[(2,4- yl)cyclopropane-1 -carboxylic acid Ex.43 following protocol dimethylphenyl) A, DMAP (1 equiv), EDCI.HCI (1 .1 equiv), 2h at rt. Sat.

(5-methylfuran- NH4CI was added to quench the reaction. The solid formed

2-yl)methyl]-1 - was collected by filtration and dried until constant weight,

(2,2-dioxo-1 ,3- yield 60%, mp: 74°C, appearance: white solid

dihydro-2- benzothiophen- - 1 H NMR (300 MHz, DMSO-d6, d in ppm): 0.97-1 .07 (m,

5- 2H), 1 .29-1 .39 (m, 2H), 2.16 (s, 3H), 2.18 (s, 3H), 2.22 (s, yl)cyclopropane 3H), 4.44 (s, 2H), 4.46 (s, 2H), 5.76 (d, 1 H, J=3.1 Hz), 5.94 -1 -carboxamide (dd, 1 H, J=3.1 Hz, J=1 .0Hz), 6.13 (d, 1 H, J=8.3Hz), 6.91 - 7.00 (m, 3H), 7.30-7.36 (m, 3H), 7.74 (d, 1 H, J=8.3Hz) ; m/z: 472 [M+Na]+ (calc. mass: 449). - From [4-methyl-2-(piperidin-1 - yl)phenyl](phenyl)methanamine Ex.1 and 2-(2-methyl-1 H-

1 ,3-benzodiazol-5-yl)acetic acid Ex.45 following protocol B, substituted amine (1 equiv), substituted acid (1 equiv),

2-(2-methyl-1 H- PyBOP (1 equiv) and triethylamine (3 equiv), 100°C for 20

1 ,3-benzodiazol- min under microwave irradiation, purification by silica gel

5-yl)-N-{[4- column chromatography (CH2CI2/MeOH, 97:3). The methyl-2- residue was triturated in diethyl ether and filtered-off, yield

(piperidin-1 - 7%, mp: 137°C, appearance: white solid

yl)phenyl](phen

yl)methyl}aceta - 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .44-1 .74 (m, mide 6H), 2.24 (s, 3H), 2.46-2.50 (m, 5H), 2.78-2.88 (m, 2H),

3.59 (s, 2H), 6.56 (d, 1 H, J=8.4Hz), 6.87 (d, 1 H, J=7.1 Hz), 6.94 (s, 1 H), 7.03 (d, 1 H, J=8.4Hz), 7.12-7.35 (m, 8H), 8.70 (d, 1 H, J=8.7Hz), 12.20 (br(s), 1 H) ; m/z: 453 [M+H]+ (calc. mass: 452).

- From 2-[amino(5-methylfuran-2-yl)methyl]-N,N,5- trimethylaniline Ex.42 and 1 -(2-methanesulfonyl-2,3-

N-{[2- dihydro-1 H-isoindol-5-yl)cyclopropane-1 -carboxylic acid

(dimethylamino) Ex.33 following protocol A, DMAP (1 equiv), EDCI.HCI (1 .1 -4- equiv), 2h at rt, purification by silica gel column

methylphenyl](5 chromatography (Cyclohexane/EtOAc, 70:30), yield 33%,

-methylfuran-2- mp: 70°C, appearance: white solid

yl)methyl}-1 -(2- methanesulfony - 1 H NMR (300 MHz, DMSO-d6, d in ppm): 0.91 -1 .06 (m, l-2,3-dihydro- 2H), 1 .27-1 .37 (m, 2H), 2.14 (s, 3H), 2.21 (s, 6H), 2.23 (s,

1 H-isoindol-5- 3H), 2.96 (s, 3H), 4.60 (s, 2H), 4.61 (s, 2H), 5.77 (dd, 1 H, yl)cyclopropane J=3.0Hz, J=0.8Hz), 5.92 (dd, 1 H, J=3.0Hz, J=1 .0Hz), 6.25

-1 -carboxamide (d, 1 H, J=8.5Hz), 6.87 (dd, 1 H, J=7.8Hz, J=0.7Hz), 6.99 (d,

1 H, J=0.7Hz), 7.12 (d, 1 H, J=7.8Hz), 7.30-7.41 (m, 3H), 7.91 (d, 1 H, J=8.6Hz) ; m/z: 508 [M+H]+ (calc. mass: 507).

- From (2-bromo-4-methylphenyl)(5-methylfuran-2- yl)methanamine Ex.18 and 2-(2-methyl-1 H-1 ,3- benzodiazol-5-yl)acetic acid Ex.45 following protocol A, DMAP (3.2 equiv), EDCI.HCI (1 .2 equiv), overnight at rt,

N-[(2-bromo-4- purification by silica gel column chromatography

methylphenyl)(5 (CH2CI2/MeOH, 96:4), yield 55%, mp: 209°C, appearance:

-methylfuran-2- white solid

yl)methyl]-2-(2- methyl-1 H-1 ,3- - 1 H NMR (300 MHz, DMSO-d6, d in ppm): 2.21 (s, 3H), 2.27 benzodiazol-5- (s, 3H), 2.44 (s, 3H), 3.54 (m, 2H), 5.76 (d, 1 H, J=3.0Hz), yl)acetamide 5.95 (dd, 1 H, J=3.0Hz, J=1 .0Hz), 6.25 (d, 1 H, J=7.8Hz),

6.98-7.02 (m, 1 H), 7.18 (d, 1 H, J=8.3Hz), 7.26-7.33 (m, 2H), 7.35-7.38 (m, 1 H), 7.41 (m, 1 H), 9.05 (d, 1 H, J=8.1 Hz), 12.05 (br(s), 1 H) ; m/z: 452 [M+H]+, 454 [M+H]+ (calc. mass: 451 ).

2-(2,2-dioxo-1 ,3- - From [4-methyl-2-(piperidin-1 -yl)phenyl](5-methylfuran-2- dihydro-2- yl)methanamine Ex.16 and 2-(2,2-dioxo-1 ,3-dihydro-2- benzothiophen- benzothiophen-5-yl)acetic acid Ex.46 following protocol A,

5-yl)-N-{[4- DMAP (1.1 equiv), EDCI.HCI (1.1 equiv), 2h at rt,

methyl-2- purification by silica gel column chromatography

(piperidin-1 - (CH2CI2/EtOAc, 50:50), yield 69%, mp: 87°C, appearance: yl)phenyl](5- white solid

methylfuran-2-

- 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .38-1 .63 (m, yl)methyl}aceta

6H), 2.17 (s, 3H), 2.24 (s, 3H), 2.54-2.63 (m, 2H), 2.74-2.83 mide

(m, 2H), 3.49 (s, 2H), 4.43 (s, 2H), 4.44 (s, 2H), 5.81 (d, 1 H, J=3.0Hz), 5.92 (dd, 1 H, J=2.9Hz, J=1.0Hz), 6.48 (d, 1 H, J=8.2Hz), 6.90 (d, 1 H, J=6.0Hz), 6.94 (s, 1 H), 7.18 (d, 1 H, J=7.7Hz), 7.20-7.29 (m, 3H), 8.78 (d, 1 H, J=8.7Hz) ; m/z: 493 [M+H]+ (calc. mass: 492).

- From (5-chlorofuran-2-yl)[4-methyl-2-(piperidin-1 - yl)phenyl]methanamine Ex.47 and 2-(2-methanesulfonyl-

N-[(5- 2,3-dihydro-1 H-isoindol-5-yl)acetic acid Ex.27 following chlorofuran-2- protocol A, DMAP (1 equiv), EDCI.HCI (1 .1 equiv),

yl)[4-methyl-2- overnight at rt, purification by silica gel column

(piperidin-1 - chromatography (Cyclohexane/EtOAc, 50:50), yield 69%, yl)phenyl]methy mp: 143°C, appearance: white solid

l]-2-(2- - 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .40-1 .60 (m, methanesulfony 6H), 2.26 (s, 3H), 2.50-2.58 (m, 2H), 2.75-2.83 (m, 2H), l-2,3-dihydro- 2.95 (s, 3H), 3.50 (s, 2H), 4.57 (s, 4H), 6.05 (dd, 1 H,

1 H-isoindol-5- J=3.3Hz, J=0.9Hz), 6.35 (d, 1 H, J=3.3Hz), 6.51 (d, 1 H, yl)acetamide J=8.2Hz), 6.92 (d, 1 H, J=8.0Hz), 6.97 (s, 1 H), 7.16-7.24 (m,

4H), 8.86 (d, 1 H, J=8.3Hz) ; m/z: 542 [M+H]+, 544 [M+H]+ (calc. mass: 541 ).

- From (5-chlorofuran-2-yl)[4-methyl-2-(pyrrolidin-1 - yl)phenyl]methanamine Ex.48 and 1 -(2-methanesulfonyl-

N-[(5- 2,3-dihydro-1 H-isoindol-5-yl)cyclopropane-1 -carboxylic acid chlorofuran-2- Ex.33 following protocol A, DMAP (1 equiv), EDCI.HCI (1 .1 yl)[4-methyl-2- equiv), 2h at rt, purification by silica gel column

(pyrrolidin-1 - chromatography (Cyclohexane/EtOAc, 70:30), yield 42%, yl)phenyl]methy mp: 82°C, appearance: white solid

l]-1 -(2- - 1 H NMR (300 MHz, DMSO-d6, d in ppm): 0.95-1 .04 (m, methanesulfony 2H), 1 .28-1 .38 (m, 2H), 1 .56-1.73 (m, 4H), 2.23 (s, 3H), l-2,3-dihydro- 2.57-2.66 (m, 2H), 2.75-2.86 (m, 2H), 2.96 (s, 3H), 4.59 (m,

1 H-isoindol-5- 4H), 6.01 (dd, 1 H, J=3.3Hz, J=1 .2Hz), 6.28 (d, 1 H,

yl)cyclopropane J=7.8Hz), 6.35 (d, 1 H, J=3.3Hz), 6.80 (dd, 1 H, J=7.7Hz,

-1 -carboxamide J=1.0Hz), 6.94 (d, 1 H, J=1 .2Hz), 7.09 (d, 1 H, J=7.7Hz),

7.30-7.35 (m, 3H), 7.67 (d, 1 H, J=8.3Hz) ; m/z: 554 [M+H]+, 556 [M+H]+ (calc. mass: 553).

- From (2-bromo-4-methylphenyl)(phenyl)methanamine

Ex.49 and 2-(2-methyl-1 H-1 ,3-benzodiazol-5-yl)acetic acid Ex.45 following protocol B, substituted amine (1 equiv),

N-[(2-bromo-4- substituted acid (1 equiv), PyBOP (1 equiv) and

methylphenyl)(p triethylamine (3 equiv), 100°C for 20 min under microwave henyl)methyl]-2- irradiation, purification by silica gel column chromatography

(2-methyl-1 H- (CH2CI2/MeOH, 95:5), yield 21 %, mp: 138°C, appearance:

1 ,3-benzodiazol- white solid

5-yl)acetamide

- 1 H NMR (300 MHz, DMSO-d6, d in ppm): 2.28 (s, 3H), 2.46 (s, 3H), 3.58 (s, 2H), 6.33 (d, 1 H, J=8.2Hz), 7.03 (d, 1 H, J=8.2Hz), 7.13-7.16 (m, 2H), 7.18-7.35 (m, 7H), 7.44 (s, 1 H), 8.98 (d, 1 H, J=8.1 Hz), 12.08 (s, 1 H) ; m/z: 448 [M+H]+, 450 [M+H]+ (calc. mass: 447).

- From [4-methyl-2-(pyrrolidin-1 - yl)phenyl](phenyl)methanamine Ex.50 and 2-(2-methyl-1 H- 1 ,3-benzodiazol-5-yl)acetic acid Ex.45 following protocol A,

2-(2-methyl-1 H- DMAP (2.2 equiv), EDCI.HCI (1.1 equiv), 18h at rt,

1 ,3-benzodiazol- purification by silica gel column chromatography

5-yl)-N-{[4- (CH2CI2/MeOH, 95:5). The residue was triturated in methyl-2- diethylether and filtered-off, yield 41 %, mp: 132°C,

(pyrrolidin-1 - appearance: white solid

yl)phenyl](phen - 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .67-4.74 (m, yl)methyl}aceta 4H), 2.22 (s, 3H), 2.44 (s, 3H), 2.72-2.78 (m, 2H), 3.01 -3.08 mide (m, 2H), 3.57 (s, 2H), 6.43 (d, 1 H, J=8.1 Hz), 6.74 (d, 1 H,

J=7.8Hz), 6.87 (s, 1 H), 6.99-7.38 (m, 9H), 8.70 (d, 1 H, J=8.2Hz), 12.05 (s, 1 H) ; m/z: 439 [M+H]+ (calc. mass: 438).

- From (5-chlorofuran-2-yl)[4-methyl-2-(piperidin-1 - yl)phenyl]methanamine Ex.47 and 2-(2-oxo-2,3-dihydro-1 H- indol-5-yl)acetic acid Ex.14 following protocol A, DMAP (1

N-[(5- equiv), EDCI.HCI (1 .1 equiv), overnight at rt, purification by chlorofuran-2- silica gel column chromatography (Cyclohexane/EtOAc, yl)[4-methyl-2- 50:50), yield 64%, mp: 105°C, appearance: white solid

(piperidin-1 - yl)phenyl]methy - 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .40-1 .60 (m, l]-2-(2-oxo-2,3- 6H), 2.25 (s, 3H), 2.50-2.59 (m, 2H), 2.75-2.84 (m, 2H), dihydro-1 H- 3.40 (s, 2H), 3.41 (s, 2H), 6.04 (dd, 1 H, J=3.3Hz, J=0.9Hz), indol-5- 6.34 (d, 1 H, J=3.3Hz), 6.49 (d, 1 H, J=8.1 Hz), 6.70 (d, 1 H, yl)acetamide J=7.8Hz), 6.92 (d, 1 H, J=7.9Hz), 6.97 (s, 1 H), 7.02 (d, 1 H,

J=8.0Hz), 7.07 (s, 1 H), 7.17 (d, 1 H, J=7.8Hz), 8.79 (d, 1 H, J=8.4Hz), 10.29 (s, 1 H) ; m/z: 478 [M+H]+, 480 [M+H]+ (calc. mass: 477).

- See Figure 3AN

- To a solution of previously synthesized 2-(2,3-dioxo-2,3- dihydro-1 H-indol-5-yl)-N-{[4-methyl-2-(piperidin-1 - yl)phenyl](5-methylfuran-2-yl)methyl}acetamide Cpd.23

2-[(3Z)-3- (100 mg, 0.21 mmol) in MeOH (2 mL) was added hydrazine hydrazinylidene hydrate 50% (w/w) (15 mg, 0.23 mmol). The reaction was

-2-oxo-2,3- heated at 100°c overnight. The solvents were removed dihydro-1 H- under reduced pressure. The crude material was purified by indol-5-yl]-N-{[4- silica gel column chromatography using

methyl-2- Cyclohexane/EtOAc (6:4) as eluent to afford 2-(3-

(piperidin-1 - hydrazinylidene-2-oxo-2,3-dihydro-1 H-indol-5-yl)-N-{[4- yl)phenyl](5- methyl-2-(piperidin-1 -yl)phenyl](5-methylfuran-2- methylfuran-2- yl)methyl}acetamide Cpd.84 (35 mg, 34%) as yellow solid, yl)methyl}aceta mp: 130°C

mide - 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .46-1 .60 (m,

6H), 2.20 (s, 3H), 2.30 (s, 3H), 2.59-2.65 (m, 2H), 2.75-2.80 (m, 2H), 3.53 (s, 1.6H), 3.54 (s, 0.4H), 5.83 (d, 1 H,

J=3.0Hz), 5.87 (dd, 1 H, J=3.1 Hz, J=1 .0Hz), 6.60 (s, 0.8H), 6.61 (s, 0.2H), 6.82 (d, 0.8H, J=8.0Hz), 6.85 (d, 0.2H, J=7.6Hz), 6.87 (dd, 1 H, J=7.0Hz, J=1.9Hz), 6.99 (d, 1 H, J=1.0Hz), 7.1 1 (dd, 0.8H, J=8.0Hz, J=1 .7Hz), 7.16 (d, 1 H, J=7.9Hz), 7.20 (d, 0.2H, J=1 .8Hz), 7.41 (d, 0.8H, J=1 .3Hz), 7.73 (d, 0.2H, J=1 .2Hz) ; m/z: 486 [M+H]+ (calc. mass: 485).

- See Figure 3AO

- The previously synthesized N-{[4-methyl-2-(piperidin-1 - yl)phenyl](5-methylfuran-2-yl)methyl}-2-(3-oxo-2,3-dihydro- 1 H-inden-5-yl)acetamide Cpd.67 (50 mg, 0.1 1 mmol) was dissolved in EtOH (5 ml_). The solution was cooled to 0°C and sodium borohydride (6 mg, 0.16 mmol) was added. The ice bath was removed and the solution was stirred at rt for

2-(3-hydroxy- 2h. The solvent was removed under reduced pressure and

2,3-dihydro-1 H- 1 N citric acid was added to neutralized the solution. The inden-5-yl)-N- aqueous layer was extracted with CH2CI2. The organic

{[4-methyl-2- layer was dried over MgS04, filtered and the solution was

(piperidin-1 - concentrated under reduced pressure. The crude material yl)phenyl](5- was purified by silica gel column chromatography eluting methylfuran-2- with Cyclohexane/EtOAc (70:30), yield 77%, mp: 60°C, yl)methyl}aceta appearance: white solid

mide

- 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .46-1 .60 (m, 6H), 1 .68-1 .78 (m, 1 H), 2.17 (s, 3H), 2.25 (s, 3H), 2.25-2.35 (m, 1 H), 2.55-2.70 (m, 3H), 2.74-2.90 (m, 3H), 3.44 (s, 2H), 4.96-5.00 (m, 1 H), 5.16 (d, 1 H, J=6.2Hz), 5.79-5.81 (m, 1 H), 5.90-5.92 (m, 1 H), 6.48 (d, 1 H, J=8.3Hz), 6.89 (d, 1 H, J=8.0Hz), 6.93 (s, 1 H), 7.04-7.10 (m, 2H), 7.19 (dd, 1 H, J=5.8Hz, J=1.1 Hz), 7.21 (d, 1 H, J=1 .2Hz), 8.71 (dd, 1 H, J=8.7Hz, J=2.4Hz) ; m/z: 459 [M+H]+ (calc. mass: 458).

- From (5-chlorofuran-2-yl)(2,4-dimethylphenyl)methanamine Ex.32 and 1 -(2-oxo-2,3-dihydro-1 H-indol-5-yl)cyclopropane-

N-[(5- 1 -carboxylic acid Ex.37 following protocol A, DMAP (1 chlorofuran-2- equiv), EDCI.HCI (1 .1 equiv), overnight at rt, purification by yl)(2,4- silica gel column chromatography (Cyclohexane/EtOAc, dimethylphenyl) 50:50), yield 26%, mp: 78°C, appearance: white solid methyl]-1 -(2- - 1 H NMR (300 MHz, DMSO-d6, d in ppm): 0.91 -1 .00 (m, oxo-2,3-dihydro- 2H), 1.26-1 .33 (m, 2H), 2.16 (s, 3H), 2.23 (s, 3H), 3.43 (s,

1 H-indol-5- 2H), 5.99 (dd, 1 H, J=3.3Hz, J=1 .1 Hz), 6.16 (d, 1 H,

yl)cyclopropane J=8.5Hz), 6.35 (d, 1 H, J=3.3Hz), 6.75 (d, 1 H, J=7.9Hz),

-1 -carboxamide 6.95 (s, 1 H), 6.95-7.01 (m, 2H), 7.15 (dd, 1 H, J=7.9Hz),

7.17 (s, 1 H), 7.56 (d, 1 H, J=8.3Hz), 10.37 (br(s), 1 H) ; m/z: 457 [M+Na]+, 459 [M+Na]+ (calc. mass: 434).

N-[(5-

- From (5-chlorofuran-2-yl)(2,4-dimethylphenyl)methanamine chlorofuran-2- Ex.32 and 1 -(2,2-dioxo-1 ,3-dihydro-2,1 -benzothiazol-5- yl)(2,4- yl)cyclopropane-1 -carboxylic acid Ex.38 following protocol dimethylphenyl)

A, DMAP (1 equiv), EDCI.HCI (1 .1 equiv), overnight at rt, methyl]-1 -(2,2- purification by silica gel column chromatography (gradient dioxo-1 ,3- of Cyclohexane/EtOAc, from [80:20] to [70:30]), yield 28%, dihydro-2,1 - mp: 86°C, appearance: white solid

benzothiazol-5- yl)cyclopropane - 1 H NMR (300 MHz, DMSO-d6, d in ppm): 0.92-1 .17 (m,

-1 -carboxamide 2H), 1 .26-1 .36 (m, 2H), 2.16 (s, 3H), 2.23 (s, 3H), 4.47 (s, 2H), 5.99 (dd, 1 H, J=3.3Hz, J=1 .1 Hz), 6.16 (d, 1 H,

J=7.9Hz), 6.35 (d, 1 H, J=3.3Hz), 6.75 (d, 1 H, J=8.0Hz), 6.94-7.00 (m, 3H), 7.22 (dd, 1 H, J=8.1 Hz, J=1 .9Hz), 7.24 (s, 1 H), 7.79 (d, 1 H, J=8.3Hz), 10.48 (br(s), 1 H) ; m/z: 493 [M+Na]+, 495 [M+Na]+ (calc. mass: 470).

- From [4-methyl-2-(piperidin-1 -yl)phenyl](5-methylfuran-2- yl)methanamine Ex.16 and 2-(1 H-indol-6-yl)acetic acid Ex.89 following protocol A, DMAP (1 equiv), EDCI.HCI (1 .1

2-(1 H-indol-6- equiv), overnight at rt, purification by silica gel column yl)-N-((4-methyl- chromatography (Cyclohexane/EtOAc, 70:30), yield 78%,

2-(piperidin-1 - mp: ND, appearance: white solid

yl)phenyl)(5- - 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .45-1 .65 (m, methylfuran-2- 6H), 2.16 (s, 3H), 2.24 (s, 3H), 2.55-2.6 (m, 2H), 2.70-2.85 yl)methyl)aceta (m, 2H), 3.51 (s, 2H), 5.80 (d, 1 H, J=2.8Hz), 5.90-5.95 (m, mide 1 H), 6.34 (t, 1 H, J=2.1 Hz), 6.48 (d, 1 H, J=8.0Hz), 6.88 (d,

2H, J=8.1 Hz), 6.92 (s, 1 H), 7.18 (d, 1 H, J=7.8Hz), 7.23-7.30 (m, 2H), 7.40 (d, 1 H, J=8.1 Hz), 8.67 (d, 1 H, J=8.6Hz), 10.96 (s, 1 H).

- See Figure 3AP

- Step 1 : to a solution of anhydrous DMF (1 mL) was added phosphorus oxychloride (32 μΙ_, 0.34 mmol) at -10°C. After 30 min, the previously synthesized 2-(1 H-indol-6-yl)-N-((4- methyl-2-(piperidin-1 -yl)phenyl)(5-methylfuran-2- yl)methyl)acetamide Cpd.88a (75 mg, 0.17 mmol) dissolved in dry DMF (1 mL) was added dropwise. The reaction mixture was warmed to rt and stirred at this temperature for 5h. Ice was added to quench the reaction. The pH of the solution was adjusted with Na2C03 powder to pH = 5-6. The resulting mixture was extracted with EtOAc. The combined organic layers were dried over MgS04, filtered

2-[3- and the solution was concentrated under reduced pressure.

(hydroxy methyl)

The crude material was purified by silica gel column

-1 H-indol-6-yl]- chromatography eluting with CH2CI2/MeOH (97:3) to give

N-{[4-methyl-2- 2-(3-formyl-1 H-indol-6-yl)-N-((4-methyl-2-(piperidin-1 -

(piperidin-1 - yl)phenyl)(5-methylfuran-2-yl)methyl)acetamide (75 mg, yl)phenyl](5- 94%) as white solid. 1 H NMR (300 MHz, DMSO-d6, d in methylfuran-2- ppm): 1 .40-1 .65 (m, 6H), 2.16 (s, 3H), 2.24 (s, 3H), 2.50- yl)methyl}aceta

2.60 (m, 2H), 2.70-2.85 (m, 2H), 3.56 (s, 2H), 5.81 (d, 1 H, mide

J=2.9Hz), 5.90-5.95 (m, 1 H), 6.48 (d, 1 H, J=8.2Hz), 6.88 (d, 1 H, J=7.7Hz), 6.93 (s, 1 H), 7.10 (dd, 1 H, J=8.2Hz,

J=1.4Hz), 7.18 (d, 1 H, J=7.8Hz), 7.39 (s, 1 H), 7.94 (d, 1 H, J=7.7Hz), 8.23 (d, 1 H, J=3.1 Hz), 8.74 (d, 1 H, J=8.2Hz), 9.88 (s, 1 H), 12.06 (br(s), 1 H).

- Step 2: 2-(3-formyl-1 H-indol-6-yl)-N-((4-methyl-2-(piperidin- 1 -yl)phenyl)(5-methylfuran-2-yl)methyl)acetamide (80 mg, 0.17 mmol) in anhydrous MeOH (2 mL) was added sodium borohydride (19 mg, 0.51 mmol). The reaction mixture was stirred at rt for 4h. Water and ice were added and the precipitate formed was collected by filtration and washed with water, yield 62%, mp: 92°C, appearance: white solid - 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1.35-1.65 (m,

6H), 2.16 (s, 3H), 2.24 (s, 3H), 2.50-2.60 (m, 2H), 2.75-2.85 (m, 2H), 3.51 (s, 2H), 4.58 (d, 2H, J=5.3Hz), 4.67 (t, 1H, J=4.7Hz), 5.80 (d, 1H, J=3.0Hz), 5.90-5.95 (m, 1H), 6.48 (d, 1H, J=8.2Hz), 6.85-6.95 (m, 3H), 7.15 (d, 1H, J=2.3Hz), 7.18 (d, 1H, J=7.8Hz), 7.23 (s, 1H), 7.45 (d, 1H, J=8.1Hz), 8.65 (d, 1H, J=8.4Hz), 10.75 (s, 1H) ; m/z: 472 [M+H]+ (calc. mass: 471).

- From [4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2- yl)methanamine Ex.16 and 1-(1 H-indol-5-yl)cyclopropane- 1-carboxylic acid Ex.61 following protocol A, DMAP (1 equiv), EDCI.HCI (1.1 equiv), 5h at rt, purification by silica gel column chromatography (Cyclohexane/EtOAc, 70:30)

1- (1H-indol-5- followed by a second purification by column

yl)-N-((4-methyl- chromatography on silica gel eluting with

2- (piperidin-1- Cyclohexane/EtOAc (80:20), yield 89%, mp: ND,

yl)phenyl)(5- appearance: white solid

89a

methylfuran-2- - 1H NMR (300 MHz, DMSO-d6, d in ppm): 1.01 (m, 2H), yl)methyl)cyclo 1.05-1.35 (m, 8H), 2.08 (s, 3H), 2.21 (s, 3H), 2.25-2.35 (m, propanecarboxa 2H), 2.50-2.60 (m, 2H), 5.80-5.81 (dd, 1H, J=3.0Hz, mide J=0.9Hz), 5.90-5.95 (dd, 1H, J=3.0Hz, J=1.1Hz), 6.30 (m,

1H, J=8.6Hz), 6.39 (m, 1H), 6.76 (d, 1H, J=8.6Hz), 6.83 (dd, 1H, J=6.8Hz, J=1.0Hz), 6.90 (d, 1H, J=7.8Hz), 6.94 (s, 1H), 7.10 (dd, 1H, J=8.4Hz, J=1.7Hz), 7.34 (t, 1H, J=2.6Hz), 7.38 (d, 1 H, J=8.4Hz), 7.55 (d, 1 H, J=1.7Hz), 11.11 (br(s), 1H).

- See Figure 3AQ

- Step 1 : to a solution of anhydrous DMF (1 mL) was added phosphorus oxychloride (80 μΙ_, 0.86 mmol) at -10°C. After 30 min, the previously synthesized 1-(1 H-indol-5-yl)-N-((4- methyl-2-(piperidin-1-yl)phenyl)(5-methylfuran-2- yl)methyl)cyclopropanecarboxamide Cpd.89a (200 mg, 0.43 mmol) dissolved in dry DMF (1 mL) was added

1-[3- dropwise. The reaction mixture was warmed to rt and stirred

(hydroxy methyl) at this temperature for 5h. Ice was added to quench the

-1H-indol-5-yl]- reaction. The pH of the solution was adjusted with Na2C03

N-{[4-methyl-2- powder to pH = 5-6. The resulting mixture was extracted

(piperidin-1- with EtOAc. The combined organic layers were dried over

89

yl)phenyl](5- MgS04, filtered and the solution was concentrated under methylfuran-2- reduced pressure. The crude material was purified by silica yl)methyl}cyclo gel column chromatography eluting with CH2CI2/MeOH propane-1- (97:3) to give 1-(3-formyl-1 H-indol-5-yl)-N-((4-methyl-2- carboxamide (piperidin-1-yl)phenyl)(5-methylfuran-2- yl)methyl)cyclopropanecarboxamide (210 mg, 99%).1H NMR (300 MHz, DMSO-d6, d in ppm): 1.00-1.30 (m, 8H), 1.30-1.40 (m, 1H), 1.40-1.50 (m, 1H), 2.08 (s, 3H), 2.21 (s, 3H), 2.25-2.35 (m, 2H), 2.45-2.50 (m, 2H), 5.81 (d, 1H, J=3.1Hz), 5.90-5.95 (m, 1H), 6.32 (d, 1H, J=8.4Hz), 6.83 (d, 1H, J=6.1Hz), 6.94 (s, 1H), 6.97 (d, 1H, J=7.9Hz), 7.01 (d, 1H, J=8.6Hz), 7.30 (dd, 1H, J=8.3Hz, J=1.8Hz), 7.49 (d, 1H, J=8.6Hz), 8.11 (s, 1H), 8.30 (d, 1H, J=3.1Hz), 9.92 (s, 1H), 12.15 (br(s), 1 H).

- Step 2: 1 -(3-formyl-1 H-indol-5-yl)-N-((4-methyl-2-(piperidin- 1 -yl)phenyl)(5-methylfuran-2- yl)methyl)cyclopropanecarboxamide (80 mg, 0.16 mmol) in anhydrous MeOH (2 mL) was added sodium borohydride (18 mg, 0.48 mmol). The reaction mixture was stirred at rt for 4h. Water and ice were added and the precipitate formed was collected by filtration and washed with water, yield 62%, mp: 1 12°C, appearance: white solidl H NMR (300 MHz, DMSO-d6, d in ppm): 0.95-1 .05 (m, 2H), 1 .10- 1 .30 (m, 6H), 1 .30-1 .35 (m, 1 H), 1 .53-1 .45 (m, 1 H), 2.08 (s, 3H), 2.21 (s, 3H), 2.25-2.40 (m, 2H), 2.50-2.55 (m, 2H), 4.60 (d, 2H, J=5.5Hz), 4.74 (t, 1 H, J=5.0Hz), 5.81 (d, 1 H, J=2.8Hz), 5.90-5.95 (m, 1 H), 6.32 (d, 1 H, J=9.1 Hz), 6.75 (d, 1 H, J=8.8Hz), 6.82 (d, 1 H, J=7.1 Hz), 6.90 (d, 1 H, J=7.7Hz), 6.94 (s, 1 H), 7.1 1 (dd, 1 H, J=8.5Hz, J=1 .8Hz), 7.24 (d, 1 H, J=2.3Hz), 7.34 (d, 1 H, J=8.6Hz), 7.62 (d, 1 H, J=1 .5Hz), 10.90 (s, 1 H) ; m/z: 498 [M+H]+ (calc. mass: 497).

- From (2-bromo-4-methylphenyl)(phenyl)methanamine

Ex.49 and 2-(2-ethoxy-1 H-1 ,3-benzodiazol-5-yl)acetic acid Ex.52 following protocol A, substituted amine (0.9 equiv), DMAP (3.2 equiv), EDCI.HCI (1.1 equiv), 1 h30 at rt. Sat. NH4CI was added to quench the reaction . The brown solid

N-[(2-bromo-4- formed was collected by filtration and dried until constant methylphenyl)(p weight. Purification by silica gel column chromatography henyl)methyl]-2- (CH2CI2/EtOAC, 80:20), yield 37%, mp: 189°C,

(2-ethoxy-1 H- appearance: pale brown solid

1 ,3-benzodiazol-

5-yl)acetamide - 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1.37 (t, 3H,

J=7.0Hz), 2.28 (s, 3H), 3.54 (s, 2H), 4.45 (q, 2H, J=7.1 Hz), 6.32 (d, 1 H, J=8.2Hz), 6.94 (dd, 1 H, J=8.2Hz, J=1 .6Hz), 7.12-7.34 (m, 9H), 7.43 (d, 1 H, J=1 .6Hz), 8.95 (d, 1 H, J=8.3Hz), 1 1 .70 (s, 1 H) ; m/z: 478 [M+H]+, 480 [M+H]+ (calc. mass: 477).

- From [4-methyl-2-(piperidin-1 -yl)phenyl](5-methylfuran-2- yl)methanamine Ex.16 and 2-[6-

(methylsulfanyl)naphthalen-2-yl]acetic acid Ex.53 following

N-{[4-methyl-2- protocol A, DMAP (2.2 equiv), EDCI.HCI (2.2 equiv),

(piperidin-1 - overnight at rt, purification by silica gel column

yl)phenyl](5- chromatography (Cyclohexane/EtOAc, 80:20), yield 47%, methylfuran-2- mp: 134°C, appearance: white solid

yl)methyl}-2-[6- - 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .38-1 .59 (m,

(methylsulfanyl) 6H), 2.17 (s, 3H), 2.24 (s, 3H), 2.53-2.60 (m, 2H), 2.56 (s, naphthalen-2- 3H), 2.73-2.82 (m, 2H), 3.61 (s, 2H), 5.82 (d, 1 H, J=3.1 Hz), yl]acetamide 5.92 (dd, 1 H, J=3.0Hz, J=1.1 Hz), 6.51 (d, 1 H, J=8.3Hz),

6.89 (d, 1 H, J=8.5Hz), 6.93 (s, 1 H), 7.20 (d, 1 H, J=7.8Hz), 7.33-7.42 (m, 2H), 7.66 (s, 2H), 7.71 -7.76 (m, 2H), 8.81 (d, 1 H, J=8.4Hz) ; m/z: 499 [M+H]+ (calc. mass: 498).

N-[(2-bromo-4- methylphenyl)(p - From (2-bromo-4-methylphenyl)(phenyl)methanamine henyl)methyl]-2- Ex.49 hydrochloride and 2-[2-(ethylsulfanyl)-1 H-1 ,3- [2- benzodiazol-5-yl]acetic acid Ex.54 following protocol A,

(ethylsulfanyl)- substituted amine (0.9 equiv), DMAP (3.2 equiv), EDCI.HCI 1 H-1 ,3- (1 .1 equiv), 1 h30 at rt. Sat. NH4CI was added to quench the benzodiazol-5- reaction . The brown solid formed was collected by filtration yl]acetamide and dried until constant weight. Purification by silica gel column chromatography (CH2CI2/EtOAC, 80:20), yield 47%, mp: 103°C, appearance: pale brown solid

- 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1.35 (t, 3H, J=7.1 Hz), 2.28 (s, 3H), 3.25 (q, 2H, J=7.3Hz), 3.58 (s, 2H), 6.33 (d, 1 H, J=8.2Hz), 7.04 (d, 1 H, J=8.1 Hz), 7.13-7.43 (m, 10H), 8.98 (d, 1 H, J=8.2Hz), 12.41 (s, 1 H) ; m/z: 494

[M+H]+, 496 [M+H]+ (calc. mass: 493).

- From [4-methyl-2-(piperidin-1 -yl)phenyl](5-methylfuran-2- yl)methanamine Ex.16 and 2-[2-(morpholin-4-yl)-1 H-1 ,3- benzodiazol-5-yl]acetic acid Ex.55 following protocol A,

N-{[4-methyl-2- DMAP (2.2 equiv), EDCI.HCI (1 .2 equiv), overnight at rt,

(piperidin-1 - purification by silica gel column chromatography eluting yl)phenyl](5- with (Cyclohexan/EtOAc, 60:40) and then with

methylfuran-2- CH2CI2/MeOH (90:10) containing 10% of NH40H, yield yl)methyl}-2-[2- 14%, mp: 125°C, appearance: yellow solid

(morpholin-4- - 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .39-1 .55 (m, yl)-1 H-1 ,3- 6H), 2.16 (s, 3H), 2.24 (s, 3H), 2.51 -2.57 (m, 2H), 2.76-2.80 benzodiazol-5- (m, 2H), 3.47-3.49 (m, 6H), 3.73 (t, 4H, J=5.1 Hz), 5.80 (d, yl]acetamide 1 H, J=2.9Hz), 5.91 (dd, 1 H, J=3.0Hz, J=1 .0Hz), 6.47 (d, 1 H,

J=8.5Hz), 6.88 (d, 1 H, J=7.9Hz), 6.93-6.94 (m, 2H), 7.14- 7.19 (m, 3H), 8.68 (d, 1 H, J=8.5Hz), 12.19 (br(s), 1 H) ; m/z: 528 [M+H]+ (calc. mass: 527).

- See Figure 3AR

- Step 1 : see step 1 of synthesis of Cpd.58

- Step 2: 2-(3-formyl-1 H-indol-5-yl)-N-((4-methyl-2-(piperidin- 1 -yl)phenyl)(5-methylfuran-2-yl)methyl)acetamide (100 mg, 0.21 mmol) was dissolved in CH2CI2 (1 ml_). Molecular sieves 4A were added. Morpholine (20 μΙ_, 0.23 mmol) was

N-{[4-methyl-2- added to the suspension. The reaction mixture was stirred

(piperidin-1 - at rt for 18h. TLC showed starting material. Additional yl)phenyl](5- morpholine (2 equiv) were added followed by two drops of methylfuran-2- acetic acid. The reaction mixture was heated at 40°C for 2h. yl)methyl}-2-[3- After cooling to rt, sodium triacetoxyborohydride (68 mg,

(morpholin-4- 0.32 mmol) was added portionwise to the reaction mixture ylmethyl)-1 H- and the stirring was kept for 1 h. Water was added to indol-5- quench the reaction. After phases separation, the aqueous yl]acetamide layer was extracted twice with CH2CI2. The combined

organic layers were dried over MgS04, filtered and the solution was concentrated under reduced pressure. The crude material was purified by silica gel column

chromatography eluting with CH2CI2/MeOH (95:5), yield 39%, mp: 100°C, appearance: white solid

- 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .42-1 .54 (m, 6H), 2.16 (s, 3H), 2.24 (s, 3H), 2.30-2.38 (m, 4H), 2.50-2.26 (m, 2H), 2.75-2.81 (m, 2H), 3.50 (s, 2H), 3.50-3.53 (m, 4H), 3.54 (s, 2H), 5.82 (d, 1 H, J=2.6Hz), 5.91 (dd, 1 H, J=3Hz, J=1.1 Hz), 6.48 (d, 1 H, J=8.4Hz), 6.88 (d, 1 H, J=7.9Hz), 6.93 (s, 1 H), 6.97 (dd, 1 H, J=8.3Hz, J=1 .6Hz), 7.17 (d, 1 H, J=2.3Hz), 7.19 (d, 1 H, J=5.1 Hz), 7.22 (d, 1 H, J=5.5Hz), 7.46 (s, 1 H), 8.65 (d, 1 H, J=8.4Hz), 10.82 (s, 1 H) ; -m/z: 541 [M+H]+ (calc. mass: 540).

- From (2,4-dimethylphenyl)(5-methylfuran-2-yl)methanamine

1 -(1 - Ex.19 and 1 -(1 -cyclopropanecarbonyl-2,3-dihydro-1 H- cyclopropaneca indol-5-yl)cyclopropane-1 -carboxylic acid Ex.56 following rbonyl-2,3- protocol A, DMAP (1.2 equiv), EDCI.HCI (1 .2 equiv), 4h at dihydro-1 H- rt, purification by silica gel column chromatography

indol-5-yl)-N- (Cyclohexane/EtOAc, 70:30), yield 53%, mp: 70°C,

[(2,4- appearance: white solid

dimethylphenyl) - 1 H NMR (300 MHz, DMSO-d6, d in ppm): 0.85-0.95 (m,

(5-methylfuran- 4H), 0.95-1 .00 (m, 2H), 1 .20-1 .35 (m, 2H), 1 .90-1 .95 (m,

2- 1 H), 2.16 (s, 3H), 2.17 (s, 3H), 2.22 (s, 3H), 3.15 (t, 2H, yl)methyl]cyclo J=8.4Hz), 4.28 (m, 2H), 5.76 (d, 1 H, J=3.1 Hz), 5.92 (dd, 1 H, propane-1 - J=3.0Hz, J=1.1 Hz), 6.1 1 (d, 1 H, J=8.3Hz), 6.85-6.95 (m, carboxamide 3H), 7.1 1 (dd, 1 H, J=8.1 Hz, J=1.9Hz), 7.20-7.25 (m, 2H),

7.95 (d, 1 H, J=5.5Hz) ; m/z: 491 [M+Na]+ (calc. mass: 468).

- From [4-methyl-2-(piperidin-1 -yl)phenyl](5-methylfuran-2- yl)methanamine Ex.16 and 2-{1 -[3-(tert-butoxy)-3- oxopropyl]-1 H-indol-5-yl}acetic acid Ex.57 following protocol A, DMAP (2.2 equiv), EDCI.HCI (1.2 equiv), tert-butyl 3-{5- overnight at rt, purification by silica gel column

[({[4-methyl-2- chromatography (Cyclohexane/EtOAc, 70:30), yield 89%,

(piperidin-1 - mp: 50°C, appearance: white solid

yl)phenyl](5- methylfuran-2- - 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .31 (s, 9H), yl)methyl}carba 1 .45-1.65 (m, 6H), 2.16 (s, 3H), 2.24 (s, 3H), 2.50-2.60 (m, moyl)methyl]- 2H), 2.68 (t, 2H, J=6.6Hz), 2.70-2.85 (m, 2H), 3.50 (s, 2H),

1 H-indol-1 - 4.34 (t, 2H, J=6.6Hz), 5.80 (d, 1 H, J=3.1 Hz), 5.90-5.95 (m, yl}propanoate 1 H), 6.31 (d, 1 H, J=0.6Hz), 6.48 (d, 1 H, J=8.5Hz), 6.88 (d,

1 H, J=7.8Hz), 6.92 (s, 1 H), 7.02 (dd, 1 H, J=8.4Hz,

J=1.7Hz), 7.19 (d, 1 H, J=7.7Hz), 7.27 (d, 1 H, J=3.1 Hz), 7.30-7.40 (m, 2H), 8.64 (d, 1 H, J=8.6Hz) ; m/z: 569 [M+H]+ (calc. mass: 569).

- See Figure 3AS

3-{5-[({[4-

- The previously synthesized tert-butyl 3-{5-[({[4-methyl-2- methyl-2- (piperidin-1 -yl)phenyl](5-methylfuran-2-

(piperidin-1 - yl)methyl}carbamoyl)methyl]-1 H-indol-1 -yl}propanoate yl)phenyl](5- Cpd.96 (2.20 g, 3.86 mmol) was dissolved in MeOH (16 methylfuran-2- ml_). 5M NaOH (3.86 ml_, 19.31 mmol) was added to the yl)methyl}carba

solution. The reaction mixture was heated at 100°C for 45 moyl)methyl]- min under mricrowave irradiation. The solvent was removed

1 H-indol-1 - under reduced pressure and 1 N citric acid was added to the yl}propanoic

residue up pH = 5 was reached. The solid formed was acid

collected by filtration, washed with water and dried until constant weight, yield 83%, mp: 95°C, appearance: white solid

- 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .43-1 .52 (m, 6H), 2.16 (s, 3H), 2.24 (s, 3H), 2.50-2.57 (m, 2H), 2.68 (t, 2H, J=6.8Hz), 2.74-2.76 (m, 2H), 3.50 (s, 2H), 4.34 (t, 2H, J=6.9Hz), 5.80 (d, 1 H, J=2.9Hz), 5.91 (dd, 1 H, J=2.9Hz, J=1.0Hz), 6.31 (d, 1 H, J=2.9Hz), 6.48 (d, 1 H, J=8.5Hz), 6.88 (d, 1 H, J=7.9Hz), 6.93 (s, 1 H), 7.02 (dd, 1 H, J=8.5Hz, J=1.4Hz), 7.20 (d, 1 H, J=7.8Hz), 7.29 (d, 1 H, J=3.1 Hz), 7.34-7.37 (m, 2H), 8.66 (d, 1 H, J=8.5Hz), 12.35 (br(s), 1 H) ; m/z: 514 [M+H]+ (calc. mass: 513).

- From [4-methyl-2-(piperidin-1 -yl)phenyl](5-methylfuran-2- yl)methanamine Ex.16 and 2-[3-(2-methanesulfonylethyl)-

2-[3-(2- 1 H-indol-5-yl]acetic acid Ex.58 following protocol A, methanesulfony substituted amine (0.9 equiv), DMAP (2.2 equiv), EDCI.HCI lethyl)-1 H-indol- (1 .2 equiv), overnight at rt, purification by preparative

5-yl]-N-{[4- HPLC, yield 46%, mp: 107°C, appearance: white solid methyl-2-

98 - 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .35-1 .63 (m,

(piperidin-1 - 6H), 2.16 (s, 3H), 2.24 (s, 3H), 2.52-2.60 (m, 2H), 2.72-2.82 yl)phenyl](5- (m, 2H), 2.99 (s, 3H), 3.04-3.13 (m, 2H), 3.37-3.46 (m, 2H), methylfuran-2- 3.51 (s, 2H), 5.81 (d, 1 H, J=3.0Hz), 5.90 (dd, 1 H, J=2.9Hz, yl)methyl}aceta J=0.9Hz), 6.48 (d, 1 H, J=8.4Hz), 6.84-6.95 (m, 2H), 7.00 mide (dd, 1 H, J=8.3Hz, J=1.4Hz), 7.17-7.26 (m, 3H), 7.41 (s, 1 H),

8.67 (d, 1 H, J=8.5Hz), 10.81 (s, 1 H) ; m/z: 548 [M+H]+ (calc. mass: 547).

- From (2,4-dimethylphenyl)(5-methylfuran-2-yl)methanamine Ex.19 and 2-{1 -[3-(tert-butoxy)-3-oxopropyl]-1 H-indol-5- yl}acetic acid Ex.57 following protocol A, substituted amine tert-butyl 3-[5- (0.9 equiv), DMAP (2.2 equiv), EDCI.HCI (1.2 equiv),

({[(2,4- overnight at rt, purification by preparative HPLC, yield 50%, dimethylphenyl) mp: 39°C, appearance: white solid

(5-methylfuran-

99 2- - 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .31 (s, 9H), 2.16 yl)methyl]carba (s, 3H), 2.19 (s, 3H), 2.22 (s, 3H), 2.69 (t, 2H, J=6.6Hz), moyl}methyl)- 3.52 (s, 2H), 4.34 (t, 2H, J=6.5Hz), 5.84 (d, 1 H, J=3.2Hz), 1 H-indol-1 - 5.95 (dd, 1 H, J=3.0Hz, J=1.OHz), 6.1 1 (d, 1 H, J=8.3Hz), yl]propanoate 6.32 (dd, 1 H, J=3.0Hz, J=0.5Hz), 6.92-6.99 (m, 2H), 7.04

(dd, 1 H, J=8.4Hz, J=1.6Hz), 7.10 (d, 1 H, J=8.4Hz), 7.28 (d, 1 H, J=3.1 Hz), 7.33-7.40 (m, 2H), 8.87 (d, 1 H, J=8.3Hz) ; m/z: 501 [M+H]+ (calc. mass: 500).

- From (2-bromo-4-methylphenyl)(5-methylfuran-2- yl)methanamine Ex.18 and 2-{1 -[3-(tert-butoxy)-3- tert-butyl 3-[5- oxopropyl]-1 H-indol-5-yl}acetic acid Ex.57 following

({[(2-bromo-4- protocol A, substituted amine (0.9 equiv), DMAP (2.2 methylphenyl)(5

equiv), EDCI.HCI (1 .2 equiv), overnight at rt, purification by

-methylfuran-2-00 silica gel column chromatography (CH2CI2/EtOAc, 95:5), yl)methyl]carba

yield 58%, mp: 149°C, appearance: white solid

moyl}methyl)-

1 H-indol-1 - - 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .31 (s, 9H), 2.21 yl]propanoate (s, 3H), 2.27 (s, 3H), 2.69 (t, 2H, J=6.6Hz), 3.53 (s, 2H),

4.34 (t, 2H, J=6.6Hz), 5.75 (d, 1 H, J=3.0Hz), 5.95 (dd, 1 H, J=3.0Hz, J=1.0Hz), 6.26 (d, 1 H, J=8.1 Hz), 6.33 (d, 1 H, J=3.2Hz), 7.04 (dd, 1 H, J=8.5Hz, J=1.5Hz), 7.17 (d, 1 H, J=7.0Hz), 7.28 (d, 1 H, J=3.1 Hz), 7.31 (d, 1 H, J=7.9Hz), 7.34-7.43 (m, 3H), 9.01 (d, 1 H, J=8.2Hz) ; m/z: 565 [M+H]+, 567 [M+H]+ (calc. mass: 564).

- See Figure 3AS

- The previously synthesized tert-butyl 3-[5-({[(2,4- dimethylphenyl)(5-methylfuran-2- yl)methyl]carbamoyl}methyl)-1 H-indol-1 -yl]propanoate

Cpd.99 (45 mg, 0.09 mmol) was dissolved in MeOH (1 .5 ml_). 5M NaOH (90 μΙ_, 0.45 mmol) was added to the

3-[5-({[(2,4- solution. The reaction mixture was heated at 100°C for 30 dimethylphenyl) min under mricrowave irradiation. The solvent was removed (5-methylfuran- under reduced pressure and 1 N citric acid was added to the 2- residue up pH = 4 was reached. The solid formed was yl)methyl]carba collected by filtration, washed with water and dried until moyl}methyl)- constant weight, yield 98%, mp: 65°C, appearance: white 1 H-indol-1 - solid

yl]propanoic

- 1 H NMR (300 MHz, DMSO-d6, d in ppm): 2.17 (s, 3H), 2.20 acid

(s, 3H), 2.23 (s, 3H), 2.71 (t, 2H, J=6.8Hz), 3.52 (s, 2H), 4.35 (t, 2H, J=6.8Hz), 5.84 (d, 1 H, J=3.1 Hz), 5.95 (dd, 1 H, J=3.0Hz, J=1.0Hz), 6.1 1 (d, 1 H, J=8.3Hz), 6.33 (d, 1 H, J=2.9Hz), 6.92-7.00 (m, 2H), 7.03 (dd, 1 H, J=8.6Hz, J=1.3Hz), 7.1 1 (d, 1 H, J=8.4Hz), 7.29 (d, 1 H, J=3.1 Hz), 7.34-7.42 (m, 2H), 8.88 (d, 1 H, J=8.4Hz), 12.32 (br(s), 1 H) ; m/z: 445 [M+H]+ (calc. mass: 444).

- See Figure 3AS

- The previously synthesized tert-butyl 3-[5-({[(2-bromo-4- methylphenyl)(5-methylfuran-2- yl)methyl]carbamoyl}methyl)-1 H-indol-1 -yl]propanoate

Cpd.100 (45 mg, 0.09 mmol) was dissolved in MeOH (1 .5 ml_). 5M NaOH (00 μΙ_, 0.40 mmol) was added to the

3-[5-({[(2-bromo- solution. The reaction mixture was heated at 100°C for 30 4- min under mricrowave irradiation. The solvent was removed methylphenyl)(5

under reduced pressure and 1 N citric acid was added to the

-methylfuran-2- residue up pH = 4 was reached. The solid formed was yl)methyl]carba

collected by filtration, washed with water and dried until moyl}methyl)- constant weight, yield 99%, mp: 70°C, appearance: white

1 H-indol-1 - solid

yl]propanoic

acid - 1 H NMR (300 MHz, DMSO-d6, d in ppm): 2.21 (s, 3H), 2.27

(s, 3H), 2.71 (t, 2H, J=6.8Hz), 3.53 (s, 2H), 4.35 (t, 2H, J=6.7Hz), 5.76 (d, 1 H, J=3.0Hz), 5.95 (dd, 1 H, J=3.0Hz, J=0.9Hz), 6.26 (d, 1 H, J=8.2Hz), 6.33 (d, 1 H, J=3.1 Hz), 7.04 (dd, 1 H, J=8.6Hz, J=1.3Hz), 7.18 (d, 1 H, J=8.2Hz), 7.28-7.43 (m, 5H), 9.03 (d, 1 H, J=8.2Hz), 12.28 (br(s), 1 H) ; m/z: 509 [M+H]+, 51 1 [M+H]+ (calc. mass: 508).

2-[3-(2- - From [4-methyl-2-(piperidin-1 -yl)phenyl](5-methylfuran-2- methanesulfony yl)methanamine Ex.16 and 2-[3-(2-methanesulfonylacetyl)- lacetyl)-1 H- 1 H-indol-5-yl]acetic acid Ex.59 following protocol A, DMAP indol-5-yl]-N-{[4- (2.2 equiv), EDCI.HCI (1 .1 equiv), overnight at rt, methyl-2- purification by silica gel column chromatography

(piperidin-1 - (CH2CI2/EtOAc, 60:40), yield 76%, mp: 139°C,

yl)phenyl](5- appearance: white solid

methylfuran-2-

- 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .42-1 .53 (m, yl)methyl}aceta

6H), 2.16 (s, 3H), 2.24 (s, 3H), 2.50-2.56 (m, 2H), 2.72-2.77 mide

(m, 2H), 3.15 (s, 3H), 3.55 (s, 2H), 4.79 (s, 2H), 5.83 (d, 1 H, J=3.0Hz), 5.91 (dd, 1 H, J=2.9Hz, J=1.0Hz), 6.47 (d, 1 H, J=8.4Hz), 6.88 (d, 1 H, J=7.9Hz), 6.92 (s, 1 H), 7.16 (dd, 1 H, J=8.4Hz, J=1 .6Hz), 7.20 (d, 1 H, J=7.8Hz), 7.38 (d, 1 H, J=8.2Hz), 8.1 1 (s, 1 H), 8.51 (s, 1 H), 8.75 (d, 1 H, J=8.4Hz), 12.14 (br(s), 1 H) ; m/z: 562 [M+H]+ (calc. mass: 561 ).

- From (2-bromo-4-methylphenyl)(5-methylfuran-2- yl)methanamine Ex.18 and 2-[3-(2-methanesulfonylacetyl)- 1 H-indol-5-yl]acetic acid Ex.59 following protocol A, DMAP

N-[(2-bromo-4- (3.2 equiv), EDCI.HCI (1 .1 equiv), overnight at rt,

methylphenyl)(5 purification by silica gel column chromatography

-methylfuran-2- (CH2CI2/EtOAc, 60:40), yield 70%, mp: 206°C,

yl)methyl]-2-[3- appearance: white solid

(2- methanesulfony - 1 H NMR (300 MHz, DMSO-d6, d in ppm): 2.20 (s, 3H), 2.26 lacetyl)-1 H- (s, 3H), 3.16 (s, 3H), 3.53-3.63 (m, 2H), 4.80 (s, 2H), 5.78 indol-5- (d, 1 H, J=2.7Hz), 5.96 (dd, 1 H, J=3.1 Hz, J=1 .1 Hz), 6.23 (d, yl]acetamide 1 H, J=8.3Hz), 7.15-7.20 (m, 2H), 7.35-7.40 (m, 3H), 8.15

(d, 1 H, J=1 .0Hz), 8.51 (s, 1 H), 9.13 (d, 1 H, J=8.1 Hz), 12.16 (br(s), 1 H) ; m/z: 579 [M+Na]+, 581 [M+Na]+ (calc. mass: 556).

- From [4-methyl-2-(piperidin-1 -yl)phenyl](5-methylfuran-2- yl)methanamine Ex.16 and 2-(1 H-indol-5-yl)acetic acid Ex.90 following protocol A, DMAP (2.2 equiv), EDCI.HCI

2-(1 H-indol-5- (1 .2 equiv), overnight at rt, purification by silica gel column yl)-N-{[4-methyl- chromatography (Cyclohexane/EtOAc, 60:40), yield 79%,

2-(piperidin-1 - mp: ND, appearance: white solid

yl)phenyl](5- - 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .40-1 .65 (m, methylfuran-2- 6H), 2.17 (s, 3H), 2.24 (s, 3H), 2.50-2.60 (m, 2H), 2.70-2.85 yl)methyl}aceta (m, 2H), 3.49 (s, 2H), 5.80 (d, 1 H, J=3.1 Hz), 5.90-5.95 (m, mide 1 H), 6.32 (m, 1 H), 6.49 (d, 1 H, J=8.5Hz), 6.87 (d, 1 H,

J=8.2Hz), 6.92 (s, 1 H), 6.97 (dd, 1 H, J=8.3Hz, J=1 .7Hz), 7.19 (d, 1 H, J=7.8Hz), 7.23-7.30 (m, 2H), 7.38 (s, 1 H), 8.63 (d, 1 H, J=8.3Hz), 10.70 (br(s), 1 H).

- See Figure 3AT

2-(1 -

- 2-(1 H-indol-5-yl)-N-{[4-methyl-2-(piperidin-1 -yl)phenyl](5- methanesulfony

methylfuran-2-yl)methyl}acetamide Cpd.106a (50 mg, 0.1 1 l-1 H-indol-5-yl)- mmol) was dissolved in dry THF (2 ml_).

N-{[4-methyl-2- Tetrabutylammonium hydrogen sulfate (4 mg, 0.01 mmol)

(piperidin-1 - was added to the solution followed by 12M NaOH (944 μΙ_, yl)phenyl](5- 0.1 1 mmol). After 5 min of stirring, methanesulfonyl chloride methylfuran-2- (13 μΙ_, 0.17 mmol) was added to the reaction mixture and yl)methyl}aceta

the solution was stirred at rt for 1 h. The solvent was mide

removed under reduced pressure. Water and EtOAc was added to the residue. After phase separation, the organic layer was dried over MgS04, filtered and the solution was concentrated to dryness. The crude material was purified by silica gel column chromatography eluting with

CH2CI2/EtOAc (95:5), yield 42%, mp: 83°C, appearance: white solid

- 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .35-1 .60 (m, 6H), 2.17 (s, 3H), 2.24 (s, 3H), 2.50-2.60 (m, 2H), 2.65-2.85 (m, 2H), 3.36 (s, 3H), 3.56 (s, 2H), 5.81 (d, 1 H, J=3.0Hz), 5.90-5.95 (m, 1 H), 6.48 (d, 1 H, J=8.2Hz), 6.78 (dd, 1 H, J=3.7Hz, J=0.7Hz), 6.88 (d, 1 H, J=8.2Hz), 6.93 (s, 1 H), 7.20 (d, 1 H, J=7.8Hz), 7.25 (dd, 1 H, J=8.6Hz, J=1 .7Hz), 7.5-7.55 (m, 2H), 7.72 (d, 1 H, J=8.6Hz), 8.78 (d, 1 H, J=8.5Hz) ; m/z: 520 [M+H]+ (calc. mass: 519).

- From (2,4-dimethylphenyl)(5-methylfuran-2-yl)methanamine Ex.19 and 2-[3-(2-methanesulfonylacetyl)-1 H-indol-5-

N-[(2,4- yl]acetic acid Ex.59 following protocol A, substituted amine dimethylphenyl) (0.9 equiv), DMAP (3.2 equiv), EDCI.HCI (1.2 equiv),

(5-methylfuran- overnight at rt, purification by preparative HPLC, yield 68%, 2-yl)methyl]-2- mp: 213°C, appearance: white solid

107 [3-(2- - 1 H NMR (300 MHz, DMSO-d6, d in ppm): 2.16 (s, 3H), 2.19

methanesulfony (s, 3H), 2.21 (s, 3H), 3.16 (s, 3H), 3.57 (s, 2H), 4.80 (s, 2H), lacetyl)-1 H- 5.86 (d, 1 H, J=2.9Hz), 5.95 (dd, 1 H, J=3.0Hz, J=1 .0Hz), indol-5- 6.10 (d, 1 H, J=8.4Hz), 6.92-7.00 (m, 2H), 7.1 1 (d, 1 H, yl]acetamide J=7.6Hz), 7.17 (dd, 1 H, J=8.4Hz, J=1.6Hz), 7.38 (d, 1 H,

J=8.5Hz), 8.14 (s, 1 H), 8.51 (s, 1 H), 8.97 (d, 1 H, J=8.3Hz), 12.15 (br(s), 1 H) ; m/z: 515 [M+Na]+ (calc. mass: 492).

- From (2,4-dimethylphenyl)(5-methylfuran-2-yl)methanamine Ex.19 and 1 -(1 H-indol-5-yl)cyclopropane-1 -carboxylic acid Ex.61 following protocol A, substituted amine (0.9 equiv),

N-[(2,4- DMAP (3.2 equiv), EDCI.HCI (1 .2 equiv), overnight at rt, dimethylphenyl) purification by preparative HPLC, yield 47%, mp: 62°C,

(5-methylfuran- appearance: white solid

108 2-yl)methyl]-1 - - 1 H NMR (300 MHz, DMSO-d6, d in ppm): 0.96-1.09 (m,

(1 H-indol-5- 2H), 1 .25-1 .42 (m, 2H), 2.1 1 (s, 3H), 2.13 (s, 3H), 2.20 (s, yl)cyclopropane 3H), 5.76 (s, 1 H), 5.90 (s, 1 H), 6.07 (d, 1 H, J=7.8Hz), 6.40

-1 -carboxamide (s, 1 H), 6.66 (d, 1 H, J=8.0Hz), 6.77 (d, 1 H, J=7.4Hz), 6.85- 6.98 (m, 2H), 7.10 (d, 1 H, J=8.5Hz), 7.30-7.45 (m, 2H), 7.56 (s, 1 H), 1 1.12 (br(s), 1 H) ; m/z: 399 [M+H]+ (calc. mass: 398).

tert-butyl 3-{5- - From [2-(azepan-1 -yl)-4-methoxyphenyl](5-methylfuran-2-

[({[2-(azepan-1 - yl)methanamine Ex.63 and 2-{1 -[3-(tert-butoxy)-3- yl)-4- oxopropyl]-1 H-indol-5-yl}acetic acid Ex.57 following

methoxyphenyl] protocol A, substituted amine (0.9 equiv), DMAP (3.2

(5-methylfuran- equiv), EDCI.HCI (1 .2 equiv), overnight at rt, purification by

110

2- preparative HPLC, yield 53%, mp: 57°C, appearance: white yl)methyl}carba solid

moyl)methyl]-

- 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .31 (s, 9H), 1 H-indol-1 - 1 .42-1 .65 (m, 8H), 2.17 (s, 3H), 2.69 (t, 2H, J=6.5Hz), 2.76- yl}propanoate

2.89 (m, 2H), 2.90-3.02 (m, 2H), 3.49 (s, 2H), 3.70 (s, 3H), 4.34 (t, 2H, J=6.4Hz), 5.72 (d, 1 H, J=2.7Hz), 5.90 (dd, 1 H, J=3.0Hz, J=1.0Hz), 6.32 (d, 1 H, J=2.5Hz), 6.53 (d, 1 H, J=8.1 Hz), 6.59-6.70 (m, 2H), 7.03 (dd, 1 H, J=8.4Hz, J=1.6Hz), 7.23 (d, 1 H, J=9.3Hz), 7.27 (d, 1 H, J=3.1 Hz), 7.31 -7.41 (m, 2H), 8.65 (d, 1 H, J=8.5Hz) ; m/z: 600 [M+H]+ (calc. mass: 599).

- Figure 3AS

- The previously synthesized tert-butyl 3-{5-[({[2-(azepan-1 - yl)-4-methoxyphenyl](5-methylfuran-2- yl)methyl}carbamoyl)methyl]-1 H-indol-1 -yl}propanoate

Cpd.110 (32 mg, 0.05 mmol) was dissolved in MeOH (1 .5 ml_). 5M NaOH (53 μΙ_, 0.26 mmol) was added to the

3-{5-[({[2- solution. The reaction mixture was heated at 100°C for 30

(azepan-1 -yl)-4- min under mricrowave irradiation. The solvent was removed methoxyphenyl] under reduced pressure and 1 N citric acid was added to the

(5-methylfuran- residue up pH = 4 was reached. The solid formed was

2- collected by filtration, washed with water and dried until yl)methyl}carba constant weight, yield 84%, mp: 80°C, appearance: white moyl)methyl]- solid

1 H-indol-1 -

- 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .41 -1 .69 (m, yl}propanoic

8H), 2.18 (s, 3H), 2.70 (t, 2H, J=6.8Hz), 2.77-2.89 (m, 2H), acid

2.89-3.02 (m, 2H), 3.49 (s, 2H), 3.71 (s, 3H), 4.35 (t, 2H, J=6.9Hz), 5.72 (d, 1 H, J=3.2Hz), 5.88-5.94 (m, 1 H), 6.32 (d, 1 H, J=3.1 Hz), 6.53 (d, 1 H, J=8.6Hz), 6.62-6.71 (m, 2H), 7.03 (dd, 1 H, J=8.6Hz, J=1.5Hz), 7.23 (d, 1 H, J=9.3Hz), 7.29 (d, 1 H, J=3.2Hz), 7.33-7.41 (m, 2H), 8.67 (d, 1 H, J=8.9Hz), 12.25 (br(s), 1 H) ; m/z: 544 [M+H]+ (calc. mass: 543).

- From (5-chlorofuran-2-yl)[4-methyl-2-(pyrrolidin-1 - yl)phenyl]methanamine Ex.48 and 2-[3-(2- methanesulfonylethyl)-1 H-indol-5-yl]acetic acid Ex.58 following protocol A, DMAP (3.2 equiv), EDCI.HCI (1 .2

N-[(5- equiv), overnight at rt, purification by silica gel column chlorofuran-2- chromatography (CH2CI2/MeOH, 98:2), yield 51 %, mp: yl)[4-methyl-2- 83°C, appearance: off-white solid

(pyrrolidin-1 - yl)phenyl]methy - 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .72-1 .76 (m, l]-2-[3-(2- 4H), 2.23 (s, 3H), 2.84-2.88 (m, 2H), 2.99 (s, 3H), 3.00-3.1 1 methanesulfony (m, 4H), 3.39-3.45 (m, 2H), 3.53 (s, 2H), 6.03 (dd, 1 H, lethyl)-1 H-indol- J=3.4Hz, J=1.1 Hz), 6.33 (d, 1 H, J=3.3Hz), 6.36 (d, 1 H,

5-yl]acetamide J=8.2Hz), 6.79 (d, 1 H, J=7.7Hz), 6.86 (s, 1 H), 7.00 (dd, 1 H,

J=8.3Hz, J=1.4Hz), 7.15 (d, 1 H, J=7.8Hz), 7.20 (d, 1 H, J=2.2Hz), 7.24 (d, 1 H, J=8.4Hz), 7.42 (s, 1 H), 8.81 (d, 1 H, J=8.2Hz), 10.82 (d, 1 H, J=2.1 Hz) ; m/z: 554 [M+H]+, 556 [M+H]+ (calc. mass: 553).

N-{[4-methyl-2-

(piperidin-1 - - See Figure 3AT

yl)phenyl](5- methylfuran-2- yl)methyl}-2-[1 - - To a solution of 2-(1 H-indol-5-yl)-N-{[4-methyl-2-(piperidin-

(oxan-4- 1 -yl)phenyl](5-methylfuran-2-yl)methyl}acetamide Cpd.106a ylmethyl)-1 H- (70 mg, 0.16 mmol) dissolved in dry THF (1 mL) was added indol-5- sodium hydride (60% in meneral oil) (1 1 mg, 0.48 mmol). yl]acetamide After few min of stirring, 4-(bromomethyl)-tetrahydro-2H- pyran (57 mg, 0.32 mmol) was added and the reaction mixture was stirred at rt for two days. Water was added to the reaction and the aqueous layer was extracted with EtOAc. The organic layer was dried over MgS04, filtered and the solution was concentrated under reduced pressure. The crude material was purified by preparative HPLC, yield 12%, mp: 67°C, appearance: pale green solid

- 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .26-1 .35 (m, 4H), 1 .37-1 .58 (m, 6H), 1 .94-2.02 (m, 1 H), 2.16 (s, 3H), 2.24 (s, 3H), 2.53-2.61 (m, 2H), 2.71 -2.80 (m, 2H), 3.12- 3.23 (m, 2H), 3.49 (s, 2H), 3.73-3.83 (m, 2H), 4.02 (d, 2H, J=7.3Hz), 5.80 (d, 1 H, J=3.2Hz), 5.89-5.93 (m, 1 H), 6.32 (d, 1 H, J=3.3Hz), 6.46 (d, 1 H, J=7.9Hz), 6.87 (d, 1 H, J=7.5Hz), 6.92 (s, 1 H), 7.01 (dd, 1 H, J=8.4Hz, J=2.0Hz), 7.18 (d, 1 H, J=7.7Hz), 7.28 (d, 1 H, J=3.1 Hz), 7.34-7.42 (m, 2H), 8.65 (d, 1 H, J=8.4Hz) ; m/z: 540 [M+H]+ (calc. mass: 539).

- See Figure 3AU

- Step 1 : to a solution of 1 ,1 '-carbonyldiimidazole (3.07 g,

18.93 mmol) in THF (20 mL) was added morpholine (1.57 g, 17.99 mmol) at rt, and then the mixture was refluxed for 12h. After cooling to rt, the mixture was concentrated under reduced pressure. CH2CI2 and water were added to quench the reaction. The pH of the solution was ajusted to pH = 8 with 1 N HCI. The organic layer was separated, dried over MgS04, filtered and the solution was concentrated under reduced pressure to afford 4-[(1 H-imidazol-1 -

N-{[4-methyl-2- yl)carbonyl]morpholine (2.75 g, 84%) as white solid. 1 H

(piperidin-1 - NMR (300 MHz, DMSO-d6, d in ppm): 3.49 (t, 4H,

yl)phenyl](5- J=4.5Hz), 3.65 (t, 4H, J=3.7Hz), 7.02 (dd, 1 H, J=1 .4Hz, methylfuran-2- J=0.9Hz), 7.47 (t, 1 H, J=1.4Hz), 8.03 (t, 1 H, J=1 .1 Hz).

yl)methyl}-2-[1 -

- Step 2: to a solution of 2-(1 H-indol-6-yl)-N-((4-methyl-2-

(morpholine-4- (piperidin-1 -yl)phenyl)(5-methylfuran-2-yl)methyl)acetamide carbonyl)-1 H- Cpd.88a (75 mg, 0.17 mmol) dissolved in dry acetonitrile (2 indol-6- mL) was added 4-[(1 H-imidazol-1 - yl]acetamide

yl)carbonyl]morpholine (46 mg, 0.26 mmol) followed by 1 ,8- diazabicyclo[5.4.0]undec-7-ene (5 μί, 0.03 mmol). The reaction mixture was stirred overnight at rt. Additional 4- [(1 H-imidazol-1 -yl)carbonyl]morpholine (46 mg, 0.26 mmol) and 1 ,8-diazabicyclo[5.4.0]undec-7-ene (5 μί, 0.03 mmol) were added to the reaction mixture and the stirring was kept for 4h. Water was added to the reaction and the aqueous layer was extracted with EtOAc. The organic layer was dried over MgS04, filtered and the solution was

concentrated under reduced pressure. The crude material was purified by silica gel column chromatography eluting with Cyclohexane/EtOAc (70:30) to give N-{[4-methyl-2- (piperidin-1 -yl)phenyl](5-methylfuran-2-yl)methyl}-2-[1 - (morpholine-4-carbonyl)-1 H-indol-6-yl]acetamide, yield

53%, mp: 85°C, appearance: white solid

- 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .40-1 .60 (m, 6H), 2.16 (s, 3H), 2.24 (s, 3H), 2.5-2.55 (m, 2H), 2.75-2.85 (m, 2H), 3.46 (t, 4H, J=2.3Hz), 3.56 (s, 2H), 3.66 (t, 4H, J=4.8Hz), 5.82 (d, 1 H, J=2.6Hz), 5.90-5.95 (m, 1 H), 6.47 (m, 1 H, J=8.7Hz), 6.60 (d, 1 H, J=2.9Hz), 6.87 (d, 1 H, J=7.3Hz), 6.92 (s, 1 H), 7.07 (dd, 1 H, J=8.1 Hz, J=1 .4Hz), 7.18 (d, 1 H, J=7.7Hz), 7.45-7.53 (m, 2H), 7.56 (s, 1 H), 8.76 (d, 1 H, J=8.8Hz) ; m/z: 555 [M+H]+ (calc. mass: 554).

- From [4-methyl-2-(piperidin-1 -yl)phenyl](5-methylfuran-2- yl)methanamine Ex.16 and 2-[3-(methylsulfamoyl)-1 H-indol- 5-yl]acetic acid Ex.64 following protocol A, DMAP (2.2 equiv), EDCI.HCI (1 .2 equiv), overnight at rt, purification by

N-{[4-methyl-2- silica gel column chromatography (Cyclohexan/EtOAc,

(piperidin-1 - 50:50), yield 74%, mp: 1 19°C, appearance: white solid yl)phenyl](5- methylfuran-2- - 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .43-1 .53 (m,

115

yl)methyl}-2-[3- 6H), 2.16 (s, 3H), 2.24 (s, 3H), 2.36 (d, 3H, J=5.1 Hz), 2.51 -

(methylsulfamo 2.57 (m, 2H), 2.76-2.80 (m, 2H), 3.54 (s, 2H), 5.82 (d, 1 H, yl)-1 H-indol-5- J=3.0Hz), 5.91 (dd, 1 H, J=3.0Hz, J=1.0Hz), 6.48 (d, 1 H, yljacetamide J=8.4Hz), 6.88 (d, 1 H, J=7.8Hz), 6.93 (s, 1 H), 7.02 (q, 1 H,

J=5.1 Hz), 7.15 (dd, 1 H, J=8.5Hz, J=1.6Hz), 7.20 (d, 1 H, J=7.8Hz), 7.38 (d, 1 H, J=8.4Hz), 7.70 (s, 1 H), 7.82 (d, 1 H, J=2.8Hz), 8.73 (d, 1 H, J=8.5Hz), 1 1 .84 (br(s), 1 H) ; m/z: 535 [M+H]+ (calc. mass: 534).

- See Figure 3 AX

- To a solution of previously synthesized 2-(1 H-indol-5-yl)-N- {[4-methyl-2-(piperidin-1 -yl)phenyl](5-methylfuran-2- yl)methyl}acetamide Cpd.106a (94 mg, 0.21 mmol) dissolved in dry acetonitrile (2 mL) was added the previously synthesized 4-[(1 H-imidazol-1 - yl)carbonyl]morpholine (58 mg, 0.32 mmol) followed by 1 ,8- diazabicyclo[5.4.0]undec-7-ene (6 μΙ_, 0.04 mmol). The

N-{[4-methyl-2- reaction mixture was stirred overnight at rt. Additional 4-

(piperidin-1 - [(1 H-imidazol-1 -yl)carbonyl]morpholine (58 mg, 0.32 mmol) yl)phenyl](5- and 1 ,8-diazabicyclo[5.4.0]undec-7-ene (6 μΙ_, 0.04 mmol) methylfuran-2- were added to the reaction mixture and the stirring was kept

116 yl)methyl}-2-[1 - for 4h. Water was added to the reaction and the aqueous

(morpholine-4- layer was extracted with EtOAc. The organic layer was carbonyl)-1 H- dried over MgS04, filtered and the solution was

indol-5- concentrated under reduced pressure. The crude material yl]acetamide was purified by silica gel column chromatography eluting with Cyclohexane/EtOAc (70:30) to give N-{[4-methyl-2- (piperidin-1 -yl)phenyl](5-methylfuran-2-yl)methyl}-2-[1 - (morpholine-4-carbonyl)-1 H-indol-5-yl]acetamide Cpd.116, yield 64%, mp: 88°C, appearance: pale blue solid

- 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .40-1 .60 (m, 6H), 2.17 (s, 3H), 2.24 (s, 3H), 2.5-2.55 (m, 2H), 2.75-2.85 (m, 2H), 3.48 (t, 4H, J=4.5Hz), 3.53 (s, 2H), 3.67 (t, 4H, J=5.2Hz), 5.82 (d, 1 H, J=2.9Hz), 5.90-5.95 (m, 1 H), 6.47 (m, 1 H, J=8.6Hz), 6.60 (dd, 1 H, J=3.5Hz, J=0.6Hz), 6.88 (d, 1 H, J=7.7Hz), 6.93 (s, 1 H), 7.15 (dd, 1 H, J=8.4Hz,

J=1.6Hz), 7.20 (d, 1 H, J=7.7Hz), 7.45 (d, 1 H, J=0.9Hz), 7.50 (d, 1 H, J=3.5Hz), 7.54 (d, 1 H, J=8.5Hz), 8.72 (d, 1 H, J=8.4Hz) ; m/z: 555 [M+H]+ (calc. mass: 554).

- See Figure 3AY

- To a solution of previously synthesized 2-(1 H-indol-6-yl)-N- ((4-methyl-2-(piperidin-1 -yl)phenyl)(5-methylfuran-2- yl)methyl)acetamide Cpd.88a (60 mg, 0.14 mmol) dissolved in dry CH2CI2 (2 mL) was added Et3N (38 μΙ_, 0.27 mmol) followed by 2-methanesulfonylacetyl chloride (53 mg, 0.34 mmol). The reaction mixture was stirred overnight at rt. TLC showed not total consumption of the

2-[3-(2- starting material. Additional 2-methanesulfonylacetyl methanesulfony chloride (53 mg, 0.34 mmol) and Et3N (38 μΙ_, 0.27 mmol) lacetyl)-1 H- were added to the reaction mixture. After 4h, water was indol-6-yl]-N-{[4- added to quench the reaction. The mixture was extracted methyl-2- with EtOAc. After phases separation, the organic layer was

(piperidin-1 - dried over MgS04, filtered and the solution was

yl)phenyl](5- concentrated to dryness. The crude material was purified by methylfuran-2- silica gel column chromatography eluting with

yl)methyl}aceta CH2CI2/MeOH (98:2), yield 33%, mp: 85°C, appearance: mide white solid

- 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .40-1 .60 (m, 6H), 2.16 (s, 3H), 2.24 (s, 3H), 2.5-2.55 (m, 2H), 2.75-2.85 (m, 2H), 3.15 (s, 3H), 3.56 (s, 2H), 4.79 (s, 2H), 5.82 (d, 1 H, J=3.1 Hz), 5.90-5.95 (m, 1 H), 6.48 (m, 1 H, J=8.2Hz), 6.88 (d, 1 H, J=7.3Hz), 6.93 (s, 1 H), 7.12 (d, 1 H, J=9.5Hz), 7.18 (d, 1 H, J=7.8Hz), 7.38 (s, 1 H), 8.04 (d, 1 H, J=8.1 Hz), 8.51 (d, 1 H, J=3.2Hz), 8.73 (d, 1 H, J=8.3Hz), 12.15 (s, 1 H) ; m/z: 562 [M+H]+ (calc. mass: 561 ).

- See Figure 3AT

- To a solution of previously synthesized 2-(1 H-indol-5-yl)-N- ((4-methyl-2-(piperidin-1 -yl)phenyl)(5-methylfuran-2- yl)methyl)acetamide Cpd.106a (80 mg, 0.18 mmol) dissolved in dry CH2CI2 were added DMAP (44 mg, 0.36

N-{[4-methyl-2- mmol) and tetrahydro-2H-pyran-4-carbonyl chloride (40 mg,

(piperidin-1 - 0.27 mmol) at 0°C and under N2 atmosphere. After few min yl)phenyl](5- of stirring, Et3N (76 μΙ_, 0.54 mmol) was added and the methylfuran-2- reaction mixture was stirred overnight at rt. Water was yl)methyl}-2-[1 - added to quench the reaction. The aqueous layer was

(oxane-4- extracted with EtOAc. The combined organic layers were carbonyl)-1 H- dried over MgS04, filtered and the solution was

indol-5- concentrated under reduced pressure. The crude material yl]acetamide was purified by silica gel column chromatography eluting with Cyclohexane/EtOAc (50:50), yield 65%, mp: 96°C, appearance: white solid

- 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .45-1 .60 (m, 6H), 1 .65-1 .85 (m, 4H), 2.16 (s, 3H), 2.24 (s, 3H), 2.55-2.6 (m, 3H), 2.70-2.80 (m, 2H), 3.45-3.53 (m, 2H), 3.54 (s, 2H), 3.85-3.95 (m, 2H), 5.80 (d, 1 H, J=3.0Hz), 5.90-5.95 (m, 1 H), 6.49 (d, 1 H, J=8.2Hz), 6.71 (dd, 1 H, J=3.8Hz,

J=0.6Hz), 6.88 (dd, 1 H, J=9.5Hz, J=1 .2Hz), 6.93 (s, 1 H), 7.15-7.25 (m, 2H), 7.46 (d, 1 H, J=1 .1 Hz), 8.03 (d, 1 H, J=3.9Hz), 8.23 (d, 1 H, J=8.5Hz), 8.74 (d, 1 H, J=8.3Hz) ; m/z: 554 [M+H]+ (calc. mass: 553).

- See Figure 3AZ

- To a solution of previously synthesized 1 -(3-formyl-1 H- indol-5-yl)-N-((4-methyl-2-(piperidin-1 -yl)phenyl)(5- methylfuran-2-yl)methyl)cyclopropanecarboxamide (see Step 1 of Cpd.89) (136 mg, 0.27 mmol) dissolved in dry toluene (4 mL) was added methanesulfonamide (39 mg, 0.41 mmol) followed by titanium (IV) ethoxide (1 15 μΙ_, 0.55 mmol). The reaction mixture was stirred at 1 10°C for 3h. After cooling to rt, the solvent was removed under reduced

1 -[3- pressure. Anhydrous MeOH (4 mL) was added and the

(methanesulfon

reaction mixture was cooled to 0°C. Sodium hydride (83 amidomethyl)- mg, 2.20 mmol) was added portionwise to the solution and

1 H-indol-5-yl]-N- the reaction mixture was stirred at rt for 2h. LCMS showed

{[4-methyl-2- incomplete conversion of the starting material. Additional

(piperidin-1 - sodium borohydride (83 mg, 2.20 mmol) was added and the yl)phenyl](5- reaction mixture was stirred overnight at rt. Water and ice methylfuran-2- were added to quench the reaction. The solid formed was yl)methyl}cyclo

collected by filtration, washed with water and dried under propane-1 - vacuo until constant weight, yield 32%, mp: 109°C, carboxamide

appearance: white solid

- 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1.0-1 .1 (m, 2H), 1 .12-1 .35 (m, 7H), 1 .35-1.45 (m, 1 H), 2.08 (s, 3H), 2.21 (s, 3H), 2.25-2.40 (m, 2H), 2.50-2.55 (m, 2H), 2.71 (s, 3H), 4.26 (d, 2H, J=6.1 Hz), 5.82 (d, 1 H, J=3.0Hz), 5.85-5.95 (m, 1 H), 6.32 (d, 1 H), 6.69 (d, 1 H, J=8.9Hz), 6.83 (d, 1 H, J=8.7Hz), 6.90 (d, 1 H, J=7.8Hz), 6.94 (s, 1 H), 7.14 (dd, 1 H, J=8.4Hz, J=1.7Hz), 7.25-7.40 (m, 3H), 7.70 (s, 1 H), 1 1.03 (s, 1 H) ; m/z: 575 [M+H]+ (calc. mass: 574).

- From [4-methyl-2-(piperidin-1 -yl)phenyl](5-methylfuran-2- yl)methanamine Ex.16 and 2-[3-(morpholine-4-carbonyl)- 1 H-indol-5-yl]acetic acid Ex.65 following protocol A, DMAP

N-{[4-methyl-2- (1 equiv), EDCI.HCI (1 .1 equiv), 3h at rt, purification by

(piperidin-1 - silica gel column chromatography (CH2CI2/MeOH, 95:5), yl)phenyl](5- yield 53%, mp: 124°C, appearance: white solid

methylfuran-2- - 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .40-1 .60 (m, yl)methyl}-2-[3- 6H), 2.16 (s, 3H), 2.24 (s, 3H), 2.50-2.54 (m, 2H), 2.75-2.80

(morpholine-4- (m, 2H), 3.52 (s, 2H), 3.53-3.60 (m, 8H), 5.81 (d, 1 H, carbonyl)-1 H- J=2.8Hz), 5.90 (dd, 1 H, J=3.0Hz, J=1.0Hz), 6.47 (d, 1 H, indol-5- J=8.4Hz), 6.87 (d, 1 H, J=7.7Hz), 6.91 (s, 1 H), 7.05 (dd, 1 H, yl]acetamide J=8.4Hz, J=1 .6Hz), 7.19 (d, 1 H, J=7.8Hz), 7.32 (d, 1 H,

J=8.3Hz), 7.57 (s, 1 H), 7.64 (d, 1 H, J=2.7Hz), 7.80 (d, 1 H, J=8.5Hz), 1 1 .49 (s, 1 H) ; m/z: 555 [M+H]+ (calc. mass: 554). - From (2,4-dimethylphenyl)(5-methylfuran-2-yl)methanamine

Ex.19 and 1 -[2-(2-methoxyacetyl)-2,3-dihydro-1 H-isoindol- 5-yl]cyclopropane-1 -carboxylic acid Ex.67 following protocol A, DMAP (1 equiv), EDCI.HCI (1 .1 equiv), overnight at rt,

N-[(2,4- purification by silica gel column chromatography

dimethylphenyl) (CH2CI2/MeOH, 97:3) followed by a second purification on (5-methylfuran- silica gel column chromatography (gradient of

2-yl)methyl]-1 - Cyclohexane/EtOAc, from [30:70] to [20:80]). The residue

[2-(2- was then triturated in Et20 and filtered-off. The solvent was

122

methoxyacetyl)- concentrated under reduced pressure to afford the title

2,3-dihydro-1 H- compound, yield 58%, mp: 55°C, appearance: off-white isoindol-5- solid

yl]cyclopropane - 1 H NMR (300 MHz, DMSO-d6, d in ppm): 0.95-1 .05 (m,

-1 -carboxamide 2H), 1 .25-1 .40 (m, 2H), 2.16 (s, 3H), 2.17 (s, 3H), 2.22 (s,

3H), 3.33 (d, 3H, J=1.2Hz), 4.12 (d, 2H, J=2.0Hz), 4.63 (s, 2H), 4.74 (s, 2H), 5.80 (m, 1 H), 5.93 (d, 1 H, J=3.0Hz), 6.12 (d, 1 H, J=8.4Hz), 6.90-7.00 (m, 3H), 7.25-7.40 (m, 3H), 7.45 (d, 1 H, J=8.7Hz) ; m/z: 495 [M+Na]+ (calc. mass: 472).

- From [4-methyl-2-(piperidin-1 -yl)phenyl](5-methylfuran-2- yl)methanamine Ex.16 and 2-(1 -cyclopropanecarbonyl-2,3-

2-(1 - dihydro-1 H-indol-5-yl)acetic acid Ex.68 following protocol A, cyclopropaneca DMAP (1.2 equiv), EDCI.HCI (2.2 equiv), 8h at rt,

rbonyl-2,3- purification by trituration in MeOH and filtration, yield 74%, dihydro-1 H- mp: 94°C, appearance: white solid

indol-5-yl)-N-{[4- - 1 H NMR (300 MHz, DMSO-d6, d in ppm): 0.80-0.90 (m,

123 methyl-2- 4H), 1 .40-1 .55 (m, 6H), 1 .85-1 .95 (m, 1 H), 2.17 (s, 3H),

(piperidin-1 - 2.25 (s, 3H), 2.55-2.60 (m, 2H), 2.75-2.85 (m, 2H), 3.1 1 (t, yl)phenyl](5- 2H, J=8.5Hz), 3.39 (s, 2H), 4.25 (t, 2H, J=7.8Hz), 5.80 (d, methylfuran-2- 1 H, J=3.1 Hz), 5.92 (dd, 1 H, J=2.9Hz, J=1 .0Hz), 6.48 (d, 1 H, yl)methyl}aceta J=8.4Hz), 6.88 (d, 1 H, J=7.4Hz), 6.94 (s, 1 H), 6.97 (d, 1 H, mide J=7.1 Hz), 7.09 (s, 1 H), 7.17 (d, 1 H, J=7.7Hz), 7.88 (d, 1 H,

J=5.5Hz), 8.69 (d, 1 H, J=8.5Hz) ; m/z: 512 [M+H]+ (calc. mass: 51 1 ).

- From (2,4-dimethylphenyl)(5-methylfuran-2-yl)methanamine Ex.19 and 1 -(2,2-dioxo-1 ,3-dihydro-4,2,1 -benzoxathiazin-6-

N-[(2,4- yl)cyclopropane-1 -carboxylic acid Ex.69 following protocol dimethylphenyl) A, DMAP (1.1 equiv), EDCI.HCI (1 .1 equiv), 2h at rt,

(5-methylfuran- purification by silica gel column chromatography

2-yl)methyl]-1 - (Cyclohexane/EtOAc, 70:30), yield 52%, mp: 96°C,

(2,2-dioxo-1 ,3-

124 appearance: white solid

dihydro-4,2,1 - benzoxathiazin- - 1 H NMR (300 MHz, DMSO-d6, d in ppm): 0.92-1 .02 (m,

6- 2H), 1 .22-1 .34 (m, 2H), 2.16 (s, 3H), 2.18 (s, 3H), 2.22 (s, yl)cyclopropane 3H), 5.17 (s, 2H), 5.76 (d, 1 H, J=3.0Hz), 5.93 (dd, 1 H,

-1 -carboxamide J=3.0Hz, J=1.0Hz), 6.13 (d, 1 H, J=8.5Hz), 6.75-6.80 (m,

1 H), 6.91 -7.05 (m, 5H), 7.63 (d, 1 H, J=8.3Hz), 10.56 (s, 1 H) ; m/z: 489 [M+Na]+ (calc. mass: 466).

N-[(2,4- - From (2,4-dimethylphenyl)(5-methylfuran-2-yl)methanamine

125 dimethylphenyl) Ex.19 and 1 -(2,3-dioxo-2,3-dihydro-1 H-indol-5- (5-methylfuran- yl)cyclopropane-1 -carboxylic acid Ex.70 following protocol 2-yl)methyl]-1 - A, DMAP (1.2 equiv), EDCI.HCI (1 .2 equiv), 2h at rt,

(2,3-dioxo-2,3- purification by silica gel column chromatography

dihydro-1 H- (CH2CI2/EtOAc, 95:5), yield 53%, mp: 192°C, appearance: indol-5- orange solid

yl)cyclopropane

- 1 H NMR (300 MHz, DMSO-d6, d in ppm): 0.93-1 .04 (m, -1 -carboxamide

2H), 1 .25-1 .37 (m, 2H), 2.16 (s, 3H), 2.18 (s, 3H), 2.22 (s, 3H), 5.72 (dd, 1 H, J=3.0Hz, J=0.6Hz), 5.93 (dd, 1 H, J=3.0Hz, J=1.0Hz), 6.14 (d, 1 H, J=8.3Hz), 6.87 (d, 1 H, J=7.8Hz), 6.90-7.01 (m, 3H), 7.44 (d, 1 H, J=1 .6Hz), 7.54 (dd, 1 H, J=8.1 Hz, J=2.0Hz), 7.85 (d, 1 H, J=8.4Hz), 1 1.05 (s, 1 H) ; m/z: 427 [M-H]- (calc. mass: 428).

- From (2,4-dimethylphenyl)(5-methylfuran-2-yl)methanamine Ex.19 and 1 -(1 -acetyl-2,3-dihydro-1 H-indol-5-

1 -(1 -acetyl-2,3- yl)cyclopropane-1 -carboxylic acid Ex.71 following protocol dihydro-1 H- A, DMAP (1.2 equiv), EDCI.HCI (2.2 equiv), 8h at rt, indol-5-yl)-N- purification by silica gel column chromatography

[(2,4- (Cyclohexane/EtOAc, 50:50), yield 60%, mp: 75°C,

dimethylphenyl) appearance: white solid

(5-methylfuran- - 1 H NMR (300 MHz, DMSO-d6, d in ppm): 0.96 (d, 2H,

2- J=2.7Hz), 1.20-1 .35 (m, 2H), 2.13 (s, 3H), 2.16 (s, 3H), 2.17 yl)methyl]cyclo (s, 3H), 2.22 (s, 3H), 3.10 (t, 2H, J=8.4Hz), 4.08 (t, 2H, propane-1 - J=8.6Hz), 5.77 (d, 1 H, J=3.0Hz), 5.93 (dd, 1 H, J=3.0Hz, carboxamide J=1.0Hz), 6.12 (d, 1 H, J=8.3Hz), 6.85-7.00 (m, 3H), 7.13 (d,

1 H, J=8.4Hz), 7.17-7.20 (m, 2H), 7.97 (d, 1 H, J=8.3Hz) ; m/z: 465 [M+Na]+ (calc. mass: 442).

- From (2,4-dimethylphenyl)(5-methylfuran-2-yl)methanamine Ex.19 and 1 -(2-acetyl-2,3-dihydro-1 H-isoindol-5-

1 -(2-acetyl-2,3- yl)cyclopropane-1 -carboxylic acid Ex.72 following protocol dihydro-1 H- A, DMAP (1.2 equiv), EDCI.HCI (2.2 equiv), 8h at rt, isoindol-5-yl)-N- purification by silica gel column chromatography

[(2,4- (Cyclohexane/EtOAc, 50:50), yield 14%, mp: 72°C,

dimethylphenyl) appearance: white solid

(5-methylfuran-

2- - 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .00 (s, 2H), yl)methyl]cyclo 1 .20-1.25 (m, 2H), 2.04 (d, 3H, J=1.7Hz), 2.16 (s, 3H), 2.17 propane-1 - (s, 3H), 2.22 (s, 3H), 4.57 (s, 2H), 4.79 (t, 2H), 5.76 (m, 1 H), carboxamide 5.93 (m, 1 H), 6.13 (d, 1 H, J=8.3Hz), 6.90-7.00 (m, 3H),

7.20-7.35 (m, 3H), 7.45 (d, 1 H, J=8.3Hz) ; m/z: 465

[M+Na]+ (calc. mass: 442).

- From (2,4-dimethylphenyl)(5-methylfuran-2-yl)methanamine

N-[(2,4- Ex.19 and 1 -(1 -methyl-2-oxo-2,3-dihydro-1 H-indol-5- dimethylphenyl) yl)cyclopropane-1 -carboxylic acid Ex.75 following protocol

(5-methylfuran- A, DMAP (1.2 equiv), EDCI.HCI (1 .1 equiv), 8h at rt,

2-yl)methyl]-1 - purification by silica gel column chromatography

(1 -methyl-2-oxo- (Cyclohexane/EtOAc, 70:30), yield 31 %, mp: 72°C,

2,3-dihydro-1 H- appearance: white solid

indol-5-

- 1 H NMR (300 MHz, DMSO-d6, d in ppm): 0.91 -1 .02 (m, yl)cyclopropane

2H), 1 .24-1 .37 (m, 2H), 2.15 (s, 3H), 2.16 (s, 3H), 2.22 (s, -1 -carboxamide

3H), 3.10 (s, 3H), 3.52 (s, 2H), 5.76 (d, 1 H, J=3.1 Hz), 5.93 (dd, 1 H, J=3.0Hz, J=0.9Hz), 6.12 (d, 1 H, J=8.5Hz), 6.86- 6.99 (m, 4H), 7.20-7.31 (m, 3H) ; m/z: 451 [M+Na]+ (calc.

mass: 428).

- From (2-bromo-4-methylphenyl)(5-methylfuran-2- yl)methanamine Ex.18 and 1-(2,2-dioxo-1,3-dihydro-4,2,1- benzoxathiazin-6-yl)cyclopropane-1-carboxylic acid Ex.69

N-[(2-bromo-4- following protocol A, DMAP (1.2 equiv), EDCI.HCI (1.1 methylphenyl)(5 equiv), 8h at rt, purification by silica gel column

-methylfuran-2- chromatography (Cyclohexane/EtOAc, 70:30) followed by a yl)methyl]-1- second purification on silica gel column chromatography

(2,2-dioxo-1,3- (CH2CI2/Cyclohexane/EtOAc, 50:30:20), yield 7%, mp:

131

dihydro-4,2,1- 112°C, appearance: white solid

benzoxathiazin- - 1 H NMR (300 MHz, DMSO-d6, d in ppm): 0.93-1.03 (m,

6- 2H), 1.24-1.35 (m, 2H), 2.18 (s, 3H), 2.27 (s, 3H), 5.15 (s, yl)cyclopropane 2H), 5.68 (d, 1H, J=3.1Hz), 5.93 (dd, 1H, J=3.1Hz,

-1-carboxamide J=1.1Hz), 6.26 (d, 1H, J=8.0Hz), 6.76 (d, 1H, J=8.7Hz),

6.96-7.04 (m, 2H), 7.14-7.25 (m, 2H), 7.42 (s, 1H), 7.90 (d, 1H, J=8.2Hz), 10.56 (br(s), 1H) ; m/z: 529 [M+H]+, 531 [M+H]+ (calc. mass: 530).

- From (2,4-dimethylphenyl)(5-methylfuran-2-yl)methanamine Ex.19 and 1-(1-ethyl-2,2-dioxo-1,3-dihydro-2,1- benzothiazol-5-yl)cyclopropane-1-carboxylic acid Ex.76

N-[(2,4- following protocol A, DMAP (1.2 equiv), EDCI.HCI (2.2 dimethylphenyl) equiv), 8h at rt, purification by silica gel column

(5-methylfuran- chromatography (Cyclohexane/EtOAc, 70:30) followed by a

2-yl)methyl]-1- second purification on silica gel column chromatography

(1-ethyl-2,2- (Cyclohexane/EtOAc, 80:20), yield 27%, mp: 68°C,

132

dioxo-1,3- appearance: white solid

dihydro-2,1- - 1H NMR (300 MHz, DMSO-d6, d in ppm): 0.98 (d, 2H, benzothiazol-5- J=2.5Hz), 1.25 (t, 3H, J=7.1Hz), 1.28-1.35 (m, 2H), 2.16 (s, yl)cyclopropane 3H), 2.17 (s, 3H), 2.22 (s, 3H), 3.61 (q, 2H, J=7.1Hz), 4.58

-1-carboxamide (s, 2H), 5.76 (d, 1H, J=2.6Hz), 5.93 (q, 1H, J=3.1Hz,

J=1.1Hz), 6.12 (d, 1H, J=8.3Hz), 6.90-7.00 (m, 4H), 7.28- 7.35 (m, 2H), 7.51 (d, 1H, J=8.2Hz) ; m/z: 501 [M+Na]+ (calc. mass: 478).

- From 2-[amino(5-methylfuran-2-yl)methyl]-N,N,5- trimethylaniline Ex.42 and 1-(1-methyl-2,2-dioxo-1,3-

N-{[2- dihydro-2,1-benzothiazol-5-yl)cyclopropane-1-carboxylic

(dimethylamino)

acid Ex.40 following protocol A, DMAP (1.2 equiv),

-4- EDCI.HCI (2.2 equiv), 8h at rt, purification by silica gel methylphenyl](5

column chromatography (CH2CI2/MeOH, 98:2) followed by

-methylfuran-2- a second purification on silica gel column chromatography yl)methyl}-1-(1-

133 (CH2CI2/EtOAc, 90:10), yield 15%, mp: 73°C, appearance:

methyl-2,2- white solid

dioxo-1,3- dihydro-2,1- - 1 H NMR (300 MHz, DMSO-d6, d in ppm): 0.90-1.00 (m, benzothiazol-5- 2H), 1.25-1.4 (m, 2H), 2.13 (s, 3H), 2.18 (s, 6H), 2.23 (s, yl)cyclopropane 3H), 3.03 (s, 3H), 4.65 (s, 2H), 5.78 (d, 1H, J=2.1Hz), 5.92

-1-carboxamide (q, 1H, J=3.0Hz, J=1.1Hz), 6.21 (d, 1H, J=8.3Hz), 6.88 (d,

1H, J=8.0Hz), 6.95 (d, 1H, J=8.2Hz), 7.00 (s, 1H), 7.13 (d, 1H, J=7.8Hz), 7.37 (s, 1H), 7.40 (d, 1H, J=8.2Hz), 7.97 (d, 1 H, J=8.3Hz) ; m/z: 494 [M+H]+ (calc. mass: 493).

- From (5-chlorofuran-2-yl)(2,4-dimethylphenyl)methanamine Ex.32 and 1 -(3-oxo-3,4-dihydro-2H-1 ,4-benzoxazin-7- yl)cyclopropane-1 -carboxylic acid Ex.35 following protocol

N-[(5- A, DMAP (1.1 equiv), EDCI.HCI (1 .1 equiv), 5h at rt. After chlorofuran-2- completion of the reaction, the solution was poured into ice yl)(2,4- and water. The solid formed was collected by filtration and dimethylphenyl) dried under vacuo until constant weight, yield 31 %, mp: methyl]-1 -(3- 94°C, appearance: white solid

oxo-3,4-dihydro-

2H-1 ,4- - 1 H NMR (300 MHz, DMSO-d6, d in ppm): 0.90-1 .02 (m, benzoxazin-7- 2H), 1 .23-1 .30 (m, 2H), 2.16 (s, 3H), 2.23 (s, 3H), 4.54 (s, yl)cyclopropane 2H), 6.00 (dd, 1 H, J=5.2Hz, J=1 .1 Hz), 6.16 (d, 1 H,

-1 -carboxamide J=8.4Hz), 6.35 (d, 1 H, J=3.3Hz), 6.82 (d, 1 H, J=8.3Hz),

6.87-6.92 (m, 2H), 6.92-7.00 (m, 3H), 7.76 (d, 1 H,

J=8.2Hz), 10.70 (s, 1 H) ; m/z: 473 [M+Na]+, 475 [M+Na]+ (calc. mass: 450).

- From (2-bromo-4-methylphenyl)(5-methylfuran-2- yl)methanamine Ex.18 and 1 -(3-oxo-3,4-dihydro-2H-1 ,4- benzoxazin-7-yl)cyclopropane-1 -carboxylic acid Ex.35

N-[(2-bromo-4- following protocol A, DMAP (1 .1 equiv), EDCI.HCI (1 .1 methylphenyl)(5 equiv), 5h at rt. After completion of the reaction, the solution

-methylfuran-2- was poured into ice and water. The solid formed was yl)methyl]-1 -(3- collected by filtration, washed with Et20 and dried under oxo-3,4-dihydro- vacuo until constant weight, yield 5%, mp: 82°C,

2H-1 ,4- appearance: white solid

benzoxazin-7- - 1 H NMR (300 MHz, DMSO-d6, d in ppm): 0.94-0.99 (m, yl)cyclopropane 2H), 1 .24-1 .29 (m, 2H), 2.18 (s, 3H), 2.27 (s, 3H), 4.55 (s,

-1 -carboxamide 2H), 5.68 (d, 1 H, J=3.2Hz), 5.92-5.95 (m, 1 H), 6.26 (d, 1 H,

J=8.0Hz), 6.83 (d, 1 H, J=8.5Hz), 6.90-6.95 (m, 2H), 7.15- 7.22 (m, 2H), 7.41 (s, 1 H), 7.76 (d, 1 H, J=8.1 Hz), 10.70 (s, 1 H) ; m/z: 517 [M+Na]+, 519 [M+Na]+ (calc. mass: 494).

- From (2,4-dimethylphenyl)(6-methylpyridin-2- yl)methanamine Ex.77 and 1 -(3-oxo-3,4-dihydro-2H-1 ,4- benzoxazin-7-yl)cyclopropane-1 -carboxylic acid Ex.35

N-[(2,4- following protocol A, DMAP (1.1 equiv), EDCI.HCI (1 .1 dimethylphenyl) equiv), overnight at rt. After completion of the reaction, the (6- solution was poured into ice and water. The solid formed methylpyridin-2- was collected by filtration and dried under vacuo until yl)methyl]-1 -(3- constant weight, yield 16%, mp: 94°C, appearance: white oxo-3,4-dihydro- solid

2H-1 ,4- benzoxazin-7- - 1 H NMR (300 MHz, DMSO-d6, d in ppm): 0.92-0.98 (m, yl)cyclopropane 2H), 1 .20-1 .25 (m, 2H), 2.17 (s, 3H), 2.30 (s, 3H), 2.32 (s,

-1 -carboxamide 3H), 4.59 (d, 2H, J=1 .2Hz), 5.94 (d, 1 H, J=6.3Hz), 6.76 (d,

1 H, J=7.8Hz), 6.83-7.02 (m, 6H), 7.07 (d, 1 H, J=7.8Hz), 7.54 (t, 1 H, J=7.7Hz), 7.91 (d, 1 H, J=6.6Hz), 10.82 (s, 1 H) ; m/z: 442 [M+H]+ (calc. mass: 441 ).

1 -(2H-1 ,3- benzodioxol-5- - From (2,4-dimethylphenyl)(5-methylfuran-2-yl)methanamine yl)-N-[(2,4- Ex.19 and 1 -(2H-1 ,3-benzodioxol-5-yl)cyclopropane-1 - dimethylphenyl) carboxylic acid Ex.88 following protocol A, DMAP (2.2

(5-methylfuran- equiv), EDCI.HCI (2.2 equiv), overnight at rt. After

2- completion of the reaction, the solution was poured into ice yl)methyl]cyclo and water. The solid formed was collected by filtration and propane-1 - dried under vacuo until constant weight, yield 46%, mp: carboxamide 52°C, appearance: yellow solid

- 1 H NMR (300 MHz, DMSO-d6, d in ppm): 0.92-1 .01 (m, 2H), 1 .23-1 .31 (m, 2H), 2.15 (s, 3H), 2.17 (s, 3H), 2.22 (s, 3H), 5.77 (d, 1 H, J=3.1 Hz), 5.94 (dd, 1 H, J=3.0Hz,

J=1.0Hz), 6.00 (s, 2H), 6.1 1 (d, 1 H, J=8.4Hz), 6.81 -6.89 (m, 2H), 6.89-6.97 (m, 4H), 7.30 (d, 1 H, J=8.3Hz) ; m/z: 426 [M+Na]+ (calc. mass: 403).

- From (2,4-dimethylphenyl)(furan-2-yl)methanamine Ex.80 and 1 -(3-0X0-3, 4-dihydro-2H-1 ,4-benzoxazin-7- yl)cyclopropane-1 -carboxylic acid Ex.35 following protocol

N-[(2,4- A, DMAP (2.1 equiv), EDCI.HCI (2.1 equiv), overnight at rt. dimethylphenyl) After completion of the reaction, the solution was poured

(furan-2- into ice and water. The solid formed was collected by yl)methyl]-1 -(3- filtration and dried under vacuo until constant weight, yield oxo-3,4-dihydro- 45%, mp: 180°C, appearance: pale yellow solid

2H-1 ,4- benzoxazin-7- - 1 H NMR (300 MHz, DMSO-d6, d in ppm): 0.92-1 .00 (m, yl)cyclopropane 2H), 1 .24-1 .31 (m, 2H), 2.16 (s, 3H), 2.22 (s, 3H), 4.55 (s,

-1 -carboxamide 2H), 5.92-5.96 (m, 1 H), 6.18 (d, 1 H, J=8.6Hz), 6.35 (dd, 1 H,

J=3.2Hz, J=2.0Hz), 6.82 (d, 1 H, J=8.4Hz), 6.87-7.00 (m, 5H), 7.50 (d, 1 H, J=8.4Hz), 7.53-7.57 (m, 1 H), 10.71 (s, 1 H) ; m/z: 417 [M+H]+ (calc. mass: 416).

- From (4-chlorophenyl)(2,4-dimethylphenyl)methanamine Ex.81 and 1 -(3-oxo-3,4-dihydro-2H-1 ,4-benzoxazin-7- yl)cyclopropane-1 -carboxylic acid Ex.35 following protocol

N-[(4- A, DMAP (2.1 equiv), EDCI.HCI (2.1 equiv), overnight at rt. chlorophenyl)(2, After completion of the reaction, the solution was poured 4- into ice and water. The solid formed was collected by dimethylphenyl) filtration and dried under vacuo until constant weight, yield methyl]-1 -(3- 37%, mp: 99°C, appearance: white solid

oxo-3,4-dihydro-

2H-1 ,4- - 1 H NMR (300 MHz, DMSO-d6, d in ppm): 0.91 -0.99 (m, benzoxazin-7- 2H), 1.27 (q, 2H, J=3.3Hz), 2.12 (s, 3H), 2.22 (s, 3H), 4.54 yl)cyclopropane (s, 2H), 6.19 (d, 1 H, J=8.5Hz), 6.81 (dd, 2H, J=7.9Hz,

-1 -carboxamide J=1.1 Hz), 6.87-6.95 (m, 3H), 6.97 (s, 1 H), 7.09 (d, 2H,

J=8.4Hz), 7.35 (d, 2H, J=8.5Hz), 7.51 (d, 1 H, J=8.5Hz), 10.69 (s, 1 H) ; m/z: 461 [M+H]+, 463 [M+H]+ (calc. mass: 460).

N-[(2,4-

- From (2,4-dimethylphenyl)(5-methylfuran-2-yl)methanamine dimethylphenyl)

Ex.19 and 1 -(1 -oxo-2,3-dihydro-1 H-inden-5-

(5-methylfuran- yl)cyclopropane-1 -carboxylic acid Ex.82 following protocol

2-yl)methyl]-1 - A, DMAP (1.1 equiv), EDCI.HCI (1 .1 equiv), overnight at rt,

(1 -oxo-2,3- purification by silica gel column chromatography

dihydro-1 H- (Cyclohexane/EtOAc, 70:30), yield 45%, mp: 56°C, inden-5- appearance: white solid

yl)cyclopropane

-1 -carboxamide - 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .06-1 .17 (m, 2H), 1 .35-1 .43 (m, 2H), 2.18 (s, 6H), 2.23 (s, 3H), 2.59-2.65 (m, 2H), 3.01 -3.10 (m, 2H), 5.74 (d, 1 H, J=3.0Hz), 5.94 (dd, 1 H, J=3.1 Hz, J=1.1 Hz), 6.18 (d, 1 H, J=8.3Hz), 6.89-7.04 (m, 3H), 7.32 (dd, 1 H, J=8.0Hz, J=1 .5Hz), 7.47 (d, 1 H, J=0.7Hz), 7.56 (d, 1 H, J=8.0Hz), 8.04 (d, 1 H, J=8.3Hz) ; m/z: 436 [M+Na]+ (calc. mass: 413).

- See Figure 3BA

- The previously synthesized 1 -(1 -acetyl-2,3-dihydro-1 H- indol-5-yl)-N-[(2,4-dimethylphenyl)(5-methylfuran-2- yl)methyl]cyclopropane-1 -carboxamide Cpd.126 (30 mg, 0.07 mmol) was dissolved in MeOH/THF (500 μΙ_/ 500 μΙ_). 5 M NaOH (136 μΙ_, 0.68 mmol) was added and the solution was stirred at rt for 2 days (over the weekend). TLC showed no conversion. The reaction mixture was heated at 120°C

1 -(2,3-dihydro- for 1 h under microwave irradiation. After cooling to rt, sat.

1 H-indol-5-yl)-N- NH4CI was added to quench the reaction. The aqueous

[(2,4- layer was extracted with EtOAc. The combined organic dimethylphenyl)

layers were dried over MgS04, filtered and the solution was

(5-methylfuran- concentrated under reduced pressure. The crude material

2- was purified by column chromatography on silica gel eluting yl)methyl]cyclo

with CH2CI2/MeOH (98:2). The desired fractions were propane-1 - collected and evaporated under reduced pressure, yield carboxamide

55%, mp: 57°C, appearance: white solid

- 1 H NMR (300 MHz, DMSO-d6, d in ppm): 0.90 (d, 2H, J=2.8Hz), 1 .20-1 .30 (m, 2H), 2.15 (s, 3H), 2.15 (s, 3H), 2.22 (s, 3H), 2.87 (t, 2H, J=8.6Hz), 3.35-3.40 (m, 2H), 5.54 (br(s), 1 H), 5.78 (d, 1 H, J=2.6Hz), 5.94 (dd, 1 H, J=3.0Hz, J=1.0Hz), 6.06 (d, 1 H, J=8.2Hz), 6.44 (d, 1 H, J=7.9Hz), 6.72 (d, 1 H, J=8.4Hz), 6.83 (d, 1 H, J=7.6Hz), 6.85-7.00 (m, 3H), 7.02 (s, 1 H) ; m/z: 401 [M+H]+ (calc. mass: 400).

- From (3-chlorophenyl)(2,4-dimethylphenyl)methanamine Ex.83 and 1 -(3-oxo-3,4-dihydro-2H-1 ,4-benzoxazin-7-

N-[(3- yl)cyclopropane-1 -carboxylic acid Ex.35 following protocol chlorophenyl)(2, A, DMAP (2.1 equiv), EDCI.HCI (2.1 equiv), overnight at rt. 4- After completion of the reaction, the solution was poured dimethylphenyl) into ice and water. The solid formed was collected by methyl]-1 -(3- filtration and dried under vacuo until constant weight, yield oxo-3,4-dihydro- 56%, mp: 181 °C, appearance: white solid

2H-1 ,4- - 1 H NMR (300 MHz, DMSO-d6, d in ppm): 0.91 -1 .02 (m, benzoxazin-7- 2H), 1 .24-1 .32 (m, 2H), 2.14 (s, 3H), 2.22 (s, 3H), 4.53 (s, yl)cyclopropane 2H), 6.21 (d, 1 H, J=8.4Hz), 6.81 (dd, 2H, J=7.8Hz,

-1 -carboxamide J=2.3Hz), 6.87-6.95 (m, 3H), 6.98 (s, 1 H), 7.03-7.1 1 (m,

2H), 7.26-7.35 (m, 2H), 7.63 (d, 1 H, J=8.4Hz), 10.69 (s, 1 H) ; m/z: 461 [M+H]+, 463 [M+H]+ (calc. mass: 460).

N-[(2,4- dimethylphenyl) - From (2,4-dimethylphenyl)(5-methylfuran-2-yl)methanamine

(5-methylfuran- Ex.19 and 1 -{2-oxo-1 H,2H,3H-pyrido[2,3-b][1 ,4]oxazin-6-

2-yl)methyl]-1 - yl}cyclopropane-1 -carboxylic acid Ex.84 following protocol

{2-oxo- A, DMAP (2.1 equiv), EDCI.HCI (2.1 equiv), overnight at rt.

1 H,2H,3H- After completion of the reaction, the solution was poured pyrido[2,3- into ice and water. The solid formed was collected by b][1 ,4]oxazin-6- filtration and dried under vacuo until constant weight, yield yl}cyclopropane 54%, mp: 84°C, appearance: white solid

-1 -carboxamide

- 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .06-1 .19 (m, 2H), 1 .24-1 .33 (m, 2H), 2.19 (s, 3H), 2.22 (s, 3H), 2.23 (s, 3H), 4.76 (s, 2H), 5.83 (d, 1 H, J=3.0Hz), 5.95 (dd, 1 H, J=3.0Hz, J=1.0Hz), 6.21 (d, 1 H, J=8.1 Hz), 6.91 (d, 1 H, J=7.9Hz), 6.94-7.01 (m, 2H), 7.08 (d, 1 H, J=8.4Hz), 7.15 (d, 1 H, J=8.0Hz), 8.76 (d, 1 H, J=8.3Hz), 10.79 (s, 1 H) ; m/z: 432 [M+H]+ (calc. mass: 431 ).

- From (5-chlorofuran-2-yl)[4-methyl-2-(piperidin-1 - yl)phenyl]methanamine Ex.47 and 1 -(3-oxo-3,4-dihydro-2H- 1 ,4-benzoxazin-7-yl)cyclopropane-1 -carboxylic acid Ex.35 following protocol A, DMAP (2.1 equiv), EDCI.HCI (2.1

N-[(5- equiv), overnight at rt. After completion of the reaction, the chlorofuran-2- solution was poured into ice and water. The solid formed yl)[4-methyl-2- was collected by filtration and dried under vacuo until

(piperidin-1 - constant weight, yield 36%, mp: 199°C, appearance: white yl)phenyl]methy solid

l]-1 -(3-0X0-3,4- dihydro-2H-1 ,4- - 1 H NMR (300 MHz, DMSO-d6, d in ppm): 0.92-1 .01 (m, benzoxazin-7- 2H), 1 .24-1 .49 (m, 8H), 2.25 (s, 3H), 2.37-2.46 (m, 2H), yl)cyclopropane 2.55-2.65 (m, 2H), 4.54 (s, 2H), 6.03 (dd, 1 H, J=3.3Hz,

-1 -carboxamide J=1.2Hz), 6.34 (d, 1 H, J=3.3Hz), 6.39 (d, 1 H, J=8.4Hz),

6.83 (d, 1 H, J=8.0Hz), 6.89 (d, 1 H, J=7.6Hz), 6.92-6.98 (m, 2H), 7.01 (s, 1 H), 7.09 (d, 1 H, J=7.8Hz), 7.47 (d, 1 H, J=8.7Hz), 10.72 (s, 1 H) ; m/z: 520 [M+H]+, 522 [M+H]+ (calc. mass: 519).

- From (2,4-dimethylphenyl)(5-methylfuran-2-yl)methanamine Ex.19 and 1 -(3,3-dimethyl-2-oxo-2,3-dihydro-1 H-indol-5-

1 -(3, 3 -dimethyl - yl)cyclopropane-1 -carboxylic acid Ex.85 following protocol

2-0X0-2,3- A, DMAP (1.1 equiv), EDCI.HCI (1 .1 equiv), 2h at rt, dihydro-1 H- purification by silica gel column chromatography

indol-5-yl)-N- (Cyclohexane/EtOAc, 70:30), yield 69%, mp: 82°C,

[(2,4- appearance: white solid

dimethylphenyl)

(5-methylfuran- - 1 H NMR (300 MHz, DMSO-d6, d in ppm): 0.92-1 .05 (m,

2- 2H), 1 .22 (s, 6H), 1 .27-1 .35 (m, 2H), 2.14 (s, 6H), 2.21 (s, yl)methyl]cyclo 3H), 5.75 (d, 1 H, J=3.1 Hz), 5.92 (dd, 1 H, J=3.0Hz,

propane-1 - J=1.0Hz), 6.09 (d, 1 H, J=8.4Hz), 6.80 (d, 1 H, J=7.9Hz), carboxamide 6.86-6.96 (m, 3H), 7.02 (d, 1 H, J=8.5Hz), 7.15 (dd, 1 H,

J=8.0Hz, J=1.8Hz), 7.30 (d, 1 H, J=1.7Hz), 10.34 (s, 1 H) ; m/z: 465 [M+Na]+ (calc. mass: 442).

N-[(2-bromo-4-

- From (2-bromo-4-methoxyphenyl)(5-methylfuran-2- methoxyphenyl)

yl)methanamine Ex.22 and 1 -(2,2-dioxo-1 ,3-dihydro-4,2,1 -

(5-methylfuran- benzoxathiazin-6-yl)cyclopropane-1 -carboxylic acid Ex.69

2-yl)methyl]-1 - following protocol A, DMAP (1.1 equiv), EDCI.HCI (1 .1

(2,2-dioxo-1 ,3- equiv), 2h at rt, purification by silica gel column

dihydro-4,2,1 - chromatography (Cyclohexane/EtOAc, 70:30), yield 46%, benzoxathiazin- mp: 1 15°C, appearance: white solid

6- yl)cyclopropane - 1 H NMR (300 MHz, DMSO-d6, d in ppm): 0.90-1 .09 (m, -1-carboxamide 2H), 1.20-1.36 (m, 2H), 2.19 (s, 3H), 3.76 (s, 3H), 5.17 (s,

2H), 5.69 (d, 1H, J=3.0Hz), 5.93 (dd, 1H, J=3.0Hz,

J=1.1Hz), 6.25 (d, 1H, J=8.2Hz), 6.77 (d, 1H, J=8.7Hz), 6.95 (dd, 1H, J=8.7Hz, J=2.6Hz), 6.98-7.05 (m, 2H), 7.15 (d, 1H, J=2.6Hz), 7.23 (d, 1H, J=8.6Hz), 7.90 (d, 1H, J=8.1Hz), 10.56 (s, 1H) ; m/z: 545 [M-H]-, 547 [M-H]- (calc. mass: 546).

- From 2-[amino(5-methylfuran-2-yl)methyl]-N,N,5-

N-{[2- trimethylaniline Ex.42 and 1-(2,2-dioxo-1 ,3-dihydro-4,2,1-

(dimethylamino) benzoxathiazin-6-yl)cyclopropane-1-carboxylic acid Ex.69 -4- following protocol A, DMAP (1.1 equiv), EDCI.HCI (1.1 methylphenyl](5 equiv), 2h at rt, purification by silica gel column

-methylfuran-2- chromatography (Cyclohexane/EtOAc, 70:30), yield 35%, yl)methyl}-1- mp: 105°C, appearance: white solid

148

(2,2-dioxo-1,3- - 1 H NMR (300 MHz, DMSO-d6, d in ppm): 0.89-1.08 (m, dihydro-4,2,1- 2H), 1.21-1.38 (m, 2H), 2.14 (s, 3H), 2.23 (s, 6H), 2.24 (s, benzoxathiazin- 3H), 5.13-5.22 (m, 2H), 5.75-5.78 (m, 1H), 5.90-5.94 (m,

6- 1H), 6.22 (d, 1H, J=8.7Hz), 6.82 (d, 1H, J=8.7Hz), 6.88 (d, yl)cyclopropane 1H, J=8.2Hz), 7.00-7.09 (m, 3H), 7.13 (d, 1H, J=7.8Hz), -1-carboxamide 8.04 (d, 1H, J=8.6Hz), 10.62 (s, 1H) ; m/z: 496 [M+H]+

(calc. mass: 495).

- From (5-chlorofuran-2-yl)(2,4-dimethylphenyl)methanamine

N-[(5- Ex.32 and 1-(2,2-dioxo-1,3-dihydro-4,2,1-benzoxathiazin-6- chlorofuran-2- yl)cyclopropane-1-carboxylic acid Ex.69 following protocol yl)(2,4- A, DMAP (1.1 equiv), EDCI.HCI (1.1 equiv), 2h at rt, dimethylphenyl) purification by silica gel column chromatography

methyl]-1-(2,2- (Cyclohexane/EtOAc, 70:30), yield 47%, mp: 102°C,

149 dioxo-1,3- appearance: white solid

dihydro-4,2,1- - 1H NMR (300 MHz, DMSO-d6, d in ppm): 0.91-1.04 (m, benzoxathiazin- 2H), 1.23-1.34 (m, 2H), 2.16 (s, 3H), 2.23 (s, 3H), 5.16 (s,

6- 2H), 6.00 (dd, 1H, J=3.3Hz, J=1.1Hz), 6.17 (d, 1H,

yl)cyclopropane J=8.4Hz), 6.35 (d, 1H, J=3.3Hz), 6.76 (d, 1H, J=8.7Hz), -1-carboxamide 6.93-7.04 (m, 5H), 7.94 (d, 1H, J=8.1Hz), 10.56 (s, 1H) ;

m/z: 485 [M-H]-, 487 [M-H]- (calc. mass: 486).

- From (2-bromo-4-methylphenyl)(5-methylfuran-2- yl)methanamine Ex.18 and 2-(2,2-dioxo-1,3-dihydro-4,2,1- benzoxathiazin-6-yl)acetic acid Ex.86 following protocol A, DMAP (2.1 equiv), EDCI.HCI (2.1 equiv), 2h at rt. After

N-[ (2-bromo-4- completion of the reaction, the solution was poured into sat. methylphenyl)(5

NH4CI. The solid formed was collected by filtration and

-methylfuran-2- dried under vacuo until constant weight, yield 84%, mp: yl)methyl]-2-

150 116°C, appearance: pale brown solid

(2,2-dioxo-1,3- dihydro-4,2,1- - 1H NMR (300 MHz, DMSO-d6, d in ppm): 2.21 (s, 3H), 2.27 benzoxathiazin- (s, 3H), 3.43 (s, 2H), 5.14 (s, 2H), 5.77 (d, 1H, J=3.1Hz),

6-yl)acetamide 5.96 (dd, 1H, J=3.0Hz, J=1.1Hz), 6.23 (d, 1H, J=8.1Hz),

6.73 (d, 1H, J=8.2Hz), 6.90 (dd, 1H, J=8.1Hz, J=1.9Hz), 6.94 (d, 1H, J=1.7Hz), 7.20 (d, 1H, J=7.2Hz), 7.29 (d, 1H, J=7.9Hz), 7.40-7.45 (m, 1H), 9.07 (d, 1H, J=8.1Hz), 10.40 (br(s), 1H) ; m/z: 527 [M+Na]+, 529 [M+Na]+ (calc. mass: 504).

- See Figure 3BC

- Step 1 : to a previously synthesized N-[(2,4- dimethylphenyl)(5-methylfuran-2-yl)methyl]-1 -(1 H-indol-5- yl)cyclopropane-1 -carboxamide Cpd.108 (150 mg, 0.38 mmol) dissolved in dry DMF (1 mL) was added sodium hydride (60% in mineral oil) (45 mg, 1.13 mmol) at rt. After 15 min of stirring, tert-butyl 3-bromopropanoate (188 μΙ_,

1 .13 mmol) was added and the reaction mixture was heated at 1 10°C for 15 min under microwave irradiation. TLC showed not total consumption of the starting material. Additional sodium hydride (60% in mineral oil) (45 mg, 1.13 mmol) and tert-butyl 3-bromopropanoate (188 μΙ_, 1.13 mmol) were added to the solution and the reaction mixture was heated at 1 10°C for 15 min under microwave irradiation. After cooling to rt, water was added to quench the reaction. The pH was adjusted to pH = 4-5 with 1 M citric acid. The resulting aqueous solution was extracted with EtOAc. The combined organic layers were dried over MgS04, filtered and the solution was concentrated under reduced pressure. A mixture of tert-butyl 3-[5-(1 -{[(2,4- dimethylphenyl)(5-methylfuran-2-

3-[5-(1 -{[(2,4- yl)methyl]carbamoyl}cyclopropyl)-1 H-indol-1 -yl]propanoate dimethylphenyl)

and 3-[5-(1 -{[(2,4-dimethylphenyl)(5-methylfuran-2- (5-methylfuran- yl)methyl]carbamoyl}cyclopropyl)-1 H-indol-1 -yl]propanoic 2- acid was observed. The mixture was used as such for the yl)methyl]carba

next step. 1 H NMR (300 MHz, DMSO-d6, d in ppm): 0.98- moyl}cycloprop

1 .07 (m, 2H), 1 .23 (s, 9H), 1 .30-1.36 (m, 2H), 2.12 (s, 3H), yl)-1 H-indol-1 -

2.14 (s, 3H), 2.20 (s, 3H), 2.68-2.75 (m, 2H), 4.37 (t, 2H, yljpropanoic

J=6.4Hz), 5.75 (d, 1 H, J=2.9Hz), 5.90 (dd, 1 H, J=3.0Hz, acid

J=1.0Hz), 6.09 (d, 1 H, J=8.3Hz), 6.35-6.45 (m, 1 H), 6.67- 6.80 (m, 2H), 6.86-6.90 (m, 2H), 7.16 (dd, 1 H, J=8.3Hz, J=1.6Hz), 7.36 (d, 1 H, J=3.1 Hz), 7.48 (d, 1 H, J=8.2Hz), 7.55 (d, 1 H, J=1 .3Hz) (ester derivative).

- Step 2: tert-butyl 3-[5-(1 -{[(2,4-dimethylphenyl)(5- methylfuran-2-yl)methyl]carbamoyl}cyclopropyl)-1 H-indol-1 - yl]propanoate (170 mg, 0.32 mmol) was dissolved in MeOH (2 mL). 5 M NaOH (323 μΙ_, 1 .61 mmol) was added and the reaction mixture was heated at 1 10°C for 30 min under microwave irradiation. The solvent was removed under reduced pressure. Water was added to the residue and the aqueous layer was extracted with Et20. After phases separation, the remaining aqueous layer was acidified up to pH = 5 with 1 M citric acid and extracted with EtOAc. The combined organic layers were dried over MgS04, filtered and the solution was concentrated to dryness. The crude material was purified by silica gel column chromatography eluting with Cyclohexane/EtOAc (60:40), yield 27%, mp: 78°C, appearance: white solid

- 1 H NMR (300 MHz, DMSO-d6, d in ppm): 0.97-1 .08 (m, 2H), 1 .27-1 .42 (m, 2H), 2.12 (s, 3H), 2.14 (s, 3H), 2.20 (s, 3H), 2.73 (t, 2H, J=6.8Hz), 4.38 (t, 2H, J=6.7Hz), 5.76 (d, 1 H, J=3.1 Hz), 5.90 (dd, 1 H, J=3.0Hz, J=1 .0Hz), 6.09 (d, 1 H, J=8.4Hz), 6.39 (d, 1 H, J=2.7Hz), 6.77-6.86 (m, 2H), 6.90 (d, 1 H, J=8.0Hz), 6.93 (br(s), 1 H), 7.15 (dd, 1 H, J=8.5Hz, J=1.6Hz), 7.36 (d, 1 H, J=3.1 Hz), 7.49 (d, 1 H, J=8.5Hz), 7.54 (d, 1 H, J=1 .3Hz), 12.34 (br(s), 1 H) ; m/z: 469 [M-H]- (calc. mass: 470).

- From (3,5-dimethylpyridin-2-yl)(5-methylfuran-2-

N-[(3,5- yl)methanamine Ex.87 and 1 -(2,2-dioxo-1 ,3-dihydro-4,2,1 - dimethylpyridin- benzoxathiazin-6-yl)cyclopropane-1 -carboxylic acid Ex.69 2-yl)(5- following protocol A, DMAP (1.1 equiv), EDCI.HCI (1 .1 methylfuran-2- equiv), 2h at rt, purification by silica gel column

yl)methyl]-1 - chromatography (Cyclohexane/EtOAc, 60:40), yield 56%,

(2,2-dioxo-1 ,3- mp: 189°C, appearance: white solid

dihydro-4,2,1 - - 1 H NMR (300 MHz, DMSO-d6, d in ppm): 0.88-1 .1 1 (m, benzoxathiazin- 2H), 1 .27-1 .39 (m, 2H), 2.1 1 (s, 3H), 2.20 (s, 3H), 2.22 (s,

6- 3H), 5.24 (s, 2H), 5.86-5.92 (m, 2H), 6.08 (d, 1 H, J=7.4Hz), yl)cyclopropane 6.86 (d, 1 H, J=8.7Hz), 7.04-7.10 (m, 2H), 7.38-7.42 (m, -1 -carboxamide 1 H), 7.55 (d, 1 H, J=7.6Hz), 8.06 (d, 1 H, J=2.0Hz), 10.69 (s,

1 H) ; m/z: 468 [M+H]+ (calc. mass: 467).

- See Figure 3BC

- Step 1 : to a previously synthesized 1 -(1 H-indol-5-yl)-N-((4- methyl-2-(piperidin-1 -yl)phenyl)(5-methylfuran-2- yl)methyl)cyclopropanecarboxamide Cpd.89a (100 mg, 0.21 mmol) dissolved in dry DMF (1 mL) was added sodium hydride (60% in mineral oil) (10 mg, 0.26 mmol) at rt. After 15 min of stirring, tert-butyl 3-bromopropanoate (71 μΙ_, 0.43 mmol) was added and the reaction mixture was stirred at rt for 3h. TLC showed no reaction. Additional sodium hydride (25 mg, 6.43 mmol) and tert-butyl 3-bromopropanoate (107

3-{5-[1 -({[4- μΙ_, 6.42 mmol) were added to the solution and the reaction methyl-2- mixture was heated at 120°C for 15 min under microwave

(piperidin-1 - irradiation. After cooling to rt, water was added to quench yl)phenyl](5- the reaction. The pH was adjusted to pH = 4-5 with 1 M methylfuran-2- citric acid. The resulting aqueous solution was extracted yl)methyl}carba

with EtOAc. The combined organic layers were dried over moyl)cycloprop

MgS04, filtered and the solution was concentrated under yl]-1 H-indol-1 - reduced pressure. A mixture of tert-butyl 3-{5-[1 -({[4-methyl- yl}propanoic

2-(piperidin-1 -yl)phenyl](5-methylfuran-2- acid

yl)methyl}carbamoyl)cyclopropyl]-1 H-indol-1 -yl}propanoate and 3-{5-[1 -({[4-methyl-2-(piperidin-1 -yl)phenyl](5- methylfuran-2-yl)methyl}carbamoyl)cyclopropyl]-1 H-indol-1 - yl}propanoic acid was observed. The mixture was used as such for the next step. 1 H NMR (300 MHz, DMSO-d6, d in ppm): 0.94-1 .45 (m, 19H), 2.09 (s, 3H), 2.21 (s, 3H), 2.24- 2.35 (m, 2H), 2.42-2.48 (m, 2H), 2.69-2.75 (m, 2H), 4.36 (t, 2H, J=6.5Hz), 5.79-5.82 (m, 1 H), 5.88-5.92 (m, 1 H), 6.30 (d, 1 H, J=9.0Hz), 6.37-6.41 (m, 1 H), 6.80-6.97 (m, 4H), 7.16 (dd, 1 H, J=8.4Hz, J=1.7Hz), 7.35 (d, 1 H, J=3.2Hz), 7.48 (d, 1 H, J=8.6Hz), 7.55 (d, 1 H, J=1 .3Hz) (ester derivative).

- Step 2: tert-butyl 3-{5-[1 -({[4-methyl-2-(piperidin-1 - yl)phenyl](5-methylfuran-2- yl)methyl}carbamoyl)cyclopropyl]-1 H-indol-1 -yl}propanoate (130 mg, 0.22 mmol) was dissolved in MeOH (2 ml_). 5 M NaOH (218 μΙ_, 1 .09 mmol) was added and the reaction mixture was heated at 1 10°C for 30 min under microwave irradiation. The solvent was removed under reduced pressure. Water was added to the residue and the aqueous layer was extracted with Et20. After phases separation, the remaining aqueous layer was acidified up to pH = 5 with 1 M citric acid and extracted with EtOAc. The combined organic layers were dried over MgS04, filtered and the solution was concentrated to dryness. The crude material was purified by silica gel column chromatography eluting with Cyclohexane/EtOAc (60:40), yield 31 %, mp: 90°C, appearance: white solid

- 1 H NMR (300 MHz, DMSO-d6, d in ppm): 0.95-1 .46 (m, 10H), 2.09 (s, 3H), 2.21 (s, 3H), 2.24-2.35 (m, 2H), 2.40- 2.48 (m, 2H), 2.72 (t, 2H, J=6.8Hz), 4.37 (t, 2H, J=6.7Hz), 5.81 (d, 1 H, J=3.0Hz), 5.90 (dd, 1 H, J=3.0Hz, J=1 .0Hz), 6.30 (d, 1 H, J=8.9Hz), 6.38 (d, 1 H, J=2.7Hz), 6.84 (d, 1 H, J=7.5Hz), 6.91 (d, 1 H, J=8.8Hz), 6.94-6.98 (m, 2H), 7.17 (dd, 1 H, J=8.4Hz, J=1.6Hz), 7.35 (d, 1 H, J=3.2Hz), 7.49 (d, 1 H, J=8.5Hz), 7.54 (d, 1 H, J=1.3Hz), 12.34 (br(s), 1 H) ; m/z: 540 [M+H]+ (calc. mass: 539).

- See Figure 3BD

- The previously synthesized N-[(2,4-dimethylphenyl)(5- methylfuran-2-yl)methyl]-1 -(1 -oxo-2,3-dihydro-1 H-inden-5- yl)cyclopropane-1 -carboxamide Cpd.141 (1 15 mg, 0.28 mmol) was dissolved in EtOH (5 ml_). The solution was cooled to 0°C and sodium borohydride (16 mg, 0.42 mmol) was added. The ice bath was removed and the solution was

N-[(2,4- stirred at rt for 2h. The solvent was removed under reduced dimethylphenyl)

pressure. Water and 1 N citric acid was added to neutralized

(5-methylfuran- the solution. The aqueous layer was extracted with EtOAc.

2-yl)methyl]-1 - The organic layer was dried over MgS04, filtered and the

(1 -hydroxy-2,3- solution was concentrated under reduced pressure. The dihydro-1 H- product was pure and no purification was done., yield 85%, inden-5- mp: 58°C, appearance: white solid

yl)cyclopropane

-1 -carboxamide - 1 H NMR (300 MHz, DMSO-d6, d in ppm): 0.95-1 .02 (m,

2H), 1 .25-1 .34 (m, 2H), 1 .69-1.83 (m, 1 H), 2.15 (s, 3H), 2.16 (s, 3H), 2.22 (s, 3H), 2.29-2.38 (m, 1 H), 2.61 -2.70 (m, 1 H), 2.81 -2.94 (m, 2H), 4.97-5.05 (m, 1 H), 5.20 (dd, 1 H, J=5.9Hz, J=0.8Hz), 5.75-5.79 (m, 1 H), 5.91 -5.96 (m, 1 H), 6.1 1 (d, 1 H, J=8.2Hz), 6.90-6.97 (m, 3H), 7.14-7.21 (m, 2H), 7.24-7.31 (m, 2H) ; m/z: 438 [M+Na]+ (calc. mass: 415).

N-{[2- - From 2-[amino(5-methylfuran-2-yl)methyl]-N,N,5-

(dimethylamino) trimethylaniline Ex.42 and 1 -(3-oxo-3,4-dihydro-2H-1 ,4- -4- benzoxazin-7-yl)cyclopropane-1 -carboxylic acid Ex.35 methylphenyl](5 following protocol A, DMAP (2.2 equiv), EDCI.HCI (2.2

-methylfuran-2- equiv), overnight at rt. After completion of the reaction, the yl)methyl}-1 -(3- solution was poured into ice and water. The solid formed oxo-3,4-dihydro- was collected by filtration and dried under vacuo until

2H-1 ,4- constant weight, yield 41 %, mp: 99°C, appearance: white benzoxazin-7- solid

yl)cyclopropane

- 1 H NMR (300 MHz, DMSO-d6, d in ppm): 0.90-1 .02 (m,

-1 -carboxamide

2H), 1 .22-1 .35 (m, 2H), 2.13 (s, 3H), 2.24 (s, 3H), 2.25 (s, 6H), 4.55 (s, 2H), 5.76 (dd, 1 H, J=3.2Hz, J=1 .1 Hz), 5.92 (dd, 1 H, J=2.9Hz, J=1 .0Hz), 6.24 (d, 1 H, J=9.3Hz), 6.84- 6.91 (m, 2H), 6.93-7.04 (m, 3H), 7.12 (d, 1 H, J=7.9Hz), 7.90 (d, 1 H, J=8.9Hz), 10.74 (s, 1 H) ; m/z: 460 [M+H]+ (calc. mass: 459).

- From (2,4-dimethylphenyl)(5-methylfuran-2-yl)methanamine Ex.19 and 1 -[1 -(oxan-4-ylmethyl)-2,2-dioxo-1 ,3-dihydro-2,1 - benzothiazol-5-yl]cyclopropane-1 -carboxylic acid Ex.91

N-[(2,4- following protocol A, DMAP (1.1 equiv), EDCI.HCI (2.2 dimethylphenyl) equiv), 2h at rt, purification by silica gel column

(5-methylfuran- chromatography (Cyclohexane/EtOAc, 70:30) followed by a

2-yl)methyl]-1 - second purification by silica gel column chromatography

[1 -(oxan-4- (CH2CI2/MeOH, 98:2), yield 59%, mp: 76°C, appearance:

157 ylmethyl)-2,2- white solid

dioxo-1 ,3- dihydro-2,1 - - 1 H NMR (300 MHz, DMSO-d6, d in ppm): 0.90-1 .10 (m, benzothiazol-5- 2H), 1 .15-1.4 (m, 4H), 1.66 (d, 2H, J=14.4Hz), 1 .85-2.0 (m, yl]cyclopropane 1 H), 2.15 (s, 3H), 2.17 (s, 3H), 2.22 (s, 3H), 3.15-3.3 (m,

-1 -carboxamide 2H), 3.35-3.45 (m, 2H), 3.85 (dd, 2H, J=1 1 .3Hz, J=2.6Hz),

4.60 (s, 2H), 5.75 (m, 1 H), 5.93 (q, 1 H, J=3.0Hz, J=1.0Hz), 6.12 (d, 1 H, J=8.3Hz), 6.88-7.0 (m, 4H), 7.25-7.35 (m, 2H), 7.55 (d, 1 H, J=8.1 Hz) ; m/z: 571 [M+Na]+ (calc. mass: 548).

- From (2,4-dimethylphenyl)(5-methylfuran-2-yl)methanamine Ex.19 and 1 -(7-fluoro-2-oxo-2,3-dihydro-1 H-indol-5-

N-[(2,4- yl)cyclopropane-1 -carboxylic acid Ex.92 following protocol dimethylphenyl) A, DMAP (1.1 equiv), EDCI.HCI (1 .1 equiv), overnight at rt,

(5-methylfuran- purification by silica gel column chromatography

2-yl)methyl]-1 - (Cyclohexane/EtOAc, 70:30), yield 31 %, mp: 102°C,

158 (7-fluoro-2-oxo- appearance: white solid

2,3-dihydro-1 H- - 1 H NMR (300 MHz, DMSO-d6, d in ppm): 0.91 -1 .06 (m, indol-5- 2H), 1 .21 -1 .37 (m, 2H), 2.16 (s, 3H), 2.18 (s, 3H), 2.22 (s, yl)cyclopropane 3H), 3.52 (s, 2H), 5.73 (d, 1 H, J=3.4Hz), 5.93 (dd, 1 H,

-1 -carboxamide J=3.0Hz, J=1.0Hz), 6.15 (d, 1 H, J=8.6Hz), 6.88-7.1 1 (m,

5H), 7.69 (d, 1 H, J=8.3Hz), 10.85 (s, 1 H) ; m/z: 455

[M+Na]+ (calc. mass: 432).

1 - (3,3-difluoro-

2- 0X0-2,3- - From (2,4-dimethylphenyl)(5-methylfuran-2-yl)methanamine dihydro-1 H- Ex.19 and 1 -(3,3-difluoro-2-oxo-2,3-dihydro-1 H-indol-5-

159 indol-5-yl)-N- yl)cyclopropane-1 -carboxylic acid Ex.93 following protocol

[(2,4- A, DMAP (1.1 equiv), EDCI.HCI (1 .1 equiv), overnight at rt, dimethylphenyl) purification by silica gel column chromatography

(5-methylfuran- (Cyclohexane/EtOAc, 80:20), yield 57%, mp: 177°C, 2- appearance: white solid

yl)methyl]cyclo

- 1 H NMR (300 MHz, DMSO-d6, d in ppm): 0.95-1.08 (m, propane-1- 2H), 1.27-1.38 (m, 2H), 2.16 (s, 3H), 2.17 (s, 3H), 2.22 (s, carboxamide

3H), 5.71 (dd, 1H, J=3.0Hz, J=0.5Hz), 5.93 (dd, 1H, J=3.0Hz, J=1.0Hz), 6.15 (d, 1H, J=8.1Hz), 6.89-6.98 (m, 3H), 7.00 (d, 1H, J=7.8Hz), 7.45 (dd, 1H, J=8.1Hz,

J=1.5Hz), 7.55-7.62 (m, 1H), 7.91 (d, 1H, J=8.4Hz), 11.18 (s, 1H) ; m/z: 449 [M-H]- (calc. mass: 450).

- From (5-chlorofuran-2-yl)(2,4-dimethylphenyl)methanamine

N-[(5- Ex.32 and 1-(1-methyl-2,2-dioxo-1,3-dihydro-2,1- chlorofuran-2- benzothiazol-5-yl)cyclopropane-1-carboxylic acid Ex.40 yl)(2,4- following protocol A, DMAP (1.1 equiv), EDCI.HCI (2.2 dimethylphenyl) equiv), 2h at rt, purification by silica gel column

methyl]-1-(1- chromatography (Cyclohexane/EtOAc, 70:30), yield 39%,

160 methyl-2,2- mp: 70°C, appearance: white solid

dioxo-1,3- - 1 H NMR (300 MHz, DMSO-d6, d in ppm): 0.90-1.10 (m, dihydro-2,1- 2H), 1.25-1.35 (m, 2H), 2.16 (s, 3H), 2.23 (s, 3H), 3.02 (s, benzothiazol-5- 3H), 4.60 (s, 2H), 5.98 (q, 1H, J=3.3Hz, J=1.1Hz), 6.16 (d, yl)cyclopropane 1H, J=7.5Hz), 6.35 (d, 1H, J=3.3Hz), 6.89 (d, 1H, J=8.2Hz),

-1-carboxamide 6.97 (s, 3H), 7.25-7.35 (m, 2H), 7.83 (d, 1H, J=8.2Hz) ; m/z:

483 [M-H]-, 485 [M-H]- (calc. mass: 484).

- From (2-bromo-4-methylphenyl)(5-methylfuran-2- yl)methanamine Ex.18 and 1-(2H-1,3-benzodioxol-5- yl)cyclopropane-1-carboxylic acid Ex.88 following protocol

1-(2H-1,3- A, DMAP (3 equiv), EDCI.HCI (3 equiv), overnight at rt. benzodioxol-5- After completion of the reaction, the solution was poured yl)-N-[(2-bromo- into ice and water. The solid formed was collected by

4- filtration and dried under vacuo until constant weight, yield

161 methylphenyl)(5 35%, mp: 55°C, appearance: white solid

-methylfuran-2- yl)methyl]cyclo - 1 H NMR (300 MHz, DMSO-d6, d in ppm): 0.90-1.04 (m, propane-1- 2H), 1.19-1.28 (m, 2H), 2.18 (s, 3H), 2.27 (s, 3H), 5.69 (d, carboxamide 1H, J=3.7Hz), 5.93 (dd, 1H, J=3.1Hz, J=1.0Hz), 6.00 (s,

2H), 6.25 (d, 1H, J=7.7Hz), 6.73-7.00 (m, 3H), 7.12-7.26 (m, 2H), 7.41 (s, 1H), 7.62 (d, 1H, J=8.2Hz) ; m/z: 468

[M+H]+, 470 [M+H]+ (calc. mass: 467).

- From [4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-

N-{[4-methyl-2- yl)methanamine Ex.16 and 1-[1-(oxan-4-ylmethyl)-2,2-

(piperidin-1- dioxo-1 ,3-dihydro-2,1-benzothiazol-5-yl]cyclopropane-1- yl)phenyl](5- carboxylic acid Ex.91 following protocol A, DMAP (1.1 methylfuran-2- equiv), EDCI.HCI (2.2 equiv), 2h at rt, purification by silica yl)methyl}-1-[1- gel column chromatography (Cyclohexane/EtOAc, 70:30),

(oxan-4- yield 61%, mp: 87°C, appearance: white solid

162

ylmethyl)-2,2-

- 1 H NMR (300 MHz, DMSO-d6, d in ppm): 0.90-1.00 (m, dioxo-1,3- 2H), 1.10-1.45 (m, 10H), 1.66 (d, 2H, J=11.2Hz), 1.85-2.00 dihydro-2,1- (m, 1H), 2.12 (s, 3H), 2.24 (s, 3H), 2.30-2.40 (m, 2H), 2.50- benzothiazol-5- 2.60 (m, 2H), 3.15-3.30 (m, 2H), 3.38 (d, 2H, J=7.3Hz), 3.85 yl]cyclopropane

(dd, 2H, J=11.2Hz, J=2.6Hz), 4.60 (s, 2H), 5.82 (d, 1H,

-1-carboxamide

J=2.2Hz), 5.92 (q, 1H, J=3.0Hz, J=1.0Hz), 6.32 (d, 1H, J=9.0Hz), 6.87 (d, 1H, J=6.8Hz), 6.95-7.0 (m, 2H), 7.08 (d, 1H, J=7.7Hz), 7.30-7.40 (m, 3H) ; m/z: 618 [M+H]+ (calc.

mass: 617).

- From (2-bromo-4-methylphenyl)(5-methylfuran-2- yl)methanamine Ex.18 and 1-[1-(oxan-4-ylmethyl)-2,2- dioxo-1 ,3-dihydro-2,1-benzothiazol-5-yl]cyclopropane-1-

N-[(2-bromo-4- carboxylic acid Ex.91 following protocol A, DMAP (1.1 methylphenyl)(5 equiv), EDCI.HCI (2.2 equiv), 2h at rt, purification by silica

-methylfuran-2- gel column chromatography (Cyclohexane/EtOAc, 70:30), yl)methyl]-1-[1- yield 70%, mp: 85°C, appearance: white solid

(oxan-4-

163 ylmethyl)-2,2- - 1H NMR (300 MHz, DMSO-d6, d in ppm): 0.98 (d, 2H,

dioxo-1,3- J=2.7Hz), 1.20-1.35 (m, 4H), 1.66 (d, 2H, J=10.9Hz), 1.85- dihydro-2,1- 2.00 (m, 1H), 2.17 (s, 3H), 2.27 (s, 3H), 3.15-3.30 (m, 2H), benzothiazol-5- 3.39 (d, 2H, J=7.3Hz), 3.85 (dd, 2H, J=11.7Hz, J=3.2Hz), yl]cyclopropane 4.61 (s, 2H), 5.68 (d, 1H, J=2.5Hz), 5.93 (q, 1H, J=3.0Hz,

-1-carboxamide J=1.1Hz), 6.25 (d, 1H, J=8.2Hz), 6.96 (d, 1H, J=9.0Hz),

7.10-7.25 (m, 2H), 7.25-7.35 (m, 2H), 7.41 (s, 1H), 7.83 (d, 1H, J=8.1Hz) ; m/z: 635 [M+H]+, 637 [M+H]+ (calc. mass: 612).

- From [4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2- yl)methanamine Ex.16 and 1-(2H-1,3-benzodioxol-5- yl)cyclopropane-1-carboxylic acid Ex.88 following protocol

1- (2H-1,3- A, DMAP (3 equiv), EDCI.HCI (3 equiv), overnight at rt, benzodioxol-5- purification by silica gel column chromatography

yl)-N-{[4-methyl- (Cyclohexane/EtOAc, 80:20), yield 31%, mp: 51 °C,

2- (piperidin-1- appearance: white solid

164 yl)phenyl](5- methylfuran-2- - 1H NMR (300 MHz, DMSO-d6, d in ppm): 0.90-0.99 (m, yl)methyl}cyclo 2H), 1.23-1.47 (m, 8H), 2.12 (s, 3H), 2.24 (s, 3H), 2.39-2.46 propane-1- (m, 2H), 2.55-2.62 (m, 2H), 5.81 (d, 1H, J=2.3Hz), 5.92 (dd, carboxamide 1H, J=3.0Hz, J=1.1Hz), 5.96-6.03 (m, 2H), 6.34 (d, 1H,

J=8.4Hz), 6.83-6.91 (m, 3H), 6.92-7.00 (m, 2H), 7.03 (d, 1H, J=7.8Hz), 7.17 (d, 1H, J=8.9Hz) ; m/z: 473 [M+H]+ (calc. mass: 472).

- From (2,4-dimethylphenyl)(5-methylfuran-2-yl)methanamine Ex.19 and 1-[1-(hydroxyimino)-2,3-dihydro-1 H-inden-5-

N-[(2,4- yl]cyclopropane-1-carboxylic acid Ex.94 following protocol dimethylphenyl) A, DMAP (1.1 equiv), EDCI.HCI (1.1 equiv), overnight at rt, (5-methylfuran- purification by silica gel column chromatography

2-yl)methyl]-1- (Cyclohexane/EtOAc, 70:30), yield 41%, mp: 68°C,

[1- appearance: white solid

165

(hydroxyimino)- - 1 H NMR (300 MHz, DMSO-d6, d in ppm): 0.99-1.06 (m,

2,3-dihydro-1H- 2H), 1.30-1.33 (m, 2H), 2.16 (s, 3H), 2.16 (s, 3H), 2.22 (s, inden-5- 3H), 2.74-2.79 (m, 2H), 2.93-2.97 (m, 2H), 5.74-5.75 (m, yl]cyclopropane 1H), 5.92-5.93 (m, 1H), 6.14 (d, 1H, J=8.1Hz), 6.94-6.95

-1-carboxamide (m, 3H), 7.20 (dd, 1H, J=8.1Hz, J=1.5Hz), 7.29-7.31 (m,

1H), 7.48 (d, 1H, J=8.1Hz), 7.62 (d, 1H, J=8.4Hz), 10.81 (s, 1H) ; m/z: 429 [M+H]+ (calc. mass: 428).

N-[(2,4-

166 dimethylphenyl) - From (2,4-dimethylphenyl)(5-methylfuran-2-yl)methanamine

(5-methylfuran- Ex.19 and 2-[1-(oxan-4-ylmethyl)-2,2-dioxo-1 ,3-dihydro-2,1- 2-yl)methyl]-2- benzothiazol-5-yl]acetic acid Ex.95 following protocol A,

[1 -(oxan-4- substituted amine (0.9 equiv), DMAP (1.1 equiv), EDCI.HCI ylmethyl)-2,2- (2.2 equiv), 8h at rt, purification by silica gel column dioxo-1 ,3- chromatography (Cyclohexane/EtOAc, 50:50), yield 57%, dihydro-2,1 - mp: 83°C, appearance: white solid

benzothiazol-5-

- 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .20-1 .35 (m, yl]acetamide

2H), 1 .65 (d, 2H, J=14.9Hz), 1 .80-2.00 (m, 1 H), 2.17 (s, 3H), 2.20 (s, 3H), 2.23 (s, 3H), 3.15-3.30 (m, 2H), 3.36 (d, 2H, J=7.3Hz), 3.44 (s, 2H), 3.84 (d, 2H, J=8.0Hz), 4.61 (s, 2H), 5.85 (d, 1 H, J=3.1 Hz), 5.95 (q, 1 H, J=2.9Hz, J=1 .0Hz), 6.10 (d, 1 H, J=8.2Hz), 6.90-7.00 (m, 3H), 7.09 (d, 1 H, J=8.0Hz), 7.15-7.25 (m, 2H), 8.93 (d, 1 H, J=8.3Hz) ; m/z: 545 [M+Na]+ (calc. mass: 522).

- From [4-methyl-2-(piperidin-1 -yl)phenyl](5-methylfuran-2- yl)methanamine Ex.16 and 2-[1 -(oxan-4-ylmethyl)-2,2-

N-{[4-methyl-2- dioxo-1 ,3-dihydro-2,1 -benzothiazol-5-yl]acetic acid Ex.95

(piperidin-1 - following protocol A, substituted amine (0.9 equiv), DMAP yl)phenyl](5- (1 .1 equiv), EDCI.HCI (2.2 equiv), 8h at rt, purification by methylfuran-2- silica gel column chromatography (Cyclohexane/EtOAc, yl)methyl}-2-[1 - 50:50), yield 60%, mp: 85°C, appearance: white solid

(oxan-4- - 1 H NMR (300 MHz, DMSO-d6, d in ppm): 1 .20-1 .35 (m, ylmethyl)-2,2- 2H), 1 .40-1 .60 (m, 6H), 1 .65 (d, 2H, J=12.4Hz), 1 .90-2.00 dioxo-1 ,3- (m, 1 H), 2.17 (s, 3H), 2.25 (s, 3H), 2.50-2.60 (m, 2H), 2.70- dihydro-2,1 - 2.80 (m, 2H), 3.15-3.30 (m, 2H), 3.36 (d, 2H, J=7.1 Hz), 3.42 benzothiazol-5- (s, 2H), 3.84 (d, 2H, J=9.0Hz), 4.60 (s, 2H), 5.81 (d, 1 H, yl]acetamide J=2.9Hz), 5.91 (q, 1 H, J=3.0Hz, J=1.0Hz), 6.46 (d, 1 H,

J=8.2Hz), 6.85-6.95 (m, 3H), 7.15-7.25 (m, 3H), 8.72 (d, 1 H, J=8.3Hz) ; m/z: 592 [M+H]+ (calc. mass: 591 ).

- From (2,4-dimethylphenyl)(5-methylfuran-2-yl)methanamine Ex.19 and 1 -(2,2-dimethyl-2,4-dihydro-1 ,3-benzodioxin-7-

1 -(2,2-dimethyl- yl)cyclopropane-1 -carboxylic acid Ex.96 following protocol

2,4-dihydro-1 ,3- A, DMAP (1.1 equiv), EDCI.HCI (1.1 equiv), 5h at rt, benzodioxin-7- purification by silica gel column chromatography

yl)-N-[(2,4- (Cyclohexane/EtOAc, 80:20), yield 61 %, mp: ND,

dimethylphenyl) appearance: colourless oil

(5-methylfuran- - 1 H NMR (300 MHz, DMSO-d6, d in ppm): 0.98-0.99 (m,

2- 2H), 1 .23-1 .28 (m, 2H), 1.44 (s, 6H), 2.15 (s, 3H), 2.16 (s, yl)methyl]cyclo 3H), 2.22 (s, 3H), 4.78 (s, 2H), 5.75-5.76 (m, 1 H), 5.92-5.93 propane-1 - (m, 1 H), 6.12 (s, 1 H, J=8.1 Hz), 6.74 (d, 1 H, J=1.8Hz), 6.86 carboxamide (dd, 1 H, J=7.8Hz, J=1.8Hz), 6.93-6.95 (m, 3H), 7.02 (d, 1 H,

J=8.1 Hz), 7.46 (d, 1 H, J=8.4Hz) ; m/z: 446 [M+H]+ (calc. mass: 445).

1 -(2,2-dimethyl-

- From (2,4-dimethylphenyl)(5-methylfuran-2-yl)methanamine

2,4-dihydro-1 ,3- Ex.19 and 1 -(2,2-dimethyl-2,4-dihydro-1 ,3-benzodioxin-6- benzodioxin-6- yl)cyclopropane-1 -carboxylic acid Ex.97 following protocol yl)-N-[(2,4- A, DMAP (1.1 equiv), EDCI.HCI (1 .1 equiv), 5h at rt, dimethylphenyl)

purification by silica gel column chromatography

(5-methylfuran- (Cyclohexane/EtOAc, 80:20), yield 63%, mp: ND,

2- appearance: colourless oil

yl)methyl]cyclo propane-1- - 1H NMR (300 MHz, DMSO-d6, d in ppm): 0.95-0.96 (m, carboxamide 2H), 1.25-1.28 (m, 2H), 1.44 (s, 6H), 2.15 (s, 3H), 2.16 (s,

3H), 2.22 (s, 3H), 4.77 (s, 2H), 5.75-5.76 (m, 1H), 5.92-5.93 (m, 1H), 6.10 (d, 1H, J=7.8Hz), 6.75 (d, 1H, J=8.4Hz), 6.93- 6.94 (m, 3H), 7.04 (d, 1H, J=2.1Hz), 7.13 (dd, 1H, J=8.4Hz, J=2.1Hz), 7.26 (d, 1H, J=8.1Hz) ; m/z: 446 [M+H]+ (calc. mass: 445).

- From (2,4-dimethylphenyl)(5-methylfuran-2-yl)methanamine Ex.19 and 1-[3-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5- yl]cyclopropane-1-carboxylic acid Ex.98 following protocol A, DMAP (1.1 equiv), EDCI.HCI (1.1 equiv), 2h at rt,

N-[(2,4- purification by silica gel column chromatography

dimethylphenyl) (Cyclohexane/EtOAc, 80:20) followed by a second

(5-methylfuran- purification by silica gel chromatography

2-yl)methyl]-1- (Cyclohexane/CH2CI2/EtOAc, 50:30:20), yield 49%, mp:

170 [3-(1-hydroxy-2- 194°C, appearance: white solid

methylpropan-2- - 1 H NMR (300 MHz, DMSO-d6, d in ppm): 0.96-1.11 (m, yl)-1H-indol-5- 2H), 1.31 (s, 6H), 1.33-1.40 (m, 2H), 2.11 (s, 3H), 2.13 (s, yljcyclopropane 3H), 2.20 (s, 3H), 3.54 (d, 2H, J=5.5Hz), 4.58 (t, 1H,

-1-carboxamide J=5.7Hz), 5.71 (d, 1H, J=3.0Hz), 5.88 (dd, 1H, J=3.0Hz,

J=1.0Hz), 6.07 (d, 1H, J=8.3Hz), 6.58 (d, 1H, J=8.5Hz), 6.75 (d, 1H, J=7.8Hz), 6.88 (d, 1H, J=7.9Hz), 6.93 (s, 1H), 7.03-7.10 (m, 2H), 7.32 (d, 1H, J=8.3Hz), 7.70 (s, 1H), 10.86 (s, 1H) ; m/z: 493 [M+Na]+ (calc. mass: 470).

- From [4-methyl-2-(trifluoromethyl)phenyl](5-methylfuran-2-

1-(2,2-dioxo-1,3- yl)methanamine Ex.99 and 1-(2,2-dioxo-1,3-dihydro-4,2,1- dihydro-4,2,1- benzoxathiazin-6-yl)cyclopropane-1-carboxylic acid Ex.69 benzoxathiazin- following protocol A, DMAP (1.1 equiv), EDCI.HCI (1.1

6-yl)-N-{[4- equiv), 2h at rt, purification by silica gel column

methyl-2- chromatography (CH2CI2/EtOAc, 90:10), yield 37%, mp:

171 (trifluoromethyl) 100°C, appearance: white solid

phenyl](5- - 1 H NMR (300 MHz, DMSO-d6, d in ppm): 0.93-1.01 (m, methylfuran-2- 2H), 1.19-1.32 (m, 2H), 2.17 (s, 3H), 2.36 (s, 3H), 5.15 (s, yl)methyl}cyclo 2H), 5.65 (d, 1H, J=3.3Hz), 5.91-5.93 (m, 1H), 6.34 (d, 1H, propane-1- J=7.8Hz), 6.75 (d, 1H, J=8.4Hz), 6.95-6.98 (m, 2H), 7.46- carboxamide 7.50 (m, 3H), 7.98 (d, 1H, J=7.8Hz), 10.34 (br(s), 1H) ; m/z:

519 [M-H]- (calc. mass: 520).

- From (2,4-dimethylphenyl)(5-methylfuran-2-yl)methanamine

N-[(2,4- Ex.19 and 1-(1-methyl-2,2-dioxo-1,3-dihydro-4,2,1- dimethylphenyl)

benzoxathiazin-6-yl)cyclopropane-1-carboxylic acid Ex.100

(5-methylfuran- following protocol A, DMAP (1.1 equiv), EDCI.HCI (1.1

2-yl)methyl]-1- equiv), overnight at rt, purification by silica gel column

(1-methyl-2,2- chromatography (Cyclohexane/EtOAc, 70:30), yield 52%,

172 dioxo-1,3- mp: 65°C, appearance: white solid

dihydro-4,2,1- benzoxathiazin- - 1 H NMR (300 MHz, DMSO-d6, d in ppm): 0.95-1.05 (m,

6- 2H), 1.22-1.36 (m, 2H), 2.17 (s, 3H), 2.18 (s, 3H), 2.23 (s, yl)cyclopropane 3H), 3.20 (s, 3H), 5.37 (s, 2H), 5.76 (d, 1H, J=3.0Hz), 5.94 -1-carboxamide (dd, 1H, J=3.0Hz, J=1.0Hz), 6.13 (d, 1H, J=8.3Hz), 6.91- 7.01 (m, 3H), 7.02 (d, 1H, J=1.9Hz), 7.06 (dd, 1H, J=8.4Hz, J=2.0Hz), 7.15 (d, 1H, J=8.5Hz), 7.79 (d, 1H, J=8.2Hz) ;

m/z: 503 [M+Na]+ (calc. mass: 480).

- From (2-bromo-4-methylphenyl)(5-methylfuran-2- yl)methanamine Ex.18 and 1-(1-methyl-2,2-dioxo-1 ,3-

N-[(2-bromo-4- dihydro-4,2,1-benzoxathiazin-6-yl)cyclopropane-1- methylphenyl)(5 carboxylic acid Ex.100 following protocol A, DMAP (1.1

-methylfuran-2- equiv), EDCI.HCI (1.1 equiv), overnight at rt, purification by yl)methyl]-1-(1- silica gel column chromatography (Cyclohexane/EtOAc, methyl-2,2- 70:30), yield 51%, mp: 71 °C, appearance: white solid

173 dioxo-1,3- - 1 H NMR (300 MHz, DMSO-d6, d in ppm): 0.95-1.06 (m,

dihydro-4,2,1- 2H), 1.22-1.36 (m, 2H), 2.19 (s, 3H), 2.28 (s, 3H), 3.20 (s, benzoxathiazin- 3H), 5.37 (s, 2H), 5.68 (dd, 1H, J=3.1Hz, J=0.6Hz), 5.93

6- (dd, 1H, J=3.0Hz, J=1.0Hz), 6.27 (d, 1H, J=8.1Hz), 7.02 (d, yl)cyclopropane 1H, J=1.9Hz), 7.06 (dd, 1H, J=8.4Hz, J=2.0Hz), 7.11-7.20 -1-carboxamide (m, 2H), 7.22 (d, 1H, J=7.9Hz), 7.42 (s, 1H), 8.05 (d, 1H,

J=8.1Hz) ; m/z: 567 [M+Na]+, 569 [M+Na]+ (calc. mass: 544).

- From (2-methoxy-4-methylphenyl)(5-methylfuran-2- yl)methanamine Ex.101 and 1-(2,2-dioxo-1,3-dihydro-4,2,1-

1-(2,2-dioxo-1,3- benzoxathiazin-6-yl)cyclopropane-1-carboxylic acid Ex.69 dihydro-4,2,1- following protocol A, DMAP (1.1 equiv), EDCI.HCI (1.1 benzoxathiazin- equiv), overnight at rt, purification by silica gel column

6-yl)-N-[(2- chromatography (CH2CI2/EtOAc, 90:10), yield 58%, mp: methoxy-4- 107°C, appearance: white solid

174

methylphenyl)(5 - 1 H NMR (300 MHz, DMSO-d6, d in ppm): 0.93-1.01 (m,

-methylfuran-2- 2H), 1.25-1.36 (m, 2H), 2.14 (s, 3H), 2.26 (s, 3H), 3.51 (s, yl)methyl]cyclo 3H), 5.19 (s, 2H), 5.67-5.68 (m, 1H), 5.87-5.89 (m, 1H), propane-1- 6.05 (d, 1H, J=9.0Hz), 6.68-6.71 (m, 1H), 6.76-6.77 (m, carboxamide 1H), 6.82-6.85 (m, 1H), 7.02-7.09 (m, 3H), 7.30 (d, 1H,

J=9.0Hz), 10.65 (br(s), 1H) ; m/z: 505 [M+Na]+ (calc. mass: 482).

- From (2,4-dimethylphenyl)(5-methylfuran-2-yl)methanamine Ex.19 and 1-(2,2-dimethyl-2H-1,3-benzodioxol-5-

1-(2,2-dimethyl- yl)cyclopropane-1-carboxylic acid Ex.102 following protocol 2H-1.3- A, DMAP (1.1 equiv), EDCI.HCI (1.1 equiv), overnight at rt, benzodioxol-5- purification by silica gel column chromatography yl)-N-[(2,4- (Cyclohexane/EtOAc, 70:30), yield 73%, mp: ND, dimethylphenyl)

175 appearance: viscous colourless oil

(5-methylfuran-

2- - 1H NMR (300 MHz, DMSO-d6, d in ppm): 0.95-0.97 (m, yl)methyl]cyclo 2H), 1.19-1.27 (m, 2H), 1.61 (s, 6H), 2.14 (s, 3H), 2.16 (s, propane-1- 3H), 2.21 (s, 3H), 5.76-5.77 (m, 1H), 5.92-5.94 (m, 1H), carboxamide 6.08 (d, 1H, J=8.1Hz), 6.77-6.78 (m, 2H), 6.81-6.82 (m,

1H), 6.93-6.94 (m, 3H), 7.27 (d, 1H, J=8.4Hz) ; m/z: 432 [M+H]+ (calc. mass: 431).

Example 3: RORE Luciferase/RORyt transactivation Assay It is well known that RORy binds to a conserved non-coding sequence (CNS) enhancer element in the IL-17 promoter. Accordingly, we have used in this assay a luciferase reporter gene construct that contains the human IL-17 promoter fragment with RORy-specific CNS enhancer element and a RORyt overexpressing plasmid, to indirectly assess the effect of compounds on RORy activity. Inhibition of RORy activity by test compounds will result in a decrease in luciferase activity in COS-7 cells transfected with the reporter construct.

COS-7 cell line culture

Monkey Kidney COS-7 cell line are maintained in a standard culture medium Dulbecco's modified Eagle's minimal (DMEM) medium supplemented with 10% fetal calf serum, 1 % sodium pyruvate, 1 % essential amino acids and 1 % antibiotics at 37°C in a humidified atmosphere of 5% C02 and 95% air. Culture medium was changed every 2 days.

Construct descriptions

The 4.3 Kb human IL-17 promoter containing the RORy-specific CNS enhancer element was PCR amplified from human genomic DNA and cloned into a pGL3- TKLuc2Cp reporter plasmid. To overexpress RORyt, the full-length cDNA of human RORyt (identical to published sequence NM 001001523) was cloned without any restriction into pcdna3.1 DV5- His-topo to generate the RORyt overexpression plasmid "RORyt_FL_h_pcDNA3.1 DV5-His- TOPO_1 ".

COS-7 cell transfection

The luciferase reporter plasmid and the RORyt overexpression plasmid were transfected into COS-7 cell line using 4μίύβίΡΕΙΤΜ/μ9 of DNA. Briefly, 150 ng of DNA (ration 1/2 between RORE-Tk Luc2Cp and cDNA RORyt or the empty vector for the negative control) was served to transfect adherent COS-7 cells in a 225 cm3 culture flask, in complete medium (see cos-7 cell line culture). Cells were incubated for 24 hours in a humidified atmosphere of 5% C02 and 95% air

Cells were then detached (using trypsin) and washed by centrifugation at 300g for 10 minutes. Cell pellet was resuspended in serum free / phenol red free DMEM and seeded in

384 well plates at a density of 10000 cells/well and then incubated for 4h at 37°C.

Assay

Compounds were dissolved in 100% DMSO to obtain 10 mM stock solutions. For each compound, test concentrations were diluted in serum free / phenol red free DMEM using the Genesis Freedom 200TM (TECAN) and added to the cells to obtain a 0.3% DMSO final concentration (in a final volume of 40 μΙ_ per well). T091317 was used as reference compound. Cells were incubated in presence of compounds for an additional 20h at 37°C in a humidified atmosphere of 5% C02 and 95% air

The luciferase activity was then measured with 40 μΙ_ / well steady-Glo Luciferase assay system (Promega, Madison, Wl) and after incubation at room temperature for 30 minutes. The luminescence was estimated using the Ultra384 reader (TECAN). Data were collected and analyzed using GraphPad Prism software (GraphPad Software V5.02, San Diego California USA). IC50 in μΜ and Emax in % were reported for each compound. Results:

Effect of reference compound on RORyt activity: in this assay, reference compound T091317 showed on RORyt activity inhibition with IC ₅ o of 0.2 μΜ and an Emax of 83.7%

Several compounds belonging to formula (I) or (la) inhibit the high transcriptional activity of RORy at different levels. In particular, Cpd.7 displayed an IC50 superior to 10 μΜ. Some compounds displayed an I C50 comprised between 1 and 10 μΜ in particular Cpds 2-3, 5-6, 9-1 1 , 13, 15, 17-18, 20, 22, 26, 29-30 and 140 . Cpds 1 , 4, 16, 21 , 23, 25, 28, 32-34, 36, 39-40, 42-46, 48, 50-51 , 55, 67, 96, 99-102, 104, 107, 1 10, 141 , 148, 150, 153, 159, 161 , 164, and 168-169 displayed an I C50 comprised between 0.1 and 1 μΜ.

Cpds 16, 24, 27, 31 , 35, 37-38, 41 , 47, 49, 52-54, 56-58, 62-66, 69-85, 87-88, 90-95, 97-98, 103, 106, 108, 1 1 1 -120, 124-127, 130-133, 136-137, 139, 142-147, 149, 152, 155- 156, 158, 160, 162-163, 165-167, and 170-171 displayed an IC ₅₀ comprised between 0.01 and 0.1 μΜ.

Best compounds (such as Cpds. 59-61 , 86, 89, 123, 134-135, 154, and 157) displayed an I C50 inferior to 0.01 μΜ.

Further, the major part of compounds from this chemical series showed no cytotoxic effect at 30 μΜ as judged from the reporter signal obtained from cells transfected with the empty vector that was used as negative control in this experiment.

Example 4: FRET

General considerations

Time-resolved FRET (TR-FRET) RORyt coactivator assay was used to identify RORy modulator compounds with ligand-dependent coactivator displacement. The assay uses a d2-labeled anti-GST antibody, synthetic N-terminally biotinylated peptide which is derived from nuclear receptor coactivator protein RIP140, and a RORyt ligand-binding domain (RORyt-LBD) that is tagged with glutathione-S-transferase (GST). The influence of compounds on the RORy-peptide interaction relies on the binding dependent energy transfer from a donor to an acceptor fluorophor attached to the binding partner of interest. Because RORy is constitutively active, streptavidin- terbium conjugate labeled-coactivator peptide is recruited in the absence of ligand and the terbium d2 on the anti-GST antibody is excited at 340 nm, energy is transferred to the terbium label on the coactivator peptide and detected as emission at 665 nm. For reduction of background from compound fluorescence, TR-FRET method makes use of generic fluorophore labels and time resolved detection.

Assay

The assays were done in a final volume of 20 μΙ in a 384 well plate in a CHAPS buffer

(2 mM CHAPS; 1 mM DTT, 2mM EDTA; 0.1 % BSA), containing 20 nM recombinantly expressed RORy-LBD fused to GST, 30 nM N-terminally biotinylated peptide, 1 nM streptavidin- terbium conjugate and 20 nM d2 labeled-anti-GST. Test compounds were diluted using 10 mM stock solution. The range of the final compound concentrations used in this test was from 0.3 nM to 30 μΜ (logarithmic scale). DMSO content of the samples was kept at 1 %. The assay was equilibrated for 2 hours in the dark at room temperature in 384 well plates (Falcon). The signal was detected by an Ultra384 reader (TECAN). The results were visualized by plotting the ratio between the emitted light at 665 nm and 620 nm. A basal level of RORy- peptide formation is observed in the absence of added compound. Compounds that promote coactivator displacement induce a concentration-dependent decrease in time-resolved fluorescent signal. Data were collected and analyzed using Graph Pad Prism software (Graph Pad Software V5.02, San Diego California USA). IC50 in μΜ and Emax in % were reported for each compound. Results:

Effect of reference compound on RORyt activity: in this assay, reference compound T091317 showed on RORyt activity inhibition with IC ₅ o of 0.097 μΜ and an Emax of 37%

Several compounds belonging to formula (I) or (la) inhibit the ligand-dependent coactivator-RORyt binding.

Cpds 12, 19-20, 32, and 50 displayed an IC50 comprised between 1 μΜ and 10 μΜ.

Cpds 1 , 3, 7-8, 1 1 , 18, 21 -23, 25, 30, 34, 40, 43-45, 48, 64, 91 -92, 100, and 1 18, displayed an IC50 comprised between 0.1 μΜ and 1 μΜ.

Cpds.2, 4-5, 9, 15-16, 26, 81 -82, 90, 98-99, and 101 -102 displayed an IC ₅₀ between 0.01 μΜ and 0.1 μΜ.

Best compounds (such as Cpds.24, 27, 52-53, 59-60, 63, 71 , 74, 77, 86-87, 124-125,

127, and 130) displayed an IC ₅ o inferior to 0.01 μΜ. Example 5: IL-17 Secretion from EL4 murine lymphoma

Murine EL-4 lymphoma cell line overexpressing human RORyt was used in this functional assay to assess compound ability to inhibit IL-17 cytokine secretion.

EL-4 cell transfection

EL-4 cells are maintained in a standard culture medium RPMI supplemented with 10% fetal calf serum, 1 % sodium pyruvate, 1 % essential amino acids and 1 % antibiotics at 37°C in a humidified atmosphere of 5% C02 and 95% air. Culture medium was changed every 2 days. EL4 cells were transfected with a plasmid encoding hRORyt (sequence identical to published sequence NM 001001523). Transfection of EL4 cells was achieved with Amaxa electroporation apparatus (Amaxa Biosystems, Germany), as per the manufacturer's protocols, for the EL4 cells (Amaxa Cell Line Nucleofector Kit L, Amaxa Biosystems). Briefly, 1 μg of DNA / 1 million cells was served to transfect EL-4 cells. Cell/DNA suspension was transferred into certified cuvette and the electroporation of RORyt plasmid was carried out using appropriate Nucleofector® program. IL-17 secretion assay

Cells were seeded in 96 well plates at a density of 150000 cells / well then treated with compounds of this invention at indicated concentrations and incubated for 24 hours at 37°C in a humidified atmosphere of 5% C02 and 95% air. EL-4 cells were pretreated with test compounds (RORy modulators) and stimulated with PMA (10 ng/mL) and ionomycin (1 μΜ final concentration) in the presence of test compound concentrations for additional 24h at 37°C in a humidified atmosphere of 5% C02 and 95% air. Subsequently, supernatants were collected (after centrifugation at 300g for 10 minutes) to determine the concentrations of IL- 17 by HTRF (CisBio, France) or ELISA (R&D Systems Europe) according to the manufacturer's protocols.

Results:

Many of the compounds listed above were evaluated for IL-17 secretion inhibition in human RORyt-transfected EL4 Tcells. Data from this assay correlate with the activity observed in RORE Tk luc/RORyt assay.

Cpd. 2 and 5 displayed an IC50 comprised superior to 10 μΜ. Cpd. 3, 10-1 1 , 25, 28, 44, 104, and 107 displayed an IC50 comprised between 1 μΜ and 10 μΜ.

Cpds. 1 , 4, 16, 23, 27, 31 , 33, 36-39, 42, 47, 52-53, 71 -72, 74-84, 90-92, 97, 106, 1 1 1 - 1 12, 1 14-1 15, 1 17, 124, and 126 displayed an IC50 comprised between 0.1 μΜ and 1 μΜ.

Best compounds (such as Cpds. 24, 35, 41 , 54, 57-62, 64, 73, 86-89, 93-94, 98, 103,

108, 1 16, 1 18-120, 125, 127 and 130) displayed an IC ₅₀ inferior to 0.1 μΜ.

Example 6: Experimental autoimmune encephalomyelitis (EAE) study

8-10 week old, female C57BL/6 mice were purchased from Janvier Lab (St Berthevin,

France) and housed for one week before the start of the studies. EAE was induced by immunization with an emulsion of peptide antigen MOG35-55 (Myelin Oligodendrocyte Glycoprotein) (MMEVGWYRSPFSRVVHLYRNG, SEQ ID NO: 1 ) in complete Freund's Adjuvant (CFA), followed by administration of Pertussis Toxin (PTX) in PBS on the day of immunization and dayl post immunization, following manufacturer recommendation (Hooke, Kit MOG35-55/CFA Emulsion PTX). Animals were treated with drug beginning 2 days before peptide injection. Animals were randomized into groups for treatment by weight, so that the average weight of each group was similar. The groups were segregated by cage. Compounds according to the invention were suspended in Labrafil (M1944 CS) by sonication and animals were dosed twice daily by gavage with 5 mL/kg body weight. The daily doses of Cpd.24 were 30 and 60 mg/kg (b.i.d.) by gavage. Clinical assessment of EAE was performed daily according to the following criteria: 0) no disease, 1 ) limp tail, 2) limp tail and weakness oh hind legs 3) limp tail and complete paralysis of hind legs or paralysis of one front one hind leg, 4) limp tail, complete hind leg and partial front leg paralysis and 5) complete paralysis or death.

Data are expressed as (figure 4A) mean (+/- SEM) of clinical score for each group per day and (figure 4B). Area under curve (AUC) of clinical score for each group through in vivo protocol duration.

Statistical evaluation of differences between the experimental groups was determined by using two-way Anova followed by a Bonferroni post test. ^** p<0.005, Vehicle compared with treatments.

Results

This example shows that Cpd.24 RORy modulator is able to delay the onset of EAE when the compound was administered p/os at 60 mg/kg (b.i.d.) for 20 days. Clinical disease score improvement was apparent with Cpd.24 by day 15 and maintained through in vivo protocol duration (figure 4A & B). Example 7: Imiquimod (IMQ) induced psoriasis study

8-10 weeks C57BL/6 female mice received a daily topical dose of 62.5 mg/mouse IMQ cream (Aldara® cream 5%; 3M pharmaceuticals, Sweden) on the shaved back and the right ear for 7 consecutive days. Control mice were treated similarly with a control vehicle cream (Vaseline). Test compound (Cpd 24) was orally administered daily from day 0 to day 7 at 3mg/ml_ (30mg/kg). Test compound was given 8 hours before IMQ application. Mice were killed at day 7, 4h after the last test compound treatment to analyse skin inflammation parameters.

The severity of inflammation of the back skin was determined using the following criteria. An objective scoring system was developed based on the clinical Psoriasis Area and Severity Index (PASI), except that for the mouse model the affected skin area is not taken into account in the overall score. Erythema, scaling, and thickening were scored independently on a scale from 0 to 4: 0: none; 1 : slight; 2: moderate; 3: marked; 4: severe. The cumulative score (erythema plus scaling plus thickening) served as a measure of the severity of inflammation (scale 0-12).

Ear skin tissue were homogenized in PBS containing a protease inhibitor cocktail (P8340, Sigma-Aldrich) by Ultra Turrax, centrifuged and the supernatant was discarded. The pellet was resuspended in 0.5 mL PBS containing 0.5% hexadecyltrimethyl ammonium bromide (HTAB) and 5 mM ethylene-diamine tetra-acetic acid (EDTA). Following centrifugation, 100 μΙ_ of supernatants were placed in test tubes with 200μΙ_ PBS-HTAB- EDTA, 1 ml_ Hanks' balanced salt solution (HBSS), 100 μΙ_ of o-dianisidine dihydrochloride (1 .25 mg/mL), and 100μΙ_ H202 0.05%. After 15 min of incubation at 37oC in an agitator, the reaction was stopped with 100μΙ_ NaN3 1 %. The MPO activity was determined as absorbance at 460 nm in comparison with medium.

Statistical evaluation of differences between the experimental groups was determined by using two-way Anova followed by a Bonferroni post test. ^*** p<0.001 , IMQ-Vehicle compared with treatment.

Results

In this experiment, no adverse effect was observed after compound test administration. Orally treatment with 30 mpk Cpd 24 induced a significant decrease of cumulative score at day 5 compared to control treatment (figure 5A). The effect of test compound on the extent of inflammation was tested using MPO activity marker. GFE6030 treatment reduced MPO activity in ear homogenates in comparison with IMQ-vehicle group (figure 5B) REFERENCES

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