WO2013064231A1 - SEVEN-MEMBERED SULFONAMIDES AS MODULATORS OF RAR-RELATED ORPHAN RECEPTOR-GAMMA (RORγ, NR1F3) - Google Patents

Abstract

The invention provides modulators for the orphan nuclear receptor RORγ and methods for treating RORγ mediated diseases by administration of these novel RORγ modulators to a human or a mammal in need thereof. Specifically, the present invention provides compounds of Formula (1) and the enantiomers, diastereomers, tautomers, solvates and pharmaceutically acceptable salts thereof as well as pharmaceutical compositions comprising said compounds as an active ingredient.

Description

Seven-membered sulfonamides as modulators of RAR-related orphan receptor-gamma (RORy, NR1 F3)

The invention provides modulators for the orphan nuclear receptor RORy and methods for treating RORy mediated chronic inflammatory and autoimmune diseases by administration of these novel RORy modulators to a human or a mammal in need thereof.

The retinoid-receptor related orphan receptors consist of three family members, namely RORa (Beckerandre et al., Biochem. Biophys. Res. Commun. 1993, 194:1371), ROR (Andre et al., Gene 1998, 516:277) and RORy (He et al., Immunity 1998, 9:797) and constitute the NR1 F (ROR/RZR) subgroup of the nuclear receptor superfamily (Mangelsdorf et al., Cell 1995, 83:835).

The nuclear receptor superfamily shares common modular structural domains consisting of a hypervariable N-terminal domain, a conserved DNA binding domain (DBD), a hinge region, and a conserved ligand-binding domain (LBD). The DBD targets the receptor to specific DNA sequences (nuclear hormone response elements or NREs), and the LBD functions in the recognition of endogenous or exogenous chemical ligands. A constitutive transcriptional activation domain is found at the N-terminus (AF1) and a ligand regulated transcriptional activation domain is embedded within the C-terminal LBD of typical NRs. The nuclear receptors can exist in a transcriptional activating or repressing state when bound to their target NREs. The basic mechanism of gene activation involves ligand dependent exchange of co-regulatory proteins, namely co-activators and co-repressors (McKenna et al., Endocrine Rev. 1999, 20:321). A NR in the repressing state is bound to its DNA recognition element and is associated with co-repressor proteins that recruit histone-deacetylases (HDACs). In the presence of an agonist, co-repressors are exchanged for coactivators that recruit transcription factors, which contribute to assembling of a chromatin-remodelling complex, which relieves transcriptional repression and stimulates transcriptional initiation via histone acetylation. The AF-2 domain of the LBD acts as a ligand dependant molecular switch presenting interaction surfaces for co- repressor or co-activator proteins and providing with a conserved mechanism for gene activation or repression that is shared by the members of the nuclear receptor superfamily.

The members of the NR1 F family of nuclear receptors (such as RORy) have been considered to be constitutively active transcription factors in the absence of known ligands, which is similar to the estrogen-related receptor alpha (Vanacker et al., Mol. Endocrinol. 1999, 13:764). Most recently, 7-oxygenated oxysterols were identified to be high affinity ligands for RORa and RORy (Wang et al., J. Biol. Chem. 2010, 285:5013). 7-Hydroxycholesterol is a key metabolite during the conversion of cholesterol into bile acids, but to date it is not clear whether it is a true endogenous ligand for the RORs. In any case it can be expected that inverse agonists of RORy should reduce the transcriptional activity of RORy and influence the biological pathways controlled by RORy. The RORs are expressed as isoforms arising from differential splicing or alternative transcriptional start sites. So far, isoforms have been described that differ only in their N- terminal domain (A/B-domain). In humans, four different RORo isoforms have been identified (RORa 1-4) while only two isoforms are known for both ROR (1 and 2) and RORy (1 and 2) (Andre et al., Gene 1998, 216:277; Villey et al., Eur. J. Immunol. 1999, 29:4072). RORy is used herein as a term describing both, RORyl and/or RORy2.

The ROR isoforms show different tissue expression patterns and regulate different target genes and physiological pathways. For example, the RORy2 (also called RORyt) is highly restricted to CD4⁺CD8⁺ thymocytes and to interleukin-17 (IL-17) producing T cells while other tissues express RORyl (Eberl et al., Science 2004, 305:248, Zhou and Littmann, Curr. Opin. Immunol. 2009, 21:146).

RORs exhibit a structural architecture that is typical of nuclear receptors. RORs contain four major functional domains: an amino-terminal (A/B) domain, a DNA-binding domain (DBD), a hinge domain, and a ligand-binding domain (LBD) (Evans et al., Science 1988, 240:889). The DBD consists of two highly conserved zinc finger motifs involved in the recognition of ROR response elements (ROREs) which consist of the consensus motif AGGTCA preceded by an AT-rich sequence (Andre et al., Gene 1998, 216:277) which is similar to that of the nuclear receptors Rev-ErbAa and Rev-Ert$ (NR1D1 and D2, respectively) (Giguere et al., Genomics 1995, 28:596). These recognition elements do also show high similarity to those identified for the estrogen related receptors and in particular ERRa (ERRs, NR3B1 , -2, -3) (Vanacker et al., Mol. Endocrinol. 1999, 13:764), steroidogenic factor 1 (SF-1 , NR5A) and NGFI-B (NR4A1 , -2, - 3) (Wilson et al., Mol. Cell. Biol. 1993, 13:5794).

RORa is highly expressed in different brain regions and most highly in cerebellum and thalamus. RORa knock-out mice show ataxia with strong cerebellar atrophy, highly similar to the symptoms displayed in the so-called staggerer mutant mouse (RORa^{SQ S9}). This mouse carries mutations in RORa that results in a truncated RORa which does not contain a LBD (Hamilton et al., Nature 1996, 379:736).

Analysis of RORa^{sg S9} staggerer-mice have revealed a strong impact on lipid metabolism beyond the CNS defects, namely significant decreases in serum and liver triglyceride, reduced serum HDL cholesterol levels and reduced adiposity. SREBPIc and the cholesterol transporters ABCA1 and ABCG1 are reduced in livers of staggerer mice and CHIP analysis suggest that RORa is directly recruited to and regulates the SREBPIc promoter. In addition, PGC1a, PGCip, lipinl and 2-adrenergic receptor were found to be increased in tissues such as liver or white and brown adipose tissue, which may help to explain the observed resistance to diet- induced obesity in staggerer mice (Lau et al., J. Biol. Chem. 2008, 283:18411).

ROR expression is mainly restricted to the brain and most abundantly found in the retina. ROR3 knock-out mice display a duck-like gait and retinal degeneration which leads to blindness (Andre et al., EMBO J. 1998, 17:3867). The molecular mechanisms behind this retinal degeneration are still poorly understood.

RORy (particularly RORy2) null-mutant mice lack lymph nodes and Peyer^'s patches (Eberl and Littmann, Immunol. Rev. 2003, 195:81) and lymphatic tissue inducer (LTi) cells are completely absent from spleen mesentery and intestine. In addition, the size of the thymus and the number of thymocytes is greatly reduced in RORy null mice (Sun et al., Science 2000, 288:2369) due to a reduction in double-positive CD4⁺CD8⁺ and single positive CD4^"CD8⁺ or CD4⁺CD8^" cells suggesting a very important role of RORy2 in thymocyte development.

Thymocyte development follows a complex program involving coordinated cycles of proliferation, differentiation, cell death and gene recombination in cell populations dedicated by their microenvironment. Pluripotent lymphocyte progenitors migrating from fetal liver or adult bone marrow to the thymus are being committed to the T-cell lineage. They develop through a series of steps from CD4^~CD8^~ double negative cells to CD4⁺CD8⁺ cells and those with low affinity towards self-MHC peptides are eliminated by negative selection. These develop further into CD4^"CD8⁺ (killer) or CD4⁺CD8^~ (helper) T-cell lineages. RORy2 is not expressed in double negative and little expressed in immature single negative thymocytes (He et al., J. Immunol. 2000, 164:5668), while highly upregulated in double-positive thymocytes and downregulated during differentiation in single-positive thymocytes. RORy deficiency results in increased apoptosis in CD4⁺CD8⁺ cells and the number of peripheral blood thymocytes is decreased by 6- fold (10-fold CD4⁺ and 3-fold CD8⁺ thymocytes).

Recent experiments in a model of ovalbumin (OVA)-induced inflammation in mice, as a model for allergic airway disease, demonstrated a severe impairment of the development of the allergic phenotype in the RORy KO mice with decreased numbers of CD4⁺ cells and lower Th2 cytokine/chemokine protein and mRNA expression in the lungs after challenge with OVA (Tilley et al., J. Immunol. 2007, 178:3208). IFN-y and IL-10 production were increased in splenocytes following re-stimulation with the OVA antigen compared to wt splenocytes suggesting a shift towards a Th1 type immune response on cost of a reduction of Th2 type response. This suggests that down-modulation of RORy transcriptional activity with a ligand could result in a similar shift of the immune response towards a Th1 type response, which could be beneficial in the treatment of certain pulmonary diseases like asthma or allergic inflammatory conditions.

T-helper cells were previously considered to consist of Th1 and Th2 cells. However, a new class of Th cells, the Th17 cells, which produce IL-17, were also identified as a unique class of T-cells that are considered to be pro-inflammatory. They are recognized as key players in autoimmune and inflammatory diseases since IL-17 expression has been associated with many inflammatory diseases such as rheumatoid arthritis, systemic lupus erythematosis (SLE) and allograft rejection. (Tesmer et al., Immunol. Rev. 2008, 223:87).

RORy2 is exclusively expressed in cells of the immune system and has been identified as a master regulator of Th17 cell differentiation. Expression of RORy2 is induced by TGF-beta or IL- 6 and overexpression of RORy2 results in increased Th17 cell lineage and IL-17 expression. RORy2 KG mice show very little Th17 cells in the intestinal lamina propria and demonstrate an attenuated response to challenges that usually lead to autoimmune disease (Ivanov et al., Cell 2006, 126:1121).

Inhibition of IL-17 production via inhibition of Th17 cell development may also be advantageous in atopic dermatitis and psoriasis where IL-17 is deeply involved. Interestingly, recent evidence was presented that IL-10 suppresses the expression of IL-17 secreted by both, macrophages and T-cells. In addition, the expression of the Th17 transcription factor ROR72 was suppressed (Gu et al., Eur. J. Immunol. 2008, 38:1807). Moreover, IL-10 deficient mice provide a good model for inflammatory bowel disease (IBD) where a shift towards a Th1 type inflammatory response is frequently observed. Oral IL-10 delivery poses a potential treatment option for IBD.

The proinflammatory actions of IL-17 producing Th17 cells are counteracted by another T- helper cell type, so-called regulatory T-cells or Tregs. Naive T cells are differentiated into Tregs upon stimulation by TGF . This results in upregulation of the transcriptional modulator FoxP3 resulting in CD4⁺FoxP3⁺ Tregs. In case the naive T-cells are co-stimulated by IL-6, FoxP3 expression is suppressed and RORTt expression is induced. These CD4⁺FoxP3^"RORyt⁺ T- helper cells then differentiate into IL-17 producing Th17 cells, (reviewed in Awasthi and Kuchroo, Int. Immunol. 2009, 21:489, and Zhou and Littmann, Curr. Opin. Immunol. 2009, 21 :146). Several lines of evidence suggest that these Th17 cells are responsible for the etiology of a whole range of autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, ankylosing spondylitis, psoriasis, Crohn^'s disease and other types of inflammatory bowel disease, lupus erythematosus and asthma. The severity of disease seems to correlate with the presence of IL-17⁺ Th17 cells and it is believed that interception of RORyt by a small molecule inverse agonist or antagonist should result in a reduction of these IL-17⁺ Th17 cells ultimately leading to alleviation of disease symptoms and outcome (Crome et al., Clin. Exp. Immunol. 2010, 159:109).

Ligands for the RORs:

It was reported that cholesterol and its sulfated derivatives might function as RORa ligands and in particular cholesterol-sulfate could restore transcriptional activity of RORa in cholesterol- depleted cells (Kallen et al., Structure 2002, 10:1697). Previously, melatonin (Missbach et al., J. Biol. Chem. 1998, 271:13515) and thiazolidinediones were suggested to bind to RORa (Wiesenberg et al., Nucleic Acid Res. 1995, 23:327). However, none of these have been shown to be functional ligands of RORa or of any other of the RORs. Certain retinoids including all- trans retinoid acid have been demonstrated to bind to ROR and function as partial antagonists for RORp but not RORa (Stehlin-Gaon et al., Nat. Struct. Biol. 2003, 10:820).

Recently, 7-oxygenated sterols such as 7-hydroxy-cholesterol and 7-keto-cholesterol were identified as highly potent modulators of RORy activity (Wang et al., J. Biol. Chem. 2010, 285:5013) in in vitro assays. The same group of investigators also found that a known LXR agonist, T0901317 ([/V-(2,2,2-trif luoroethyl)-/V-[4-[2,2,2-trif luoro-1 -hydroxy- 1 -(trif luoro- methyl)ethyl]phenyl]-benzenesulfonamide]) acts as a RORy inverse agonist at submicromolar potency (Kumar et al., Mol. Pharmacol. 2010, 77:228). In neither case, however, in vivo data were obtained that demonstrate a beneficial impact of these RORy modulating compounds. In case of the 7-oxysterols their endogenous presence as metabolites naturally produced by the body itself as well as their rapid turnover and their biological activities on many cellular proteins prevent a meaningful animal study that allows drawing conclusions on the role of RORy. In case of the T0901317 its polypharmacodynamic properties, acting on at least six different nuclear receptors (LXRa/β, FXR, PXR, RORa/γ) prevents its usefulness as a drug candidate for the development in an autoimmune disease application (Houck et al., Mol. Genet. Metab. 2004, 83:184; Xue et al., Bioorg. Med. Chem. 2007, 15:2156).

Modulators of the RORy receptor were recently disclosed in WO201 1/107248, WO201 1/1 12263, WO201 1/1 12264, WO201 1/1 15892, WO2012/027965, WO2012/028100, WO2012/064744, WO2012/100732, WO2012/100734, WO2012/106995 and WO2012/139775, which are based upon other structural classes.

JP-A-2006/056881 and WO2004/067008 describe 6 to 9-membered heterocyclic fused pyridine compounds as TGF receptor agonists for the treatment of e.g. heart failure or myocardial infarction. As shown exemplarily in Formula (A), all examples in JP-A-2006/056881 and WO2004/067008 bear a cyclic structure as substituent at the atom position neighbouring the bridgehead atom "*".

(A)

B.-C. Chen et al. (Tetrahedron Lett. 2001 , 42:1245) describe the reductive alkylation of 7- membered amines of Formula (B) towards 1 -(imidazolyl)methyl substituted 4-sulfonylbenzo- diazapines as inhibitors of farnesyltransferases.

In WO2004/033436 bradykinin antagonsits of Formula (C) are described, which contain a Chester, CH₂-thioester or CH₂-amide group in the 3-position of the 4,5-dihydro-1 H- benzo[e][1 ,4]diazepin-2(3H)-one core.

W01997/030992 describe farnesyl transferase inhibitors of general Formula (D), which have an imidazolyl residue in the 1 -position of the 7-membered cyclic ring. The derivative (D1) serves as an intermediate t

US6458783 and WO2001/081322 describe compounds with similar structure as described with Formula (D), wherein the imidazolyl residue is replaced by other heterocycles, phenyl or sulfur/nitrogen containing residues. W01999/001434 discloses benzazepine derivatives with an imidazolyl residue.

K. Samanta et al. (Bioorg. Med. Chem. Lett. 2010, 20:283) describe benzoxazepine derivatives of Formula (E) for the treatment of cancer. The only sulfonamide residue described therein is phenyl para-substituted with CH₃. This moiety S0₂-C₆H₄-pa -a-CH₃ is a widely used protecting group for amines. The specific targeting of the insulin-like growth factor 1 receptor signaling in human estrogen dependent breast cancer was reported by B. Chakravarti et al. with the compound of Formula (E) wherein R = H and R' = para-hydroxy substituted benzyl (Mol. Cell. Endorinol. 201 1 , 338:68)

(E)

WO2004/018432 disclosed substituted azepines as histamine H3 receptor antagonists of general Formula (F), wherein the sulfonamide residue is limited to phenyl.

1 ,4-Benzothiazepines of general Formula (G) are disclosed in US201 1/0172190, WO2006/ 01496, WO2001/000185 and W01994/011360.

(G)

The following derivatives (H), (J) and (K) are commercially available from Asinex Ltd. (CAS database entry in July 2012):

Summary of the invention

It is therefore the object of the present invention to provide compounds, which bind to the orphan nuclear receptors RORyl and/or RORy2 and, thus, to open new ways for treating diseases associated with the modulation of RORy, such as autoimmune diseases, inflammatory skin diseases or multiple sclerosis.

This object is solved by claims 1 to 16.

Thus, the present invention provides RORy modulators, which can be used for treating or preventing a disease or disorder associated with the inactivation or activation of the RORy receptor.

The present invention relates to a RORy modulator for use in the treatment or prophylaxis of a disease or disorder associated with the inhibition or activation of RORy.

When treating the disease or disorder associated with the modulation of the RORy receptor, the activity of said receptor is preferably reduced.

Preferably, the disease or disorder is selected from the group consisting of autoimmune diseases. Autoimmune diseases comprise a group of diseases with a similar etiology of an overshooting immune response against endogenous targets resulting in chronic inflammation and physical disabilities or other severe symptoms. Autoimmune diseases comprise e.g. rheumatoid arthritis, ankylosing spondylitis, lupus erythematosus, psoriasis, atopic eczema, inflammatory bowel diseases such as Crohn^'s disease, asthma, multiple sclerosis, type 1 diabetes and amyotrophic lateral sclerosis.

Detailed description of the invention

The present invention provides a compound of Formula (1)

(1)

an enantiomer, diastereomer, tautomer, solvate or pharmaceutically acceptable salt thereof, wherein:

R¹ is hydrogen, C _-12-alkyl, C₂-i 2-alkenyl, C₂-i 2-alkynyl, C₃.i₀-cycloalkyl, C₃.i₀-heterocycloalkyl, a 5-10 membered mono- or bicyclic heteroaromatic ring system containing 1 , 2, 3 or 4 heteroatoms independently selected from N, O or S, or a 6-10 membered mono- or bicyclic aromatic ring system,

wherein said alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl groups are unsubstituted or substituted by 1 , 2 or 3 substituents independently selected from OH, oxo, halogen, halo-Ci.₆-alkyl, 0-Ci.₆-alkyl or CHhalo-^-e-alkyl),

wherein said heteroaromatic and aromatic ring systems are independently from each other unsubstituted or substituted by 1 , 2 or 3 substituents independently selected from OH, oxo, halogen, cyano, C_1-6-alkyl, C₃.₆-cycloalkyl, C₃.i₀-heterocycloalkyl, 0-Ci.₆-alkyl, a 5-10 membered mono- or bicyclic heteroaromatic ring system containing 1 , 2 or 3 heteroatoms independently selected from N, O or S, or a 6-10 membered mono- or bicyclic aromatic ring system,

wherein each of the Ci_-6-alkyl, C₃.₆-cycloalkyl, C₃.₁₀-heterocycloalkyl, O-C e-alkyl, the 5-10 membered mono- or bicyclic heteroaromatic ring system containing 1 , 2 or 3 heteroatoms independently selected from N, O or S, and the 6-10 membered mono- or bicyclic aromatic ring system is independently of one another unsubstituted or substituted by 1 , 2 or 3 substituents selected from OH, oxo, halogen, cyano, C_1-6-alkyl, halo-C_1-6-alkyl, O-C^-alkyl or 0-(halo-Ci.₆-alkyl); R² is a 5-10 membered mono- or bicyclic heteroaromatic ring system containing 1 , 2, 3 or 4 heteroatoms independently selected from N, O or S, or a 6-10 membered mono- or bicyclic aromatic ring system

wherein said heteroaromatic and aromatic ring systems are independently from each other unsubstituted or substituted by 1 , 2 or 3 substituents independently selected from oxo, halogen, cyano, Ci-₆-alkyl, halo-C_{M 2}-alkyl, C₃.₆-cycloalkyl, C₃.₆-heterocycloalkyl, C₀. e-alkylene-OR¹⁶, COOH, COO-(d.₆-alkyl), CO-N(R¹⁰)(R¹¹), SO₂-N(R¹⁰)(R¹¹), SO_y-(d.₆- alkyl), or SO_y-(halo-d-6-alkyl); or

wherein the heteroaromatic and the aromatic ring systems are fused with a saturated 5-8 membered carbocycle or a saturated 5-8 membered heterocycle containing 1 , 2 or 3 heteroatoms independently selected from N, O or S, and the fused ring system is unsubstituted or substituted by 1 , 2, 3 or 4 substituents independently selected from OH, oxo, halogen, cyano, Ci.₆-alkyl, halo-d-e-alkyl, C₃.₆-cycIoalkyl, C₃.₆-heterocycloalkyl, O- Ci.₆-alkyl or 0-(halo-Ci_-6-alkyl);

R¹⁰ is independently in each instance selected from H, d-10-alkyl, C₂.i₀-alkenyl, C₂-io-alkynyl, C₀-₆-alkylene-C₃.io-cycloalkyl, C₀-6-alkylene-C₃.i₀-heterocycloalkyl or C₀-6-alkylene-5-membered heteroaromatic ring system containing 1 , 2 or 3 heteroatoms independently selected from N, O or S, wherein said alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl and 5-membered heteroaromatic ring system are unsubstituted or substituted with 1 to 6 substituents independently selected from OH, oxo, CN, O-C^-alkyl, O-halo-d-e-alkyl, d-₆-alkyl, halogen, COOR⁷, CO-N(R⁷)₂, S0₂R⁷, S0₂N(R⁷)₂, NR⁷-CO-R⁷, NR⁷-S0₂-R⁷ or N(R⁷)₂;

R¹¹ is independently in each instance selected from H, d-e-alkyl, halo-d-e-alkyl or C₃.₆-cycloalkyl; or

R¹⁰ and R¹ when taken together with the nitrogen to which they are attached form a 3- to 8-membered ring containing carbon atoms and optionally containing 1 or 2 heteroatoms selected from O, S, S(O), S(0₂) or N(R⁷), wherein said ring is unsubstituted or substituted with one or more halogen, OH, oxo or d.₆-alkyl;

L is -(CR⁶ ₂)_X-, -(CR⁶ ₂)_X-NR⁷-, -(CR⁶ ₂)_x-0- or -(CR⁶ ₂)_x-0-(CR⁶ ₂)_x-;

R⁶ is independently in each instance H, F, d-e-alkyl, C₃-₆-cycloalkyl, halo-d-e-alkyl or halo-C₃_6-cycloalkyl;

R⁷ is independently in each instance H, C e-alkyl, C₃.₆-cycloalkyl, halo-Ci-₆-alkyl, halo-C₃. 6-cycloalkyl or hydroxy-C₂.₆-alkyl;

R¹², R ³ and R¹⁴ are independently of one another selected from H, F, d.₆-alkyl or halo-d-e- alkyl;

Y is selected from C or N; Z is selected from C or N; wherein at least one of Y and Z is C;

Ar together with Y and Z is a 5-6 membered monocyclic heteroaromatic ring system containing 1 , 2 or 3 heteroatoms independently selected from N, O or S, or a 6 membered monocyclic aromatic ring system

wherein said heteroaromatic and aromatic ring system is unsubstituted or substituted by 1 , 2 or 3 substituents independently selected from OH, halogen, halo-C -₆-alkyl, Chalky!, C₃-₆-cycloalkyl, 0-Ci.₆-alkyl or 0-(halo-Ci.₆-alkyl);

X is selected from -NR¹⁶-CO-, -C(R²²)(R²³)-C(R²²)(R¹⁷)-, -C(R² )(R²³)-(C=0)-, -(C=0)- C(R²²)(R¹⁷)-, -0-C(R²²)(R²³)-, -S(0)_y-C(R²²)(R¹⁷)- or -X¹(R¹⁸)-X²(R¹⁹)-,

X¹ is selected from C or N;

X² is selected from C or N;

R¹⁶ is independently in each instance selected from H, Ci_-6-alkyl or halo-d.₆-alkyl;

R¹⁷ is independently in each instance selected from H, OH, F, C_1-6-alkyl, C₃.₆-cycloalkyl, O-Ci-6-alkyl, 0-C₃.₆-cycloalkyl, halo-C_!-e-alkyl or O-halo-d-e-alkyl;

R¹⁸ and R¹⁹ together with X¹ and X² form a 5-membered ring containing 1 , 2 or 3 heteroatoms independently selected from N, O or S, said 5-membered ring being unsubstituted or substituted by 1 or 2 substituents independently selected from OH, oxo, halogen, CN, C_1-6-alkyl, halo-C_1-6-alkyl, C₃.₆-cycloalkyl, 0-Ci-₆-alkyl, 0-(halo-Ci.₆-alkyl), COOH, C0₂N(R¹⁶)₂ or N(R¹⁶)₂;

each of R²² and R²³ is independently of one another selected from H, F, Ci.₆-alkyl or halo-Ci-6-alkyl;

x is independently selected from 1 , 2, 3 or 4;

y is independently selected from 0, 1 or 2;

with the proviso that (a) when X is -0-CH₂- then R² is not 4-methylphenyl; and (b) when X is -O- CH₂- then L-R¹ is not CH₂NMe₂.

In a preferred embodiment in combination with any of the above or below embodiments, Ar together with Y and Z is a 6-membered aromatic or heteroaromatic ring system containing 1 or 2 nitrogen atoms, said heteroaromatic or aromatic ring system being unsubstituted or substituted by 1 , 2 or 3 substituents independently selected from OH, halogen, Ci.₆-alkyl, halo- d-e-alkyl, C₃.₆-cycloalkyl, O-d-e-alkyl or 0-(halo-d.₆-alkyl), more preferably being unsubstituted.

In another preferred embodiment in combination with any of the above or below embodiments, Ar together with Y and Z is a 5-membered heteroaromatic ring system containing 1 , 2 or 3 nitrogen atoms, in particular 2 or 3 nitrogen atoms, said heteroaromatic ring system being unsubstituted or substituted by 1 , 2 or 3 substituents independently selected from OH, halogen, d-e-alkyl, halo-d-e-alkyl, C₃.₆-cycloalkyl, O-C^-alkyl or 0-(halo-Ci.₆-alkyl). In another preferred embodiment in combination with any of the above or below embodiments, said heteroaromatic ring system is unsubstituted or substituted by 1 or 2 substituents independently selected from C_1-6-alkyl.

In a further preferred embodiment in combination with any of the above or below embodiments, Ar is selected from the group consisting of

more preferably Ar is selected from the group consisting of

even more preferabl

y Ar is .

In a preferred embodiment in combination with any of the above or below embodiments, R¹ is hydrogen, C _-12-alkyl, C₃.i₀-cycloalkyl, C_3-10-heterocycloalkyl, a 5-10 membered mono- or bicyclic heteroaromatic ring system containing 1 , 2, 3 or 4 heteroatoms independently selected from N, O or S, or a 6-10 membered mono- or bicyclic aromatic ring system,

wherein said alkyl, cycloalkyl and heterocycloalkyl groups are unsubstituted or substituted by 1 , 2 or 3 substituents independently selected from OH, oxo, halogen, halo-Ci-6-alkyl, O-d-e-alkyl or O-ihalo-d-e-alkyl),

wherein said heteroaromatic and aromatic ring systems are independently from each other unsubstituted or substituted by 1 , 2 or 3 substituents independently selected from OH, oxo, halogen, cyano, C_1-6-alkyl, C₃.₆-cycloalkyl, C₃.i₀-heterocycloalkyl, O-d-e-alkyl, a 5-10 membered mono- or bicyclic heteroaromatic ring system containing 1 , 2 or 3 heteroatoms independently selected from N, O or S, or a 6-10 membered mono- or bicyclic aromatic ring system, wherein each of the Ci.₆-alkyl, C₃.₆-cycloalkyl, C₃-io-heterocycloalkyl, 0-Ci-₆-alkyl, the 5-10 membered mono- or bicyclic heteroaromatic ring system containing 1 , 2 or 3 heteroatoms independently selected from N, O or S, and the 6-10 membered mono- or bicyclic aromatic ring system is independently of one another unsubstituted or substituted by 1 , 2 or 3 substituents selected from OH, oxo, halogen, cyano, Ci.₆-alkyl, halo-Ci.₆-alkyl, 0-Ci.₆-alkyl or O-ihalo-C e-alkyl);

L is -(CR⁶ ₂)_X-, -(CR⁶ ₂)_x-0- or -(CR⁶ ₂)_x-0-(CR⁶ ₂)_x-;

R⁶ is independently H, F or Ci.₆-alkyl; and

x is independently selected from 1 or 2.

In a preferred embodiment in combination with any of the above or below embodiments, R is hydrogen, d.^-alkyl, C₃-i₀-cycloalkyl, C₃.i₀-heterocycloalkyl, a 5-10 membered mono- or bicyclic heteroaromatic ring system containing 1 , 2, 3 or 4 heteroatoms independently selected from N, O or S, or a 6-10 membered mono- or bicyclic aromatic ring system,

wherein said alkyl, cycloalkyl and heterocycloalkyl groups are unsubstituted or substituted by 1 , 2 or 3 substituents independently selected from OH, oxo, halogen, halo-d-e-alkyl, 0-d.₆-alkyl or O-ihalo-C_!-e-alkyl),

wherein said heteroaromatic and aromatic ring systems are independently from each other unsubstituted or substituted by 1 , 2 or 3 substituents independently selected from OH, oxo, halogen, cyano, C_1-6-alkyl, C₃.₆-cycloalkyl, C₃.₁₀-heterocycloalkyl, 0-Ci-₆-alkyl, a 5-10 membered mono- or bicyclic heteroaromatic ring system containing 1 , 2 or 3 heteroatoms independently selected from N, O or S, or a 6-10 membered mono- or bicyclic aromatic ring system,

wherein each of the d-e-alkyl, C₃-6-cycloalkyl, C₃.₁₀-heterocycloalkyl, 0-Ci_₆-alkyl, the 5-10 membered mono- or bicyclic heteroaromatic ring system containing 1 , 2 or 3 heteroatoms independently selected from N, O or S, and the 6-10 membered mono- or bicyclic aromatic ring system is independently of one another unsubstituted or substituted by 1 , 2 or 3 substituents selected from OH, oxo, halogen, cyano, Ci.₆-alkyl, halo-Ci_₆-alkyl, O-d-e-alkyl or O-ihalo-C^-alkyl).

In another preferred embodiment in combination with any of the above or below embodiments, R¹ is hydrogen, C -₆-alkyl, C₃.₆-cycloalkyl, C₄.₈-heterocycloalkyl, a 5-10 membered mono- or bicyclic heteroaromatic ring system containing 1 , 2, or 3 heteroatoms independently selected from N or O, or a 6-10 membered mono- or bicyclic aromatic ring system,

wherein said alkyl, cycloalkyl and heterocycloalkyl groups are unsubstituted or substituted by 1 , 2 or 3 substituents independently selected from OH, oxo, halogen, halo-d-e-alkyl, 0-Ci-₆-alkyl or O-Chalo-C_t-e-alkyl), in particular unsubstituted, wherein said heteroaromatic and aromatic ring systems are independently from each other unsubstituted or substituted by 1 , 2 or 3 substituents independently selected from Ci-e-alkyl, 0-Ci-₆-alkyl or a 6-membered aromatic ring system, in particular unsubstituted, wherein each of the C_1-6-alkyl, O-d-e-alkyl, and the 6-membered mono- or bicyclic aromatic ring system is independently of one another unsubstituted or substituted by 1, 2 or 3 substituents selected from halogen, d-e-alkyl, halo-Ci.₆- alkyl, 0-Ci.₆-alkyl or 0-(halo-d-6-alkyl).

In another preferred embodiment in combination with any of the above or below embodiments, R¹ is hydrogen, Ci.₆-alkyl, C₅.₆-cycloalkyl, C₆-heterocycloalkyl, a 6-10 membered mono- or bicyclic aromatic ring system,

wherein said alkyl, cycloalkyl and heterocycloalkyl groups are unsubstituted or substituted by 1 , 2 or 3 substituents independently selected from OH, oxo, halogen, halo-Ci-e-alkyl, 0-Ci.₆-alkyl or 0-(halo-d.6-alkyl), in particular unsubstituted,

wherein said aromatic ring system is unsubstituted or substituted by 1 , 2 or 3 substituents independently selected from C_1-6-alkyl, 0-Ci.₆-alkyl or a 6-membered aromatic ring system, in particular unsubstituted,

wherein each of the Ci.₆-alkyl, 0-C_1-6-alkyl, and the 6-10 membered mono- or bicyclic aromatic ring system is independently of one another unsubstituted or substituted by 1 , 2 or 3 substituents selected from halogen, Ci-₆-alkyl, halo-Ci.₆- alkyl, 0-d.₆-alkyl or 0-(halo-Ci.₆-alkyl).

In another preferred embodiment in combination with any of the above or below embodiments, R¹ is hydrogen, C₃.₆-cycloalkyl, C₄.₈-heterocycloalkyl containing 1 or 2 heteroatoms independently selected from N and O, or a 6-membered monocyclic aromatic ring system which is unsubstituted or substituted by d.₆-alkyl or 0-Ci_-6-alkyl, said Ci-e-alkyl or 0-d.₆-alkyl being unsubstituted or substituted by 1 , 2 or 3 halogen atoms.

In a preferred embodiment in combination with any of the above or below embodiments, R² is a 5-10 membered mono- or bicyclic heteroaromatic ring system containing 1 , 2, 3 or 4 heteroatoms independently selected from N, O or S, or a 6 membered monocyclic aromatic ring system,

wherein said heteroaromatic and aromatic ring systems are independently from each other unsubstituted or substituted by 1 , 2 or 3 substituents independently selected from oxo, halogen, cyano, d.₆-alkyl, halo-Ci-i₂-alkyl, C₃.₆-cycloalkyl, C₃.₆-heterocycloalkyl, C₀. 6-alkylene-OR ⁶, COOH, COO-(Ci-e-alkyl), CO-N(R ⁰)(R¹¹), SO₂-N(R¹⁰)(R¹¹), SO_y-(d.₆- alkyl) or SO_y-(halo-d.₆-alkyl);

or the heteroaromatic and the aromatic ring systems are fused with a saturated 5-8 membered carbocycle or a saturated 5-8 membered heterocycle containing 1 , 2 or 3 heteroatoms independently selected from N, O or S, and the fused ring system is unsubstituted or substituted by 1 , 2, 3 or 4 substituents independently selected from OH, oxo, halogen, cyano, Ci_-6-alkyl, halo-^-e-alkyl, C₃-₆-cycloalkyl, C₃.₆-heterocycloalkyl, O- d-e-alkyl or 0-(halo-Ci.₆-alkyl).

In a further preferred embodiment in combination with any of the above and below embodiments, R² is a 5-10 membered mono- or bicyclic heteroaromatic ring system containing 1 , 2, 3 or 4 heteroatoms independently selected from N, O or S, or a 6 membered monocyclic aromatic ring system,

wherein said heteroaromatic and aromatic ring systems are independently from each other unsubstituted or substituted by 1 , 2 or 3 substituents independently selected from oxo, halogen, cyano, C_1-6-alkyl, halo-C^-alkyl, C₃-₆-cycloalkyl, C₃.₆-heterocycloalkyl, C₀. 6-alkylene-OR¹⁶, COOH, COO-(d-6-alkyl), CO-N(R¹⁰)(R¹¹), SO₂-N(R ⁰)(R¹¹), SO_y-(d-₆- alkyl), or SO_y-(halo-d-6-alkyl); or

wherein the heteroaromatic and the aromatic ring systems are fused with a saturated 5-8 membered carbocycle or a saturated 5-8 membered heterocycle containing 1 , 2 or 3 heteroatoms independently selected from N, O or S, and the fused ring system is unsubstituted or substituted by 1 , 2, 3 or 4 substituents independently selected from OH, oxo, halogen, cyano, C_1-6-alkyl, halo-d-e-alkyl, C₃.₆-cycloalkyl, C₃.₆-heterocycloalkyl, O- Ci-e-alkyl or 0-(halo-Ci.₆-alkyl).

In a further preferred embodiment in combination with any of the above and below embodiments, R² is a 5-10 membered mono- or bicyclic heteroaromatic ring system containing 1 , 2 or 3 heteroatoms independently selected from N or O, or a 6 membered monocyclic aromatic ring system,

wherein said heteroaromatic and aromatic ring systems are independently from each other unsubstituted or substituted by 1 , 2 or 3 substituents independently selected from halogen, cyano, C e-alkyl, halo-Ci-e-alkyl, C₃.₆-cycloalkyl, C₃-₆-heterocycloalkyl, C₀-₆- alkylene-OR¹⁶, COOH, COO-(d.₆-alkyl), CO-N(R ⁰)(R¹¹), SO₂-N(R ⁰)(R¹¹), SO_y-(d r alkyl), or SO_y-(halo-d.₆-alkyl); or

wherein the heteroaromatic and the aromatic ring systems are fused with a saturated 5-6 membered carbocycle or a saturated 5-6 membered heterocycle containing 1 , 2 or 3 heteroatoms independently selected from N or O, and the fused ring system is unsubstituted or substituted by 1 , 2 or 3 substituents independently selected from halogen, cyano, C e-alkyl, halo-d-₆-alkyl, C₃.₆-cycloalkyl, C₃.₆-heterocycloalkyl, O-d-e- alkyl or 0-(halo-d.₆-alkyl).

In another preferred embodiment in combination with any of the above and below embodiments, R² is a 6 membered heteroaromatic ring system containing 1 or 2 heteroatoms independently selected from N and O, a 9-10 membered bicyclic heteroaromatic ring system containing 1 or 2 heteroatoms independently selected from N and O, or a 6 membered aromatic ring system wherein said heteroaromatic and aromatic ring systems are independently from each other unsubstituted or substituted by 1 , 2 or 3 substituents independently selected from halogen, cyano, C_1-6-alkyl, halo-Ci-₆-alkyl, C₃.₆-cycloalkyl, C₃.₆-heterocycloalkyl, C₀-e- alkylene-OR ⁶, COOH, COO-(C^-alkyl), CO-N(R¹⁰)(R¹¹), SO₂-N(R¹⁰)(R¹¹), SO_y-(Ci-e- alkyl), or SO_y-Chalo-d-e-alkyl); or

wherein the heteroaromatic and the aromatic ring systems are fused with a saturated 5-6 membered carbocycle or a saturated 5-6 membered heterocycle containing 1 , 2 or 3 heteroatoms independently selected from N or O, and the fused ring system is unsubstituted or substituted by 1 , 2 or 3 substituents independently selected from halogen, cyano, C alkyl, halo-C_1-6-alkyl, C₃.₆-cycloalkyl, C₃.₆-heterocycloalkyl, 0-Ci-₆- alkyl or 0-(halo-Ci.₆-alkyl).

In another preferred embodiment in combination with any of the above and below embodiments, R² is a 6 membered aromatic ring system

wherein said aromatic ring system is substituted in ortho-position by a substituent selected from with Ci-3-alkyl, fluoro-C_1-3-alkyl, 0-C_1-3-alkyl or fluoro-Ci-₃-alkyl; and

wherein said aromatic ring system is optionally unsubstituted or substituted by 1 or 2 substituents independently selected from halogen, cyano, C_n-3-aikyl, halo-Ci.₃-alkyl, C₃.₄- cycloalkyl or C₀.₃-alkylene-OR¹⁶;

In yet another preferred embodiment in combination with any of the above and below embodiments, R² is selected from

In yet another preferred embodiment in combination with any of the above and below em

In a preferred embodiment in combination with any of the above or below embodiments, R² is not 4-methylphenyl. In another preferred embodiment in combination with any of the above or below embodiments, R² is not phenyl substituted by alkyl.

In a preferred embodiment in combination with any of the above or below embodiments, X is selected from -NR¹⁶-CO-, -C(R²²)(R²³)-C(R²²)(R¹⁷)-, -0-C(R²²)(R²³)- or -X (R¹⁸)-X²(R¹⁹)-, wherein R¹⁸ and R ⁹ together with the atoms to which they are connected form a 5-membered ring containing 1 , 2 or 3 heteroatoms independently selected from N, O or S, said 5-membered ring being unsubstituted or substituted by 1 or 2 substituents independently selected from OH, oxo, halogen, CN, Ci_-6-alkyl, halo-Ci.₆-alkyl, C₃.₆-cycloalkyl, 0-Ci.₆-alkyl, 0- (halo-d-e-alkyl), COOH, C0₂N(R¹⁶)₂ or N(R¹⁶)₂.

In another preferred embodiment in combination with any of the above or below embodiments, X is selected from -NR¹⁶-CO-, -C(R²²)(R²³)-C(R²²)(R¹⁷)-, -0-C(R²²)(R²³)- or -X (R¹⁸)-X²(R¹⁹)-, wherein R¹⁸ and R¹⁹ together with the atoms to which they are connected form a 5-membered ring containing 1 or 2 heteroatoms independently selected from N or O, said 5-membered ring being unsubstituted or substituted by 1 or 2 substituents independently selected from halogen, CN, Ci.₆-alkyl, halo-d-e-alkyl, O-C^-alkyl, 0-(halo-Ci.₆-alkyl), C0₂N(R¹⁶)₂ or N(R¹⁶)₂.

In a preferred embodiment in combination with any of the above or below embodiments, X is selected from the group consisting of -NH-CO-, -NMe-CO-, -CH₂CH₂-, -OCH₂-, -SCH₂-, - S0₂CH₂-, -CH -, -CH₂CHOMe-, -CH₂(C=0)-,

In a preferred embodiment in combination with any of the above or below embodiments, R¹² is selected from H, F, d-e-alkyl or halo-Ci.₆-alkyl, more preferably from H or Ci.₃-alkyl, in particular H or methyl.

In a preferred embodiment in combination with any of the above or below embodiments, R¹³ is selected from H, F, C^-alkyl or halo-d-e-alkyl, more preferably from H or C_1-3-alkyl, in particular H or methyl.

In a preferred embodiment in combination with any of the above or below embodiments, R¹⁴ is selected from H, F, Ci.₆-alkyl or halo-Ci.₆-alkyl, more preferably from H or Ci.₃-alkyl, in particular H or methyl.

In another preferred embodiment in combination with any of the above or below embodiments, one or R¹³ and R ⁴ is hydrogen and the other of R¹³ and R ⁴ is C_1-3-alkyl.

In another preferred embodiment in combination with any of the above or below embodiments, each of R¹², R¹³ and R¹⁴ is hydrogen.

In a preferred embodiment in combination with any of the above or below embodiments, R²² is selected from H, F, Ci_₆-alkyl or halo-d-e-alkyl, more preferably from H or C _-3-alkyl, in particular H or methyl. In a preferred embodiment in combination with any of the above or below embodiments, R is selected from H, F, C_1-6-alkyl or halo-Ci.₆-alkyl, more preferably from H or C^-alkyl, in particular H or methyl.

In a further embodiment in combination with any of the above and below embodiments, L is - (CR⁶ ₂)_X-, -(CR⁶ ₂)_x-0- or -(CR⁶ ₂)_x-0-(CR⁶ ₂)_x-.

In a preferred embodiment in combination with any of the above or below embodiments, L-R¹ is selected from the group consisting of

In another preferred embodiment in combination with any of the above and below embodiments, R⁶ is independently in each instance H, F, OH, C_1-6-alkyl, C₃.₆-cycloalkyl, halo-C^-alkyl or halo- C₃.₆-cycloalkyl, or two R⁶ at the same carbon atom to which they are attached together are oxo, more preferably H.

In another preferred embodiment in combination with any of the above and below embodiments, R⁷ is independently in each instance H, C _-6-alkyl, C₃.₆-cycloalkyl, halo-Ci.₆-alkyl, halo-C₃.₆- cycloalkyl or hydroxy-C₂.₆-alkyl, more preferably H or C₁.₆-alkyl.

In another preferred embodiment in combination with any of the above and below embodiments, R¹⁰ is selected from H, Ci-i₀-alkyl, C₂-i₀-alkenyl, C₂.₁₀-alkynyl, C₀-₆-alkylene-C₃.i₀-cycloalkyl, C₀-₆- alkylene-C₃_io-heterocycloalkyl or C₀-₆-alkylene-5-membered heteroaromatic ring system containing 1 , 2 or 3 heteroatoms independently selected from N, O or S, wherein said alkyl, alkylene, alkenyl, alkynyl, cycloalkyi, heterocycloalkyi and 5-membered heteroaromatic ring system are unsubstituted or substituted with 1 to 6 substituents independently selected from OH, oxo, CN, O-d-e-alkyl, 0-halo-Ci.₆-alkyl, Ci_-6-alkyl, halogen, COOR⁷, CO-N(R⁷)₂, S0₂R⁷, S0₂N(R⁷)₂, NR⁷-C0-R⁷, NR⁷-S0₂-R⁷ or N(R⁷)₂; more preferably R ⁰ is selected from H, C_M0- alkyl, C₂.₁₀-alkenyl, C₂.i₀-alkynyl, Co-₆-alkylene-C₃-₁₀-cycloalkyl or C₀-₆-alkylene-C₃-₁₀- heterocycloalkyl, wherein said alkyl, alkylene, alkenyl, alkynyl, cycloalkyi and heterocycloalkyi are unsubstituted or substituted with 1 to 3 substituents independently selected from OH, O-C1. ₆-alkyl, O-halo-C_!-e-alkyl, Ci_-6-alkyl, or halogen.

In another preferred embodiment in combination with any of the above and below embodiments, R¹¹ is independently selected from H, d-₆-alkyl, halo-Ci.₆-alkyl or C₃.₆-cycloalkyl, more preferably H or Ci.₆-alkyl. In another preferred embodiment in combination with any of the above and below embodiments, R ⁰ and R¹¹ when taken together with the nitrogen to which they are attached form a 3- to 8- membered ring containing carbon atoms and optionally containing 1 or 2 heteroatoms selected from O, S, S(O), S(0)₂ or N(R⁷), wherein said ring is unsubstituted or substituted with one or more halogen, OH, oxo or C_1-6-alkyl.

In another preferred embodiment in combination with any of the above and below embodiments each R¹⁶ is independently in each instance selected from H, C_1-6-alkyl or halo-Ci.₆-alkyl, more preferably from H, d-4-alkyl or fluoro-C^-alkyl.

In another preferred embodiment in combination with any of the above and below embodiments, each R¹⁷ is independently in each instance selected from H, OH, F, C_1-6-alkyl, C₃.₆-cycloalkyl, O- Ci-e-alkyl, 0-C₃.₆-cycloalkyl, halo-C₁.₆-alkyl or 0-halo-Ci_-6-alkyl, more preferably H or Ci.₄-alkyl.

In another preferred embodiment in combination with any of the above and below embodiments, R¹⁸ and R¹⁹ together with X¹ and X² form a 5-membered ring containing 1 , 2 or 3 heteroatoms independently selected from N, O or S, said 5-membered ring being unsubstituted or substituted by 1 or 2 substituents independently selected from OH, oxo, halogen, CN, d-e-alkyl, halo-Ci_-6- alkyl, C₃.₆-cycloalkyl, O-d-e-alkyl, O-(halo-Ci-e-alkyl), COOH, C0₂N(R¹⁶)₂ or N(R¹⁶)₂, more preferably R¹⁸ and R ⁹ together with X¹ and X² form a 5-membered ring containing 1 or 2 heteroatoms independently selected from N or O, said 5-membered ring being unsubstituted or substituted by 1 or 2 substituents independently selected from halogen, CN, C_1-6-alkyl, halo-Ci- 6-alkyl or C0₂N(R¹⁶)₂, even more preferably R¹⁸ and R¹⁹ together with X¹ and X² form a 5- membered ring containing 2 N atoms, said 5-membered ring being unsubstituted or substituted by 1 or 2 substituents independently selected from halogen, CN or C0₂N(R¹⁶)₂.

In another preferred embodiment in combination with any of the above and below embodiments, x is independently selected from 1 , 2, 3 or 4, in particular 1 or 2.

In another preferred embodiment in combination with any of the above and below embodiments, y is independently selected from 0, 1 or 2.

In a preferred embodiment in combination with any of the above or below embodiments, the compound is selected from the group consisting of

and the enantiomers, diastereomers, tautomers, solvates and pharmaceutically acceptable salts thereof.

The invention also provides the compound of the invention for use as a medicament.

Also provided is the compound of the invention for use in the treatment of diseases or disorders which are Th17 mediated tissue inflammation or of autoimmune etiology or which are a skin disease with associated symptoms such as pain, itching or excoriations. Preferred diseases or disorders are rheumatoid arthritis, ankylosing spondylitis, lupus erythematosus, psoriasis, atopic eczema, inflammatory bowel diseases such as Crohn^'s disease or ulcerative colitis, asthma, multiple sclerosis, type 1 diabetes and amyotrophic lateral sclerosis.

The invention further relates to the compound of the invention for use in the treatment or prophylaxis of a disease or disorder associated with the inhibition or activation of the RORy receptor.

Also provided is a pharmaceutical composition comprising the compound of the invention and a pharmaceutically acceptable carrier.

In the context of the present invention d-12-alkyl means a saturated alkyl chain having 1 to 12 carbon atoms, i.e, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms, which may be straight chained or branched. Examples of Ci.₁₂-alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl and dodecyl.

The term "halo-C^-alkyl" means that one or more hydrogen atoms in the alkyl chain are replaced by a halogen. Preferably, halo-C^-alkyl is selected from CF₃, CH₂CF₃ or CH₂CH₂F.

C₂_i₂-alkenyl means an alkyl chain having 2 to 12 carbon atoms, i.e, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms, which may be straight chained or branched, containing at least one carbon to carbon double bond. Examples thereof include ethenyl, propenyl, dodecenyl, 2- methylenehexyl and (2E,4£)-hexa-2,4-dienyl. C₂-i₂-alkynyl means an alkyl chain having 2 to 12, i.e. 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms, carbon atoms which may be straight chained or branched, containing at least one carbon to carbon triple bond. Examples thereof include ethynyl, propynyl and dodecynyl.

A "Co-e-alkylene" means that the respective group is divalent and connects the attached residue with the remaining part of the molecule. Moreover, in the context of the present invention, "C₀- alkylene" is meant to represent a bond.

A C₃.io-cycloalkyl group means a saturated mono-, bi- or multicyclic ring system comprising 3 to 10 carbon atoms, i.e, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.2]octyl, bicyclo[2.2.1]heptyl, pentacyclo[4.2.0.0²'⁵.0³⁸.0⁴'⁷]octyl and adamantyl.

A C₃.io-heterocycloalkyl group means a saturated or partially unsaturated 3, 4, 5, 6, 7, 8, 9 or 10 membered carbon mono-, bi- or multicyclic ring wherein 1 , 2 or 3 carbon atoms are replaced by 1 , 2 or 3 heteroatoms, respectively, said heteroatoms being independently selected from N, O and S. When the C₃.₁₀-heterocycloalkyl is substituted, the substitution can be at the carbon atoms of the cycle or at the nitrogen or sulfur heteroatom(s) of the cycle. Examples of the substituted S or N atom are SO, S0₂ or N-Ci-₆-alkyl. Examples of the C₃.i₀-heterocycloalkyl include epoxidyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, ,4-dioxanyl, morpholinyl, 4-quinuclidinyl, 1 ,4-dihydropyridinyl and 3,6- dihydro-2H-thiopyranyl.

A 5-10 membered mono- or bicyclic heteroaromatic ring system containing up to 4 heteroatoms means a monocyclic heteroaromatic ring (such as pyrrolyl, imidazolyl, furanyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrazolyl, oxazolyl, isoxazolyl, triazolyl, oxadiazolyl and thiadiazolyl), or a bicyclic ring system wherein the heteroatom(s) may be present in one or both rings including the bridgehead atoms, respectively. Examples of a bicyclic heteroaromatic ring system include quinolinyl, isoquinolinyl, quinoxalinyl, benzimidazolyl, benzisoxazolyl, benzodioxanyl, benzofuranyl, benzoxazolyl, indolyl, indolizinyl and pyrazolo[1 ,5-a]pyrimidinyl.

A 6-10 membered mono- or bicyclic aromatic ring system means an aromatic carbon cycle containing 6, 7, 8, 9 or 10 carbon atoms. Examples thereof are phenyl or naphthalenyl.

Halogen is selected from fluorine, chlorine, bromine and iodine.

The compounds of the present invention are optical isomers. The stereoisomer of Formula (V) with the following structure is preferred:

(1^*) Furthermore, the compounds of the present invention are partly subject to tautomerism. For example, if a heteroaromatic group containing a nitrogen atom in the ring is substituted with a hydroxy group on the carbon atom adjacent to the nitrogen atom, the following tautomerism can appear:

When a substitution of a residue with C₃.i₀-cycloalkyl or C₃.i₀-heterocycloalkyl is described, it is understood that the substitution can be connected straight and, when the connecting carbon atom is sp³-hybridized, in addition spirocyclic. For example, when cyclohexane is substitued with the heterocycloalkyl group o s are possible:

The compounds of the present invention can be in the form of a pharmaceutically acceptable salt or a solvate. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids, including inorganic bases or acids and organic bases or acids. In case the compounds of the present invention contain one or more acidic or basic groups, the invention also comprises their corresponding pharmaceutically or toxicologically acceptable salts, in particular their pharmaceutically utilizable salts. Thus, the compounds of the present invention which contain acidic groups can be used according to the invention, for example, as alkali metal salts, alkaline earth metal salts or ammonium salts. More precise examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts or salts with ammonia or organic amines such as, for example, ethylamine, ethanolamine, triethanolamine or amino acids. The compounds of the present invention which contain one or more basic groups, i.e. groups which can be protonated, can be used according to the invention in the form of their addition salts with inorganic or organic acids. Examples of suitable acids include hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acids, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfaminic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, and other acids known to the person skilled in the art. If the compounds of the present invention simultaneously contain acidic and basic groups in the molecule, the invention also includes, in addition to the salt forms mentioned, inner salts or betaines (zwitterions). The respective salts can be obtained by customary methods which are known to the person skilled in the art like, for example, by contacting these with an organic or inorganic acid or base in a solvent or dispersant, or by anion exchange or cation exchange with other salts.

In practical use, the compounds of the present invention can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). In preparing the compositions for oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, hard and soft capsules and tablets, with the solid oral preparations being preferred over the liquid preparations.

Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated by standard aqueous or non-aqueous techniques. Such compositions and preparations should contain at least 0.1 percent of active compound. The percentage of active compound in these compositions may, of course, be varied and may conveniently be between about 2 percent to about 60 percent of the weight of the unit. The amount of active compound in such therapeutically useful compositions is such that an effective dosage will be obtained. The active compounds can also be administered intranasally as, for example, liquid drops or spray.

The tablets, pills, capsules, and the like may also contain a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin. When a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.

Various other materials may be present as coatings or to modify the physical form of the dosage unit. For instance, tablets may be coated with shellac, sugar or both. A syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor.

The compounds of the present invention may also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxy-propylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

Any suitable route of administration may be employed for providing a mammal, especially a human, with an effective dose of a compound of the present invention. For example, oral, rectal, topical, parenteral (including intravenous), ocular, pulmonary, nasal, and the like may be employed. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like. Preferably compounds of the present invention are administered orally.

The effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration, the condition being treated and the severity of the condition being treated. Such dosage may be ascertained readily by a person skilled in the art.

When treating or preventing RORy-mediated conditions with the compounds of Formula (1), generally satisfactory results are obtained when the compounds are administered at a daily dosage of from about 0.1 milligram to about 100 milligram per kilogram of mammal body weight, preferably given as a single daily dose or in divided doses two to six times a day, or in sustained release form. For most large mammals, the total daily dosage is from about 1.0 milligram to about 1000 milligrams, preferably from about 1 milligram to about 50 milligrams. In the case of a 70 kg adult human, the total daily dose will generally be from about 7 milligrams to about 350 milligrams. This dosage regimen may be adjusted to provide the optimal therapeutic response.

The present invention describes modulators, in the following also referred to as ligands, which bind to the RORy receptor. Surprisingly, it has been found that compounds of Formula (1) act as modulators of the RORy receptor.

The RORy receptor is considered to be involved in thymocyte development, thus the modulators described herein may be useful in the treatment of inflammatory skin diseases such as atopic eczema and psoriasis. It is further suggested that down-modulation of RORy transcriptional activity with a ligand could result in a shift of the immune response towards a Th2 type response which could be beneficial in the treatment of certain allergic inflammatory conditions such as rheumatoid arthritis, systemic lupus erythomatosis, inflammatory bowel disease (Crohn^'s Disease) and multiple sclerosis (Tesmer et. al., Immunol. Rev. 2008, 223:97). The compounds of Formula (1) show antagonistic activity, with respect to the dose dependent modulation of the constitutive interaction of the RORy ligand binding domain with peptides derived from the co-activators such as SRC-1 , TRAP 220 or TIF-2.

It has been surprisingly found that the interaction between RORy ligand binding domain and the peptides can be determined by a homogenous FRET based ligand-sensing assays. Even more surprising was the identification of compounds of Formula (1) as ligands for RORy.

The identification of high affinity ligands for RORy with agonistic and antagonistic properties is the basis to enable experts knowledgeable in the field to establish assays for the identification of novel agonistic and antagonistic RORy ligands from libraries of small molecules. The identification of ligands which bind to and modulate the activity of RORyl and RORy2 is the first mandatory step to develop new small molecule based medicines with a potential to be developed for the treatment of diseases which are directly or indirectly controlled by the activity of RORyl or RORy2. Such diseases include but are not restricted to inflammatory diseases, asthma, rheumatoid arthritis, autoimmune diseases or diseases with an autoimmune component such as systemic lupus erythomatosis, inflammatory bowel disease (Crohn^'s disease), ulcerative colitis, inflammatory skin diseases such as atopic eczema or psoriasis, multiple sclerosis or similar diseases.

The compounds of the present invention can be prepared by a combination of methods known in the art including the procedures described in Schemes I to X below. Oxazepines with a free secondary amino function and the general structure as shown in Scheme I can be transformed into sulfonamides by reaction with sulfonyl chlorides in the presence of suitable base and solvent.

Scheme I

Compounds of the present invention belonging to the class of 1 ,4-diazepin-2-ones can be prepared as shown in Scheme II. Substituted aromatic aldehydes or carbonyl compounds which bear a nitro group or a protected amino group in the 2-position are reacted with amino esters under reductive conditions as shown in Scheme II. A subsequent conversion of the nitro group or the protected amino group into a primary amino group promotes the cyciization to annulated 1 ,4-diazepin-2-ones under basic conditions. The free secondary amino group of the diazepinone core can be transformed into sulfonamides by reaction with sulfonyl chlorides in the presence of a suitable base and solvent. The lactam amide bond can be alkylated by standard methods. Scheme II

The lactam amide bond of the 1 ,4-diazepin-2-ones of the compounds of the present invention can be transformed into 5-membered heterocycles as shown in Schemes III. Transformation of the lactam into a thiolactam by use of Lawesson's reagent and subsequent treatment with acylhydrazides affords annulated 2-substituted triazoles. Alternatively the thiolactam can be S- alkylated and heated with 2,2-dimethoxyethanamine. The resulting amidine can be treated with acid to afford annulated imidazoles. The methyl iminothioester can be oxidized to a methyl sulfone functionality in order to facilitate the reaction with 2,2-dimethoxyethanamine or other reagents.

Scheme III

As shown in Scheme IV, for the purpose of late stage diversification in the synthesis the 4- amino group of the 1 ,4-diazepin-2-ones can be protected e.g. as a Boc-group, which can be cleaved of after the formation of the annulated 5-membered heterocycles. Again, the free secondary amino group of the diazepinone core can be transformed into sulfonamides by reaction with sulfonyl chlorides in the presence of a suitable base and solvent.

Scheme IV

The class of annulated 2-azepines with a 4-subsituent of the present invention can be prepared as depicted in Scheme V. Ortho methyl-substituted aromatic carboxylic acids or oxazolidines can be reacted with /V-protected 2-amino aldehydes under strongly basic conditions at low temperature to afford annulated 6-membered lactones I or the corresponding hydroxy-carboxylic acids la, similar as described in J. Chem. Soc, Chem. Commun. 1991 , 708. After amino- deprotection the lactones can isomerize under basic conditions to 4-hydroxy-2,3,4,5-tetrahydro- 1 H-benzo[c]azepin-1-ones (II). After reduction of the lactam to a secondary amine (III), sulfonamides can be obatined by reaction with sulfonyl chlorides. The free hydroxyl group can be alkylated or oxidized to the ketone by standard methods.

Sche

As shown in Scheme VI, for the purpose of late stage diversification, the /V-protected 4-hydroxy- 2,3,4,5-tetrahydro-1 H-benzo[c7azepin-1-ones (II) can be first alkylated, then reduced to the amine and the protecting group removed. Finally, the free secondary amino group can be transformed into sulfonamides by reaction with sulfonyl chlorides.

R = alkyl, haloalkyl or cycloalkyl

Compounds of the present invention that are 1 ,4-diazepines wherein Ar is a [1 ,2]-annulated 5- membered heteroaromatic ring can be prepared as shown in Scheme VII. A substituted 3-amino carboxylic acid can be converted to the corresponding nitrile by a reaction sequence of N- protection, primary amide formation and dehydratisation. After N-deprotection the amine can be sulfonylated using sulfonyl chloride and base followed by /V-alkylation with a 2-bromo carboxylic acid ester. Reduction of the nitrile followed by amine protection, ester saponification and amine deprotection gives an intermediate that can be cyclised by lactamisation using amide coupling reagents. The lactam is converted to a thiolactam using Lawesson^'s reagent which can be converted into an annulated 5-membered heteroaromatic ring using suitable reagents.

Scheme VII

1. deprotection

R¹-L 2. R²S0₂CI, TEA

Compounds of the present invention that are azepines can be prepared as shown in Scheme VIII. A substituted aldehyde can be reacted with litiated trimethylsilyl acetylene followed by treatment with sodium carbonate and subsequent Sonogashira coupling to give the coressponding alkyne intermediate which can be completely hygrogenated using a Pd catalyst. The hydroxy group can be converted to an amine by a sequence of mesylation, azide formation and reduction. Amine protection is followed by ester reduction, transformation of the alcohol to a bromide and amine deprotection. Treatment of this intermediate with a suitable base like potassium carbonate leads to the corresponding azepine that can be sulfonylated.

Scheme VIII

1 ,4-Thiazepines and its corresponding 1 ,1 -dioxides (sulfones) that are compounds of the present invention can be prepared as shown in Scheme IX. A 2-mercaptobenzoic acid is converted to the ester followed by S-alkylation with a suitable, /V-protected 2-amino-1-bromo derivative obtained from an amino alkohol through /V-protection and halogenation. The resulting thioether is saponified and A/-deprotected to give an amino carboxylic acid intermediate that can be lactamised using amide coupling reagents. Reduction leads to the 1 ,4-thiazepine derivative that can be sulfonylated. Alternatively a reaction sequence of AAprotection, sulfide oxidation, deprotection and sulfonylation leads to the corresponding 1 ,1 -dioxides.

Scheme IX

R1-^L

For the purpose of late stage diversification 1 ,4-oxazepines can be prepared by derivatisation of a 3-hydroxymethylene scaffold IV as shown in Scheme X: A suitable protected serine derivative is reduced to the alcohol followed by Mitsunobu reaction with a 2-hydroxy aryl carboxylic acid ester. Reduction of the ester to the benzylic alcohol and conversion to bromide is followed by ΛΑ deprotection and cyclisation using a suitable base like potassium carbonate. O-deprotection leads to the hydroxy compound IV, which can be further derivatised by O-alkylation or mesylation followed by nucleophilic subsitution with an amine and a suitable base.

Scheme X

r^eaCti0n NHPg _NHPg

The compounds described in the present invention are usually single enantiomers, however racemates can be prepared as well. The stereoisomer of Formula (1") with the following structure usually shows a higher biological activity:

(1')

In the following examples the abbreviations listed above and below are used:

ACN acetonitrile

Bn benzyl

Boc ferf-butyloxycarbonyl

Cbz carboxybenzyloxy

CC column chromatography (on silica gel)

DCM dichloromethane

DMF dimethylformamide

EA ethyl acetate

MOM Methoxymethyl ether

Ms mesyl

PE petroleum ether

rt room temperature

TEA triethylamine

TFA trifluoro acetic acid

THF tetrahydrofuran TLC thin layer chromatography

Ts tosyl

Examples

Example 1

Step 1: 3-Benzyl-4-(2-methoxyphenylsulfonvn-2,3,4,5-tetrahvdrobenzorflri,41oxazepine (1)

To a solution of 3-benzyl-2,3,4,5-tetrahydrobenzo[ [1,4]oxazepine (50 mg, 0.21 mmol; obtained according J. Comb. Chem.2007, 9:321) and 2-methoxybenzene-1-sulfonyl chloride (86 mg, 0.42 mmol) in dry DCM (1 mL) was added Et₃N (0.28 mL, 2.0 mmol). The mixture was stirred at rt for 4 h, then diluted with water (10 mL) and extracted with DCM (2x 10 mL). The combined organic phases were washed sequentially with sat. aq. NaHC0₃ (2x 10 mL) and brine (2x 10 mL) and dried over anhydrous Na₂S0₄. Concentration and purification by CC gave compound 1 (62 mg, 72%) as a white solid.¹H-NMR (400 MHz, DMSO-d₆) δ: 2.90-2.85 (m, 1H), 3.25-3.16 (m, 1H), 3.71 (s, 3H), 4.00-3.89 (m, 1H), 4.20-4.13 (m, 1H), 4.50-4.39 (m, 1H), 4.54 (d, J = 16.0 Hz, 1H), 4.69 (d, J = 16.0 Hz, 1H), 7.35-6.74 (m, 10H), 7.39 (t, J = 7.6 Hz, 1H), 7.87 (d, J = 7.6 Hz, 1H). MS Found: 410.5 (M+1).

Examples 1/1 to 1/2

The following Examples were prepared similar as described in Example 1:

# Structure Analytical data

H-NMR (400 MHz, DMSO-d₆) δ: 8.98 (s, 1H), 8.38 (d, J = 7.6 Hz, 1H), 8.25-8.15 (m, 2H), 7.70-7.51 (m, 2H), 7.35-6.75

1/1 (m, 9H), 5.10 (d, J = 16.0 Hz, 1H), 4.80-4.65 (m, 2H), 4.30- 4.21 (m, 1H), 3.90-3.80 (m, 1H), 2.95-2.86 (m, 1H), 2.80- 2.74 (m, 1H). MS Found: 431.3 (M+1).

H-NMR (400 MHz, CDCI₃) δ: 7.98 (d, J = 7.6 Hz, 1H), 7.40- 6.86 (m, 12H), 4.75 (d, J = 16.0 Hz, 1H), 4.62 (d, J = 16.0

1/2 Hz, 1H), 4.25-4.17 (m, 2H), 4.00-3.93 (m, 1H), 3.25-3.17 (m,

1H), 2.93-2.85 (m, 1H). MS Found: 414.2 (M+1).

Example 2 and 3

Step 1 : (fl)-Methyl 2-(2-nitrobenzylamino)-3-phenylpropanoate (2a)

To a suspension of 2-nitrobenzaldehyde (5.0 g, 33 mmol) and (f?)-1-methoxy-1-oxo-3- phenylpropan-2-ammonium chloride (5.9 g, 33 mmol) in /V-methyl-2-pyrrolidone (100 mL) was added AcOH (0.2 mL) at rt and the mixture was stirred at rt for 1 h. To this mixture was added NaBH(OAc)₃ (10.6 g, 50 mmol) at rt and the mixture was stirred overnight at rt. The mixture was diluted with EA and quenched with 1 N NaOH (280 mL). The organic layer was washed with brine twice, dried over MgS0₄, filtered and concentrated in vacuo. The product was purified by CC (eluent: PE/EA = 10/1) to give compound 2a (6.7 g, 65%) as a white solid.

Step 2: (ff)-3-Benzyl-4,5-dihvdro-1 H-benzofeiri .41diazeoin-2(3/-/)-one (2b)

A solution of compound 2a (1.57 g, 5 mmol) in 50 mL of AcOH was stirred at 50°C for 1 h. Fe powder (0.7 g, 12.5 mmol) was added and the solution was refluxed at 110°C for 30 min. The mixture was filtered through celite, washed with AcOH (3 x 30 mL) and the solution was concentrated under reduced pressure. The crude product was diluted with EA. The solution was washed with brine twice, dried over MgS0_4, concentrated in vacuo and purified by CC (PE/EA = 2/1) to give compound 2b (0.5 g, 40%) as a solid.

Step 3: (fl)-3-Benzyl-4-(quinolin-8-ylsulfonyl)-4,5-dihvdro-1 H-benzoiein ,41diazepin-2(3H)-one

To a solution of compound 2b (478 mg, 1.9 mmol) in dry pyridine (20 mL) was added quinoline- 8-sulfonyl chloride (520 mg, 2.28 mmol) and the solution was heated under microwave irradiation at 100°C for 2 h. The mixture was concentrated under reduced pressure and purified by CC (PE/EA = 3/1) to give the title compound 2 (0.5 g, 59%) as a white solid.¹ H-NMR (CDCI₃, 400 MHz): 3.44-3.46 (m, 1H), 3.60-3.62 (m, 1 H), 4.08 (d, J = 16.4 Hz, 1H), 4.56 (d, J = 16.0 Hz, 1 H), 6.01-6.03 (m, 1H), 6.16 (t, 1H), 6.49-6.51 (m, 1 H), 6.61-6.70 (m, 2H), 7.25-7.27 (m, 1 H), 7.31-7.41 (m, 3H), 7.42-7.46 (m, 4H), 7.76 (d, J = 8.0 Hz, 1 H), 8.02 (d, J = 8.0 Hz, 1 H), 8.25 (d, J = 7.2 Hz, 1H), 8.95 (d, J = 3.2 Hz, 1H). MS Found: 444 (M+1).

Step 4: (R)-3-Benzyl-1-methyl-4-(auinolin-8-ylsulfonyl)-4.5-dihvdro-1 H-benzofelH ,41diazepin- 2(3H)-one (3)

To a solution of compound 2 (100 mg, 0.23 mmol) in dry THF (5 mL) was added NaH (11 mg, 0.25 mmol) and the solution was stirred at 0°C for 30 min. Then a solution of Mel (64 mg, 0.45 mmol) in anhydrous THF (1 mL) was added and the mixture was stirred overnight at rt. Water was added and the mixture was extracted with EA. The organic layer was washed with brine, dried over MgS0₄, concentrated in vacuo and purified by CC (PE/EA = 2/1) to give the title compound 3 (45 mg, 43%) as a white solid. H-NMR (CDCI₃₎ 400 MHz): 2.08-2.17 (m, 1H), 2.98- 3.03 (m, 1 H), 3.16 (s, 3H), 4.43 (d, J = 12.8 Hz, 1 H), 5.07 (d, J = 12.8 Hz, 1H), 5.21-5.26 (m, 1H), 6.98-6.70 (m, 2H), 7.15-7.26 (m, 4H), 7.32-7.36 (m, 1 H), 7.51-7.60 (m, 3H), 7.65-7.69 (m, 1H), 8.07 (d, J = 8.0 Hz, 1H), 8.26 (d, J = 6.8 Hz, 1H), 8.59 (d, J = 6.4 Hz, 1 H), 9.13-9.14 (m, 1 H-). MS Found: 458 (M+1).

Example 4

Step 1 : Methyl 2-(((benzyloxy)carbonyl)amino)-3-(methoxymethoxy)propanoate (4a)

To a solution of methyl 2-(benzyloxycarbonylamino)-3-hydroxypropanoate (90 g, 360 mmol) in dry DCM (500 mL) was added diisopropylethylamine (92 g, 530 mmol) at 0°C under N₂ atmosphere and the mixture was stirred at 0°C for 30 min. Then MeOCH₂CI (40 mL, 530 mmol) was added and the solution was heated at reflux overnight. The mixture was concentrated under reduced pressure and to the residue was added water. The mixture was extracted twice with diethyl ether. The combined organic layers were washed with water three times and brine consecutively, dried over Na₂S0₄, filtered, concentrated under reduced pressure and purified by CC (DCM/PE = 1/10) to give compound 4a (50 g, 47%) as a white solid.

Step 2: Methyl 2-amino-3-(methoxymethoxy)propanoate (4b)

A solution of compound 4a (50 g, 160 mmol) and Pd/C (5.0 g) in MeOH (500 mL) under H₂ (0.35 MPa) was stirred at 40°C overnight. The mixture was filtered and concentrated under reduced pressure to give compound 4b (30 g, 97%) as a white solid.

Step 3: Methyl 3-(methoxymethoxy)-2-(2-nitrobenzylamino)propanoate (4c)

A mixture of compound 4b (22 g, 130 mmol) and 2-nitrobenzaldehyde (20 g, 130 mmol) in DCM (200 mL) was added AcOH (1 mL) under N₂ atmosphere. The solution was stirred at rt for 1.5 h and NaBH(OAc)₃ (57 g, 260 mmol) was added. The suspension was stirred at rt overnight. Water was added and the solution was extracted with DCM. The organic layer was washed with brine, dried over NaS0₄, filtered and concentrated under reduced pressure. The product was purified by CC (PE/EA = 2/1) to afford compound 4c (35 g, 88%) as a colorless oil.

Step 4: 3-((Methoxymethoxy)methyl)-4.5-dihvdro- H-benzofe1f1,41diazepin-2(3 - )-one (4d)

A solution of compound 4c (35 g, 0.12 mol) in AcOH (1000 mL) was heated at 55°C for 30 min and Fe power (16.4 g, 0.29 mol) was slowly added. The mixture was heated at 110°C for 1 h. The suspension was filtered and the filtered solution was concentrated under reduced pressure. The crude product was purified by CC (PE/EA = 1/1) to give compound 4d (8.0 g, 30%) as a solid.

Step 5: 3-((Methoxymethoxy)methyl)-4-(2-(trifluoromethoxy)phenylsulfonyl)-4,5-dihvdro-1 H- benzofein ,41diazepin-2(3/- )-one (4e)

A solution of compound 4d (8.0 g, 34.1 mmol) and 2-(trifluoromethoxy)benzene-1 -sulfonyl chloride (13.2 g, 50.8 mmol) in pyridine (20 mL) was stirred at 85°C under microwave irradiation for 1.5 h. The reaction mixture was concentrated and the residue was purified by CC (PE/EA = 1/1) to give compound 4e (5.0 g, 32%) as a yellow solid.

Step 6: 3-(Hvdroxymethyl)-4-(2-(trifluoromethoxy)phenylsulfonyl)-4,5-dihydro-1 H-benzofel- Π ,41diazepin-2(3H)-one (4f)

A solution of compound 4e (5.0 g, 10.9 mmol) in 50 mL of HCI/dioxane (3 M) was stirred at rt for 4 h. NaHC0₃ was added to adjust the pH to approx. 7 and the solution was extracted with Et₂0. The organic layer was washed with brine, dried over NaS0₄, filtered and concentrated under reduced pressure to give compound 4f (4.0 g, 89%) as a white solid.

Step 7: 3-(Hvdroxymethyl)-1-methyl-4-(2-(trifluoromethoxy)phenylsulfonyl)-4.5-dihvdro-1 H- benzofein ,41diazepin-2(3H)-one (4q)

To a mixture of compound 4f (4.0 g, 9.6 mmol) and Cs₂C0₃ (4.1 g, 12.6 mmol) in DMF (40 mL) was added Mel (1.8 g, 12.6 mmol) under N₂ atmosphere. The solution was stirred at rt overnight. Water was added and the solution was extracted with EA. The organic layer was washed with brine, dried over NaS0₄, filtered, concentrated under reduced pressure and purified by CC (PE/EA = 2/1 ) to give compound 4g (2.5 g, 64%) as a white solid.

Step 8: (1-Methyl-2-oxo-4- 2-(trifluoromethoxy)phenylsulfonyl)-2,3,4,5-tetrahvdro-1 /7-benzo- Tein ,41diazepin-3-yl)methyl methanesulfonate (4h)

A mixture of compound 4g (2.5 g, 5.8 mmol) and Et₃N (0.9 g, 8.7 mmol) in DCM (30 mL) was added MeS0₂CI (1.0 g, 8.7 mmol) at 0°C under N₂ atmosphere. The solution was stirred at rt for 1 h. Water was added and the solution was extracted with DCM. The organic layer was washed with brine, dried over NaS0₄, filtered, concentrated under reduced pressure and purified by CC (PE/EA = 2/1 ) to give compound 4h (3.0 g, 97%) as a white solid.

Step 9: 1 -Methyl-3-(3-methylbenzvn-1 H-benzorelf1.41diazepin-2(5 -ft-one (4i)

To a mixture of compound 4h (300 mg, 0.6 mmol) in anhydrous THF (3 mL) was added m- toluoylmagnesium bromide (3.0 mL, 1.5 mmol) at -78°C under N₂ atmosphere. The solution was stirred at rt for 1 d. Aq. sat. NH₄CI was added and the solution was extracted with EA. The organic layer was washed with brine, dried over NaS0₄, filtered, concentrated under reduced pressure and purified by CC (PE/EA = 2/1) to give compound 4i (50 mg, 30%) as a yellow oil.

Step 10: 1-Methyl-3-(3-methylbenzyl)-4.5-dihvdro-1 H-benzoreiri .41diazepin-2(3H)-one (41) To a mixture of compound 4i (50 mg, 0.16 mmol) in MeOH (2 mL) was added NaBH₄ (50 mg, 1.3 mmol) at 0°C under N₂ atmosphere. The solution was stirred at rt for 1 d. It was concentrated and to the residue was added 2M KOH. The mixture was extracted with EA. The organic layer was washed with brine, dried over NaS0₄, filtered and concentrated under reduced pressure to give compound 4j (50 mg, 99%) as a yellow oil.

Step 1 1 : 1 -Methyl-3-(3-methylbenzyl)-4-(2-(trifluoromethoxy)phenylsulfonyl)-4.5-dihvdro-1 H- benzoiein ,41diazepin-2(3H)-one (4)

A solution of compound 4j (50 mg, 0.18 mmol) and 2-(trifluoromethoxy)benzene-1-sulfonyl chloride (70 mg, 0.27 mmol) in pyridine (2 mL) was stirred at 85°C under microwave irradiation for 1.5 h. The reaction mixture was concentrated and the residue was purified by prep-TLC to give the title compound 4 (40 mg, 44%) as a white solid. ¹H-N R (CDCI₃, 400 MHz): δ 1.94- 2.00 (m, 1 H), 2.26 (s, 3H), 2.74-2.79 (m, 1 H), 3.23 (s, 3H), 4.17-4.21 (m, 1 H), 4.66-4.70 (m, 1 H), 4.82-4.86 (m, 1 H), 6.66-6.73 (m, 2H), 6.94-6.96 (m, 1 H), 7.06-7.10 (m, 1 H), 7.26-7.28 (m, 1 H), 7.32-7.36 (m, 1 H), 7.41 -7.45 (m, 2H), 7.51 -7.65 (m, 3H), 8.07-8.10 (m, 1 H). MS Found: 505 (M+1 )⁺.

Examples 4/1 to 4/7

The following Examples were prepared similar as described in Example 4:

# Analytical data

H-NMR (CDCI₃, 400 MHz): δ 0.62-0.71 (3H, m), 0.98-1.16 (5H, m), 1.25-1.28 (1 H, m), 1.52-1.63 (4H, m), 3.31 (3H, s), 4.12-

4/1 4.15 (1 H, m), 4.50-4.54 (1 H, m), 4.76-4.79 (1 H, m), 7.14-7.16

(1 H, m), 7.26-7.29 (1 H, m), 7.42-7.46 (4H, m), 7.63-7.66 (1 H, m), 8.06-8.08 (1 H, m). MS Found: 497 (M+1 )⁺.

4/2

4/3

4/4

Structure Analytical data

1H-NMR (CDCI₃, 400 MHz): δ 1.17-1.25 (3H, m), 1.94-2.01 (1 H, m), 2.54-2.59 (2H, m), 2.76-2.81 (1 H, m), 3.22 (3H, s), 4.17- 4.20 (1 H, m), 4.68-4.72 (1 H, m), 4.82-4.85 (1 H, m), 6.70-6.72

4/5 (2H, m), 6.97-6.99 (1 H, m), 7.10-7.12 (1 H, m), 7.25-7.27 (1 H,

m), 7.32-7.36 (1 H, m), 7.41 -7.44 (2H, m), 7.51-7.56 (2H, m), 7.60-7.64 (1 H, m), 8.08-8.10 (1H, m). MS Found: 519 (M+1 )⁺.

¹H-NMR (CDCI₃, 400 MHz): δ 2.04-2.11 (1H, m), 2.86-2.94 (1 H, m), 3.21 (3H, s), 4.16-4.19 (1 H, m), 4.69-4.74 (1 H, m), 4.82-

4/6 4.85 (1 H, m), 7.07 (1 H, s), 7.18-7.20 (1 H, m), 7.26-7.28 (1 H,

m), 7.33-7.38 (2H, m), 7.42-7.46 (3H, m), 7.53-7.60 (2H, m), 7.62-7.66 (1 H, m), 8.07-8.09 (1 H, m). MS Found: 559 (M+1 )⁺.

¹H-NMR (CDCI₃, 400 MHz): δ 1.98-2.04 (1 H, m), 2.82-2.87 (1 H, m), 3.22 (3H, s), 4.16-4.19 (1 H, m), 4.67-4.71 (1 H, m), 4.81- 4.84 (1 H, m), 6.69 (1 H, s), 6.92-6.94 (1 H, m), 7.00-7.02 (1 H, m), 7.23-7.26 (1 H, m), 7.34-7.36 (1 H, m), 7.37-7.42 (1 H, m), 7.42-7.46 (2H, m), 7.52-7.58 (2H, m), 7.62-7.66 (1 H, m), 8.07- 8.09 (1 H, m). MS Found: 575 (M+1)⁺.

Examples 5 and 5'

5 and 5' (diastereomers)

Step 1 : 3-Benzyl-5-methyl-1 H-benzorein .4ldiazeDin-2(3H)-one (5a)

A mixture of 1 -(2-nitrophenyl)ethanone (25 g, 175 mmol) and methyl 2-amino-3- phenylpropanoate (42.5 g, 200 mmol) in pyridine (150 mL) was stirred at 150°C overnight in a sealed tube. The resulting mixture was concentrated under reduced pressure. The residue was poured into water and extracted with DCM twice. The combined organic layers were concentrated under reduced pressure and purified by CC (PE/EA = 4/1 ) to give compound 5a (1 1 g, 25%) as a white solid.

Step 2: 3-Benzyl-5-methyl-4,5-dihvdro-1 /-/-benzofeiri .4ldiazepin-2(3H)-one (5b)

To a mixture of compound 5a (2.5 g, 9.4 mmol) in MeOH (30 mL) was added NaBH₄ (1 g, 28 mmol) portionwise at rt and the mixture was stirred overnight. The reaction was quenched with aq. NH₄CI (50 mL) and concentrated under reduced pressure. The residue was poured into water and extracted with DCM. The organic layer was concentrated under reduced pressure to give compound 5b (2.0 g, 80%) as a white solid.

Step 3: 3-Benzyl-5-methyl-4-(2-(trifluoromethoxy)phenylsulfonyl)-4.5-dihvdro-1 H- benzofelH ,41diazepin-2(3H)-one (5c) A mixture of compound 5b (100 mg, 0.38 mmol), 2-(trifluoromethoxy)benzene-1 -sulfonyl chloride (127 mg, 0.49 mmol) and pyridine (2 mL) in a sealed tube was irradiated in a microwave oven at 80°C overnight. The resulting mixture was concentrated under reduced pressure and purified by CC (PE/EA = 8/1 ) to give compound 5c (55 mg, 30%) as a yellow solid.

Step 4: 3-Benzyl-1 ,5-dimethyl-4-(2-(trifluoromethoxy)phenylsulfonyl)-4,5-dihvdro-1 H- benzofelM ,41diazepin-2(3 -/)-one (5 and 5', diastereomers)

To a solution of 5c (200 mg, 0.4 mmol) in THF (2 mL) was added NaH (19 mg, 0.8 mmol) and the mixture was stirred for 0.5 h at rt. Then Mel (1 13 mg, 0.8 mmol) was added. The mixture was stirred at rt for 4 h and then concentrated under reduced pressure. Water was added and the mixture was extracted with EA (3 x). The combined organic layers were washed with water (3 x) and brine (3 x) consecutively, concentrated under reduced pressure and purified by CC (PE/EA = 5/1) to give compound 5 (32 mg, 16%) as a yellow solid and compound 5' (50 mg, 40%) as a yellow solid. For compound 5: ¹H-NMR (CDCI₃, 400 MHz): δ 1.33-1.35 (3H, d, J = 7.2 Hz), 1.88-1.94 (1 H, t, J = 12.4 Hz), 2.41 -2.46 (1 H, dd, J = 5.2 Hz, 14.0 Hz), 3.3 (3H, s), 5.03- 5.07 (1 H, dd, J = 5.2 Hz, 12.8 Hz), 5.36-5.41 (1 H, t, J = 1.2 Hz), 6.79-6.81 (2H, d, J = 6.8 Hz), 7.16-7.23 (3H, m), 7.30-7.36 (2H, m), 7.43-7.46 (3H, m), 7.53-7.57 (1 H, t, J = 1.6 Hz), 7.62-7.66 (1 H, t, J = 1.6 Hz), 8.17-8.20 (1 H, d, J = 10.0 Hz). MS Calcd.: 504; MS Found: 505 (M+1). For compound 5': ¹H-NMR (CDCI₃, 400 MHz): δ 1.59-1.61 (3H, d, J = 7.2 Hz), 2.97-3.03 (1 H, t, J = 12.4 Hz), 3.1 1 -3.15 (1 H, dd, J = 5.2 Hz, 14.0 Hz), 3.26 (3H, s), 4.36-4.39 (1 H, dd, J = 5.2 Hz, 12.8 Hz), 5.53-5.58 (1 H, t, J = 1.0 Hz), 7.12-7.23 (6H, m), 7.27-7.31 (2H, m), 7.39-7.45 (4H, m), 7.61 -7.66 (1 H, t, J = 15.2 Hz), 8.07-8.05 (1 H, d, J = 10.0 Hz). MS Found: 505 (M+1).

Example 6

Step 1 : 3-Benzyl-5-methyl-4-(2-(trifluoromethoxy)phenylsulfonyl)-4.5-dihvdro-1 H-benzofel- [1 ,41diazepine-2(3HHhione (6a)

To a solution of compound 5c (1.0 g, 2.0 mmol) in toluene (10 mL) was added Lawesson's reagent (1.2 g, 3.0 mmol) in one portion at rt and the mixture was heated at 105°C for 2 h. The mixture was partitioned between EA and water and the organic layer was concentrated under reduced pressure. The residue was purified by CC (PE/EA = 5/1) to give compound 6a (0.82 g, 80%) as a yellow solid. Step 2: 3-Benzyl-5-methyl-2-(methylthio)-4-(2-(tr^

benzofelM ,41diazepine (6b)

To a solution of compound 6a (820 mg, 1.6 mmol) and K₂C0₃ (440 mg, 3.2 mmol) in DMF (8 ml_) was added Mel (340 mg, 2.4 mmol) via a syringe over 1 min and the mixture was stirred for 1 h at rt. Then the mixture was quenched with water and extracted with EA three times. The combined organic layers were concentrated under reduced pressure to give compound 6b (600 mg, 73%) as a yellow solid.

Step 3: 3-Benzyl-5-methyl-2-(methylsulfonyl)-4-(2-(trifluoromethoxy)phenylsulfonyl)-4.5-dihvdro- 3/- -benzoreiri .41diazepine (6c)

To a solution of compound 6b (100 mg, 0.1 mmol) in 10 ml_ of DCM was added meta- chloroperoxybenzoic acid (49 mg, 0.23 mmol) at 0°C and the mixture was stirred for 0.5 h at rt. The mixture was quenched with aq. NaHC0₃ and washed with aq. Na₂S₂0₃. The organic layer was concentrated under reduced pressure to give crude compound 6c (120 mg, 100%) as a yellow oil.

Step 4: (Z)-/V-(3-Benzyl-5-methyl-4-(2-(trifluoromethoxy)phenylsulfonyl)-4.5-dihvdro-1 H- benzoreiri ,41diazepin-2(3H)-ylidene)-2,2-dimethoxyethanamine (6d)

A mixture of compound 6c (120 mg, 0.2 mmol) and 2,2-dimethoxyethanamine (2 ml_) was stirred at 90°C for 10 h in a sealed tube. The mixture was concentrated under reduced pressure and purified by CC (PE/EA = 6/1 ) to give compound 6d (20 mg, 17% over two steps) as a brown oil.

Step 5: 4-Benzyl-6-methyl-5-(2-(trifluoromethoxy)phenylsulfonyl)-5.6-dihvdro-4 -/-benzo- rflimidazoH ,2-alH ,41diazepine (6)

To a solution of compound 6d (110 mg, 0.19 mmol) in 10 ml_ of toluene was added TsOH H₂0 (10 mg, 0.035 mmol) in one portion and the mixture was heated at reflux for 1 h. Then the mixture was concentrated under reduced pressure. The residue was diluted with DCM and washed with water and brine consecutively. The organic layer was concentrated under reduced pressure and purified by prep-HPLC to give compound 6 (36 mg, 36%) as a brown solid. ¹H- NMR (CDCI₃, 400 MHz): δ 0.68-0.70 (3H, d, J = 7.2 Hz), 2.25-2.31 (1 H, t, J = 12.8 Hz), 2.82- 2.87 (1 H, dd, J = 4.8 Hz, 12.8 Hz), 5.36-5.41 (1 H, t, J = 1.2 Hz), 5.60-5.64 (1 H, dd, J = 4.8 Hz, 12.8 Hz), 6.59-6.61 (2H, d, J = 3.6 Hz), 6.96 (1 H, s), 7.06-7.08 (3H, m), 7.17 (1 H, s), 7.41 -7.63 (7H, m), 8.16-8.18 (1 H, d, J = 8.0 Hz). MS Found: 514 (M+1 ).

Example 6/1 to 6/3

The following Example 6/1 was prepared from compound 2 similar as described for Example 6. Example 6/2 was prepared from 10f similar as in described in Example 6. Example 6/3 was prepared from BB1 respectively similar as in described in the Example 10 (10b to 10f) and after formation of the seven-membered ring as described in Example 6: Structure Analytical data

¹H-NMR (CDCI₃, 400 MHz): δ 2.20 (2H, s), 2.73 (1 H, m),

3.51- 3.56 (1 H, m), 4.14 (1 H, m), 4.71 (1 H, m), 5.16 (1 H, m), 6.86-6.93 (2H, m), 7.07-7.22 (5H, m), 7.12-7.31 (1 H, m),

6/1 7.43- 7.45 (2H, m), 7.59-7.63 (1 H, t), 7.97-7.99 (1 H, d), 8.14- 8.16 (1 H, d), 8.54-8.56 (1 H, d), 8.95-8.96 (1 H, d). MS

Found: 467 (M+1).

¹H-NMR (DMSO-de, 400 MHz): δ 2.51-2.55 (1 H, m), 3.11- 3.16 (1 H, m), 4.09-4.13 (1 H, d, J = 14.0 Hz), 4.80-4.84 (1 H, d, J = 14.0 Hz), 5.35-5.39 (1 H, m), 6.76-6.78 (2H, m), 6.90

6/2 (1 H, m), 7.12-7.17 (3H, m), 7.48-7.61 (3H, m), 7.67 (1 H, s),

7.73-7.78 (1 H, m), 7.94-7.97 (1 H, m), 8.09-8.12 (1 H, m),

8.52- 8.54 (1 H, m). MS Found: 501 (M+1).

¹H-NMR (CDCI₃, 400 MHz): δ 3.09-3.28 (2H, m), 4.75 (1 H, d, J = 18.0 Hz), 5.43 (1 H, d, J = 18.0 Hz), 5.69 (1 H, t, J = 4.4

6/3 Hz), 6.79 (1 H, s), 6.96-6.98 (1 H, m), 7.04-7.26 (6H, m),

7.44- 7.56 (2H, m), 7.87-7.89 (1 H, m), 8.67 (1 H, s). MS

Found: 507 (M+1).

Preparative Example BB1

BB1

Step 1 : terf-Butyl 5-(hvdroxymethyl)thiazol-4-ylcarbamate (BB1a)

To an ice-cooled solution of methyl 4-(bis(reri-butoxycarbonyl)amino)thiazole-5-carboxylate (17.5 g, 49 mmol) in THF (200 mL) was added LiAIH₄ (7.5 g, 196 mmol) in one portion. Then the mixture was warmed to rt and stirred for 3 h. The mixture was quenched with water, 15% aq. NaOH and water consecutively and the formed suspension was filtered and concentrated in vacuo. The residue was purified by CC (PE/EA = 2/1) to give compound BB1a (5.0 g, 45%) as a white solid.

Step 2: tert-Butyl 5-formylthiazol-4-ylcarbamate (BB1)

To a solution of compound BB1a (5.0 g, 20 mmol) in CHCI₃ (100 mL) was added active Mn0₂ (15 g, 200 mmol) and the mixture was stirred at reflux overnight. Then the mixture was filtered, concentrated under reduced pressure and purified by CC (PE/EA = 4/1) to give BB1 (1.7 g, 37%) as a yellow solid.

Step 1 : (F?)-2-(2-(Dibenzylamino)-1 -hvclroxy-3-phenylpropyl)nicotinic acid (7a)

n-Butyllithium (2.5M, 85.4 mL, 213 mmol) was added to a solution of diisopropylamine (35.9 mL, 255 mmol) in dry THF at -70°C, and the mixture stirred under N₂ for 40 min. 2-Methyl-nicotinic acid (9.74 g, 71 mmol) was added quickly and after stirring for 20 min, a solution of (H)-2- (dibenzylamino)-3-phenylpropanal (19.5 g, 0.059 mol) in anhydrous THF (170 mL) was added dropwise at -70°C. The resulting mixture was stirred at -70°C for 20 min. Sat. aq. NH₄CI was added and the mixture was allowed to warm to rt. The pH of the mixture was adjusted to 5 with 1 N aq. HCI. Then the mixture was extracted with EA (3 x). The combined organic layers were washed with brine, dried over Na₂S0₄, filtered and concentrated under reduced pressure to give crude product 7a (23 g), which was used in the next step without further purification.

Step 2: (ff)-7-(1-(Dibenzylamino)-2-phenylethyl)-7.8-dihvdro-5 -/-pyranor4,3-- lPyridin-5-one (7b)

Oxalyl dichloride (6.76 mL, 71 mmol) was added to 7a (23 g, 59 mmol) in dry DCM (70 mL) at 0°C and one drop of DMF was added. The resulting mixture was stirred at rt for 1 h. Sat. aq. NaHC0₃ was added to quench the reaction and the pH was changed to 8. Then the mixture was extracted with DCM twice and the combined organic layers were dried over Na₂S0₄, filtered, concentrated under reduced pressure and purified by CC (PE/EA = 1/1 ) to give intermediate 7b (1 .4 g) with -75% HPLC purity as a brown oil.

Step 3: (ff)-6.7-Dibenzyl-8-hvdroxy-6.7,8,9-tetrahvdro-5H-pyridor3,2-clazepin-5-one (7c)

A suspension of crude intermediate 7b (1 .1 g, 2.5 mmol), 10% Pd/C (330 mg) and 2N aq. HCI (10 mL) in MeOH (30 mL) was stirred at rt overnight under H₂. The resulting suspension was filtrated and the filtrate was concentrated under reduced pressure. The residue was treated with sat. aq. NaHC0₃ and THF, and the solution was stirred for 2 h. Then the solution was extracted with EA (3 x) and the combined organic layers were dried with Na₂S0₄, filtered and concentrated under reduced pressure. The product was purified by CC (PE/EA = 1/3) to give intermediate 7c (0.37 g, 42%).

Step 4: (ff¾-6.7-Dibenzyl-8-methoxy-6.7.8.9-tetrahvdro-5H-pyridor3,2-c1azepin-5-one (7d)

To a solution of compound 7c (700 mg, 1.96 mmol) in THF (70 mL) was added NaH (60%, 149 mg, 3.72 mmol) and the mixture was stirred at rt for 30 min. Then Mel (1 .06 g, 7.43 mmol) was added and the resulting mixture was stirred at rt overnight. It was diluted with H₂0 (100 mL) and extracted twice with EA. The combined organic phases were dried over Na₂S0₄, filtered, concentrated under reduced pressure and purified by CC (PE/EA = 1/1 ) to give compound 7d (482 mg, 66%) as a white solid.

Step 5: (fn-6.7-Dibenzyl-8-methoxy-6.7.8.9-tetrahvdro-5H-pyridor3.2-clazepine (7eV

To a solution of compound 7d (100 mg, 268 μητιοΙ) in anhydrous THF (10 mL) was added LiAIH₄ (204 mg, 5.38 mmol) slowly in small portions at 0°C and then the mixture was heated at reflux for 24 h, cooled to rt and quenched with H₂0 (0.2 mL), 15% aq NaOH solution (0.2 mL) and H₂0 (0.6 mL). The salts were removed by filtration and the filtrate was concentrated and purified by CC (PE/EA = 2/1) to give compound 7e (40 mg, 42%) as a white solid.

Step 6: (ff)-7-Benzyl-8-methoxy-6,7,8.9-tetrahvdro-5H-pyridor3.2-c1azepine (7f)

A suspension of compound 7e (122 mg, 340 μιηοΙ), 10% Pd/C (37 mg) and 2N aq. HCI (1 mL) in MeOH (8 mL) was stirred at rt for 5 h under H₂. The suspension was filtered and sat. aq. NaHC0₃ was added. The pH was adjusted to 8. Then the solution was extracted with EA twice and the combined organic layers were dried with Na₂S0₄, filtered and concentrated under reduced pressure to give intermediate 71 (75 mg, 82%) as a yellow oil.

Step 7: (ff)-7-Benzyl-8-methoxy-6-(2-(trifluoromethoxy)phenylsulfonyl)-6.7.8.9-tetrahvdro-5 - - pyridof3,2-c1azepine (7)

Compound 7f (75 mg, 280 μιηοΙ) was dissolved in a mixture of THF (3 mL) and H₂0 (3 mL). NaHC0₃ (47 mg, 560 μηηοΙ) and 2-trifluoromethoxy-benzenesulfonyl chloride (146 mg, 560 μηηοΙ) was added at rt and stirred overnight. Then the mixture was diluted with H₂0 (5 mL) and extract twice with EA. The combined organic layers were dried over Na₂S0₄, filtered, concentrated under reduced pressure and purified by CC (PE/EA = 1/3) to give compound 7 (45 mg of single isomer, 33%). ¹H-NMR (400 MHz, CDCI₃): δ 2.76-2.81 (m, 1H), 2.94-2.99 (m, 1 H), 3.17 (s, 3H), 3.19-3.25 (m, 1 H), 3.32-3.41 (m, 2H), 4.24 (d, J = 16.8 Hz, 1 H), 4.28-4.33 (m, 1 H), 4.75 (d, J = 16.8 Hz, 1 H), 6.98 (d, J = 6.8 Hz, 2H), 7.01 -7.04 (m, 1 H), 7.06-7.18 (m, 5H), 7.39- 7.44 (m, 2H), 7.83 (dd, J = 1.6 Hz, 8.0 Hz, 1 H), 8.31 (d, J = 3.6 Hz, 1 H). MS Found: 493 (M+1).

Example 8

Step 1 : (fl)-3-Benzyl-4-(guinolin-8-ylsulfonyl)-4,5-dihvdro-1 H-benzofelH ,41diazepine-2(3H)- thione (8a)

Compound 8a was prepared from 2 similar as described in Example 6. Step 2: (ff)-4-Benzyl-5-(auinolin-8-ylsulfonyl)-5.6-dihvdro-4H-benzor iri ,2,41triazolor4,3- ain,41diazepine (8)

To a solution of compound 8a (0.1 g, 0.2 mmol) in n-BuOH (10 mL) was added formohydrazide (1.0 g, 17 mmol). The resulting mixture was heated at reflux for 2 h. Then the mixture was poured into water and the organic layer was concentrated in vacuo. The residue was washed with MeOH to give 8 (50 mg, 50%) as a white solid. ¹H-NMR (DMSO-d₆, 400 MHz): δ 2.90 (1 H, m), 3.40-3.44 (1 H, m), 4.06-4.10 (1 H, m), 4.47-4.51 (1 H, m), 6.42-6.43 (1 H, m), 7.02-7.04 (1 H, m), 7.11-7.28 (7H, m), 7.57-7.69 (2H, m), 8.16-8.18 (1 H, m), 8.33-8.41 (2H, m), 8.66-8.67 (1 H, m), 8.23 (1 H, s). MS Found: 468 (M+1).

Examples 8/1 to 8/6

The following Examples were prepared similar as described in Example 8 using the corresponding substituted aminoesters and sulfonyl chlorides as building blocks. Example 8/6 was prepared using 2,2,2-trifluoroacetohydrazide in place of formohydrazide in the last step:

# Anal tical data

8/1

8/2

8/3

8/4

8/5

# Structure Analytical data

¹H-NMR (DMSO-d_6l 400 MHz): δ 2.13 (m, 1 H), 3.19-3.23 (dd, 1 H, J = 5.2 Hz, 13.2 Hz), 3.75-3.78 (d, 1 H, J = 13.2 Hz), 4.89- 4.93 (d, 1 H, J = 13.2 Hz), 5.54-5.58 (dd, 1H, J = 5.2 Hz, 11.0

8/6 Hz), 6.74-6.75 (d, 2H, J = 6.0 Hz), 7.11 -7.16 (m, 3H), 7.41-7.49

(m, 2H), 7.61 -7.75 (m, 5H), 8.10-8.12 (d, 1H, J = 8.0 Hz). MS Found: 569 (M+1).

Example 9

Step 1 : fert-Butyl pyridin-2-ylcarbamate (9a)

To a solution of (Boc)₂0 (218 g, 1.0 mol) in tert-butyl alcohol (1.5 L) was added 2-aminopyridine (94 g, 1.0 mol) slowly and the mixture was stirred at rt for 24 h, then concentrated under reduced pressure and purified by CC (PE/EA = 1/1) to give compound 9a (100 g, 51%) as a white solid.

Step 2: tert-Butyl 3-formylpyridin-2-ylcarbamate (9b)

To a solution of compound 9a (14.0 g, 72 mmol) in Et₂0 (500 mL) was added tert-BuLi (1.7M, 106 mL, 180 mmol) at -78°C under N₂ atmosphere and the resulting mixture was warmed to 0°C and stirred for 1 h. Anhydrous DMF (8.0 mL, 103 mmol) was added with rapid stirring. The mixture was stirred at 0°C for 10 min, then quenched with half -saturated aq. NH₄CI solution. The aqueous layer was extracted with EA twice, the combined organic layers were dried over Na₂S0₄ and concentrated under reduced pressure. The residue was purified by CC (PE/EA = 3/1) to give compound 9b (8.0 g, 52%) as a white solid.

Step 3: Methyl 2-((2-(re/ -butoxycarbonylamino)pyridin-3-yl)methylamino)-3-phenylpropa-noate (9c)

To a suspension of compound 9b (8.0 g, 36 mmol) and methyl 2-amino-3-phenylpropanoate (6.5 g, 36 mmol) in DCM (200 mL) was added AcOH (0.2 mL) at rt and the mixture was stirred at rt for 1 h. To this mixture was added NaBH(OAc)₃ (10.6 g, 50 mmol) at rt and the mixture was stirred overnight. The mixture was diluted with EA and quenched with aq. NaOH (1 N, 280 mL). The organic layer was washed with brine twice, dried over MgS0₄, concentrated in vacuo and purified by CC (PE/EA = 10/1) to give compound 9c (6.7 g, 48%) as a white solid.

Step 4: Methyl 2-((2-aminopyridin-3-yl)methylamino)-3-phenylpropanoate hydrochloride (9d)

To a solution of HCI/MeOH (~3M, 30 mL) was added compound 9c (6.0 g, 16 mmol) and the solution was stirred at rt for 2 h and concentrated under reduced pressure to give crude compound 9d (1 g) as a brown solid which was used in the next reaction without further purification.

Step 5: 3-Benzyl-4,5-dihvdro-1 H-Dyridof2.3-eiri.4ldiazepin-2(3H)-one (9e)

To a solution of NaH (3.2 g, -80 mmol) in anhydrous DMF (80 ml_) was added a solution of compound 9d (4.5 g, 16 mmol) in anhydrous DMF (50 ml_) at 0°C under N₂ atmosphere and the solution was stirred at rt for 2 h. Water was added for quenching and EA was added to extract three times. The combined organic layers were washed with water and brine (3 x consecutively), dried over Na₂S0₄, filtered and concentrated under reduced pressure to give crude compound 9e (1 g) as a yellow solid, which was used in the following step without further purification.

Step 6: terf-Butyl 3-benzyl-2-oxo-2,3-dihvdro-1 A7-pyridof2,3-e1M .41diazepine-4(5/-fl-carboxylate i£f]

To a solution of crude compound 9e (4.0 g, -16 mmol) in DCM (30 ml_) and ACN (20 ml_) was added (Boc)₂0 (3.5 g, 16 mmol) and the solution was heated to reflux overnight, cooled and concentrated under reduced pressure and purified by CC (PE/EA = 1/3) to give compound 9f (4.0 g, 70% over 3 steps) as a yellow solid.

Step 7: terf-Butyl 3-benzyl-2-thioxo-2.3-dihvdro-1 --pyridof2.3-eiri.4ldiazepine-4(5/-/)- carboxylate (9q)

To a solution of compound 9f (4.0 g, 11 mmol) in toluene (50 ml_) was added Lawesson's reagent (5.5 g, 13 mmol) in one portion at rt. Then the mixture was heated to 90°C and stirred for 3 h. The mixture was partitioned between EA and water, the organic layer was concentrated in vacuo and purified by CC (PE/EA = 3/1) to give compound 9g (2.0 g, 49%) as a yellow solid.

Step 8: terf-Butyl 3-benzyl-2-(methylthio)-3H-pyridor2.3-eiri.41diazepine-4(5 -/)-carboxylate (9h)

To a solution of compound 9g (1.6 g, 4.3 mmol) and K₂C0₃ (1.2 g, 8.6 mmol) in DMF (40 ml_) was added Mel (0.8 g, 5.6 mmol) via a syringe over 1 min. The resulting mixture was stirred at rt for 1 h. Then the mixture was quenched with water and extracted with EA. The organic layer was concentrated in vacuo to give crude compound 9h (1.6 g, 97%) as a yellow solid.

Step 9: (Z)-terf-Butyl 3-benzyl-2-(2,2-dimethoxyethylimino)-2.3-dihvdro-1 H-pyridor2.3- ein ,41diazepine-4(5H)-carboxylate (9i)

A mixture of compound 9h (6.9 g, 18 mmol) and 2,2-dimethoxyethanamine (20 mL) was irradiated in a microwave oven at 90°C for 1 h in a sealed tube. The mixture was concentrated under reduced pressure and the product was purified by CC (PE/EA = 2/1) to give compound 9i (1.6 g, 20%) as a brown oil.

Step 10: terf-Butyl 7-benzyl-5H-imidazori .2-alpyridof3,2-riri .41diazepine-6(7H)-carboxylate (9i)

To a solution of compound 9i (1.6 g, 3.6 mmol) in toluene (20 mL) was added TsOH-H₂0 (1.0 g, 5.8 mmol) in one portion. The mixture was heated at reflux for 1 h, then concentrated under reduced pressure and diluted with DCM. The organic layer was washed with water, concentrated under reduced pressure and purified by CC (PE/EA = 1/1) to give compound 9j (1.2 g, 80%) as a brown solid.

Step 11 : 7-Benzyl-6.7-dihvdro-5/-/-imidazori .2-alPyridof3,2- iri,4ldiazepine hydrochloride (9k)

To a solution of HCI/MeOH (3M, 30 mL) was added compound 9j (1.2 g, 3.2 mmol) and the solution was stirred at rt for 2 h and then concentrated under reduced pressure to give crude compound 9k (1 g) as a brown solid which was used in the next reaction without further purification.

Step 12: 7-Benzyl-6-(auinolin-8-ylsulfonyl)-6,7-dihvdro-5/-/-imidazori ,2-alpyridor3,2- flH ,41diazepine (9)

To a solution of compound 9k (138 mg, 0.5 mmol) in dry DCM (10 mL) was added TEA (200 mg, 1.5 mmol) and the solution was stirred at rt for 10 min. Then quinoline-8-sulfonyl chloride (0.75 mmol) was added and the solution was stirred at rt for 2 d, concentrated under reduced pressure and purified by CC (PE/EA = 1/1) to give 9 as a white solid. ¹H-NMR (DMSO-d₆, 400 MHz): 3.09-3.14 (1 H, m), 3.34-3.52 (1 H, m), 4.43 (1 H, d, J = 15.2 Hz), 4.53 (1 H, d, J = 15.2 Hz), 6.15-6.19 (1 H, m), 6.91-6.95 (2H, m), 7.09-7.23 (5H, m), 7.48-7.61 (4H, m), 7.99-8.00 (1 H, m), 8.08-8.10 (1 H, m), 8.22-8.24 (1 H, m), 8.30-8.33 (1 H, m), 8.42-8.44 (1H, m). MS Found: 468 (M+1).

Examples 9/1 to 9/23

The following Examples were prepared similar as in Example 9:

Analytical data

¹H-NMR (CDCI₃, 400 MHz): δ 2.67-2.73 (1 H, m), 3.35-3.40 (1 H, m), 4.17 (1 H, d, J = 14.4 Hz), 4.67 (1 H, d, J = 14.4 Hz), 5.42-5.45 (1 H, m), 6.84-6.86 (2H, m), 6.92 (1H, d, J = 0.8 Hz), 7.10-7.13 (3H, m), 7.21-7.26 (2H, m), 7.36-7.38 (1 H, m), 7.52-7.54 (1 H, m), 7.66 (1 H, d, J = 0.8 Hz), 7.73-7.75 (1 H, m), 8.02-8.04 (1 H, m), 8.45-8.50 (1 H, m . MS Found: 501 (M+1).

,

,

# Analytical data

¹H-NMR (CDCI₃, 400 MHz): δ 2.75-2.81 (1H, m), 3.22-3.27 (1H, m), 4.46 (1H, d, J = 14.4 Hz), 4.98 (1H, d, J = 14.4 Hz), 5.54-5.57 (1H, m), 6.80-6.85 (3H, m), 7.03-7.05 (3H, m), 7.29-7.32 (1H, m), 7.45- 7.49 (1H, m), 7.62 (1H, m), 7.91-7.93 (1H, m), 7.97-8.01 (2H, m), 8.48-8.50 (1H, m). MS Found: 459 (M+1).

¹H-NMR (CDCI₃, 300 MHz): δ 1.01-1.06 (3H, t, J = 9.2 Hz), 3.17- 3.23 (1H, m), 3.62-3.67 (1H, m), 3.76-3.88 (3H, m), 4.13-4.18 (1H, m), 5.86-5.90 (1H, m), 6.46-6.50 (1H, m), 6.81-6.86 (1H, m), 6.94- 7.01 (1H, m), 7.13-7.16 (1H, m), 7.17-7.25 (6H, m), 7.53-7.56 (1H, m), 7.70-7.72 (1H, m), 8.21-8.23 (1H, m). MS Found: 479 (M+1)⁺.

¹ H-NMR (DMSO-d₆, 300 MHz): δ 3.27-3.29 (2H, m), 3.38-3.41 (1H, m), 4.77 (1H, d, J = 17.4 Hz ), 5.03 (1H, d, J = 17.1 Hz), 5.58-5.59 (1H, m), 6.97-7.02 (2H, m), 7.09-7.12 (2H, m), 7.17-7.25 (4H, m), 7.52-7.54 (1H, m), 7.63-7.66 (1H, m), 7.85-7.86 (1H, m), 8.40-8.44 (2H, m). MS Found: 484 (M+1).

¹H-NMR (CDCI₃, 400 MHz): δ 3.29-3.31 (1H, m), 3.44-3.49 (1H, m), 4.50 (1H, d, J = 16.8 Hz), 4.79 (1H, d, J = 17.6 Hz), 5.75 (1H, m), 7.06-7.10 (4H, m), 7.16-7.20 (4H, m), 7.29-7.33 (1H, m), 7.47-7.49 (1 H, m), 7.97-7.99 (1 H, m), 8.66 (1 H, s), 8.83 (1 H, s). MS Found: 502 (M+1).

¹H-NMR (DMSO-d₆, 300 MHz): δ 3.39-3.43 (2H, m), 4.81 (1H, d, J = 17.6 Hz ), 5.22 (1H, d, J = 16.8 Hz), 5.64-5.67 (1H, m), 7.01-7.04 (3H, m), 7.08-7.23 (5H, m), 7.53 (1H, d, J = 7.6 Hz), 7.82 (1H, m), 8.46-8.53 (2H, m). MS Found: 498.0 (M+1). /12

/13

J

/14 , /15

/16

/17

/18

¹H-NMR (CDCI₃, 400 MHz): δ 8.47-8.50 (m, 1H), 7.94-7.95 (m,1H), 7.72-7.76 (m, 1H), 7.65-7.67 (m, 1H), 7.48-7.52 (m, 1H), 7.20-7.25 (m, 2H), 7.09-7.13 (m, 3H), 6.92-6.93 (m, 1H), 6.83-6.86 (m, 2H),/19 5.43-5.46 (m, 1H), 4.63-4.68 (m, 1H), 4.46 (s, 2H), 4.14-4.20 (m,

1H), 3.42(s, 3H), 3.33-3.39 (m, 1H), 2.66-2.74 (m, 1H). MS Found: 545.0 (M+1).

/20/21 /22 /23/24/25 /26 /27

Example 10

Step 1 : fert-Butyl 2-bromopyridin-3-ylcarbamate (10a)

To a solution of 2-bromopyridin-3-amine (3.0 g, 17.3 mmol) in THF (30 mL) was added lithium bis(trimethylsilyl)amide (1 M, 35 mL, 35 mmol) slowly at 0°C and the mixture was stirred at this temperature for 30 min. (Boc)₂0 (3.9 g, 17.3 mmol) in THF (20 mL) was added and the mixture was stirred at rt for 1.5 h. The reaction mixture was poured into 0.1 M of HCI and extracted with EA. The combined organic layers were extracted with brine, dried and concentrated under reduced pressure. The crude product was purified by CC (PE/EA = 5/1) to give compound 10a (2.9 g, 62%) as a white solid.

Step 2: fert-Butyl 2-formylpyridin-3-ylcarbamate (10b)

To a solution of compound 10a (2.9 g, 10.7 mmol) in THF (30 mL) was added n-BuLi (2.5M, 8.5 mL, 21.4 mmol) at -78°C under N₂ atmosphere and the resulting mixture was stirred for 1 h at this temperature. /V-Formylpiperidine (1.3 mL, 11.8 mmol) was added with rapid stirring. The mixture was stirred at 0°C for 1 h and then partitioned with 1.5M HCI solution. The pH was adjusted to 7 by the addition of solid Na₂C0₃. The aqueous layer was extracted with EA twice and the combined organic layers were dried over Na₂S0₄, concentrated under reduced pressure and purified by CC (PE/EA = 3/1) to give compound 10b (1.5 g, 65%) as a white solid.

Step 3: Methyl 2-((3-(tert-butoxycarbonylamino)pyridin-2-yl)methylamino)-3-phenylpropanoate Lt

To a suspension of compound 10b (1.5 g, 6.7 mmol) and methyl 2-amino-3-phenylpropanoate (1.3 g, 7.4 mmol) in DCM (30 mL) were added two drops of AcOH at rt and the mixture was stirred at rt for 1 h. To this mixture was added NaBH(OAc)₃ (2.8 g, 13.5 mmol) and the mixture was stirred overnight at rt, then diluted with EA and quenched with aq. NaOH (1 N, 40 mL). The organic layer was washed with brine twice, dried over MgS0_4, concentrated in vacuo and purified by CC (PE/EA = 2/1) to give compound 10c (2.3 g, 88%) as a white solid.

Step 4: Methyl 2-((3-aminopyridin-2-yl)methylamino)-3-phenylpropanoate hydrochloride (10d)

To a solution of HCI/MeOH (~3M, 40 mL) was added compound 10c (2.3 g, 6.0 mmol), stirred at rt for 2 h and concentrated under reduced pressure to give crude compound 10d (1.9 g) as a brown solid used in the next reaction without further purification.

Step 5: 3-Benzyl-4,5-dihvdro-1 H-pyridor3.2-eiri,41diazepin-2(3H)-one (10e) To a solution of NaH (1.6 g, 40 mmol) in anhydrous DMF (20 mL) was added a solution of compound lOd (1.9 g, 6.6 mmol) in anhydrous DMF (20 mL) at 0°C under N₂ atmosphere and the solution was stirred at rt for 2 h. Water was added for quenching and EA was added to extract three times. The combined organic layers were washed with water (3 x) and brine (3 x) consecutively, dried over Na₂S0₄, filtered and concentrated under reduced pressure to give crude compound 10e (1.6 g) as a yellow solid used in the next step without further purification.

Step 6: 3-Benzyl-4-(2-(trifluoromethoxy)phenylsulfonyl)-4,5-dihvdro-1 H-pyrido[3,2- ein ,41diazepin-2(3H)-one dot)

A solution of crude compound 10e (1.6 g, 6.3 mmol) and 2-(trifluoromethoxy)benzene-1-sulfonyl chloride (2.0 g, 7.6 mmol) in pyridine (20 mL) was stirred and heated by microwave irradiation at 85°C for 1 h, then concentrated under reduced pressure and purified by CC (PE/EA = 1/2) to give compound lOf (1.1 g, 37% over 3 steps) as a yellow solid.

Step 7: 3-Benzyl-1 -methyl-4-(2-(trifluoromethoxy)phenylsulfonyl)-4,5-dihvdro-1 H-pyridof3,2- e1f1 ,41diazepin-2(3H)-one (10)

To a solution of compound 10f (300 mg, 0.6 mmol) in THF (10 mL) was added NaH (30 mg, 0.7 mmol) in one portion at 0°C. The mixture was stirred for 30 min, then Mel (134 mg, 0.94 mmol) was added dropwise. The mixture was stirred at rt overnight, partitioned between EA and water and the organic layer was concentrated in vacuo. The residue was purified by CC (PE/EA = 2/1) to give 10 (145 mg, 48%) as a yellow solid. ¹H-NMR (DMSO-d₆, 400 MHz): δ 1.84-1.91 (1H, t, J = 8.8 Hz), 2.63-2.68 (1H, m), 3.14 (3H, s), 4.28-4.31 (1H, d, J = 8.8 Hz), 4.61-4.66 (1H, m), 4.75-4.78 (1 H, d, J = 8.8 Hz), 6.89 (2H, d, J = 9.8 Hz), 7.20-7.27 (3H, m), 7.63-7.69 (3H, m), 7.85-7.87 (1 H, m), 8.05-8.09 (2H, m), 8.55 (1H, d, J = 4.4 Hz). MS Found: 492 (M+1).

Example 10/1

The following Example was prepared from 10b and methyl 2-amino-2-methyl-3- phenylpropanoate similar as described in Example 10:

# Analytical data

Ή-N R (CDCI₃, 300 MHz): δ 1.66 (3H, s), 2.61 -2.66 (1H, d, J = 18.4 Hz), 3.39 (3H, s), 3.48-3.53 (1 H, d, J = 18.8 Hz), 4.49-4.55 (1 H, d, J =

10/1 19.2 Hz), 4.43-4.48 (1 H, d, J = 19.6 Hz), 6.94-7.04 (4H, m), 7.17-7.22

(3H, m), 7.42-7.49 (2H, m), 7.59-7.62 (1H, m), 8.54-8.56 (1 H, d, J = 9.6

Ex '. 12, 12' and 13

Step 1 : Benzyl (f?)-1 -((f?)-1 -oxoisochroman-3-yl)-2-phenylethylcarbamate (11 a) and benzyl (R)- 1 -((S)-1 -oxoisochroman-3-yl)-2-phenylethylcarbamate (11 a')

/>Butyllithium (2.5M, 20 mL, 50 mmol) was added to a solution of 2-o-tolyl-4,5-dihydrooxazole (6.6 g, 41 mmol) in THF at -78°C and the mixture was stirred for 20 min. tert-Butylmagnesium chloride (2M, 25 mL, 50 mmol) was added to a solution of (fl)-benzyl 1 -oxo-3-phenylpropan-2- ylcarbamate (14 g, 50 mmol) in THF at -78°C and the mixture was stirred for 5 min. The solution of the lithiated oxazoline was added via cannula to the solution of the deprotonated aldehyde and the mixture was stirred for 20 min at -78°C. Saturated aqueous NH₄CI was added, the mixture was allowed to warm to rt and extracted with DCM. The organic layer was washed with water and brine, dried with Na₂S0 and concentrated. The residue was dissolved in DCM and silica (100 g) was added. The slurry was stirred for 18 h, then filtered and the filtrate was concentrated under reduced pressure. The two products were purified by CC to afford 11a (1 .1 g) and 11 a' (320 mg).

Step 2: (3ff.4ffl-3-Benzyl-4-hvdroxy-2.3.4,5-tetrahvdro-1 H-benzofdazepin-1 -one (11 b)

Compound 11 a (1 .1 g, 2.6 mmol) was dissolved in ethanol and Pd/C (10%, 300 mg) and HCI (3M, 0.5 mL) was added. The suspension was stirred for 18 h under H₂. Pd/C was filtered off and the filtrate was concentrated under reduced pressure. The residue was treated with NaHC0₃ (sat.) in THF for 2 h. The solution was extracted with DCM, the combined organic layer was dried with Na₂S0_4l concentrated and purified by CC to afford 11 b (0.53 g, 75%).

Step 3: (3f?.4ffl-3-Benzyl-2,3,4,5-tetrahvdro-1 H-benzorclazepin-4-ol (11 c)

Compound 11 b (400 mg, 1 .5 mmol) was dissolved in THF (20 mL) and cooled to 0°C, LiAIH₄ (2.4M in THF, 12.5 mL, 30 mmol) was added slowly in small portions. The resulting mixture was heated at reflux for 24 h, cooled to rt and quenched with successive dropwise addition of H₂0 (1 mL), 15% aq. NaOH solution (1 mL) and H₂0 (3 mL). The salts were removed by filtration and the filtrate was concentrated to afford 11 c (370 mg, 98%).

Step 4: (3fl.4ff)-3-Benzyl-2-(guinolin-8-ylsulfonyl)-2.3.4.5-tetrahvdro-1 H-benzoiclazepin-4-ol ill)

Compound 11 c (300 mg, 1.2 mmol) was dissolved in THF (10 mL) and H₂0 (1 mL), NaHC0₃ (200 mg, 2.4 mmol) and quinoline-8-sulfonyl chloride (550 mg, 2.4 mmol) were added with stirring at rt. The resulting mixture was stirred at rt overnight, then diluted with 5 mL of H₂0, EA was added to extract twice and the combined organic phases were dried over Na₂S0₄, filtered, concentrated under reduced pressure to give the crude intermediate, which was purified by prep-TLC (PE/EA = 1/1) to give Example 11 (200 mg, 38%). H-NMR (400 MHz, CD₃OD): δ 2.76-2.80 (m, 1 H), 2.99-3.05 (m, 2H), 3.52-3.59 (m, 1 H), 4.17-4.21 (m, 1 H), 4.43-4.46 (m, 1 H), 4.73 (d, J = 16.4 Hz, 1 H), 5.51 (d, J = 16.4 Hz, 1 H), 6.43-6.45 (m, 3H), 6.64-6.66 (m, 2H), 7.16- 7.23 (m, 3H), 7.36 (d, J = 6.4 Hz, 1 H), 7.47 (t, J = 8.0 Hz, 1 H), 7.57 (dd, J = 8.8 Hz, J = 4.0 Hz, 1 H), 8.14 (d, J = 6.4 Hz, 1 H), 8.23 (dd, J = 8.8 Hz, J = 1.6 Hz, 1 H), 8.23 (dd, J = 6.4 Hz, J = 1.6 Hz, 1 H), 9.00 (dd, J = 8.8 Hz, J = 1.6 Hz, 1 H). MS Found: 445 (M+1).

Step 4a: (3ff.4/^:?)-3-Benzyl-4-methoxy-2-(auinolin-8-ylsulfonyl)-2.3.4.5-tetrahvdro-1 H- benzofclazepine (12)

To a solution of 11 (50 mg, 0.12 mmol) in THF (10 mL) was added NaH (60%, 100 mg, 2.3 mmol) and then the mixture was stirred at rt for 30 min and CH₃I (653 mg, 4.6 mmol) was added. The resulting mixture was stirred at rt overnight, then diluted with 5 mL of H₂0, EA was added to extract twice and the combined organic phases were dried over Na₂S0₄, filtered and concentrated under reduced pressure. The crude product was purified by prep-TLC (PE/EA = 1/1 ) to give 12 (33 mg, 66%). ¹H-NMR (400 MHz, CD₃OD): δ 2.86-2.95 (m, 3H), 3.33-3.40 (m, 1 H), 3.43 (s, 3H), 3.64-3.65 (m, 1 H), 4.55-4.58 (m, 1 H), 4.74 (d, J = 16.4 Hz, 1 H), 5.48 (d, J = 16.4 Hz, 1 H), 6.58-6.60 (m, 3H), 6.70-6.72 (m, 2H), 7.14-7.18 (m, 3H), 7.31 (d, J = 8.8 Hz, 1 H), 7.51 (t, J = 7.2 Hz, 1 H), 7.58 (dd, J = 8.8 Hz, J = 4.0 Hz, 1 H), 8.00 (d, J = 8.8 Hz, 1 H), 8.21 (dd, J = 8.8 Hz, J = 1.2 Hz, 1 H), 8.26 (dd, J = 8.4 Hz, J = 1 .6 Hz, 1 H), 9.00 (dd, J = 8.4 Hz, J = 1.6 Hz, 1 H). MS Found: 459 (M+1 ).

Step 4b: (ff)-3-Benzyl-2-(quinolin-8-ylsulfonyl)-2.3-dihvdro-1 -/-benzorc1azepin-4(5H)-one (13)

To a solution of compound 11 (70 mg, 0.15 mmol) in DCM (5 mL) was added Dess-Martin periodinane (440 mg, 1.05 mmol) and the mixture was stirred at rt for 30 min. After the reaction was quenched with aqueous NaHC0₃ (10 mL) the organic layer was separated and the aqueous layer was extracted with DCM. All organic layers were combined, washed with brine, dried (MgS0₄), concentrated in vacuo and purified by prep-TLC (PE/EA = 1/1 ) to give 13 (60 mg, 90%). ¹H-NMP» (400 MHz, CD₃OD): δ 2.80 (dd, J = 14.4 Hz, J = 10.4 Hz, 1 H), 3.17-3.40 (dd, J = 14.4 Hz, J = 5.2 Hz, 1 H), 3.80 (d, J = 14.4 Hz, 1 H), 4.31 (d, J = 14.4 Hz, 1 H), 4.85 (d, J = 17.6 Hz, 1 H), 5.25 (dd, J = 10.4 Hz, J = 5.2 Hz, 1 H), 5.55 (d, J = 17.6 Hz, 1 H), 6.86-7.07 (m, 9H), 7.53-7.59 (m, 2H), 8.02-8.04 (m, 1 H), 8.23-8.29 (m, 2H), 8.80-8.82 (m, 1 H). MS Found: 443 (M+1).

Step 5: (3ff,4S)-3-Benzyl-2-(quinolin-8-ylsulfonyl)-2,3,4.5-tetrahvdro-1 -/-benzofdazepin-4-ol

Example 11 ' was prepared from 11a' similar as described for 11. H-NMR (400 MHz, CD₃OD) δ 2.85-2.91 (m, 1 H), 3.06-3.16 (m, 2H), 3.39-3.43 (m, 1 H), 3.92-3.95 (m, 1 H), 4.61-4.65 (m, 1 H), 4.70-4.72 (m, 1 H), 4.95-4.99 (m, 1 H), 6.55 (d, J = 6.4 Hz, 1 H), 6.74 (t, J = 7.2 Hz, 1 H), 7.93- 7.07 (m, 7H), 7.53 (dd, J = 8.4 Hz, J = 4.4 Hz, 1 H), 7.68 (t, J = 8.0 Hz, 1 H), 8.16 (d, J = 8.4 Hz, 1 H), 8.34 (dd, J = 8.4 Hz, J = 1.6 Hz, 1 H), 8.46 (d, J = 8.0 Hz, 1 H), 8.78 (d, J = 2.8 Hz, 1H). MS Found: 445 (M+1).

Step 6: (3fi.4SV3-Benzyl-4-methoxy-2-(quinolin-8-ylsulfonyl)-2,3.4.5-tetrahvdro-1 H- benzofclazepine (12')

Example 12' was prepared from 11 " similar as described for Example 12. ¹H-NMR (400 MHz, CDCI₃): δ 2.70 (dd, J = 14.0 Hz, J = 6.0 Hz, 1 H), 2.90 (dd, J = 14.0 Hz, J = 7.6 Hz, 1H), 3.15 (d, J = 5.2 Hz, 2H), 3.25 (s, 3H), 3.38 (dd, J = 10.4 Hz, J = 5.2 Hz, 1 H), 4.41 (d, J = 16.4 Hz, 1 H), 4.58 (dd, J = 12.4 Hz, J = 6.0 Hz, 1 H), 5.53 (d, J = 16.4 Hz, 1 H), 6.86-6.97 (m, 2H), 6.97-6.98 (m, 3H), 7.12-7.20 (m, 3H), 7.31 (s, 1 H), 7.47-7.51 (m, 1 H), 7.91 (d, J = 8.0 Hz, 1 H), 8.17 (d, J = 8.0 Hz, 1 H), 8.39 (d, J = 7.2 Hz, 1 H), 9.03 (d, J = 2.8 Hz, 1 H). MS Found: 459 (M+1 ).

Example 14

Step 1 : (fl)-3-((terf-Butoxycarbonyl)amino)-4-phenylbutanoic acid (14a)

(fl)-3-Amino-4-phenylbutanoic acid (10 g, 39.8 mmol) was dissolved in 2M NaOH (100 mL) and cooled to 0°C. Di-fert-butyl dicarbonate (10.4 g, 47.8 mmol) was slowly added. After 0.5 h the reaction mixture was warmed to rt and stirred for further 2 h. The reaction mixture was then acidified to pH 2 using concentrated HCI and extracted with EA (3 x 50 mL). The resulting organic layer was dried (Na₂S0₄) and concentrated in vacuo. The product was used directly in the next reaction without further purification.

Step 2: (fl)-tert-Butyl (4-amino-4-oxo-1-phenylbutan-2-yl)carbamate (14b)

A solution of compound 14a (11 g, 39.Ms4 mmol) in DMF (150 mL) was treated with O- (benzotriazol-1-yl)-/V,/VJ\/',A -tetramethyluronium hexafluorophosphate (HBTU) (18.0 g, 47.3 mmol) and diisopropylethylamine (DIPEA) (15.2 g, 118 mmol) and stirred for 1 h at rt. Then NH₄CI (2.5 g, 47.3 mmol) was added, stirred at rt for 12 h and then water (100 mL) was added into the mixture. The mixture was extracted with EA three times and the combined organic layer was washed with brine and dried over anhydrous Na₂S0₄. After filtration, the filtrate was concentrated in vacuo and the residue was purified by CC (hexane/EA = 2:1) to give compound 14b (9.0 g, 82% over two steps).

Step 3: (flHerf-Butyl (1-cvano-3-phenylpropan-2-yl)carbamate (14c)

To a stirred solution of compound 14b (9.0 g, 32.4 mmol) in DMF (100 mL) at rt was added at once cyanuric chloride (3.9 g, 21.1 mmol). Upon completion of the reaction, water (100 mL) and EA (300 mL) were added to the mixture. The organic phase was separated and washed three times with water (100 ml_) and then dried over Na₂S0₄. The material was filtered, concentrated in vacuo and purified by CC (hexane/EA = 6:1) to give compound 14c (7.1 g, 84%).

Step 4: ( ?)-3-Amino-4-phenylbutanenitrile hydrochloride (14d)

Compound 14c (7.0 g, 26.9 mmol) was treated with 2M HCI in MeOH (200 ml_). After completion of the reaction, the solvents were removed under reduced pressure to give a colorless solid. The intermediate 14d was used directly in the next reaction step without further purification.

Step 5: (f?)-/V-(1-Cvano-3-phenylpropan-2-yl)-2-(trifluoromethoxy)benzenesulfonamide (14e)

To a solution of compound 14d (4.3 g, 26.9 mmol) in DCM (100 mL) was added 2- (trifluoromethoxy)benzenesulfonyl chloride (7.0 g, 26.9 mmol) and TEA (8.2 g, 80.7 mmol). The mixture was stirred at rt for 12 h, then DCM (50 mL) and 2N HCI (20 mL) were added into the mixture. The organic layer was separated and washed with brine and dried over anhydrous Na₂S0₄. After filtration, the filtrate was concentrated in vacuo and the residue was purified by CC (hexane/EA = 5:1) to give compound 14e (7.6 g, 74% over two steps).

Step 6: (fl)-Ethyl 2-(A/-(1-cvano-3-phenylpropan-2-yl)-2- (trif luoromethoxy)phenylsulfonamido)acetate (14f)

To a solution of compound 14e (7.6 g, 19.8 mmol) in DMF (100 mL) was added ethyl bromoacetate (4.0 g, 23.8 mmol) and K₂C0₃ (5.5 g, 39.6 mmol). The mixture was stirred at rt for 12 h, then water (100 mL) was added to the mixture. The mixture was extracted with EA three times and the combined organic layer was washed with brine and dried over anhydrous Na₂S0₄. After filtration, the filtrate was evaporated and the residue was purified by CC (hexane/EA = 5:1) to give compound 14f (6.6 g, 71%).

Step 7: (ffl-Ethyl 2-(/V-(4-amino-1-phenylbutan-2-yl)-2- (trifluoromethoxy)phenylsulfonamido)acetate TFA salt(14q)

To a solution of compound 14f (6.6 g, 14.0 mmol) in MeOH (200 mL) were added Pt0₂ (0.1 g), Pt/C (0.3 g) and TFA (3.5 g). The mixture was hydrogenated in a Parr shaker at 48 psi for 12 h. The mixture was filtered and concentrated. The product 14g was used directly in the next reaction without further purification.

Step 8: (fll-Ethyl 2-(/V-(4-((tetf-butoxycarbonyl)amino)-1-phenylbutan-2-yl)-2- (trifluoromethoxy)phenylsulfonamido)acetate (14h)

To an ice-cooled solution of compound 14g (6.0 g, 12.7 mmol) in DCM (150 mL), TEA (5.1 g, 50.8 mmol) and 4-(dimethylamino)-pyridine (50 mg, 0.4 mmol) were added, followed by the dropwise addition of a solution of di-tert-butyl dicarbonate (3.1 g, 14.0 mmol) in DCM (50 mL). The reaction mixture was stirred for 12 h at rt. The solvent was evaporated and the crude product was dissolved in EA. The organic layer was washed with water, 10% citric acid and brine, dried over anhydrous Na₂S0₄, concentrated in vacuo and purified by CC (hexane/EA = 4:1) to give compound 14h (5.8 g, 80% over two steps). Step 9: (fl)-2-(A/-(4-((ferf-Butoxycarbonyl)amino)-1-phenylbutan-2-yl)-2- (trifluoromethoxy)phenylsulfonamido)acetic acid (140

To a solution of compound 14h (5.8 g, 10.1 mmol) in MeOH/THF (1 :1 , 100 mL) was added aq. LiOH (2N, 50 mL). The mixture was stirred at rt for 2 h. After the reaction was over, 2N HCI (50 mL) was added into the reaction. The mixture was extracted with EA three times and the combined organic layer was washed with brine and dried over anhydrous Na₂S0₄. After filtration, the filtrate was concentrated in vacuo and the residue was purified by CC (hexane/EA = 1 :1) to give compound 14i (4.7 g, 84%).

Step 10: (f?)-2-(A/-(4-Amino-1 -phenylbutan-2-yl)-2-(trif luoromethoxy)phenylsulfonamido)acetic acid TFA salt (14i)

A solution of compound 14i (4.7 g, 8.6 mmol) in DCM (100 mL) was treated with TFA (35 mL). After the reaction was over, the solvents were removed under reduced pressure to give product 14j as a white solid, which was used in the next step without purification.

Step 11 : (ff)-5-Benzyl-4-((2-(trifluoromethoxy)phenyl)sulfonyl)-1 ,4-diazepan-2-one (14k)

To a solution of compound 14j (3.5 g, 7.8 mmol) in DCM (80 mL) was added diisopropyl- ethylamine (4.0 g, 31.2 mmol) and (bis(2-oxo-3-oxazolidin)yl)phosphinic chloride (2.4 g, 9.4 mmol). The reaction mixture was stirred at rt for 5 h under N₂, then DCM (50 mL) and 10% citric acid were added into the mixture. The organic layer was separated and washed with brine, dried over anhydrous Na₂S0₄, concentrated in vacuo and purified by CC (hexane/EA = 3:1) to give compound 14k (2.8 g, 83% over two steps).

Step 12: (ff)-5-Benzyl-4-((2-(trifluoromethoxy)phenyl)sulfonyl)-1 ,4-diazepane-2-thione (14m)

A solution of compound 14k (2.7 g, 6.3 mmol) in toluene (50 mL) was treated with Lawesson's reagent (2.5 g, 6.3 mmol), heated at 80°C for 30 min, cooled to rt, treated with NaHC0₃ (532 mg, 6.3 mmol) and stirred for 10 min. The mixture was extracted with EA (3 x) and the combined organic layer was washed with brine, dried over anhydrous Na₂S0₄, evaporated and purified by CC (hexane/EA = 4:1) to give compound 14m (2.2 g, 80%).

Step 13: (ffl-7-Benzyl-8-((2-(trifluoromethoxy)phenvhsulfonyl)-6.7,8.9-tetrahvdro-5H- imidazoM ,2-a1f1 ,4ldiazepine (14)

A solution of compound 14m (150 mg, 0.34 mmol) in THF (15 mL) was cooled to 0°C, treated with Hg(OAc)₂ (121 mg, 0.37 mmol) and H₂NCH₂CH(OCH₃)₂ (178 mg, 1.7 mmol), stirred for 2 h, diluted with Et₂0 (20 mL), filtered through Celite and concentrated to dryness. A solution of the residue in toluene/H₂0 (30:1 , 15 mL) was treated with TsOH-H₂0 (256 mg, 1.36 mmol) and stirred at 75°C for 12 h. The mixture was diluted with EA (30 mL) and washed with saturated K₂C0₃. The aqueous layer was extracted with EA (20 mL). The combined organic layers were dried over Na₂S0₄, filtered, concentrated in vacuo and purified by prep-HPLC to give compound 14 as a white solid (98 mg, 64%). 'H-NMR (400 MHz, CDCI₃): δ 7.95 (d, 1H), 7.61 (t, 1H), 7.39 (t, 1 H), 7.31 (d, 1 H), 7.24-7.12 (m, 4H), 7.08-6.95 (m, 3H), 5.31 (d, 1 H), 4.65 (d, 1 H), 4.55-4.15 (m, 1 H), 4.35-4.15 (m, 2H), 2.80 (d, 1 H), 2.35-2.23 (m, 1 H), 2.20-2.06 (m, 1 H). MS Found: 451.7 [M+H]⁺.

Example 15

Step 1 : (ff)-7-Benzyl-3-met yl-8-((2-ftrifluoromethoxy)phenyl)sulfonyl)-6.7.8.9-tetrahvdro-5H- Π .2.41triazolor4.3-airi .41diazepine (15)

A solution of compound 14m (150 mg, 0.34 mmol) in THF (15 mL) was cooled to 0°C, treated with Hg(OAc)₂ (121 mg, 0.37 mmol) and CH₃CONHNH₂ (126 mg, 1 .7 mmol), stirred for 2 h, diluted with Et₂0 (20 mL), filtered through Celite and concentrated to dryness. A solution of the residue in toluene/H₂0 (30:1 , 15 mL) was treated with TsOH H₂0 (256 mg, 1.36 mmol) and stirred at 75°C for 12 h. The mixture was diluted with EA (30 mL) and washed with saturated K₂C0₃. The aqueous layer was extracted with EA (20 mL). The combined organic layers were dried over Na₂S0₄, filtered, concentrated in vacuo and purified by prep-HPLC to give compound 15 as a white solid (87 mg, 55%). ¹H-NMR (400 MHz, CDCI₃): δ 7.96 (d, 1 H), 7.63 (t, 1 H) 7.40 (t, 1 H), 7.32 (d, 1 H), 7.23-7.15 (m, 3H), 7.00 (d, 2H), 5.20 (d, 1 H), 4.60-4.42 (m, 2H), 4.30-4.18 (m, 1 H), 3.96 (t, 1 H), 2.85-2.70 (m, 2H), 2.56 (s, 3H), 2.35-2.10 (m, 2H). MS Found: 467.0 [M+H]⁺.

Example 16

Step 1 : (ff)-7-Benzyl-8-((2-(trifluoromethoxy)phenvnsulfonyl)-6.7.8,9-tetrahvdro-5/- - Π .2.41triazolor4.3-airi ,41diazepine (16)

A solution of compound 14m (150 mg, 0.34 mmol) and NH₂NHCHO (82 mg, 1.36 mmol) in n- BuOH (2 mL) was heated under microwave irradiation to 160°C for 3 h. The mixture was purified by prep-HPLC to give target compound 16 as a white solid (80 mg, 52%). ¹H-NMR (400 MHz, CDCI₃): δ 8.52 (br s, 1 H), 7.99 (d, 1 H), 7.62 (t, 1 H), 7.40 (t, 1 H), 7.31 (d, 1 H), 7.25-7.15 (m, 3H), 7.00-7.05 (m, 2H), 5.35 (d, 1 H), 4.58-4.40 (m, 2H), 4.38-4.30 (m, 1 H), 4.13 (t, 1 H), 2.84 (d, 2H), 2.38-2.25 (m, 1 H), 2.10-2.00 (m, 1 H). MS Found: 452.7 [M+H]⁺. Example 17

Step 1 : 1-Phenyl-4-(trimethylsilyl)but-3-vn-2-ol (17a)

To a solution of trimethylsilylacetylene (12.7 mL, 90 mmol) in THF (350 mL), n-BuLi (57.6 mL, 108 mmol) was added dropwise at -78°C. The mixture was stirred at this temperature for 20 min and then phenylacetaldehyde (14.4 mL, 90 mmol) was added dropwise. The resulting solution was stirred at -78°C for 50 min, then a saturated NH₄CI solution (80 mL) was added. The mixture was extracted with DCM (3 x 250 mL), dried over Na₂S0₄, filtered and concentrated. The residue was purified by CC (PE/EA = 9:1) to afford compound 17a (10.3 g, 53%) as a yellow oil.

Step 2: 1-Phenylbut-3-vn-2-ol (17b)

To a solution of compound 17a (7.52 g, 34.5 mmol) in MeOH/DCM (1 :1 , 200 mL) was added Na₂C0₃ (21.9 g, 207 mmol). The solution was stirred at rt overnight. Water (200 mL) was added, the mixture was extracted with DCM (3 x 200 mL) and the combined organic layers were dried over anhydrous Na₂S0₄ and concentrated under reduced pressure to afford compound 17b (5.3 g), which was used without further purification in the next step.

Step 3: Methyl 2-(3-hvdroxy-4-phenylbut-1-vn-1-yl)benzoate (17c)

To a solution of Et₃N (150 mL), Pd(PPh₃)₂CI₂ (2 mol%), compound 17b (crude 34.5 mmol) and methyl-2-iodobenzoate (9.0 g, 34.5 mmol) was added Cul (1 mol%). The reaction mixture was flushed with Ar and the flask was sealed. The mixture was stirred at rt for 2 h. The resulting solution was filtered, water (200 mL) was added and the mixture was extracted with DCM (3 x 200 mL). The combined organic layer was washed with brine (3 x 150 mL), dried over Na₂S0₄ and concentrated under vacuum and purified by CC (PE/EA = 5:1) to afford compound 17c (7.6 g, 79% over two steps) as a yellow oil.

Step 4: Methyl 2-(3-hvdroxy-4-phenylbutyl)benzoate (17d)

A solution of compound 17c (3.8 g, 13.6 mmol) in MeOH (60 mL) was hydrogenated using 10% Pd/C (1.36 g) as catalyst at atmospheric pressure overnight. The catalyst was removed by filtration and the solvent was evaporated under reduced pressure to afford crude compound 17d (3.8 g) as a yellow oil.

Step 5: Methyl 2-(3-((methylsulfonyl)oxy)-4-phenylbutyl)benzoate (17e)

To a solution of compound 17d (crude 13.6 mmol) and Et₃N (3.78 mL, 27.1 mmol), MeS0₂CI (1.6 mL, 20.4 mmol) was added dropwise at 0°C. After addition was complete, the mixture was stirred at rt until LC-MS analysis indicated the total consumption of the starting material. The solvent was removed and the residue was purified by CC (ΡΕΞ/ΕΑ = 5:1) to afford of compound 17e (3.42 g, 70% over two steps) as a white solid.

Step 6: Methyl 2-(3-azido-4-phenylbutvnbenzoate (17f)

Sodium azide (1.5 g, 18.9 mmol) and 15-crown-5 (0.21 mL, 0.95 mmol) were added to a stirred solution of compound 17e (3.42 g, 9.45 mmol) in DMF (60 mL). The mixture was heated to 85°C for 24 h under argon atmosphere. Then DCM (300 mL) was added, the solution was washed with saturated NaHC0₃ solution (2 x 150 mL) and brine (3 x 200 mL) and dried with Na₂S0₄. After removal of the solvent under reduced pressure, crude compound 17f (2.95 g) was obtained as a yellow oil. It was used without further purification in the next step.

Step 7: Methyl 2-(3-amino-4-phenylbutyl)benzoate (17q)

A solution of compound 17f (crude 4.73 mmol) in MeOH (40 mL) was hydrogenated using 10% Pd/C (473 mg) as catalyst at atmospheric pressure overnight. The catalyst was removed by filtration and the solvent was evaporated at reduced pressure to afford crude compound 17g (1.35 g) as a yellow oil.

Step 8: Methyl 2-(3-((fert-butoxycarbonyl)amino)-4-phenylbutyl)benzoate (17h)

To a solution of compound 17g (crude 9.45 mmol) and Et₃N (1.3 mL, 9.45 mmol) in DCM (60 mL), (Boc)₂0 (2 mL, 9.45 mmol) was added dropwise at 0°C. The mixture was stirred at rt until TLC analysis indicated the total consumption of the starting material. The solvent was removed and the residue was purified by CC (PE/EA = 7:1) to afford compound 17h (2.48 g) as a white solid.

Step 9: tert-Butyl (4-(2-(hvdroxymethyl)phenyl)-1-phenylbutan-2-yl)carbamate (17i)

Compound 17h (1.0 g, 2.6 mmol) in THF (5 mL) was added dropwise to a stirred solution of UAIH₄ (198 mg, 5.22 mmol) in THF (25 mL) at 0°C. Then the mixture was stirred at rt until TLC analysis indicated the total consumption of the starting material. The reaction was quenched carefully by the slow addition of water (10 mL) and then the liquid was decanted from the precipitate. The precipitate was washed with DCM (3 x 50 mL) and the organic layers were combined and dried over Na₂S0₄, evaporated and purified by CC (PE/EA = 6:1) to afford compound 17i (678 mg, 73%) as a white solid.

Step 10: tert-Butyl (4-(2-(bromomethyl)phenyl)-1-phenylbutan-2-yl)carbamate (17j)

To a mixture of /V-bromo-succinimide (267 mg, 1.5 mmol) and PPh₃ (393 mg, 1.5 mmol) in DCM (25 mL) was added a solution of compound 17i (355 mg, 1.0 mmol) in DCM (15 mL) at rt. The mixture was stirred at rt until TLC analysis indicated the total consumption of the starting material. The solvent was removed and the residue was purified by CC (PE/EA = 8:1) to afford compound 17j (300 mg, 72%) as a white solid.

Step 11 : 4-(2-(Bromomethyl)phenyl)-1-phenylbutan-2-amine TFA salt (17k) To a solution of compound 17j (0.2 g, 0.48 mmol) in DCM (20 mL) was added TFA (547 mg, 4.8 mmol). The solution was stirred at rt until TLC analysis indicated the total consumption of the starting material. Then the solvent was removed to get crude compound 17k (160 mg) as a yellow oil.

Step 12: 3-Benzyl-2,3A5-tetrahvdro-1 /-/-benzodiazepine (17m)

To a solution of compound 17k (crude 0.48 mmol th.) in THF (30 mL) was added K₂C0₃ (132 mg, 0.96 mmol). The mixture was stirred at rt until LC-MS analysis indicated the total consumption of the starting material in about 3 h. Then the solid was removed by filtration and the solution was concentrated under reduced pressure to obtain crude compound 17m (120 mg).

Step 13: 3-Benzyl-2-(quinolin-8-ylsulfonyl)-2,3,4,5-tetrahvdro-1 -/-benzorc1azepine (17)

To a solution of compound 17m (crude 0.48 mmol th.), Et₃N (0.1 mL, 0.72 mmol) and 4- (dimethylamino)-pyridine (11.7 mg, 96 μιτιοΙ) in DCM (25 mL), quinoline-8-sulfonyl chloride (163 mg, 0.72 mmol) in DCM (5 mL) was added dropwise at 0°C. After the addition was complete, the solution was stirred at rt overnight. The mixture was washed with water (2 x 30 mL) and brine. The organic layer was combined, dried over Na₂S0₄ and concentrated in vacuo. MeOH (10 mL) was added to the residue and the precipitate was filtered to give compound 17 (100 mg, 49% over three steps) as a white solid. ¹H-NMR (500 MHz, CDCI₃): δ 8.97 (dd, 1 H), 8.45 (dd, 1 H), 8.11 (dd, 1 H), 7.90 (dd, 1 H), 7.53 (t, 1 H), 7.44 (dd, 1 H), 7.19 (d, 1 H), 7.03-6.95 (m, 5H), 6.88-6.91 (m, 3H), 5.33 (d, 1 H), 4.57 (m, 1 H), 4.51 (d, 1 H), 2.95 (m, 1 H), 2.78 (m, 1 H), 2.68- 2.57 (m, 2H), 1.92 (m, 1H), 1.78 (m, 1 H). MS Found: 429.1 [M+H]⁺.

Example 18

Step 1 : (f?)-fert-Butyl (1-hvdroxy-3-phenylpropan-2-yl)carbamate (18a)

To a solution of (f?)-2-amino-3-phenylpropan-1-ol (20 g, 132 mmol) in dry DCM (350 mL) was added (Boc)₂0 (29 g, 132 mmol) at 0°C. The solution was stirred at 0°C for 0.5 h and then stirred overnight at rt. The solution was washed with 20% phosphoric acid, sat. NaHC0₃ solution and brine, then dried (Na₂S0₄) and concentrated under reduced pressure to give compound 18a (33 g, 100%) as a solid.

Step 2: (f?)-terf-Butyl (1-bromo-3-phenylpropan-2-yl)carbamate (18b) To a solution of compound 18a (33 g, 132 mmol) and CBr₄ (57.2 g, 172 mmol) in DCM (350 mL) was added PPh₃ (46.9 g, 179 mmol) at 0°C under a N₂ atmosphere. The solution was stirred overnight at rt. The mixture was concentrated under reduced pressure and purified by CC (PE/EA = 8:1) to give compound 18b (15 g, 36%) as a white solid.

Step 3: Methyl 2-mercaptobenzoate (18c)

To a solution of 2-mercaptobenzoic acid (34 g, 220 mmol) in dry MeOH (150 mL) was added cone. H₂S0₄ (4 mL) and the reaction was refluxed for 48 h. The solution was concentrated under reduced pressure and the residue was diluted with DCM and then sat. NaHC0₃ solution. The organic phase was washed with brine, dried over Na₂S0₄ and concentrated under reduced pressure to give compound 18c (35 g, 94%) as a yellow oil.

Step 4: (flVMethyl 2-((2-((te/ -butoxycarbonyl)amino)-3-phenylpropyl)thio)benzoate (18d)

To a solution of compound 18c (6.0 g, 36 mmol) in dry DMF (160 mL) was added K₂C0₃ (10.4 g, 74 mmol) and the solution was stirred at rt for 10 min. Then a solution of compound 18b (10 g, 32 mmol) in DMF (60 mL) was added and the mixture was stirred at 60°C for another 4 h. The mixture was filtered, concentrated in vacuo and purified by CC (PE/EA = 8:1) to give compound 18d (11 g, 86%) as a white solid.

Step 5: (/^-2-((2-((ferf-Butoxycarbonyl)amino)-3-phenylpropyl)thio)benzoic acid (18e)

To a solution of compound 18d (11 g, 27 mmol) in THF (100 mL) was added a solution of LiOH-H₂0 (5.7 g, 137 mmol) in H₂0 (40 mL). After stirring at 55°C overnight, the resulting solution was concentrated under reduced pressure and then sat. citric acid solution was added to adjust pH = 5. The solution was lyophilized, the obtained solid was dissolved in MeOH (20 mL) and the insoluble solid was filtered off. The cake was washed with MeOH (5 mL) and the combined filtrates were concentrated under reduced pressure to give crude compound 18e (9.7 g, 93%) as a white solid.

Step 6: (fl)-2-((2-Amino-3-phenylpropyl)thio)benzoic acid (18f)

To a solution of compound 18e (9.7 g, 25 mmol) in dry MeOH (50 mL) was added HCI/EA solution and the solution was stirred at rt for 1 h. The mixture was concentrated in vacuo and Et₂0 was added to the residue. The formed solid was filtered to give compound 18f (7.3 g, 90%) as a white solid.

Step 7: (ff)-3-Benzyl-3.4-dihvdrobenzor in,41thiazepin-5(2 y)-one (18q)

To a solution of compound 18f (7.3 g, 22.5 mmol) in dry DMF (200 mL) was added diisopropylethylamine (3.7 g, 29 mmol) and 2-(1 /-/-7-azabenzotriazol-1-yl)-1 ,1 ,3,3-tetramethyl uronium hexafluorophosphate (HATU) (11 g, 29 mmol). The reaction mixture was stirred at rt overnight, concentrated under reduced pressure and purified by CC (PE/EA = 1 :1) to give compound 18g (4.1 g, 68%) as a white solid.

Step 8: (fi)-3-Benzyl-2.3.4.5-tetrahvdrobenzorfin .41thiazepine (18h) To a solution of compound 18g (2.7 g, 10 mmol) in dry THF (50 mL) was added LiAIH₄ (1.9 g, 50 mmol) and the solution was heated at reflux for 30 h. The mixture was concentrated under reduced pressure and purified by CC (EA/PE = 1:1) to give compound 18h (1.8 g, 70%) as a white solid.

Step 9: (fi)-3-Benzyl-4-(auinolin-8-ylsulfonyl)-2.3.4.5-tetrahvdrobenzor/iri,41thiazeDine (18)

To a solution of compound 18h (200 mg, 0.78 mmol) in dry DCM (10 mL) was added TEA (200 mg, 1.98 mmol) and the solution was stirred at rt for 10 min. Then a solution of quinoline-8- sulfonyl chloride (370 mg, 1.8 mmol) in dry DCM (10 mL) was added. After stirring overnight at rt, the resulting solution was concentrated under reduced pressure and purified by prep-HPLC to give compound 18 (85 mg, 24%) as a white solid. H-NMR (CDCI₃, 400 MHz): δ 2.50-2.54 (1 H, m), 2.75-2.79 (1 H, m), 3.10-3.14 (1 H, m), 3.26-3.32 (1 H, m), 4.64-4.67 (1 H, m), 4.77 (1 H, d, J = 16.0 Hz), 5.47 (1 H, d, J = 16.0 Hz), 6.82 (1 H, d, J = 6.0 Hz), 6.99-7.05 (3H, m), 7.12-7.23 (2H, m), 7.48-7.52 (3H, m), 7.62-7.66 (1 H, m), 8.02 (1 H, dd, J = 8.0 Hz, 1.2 Hz), 8.19 (1 H, dd, J = 8.4 Hz, 2.0 Hz), 8.52 (1 H, dd, J = 6.8 Hz, 1.2 Hz), 9.05 (1 H, dd, J = 4.0 Hz, 2.0 Hz). MS Found: 447 (M+1).

Example 19

Step 1 : (flHert-Butyl 3-benzyl-2.3-dihvdrobenzor in .41thiazepine-4(5H)-carboxylate (19a)

To a solution of compound 18h (1.15 g, 4.5 mmol) in dry DCM (40 mL) was added solid (Boc)₂0 (1.08 g, 4.9 mmmol) at 0°C. The solution was stirred at 0°C for 0.5 h and then stirred at rt overnight. The solution was washed with 20% phosphoric acid, sat. NaHC0₃ solution and brine consecutively, dried over Na₂S0₄, filtered and concentrated under reduced pressure to give compound 19a (1.2 g, 75%) as a solid.

Step 2: (ffl-tert-Butyl 3-benzyl-2.3-dihvdrobenzorr1f1 ,41thiazepine-4(5/-/)-carboxylate 1.1-dioxide 09bl

To the solution of compound 19a (1.2 g, 3.4 mmol) in dry DCM (30 mL) was added meta- chloroperoxybenzoic acid (1.16 g, 6.8 mmol) at 0°C and the solution was stirred at 0°C for 2 h. The solution was washed with 5% NaOH solution and brine, dried over Na₂S0₄ and concentrated under reduced pressure to give compound 19b (0.9 g, 68%) as a solid.

Step 3: (f?)-3-Benzyl-2.3.4,5-tetrahvdrobenzof iri .41thiazepine 1.1-dioxide hydrochloride (19c) To a solution of compound 19b (0.9 g, 2.3 mmol) in dry EA (5 mL) was added HCI/EA solution and the solution was stirred at rt overnight. The mixture was concentrated in vacuo and Et₂0 was added to the residue. The formed solid was filtered off to give of compound 19c (0.5 g, 75%) as a white solid.

Step 4: (f?)-3-Benzyl-4-(quinolin-8-ylsulfonyl)-2,3,4.5-tetrahvdrobenzofriri .41thiazepine 1 ,1- dioxide (19)

To a solution of compound 19c (288 mg, 1 mmol) in dry pyridine (5 mL) was added quinoline-8- sulfonyl chloride (250 mg, 1.1 mmol) and the solution was reacted under microwave at 100°C for 2 h. The mixture was concentrated under reduced pressure and purified by prep-HPLC to give compound 19 (60 mg, 13%) as a yellow solid. H-NMR (CDCI₃, 400 MHz): δ 3.03-3.08 (1H, m), 3.20-3.25 (1H, m), 3.79 (1 H, d, J = 3.6 Hz), 4.76 (1H, m), 5.16 (1H, d, J = 16.8 Hz), 5.40 (1 H, d, J = 16.4 Hz), 6.92-6.94 (5H, m), 7.35-7.45 (3H, m), 7.61-7.69 (2H, m), 7.75 (1H, d, J = 7.2 Hz), 8.18 (1 H, d, J = 8.0 Hz), 8.3 (1 H, d, J = 7.2 Hz), 8.39 (1H, d, J = 8.0 Hz), 8.99 (1 H, d, J = 2.8 Hz). MS Found: 479 (M+1).

Example 20

Step 1 : (S)-Benzyl (1-(fert-butoxy)-3-hvdroxypropan-2-yl)carbamate (20a)

To BH₃ (136 mL, 136 mmol, 1 M in THF) at 0°C was added dropwise over 30 min a solution of (f?)-2-(benzyloxycarbonylamino)-3-terf-butoxypropanoic acid (20 g, 67.8 mmol) in THF (150 mL). The reaction mixture was stirred at 0°C for 2 h. Excess borane was quenched with AcOH (10% in MeOH, 200 mL). The volatiles were removed in vacuo and the residue was purified by CC to give compound 20a (14 g, 74%). LCMS (m/ ): 282.2 (MH⁺).

Step 2: (S)-Methyl 2-(2-(((benzyloxy)carbonyl)amino)-3-(te/t-butoxy)propoxy)benzoate (20b)

To a solution of PPh₃ (16.6 g, 60 mmol) in THF (100 mL) at 0°C was dropped diisopropyl azodicarboxylate (12.8 g, 60 mmol). The mixture was stirred for 0.5 h and then compound 20a (14 g, 50 mmol) and methyl salicylate (7.6 g, 60 mmol) were added. The resulting mixture was allowed to warm to rt and stirred for 16 h. The mixture was concentrated under reduced pressure and purified by CC to give compound 20b (16 g, 77%). LCMS (m/z): 416.1 (MH⁺).

Step 3: (5)-Benzyl (1-(ferf-butoxy)-3-(2-(hvdroxymethyl)phenoxy)propan-2-yl)carbamate (20c)

A solution of compound 20b (16 g, 38.5 mmol) in EtOH/THF (300 mL, v/v = 1/1) was treated with CaCI₂ (16.9 g, 154 mmol) and the resulting slurry was cooled in an ice bath under argon. To this mixture was added NaBH₄ (11.7 g, 308 mmol) portionwise. After 1 h the ice bath was removed and the reaction mixture was allowed to warm to rt and stirred for 16 h. The mixture was quenched with 10% Na₂C0₃ and water and the resulting thick, white slurry was extracted with EA (3 x 50 ml_). The combined organic layers were washed with brine, dried over Na₂S0₄, concentrated and purified by CC to give compound 20c (12.2 g, 82%). LCMS (m/z): 388.2 (MH⁺).

Step 4: (5H2-(2-Amino-3-(tert-butoxy)propoxy)phenyl)methanol (20d)

To a solution of compound 20c (12.2 g, 31.5 mmol) in MeOH (150 ml_) was added 10% Pd/C (1.5 g). The mixture was stirred at rt under a H₂ atmosphere overnight. The mixture was filtered and the filtrate was concentrated under reduced pressure and the residue 20d (7.0 g, 88%) was used without purification. LCMS {m/z): 254.1 (MH⁺).

Step 5: (SRert-butyl (1 -(fe/i-butoxy)-3-(2-(hvdroxymethyl)phenoxy)propan-2-yl)carbamate (20e)

A solution of compound 20d (7.0 g, 27.6 mmol) in DCM (50 mL) containing (Boc)₂0 (9.0 g, 41.5 mmol) and TEA (8.4 g, 81.8 mmol) was stirred at rt for 1 h, then concentrated under reduced pressure and the residue (8.6 g, 88%) was used in the next step without purification. LCMS (m/z): 354.1 (MH⁺)

Step 6: (SHert-Butyl (1-(2-(bromomethyl)phenoxy)-3-(feff-butoxy)propan-2-yl)carbamate (20f) A solution of compound 20e (8.6 g, 24.3 mmol) in CCI₄ (50 mL) was cooled in an ice bath. To this mixture was added PBr₃ (2.8 g, 12.2 mmol) dropwise and the mixture was stirred at 0°C for 2 h. The mixture was quenched with water and extracted with DCM. The combined organic layers were washed with brine and concentrated. The crude product 20f (6.6 g, 65%) was used in the next step without purification. LCMS (m/z): AM A (MH⁺).

Step 7: (S)-1-(2-(Bromomethyl)phenoxy)-3-(ferf-butoxy)propan-2-amine TFA salt (20q)

A solution of compound 20f (6.6 g, 15.8 mmol) in TFA/DCM (60 mL, v/v = 1/4) was stirred at rt for 1 h. The mixture was concentrated under reduced pressure and the residue 20g (4.6 g) was used in the next step without further purification. LCMS (m/z): 317.1 (MH⁺).

Step 8: (S)-3-(te/†-Butoxymethyl)-2.3.4.5-tetrahvdrobenzorfln .41oxazepine (20h)

To a solution of compound 20g (4.6 g, 14.5 mmol) in THF (30 mL) was added K₂C0₃ (10.0 g, 72.5 mmol) portionwise. The mixture was stirred at rt overnight, concentrated under reduced pressure and purified by CC to give compound 20h (660 mg, 19%). LCMS (m/z): 236.1 (MH⁺).

Step 9: (S)-3-(tert-Butoxymethyl)-4-(auinolin-8-ylsulfonyl)-2.3,4,5

tetrahydrobenzofflfl ,41oxazepine (20)

A solution of compound 20h (660 mg, 2.8 mmol), quinoline-8-sulfonyl chloride (770 mg, 3.4 mmol), TEA (850 mg, 8.4 mmol) and 4-(dimethylamino)-pyridine (245 mg, 1.4 mmol) in DCM (20 mL) was stirred at rt overnight. The mixture was concentrated and purified by CC to give compound 20 (600 mg, 50%) as a white solid. ¹H-NMR (500 MHz, CDCI₃): δ 8.98 (m, 1 H), 8.32 (d, 1 H), 8.10 (d, 1 H), 7.84 (d, 1 H), 7.45-7.38 (m, 2H), 6.96 (d, 1 H), 6.85 (t, 1 H), 6.73 (t, 1 H), 6.37 (d, 1H), 5.05 (d, 1H), 4.95 (m, 1H), 4.85 (d, 1H), 4.46 (dd, 1H), 4.10 (dd, 1H), 3.70 (dd, 1H), 3.52 (m, 1H), 1.01 (s, 1H). MS Found: 427.5 (MH⁺).

Example 21

(fl)-(4-(Quinolin-8-ylsulfonyl)-2.3.4.5-tetrahvdrobenzorflri.41oxazepin-3-yl)methanol (21)

A solution of compound 20 (500 mg, 1.2 mmol) in TFA (10 mL) was stirred at 0°C for 1 h. The mixture was diluted with DCM and aqueous K₂C0₃ was added portionwise until the pH was up to 7. The mixture was extracted with DCM and the combined organic layers were concentrated under reduced pressure and purified by CC to give compound 21 (370 mg, 84%). H-NMR (500 MHz, CDCI₃): δ 8.99 (m, 1H), 8.48 (d, 1H), 8.21 (d, 1H), 7.99 (d, 1H), 7.57-7.51 (m, 2H), 7.04- 7.00 (m, 2H), 6.88 (t, 1H), 6.65 (d, 1H), 5.01 (m, 1H), 4.66 (m, 2H), 4.36 (dd, 1H), 4.14 (dd, 1H), 4.03 (dd, 1H), 3.85 (m, 1H), 2.19 (br s, 1H). MS Found: 371.1 (MH⁺).

Example 22

( f?)-3-(Methoxymethyl)-4-(auinolin-8-ylsulfonyl)-2.3.4.5-tetrahvdrobenzorrin .41oxazepine (22)

NaH (21 mg, 60% in oil, 0.54 mmol) was added portionwise to a solution of compound 21 (100 mg, 0.27 mmol) in anhydrous THF (10 mL) at 0°C. To this mixture was added Mel (57 mg, 0.40 mmol) dropwise and the mixture was allowed to reach rt and stirred for 3 h. The reaction was quenched by the addition of ice and EA, extracted with EA and the combined organic phase was washed with brine and dried (Na₂S0₄). Evaporation of the solvent provided the crude product, which was purified by prep-TLC to afford compound 22 (35 mg, 34%). H-NMR (500 MHz, CDCI₃): δ 9.00 (m, 1H), 8.32 (d, 1H), 8.11 (d, 1H), 7.85 (d, 1H), 7.46-7.40 (m, 2H), 6.93 (d, 1H), 6.83 (m, 1H), 6.71 (t, 1H), 6.37 (d, 1H), 5.07 (m, 1H), 5.00 (d, 1H), 4.78 (d, 1H), 4.41 (dd, 1H), 4.07 (dd, 1H), 3.71 (dd, 1H), 3.57 (dd, 1H), 3.19 (s, 1H). MS Found: 385.1 (MH⁺). Example 23

(fl)-3-((Benzyloxy)methyl)-4-(quinolin-^ (23)

In a similar manner as that described in Example 22 compound 23 was prepared. ¹H-NMR (500 MHz, DMF-d₇): δ 8.95 (m, 1H), 8.45 (d, 1 H), 8.07 (d, 1 H), 7.82 (d, 1H), 7.43-7.38 (m, 2H), 7.32- 7.27 (m, 3H), 7.18 (d, 1 H), 6.92 (d, 1 H), 6.84 (t, 1 H), 6.72 (t, 1 H), 6.37 (d, 1 H), 5.15 (m, 1 H), 4.99 (d, 1H), 4.80 (d, 1 H), 4.50-4.33 (m, 3H), 4.12 (d, 1 H), 3.82 (m, 1 H), 3.68 (m, 1 H). MS Found: 461.1 (MH⁺).

Example 24

Step 1 : (S)-(4-(Quinolin-8-ylsulfonyl)-2.3,4,5-tetrahvdrobenzorriri ,41oxazepin-3-yl)methyl methanesulfonate (24a)

A solution of compound 21 (400 mg, 1.08 mmol) and TEA (327 mg, 3.24 mmol) in DCM (10 mL) was cooled in an ice bath under nitrogen. To this mixture was added MeS0₂CI (369 mg, 3.24 mmol). The reaction mixture was stirred at 0°C for 3 h and quenched with aq. NaHC0₃ and the aqueous layers was extracted with EA (3 x 20 mL). The combined extracts were concentrated to get compound 24a (300 mg, 62%). MS Found: 449.1 (MH⁺).

Step 2: ( ff)-3-(Morpholinomethyl)-4-(auinolin-8-ylsulfonyl)-2.3.4,5- tetrahydrobenzof f\ 1 ,41oxazepine (24)

A mixture of compound 24a (100 mg, 0.22 mmol), anhydrous K₂C0₃ (92 mg, 0.66 mmol) and morpholine (38 mg, 0.44 mmol) in anhydrous EtOH (10 mL) was stirred at rt for 18 h. The solvent was evaporated and the residue was diluted with DCM and washed with water and brine. The organic extracts were dried over anhydrous Na₂S0₄, filtered, concentrated and purified by prep-TLC to give compound 24 (34 mg, 34%). ¹H-NMR (500 MHz, CDCI₃): δ 8.95 (m, 1 H), 8.10 (dd, 2H), 7.80 (d, 1H), 7.44 (m, 1 H), 7.28 (t, 1 H), 6.77 (d, 1H), 6.72 (t, 1 H), 6.62 (t, 1 H), 6.12 (d, 1 H), 6.00 (br s, 1 H), 4.66 (m, 2H), 4.15 (m, 1 H), 3.97-3.92 (m, 7H), 4.44 (m, 2H), 3.10 (m, 2H). MS Found: 440.1 (MH⁺). Example 25

( ^-3-(Piperidin-1-ylmethyl)-4-(guinolin-8-ylsulfo^

(25)

In a similar manner as that described in Example 24 compound 25 was prepared. ¹H-NMR (500 MHz, CDCI₃): δ 9.00 (m, 1 H), 8.40 (d, 1 H), 8.14 (d, 1H), 7.91 (d, 1H), 7.49-7.45 (m, 2H), 7.04 (m, 1H), 6.96 (m, H), 6.82 (m, 1H), 6.60 (m, 1H), 5.05 (d, 1H), 4.69 (m, 1H), 4.62 (d, 1H), 4.41 (m, 1 H), 4.07 (m, 1H), 2.75 (m, 1H), 2.29-2.17 (m, 5H), 1.34-1.25 (m, 6H). MS Found: 438.1 (MH⁺).

Example 26/1 to 26/2

If one were to use the appropriate building blocks as described in Example 9, one would obtain the following compounds:

# structure # structure

Step 1 : Phenyl(6-((2-(trifluoromethoxy)phenyl)sulfonyl)-6,7-dihvdro-5H-imidazo[1.2-alPyridoi3,2- flf ,41diazepin-7-yl)methanol (27)

If one were to use ethyl 2-amino-3-hydroxy-3-phenylpropanoate similar as described in Example 9, one would obtain Example 27.

Step 2: Phenyl(6-((2-(trifluoromethoxy)phenyl)sulfonyl)-6.7-dihvdro-5H-imidazori.2-alPyridor3.2- f\\ 1 ,41diazepin-7-yl)methanone (28) If one were to treat Example 27 with Mn0₂ or another oxidation reagent (e.g. Swern reagent) one would obtain Example 28.

Step 3: 7-(Difluoro(phenyl)methyl)-6-((2-(trifluoromethoxy)phenyl)sulfonyl)-6.7-dihvdro-5H- imidazoH ,2-alpyridor3,2-firi ,41diazepine (29)

If one were to treat Example 28 with a fluorinating reagent e.g. diethylaminosulfur trifluoride or Fluolead (J. Am. Chem. Soc. 2010, 132:18199) one would obtain Example 29.

Step 4: 7-(Fluoro(phenyl)methyl)-6-((2-(trifluoromethoxy)phenyl)sulfonyl)-6,7-dihvdro-5H- imidazof 1 ,2-a]Dyr\do\3,2-f\[ 1 ,41diazepine (30)

If one were to treat Example 27 with a fluorinating reagent e.g. diethylaminosulfur trifluoride or Fluolead (J. Am. Chem. Soc. 2010, 132:18199) one would obtain Example 30.

Example 31 to 35

Step 1 : (7ff)-7-Benzyl-10-bromo-6-((5-fluoro-2-(trifluoromethoxy)phenyl)sulfonyl)-6,7-dihydro- 5H-imidazof1 ,2-alPyrazinoF2.3- li1 ,41diazepine (31)

If one were to treat the final compound from Example 9/12 with A/-bromosuccinimide similar as described in WO2007/121390 one would obtain Example 31.

Step 2: (7ff)-7-Benzyl-10-fluoro-6-((5-fluoro-2-(trifluoromethoxy)phenyl)sulfonyl)-6,7-dihvdro-5H- imidazoH .2-alpyrazinof2,3-flf1 ,41diazepine (32)

If one were to treat the final compound from Example 31 similar as outlined in Org. Lett. 2009, 11 :2860 or J. Am. Chem. Soc. 2010, 132:12150 one would obtain Example 32.

Step 3: (7f?)-7-Benzyl-10-chloro-6-((5-fluoro-2-(tnfluoromethoxy)phenyl)sulfonyl)-6.7-dihvdro- 5H-imidazof 1 ,2-a1pyrazinor2,3-flH ,41diazepine (33)

If one were to treat the final compound from Example 9/12 similar as described in Perkin Trans. 1 , 1990, 1645 or Bioorg. Med. Chem. Lett. 2010, 20:4045 one would obtain Example 33.

Step 4: (7f?)-7-benzyl-6-((5-fluoro-2-(trifluoromethoxy)phenyl)sulfonyl)-6,7-dihvdro-5 -/- imidazoH ,2-alpyrazinof2,3-f1H ,4ldiazepine-10-carbonitrile (34)

If one were to treat the final compound from Example 31 with Zn(CN)₂ using Pd(PPh₃)₄ as catalyst one would obtain Example 34. Step 5: (7^-7-benzyl-6-((5-fluoro-2-(trifluoromethoxy)phenyl)sulfonyl)-6J-dihvclro-5H- irriidazori ,2-alpyrazinor2,3-/iri,41diazepine-10-carboxamide (35)

If one were to treat the final compound from Example 34 with H₂0₂ and aq. NaOH as catalyst one would obtain Example 35.

Example 36

Step 1 : (ff)-3-benzyl-4,4-difluoro-2-(quinolin-8-ylsulfonyl)-2,3,4,5-tetrahydro-1 H-benzolclazepine (36)

If one were to treat the final compound from Example 13 with an fluorinating reagent e.g. diethylaminosulfur trifluoride or Fluolead (J. Am. Chem. Soc. 2010, 132:18199) one would obtain Example 36.

Protein Expression and Purification

Protein expression and purification was done as described in WO2010/049144.

TR-FRET Activity Assay

This method measures the ability of putative ligands to modulate the interaction between the purified bacterial expressed RORy ligand binding domain (LBD) and synthetic A/-terminally biotinylated peptides which are derived from nuclear receptor coactivator proteins such as but not limited to SRC1 (NcoA1), SRC2 (NcoA2, TIF2), SRC3 (NcoA3), PGC1a, ΡΘΟΙβ, CBP, GRIP1 , TRAP220, RIP140. The peptides used are listed in Table 1 below:

Table 1

The LBD of RORy was expressed as fusion protein with GST in BL-21 (BL3) cells using the vector pDEST15. Cells were lysed by lysozyme-treatment and sonication, and the fusion proteins purified over glutathione sepharose (Pharmacia) according to the manufacturers instructions. For screening of compounds for their influence on the RORy-peptide interaction, the LANCE technology (Perkin Elmer) was applied. This method relies on the binding dependent energy transfer from a donor to an acceptor fluorophor attached to the binding partner of interest. For ease of handling and reduction of background from compound fluorescence LANCE technology makes use of generic fluorophore labels and time resolved detection assays were done in a final volume of 25 iL in a 384 well plate, in a Tris-based buffer system (20 mM Tris-HCI pH6.8; 60 mM KCI, 1 mM DTT; 5 mM MgCI₂; 35 ng/pL BSA), containing 20-60 ng/well recombinantly expressed RORy-LBD fused to GST, 200-600 nM N- terminally biotinylated peptide, 200 ng/well Streptavidin-xlAPC conjugate (Prozyme) and 6-10 ng/well Eu W1024 - antiGST (Perkin Elmer). DMSO content of the samples was kept at 1%.

After generation of the Tris-based buffer system, the potentially RORy modulating ligands were diluted. After his step, protein, peptide and fluorescent acceptor and donor solutions were mixed in the Tris-based buffer system and have been added to the compound dilutions, after this addition of 'detection mix', the assay was equilibrated for one hour in the dark at rt in FIA-plates black 384 well (Corning). The LANCE signal was detected by a Perkin Elmer EnVision™ Multilabel Counter. The results were visualized by plotting the ratio between the emitted light at 665 nm and 615 nm. A basal level of RORy-peptide formation is observed in the absence of added ligand. Ligands that promote the complex formation induce a concentration-dependent increase in time-resolved fluorescent signal. Compounds which bind equally well to both monomeric RORy and to the RORy-peptide complex would be expected to give no change in signal, whereas ligands, which bind preferentially to the monomeric receptor would be expected to induce a concentration-dependent decrease in the observed signal.

To assess the antagonistic potential of the compounds, IC₅₀ values were determined using a Ligand Sensing Assay based on Time-resolved Fluorescence Energy Transfer (TR-FRET) as described above. The normalised TR-FRET assay values, using the following equation: 1000 * 665 nm measurement value/615 nm measurement value, were transferred to the program GraphPad Prism to generate graphs and dose response curves using the following equation:

Equation: Sigmoidal dose-response (variable slope)

Y = Bottom + (Top-Bottom)/(1 +10^A((LogEC50-X)*HillSlope))

X is the logarithm of the concentration. Y is the response.

Y starts at Bottom and goes to Top with a sigmoidal shape.

This is identical to the "four parameter logistic equation". The IC₅₀ values are calculated using this equation. Examples listed below do reduce the signal in the TR-FRET assay in a dose dependent manner. The Examples of the present invention usually have an inhibition activity (IC₅₀ FRET) ranging from below 150 nM to about 20 μΜ, and, typically, from about 150 nM to about 2 μΜ. The RORy modulating compounds of the invention desirably have an inhibition in the TR-FRET Activity Assay ranging from below 150 nM to about 1 μΜ. Table 2 lists typical examples of compounds of the invention that have an RORy activity in the TR-FRET Activity Assay lower than 500 nM (Group A), from about 500 nM to 2 μΜ (Group B) and above 2 μΜ (Group C).

Table 2

RORY Gal4 Reporter Gene Assay

Determination of a ligand mediated Gal4 promoter driven transactivation to quantify ligand binding to RORy was performed as follows: DNA encoding three different RORy protein fragments was cloned into vector pCMV-BD (Stratagene). Expression was under control of a CMV promoter and as fusion to the DNA-binding domain of the yeast protein GAL4. The amino acid boundaries of the three proteins and the respective database entries are listed in Table 3. Other vectors used were pFR-Luc (Stratagene) as regulated reporter plasmid. pFR-Luc contains a synthetic promoter with five tandem repeats of the yeast GAL4 binding sites that control expression of the Photinus pyralis (American firefly) luciferase gene. In order to improve experimental accuracy the plasmid pRL-CMV was cotransfected. pRL-C V contains the constitutive CMV promoter, controlling the expression of the Renilla reniformis luciferase.

Table 3

All Gal4 reporter gene assays were done in 293T cells (DSMZ (German Collection of Microorganisms and Cell Cultures), Braunschweig, Germany, ACC635) grown in Minimum Essential Medium (MEM) with Phenol Red. The medium is supplemented with 10% fetal bovine serum, 0.1 mM nonessential amino acids, 1 mM sodium pyruvate, 1% Glutamax and 100 units Penicilin/Streptavidin per mt_ at 37°C in 5% C0₂.

For the assay, 5x10⁵ cells were plated per well in 96well plates in 100 μί. per well, incubated over night at 37°C in 5% C0₂. The following day, medium was discarded and the cells were transiently transfected using 20 [it per well of a OptiMEM - PEI-based transfection-reagent (Sigma-Aldrich, 408727) including the three plasmids described above. About 4 h after addition of the transfection solution, fresh Minimal Essential Medium (MEM, same composition as used for plating cells, but without serum) was added. Then compound stocks, prediluted in MEM (same composition as used for plating cells) were added (final vehicle concentration not exceeding 0.1%).

Cells were incubated for additional 16 h before firefly (FF) and renilla (REN) luciferase activities were measured sequentially in the same cell extract using a Dual-Light-Luciferase-Assay system (Dyer et al., Anal. Biochem. 2000, 282:158). All experiments were done in triplicates.

Applying the Gal4 reporter gene assay as described above, the Examples of the present invention usually have an inhibition activity (IC₅₀ FF resp. IC₅₀ RENnorm) ranging from below 150 nM to about 20 μΜ, and typically, from about 200 nM to about 2 μΜ. The RORy modulating compounds of the invention desirably have an inhibition in the Gal4 reporter gene assay ranging from below 150 nM to about 1 μΜ. Table 4 and 5 list typical examples of compounds of the invention that have an RORy activity in the Gal4 reporter gene assay lower than 500 nM (Group A), from about 500 nM to 2 μΜ (Group B) and above 2 μΜ (Group C) for firefly (FF, Table 4) and renilla normalised (RENnorm, Table 5) luciferase measurements.

Table 4

Group Example #

A 4/2, 4/4, 6/1 , 6/2, 9/8, 9/10, 9/11 , 9/12, 9/14, 9/19, 9/20, 12, 13

B 1/2, 3, 4, 4/1 , 4/3, 4/5, 4/6, 5, 6/3, 7, 8, 9, 9/1 , 9/5, 9/9, 9/13, 9/21 , 9/22, 9/23, 9/24, 10, 11', 12', 14, 17, 18, 19

C 1 , 1/1 , 2, 4/7, 5', 6, 8/1 , 8/5, 8/6, 9/3, 16

Table 5

Group Example #

A 2, 4/2, 4/4, 6/1 , 6/2, 9/8, 9/10, 9/11 , 9/12, 9/14, 9/19, 9/20, 11', 12, 13, 19

B 1/2, 3, 4, 4/1, 4/3, 4/5, 4/6, 4/7, 5, 5', 6/3, 7, 8, 8/1, 9, 9/1, 9/5, 9/9, 9/21 , 9/22, 9/23, 9/24, 10, 12', 14, 17, 18

C 1 , 1/1 , 6, 8/5, 9/3, 9/13, 16

Claims

Claims:

1. A compound represented by Formula (1)

(1) an enantiomer, diastereomer, tautomer, solvate or pharmaceutically acceptable salt thereof, wherein:

R¹ is hydrogen, C _-12-alkyl, C₂.i₂-alkenyl, C₂-i₂-alkynyl, C₃-₁₀-cycloalkyl, C₃.₁₀-heterocycloalkyl, a 5-10 membered mono- or bicyclic heteroaromatic ring system containing 1 , 2, 3 or 4 heteroatoms independently selected from N, O or S, or a 6-10 membered mono- or bicyclic aromatic ring system,

wherein said alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl groups are unsubstituted or substituted by 1 , 2 or 3 substituents independently selected from OH, oxo, halogen, halo-C^-alkyl, C ^-e-alkyl or 0-(halo-Ci.₆-alkyl),

wherein said heteroaromatic and aromatic ring systems are independently from each other unsubstituted or substituted by 1 , 2 or 3 substituents independently selected from OH, oxo, halogen, cyano, Ci.₆-alkyl, C₃.₆-cycloalkyl, C₃.i₀-heterocycloalkyl, 0-Ci.₆-alkyl, a 5-10 membered mono- or bicyclic heteroaromatic ring system containing 1 , 2 or 3 heteroatoms independently selected from N, O or S, or a 6-10 membered mono- or bicyclic aromatic ring system,

wherein each of the C_1-6-alkyl, C₃.₆-cycloalkyl, C₃.i₀-heterocycloalkyl, 0-Ci-₆-alkyl, the 5-10 membered mono- or bicyclic heteroaromatic ring system containing 1 , 2 or 3 heteroatoms independently selected from N, O or S, and the 6-10 membered mono- or bicyclic aromatic ring system is independently of one another unsubstituted or substituted by 1 , 2 or 3 substituents selected from OH, oxo, halogen, cyano, C_1-6-alkyl, halo-d-e-alkyl, 0-Ci-₆-alkyl or O-ihalo-Ci-e-alkyl);

R² is a 5-10 membered mono- or bicyclic heteroaromatic ring system containing 1 , 2, 3 or 4 heteroatoms independently selected from N, O or S, or a 6-10 membered mono- or bicyclic aromatic ring system

wherein said heteroaromatic and aromatic ring systems are independently from each other unsubstituted or substituted by 1 , 2 or 3 substituents independently selected from oxo, halogen, cyano, C_1-6-alkyl, halo-Ci-12-alkyl, C₃.₆-cycloalkyl, C₃.₆-heterocycloalkyl, C₀. 6-alkylene-OR¹⁶, COOH, COO-(Ci-e-alkyl), CO-N(R¹⁰)(R¹¹), SO₂-N(R ⁰)(R¹¹), SO (C^.₆- alkyl), or SCy(halo-Ci.₆-alkyl); or

wherein the heteroaromatic and the aromatic ring systems are fused with a saturated 5-8 membered carbocycle or a saturated 5-8 membered heterocycle containing 1 , 2 or 3 heteroatoms independently selected from N, O or S, and the fused ring system is unsubstituted or substituted by 1 , 2, 3 or 4 substituents independently selected from OH, oxo, halogen, cyano, C_1-6-alkyl, halo-Ci.₆-alkyl, C₃.₆-cycloalkyl, C₃-₆-heterocycloalkyl, O- Ci_6-alkyl or 0-(halo-Ci_₆-alkyl);

R ⁰ is independently in each instance selected from H, Ci-i₀-alkyl, C_2-io-alkenyl, C₂-io-alkynyl, C₀-₆-alkylene-C₃.₁₀-cycloalkyl, Co-6-alkylene-C₃-₁₀-heterocycloalkyl or C₀-6-alkylene-5-membered heteroaromatic ring system containing 1 , 2 or 3 heteroatoms independently selected from N, O or S, wherein said alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl and 5-membered heteroaromatic ring system are unsubstituted or substituted with 1 to 6 substituents independently selected from OH, oxo, CN, 0-Ci_-6-alkyl, 0-halo-Ci.₆-alkyl, C_1-6-alkyl, halogen, COOR⁷, CO-N(R⁷)₂, S0₂R⁷, S0₂N(R⁷)₂₎ NR⁷-C0-R⁷, NR⁷-S0₂-R⁷ or N(R⁷)₂;

R ¹ is independently in each instance selected from H, C_1-6-alkyl, halo-Ci-₆-alkyl or C₃-₆-cycloalkyl; or

R¹⁰ and R ¹ when taken together with the nitrogen to which they are attached form a 3- to 8-membered ring containing carbon atoms and optionally containing 1 or 2 heteroatoms selected from O, S, S(0), S(0)₂ or N(R⁷), wherein said ring is unsubstituted or substituted with one or more halogen, OH, oxo or Ci.₆-alkyl;

L is -(CR⁶ ₂)_X-, -(CR⁶ ₂)_X-NR⁷-, -(CR⁶ ₂)_x-0- or -(CR⁶ ₂)_x-0-(CR⁶ ₂)_x-;

R⁶ is independently in each instance H, F, OH, C_1-e-alkyl, C₃.₆-cycloalkyl, halo-Ci.₆-alkyl or halo-C₃-₆-cycloalkyl; or

two R⁶ at the same carbon atom to which they are attached together are oxo;

R⁷ is independently in each instance H, C_1-6-alkyl, C₃.₆-cycloalkyl, halo-Ci.₆-alkyl, halo-C₃. 6-cycloalkyl or hydroxy-C₂.₆-alkyl;

R ², R¹³ and R¹⁴ are independently of one another selected from H, F, Ci_-6-alkyl or halo-Ci_-6- alkyl;

Y is selected from C or N;

Z is selected from C or N; wherein at least one of Y and Z is C; Ar together with Y and Z is a 5-6 membered monocyclic heteroaromatic ring system containing

1 , 2 or 3 heteroatoms independently selected from N, O or S, or a 6 membered monocyclic aromatic ring system

wherein said heteroaromatic and aromatic ring system is unsubstituted or substituted by 1 , 2 or 3 substituents independently selected from OH, halogen, halo-C alkyl, C1.6- alkyl, C₃.₆-cycloalkyl, O-C e-alkyl or 0-(halo-Ci.₆-alkyl);

X is selected from -NR¹⁶-CO-, -C(R² )(R²³)-C(R²²)(R¹⁷)-, -C(R²²)(R²³)-(C=0)-, -(C=0)- C(R²²)(R¹⁷)-, -0-C(R²²)(R²³)-, -S(0)_y-C(R²²)(R¹⁷)- or -X¹(R¹⁸)-X²(R¹⁹)-,

X¹ is selected from C or N;

X² is selected from C or N;

R¹⁶ is independently in each instance selected from H, C_1-6-alkyl or halo-Ci-₆-alkyl;

R¹⁷ is independently in each instance selected from H, OH, F, d-e-alkyl, C₃.₆-cycloalkyl, O-Ci-e-alkyl, 0-C₃.₆-cycloalkyl, halo-Ci-e-alkyl or O-halo-Ci.₆-alkyl;

R ⁸ and R ⁹ together with X¹ and X² form a 5-membered ring containing 1 , 2 or 3 heteroatoms independently selected from N, O or S, said 5-membered ring being unsubstituted or substituted by 1 or 2 substituents independently selected from OH, oxo, halogen, CN, Ci_-6-alkyl, halo-Ci.₆-alkyl, C₃-6-cycloalkyl, 0-Ci_-e-alkyl, O-ihalo-C^-alkyl), COOH, C0₂N(R¹⁶)₂ or N(R ⁶)₂;

R²² and R²³ are independently of one another selected from H, F, C _-6-alkyl or halo-Ci_-6- alkyl;

x is independently selected from 1 , 2, 3 or 4;

y is independently selected from 0, 1 or 2;

with the proviso that

(a) when X is -0-CH₂- then R² is not 4-methylphenyl.

2. The compound of claim 1 wherein

Ar together with Y and Z is a 6-membered aromatic or heteroaromatic ring system containing 1 or 2 nitrogen atoms, said heteroaromatic or aromatic ring system being unsubstituted or substituted by 1 , 2 or 3 substituents independently selected from OH, halogen, C_1-6-alkyl, halo- d-e-alkyl, C₃-₆-cycloalkyl, O-d-e-alkyl or O-ihalo-d-e-alkyl).

3. The compound of claim 1 or 2 wherein R is hydrogen, Ci-i₂-alkyl, C₃-i₀-cycloalkyl, C_3-10-heterocycloalkyl, a 5-10 membered mono- or bicyclic heteroaromatic ring system containing 1 , 2, 3 or 4 heteroatoms independently selected from N, O or S, or a 6-10 membered mono- or bicyclic aromatic ring system,

wherein said alkyl, cycloalkyl and heterocycloalkyl groups are unsubstituted or substituted by 1 , 2 or 3 substituents independently selected from OH, oxo, halogen, halo-d-e-alkyl, 0-d.₆-alkyl or 0-(halo-d-6-alkyl),

wherein said heteroaromatic and aromatic ring systems are independently from each other unsubstituted or substituted by 1 , 2 or 3 substituents independently selected from OH, oxo, halogen, cyano, C_1-6-alkyl, C₃.₆-cycloalkyl, C₃.₁₀-heterocycloalkyl, O-d-e-alkyl, a

5- 10 membered mono- or bicyclic heteroaromatic ring system containing 1 , 2 or 3 heteroatoms independently selected from N, O or S, or a 6-10 membered mono- or bicyclic aromatic ring system,

wherein each of the C_1-6-alkyl, C₃.₆-cycloalkyl, C₃.i₀-heterocycloalkyl, 0-Ci.₆-alkyl, the 5-10 membered mono- or bicyclic heteroaromatic ring system containing 1 , 2 or 3 heteroatoms independently selected from N, O or S, and the 6-10 membered mono- or bicyclic aromatic ring system is independently of one another unsubstituted or substituted by 1 , 2 or 3 substituents selected from OH, oxo, halogen, cyano, C_1-6-alkyl, halo-C_1-6-alkyl, O-Ci-6-alkyl or 0-(halo-C_1-6-alkyl);

L is -(CR⁶ ₂)_X-, -(CR⁶ ₂)_x-0- or -(CR⁶ ₂)_x-0-(CR⁶ ₂)_x-;

R⁶ is independently H, F or d^-alkyl; and

x is independently selected from 1 or 2.

4. The compound of any of claims 1 to 3 wherein

R² is a 5-10 membered mono- or bicyclic heteroaromatic ring system containing 1 , 2, 3 or 4 heteroatoms independently selected from N, O or S, or a 6 membered monocyclic aromatic ring system,

wherein said heteroaromatic and aromatic ring systems are independently from each other unsubstituted or substituted by 1 , 2 or 3 substituents independently selected from oxo, halogen, cyano, d-e-alkyl, halo-d-12-alkyl, C₃.₆-cycloalkyl, C₃.₆-heterocycloalkyl, C₀.

₆- alkylene-OR¹⁶, COOH, COO-(d.₆-alkyl), CO-N(R¹⁰)(R¹¹), SO₂-N(R¹⁰)(R¹¹), SO_y-(C_1-6- alkyl) or SO_y-(halo-C^-alkyl);

or the heteroaromatic and the aromatic ring systems are fused with a saturated 5-8 membered carbocycle or a saturated 5-8 membered heterocycle containing 1 , 2 or 3 heteroatoms independently selected from N, O or S, and the fused ring system is unsubstituted or substituted by 1 , 2, 3 or 4 substituents independently selected from OH, oxo, halogen, cyano, Ci_-6-alkyl, halo-C^-alkyl, C₃.₆-cycloalkyl, C₃.₆-heterocycloalkyl, O- Ci-6-alkyl or CHhalo-Ci-e-alkyl).

5. The compound of any of claims 1 to 4 wherein

X is selected from -NR¹⁶-CO-, -C(R²²)(R²³)-C(R²²)(R¹⁷)-, -0-C(R²²)(R²³)- or -X¹(R ⁸)-X²(R¹⁹)-, wherein R¹⁸ and R¹⁹ together with the atoms to which they are connected form a 5-membered ring containing 1 , 2 or 3 heteroatoms independently selected from N, O or

5, said 5-membered ring being unsubstituted or substituted by 1 or 2 substituents independently selected from OH, oxo, halogen, CN, d-e-alkyl, halo-Ci-₆-alkyl, C₃.₆-cycloalkyl, 0-Ci.₆-alkyl, O- (halo-Ci.₆-alkyl), COOH, C0₂N(R¹⁶)₂ or N(R¹⁶)₂.

6. The compound of any of claims 1 to 5 wherein

R¹², R¹³ and R¹⁴ are independently selected from H or Ci-₃-alkyl.

7. The compound of any of claims 1 to 6 wherein

is selected from the group consisting of

8. The compound of any of claims 1 to 7 wherein

R² is selected from the group consisting of

. The compound of any of claims 1 to 8 wherein Ar is selected from the group consisting of

10. The compound of any of claims 1 to 9 wherein X is selected from the group consisting of - NH-CO-, -NMe-CO-, -CH₂CH₂-, -OCH₂-, -SCH₂-, -S0₂CH₂-, -CH₂CHOH-, -CH₂CHOMe-, - CH₂(C=0)-,

11. The compound of any of claims 1 to 10 selected from the group consisting of

and the enantiomers, diastereomers, tautomers, solvates and pharmaceutically acceptable salts thereof.

12. The compound of any of claims 1 to 11 as a medicament.

13. The compound of any of claims 1 to 11 for use in the treatment of a disease or disorder which is Th17 mediated tissue inflammation or of autoimmune etiology or which is a skin disease with associated symptoms such as pain, itching or excoriations.

14. The compound of any of claims 1 to 11 for use in the treatment of a disease or disorder wherein the disease or disorder is selected from the group consisting of rheumatoid arthritis, ankylosing spondylitis, lupus erythematosus, psoriasis, atopic eczema, inflammatory bowel diseases such as Crohn^'s disease or ulcerative colitis, asthma, multiple sclerosis, type 1 diabetes and amyotrophic lateral sclerosis.

15. The compound of any of claims 1 to 11 for use in the treatment or prophylaxis of a disease or disorder associated with the inhibition or activation of the RORy receptor.

16. A pharmaceutical composition comprising a compound of any of claims 1 to 11 and a pharmaceutically acceptable carrier.