STATEMENT OF GOVE NME T SUPPORT

This invention was made with government support under MH108173 awarded by the National institutes of Health. The government has certain rights in the invention.

CROSS-REFERENCE TO RELATED APPLICATIO Reference is made to PCT application PCT/US201 1/028320, published as WO 2011/115892, "MODULATORS OF THE RETIMOIC ACID RECEPTOR- RELATED ORPHAN RECEPTORS", which is incorporated herein by reference In its entirety. This application claims the priority of U.S. provisional application serial number 62/250,872, filed November 4, 2015, the disclosure of which is incorporated by reference herein in sis entirety,

BACKGROUND

The nuclear receptor (MR) superfami y of transcription factors has proven to be rich source of targets for development of therapeutics for a myriad of human diseases. In addition to control by cellular localization and PTM status, the transcriptional activity of most NRs can be modulated (activated or repressed) by small lipophilic molecules such as hormones, vitamins, steroids, oxysterote, retinoids, fatty acids, and synthetic molecules ¹ . The NR1F subfamily of NRs contains the retinoic acid receptor-related orphan receptors (RORs) that include RORa, RORp, and RORy. These receptors have been shown to regulate a wide range of physiological processes, have been implicated in the pathophysiology of disease, and their basal activity can be modulated by sterols ^~

The I cell specific isoform of RORy, known as RORyt, is expressed in

thymocytes and regulates survival of T cells during differentiation - and drives the activation and differentiation of CD4 ^÷ and CD8 ^÷ cells into IL17-producing helper T ceils (TH17) and cytotoxic T cells (Tc17) ^§ „ T _H 17 and Tc17 are effector cells that promote inflammation, adaptive immunity and autoimmunity by producing IL17 and other inflammatory cytokines such as IL21 . Since TM17 cells do not express granzyme B or perforin and do not appear to have a direct effect on cancer cell proliferation and apoptosis, it is thought that these cells may not mediate direct cytotoxic activity against tumors ^m .

The programmed cel death 1 receptor PD~1 can inhibit T cell activation when bound by the !igand PD-L Tumor expression of PP-L1 leads to an inactivation of a T cell immune response to the cancer ceils. Activated T cells produce interferon and stimulate PD-L1 on tumor cells and the PD 1/PD-L1 interaction triggers a process that shuts down the immune response reducing proliferation of these effector ceils. In the tumor microenvironmenf, T cells overexpress PD-1 and act in concert to blunt T cell antitumor effects Among the most promising approaches to activating therapeutic antitumor immunity is the blockade of immune checkpoints. While TH17 cells have a weli described role in autoimmune disease, recent evidence suggests that this subset of effector T cells may play a role in immunotherapy if the PD-1 pathway is inactivated . Enhanced immunity through T-cell activation and btockage of immune checkpoints has transformed cancer treatment with therapies targeting PD-1 showing unprecedented rates of durable clinical responses in patients with various cancers

Severaf reports have described RORyt synthetic agonists including SR1Q78, a compound that induced the expression of the ROR target genes FGF21 and GBPass in cells and in vivo In Rene et a/, the authors show that a minor substitution of a phenylsulfonamide for a benzylsulfonamide within the same chemical scaffold changes the compound from an inverse agonist to an agonist on RORyt with no activity on RORa ^~ . Co-crystal structures of the benzylsuifonamide and pheny!suifonamide derivat ves bound to RORyt provided further structural insights into the opposing MOA of these compounds. These studies cleariy demonstrate that it is possible to upreguiate basal RORyt activity with synthetic modulators.

SUMMARY

Our recent efforts to optimize the SR1078 scaffold provided many analogs with improved biochemical and physiochemical properties. These compounds were

evaluated for their ability to positively modulate IL17 to aid activation of T _!H 17 cells and for their ability to impact PD-1 ceil surface expression. Here we show that activation of RO yt with the SR1G78 analog SR0987, ieads to increased expression of IL17 while repressing the expression of the checkpoint receptor PO-1 , activities that the recently identified endogenous sterol agonists do not engender.

Accordingly, the invention provides, in various embodiments, a method for enhancing immunity in a patient, comprising administering to the patient an effective amount of an agonist of RORyt comprisin a compound of formula (I)

wherein X is C(O) or Β{0) ₂ ,

R ¹ is phenyl, mono- or independently multi-substituted with J ¹ ;

R ² is H or alkyl, wherein any alkyi is optionally mono- or independentiy multi- substituted with J ² ;

3 is phenyl wherein R ³ substituted with J ³ comprises or an alkyl, aryl, or ary!aikyi ester of the hydroxy! group thereof, or an alkyi, aryl, or ary!a!kyl ether of the hydroxy! group thereof, wherein a wavy Sine indicates a point of attachment of -substituted R ³ to the nitrogen atom bearing R ³

j when present is halo, cyano, nitro, alkoxy, or haloalkoxy; unsubstituted or substituted alkyl, haioalkyJ, alkylcarboxarnido, aryicarboxamido, or alkoxycarbonyl; unsubstituted or substituted aryl; unsubstituted or substituted arylsulfonyl; unsubstituted or substituted heteroaryl; unsubstituted or substituted heteroarylsulfonyl; or

unsubstituted or substituted aryisuifonamido;

J ² when present is halo, cyano, nitro, alkoxy, or haloalkoxy; unsubstituted or substituted alkyl, haloalkyl, alkylcarboxarnido, ary!carboxamido or alkoxycarbonyl;

unsubstituted or substituted aryl; unsubstituted or substituted arylsulfonyl; unsubstituted or substituted heteroaryl; unsubstituted or substituted heteroarylsulfonyl; or

unsubstituted or substituted aryisuifonamido;

including any stereoisomer thereof, or any salt, solvate, hydrate, metabolite, or prodrug thereof. For instance, administration of an effective amount of an agonist of RORyt comprising a compound of formula (I) care increase production of IL17 in situ, which can be associated with an increase in immunity in a patient,

The invention further provides a method of treating a cancer, comprising administering to a patient afflicted therewith an effective amount of an agonist of RORyt comprising a compound of formula (I).

For practice of the methods of the invention, the compound of formula (I) can be SR0987

For practice of the methods of the invention, the compound of formula (I) can be any of the compounds shown in Table 3. below.

BRIEF DESCRIPTION OF THE FIGURES

Figure 1. Ira vitro characterk&tiort of synthetic RORy agonist arid

endogenous Sigand. a) compound structure, b) RO yt agonist transactivafic-n.

Activation of Gal4- RORy::UAS-Luc reporter assay for SR1078, SR0987, and

desmosteroi at a 30 μ concentration, c) CRC for SR0987 and desmosterol in the presence of ursolic acid (2μΜ) in the Gal4-RORy::UAS~Luc reporter assay in HE 293T ceils (right panel). Ail error bars denote s.e.m. d) Activation of full-length RORy in the presence of ursolic acid (2μΜ) in HE 293T cells and co-transfected with 5XRORE~Luc reporter, e) Activation of full-length RORy receptor in the presence of ursolic acid (2μΜ) in HE 293T cells and co-transfected with IL17-Luc reporter.

Figure 2, Decreasing PD-1 by synthetic RORy agonist, a) IL17A, PD-1 and granzyme B mR A expression in stimulated EL4 cells (activated with PMA/lonomycin for 5 hr). b) PD-1 surface expression in EL4 cells. Celis were pretreated with compound (desmotero!, SR0987) for 48 hr. c) intracellular staining of IL17A in T _H 17 cells, d) ceil surface expression of PD-1 , e) CD82L-P01 - cell population, f) PD-1 expression in human Jurkat T cells.

Figym 3. a) Differential HDX kinetics of RORyt LBD ± compounds plotted over the crystal structure PDB:3LOL b) Differential HDX kinetics of ursolic acid treated RORyt LBD ± compounds plotted over the crystal structure PDB:3LOL Cool colors are increased protection to solvent exchange (increased stabilization) and warm colors are decreased protection to solvent exchange (decreased stabilization). Grey coior represents no statistically significant change with and without iigands.

Competitive radioligand binding assays illustrated direct binding of SR1078 to the ligand binding domain (LBD) of RORyt albeit with weak affinity (IC ₅ Q - ^» 1 5 μΜ) SR1078 was also shown to have direct interaction with RORyt via thermal shift assay as measured by Circular Dicbroism (CD) ^~ . initial SAR of the benzamide ring suggests that substituents are tolerated at the ortho-position leading to SR0987 (Fig. 1a).

Compounds were subsequently screened in a Gal4 UAS-Luc cotransfection system in order to determine their ability to modulate RORy activity in a cellular environment. Given that RORyt has high basal activity when expressed in ceils, repression by the receptors' activity using an inverse agonist (e.g., ursolic acid) followed by test compound treatment offered the best window to detect agonism ~. Here cells were pre-treated with 2 μΜ ursolic acid (IC5CM3.8 μΜ) which afforded approximately 60- 70% of RORyt activity prior to the addition of test compounds. Desmosterol was used as a control for agonism as it was recently identified as a putative endogenous agonist for RORyt capable of restoring RORyt activity in the presence of ursolic acid.

Importantly, in this assay format, the potent inverse agonist SR221 demonstrated the ability to further repress the expression of the luciferase reporter gene in the presence of ursolic acid.

Initial screening of compounds was performed at a single concentration of 30p looking for compounds with improved reporter gene expression relative to desmosterol. In this screening format SR0987 afforded the highest foid induction of reporter gene expression (-8 fold), whereas desmostero and SR1078 resulted in only a minor induction of luciferase expression ( 2 foid) (Fig. 1 ). Furthermore, SR0987 clearly shows a concentration dependent induction of reporter gene expression with an EC50 of ~80QnM (Fig, 1c). interestingly, desmosterol onl induced luciferase expression at the highest concentration tested (-2 fold at 30μ ), The concentration response curve for SR1078 confirms the improved agonist activity of SR0987. In addition, SR1078 and SR0987 demonstrate concentration dependent increase in interaction of RO yt with the SRC1-3 MR box peptide further validating that these compounds drive the agonist conformation of the receptor. As expected, SR2211 decreases interaction with this co- activator peptide in a concentration dependent fashion.

In order to determine if these compounds could modulate RORyt activity in the context of the full-length receptor, we used a co-transfection system in HE 293T ceils in which full length RORyt was co ransfected along with a luciferase reporter under the control of either a basic promoter containing five copies of an ROR response element (SxRORE) or a minimal IL17 promoter. For all subsequent in vitro pharmacology studies we focused on the more efficacious synthetic agonist SR0987. As shown in F g. 1d and 1e, SR0987 demonstrated a concentration-dependent induction of reporter gene expression in both the SxRORE and IL17 promoter transfected cells in the presence of full-length RORyt whereas minimal induction of the reporter gene was observed with desmosterol treatment. As expected, the inverse agonist SR2211 repressed both promoters in a concentration-dependent manner.

PD-1 is not expressed on resting T cells but its expression is induced within 24 hours after T cell receptor stimulation ^~ and is involved in the establishment and maintenance of immunological tolerance in the spontaneous development of

autoimmune diseases by PD-1 deficient mice Given that PD-L1 is expressed on various tumor cells and PD-1 expression is upregulated and sustained on T cells, it is clear that the PD-1/PD-L1 pathway plays an important role in tumor immunity. Here we used murine EL4 T lymphocytes or human Jurkat T ceils as model systems to analyze gene expression upon T cell activation. Following treatment of cells with Phorbol 12- rnyristate 13~acetate (PMA) and ionomydn, the expression of granzyme B (cytotoxicity marker), PD-1 (immune checkpoint) and the RGRvt target gene IL17 were analyzed by qPCR. As shown in Fig, 2a stimulation of EL4 cells led to an increase in the expression of all three genes and when coupled with treatment with the synthetic RORvt agonist SRG987 a further increase in expression of IL17 was observed suggesting that there was in induction of T cell activation. Surprisingly and unexpected, treatment with SR0987 led to a decrease in expression of PD-1. Compound treatment did not impact the expression of granzyme B. Combined these results suggest that treatment with SR0987 may enhance protective immunity by regulating expression of IL17 and PD-1 while maintaining the cytotoxic ability of these cells.

Using flow cytometery surface PD-1 expression was analyzed to determine if the decrease in gene expression of PD-1 correlates to a decrease of the protein on the ceil surface. Cell surface PD-1 expression was measured in murine and human T ceil lines as well as in ex vivo differentiated murine T _H 1 cells, SR0987 treatment resulted in a statistically significant reduction of the surface expression of PD-1 whereas de mostrol treatment showed no effect (Fig. 21s). Next we examined the impact of compound treatment on differentiated murine T _H 17 cells. Treatment with SR0987 and or desmosterol resulted in a trend towards increased IL17 production (Fig. 2c). However, in this system SR0987 again demonstrated the ability to repress surface PD-1 expression whereas desmosterol had no effect (Fig, 2d). To determine if there was an increase in the active T cell population during TH17 cell d fferentiation, the population of CD62LPD1 ^* double negative cells was measured using flow cytometry. Naive CD4+ T cells isolated from mice were differentiated using a cytokine cocktail in the presence or absence of ursolic acid. S 0987 resulted in a statistically significant increase in the CD82L ^" PD CD4 ^÷ cell population as compared when compared to DMSO treated cells (Fig, 2e). To determine if the effects of SR0987 on PD-1 expression would be observed in a human cell line, Jurkat T cells were treated with the compound. As shown in Fig. 2 , exposure of Jurkat T cells to SR0987 resulted in decreased ceil surface PD-1 expression (Fig, 2f). Taken together, these results suggest that SR0987 acts as a RORyt agonist and that use of such synthetic ligands may enhance immune response in the context of cancer, White the mechanism of action of RORyt agonists on regu ation of the immune checkpoint receptor PD-1 is unclear, a correlation between RORyt and PD-1 expression has been observed in PD-1 knockout mice— . Regardless, to gain insights into the structural mechanism for agonist activity we examined the impact of putative agonist figands on the conformational dynamics of RORyt To achieve this, we utilized differential hydrogen/deuterium exchange (HDX) mass spectrometry. Previously, we have demonstrated the utility of HDX to monitor ligand-induced conformational changes in NRs including RORyt The differential HDX kinetics of RORyt LBD in the presence and absence of ursolic acid (inverse agonist), SR2211 (inverse agonist) _s and desmosterol (putative endogenous agonist) are shown overlaid on the 25- -OHC:RORy co-crystal structure {PDB ID: SLOL) ²² (Fig, 3a). HDX revealed that helices 11 (H11) shows increased protection to solvent exchange (stabilization) with all RORyt figands tested, suggesting common sites of direct interaction for ligands within the iigand- binding pocket (LBP) of RORvt No statistically significant change in HDX kinetics was observed in the activation function-2 helix, helix 12 (H12), for these three complexes (Table 1a). In contrast, Fig. 3b shows differential HDX kinetics of RORyt exposed to ursolic acid followed by addition of desmosterol (putative endogenous agonist), SR1078 (agonist) and SR0987 (agonist) also overlaid on PDB ID: 3L0L Protection to solvent exchange was again observed in H11 ; In addition, treatment with either SR1078 or SR0987, induced protection to solvent exchange in H12 that was not observed with desmosterol (Table 1 b). This observation is consistent with the concentration- dependent activation of RORyt observed in cells with these two synthetic agonists. Similar agonist induced Hi 2 protections have been previously observed with other NRs such as PPARy . The differential patterns of H12 protection seen between agonists and inverse agonist are in line with the recently published crystal structures of RORyt- LBD in complex with synthetic inverse agonist and a synthetic agonist (PDB ID: 4WQP and 4WPF) . These structures revealed that synthetic agonists pack against H3 and H11/12 interface and engages with RORyt LBD residues W317 (H3), H479 (H11) and Y502 (H12) resulting in a stable H12 conformation through a direct hydrogen bond between H479 and Y502 side chains. Whereas a synthetic inverse agonist disiodges H479 side chain into an orientation that is unfavorable for forming the hydrogen bond with Y502, which destabilized H12 (disordered in the structure) and disrupted co- activator interactions. Collectively, the HDX studies provide a structural basis for the agonist properties of SR0987.

Enhanced immunity and blockage of immune checkpoints has transformed cancer treatment with therapies targeting PD-1 showing unprecedented rates of durable clinical responses in patients with various cancers. The results presented here suggest that RORy agonists may enhance T cell activation while repressing PD-1 without reducing the cytotoxic activity of these cells. Therefore, RORyt agonists can provide a unique combination therapy with approved anti-PD-1 molecules for treatment of cancer and can provide utility in the context of anti-PD-1 resistance.

Table 2: Primer sequences for Q-PCR analysis

Gene name Primer sequence

Gmnzyme B CCT CCT GCT ACT GCT GAC (forward)

Granzyme 8 GTC AGC ACA AAG TCC TCT (reverse) C

IL17A (forward) CTC CAG AAG GCC CTC AGA

CTA C

IL17A (reverse) GGG TCT TCA TIG CGG TGG

PD~1 (forward) CGI CCC TCA GTC AAG AGG

AG j PD-1 (reverse) GTC CCT AGA AGT GCC CAA

CA

EXAMPLES

Table 3: Compounds for practice of a method of the invention

Compounds. Chemicals and solvents were purchased from commercial suppliers. Sterols were purchased from Avanti Polar Lipids and all other chemicals were purchased from Sigma. Compounds were purified using CombiFlash Rf 200 flash chromatography on silica gel on RediSEp Rf from Teledyme Isco, Inc. Yields refer to isolated compounds, estimated to be > 98% pure as determined by ¹ H NlvlR or HPLC. Melting points were measured on a Stuart automatic melting point SMP4Q. ¹ H, ¹³ CMIV1R spectra were recorded on Bruker Spectrometer operating at 400 MHz and 101 IV!Hz respectively, All chemical shift values, δ, and coupling constants, J, are quoted in ppm and Hz, respectively. Infra-Red spectrums were recorded on Perkin Elmer FT-IR Spectrometer, Synthesis of SR1078 was performed as previously described ¹³ .

Synthetic Example 2 (SR987): -chloro-N^-Cl.l. S.S^-hexafluoro- -hydroxypropan- 2-yl)phenyi)benzamide :

To a solution of 4-(1-hydroxy"1"tr!fiuoromethy!-2 _f 2,2 rifluoroethyi}anil!ne (80mg, 0.232 mmol) in CH ₂ CI ₂ (2 rnL) were successively added at RT ^-diisopropylethy!amine (80 ί, 0.463 mmol) and 2~chiorobenzoyl chloride (41 pL, 0.324 mmo!). The mixture was stirred for 3 h and concentrated under reduce pressure. The crude residue was directly purified by column chromatography on silica gel without any workup by hexane/AcOEt {8/2} to obtain 85 mg (71 %) of SR987 as a white powder: FOR cm ^"1 3338, 3028, 1643, 1521 , 1410, 1254, 1219, 1188, 1 112, 988, 944, 828; ¹ H NMR (400 MHz, lvleGD~d4) δ = 7.97 (t, J = 1.8 Hz, 1 H), 7.91 - 7.88 (m, 1 H), 7.85 - 7.80 (m, 2 H), 7.75 - 7.70 (m, 2 H), 7.83 - 7.58 (m, 1 H), 7.51 (t, J - 7.8 Hz, 1 H); ¹³ C HMR (101 MHz, WeGD-d4) δ - 167.5, 141.5, 138.2, 135.9, 133.1 , 131.4, 129.0 (2C), 128.9, 128.5, 127.3 (2C), 121.7 There are tree carbons missing for the description of SR1078. They correspond to the three carbons of the (l-hydroxy-l^rr iuoromethy!^^^-tnfSuoroethyi) moiety. The fluorine coupling with these carbons give mulfipiets that are very difficult to see on the ¹³ C spectrum even with a prolonged number of scans. H S (ESI) m/z p+H ⁺ ] calcd for C ₁₆ H- _! oCIF ₆ N0 ₂ , 398.0377; found, 398.0395; Mp = 170-172°C.

Synthetic Example 3: ^« (4-(1 _! 1 _! 1 _i 3,3,3~hexafluoro-2-hydroxypropan-2- e

The title compound was prepared according to the Synthetic Example 2 from 4-(1- hydroxy-1-trif!uoromethyl-2,2,2-trif[uoroethyl)aniiine (150 mg, 0.58 mmol) and benzoyl chloride (94 pL, 0.81 mmol). The crude product was purified by preparative HPLC (20- 100% CHsCN/ eOH (1 :1) in H ₂ 0 (0.01% TFA)) which provided after iyophilization 174 mg (83%) of the titie compound as a colorless solid; ¹ H MR (400 MHz, CDCI ₃ ) δ ~ 7.91 (br.s, 1 H), 7.88 - 7.90 (m, 2H), 7.72 - 7,79 (m, 4H), 7.58 ·· 7.83 (m, 1 H), 7.50 - 7.58 (m, 2H).

Synthetic Example 4; 3~chloro~N"(4-(1 _J 1 _! 1 _l 3,3 _l 3~hexafiuoro~2-hydroxypropan~2~ y!)phenyi)ben∑amide

The title compound was prepared according to the Synthetic Example 2 from 4-{i~ hydroxy-1 rifSuorornethyi-2,2,2-tnfluoroethyl)aniline (50 mg, 0.19 mmol) and 3- chlorc-benzoyl chloride (30 pL, 0.23 mmol). The crude product was purified by column chromatogra hy on silica gel without any workup by hexane/AcOEt (8/2) to obtain 53 mg (89%) of the title compound as a white powder. H N R (400 MHz, MeOD-d4) δ = 7.96 (t, J = 1.64 Hz, 1 H), 7.84 - 7.89 (m, 1 H), 7.80 - 7.84 (m, 2H), 7.89 - 7.75 (m, 2H), 7.57 (m, 1 H), 7.48 (t, J ~ 7.89 Hz, 1 H).

Synthetic Example 5: 4-chioro-N-{4-(1 , 1 ,1 ,3,3, 3~hexafluoro~2-hydroxypropan~2- yl)pheny benzamfde

The title compound was prepared according to the Synthetic Example 2 from 4~(1~ hydroxy-1 -trifiuoromethyl-2,2,2-trifluoroethyl)aniline (40 mg, 0,15 mmo!) and 4- ch!orobenzoyl chloride (24 pi, 0.18 mmol). The crude product was purified by column chromatography on silica gel without any workup by hexane/AcOEt (7/3) to obtain 46 mg (75%) of the title compound as a white powder, ¹ H NMR (400 MHz, eOD-d4) δ ^:» 7.90 - 7.95 (m, 2H), 7.78 - 7.85 (m, 2H), 7.69 - 7.75 (m, 2H), 7.49 - 7.58 (m, 2H).

Synthetic Example 8: 2-bromo-N-(4~(1 ,1 ,1 ,3,3 _t 3-hexaf!uoro-2-hydroxypropan-2- yl)phenyl)benzamsde

The title compound was prepared according to the Synthetic Example 2 from 4-(1 - hydroxy-1-tf}fluoromethyl-2,2,2-trif!uoroethyl)ar5iiine (600 mg, 2.31 mmol) and 2- bromobenzoyl chloride (383 μί, 2.78 mmol). The crude product was purified by column chromatography on silica gel without any workup by hexane/AcOEt (8/2) to obtain 941 mg (92%) of the title compound as a white powder. Ή HMR (400 MHz, CDCI ₃ ) δ ~ 7,78 - 7.82 (m, 2H), 7.87 - 7.75 (m, 3H) ₅ 7.55 (dd, J ~ 1,77, 7.58 Hz, 1H), 7,48 (dt, J ~ 1,77, 7.58 Hz, 1H), 7.40 (dt, J~ 1.77, 7,58 Hz, 1H).

Synthetic Example 7; 2-iodo-N-(4-(1,1,1,3 _l 3 _! 3-hexafiuoro-2-hydroxypropan-2- yl)phenyl)benzamide

The title compound was prepared according to the Synthetic Example 2 from 4~(1- hydroxy-l^riiluoromethyi^^^-trif!uoroethyljaniline (300 mg, 1.16 rnmol) and 2- iodobenzoyl chloride (345 mg, 1,39 mmo!). The crude product was purified by column chromatography on siiica gel without any workup by hexane/AcOEt (8/2) to obtain 539 mg (95%) of the title compound as a white powder. ¹ H HMR (400 MHz, CDC ) δ™ 7.93 (dd, J - 0.88, 7.96 Hz, 1H), 7.74 - 7.78 (m, 4H), 7.59 (br. s., 1H), 7,50 - 7.58 (m, 1H), 7,43 - 7.48 (m, 1H), 7.15 - 7.21 (m _f 1H).

Synthetic Example 8: 2"fluoro-N-(4-(1 _f 1,1,3,3,3-hexaf!uoro-2-hydroxypropan-2- yi)phenyl)benzamide

The title compound was prepared according to the Synthetic Example 2 from 4-(1- hydroxy-1-influoromethyl-2,2,2-trif!uoroethyl)aniIlne (60 mg, 0.23 mmoi) and 2~ fluorobenzoyl chloride (39 pL, 0.32 mmol), The crude product was purified by

preparative HPLC (20-100% CH ₃ CN/MeOH (1:1) in H ₂ 0 (0.01% TFA)) which provided after lyophilization 57 mg (85%) of the title compound as a colorless solid; Η HMR (400 MHz, CDCis) δ = 8.56 (d, J- 15,41 Hz, 1H), 8.19 (t, J- 7.45 Hz, 1H), 7.69 - 7.82 (m, 4H), 7.51 -7.61 (m, 1H).7.35 (t, J™ 7.58 Hz, 1H), 7.21 (dd, J -7.58, 15.4 Hz, 1H). Synthetic Example 9: S-fluoro- ^-CI .S.S^-hexaflyoro^-h droxy ro an^- leny benzamide

The title compound was prepared according to the Synthetic Example 2 from 4-(1- hydrox -l-irifiuoromethyi^^^-trifluoroeihy ani!ine (80 mg, 0,23 mmoi) and 3~ ffuorobenzoyi chloride (39 pL, 0.32 mmol). The crude product was purified by preparative HPLC (20-100% CH ₃ C / eOH (1 :1) in H ₂ 0 (0.01 % TFA)) which provided after !yophilizatton 86 mg (75%) of the title compound as a colorless soiid; ¹ H NMR (40C MHz, CDCIg) δ - 7.90 (br. s., 1 H), 7.74 - 7.78 (m, 4H), 7.65 ^» 7.88 (m, 1 H), 7.58 - 7.83 (m, 1H), 7.48 - 7.54 (m, 1H), 7.26 - 7.32 (m, 1 H).

Synthetic Example 10: 4-fluoro-N-(4-(1 , 1 , 1 ,3, 3,3-hexafiuoro-2-hydroxypropan-2- yl)phenyl)ben2

The title compound was prepared according to the Synthetic Example 2 from 4-(1- hydroxy-1-trifluoromethyl-2,2,2-trifiuoroeihyl)aniline (60 mg, 0.23 mmol) and 4~ fluorobenzoy! chloride (38 pL, 0.32 mmol). The crude product was purified by

preparative HPLC (20-100% CH ₃ CN/MeOH (1 :1) in H ₂ 0 (0.01 % TFA)) which provided after lyophilization 85 mg (74%) of the title compound as a colorless solid; Ή R (400 MHz, CDCb) δ = 7,95 (br, s, 1 H), 7.86 - 7,92 (m, 2H), 7.69 - 7.76 (m, 4H), 7.15 - 7.22 (m, 2H). Synthetic Example 11 : N~(4-( 1 , 1 , 1 _r 3,3 _r 3-hexaf!uoro-2-hydroxypropan-2-yl}phenyl)"2- methy I benzarn ide

The title compound was prepared according to the Synthetic Example 2 from 4~{1- hydroxy-1~trif!uoromeihyi--2,2,2-trifluoroethyi}aniiine (50 mg, 0, 19 mrnol) and o-ioluoyl chloride (36 mg, 0.23 rnmo!). The crude product was purified by column

chromatography on silica gel without any workup by hexane/AcOEt (8/2) to obtain 50 mg (89%) of the title compound as a white powder. ¹ H HMR (400 MHz, MeOD-d4) 6 -™ 7.80 (d, J = 8.99 Hz, 2H), 7.72 (d, J ^« 8.77 Hz, 2H), 7.45 ~ 7.51 (m, 1 H), 7.37 (m, 1 H), 7.28 - 7.33 (m, 2H), 2.46 (s, 3H).

Synthetic Example 12: N-(4-{1 ,1 ,1 ,3,3,3-h8xaf!uoro-2-hydroxypropan-2-y])pheny!)-3- methylbenzamide

The title compound was prepared according to the Synthetic Example 2 from 4~(1~ hydroxy-l-trilluoromethyl^^^-trifluoroethy aniline (50 mg, 0.19 mrnol) and m-toluoyi chloride (36 mg, 0.23 mrnol). The crude product was purified by column

chromatography on silica gel without any workup by hexane/AcOEt (8/2) to obtain 49 mg (87%) of the title compound as a white powder. ¹ H NMR (400 MHz, MeOD-d4) δ - 7.80 - 7.85 (m, 2H), 7.77 (s, 1 H), 7.89 - 7.75 (m, 3H), 7.36 - 7.43 (m, 2H), 2.43 (s, 3H).

Synthetic Example 13: ~(4"(1 , 1 _l 1 _f 3,3.3-hexafluoro-2~hydroxypropan~2-yi)pheny!)-4-- methylbenzamide

The title compound was prepared according to the Synthetic Example 2 from 4~{1 - hydroxy-1 rifluoromeihyl-2,2,2-trifluoroethyl)aniiine (50 mg, 0.19 mmol) and p-toluoyl chloride (31 pL, 0.23 mmol). The crude product was purified by preparative HPLC (20- 100% CHsC /MeOH (1 : 1 ) in H ₂ 0 (0.01% TFA)) which provided after i ophilization 43 mg (83%) of the title compound as a colorless solid; H HMR (400 MHz, eOD~d4) δ ^™ 7,78 ~ 7.87 (m, 4H), 7.87 - 7.74 (m, 2H), 7.29 - 7.38 (m, 2H), 2.41 (s, 3H).

Synthetic Example 14: N-(4-(1 _! 1 ,1 ,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyi)-2- (trifluoromethyi)benzamide

The title compound was prepared according to the Synthetic Example 2 from 4-(1~ hydroxy-1-trifluoromethyl-2,2,2-trifluoroethyl)a!iiline (50 mg, 0.19 mmol) and 2- trifluoromethylbenzoyl chloride (30 pL, 0.23 mmol). The crude product was purified by preparative HPLC (20-100% CH ₃ CN/MeOH (1 :1) in H ₂ 0 (0.01 % TFA)) which provided after lyophiiizafion 86 mg (79%) of the title compound as a colorless solid; H NiVIR (400

MHz, MeOD-d4) δ = 7.80 - 7.84 (m, 1H), 7.69 - 7.78 (m, 5H), 7.85 - 7.89 (m, 2H).

Synthetic Example 15: ^^I .I ^ ^^.S- exafluoro^-h dro pro an^- ph n l)^- (trifluoromethyl)benzamide

The title compound was prepared according to the Synthetic Example 2 from 4-(1 ~ hydrox -1~trff!uoromethyi"2,2 ₍ 2-irifluoroethyl)aniline (40 mg, 0.15 mmo!) and 3- trif!uoromethylbenzoyi chtorlde (25 pL, 0.18 mmo!). The crude product was purified by column chromatography on silica gel without any workup by hexane/AcOEt (8/2) to obtain 47 mg (71 %) of the title compound as a white powder. ¹ H M (400 MHz, eGD- d4) 5 ^ 8.28 (s, 1 H), 8.19 - 8.23 (m, 1 H), 7.87 - 7.91 (m, 1 H), 7,82 - 7.87 (m, 2H), 7.89 - 7.76 (m, 3H),

Synthetic Example 16; 2~bromo-5-chloro-N-(4-(1 ,1 ,1 ,3,3,3-hexafluoro-2-hydraxypropan-

2-yl)phenyl)benzamide

The title compound was prepared according to the Synthetic Example 2 from 4-(1- hydroxy-1 rif!uoromethyl-2,2,2 rifluoroethyl)aniline (100 mg. 0.39 mrnol} and 2-bromo- 5-chlorobenzoyl chloride (120 mg, 0.46 mrnol). The crude product was purified by column chromatography on silica gel without any workup by hexane/AcOEt (7/3) to obtain 130 mg (71 %) of the title compound as a white powder; ¹ H NMR (400 MHz, CDCi ₃ ) δ = 8.12 (br. s„ 1 H), 7.67 - 7.78 (m, 4H), 7.51 - 7.58 (m, 2H} ₅ 7.28 - 7.31 (m, 1 H).

Synthetic Example 17: N-(4-(1 ,i .,3,3, 3~hexa†!uoro~2-hydroxypropan-2-yi)phenyl)-2- methoxybenzamide

The title compound was prepared according to the Synthetic Example 2 from 4-(1 - hydrox7-1 nfiuofOmethyl-2,2,2-trif!uoroethyl)ani!ine (40 mg, 0.15 mrnol) and o-anisole chloride (28 pL, 0.18 mrnol). The crude product was purified by column chromatography on silica gel without any workup by hexane/AcOEt (8/2) to obtain 60 mg (99%) of the title compound as a white powder. H NMR (400 MHz, MeOD-d4) δ ~ 7.90 (d, J ~ 7.89 Hz, 1 H), 7.78 - 7,80 (m, 2H), 7.70 - 7.72 (m, 2H), 7,47 - 7.55 (m, 1 H), 7.18 (d, J ~ 8.11 Hz, 1 H), 7.04 - 7.1 1 (m, 1 H), 4.00 (s, 3H).

Synthetic Example 18: M^-CI .I ^.S.S-he afS o o^-h dro pro an^-y^ heny -S- methoxybenzamide

The titie compound was prepared according to the Synthetic Example 2 from 4-(1- hydroxy-1-tnfluorornethyi-2,2,2 nfluoroethyl)any!ne (40 mg, 0.15 mmo!) and 3- methoxybenzoyi chloride (26 pi, 0.18 mmol). The crude product was purified by column chromatography on silica gel without any workup by hexane/AcOEt (8/2) to obtain 59 mg (97%) of the title compound as a white powder. ¹ H NMR (400 MHz, MeOD-d4) δ - 7.80 - 7.85 (m, 2H), 7.89 - 7.75 (m, 2H), 7.47 - 7.53 (m, 2H), 7.38 - 7.43 (m, 1 H), 7.12 ~. 7.14 (m, 1 H), 3.85 (s, 3H).

Synthetic Example 19: N~(4-{1 _:s 1 ,1 ,3 _t 3,3-hexaf!uoro~2~hydroxypropan~2~yl}phenyi)-4- methox benzamide

The title compound was prepared according to the Synthetic Example 2 from 4~(1- ydroxy-1 -trifluoromeihyl-2,2 _J 2-trifluoroethyl)aniline (60 mg, 0.23 mmol) and 4- methox benzoyl chloride (44 pL, 0.32 mmol). The crude product was purified by preparative HPLC (20-100% CH ₃ CN/MeOH (1 :1) in H ₂ 0 (0.01 % TFA)) which provided after lyophiSizaiion 63 mg (69%) of the title compound as a cotorless solid; H HMR (400

MHz, CDCIg) δ - 7.83 - 7.90 (m, 2H), 7.82 (br. s, 1 H), 7.70 ~ 7.78 (m, 4H), 6.98 -· 7.04 (m, 2H), 3.90 (s, 3H).

Synthetic Example 20: ^^I . I ^^^-hexsfiuoro^-h dro y ro an^-y phenyl)^- nitrobenzamide

The title compound was prepared according to the Synthetic Example 2 from 4-(1 ~ hydroxy-1 -irifluoromethyl~2,2 _i 2-irifluoroethyl)aniiirie (40 mg, 0.15 mmo!) and 2- nitrobenzoyf chloride (24 μί, 0.18 mmol). The crude product was purified by column chromatography on silica gel without any workup by hexane/AcOEt (8/2) to obtain 62 mg (98%) of the title compound as a white powder. ¹ H MMR (400 MHz, MeOD-d4) δ ~ 8.18 (dd, J - 1.21 , 8.44 Hz, 1 H), 7.79 - 7.85 (m, 1 H), 7.68 - 7.78 (m, 6H).

Synthetic Example 21 : N-(4-(1 ,1 , 1 ,3, 3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)-3- nitrobenzamsde

The title compound was prepared according to the Synthetic Example 2 from 4-(1- h droxy~1~trifluoromethyl~2,2,2 riflyoroethyl)an!line (40 mg, 0.15 mmol) and 3- nitrobenzoyl chloride (34 mg, 0.18 mmol). The crude product was purified by column chromatography on silica gel without any workup by hexane/AcOEt (8/2) to obtain 35 mg (56%) of the title compound as a white powder, ¹ H NMR (400 MHz, MeOD~d4) δ - 8,82 (t, J - 1.88 Hz, 1 H), 8,43 - 8.46 (m, 1 H), 8.34 - 8.36 (m, 1 H), 7.82 - 7.89 (m, 2H), 7,77 - 7,81 (m, 1 H), 7.71 ·· 7.77 (m, 2H). Synthetic Example 22: N-(4-(1 ,.1 _¾ 1 _I 3 _i 3,3"hexafSuoro~2-hydroxyprQpan~2~yl)phenyl)-4- nitrobenzamide

The title compound was prepared according to the Synthetic Example 2 from 4~{1- hydroxy-1-trifiuorornethyl-2,2,2-tnfluoroethyl)aniiine (80 mg, 0.23 mmol) and 4- nitrobenzoyl chloride (57 mg, 0.30 mmol). The crude product was purified by

preparative HPLC (20-100% CH ₃ CN/MeOH (1 :1) in H ₂ 0 (0.01% TFA)) which provided after lyophilization 38 mg (42%) of the title compound as a colorless solid; ¹ H NMR (400 MHz _t MeQD~d4) δ™ 8,30 - 8.35 (m, 2H), 8,08 - 8.13 (m, 2H), 7.78 - 7.83 (m, 2H), 7.87 ~ 7.73 (m, 2H).

Synthetic Example 23: S-cyaoo- ^-CI .I ^ J^^-hex fluoro^-hydro pro an^- yi)pheny[)benzamide

The title compound was prepared according to the Synthetic Exampie 2 from 4-(1 ^» hydroxy-1~trifiuoromethyi-2 ₍ 2,2-trifSuoroeihyi}aniline (60 mg, 0.23 mmol) and 3- cyanobenzoyl chloride (51 mg, 0.30 mmol). The crude product was purified by preparative HPLC (20-100% CH ₃ CN/MeOH (1 :1) in H ₂ 0 (0.01 % TFA)) which provided after lyophiHzation 80 mg (94%) of the title compound as a colortess solid; ¹ H NMR (400 MHz, MeOD~d4) δ - 8.31 (s, 1 H), 8.20 - 8.27 (m, 1 H), 7.90 - 7.96 (m, 1 H), 7.80 - 7.86 (m, 2H), 7.88 - 7.76 (m, 3H). Synthetic Example 24: 4~cyano- -{4-(1 A _^ I .S^.S-hexafiuoro^-hydro ypropan-Z- yl)phenyl)benzamide

The title compound was prepared according to the Synthetic Example 2 from 4~(1- hydroxy~1-tnflyoromethyl~2,2,2~tnfluoroethyi)an ine (50 mg, 0,1 mmol) and p~toluoyl chloride (38 mg, 0.23 mrnoi). The crude product was purified by preparative HPLC (20- 100% CH ₃ CN/MeOH (1 :1 ) in H ₂ 0 (0,01 % TFA)) which provided after lyophifeation 49 mg (65%) of the title compound as a colorless solid; ¹ H NM (400 MHz, MeOD-d4) δ - 8.08 - 8,11 (m, 2H), 7.88 - 7.91 (m, 2H), 7,81 - 7.86 (m, 2H), 7.71 - 7.76 (m, 2H).

Synthetic Example 25: N-(4-{1 ,1 ,1 ,3,3,3-hexafiuoro-2-hydroxypropan~2-yi)phenylH1 _i 1'- biphenyl]-2-carboxamide

In a dried W flask under Ar were introduced 2-chloro~N-(4-(1 _l 1 ,1,3,3,3-hexafiuoro-2- hydraxypropan~2-yl)phenyl)benzamide (SR0987) (30 mg, 0,075 mmol), phenyl boronic acid (1 1 mg, 0.091 mmol), K ₂ C0 ₃ (52 mg, 0.38 mmol), 0,4 mL of dioxane and 0.08 ml H ₂ O, The flask was purged three times with Ar before the addition of Pd(dppf)Cb (8 mg 0,008 mmol). The flask was sealed and the reaction mixture was stirred 5h at 120 °C. After removal of the solvent in vacuo, the crude product was purified by preparative HPLC (20-100% CHsCN/MeOH (1 :1) in H ₂ 0 (0.01% TFA)) which provided after lyophifization 7 mg (21%) of the title compound as a colorless solid; ¹ H NMR (400 MHz, yeGD-d4) δ = 8.21 (t, J = 1 ,77 Hz, 1 H), 7.91 - 7,98 (m, 1H), 7,83 - 7.88 (m, 3H), 7.70 - 7.78 (m, 4H), 7.58 - 7.84 (m, 1H), 7.46 - 7.51 (m, 2H), 7.38 - 7.41 (m, 1 H). Synthetic Example 26; N-(4-(1 _¾ 1 »1 ,3,3,3-hexaf!uoro-2-hydroxypropan"2-yl)phenyl)-[1 , 1S biphenyl]-3-carboxamide

The title compound was prepared according to the Synthetic Example 2 from 4-(1- hydroxy-1-tnfluoromethy!~2 _[ 2 ₍ 2-trifiuoroethyi}an!lsne (50 mg, 0.19 mmol) and biphenyl-3- carbonyl chloride (50 mg, 0,23 mmol). The crude product was purified by column chromatography on silica gel without any workup by hexane/AcOEt (8/2) to obtain 32 mg (38%) of the title compound as a light yellow powder. ¹ H HMR (400 MHz. MeOD~d4) δ * 8.20 (t, J = 1.64 Hz, 1 H), 7.91 - 7.94 (m, 1 H), 7.83 - 7.88 (m, 3H), 7.69 - 7.78 (m, 4H), 7.57 ^■■ 7.62 (m, 1H), 7.45 ~ 7.50 (m, 2H), 7.35 - 7.41 (m, 1 H).

Synthetic Example 27: N~(4-(1 _! 1 _l 1 _! 3.3,3-hexafluoro-2-hydroxypropan-2-yl)phenylH1 ,1 '- bsphenyl]-4-carboxarnide

The title compound was prepared according to the Synthetic Example 2 from 4-(1 - hydroxy-l-trifluoromethyl^^^-trifSuoroethy^aniline (50 mg, 0.19 mrnoi) and 4- biphenylbenzoyl chloride (50 mg, 0,23 mmol). The crude product was purified by preparative HPLC (20-100% CH ₃ CN/MeOH (1 :1) in H ₂ 0 (0.01 % TFA)) which provided after iyophilizstion 80 mg (94%) of the title compound as a colorless solid; ¹ H NMR (400 MHz, MeOD-d4) δ = 8.01 - 8.08 (m, 2H), 7.83 - 7.88 (m, 2H), 7.75 - 7.80 (m, 2H), 7.71 ... 7,75 (m, 2H), 7.86 - 7.71 (m, 2H), 7.45 - 7.50 (m, 2H), 7.40 (d, J - 7.45 Hz, 1 H).

Synthetic Example 28: 2 _: 4-dichloro-N~(4-(1 , 1 ,1 ,3, 3 _i 3-hexafiuoro-2-hydroxypropan»2- yl)pheny!)benzamide

The title compound was prepared according to the Synthetic Example 2 from 4-(1- hydroxy~1-trifluoromethyl-2,2 _r 2-trifluoroeihyl)an!line (40 mg, 0.15 mmoi) and 2,4- dichlorobenzoyi chloride (28 pL, 0.18 mmoi). The crude product was purified by column chromatography on silica gel without any workup by hexane/AcOEt (8/2) to obtain 83 rng (94%) of the title compound as a white powder; H NMR (400 MHz, MaOD-d4) δ = 7.70 ·· 7.81 (m, 4H), 7.53 - 7.63 (m, 2H), 7.45 (dd, J - 1.77, 8.34 Hz, 1 H).

Synthetic Example 29; 2,6-dichSoro-N~{4-(1 ,1 ,1 ,3,3 _i 3~hexaf!uoro-2 ^» hydroxypropan-2-- yl)phenyl)benzamide

The title compound was prepared according to the Synthetic Example 2 from 4-(1- hydroxy-l ^rifluoromethy!^^^-trif!uoroethyijaniline (40 rng, 0.15 mmoi) and 2,6- dich!orobenzoyl chloride (27 pL, 0.18 mmoi), The crude product was purified by preparative HPLC (20-100% CH ₃ CN/MeOH (1 :1) in H ₂ 0 (0,01% TFA)) which provided after lyophilization 20 mg (30%) of the title compound as a colorless solid; ¹ H MR (400 MHz, CDCb) δ ^« 7.74 - 7.78 (m, 4H), 7.82 (br. s, 1 H), 7.30 -· 7.40 (m, 3H).

Synthetic Example 30: 3,5-dichioro™N-(4~(1 ,1 ,1 ,3,3 _l 3-hexafiuoro-2-hydroxypropan-2- yl)phenyl)benzamide

The title compound was prepared according to the Synthetic Example 2 from 4-(1- hydroKy-1-irrf!uoromeihyl-2,2,2"trif1uoroeihyl)aniiine (40 mg, 0.15 mmol) and 3,5- dichiorobenzoyl chloride (35 mg, 0,18 mmol). The erode product was purified by column chromatography on silica gel without any workup by hexane/AcOEt (7/3) to obtain 52 mg (78%) of the title compound as a white powder; ¹ H HMR (400 MHz, IVfeOD-d4) δ = 7,91 (d, J = 1.77 Hz, 2H), 7.79 - 7,85 (m, 2H), 7.89 - 7.75 (m, 2H), 7.65 (t, J - 1.77 Hz, 1H).

Synthetic Example 31 : 2 "dichloro- ~(4-(t; _i 1 _! 3,3,3-hexafluoro-2~hydroxypropan~2- y1)pheny])benzamsde

The title compound was prepared according to the Synthetic Example 2 from 4-(1~ hydroxy-l-trifiuoromethyl^^^-trifluoroethyljaniline (40 mg, 0.15 mmol) and 2,3- dschiorobenzoyl chloride (28 μΙ_, 0.18 mmol). The crude product was purified by preparative HPLC (20-100% CH ₃ CH/MeOH (1 :1) in H ₂ 0 (0.01 % TFA)) which provided after lyophilization 51 mg (76%) of the title compound as a colorless solid; Ή NMR (400 MHz, CDC ) δ = 7.80 (br. s., 1 H), 7.74 - 7.78 (m, 4H), 7.59 (dd, J - 7.78, 1 195 Hz, 1 H), 7.59 (dd, J = 7.89, 15.13 Hz, 1H), 7.31 - 7.38 (m, 1 H).

Synthetic Example 32: S-bromo^-chioro-N^^ l ^.S.S-hexafluoro^-hydroxypropan- 2-yi)phenyl)benzamide

The title compound was prepared according to the Synthetic Example 2 from 4-{1- hydroxy-1 r!fiuoromethyl-2,2,2-trifluoroethyi)aniiin8 (50 rng, 0.19 mmol) and S-bromo~2- -chJorobenzoyl chloride (80 mg, 0.23 mmol). The crude product was purified by column chromatography on silica gel without any workup b hexane/AcOEt (7/3) to obtain 74 mg (80%) of the titie compound as a white powder; ¹ H HMR (400 MHz, MeOD-d4) δ = 7.76 - 7.81 (m, 2H), 7.70 - 7.78 (m, 3H), 7.63 (dd, J = 2.41 , 8.55 Hz, 1 H), 7.43 (d, J = 8,55 Hz, 1 H).

Synthetic Example 33: -i^l .l ^ .S^.S-hexafSuoro-S-h dro y ro an^- hen furan- 2-carboxarnide

The title compound was prepared according to the Synthetic Example 2 from 4-(1- hydroxy-1~tnfiuoromethyi-2 _t 2,2-trifluoroethyl)aniline (50 mg, 0.19 mmol) and 2~furayj chloride (23 pL 0.23 mmol). The crude product was purified by preparative HPLC (20- 100% CH ₃ CN MeOH (1 :1) in H ₂ 0 (0.01 % TFA)) which provided after lyophillzation 29 mg (48%) of the titie compound as a colorless soiid; ¹ H NMR (400 MHz, MeOD-d4) 6 ~ 7.79 - 7.85 (m, 2H), 7.75 (dd, J = 0.78, 1 .77 Hz, 1 H), 7.67 - 7.73 (m, 2H), 7.29 (dd, J = 0.76, 3.54 Hz, 1 H), 8.85 (dd, J * 177, 3.54 Hz, 1 H).

Synthetic Example 34: N-(4~(1 ,1 _f 1 _I 3,3,3-hexaf!uoro~2-hydroxypropan~2~

yl}phenyl)th ophene-2-carboxarnide

The title compound was prepared according to the Synthetic Exampie 2 from 4-(1- hydroxy-l-trifluoromethyl^^^-trifiuoroethy aniline (200 mg, 0.77 mmol) and 2- thiophenecarbonyi chloride (118 pL, 1.08 mmol). The crude product was purified by preparative HPLC (20-100% CH ₃ CN/iVleOH (1 :1) in H ₂ 0 (0,01% TFA)) which provided after lyophilization 280 mg (91 %) of the title compound as a colorless soiid; ¹ H NMR (400 MHz, CDC ) δ = 7.78 (br. s„ 1 H), 7.72 ~ 7.74 (m, 4H), 7.86 (dd, J

1 H), 7.80 (dd, J = 1.21 , 4.93 Hz, 1 H), 7.18 (dd, J * 3,84, 4.93 Hz, 1 H).

Synthetic Exampte 35: N~(4-(1 , 1 _$ 1 _l 3 _l 3 _l 3-hexafiuoro-2-hydFox propan-2'

yl)phenyl)picolinamide

The title compound was prepared according to the Synthetic Exampte 2 from 4-(1 - hydroxy-i-tnfiuoromethy^^^-trifluoroethy^aniline (50 mg, 0.19 mmol) and picolinoyl chloride hydrochloride (41 mg, 0.23 mmol). The crude product was purified by column chromatography on silica gel without any workup by hexane/AcOEt (8/4) to obtain 60 mg (85%) of the title compound as a light yellow powder. ¹ H HMR (400 MHz, MeOD-d4) δ = 8.65 - 8.72 (m, 1 H), 8,21 (td _f J = 0.99, 7.89 Hz, 1 H), 7.99 (dt, J - 1.75, 7.89 Hz, 1 H), 7.89 - 7.95 (m, 2H), 7.69 - 7.78 (m, J = 8.77 Hz, 2H), 7.58 - 7.60 (m, 1 H).

Synthetic Example 38: N~(4~(1 ,1 ,1 ,3,3,3-hexafiuoro~2-hydroxypropan-2~

yl)phenyl)nicotsnamide

The title compound was prepared according to the Synthetic Exampte 2 from 4~(1- hydroxy-l-trifluoromethyi- ^^-tnfluoroethy ani!ine (60 mg, 0.22 mmoi) and nicotinoyl chloride hydrochloride (58 mg, 0.32 mmol). The erode product was purified by

preparative HPLC (20-100% CH ₃ CN/MeOH (1 :1) in H ₂ 0 (0.01 % TFA)) whtch provided after SyophiMzation 47 mg (56%) of the title compound as a cotortess solid as a TFA salt H HMR (400 MHz, MeOD-d4) δ = 9.27 (s, 1 H), 8.87 - 8.97 (m, 1 H), 8.84 (d, J = 8,1 1 Hz, 1 H), 8.02 (dd, J ^« 5.48, 8.1 1 Hz, 1 H), 7.81 - 7.90 (m, 2H), 7.71 - 7.80 (m, 2H). Synthetic Example 37; ^-i^ l ^^^-heK f!uoro^-h drox propen^

yf)phenyl)isonicotinamide

The title compound was prepared according to the Synthetic Example 2 from 4-(1- hydroxy-'1-frifluorornethyi-'2 _! 2 _i 2~tril1uoroethyl)anil!ne (50 mg, 0.19 mmol) and

isonicotinoyl chioride hydrochloride (41 mg, 0.23 mmol). The crude product was purified by preparative HPLC (20-100% CH ₃ CN/MeOH (1 :1) in H ₂ 0 (0.01% TFA)} which provided after jyophi!izaiion 24 mg (28 %) of the title compound as a colorless solid as TFA salt; ¹ H NMR (400 MHz, MeOD-d4) 5 = 8.93 (d, J = 4.80 Hz, 2H) _S 8.21 - 8.29 (m, 2H), 7,84 » 7.91 (m, 2H), 7.72 - 7.79 (m, 2H).

Synthetic Example 38: N~(4~(1 _! 1 _! 1 _! 3 _I 3,3-heKafluoro-2-hydroxypropan-2-yl)phenyl)-1- naphthamide

The title compound was prepared according to the Synthetic Example 2 from 4~(1- hydroxy-1 rifIuoromethyl-2,2,2-irifluoraethyl)aniline (80 mg, 0.22 mmol) and 1-naphthoy chloride (59 mg, 0,30 mmol). The crude product was purified by preparative HPLC (20- 100% CH ₃ CN/MeOH (1 :1) in H ₂ 0 (0.01% TFA)) which provided after lyophilszation 47 mg (52%) of the title compound as a colorless solid; ¹ H NMR (400 MHz, IV1eOD~d4) δ ^« 8.21 - 8.27 (m, 1 H), 8.02 (d, J = 8.33 Hz, 1 H), 7.92 - 7.97 (m, 1 H), 7.87 (d, J ~ 8.99 Hz, 2H), 7.72 - 7.78 (m, 3H), 7.52 - 7,80 (m, 3H).

Synthetic Example 39; S-chioro-N-i^i .l .l .S^.S-hexafSuoro^-hydroxypropan^- y!)phenyS)picolinamide

The title compound was prepared according to the Synthetic Exampte 2 from 4-(1- hydroxy-1-trif!uoromeihyl~2,2,2-trifluoroethyl)aniline (50 mg, 0.19 mmof) and 3- ohioropicoiinoyl chloride (40 mg, 0.23 mmol). The crude product was purified by co umn chromatography on silica gel without any workup by hexane/AcOEt (7/3) to obtain 75 mg (97%) of the title compound as a white powder; H MR (400 MHz, MeOD-d4) δ ^™ 8.57 (dd, J - 1.32, 4.80 Hz, 1 H>, 7.98 - 8.03 (m, 1 H), 7.81 - 7.89 (m, 2H), 7.70 ~ 7.77 (m, 2H), 7.53 (dd, J = 4.60, 8.22 Hz, 1 H).

Synthetic Exampte 40: 2-chloro- -{4-(1 ₍ 1 _i 1 ,3,3.3-hexafluoro»2-hydroxypropan-2-yl)-2- meihylphenyl)benzamide

The title compound was prepared according to the Synthetic Exampte 2 from 2-(4- amino-S-methylpheny -I . I J .S^^-hexafluoropropan^-oi (100 mg, 0.37 mmol) and 2 ^» chlorobenzoyl chloride (56 μί_, 0.44 mmol). The crude product was purified by column chromatography on silica gel without any workup by hexane/AcOEt (7/3) to obtain 122 mg (81%) of the title compound as a white powder; ^' Ή NMR (400 MHz, ¾feOD-d4) δ - 7.88 (s, 1 H), 7.58 - 7.65 (m, 3H), 7.50 ^» 7.55 (m, 1 H), 7.39 - 7.50 (m, 2H), 2.41 (s, 3H).

Synthetic Exampfe 41 : 2-chloro-N-(2-chloro-4~(2-chtoro-1 ,1 _! 1 _! 3 _! 3,3-hexafluoropropan-2- yf)phenyl)benzamide

The title compound was prepared according to the Synthetic Example 2 from 2-{4- amino-S-chlorophenyiJ-I . I .S^^-hexa^uoropropan^-o! (50 mg, 0.17 mmol) and 2- chtorobenzoyi chloride (28 pL, 0,20 mmol). The crude product was purified by coiumn chromatography on silica gel without any workup by hexane/AoOEt (7/3) to obtain 51 mg (89%) of the title compound as a white powder; ¹ H MR (400 MHz _t MeOD~d4) δ™ 8.08 (d, - 8.59 Hz, 1 H) _P 7.86 (d, J ~ 1.77 Hz, 1H), 7,63 - 7.78 (m, 2H), 7.39 - 7.57 (m, 3H),

Synthetic Example 42: 2~chtoro~N-(4~(2~chIoro~1 _! 1 ,1 ,3 _! 3,3-hexafluoropropan-2~y!)-2~ methoxyphenyi)benzamide

The title compound was prepared according to the Synthetic Example 2 from 2~{4~ amino-S-methoxypheny -l . l . i .S^.S-hexafluoropropan^-ol (100 mg, 0.35 mmol) and 2-GhJorobenzGyl chloride (53 μί_, 0.41 mmol). The crude product was purified by column chromatography on silica gel without any workup by hexane/AcOEt (7/3) to obtain 105 mg (71 %) of the title compound as a white powder; ¹ H NMR (400 MHz, MeOD-d4) δ™ 8,27 (d, J - 8.59 H , 1H), 7,63 (d, J - 7.33 Hz, 1 H), 7.39 ·· 7.55 (m, 4H), 7.35 (d, J * 8.59 Hz, 1 H), 3.90 (s, 3H).

Synthetic Example 43: 2-Gh!oro- -(4-(1. _s 1 ,1 ,3,3,3-h8xafSuoro-2-hydraxypropan-2-y!)-3- me†hylphenyl)benzamide

The title compound was prepared according to the Synthetic Example 2 from 2~(4- am]no-2-methy!phenyl)-1 ,1 ,1 ,3,3,3-hexaf!uoropropan-2-oi (100 mg, 0.37 mmol) and 2- chiorobenzoyl chloride (58 pL, 0,44 mmol). The crude product was purified by preparative HPLC (20-100% CH ₃ CN/IVieGH (1 :1) in H ₂ 0 (0.01% TFA)) which provided after iyophilization 101 mg (87%) of the title compound as a colorless solid; H HMR

(400 MHz, yeOD-d4) δ = 8.35 (s, 1 H), 7.82 (dd, J - 1.64, 7.34 Hz, 1 H), 7,42 - 7,56 (m, 4H), 7,07 - 7.10 (m, 1 H), 2.41 {s, 3H).

Synthetic Example 44: 2-chloro- -(3-chioro-4-(1 , 1 , 1 ,3, 3 _s 3-hexafluoro-2-hydroxypropan- 2~yi)phenyi)benzamide

The title compound was prepared according to the Synthetic Example 2 from 2~(4~ amino~2-chlorophenyl}-1 _! 1 ,1 ,3,3 _f 3~hexafluoropropan-2"Ol (100 mg, 0.34 mmol) and 2- ehlorobenzoyi chloride (52 pL, 0.41 mmol). The crude product was purified by column chromatography oo siiica gel without any workup by hexane/AcOEt (7/3) to obtain 103 mg (70%) of the title compound as a white powder; H NMR (400 MHz, MeOD~d4) δ ^™ 8.76 (d, J ~ 2.02 Hz, 1 H), 7.83 - 7.73 (m, 1 H), 7,38 - 7.57 (m, 4H), 7.07 - 7.17 (m, 1 H).

Synthetic Example 45: 2-chloro-N-(4~(1 ,1 ,1 _! 3 _[ 3,3-hexafluoro-2-hydroxypropan-2-yl)-3~ methoxyphenyl)benzamide

The title compound was prepared according to the Synthetic Example 2 from 2-(4- amino^-methoxypheny^-I ^ .I ^.S^-hexafluoropropan^-ol (100 mg, 0.35 mmol) and 2- chiorobenzoyl chloride (53 pL, 0.41 mmol). The crude product was purified by preparative HPLC (20-100% CH ₃ CN/MeOH (1 :1 ) in H ₂ 0 (0.01% TFA)) which provided after lyophilization 42 mg (28%) of the title compound as a colorless solid; ¹ H MR (400 MHz, MeOD-d4) δ = 7.71 (d, 2.19 Hz, 1 H), 7.68 (d, J = 8.77 Hz, 1 H), 7.55 - 7.59 (m, 1 H), 7.40 - 7.53 (m, 3H), 7.28 (dd, J - 2.19, 8.77 Hz, 1 H), 3.91 (s, 3H). Synthetic Example 48: 2-chioro-N-(4-(1 ,1 ,1 ,3,3 _l 3-hexafjuoro-2-meihoxypropan-2- yl)phenyl)benzamide

The title compound was prepared according to the Synthetic Example 2 from 4- {1 ,1 _i 1 ,3.3,3-hexafluoro~2-methoxypropan-2"'y )aniyne (50 mg, 0.18 mmol) and 2~ chloroben oy chlonde (28 pL, 0.22 mmol). The crude product was punfled by column chromatography on silica gel without any workup by hexane/AcOEt (7/3) to obtain 63 mg (84%) of the title compound as a white powder; ¹ H N R (400 MHz, MeOD-d4) δ™ 7.79 - 7,97 (m, 2H), 7.55 - 7,64 (m, 3H), 7.40 - 7.54 (m, 3H), 3.50 (s, 3H).

Synthetic Example 47: 2-chloro~N-(4~(perfiuoropropan~2~y phen )ben amide

In a dried MW flask under Ar were introduced 2-chtoro-N-{4-( 1 ,1 ,1, 3,3,3-hexafluoro-2~ hydroxypropan-2~ l)phenyl)benzarnide (SR0987) (50 mg, 0.13 mmol), Deoxo-Fluor ^® (70 pL, 0.38 mmol) and 0.4 mL of anhydroos DCM. The flask was sealed and the reaction mixture was stirred overnight at 50 °C; The crude product was purified by preparative HPLC {20-100% CH ₃ CN/ eOH (1 : 1) in ₂ 0 (0,01% TEA)) which provided after lyophilization 24 mg (48%) of the title compound as a colorless solid; ¹ H NMR (400 MHz, DMSO~d6) δ = 10.90 (s, 1 H), 7.93 - 8.00 (m, 2H), 7.64 - 7.72 (m, 2H), 7.58 - 7,63 (m, 2H), 7.51 - 7.55 (m, 1 H), 7.45 - 7,50 (m, 1 H),

Synthetic Example 48: 4-(2-chlorobenzamido)benzoic add

To the solution of 4~arninQbenzQic acid (47 rng, 0.34 mmol) in 2 ml of anhydrous THF was introduced 2~chlorobenzoyl chloride (38 pL, 0.29 mmol). The obtained solution was cooled at 0 ^Q C followed by the addition dropwise of Et ₃ (60 pL, 0.43 mmol). After 4h at room temperature, iced cooled HCI I N was added. The obtained solid was filtered and purified by preparative HPLC (20-100% CH ₃ CN/MeOH (1 :1) in H ₂ 0 (0.01% TFA)) which provided after lyophilization 38 mg (48%) of the title compound as a colorless solid; ¹ H NMR (400 MHz, yeGD-d4) δ ~ B.00 - 8.08 (m, 2H), 7.77 - 7.83 (m, 2H), 7.55 - 7.80 (m, 1 H) _f 7.41 - 7.55 (m, 3H).

Synthetic Example 49: N-(4~(tert~butyl)phenyl)~2-chiorobenzamide

The title compound was prepared according to the Synthetic Example 2 from 4-tert- butylaniiine (43 pL, 0.27 mmol) and 2-chlorobenzoyl chloride (41 μΙ_, 0.32 mmol). The crude product was purified by column chromatography on silica gel without any workup by hexane/AcOEt (7/3) to obtain 86 mg (86%) of the title compound as a white powder; H N R (400 MHz, eOD44) δ * 7.57 - 7.62 (m, 2H), 7.51 - 7.55 (m, 1H), 7.45 - 7.51 (m, 1 H), 7.37 ^■ · 7.45 (m, 4H), 1.33 (s, 9H).

Synthetic Example 50: -(4-benzamidophenyl)-2-chlorobenzamide

The title compound was prepared according to the Synthetic Example 2 from N-(4- aminophenyl)benzarnide (40 mg, 0.19 mmol) and 2-chlorobenzoyl chloride (29 pL, 0.23 mmoi). The crude product was purified by column chromatography on silica gal without any workup by hexarie/AcGEt (7/3) to obtain 82 mg (84%) of the title compound as a white powder; ¹ H NMR (400 MHz, f¾feOB~d4) δ * 7.91 - 7.97 (m, 2H), 7 87 - 7.74 (m, 4H), 7.41 - 7.61 (m, 7H).

Synthetic Example 51 : 2-chioro-N-(4-(phenylsulfonamido)phenyl)benzam!de

The title compound was prepared according to the Synthetic Example 2 from -(4- aminophenyl)benzenesulfonamide (50 mg. 0.20 mrnol) and 2~chlorobenzoyl chloride (31 pi, 0.24 mrnol). The crude product was purified by column chromatography on silica gel without any workup by hexane/AcOEt (7/3) to obtain 51 mg (85%) of the title compound as a white powder; H NMR (400 MHz, MeOD-d4) δ ~ 7.72 - 7.78 (m, 2H), 7.37 - 7.80 (m, 9H), 7,05 - 7.11 (m, 2H).

Synthetic Example 52: 2-chjoro-N~(4-(1 ₍ 1 _s 1 _f 3 _! 3,3-hexafluoro-2~hydroxypropan-2- yl)phenyl)benzenesulfonam de

To the solution of 4-(1-hydroxy-1-tril yoromethyl-2 _! 2,2-tnfluoroethyl)aniline (40 mg, 0.15 mmol) n 250 μί. of pyridine was added 2~chlorobenzenesoifonyl chloride (25 pL, 0.18 mmol). The reaction was stirred overnight at 80X. Removal of the solvent provided the crude product, which was purified by preparative HPLC (20-100% CHsCN/iVleOH (1 :1) in H ₂ 0 (0,01% TFA)) which provided after lyophilization 58 mg (87%) of the ti compound as a coloriess solid; ¹ H NMR (400 MHz, CDCb) δ - 8.07 - 8.10 (m, 1 H), 7.54 - 7.61 (m, 2H), 7,47 7.54 (m, 2H), 7,38 - 7 43 (m, 1 H), 7,26 (or, s., 1 H), 7 18 7.22 (m, 2H).

Synthetic Example 53: 2-(4-((2~chlorobenzy!)amino)pheny!)~1 ₍ 1 _; 1 ,3,3,3- hexafluoropropan-2-ol

To the solution of 4~(1"hydroxy-1 nfiuorornethyl-2,2,2-thfluoroethyl)aniline (80 mg , 0.31 mmol) in 3 mL of MeOH were added 2-chlorobenzaIdehyde (104 pL, 0.93 mmol) and acetic acid (88 pi, 1.54 mmol). The reaction mixture was stirred 30 min followed by the addition of NaBH ₃ C (97 mg, 1.54 mmol). The reaction was stirred overnight at 80 ^* 0. Removal of the solvent provided the crude product, which was purified by preparative HPLC (20-100% CHgC /MeOH (1 :1) in H ₂ 0 (0.01% TFA)) which provided after lyophilization 95 mg (75%) of the title compound as a colorless solid as TFA salt; ¹ H HMR (400 MHz, MeOD-d4) δ ^« 7.30 ~ 7.53 (m, 4H), 7.11 - 7.28 (m, 2H), 6.57 - 6.73 (m, 2H), 4.42 (s, 2H).

Synthetic Example 54: N~(2-chlorophenyl)~4~(1 _! 1 ,1 ,3, 3,3-hexafluoro-2-hydroxypropan-2- yl)benzamide

To the solution of 4-(1 ,1 , 1 ,3,3 _! 3-hexafluoro-2-hydrQxypropan~2~yl)benzQic acid (50 mg, 0.17 mmol) in 3 mL of anhydrous OCM were added oxalyi chloride (22 pL, 0.28 mmol) and DMF (4 μί, 0.05 mmol). The reaction was stirred at room temperature for 2h.

Removal of the solvent provided 4-(1 ,1 ,1 ₍ 3 _l 3 _[ 3-hexafluoro-2-hydroxypropan~2" yl)benzoyl chloride. The title compound was prepared according to the Synthetic Example 2 from 2- chloroaniline (19 μί, 0.18 mrnoi) and 4~(1 , 1 ,1 ,3, 3 -hexafluoro-2~hydroxypropan-2- yl)benzoyl chloride. The erode product was purified by preparative HPLC (20-100% CHsCN/MeOH (1 :1) in H ₂ Q (0.01 % TFA)) which provided after lyophilization 37 mg (54%) of the title compound as a colorless solid; ^j H MR (400 MHz, MeOD~d4) δ - 8.03 - 8.14 (m, J - 8.55 Hz, 2H), 7.88 - 7.96 (m, J™ 8.1 1 Hz, 2H), 7.73 ^« 7.75 (m, 1 H), 7.50 7.57 (m, 1 H), 7.34 - 7.43 (m, 1 H), 7,26 - 7.34 (m, 1 H).

Synthetic Example 55: 2-ch!oro-N-(4~(1 , 1 _! 1 ,3 _! 3 _! 3-hexafluoro-2~hydroxyprapan-2~ yl)phenyl)-N-methylbenzamide

The title compound was prepared according to the Synthetic Example 2 from

1 , 1 ,1 ,3,3,3-hexaf]uoro-2-(4~(iTiethytemino)phenyl)propan--2~ol (100 mg, 0,37 mmol) and 2-chlorobenzoyl chloride (58 pL, 0,44 mmo!). The crude product was purified by preparative HPLC (20-100% CH ₃ CN/ eOH (1 :1) in H ₂ 0 (0.01 % TFA)) which provided after lyophilization 55 mg (36%) of the title compound as a colorless solid; ¹ H NMR (400 MHz, MeOD~d4) δ ~ 7.50 - 7.59 (m, 2H) _S 7.32 - 7.34 (m, 2H), 7.11 - 7.29 (m, 4H), 3.51 (s, 3H)

HDX"HS„ Solution-phase amide HDX was performed with a fully automated system as described previously with minor modifications ^™ ' ²¹ . For differential HDX experiments, 5μ1 of a 10μ RGRyt LBD solution (Apo or in complex with 10-excess compound) was diluted to 25μί with D ₂ 0~containlng HDX buffer, and incubated at 4 ^e C for; 10s, 30s, 80s, 900s, and 3,800s. Following on-exchange, unwanted forward or back exchange is minimized and the protein is denatured by dilution to 50μί. with 0.1 % TFA in 3M urea (held at 4° C, pH 2.5). Samples are then passed across an immobilized pepsin column (prepared in house) at 50μΙ mirs-1 (0.1 % TFA.15°C) and the resulting peptides are trapped onto a G ₈ trap cartridge (Thermo Fisher, Hypersil Gold). Peptides were then gradient elufed (4% CH ₃ C to 40% CH ₃ CN, 0.3% formic acid over 5 minutes, 4°C) across a 1 mm x 50mm C s HPLC column (Hypersil Gold, Thermo Fisher) and electrosprayed directly into a high resolution orbitrap mass spectrometer (Exactive, Thermo Fisher), Percent deuterium exchange values for peptide isotopic envelopes at each time point were calculated and processed using HDX Workbench - and overlaid onto RORyt crystal structures using py OL (OeLano Scientific). HDX data is presented as an average of three individual replicates across 6 time points (10s, 80s, 300s, 900s ₍ and 3800s).

NR box peptide interaction ssay. A TR~F ET~based interaction assay was used. The His-Sumo RORy ligand binding domain (LBD) and FITC-labeled SRC1 -3 peptide (sequence; ASNLGLEDIIRKALMGSFD) was used. T -FRET reaction contains 2.5πΜ RORy L8D _s 450 SRC1-3 peptide in assay buffer (TR-FRET Coreguiator Buffer D, Lifetechnologies). The mixtures were incubated for 2hr at R.T., and fluorescence intensity was measured on an Envision pate reader with excitation at 340nm and emission at 490nm and 520 nm, The ratio of intensity at 520 nm/490nm was used to calculate cofactor recruitment activity.

Lociferas® reporter assay. HEK 293T cells were transfected with a UAS: luciferase reporter and a Gal4-RORy encoding plasmid (using X-trememGE E 9, Roche). Ursolic acid was pretreated before compounds were added. Luciferase activity was measured 20 hr after compound addition.

Gen© expression and Cell sorting. Jurkat T cells were pre-incubated with compounds for 48 hr and activated with phorbol 12-myristate 13-acetate (P A, 50 ng/mL; Sigma) and sonomycin (1 pg/mL; Sigma) for 5hr. For qPCR, mR A was isolated with an RNeasy midi kit using DNase I (Giagen), and cDMA was synthesized with high capacity cDNA Reverse Transcription kit (Applied Biosystems), IL17A, PD-1 , and granzyme B gene expression were normalized to the expression of GAPDH, The sequence of primers used in this study are found in Table 2. For cell sorting, activated Jurkat T cells were stained with ARC conjugated anti-human PD-1 antibody (eBioscience). Cell sorting was performed using LSRII (BD Bioscience),

T i ? cell differentiation. For naive T cell differentiation, CD4 ⁺ T ceils were enriched by negative selection using a magnetic-activated ceil sorter kit ( illipore). Enriched CD4* T cells activated with 5pg/mL of plate- abound anti CD3 antibody and 1 pg/mL of anti- CD28 antibody in the presence of 20 pg/mL of anti- iF y, 20 pg/mL of anti- IL-4, 1 ng/mL of ΤΟΡβ, AND 10 ng/mL of IL-6, Four-five days post differentiation, all cells were stimulated for 5 hr with 5 ng/mL of phorbol-12-rnyristate-13-acetate (Sigma) and 500 ng/mL of ionomycin (Sigma) contained with brefeldin A solution (eBioscience). Data analysis and statistics. All experiments were done with three or more biological replicates. Error bars represent standard deviation, Statistics were caicuiated using an unpaired, two sample Student's t-test

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Ail patents and publications referred to herein are incorporated by reference herein to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference in its entirety.

The terms and expressions which have been employed are used as terms of description and not of limitation, and there is no intention that in the use of such terms and expressions of exciuding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention claimed. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this invention as defined by the appended claims,