WO2018052903A1 - RORγ MODULATORS - Google Patents

RORγ MODULATORS Download PDF

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WO2018052903A1
WO2018052903A1 PCT/US2017/051178 US2017051178W WO2018052903A1 WO 2018052903 A1 WO2018052903 A1 WO 2018052903A1 US 2017051178 W US2017051178 W US 2017051178W WO 2018052903 A1 WO2018052903 A1 WO 2018052903A1
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mmol
title compound
mhz
nmr
mmoi
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PCT/US2017/051178
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French (fr)
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Patrick R. GRIFFIN
Theodore M. Kamenecka
Christelle DOEBELIN
Mi Ra CHANG
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The Scripps Research Intitute
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/12—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • RORs Orphan retinoic acid receptors
  • N ' R nuclear receptor
  • the RORs subfamily is composed of three members RORa, ROR$ and RORy also known as NRF1-NRF3 and RORa-RORc respectively.
  • sterols as RORy modulators, but its endogenous Iigand is still unknown or controversial 1"41
  • Two isoforms of RORy have been characterized, only differing by their N-terminai sequence and conserving the same iigand binding domain (LBD).
  • LBD iigand binding domain
  • RORyt is oniy found In lymphoid organs, like the thyrnus. 161
  • Liftman et ai. described RORyt as a key transcription factor involved in differentiation and function of CD4 + /CD8 + into T helper 17 (Th17) cells, lnterleukin- (IL-17) is.
  • Th17 ceils a .major cytokine produced by Th17 ceils.
  • autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, inflammatory bowel diseases and psoriasis.'- 8"11
  • Th17 ceils are produced to defend the host organism against external agents like bacteria, fungi, viruses and protozoa.
  • Numerous studies showed the presence of Th1 7 cells in tumor microenvironment. 112, 31 Currently, it is unclear whether Th17 cells are induced or recruited by tumors. Th17 cells alone have .
  • the invention is directed, in various embodiments, to agonists of the nuclear receptor RORy.
  • the invention can provide an RORy receptor agonist comprising a compound of formula ( I),
  • X-Y together is ⁇ CH 2 ⁇ 0-, -O-CHV, CH(R)-0-, -O-CH(R)-, -00-0-, -0-CO-, -CH2-NH-, - CH2- H(RK -NHCH ⁇ R) ⁇ , -NH-CO-, or -N(R)-CO;
  • the ring bonded to Y and B optionally further comprises 1 or 2 nitrogen atoms at an unsubstituted position thereof;
  • each R is independently H or ⁇ C1-C6)alkyl, halo, ha!o(C1-C6)alkyl.
  • aryL carboxyi, or carboxyaikyi;
  • ring bonded to X can optionally further comprise 1 or 2 nitrogen atoms;
  • R 2 is halo, ⁇ C1-C6)alkyl, (Ci -C6)a!koxyi, .ha!o(C 1 -G6)aikyt, halo(C1-C6)alkoxy, cyano, carboxy (C1 -C6)a!kyi; unsubstituted or substituted phenyl, or unsubstituted or substituted pyridyl; n2 ⁇ 0, 1 , 2, or 3; wherein the ring bonded to R 2 can optionally further comprise 1 or 2 nitrogen atoms; or a pharmaceutically acceptable salt there.
  • the inventions can provide a compound of formula (I) wherein n1 ⁇ 2 and R is halo; or where n2 ⁇ 1 and R 2 is trifiuoromethyl; or wherein each R is independently H or methyl; or X-Y is -CH2-.O-, or -O-CH2-; or any combination thereof.
  • X, Y, A, B, and R are as defined In claim 1 ;
  • the invention provides a method of activating the nuclear receptor RORy, comprising contacting the RORy with an effective amou t or concentration of a compound of the invention; and a method of treating cancer in a patient, comprising
  • Figure 1 depicts the chemical structures of various scaffolds binding the RORy LBD.
  • Figure 2 shows relationships between the chemical structures of RORy inverse agonists (lefthand column) and related RORy agonists derived therefrom (nghthand column).
  • Figure 3 is a schematic diagram showing Blockage Immune checkpoint by RORyt agonist.
  • Figure 4 is a block diagram illustrating the efficacy of anti-PDI therapy depends largely on an initial strong endogenous anti-tumor immune response. In absence of such a response, a combination approach using a RORyt agonist to induce anti-tumor immunity coupled with use of anti-PDt therapy should provide improved tumor regression.
  • RORy inverse agonists During the development of RORy inverse agonists, minor changes on the structure such as removal of one carbon 4a-fo tZ9i replacement of the amide by a benzyl alcohol 5a [30i to 5b, I31) or the methylation of the amide in compounds 6a-fo f32 ) led to an opposite mechanism of action, RORy agonists ( Figure 2). Based on previous studies performed on RORy inverse agonists by GiaxoSmithKiine 5231 and Genentech '1333 it seems that N-arylsulfonyl indo(e is a good starting point for the development of new RORy agonists. The work presented herein was focused on the development of a new class of RORy agonists for its possible application In cancer treatment.
  • N-arylsulfonamide and the phenoxy group showed low stability in protic/bas ' ic and acidic conditions, which limited the synthetic exploration of the indole.
  • reduction of the indole indoiine conducted generally to more poteni compounds in cell- based assays without increasing binding affinity for RORy LBD (189S7 «19453).
  • the ' indoline scaffold looks like a more promising scaffold for our optimization, in an effort to further improve the activity of 19170, we investigated the N-arylsulfonamide part (Table 4).
  • the indole scaffold removal of the trifluoroethyl group or introduction of substituenls in orlho or para positions led to less potent compounds (19262-19261 ).
  • the T .cell specific nuclear receptor RORyt has been shown to be the key lineage- defining transcription factor to initiate the differentiation program of TH1 7 ceils making RORyt the master regulator for TH17 and TY17 differentiation, cells that have demonstrated anti-tumor efficacy, and RORyt controls gene programs that enhance immunity (including increased IL17 production) and decrease immune suppression.
  • Procedure E Formation of benzyl bromide, To the solution of benzyl alcohol or pyridinemethanol (1 eq.) in THF (G: 0.2 mmol) at 0 °C were added ⁇ 3 ⁇ 4 ⁇ . (1 .5 eq.) and MsC.I (1 .2 eq,). The reaction was stirred at the same temperature for 1-2b. The completion of the reaction was monitored by HPLC. Upon completion, LIBr (5 eq.) was added and the reaction was stirred for another hour. The completion of the reaction was monitored by HPLC.
  • the title compound was prepared by the introduction of 3-(trifSuoromethyl)benzenesiilfqnyi chloride (137 L, 0.86 mmol) on the methyi indoie ⁇ 5-carboxyiate (100 mg, 0.57 mmol) according to General Procedure A.
  • the crude product was purified by Combifiash silica gel
  • the title compound was prepared according to General Procedure C from (1-((3- (trif uoromethyl)ph ' enyl)su!fony!-lH-inddl ⁇ -y])meihanpl (50 mg, 0.14 mmol) and phenol (14 mg, 0. 5 mmol).
  • the crude product was purified by preparative HPLC (20-100% CHsCN/lvle-OH (1 :1 ) in H2O (0.01 % TFA)) which provided after lyophi!ization 43 mg (71 %) of the title compound as a colorless solid; 1 H NMR (400 MHz, CDC! 3 ) ⁇ .
  • the title compound was prepared according to General Procedure- C from ⁇ ( ⁇ 3- (tn ' fluoromethyl)phenyi)sulfonyl)- 1 H-s dQi-6-yl)methanol (50 mg, 0.14 mmol) and 2-fluorop enol (17 mg, 0.15 mmol).
  • T e title compound was prepared according to General Procedure C from (1-((3- (trifluoromethyl)pheny!sulfonyl)-1 H-indoi-6-yi )methanol (50 mg, 0.14 mmol) and o-cresol (16 mg, 0.15 mmol).
  • the title compound was prepared according to General Procedure C from (1-((3- (triflUoromethy phenyi)su fonyi)-1 H-indoi-6-yl)meihanol (50 mg, 0.14 mmol) and 2,3- dichiorophenol (24 mg, 0.15 mmol).
  • the crude product was purified by preparative HPLC (20- 100% CHaC / eQH (1 :1 ) in H 2 0 (0.01 % TFA)) which provided after lyophilizatipn 55 mg (78%) of the title compound as a colorless solid; H NMR (400 MHz, CDC!
  • the title compound was prepared according to General Procedure C from (1 - ⁇ 3- (trifluoromethyl)phenyl)su!fonyi)-l H-indoi-6-yl)methanol (50 mg, 0.14 mmol) and 2,5- difluoropheno! (19 mg, 0.15 mmoi).
  • the title compound was prepared according to General Procedure C from (1 H-indol ⁇ 6- ⁇ y1)methanol (530 mg, 3,60 mmol) and 2 ⁇ chloro-6-fluorophenol (554 mg, 3.78 mmol).
  • the crude product was purified by Combiilash silica gel chromatography (0-20% of EtOAc In hexane), which provided 300 mg (30%) of the title compound as a colorless solid;
  • the title compound was prepared by the introduction of m-toiuenesuifonyi chloride (16 p , 0.11 mmol) on the 6-( ⁇ 2-chioro-6-fiuorophenoxy)methyl) ⁇ 1 H-indole (20 mg, 0.07 mmol) according to General Procedure A.
  • the crude product was purified by preparative H PLC (20-100%
  • the title compound was prepared by the introduction of 3-methoxybenzenesulfonyi chloride (15 ⁇ _, 0.1 mmol) on the 6-((2-chloro-6-fJuorophenoxy)methyl)-1 H-indoie (20 mg, 0.07 mmol) according to General Procedure A.
  • the title: compound was prepared by .the introduction of 2-(trifiuoromethyl)benzenesulfonyl chloride (17 ⁇ , ; 0.1 1 mrnol) on the 6-((2-chioro-6-fluorophenoxy)rnethyi)-1 H-lndoie (20 mg, 0.07 mmo! according to General Procedure A.
  • the crude product was purified by preparative HPLC (20-100% CHsCN/ eOH. (1:1) In HaO (0.01% TFA)) which provided after lyophiiization 6 mg (17%) of the title compound as a.
  • the title compound was prepared by the introduction of p-toiuenesulfonyi chloride (21 mg, 0.1 1 mmol) o the 6 ⁇ ((2 ⁇ chloro-6-fluorophenoxy)meihyl)-1 H-indoie (20 mg, 0.07 mmol) according to General Procedure A.
  • the crude product was purified by preparative HPLC (20-100%
  • the title compound was prepared by the introduction of 4-(tnf1uoromet yi ⁇ benzenesuifonyl chloride ⁇ 27 mg, 0.1 1 mmoi) : on. the 6- ⁇ (2-chlofo-6-fjuorop enoxy)rnethyi)-1 H-indote (20 mg, 0.07 mmoi) according to General Procedure A
  • the crude product was purified by preparative HPLC (20-100% CHaCN/ eOH (1 :1 ) in H 2.
  • infiuoro ethanesuifonaie (1 ,25 g) in 30 ml CH 3 C was added E3 ⁇ 4N (1 .14 ml, 8.19 mmoi). The flask was purged three times with Ar before the addition of trimethyisil y!acetyiene (1 .16 mL, 8.19 mmoi) and P C ⁇ s) ? (192 mg, 0.27 mmoi). The flask was sealed: and the reaction mixture was stirred overnight at 85 °C.
  • the title compound was prepared according to General Procedure C from 1 -((3- (trifl.uorQmethyl ⁇ pheny!suifonyS)indolin-6-oi (40 mg, 0,12 mmoi) and (2 ⁇ ch!orQ » 6-- f!uorophenyi ⁇ methanpi (20 mg, 0.12 mmo!).
  • the crude product was purified by preparative HPLC (20-100% CHsCN/MeOH (1 : 1 ) in H 2 0 (0.01 % TFA)) which provided after !yophiiization 21 mg (31 %) of the title compound as a colorless solid; 1 H NMR (400 MHz, CDC!
  • the title compound was prepared according to General Procedure H from 6-( ⁇ 2-chloro. ⁇ 6 ⁇ ftuorobenzyf)oxy)indoiine (20 mg, 0.0 . 7 mmoi) and benzenesulfonyl chloride (14 ⁇ , 0.11 mmol).
  • the crude product was purified by preparative HPLC (20-100% CH 3 CN/MeOH (1 :1 ) in H 2 0
  • the title compound was prepared according to Genera! Procedure H from 6-( ⁇ 2-chlorQ-6- fluorob:enzyS)oxy)indoline (20 mg, 0.07-mmol) and m-toluenesulfonyl chloride (16 pL, 0.11 mmoi).
  • the crude product was purified by preparative HPLC ⁇ 20-100% CH 3 CN/MeOH (1 : 1 ) in H2O (0,01 % TFA)) which provided after iyoph .
  • the title compound was prepared according to Genera! Procedure H from 6 ⁇ ((2 ⁇ chloro ⁇ 6- fluorobenzyi)oxy)indoline (25 mg, 0.09 mmol) and 3-chlorobenzenesuffGny! chloride (19 ⁇ , 0.13 mmol).
  • the crude product was purified by preparative HPLC (20-100% CH 3 CN/ eOH (1 :1 ) n HzO (0.01 % TFA ⁇ ) which provided after tyophilization 35 mg (88%) of the title compound as a colorless solid; 1 H NMR (400 MHz, C .
  • the titl compound was prepared according to Genera! Procedure 1 from 3-bromo-1 ,1 '-bipheny! (390 mg, 1 .67 mmol).
  • the crude product was purified by Comhif!ash silica gel chromatography (0-40% of EtOAc in hexane), which provided 450 mg (97%) of the title compound as a yellow oil; ⁇ NMR (400 MHz, CDCb) ⁇ - 7.54 - 7.50 (m, 3 H), 7.47 - 7.40 (m, 3 H), 7.38 - 7.27 (m, 8 H), 4.18 (8, 2 H).
  • the title compound was prepared according to General Procedure J from [1 ,1'-biphenyi]-3- yl(benzyl)s.ulfane (450 mg, 1.63 mmoS).
  • the crude product was purified by Gombiflash silica gel chromatography ( 00% hexane), which provided 250 mg (5.9%) of the title compound as a .
  • the title compound was prepared according to Genera! Procedure H from 6-((2-chloro-6- fluorobenzyl )oxy)indoline (25 mg, 0.09 mmoi) and [1 , 1'-biphenyl]-3-sulfonyi chloride (34 mg, 0.13 mmo ).
  • the crude product was purified by preparative HPLC (20-100% CH 3 CN/MeOH (1 :1 ) in H2O (0.01% TF.A)) which provided after lyophilization 28 mg (63%) of the title.
  • the title compound was prepared according to General Procedure J from 2- ⁇ benzy!thio)-6- (tnfiuoromeihyl)pyridine (410 mg, 1.52 mmoi), The crude product was purified by Combiflash silica gel chromatography (0- 0% EtOAc in hexane), which provided 210 mg (56%) of the title compound as a colorless solid; 1 H NMR (400 MHz, CDCb) ⁇ - 8.34 - 8.26 (m, 3 H), 8.08 - 8.05 (m, 1 H).
  • the title compound was prepared according to General Procedure H from 6-((2-ch!oro-6- fiuoroben2yl)ox.y)indoline (25 mg, 0.09 mmoi) and 6 ⁇ (trif!uororaethyl)pyridine-2-sulfonyl chioride (23 mg, 0.13 mmoi).
  • the crude product was purified by preparative HPLC (20-100%
  • the title compound was prepared according to General Procedure I from 4 ⁇ ebloro-2- (trifiuoromethyi)pyndine (150 mg, 0.82 mmo!).
  • the crude product was purified by Combiflash silica gel chromatography (0-40% of EtGAc in hexane), which provided 130 mg (58%) of the title compound as a colorless oil;
  • CCHHssCC //MMeeOOHH ((11 :: 11 )) iinn HH 22 00 ((00..0011 %% TTFFAA)))) wwhhiicchh pprroovviiddeedd aafftteerr llyyoopphh '' iiiiizzaattiioorrii 1199 mmgg ((4444%%)) ooff tthhee t tiittllee ccoommppoouunndd aass aa c coolloorrlleessss soolliidd aass tthhee TTFFAA ssaalltt;; HH NNMMRR ((440000 MMHHzz,, CCDDCCbb)) ⁇ ⁇ 99..1199 ((dd,, JJ ⁇ 22..33 H Hzz,, 11 H H)),, 99..0055
  • the title compound was prepared according to General Procedure I from 2-chloro-4- (triiluoromethyl)pyridine (213 pL, 1.65 mmol).
  • the crude product was purified by Combiflash silica gel chromatography ⁇ 0-40% of EtOAc in hexane), which provided 440 mg (99%) of the title compound as an orange oil;
  • the title compound was prepared according to General Procedure C from 1-((3- (trif!uoromethyl)phenyi)suifonyi)indolin ⁇ 6-ol (40 mg, 0.12 mmol) and (2-bromo-6- methylpheny methanol (22 mg, 0,12 mmoi).
  • the title compound was prepared according to General Procedure D2 from 2,8-dsrnethylbenzo c acid (200 mg, 1.33 mmoi). The extraction provided 175 mg (96%) of the title compound as a colorless solid which was used without further purification; r H NMR (400 MHz, CDC ) ⁇ - 7,15 - 7,10 (m, 1 H), 7,08 - 7.03 (m, 2 H), 4.77 (s, 2 H), 2.45 (s, 6 H).
  • CCHHasCGNN//MMeeGOHH ((11 :: 11 )) iinn HH 22 00 ((00..0011 %% TTFFAA)))) wwhhiicchh pprroovviiddeedd aafftteerr llyyoopphhiilliizzaattiioonn 2288 mmgg ((5522%%)) ooff tthhee ttiittllee ccoommppoouunndd aass aa ccoolloorrlleessss soolliidd;; 11 HH NNMMRR ((440000 MMHHzz,, CCDDCCbb)) 5& - ⁇ 88..QQ99 ((ss,, 11 HH)),, 77,,8822 -- 77..7777 ((mm,, 22 HH)),, 77..5588 -- 77,,5511 (
  • the title compound was prepared according to General Procedure from 2- (irifluoromethoxy)beozaldehyde (225 ⁇ , 1 ,58 mmoi). The extraction provided the title compound ' .as a colorless oil which was used without further purification; 1 H R ⁇ 400 MHz, CPCfa) 5 - 7.60 - 7,54 (m, 1 H), 7.38 - 7.30 (m, 2 H), 7.27 - 7.22 (m, 1 H), 4.80 (s, 2 H).
  • Step 1 To the solution of 3-ch!oro-2-methoxybenz.osc acid (150 mg, 0.80 mmol) in 5 ml of MeOH was added 0,5 ml. of H2SG4, The reaction was stirred overnight at 80 X ⁇ . The completion of the reaction was monitored by HRLC. Upon completion, solvent was removed ihen H 2 G was added to the crude residue and the reaction mixture was extracted with EiOAc. The combined organic layers were washed with saturated aqueous NaHCOs, brine and dried over agSCt.
  • Step 2 To the solution of methyl 3-cbiaro ⁇ 2 ⁇ methoxybenzoate in 5 mL of MeOH was added NaBH.4 (304 mg, 8.04 mmol). The reactio was stirred at 60 °C for 4h. The completion of the reaction was monitored by HPLC. Upo completion, the solvent was removed in vacuo, H2O was added to the crude residue and the reaction mixture was extracted with EtOAc. The combined organic layers were washed with saturated aqueous NaHCQ 3 , brine and dried over Na ⁇ SG*.
  • Step 1 To the solution of 4-chloro ⁇ 2-methoxybenzoic acid (150 mg, 0.80 mmol ⁇ in 5 mL of MeOH was added 0.5 mL of H2SO4. The reaction was stirred overnight at 80 °C. The compleiion of the reaction was monitored by HPLC. Upon completion, the solvent was removed in vacuo, H.2O was added to the crude residue and the reaction mixture was extracted with EtOAc. The combined organic layers were washed with saturated aqueous NaHCOs, brine and dried over Na2$0 . Filtration and removal of the solvent in vacuo provided methyl 4 ⁇ eh!oro ⁇ 2 ⁇
  • Step 2 To the solution of meihyl 4-chioro-2-methoxybenzoate in 5 mL of MeOH was added aBH 4 (304 mg, 8.04 mmol). The reaction was stirred at 60 °C for 4h. The completion of the reaction was monitored by HPLC. Upon completion, solvent was removed in vacuo, H 2 O was added to the crude residue and the reaction mixture was extracted with EtOAc. The combined organic layers were washed with saturated aqueous NaHC0 3 , brine and dried over Na 2 $ ' 0 4 . Filtration and removal of the solvent provided 49 mg (35% overall yield) of the title compound as a colorless oil, which was used without further purification; .
  • aBH 4 304 mg, 8.04 mmol
  • Step 1 The solution of 5-chloro-2-methoxybenzoic acid (150 mg, 0.80 mmol) in 5 mL of SOCI 2 was stirred at 80 °C for 2h. The completion of the reaction was monitored by HPLC. Upon completion, removal of the solvent in vacuo provided the 5 ⁇ cbior0"2-methoxybenzoyl chloride, which was used without further purification.
  • Step 2 To the solution of NaBH (61 mg, 1.61 rnmoi) in 5 ml H2O at 0 °G was added 5-chloro- 2-methoxybenzoyt chloride. The reaction was stirred at 60 °.C for 4h. The completion of the reaction was monitored by HPLC. Upon completion, brine was added and the reaction mixture was extracted with EfcQ. The combined organic layers were dried over MasSC ⁇ .
  • the title compound was prepared according to General Procedur F from 1 -((3- (trifluoromethyi)phenyi)sulfonyl)indo!in-6 ⁇ ol (30 mg, 0.09 mmol) and ' 2-(bromomethy.l)-3- methoxypyridine (26 mg, 0.13 mrnoi).
  • Step 1 The solution of 2,4-d(.chiorppyridine-3-carboxyiio acid (150 mg, 0.78 mmor) in 5 mL of
  • Step 2 To the solution of NaBH 4 (59 mg, 1.56 mmol) in 5 mL of H2O at 0 °C was added 2,4- dich!oronicGtinoyi chloride. The reaction was stirred at 60 "C for 4h. The completion of the reaction was monitored by HPLC. Upon compietion, brine was added and the reaction mixture was extracted with £ ⁇ 40, The combined organic layers were dried ove NasSO,*.
  • TToo tthhee ssoolluuttiioonn ooff 33--cchhlloorroo--55--ffiluuoorrooppyyrrliddiinnee ((330000 m mgg,, 22..2288 mmmmooll)) iinn 55 mmLL ooff aannhhyyddrroouuss T THHFF aatt -- 7788 °°CC wwaass aaddddeedd LLDDAA 11 iinn T THHFF ((22..7744 mmll,, 22..7744 m mmmooll)).
  • the title compound was prepared according to General Procedure E from (3-chloro-5- fluoropynd.in-4-yl )methahol (50 mg, 0.31 mmol). The extraction provided 60 mg (87%) of the title compound as a colorless oil which was used without further purification; 1 H NMR (40G MHz, CDCIs) ⁇ - 8.44 (s, 1 H), 8,38 (s, 1 H), 4.52 (d, J ⁇ 1.5 Hz, 2 H).
  • the title compound was prepared according to Genera! Procedure F from 1-( 3- ⁇ Wfluoromethyl)phenyi)sulfonyl)indoitn-6-Ql (20 mg, 0,06 mmoi) and 4-(bromomeihyl)-3-chloro-5- fiuoropyridine (16 mg, 0,07 mmol).
  • the crude product was purified by preparative HPLG (20- 100% CHaCN/MeOH (1 :1 ) in H 2 0 (0.01 % TFA)) which provided after !yophiiization 24 mg (69%) of the .title compound as a colorless -solid as the TFA salt; !
  • the title compound was prepared according to .General Procedure F from 1 -((3- (trifluoromethyl)phenyi)sulfonyl)indo[in-6-ol (20 mg, 0.06 mmoi) and 4-(bromomeihy1)-3-chloro-5- (trifluoromethyi)pyridine (18 mg, 0,07 mmoi, obtained by the same synthetic pathway than 4- ⁇ bromomethyi)-3-ch!oro-5-f1uo ' ropyridine).
  • Step 1 To a vigorously stirred solution of 3-( ⁇ 2-chioro-6-fluord ' benzyl)pxy ⁇ aniiine (1 .00 g, 3.97 mmol) in 20 mL of DCM at -78 °C was added dropwise a solution of tert-butyl hypochlorite (447 pL, 3.97 mmol) in 4 mL of the same solvent. After 10 min, a solution of methylthio-2-propanone ⁇ 407 3.97 mmol) in DCM (4 ml.) was added slowly over 10 min.
  • Step 2 To the -solution of the crude product formed in step 1 in 50 mL of ethane! was added 5 mL of Raney-Ni suspended in H2O. The reaction was stirred at room temperature for 1 h. The completion of the reaction was monitored by HPLG. Upon completion, The Raney Rickel was removed by filtration through Celste ® and washed with ethanoi, The combined ethartoiic solutions were concentrated in vacuo.
  • the title compound was prepared according to General Procedure H from 6- ⁇ (2-chloro-6 ⁇ fluprobe ' n2yl)axy)-2-methy)tndolirie (25 mg, 0.09 mmol) and ' 3-(trinuorofTiethyl)benzen ' esulfony chloride (27 ⁇ _, 0.17 mmol).
  • Step 1 To the solution of 4-bromo-2-riitrotoiuene (8.00 g, 37.03mmol) in 100 mL of ethanol and 100 mL of H 2 0 were added NhUCi (19.8 g, 370.3 mmol) and Fe (14.4 g, 259.2 mmol). The reaction was stirred at 80 "C for 2h. The completion of the reaction was monitored by HPLC. Upon completion, the reaction mixture was filtered over Celite®. The cake was washed with MeOH and the filtrated was concentrated in vacuo. To the crude residue was added H 2 O and the reaction mixture was extracted with EtOAc.
  • CDCI3 ⁇ 7.87 (s, 1 H), 7.80 - 7.76 (m, 2 ⁇ ), 7.72 (s, 1 H), 7.58 - 7.51 (m, 1 H), 7.18 (d, J - 8.6 Hz, 1 H), 6.90 (d, J * 7.9 Hz, 1 H), 4.76 - 4.62 (m, 1 H), 2,88 (dd, J * 1.8, 1 .3 Hz, 1 H), 2.76
  • the flask was purged three times w th Ar before the addition of Pd(dba ⁇ ' 2 (4 mg, 0.007 mmol) and PPha (3 mg, 0.01 mmol). The flask was sealed and the reaction mixture was stirred overnight at 90 °C.
  • Step 1 To a solution of 6-chloro ⁇ 1-H-pyrrota[2,3-b]pyridine (200 mg, 1 .31 mmol) in 1 mi of DM . E and 2 ml. of TFA was added Et 3 S!H ⁇ 2.1 mL, 13.1 mmol). The reaction mixture was stirred overnight at 70 e C. The completion of the reaction was monitored by HPLC. Upon completion, solvents were removed in vacuo. To the crude residue was added saturated aqueous NaHGOa and the reaction mixture was extracted with EtOAc. The combined organic layers were washed with brine and dried over ' Na2S0 4 . Fiitration and removal of the solvent in vacuo provided 6- chloro-2,3-dihyd-ro-1 H-pyrrolo[2,3-b ⁇ pyridine, which was used without further purification.
  • Step 2 To a solution of 6--chlQro-2 ! 3 ⁇ d!hydro-1 H-pynOio[2,3--b
  • Step 3 * In a dried W flask under Ar were introduced 6-chloro-1 -( ⁇ 3- . ⁇ trif)uorome ⁇ hyl)phenyi)sylfo ⁇ mg, 0,14mol), (2- chtorQ-6-f!uoropheny methanoi (29 mg, 0.18 mmol), CS2CO3 (90 mg, Q.28 mmol) and 1 ,2 mL of anhydrous toluene. The flask was purged three times with Ar before the addition of Pd ⁇ OAc)2 (2 mg, G.G07 mmoi) and Xantphos (8 mg, 0.014 nrtmol). The flask was sealed and the reaction mixture was stirred overnight at 100 °C.
  • Step 1 To a solution of 6-chloro-5-azaindoie (200 mg, 1.31 mmoi) in 3.3 mL of THF was added BHs-Slvle (622 pL, 6.55 mmoi). The reaction mixture was stirred overnight at 70 °G. The completion of the reaction was monitored by HPLC, Upon completion, methanol was added and solvents were removed in vacuo. To the crude residue was added saturated aqueous NaHC(1 ⁇ 4 and extracted with EiOAc. The combined organic layers were washed with brine and dried over a2 . S04. Filtration and removal of the solvent provided 6-ch Qro-2,3-dihydro-1 H-pyrrolo[3, : 2 ⁇ c]pyridine, which was used without further purification.
  • Step 2 To a solution of 6-chioro-2,3-dihydro-1H-pyrro!o[3,2-c3pyrid)ne in 5 mL of acetone were added K2CO3 (725 mg, 5.24 mmo! and 3-(trifluoromethyl)benzenesuifonyj chloride (420 ⁇ , 2,62 mmoi). The reaction mixture was stirred overnight at room temperature. The completion of the reaction was monitored by HPLC. Upon completion, solvents were removed in vacuo. To the crude residue was added saturated aqueous hiaHCQa and extracted with EtOAc. The combined organic layers were washed with brine and dried over ' NasSG*. Filtration and removal of the solvent in vacuo provided ' the.
  • Step 3 In a dried MW flask under Ar were introduced 6 ⁇ chioro-1 ⁇ ((3- (trifluorome.thy!phen l)su!fonyi)-2,3-dihydro-1H-pyfro.io ⁇ 3, ⁇ (50 mg, .0.14moi), (2- ehioro-6-iiUGrophenyi)methanoS (66 mg, 0.41 mmoi), GsgC(3 ⁇ 4 (180 mg, 0.55 mmoi) and 1.2 mL of anhydrous toluene.
  • Step 1 In a dried W flask under Ar were introduced 8- ⁇ 2-chloro-6-fiuoro enzyi)oxy) ⁇ 1 H ⁇ indole (200 mg, 0,73 .mmoi), K2CO3 (301 mg, 2.18 mmol) and 2.5 mL of anhydrous toluene. The flask was purged three limes with Ar before the addition of methyl 4-bromcbenzoate (199 mg, 0.87 mmoi), Br3 ⁇ 4BLi3 Ci ⁇ 45 mg, 0.14 mmoi) and Pd ⁇ OAc)s (8 mg, 0,04 mmoi) The flask was sealed and the reaction mixture was stirred overnight at 90 °C.
  • Step 2 To a solution of methyl 4-(6 ⁇ ((2 ⁇ chipro-6-fluoiObenzy!)oxy)-1 H ⁇ indol-3-y!benzoate ⁇ 5 mg, 0.43 mmol) in 1 mL of DME and 2 mL of TFA was added Et 3 SiH (1 .0 ml, 6.41 mmol) The flask was sealed and the reaction mixture was stirred overnight at 50 °C, After removal of solvents in vacuo, the crude product was purified by preparative HPLC (20-100% CH 3 CN/MeOH (1 :1 ) in H2O (0.01 % TFA)) which provided methyl 4 ⁇ (6-((2-chjoro-6-fSuorobenzyi)oxy)indol!i>3- yl)benzoate.
  • Step 3 To a solution of methyi 4 ⁇ (6-((2-chloro-6 ⁇ fiuorobenzyl)oxy)indolin-3-y1)benzoate in 2 mL of DC. were added Et ⁇ (298 pL, 2.14 mmoi) and -3-(trifiuoromethyl)benzenesuifony.i chloride (137 uL, 0.85 mmoi). The.

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Abstract

The invention provides an RORγ receptor agonist comprising a compound of formula (I), wherein the variables are as defined herein. These compounds are analogous to known RORγ receptor antagonists. The invention further provides a method of activating -the nuclear receptor RORγ, comprising -contacting the RORγ with an effective amount or concentration of a compound of the invention; and a method of treating cancer in a patient, comprising administering to the patient an effective dose of a compound of the invention.

Description

O y modulators
CROSS-REFERENCES TO RELATED APPLICATIONS
This application claims the priority of U.S. provisional application Serial Number 62/393,802 filed on September 1.3, 2016, the disclosure of which is incorporated herein by reference in its entirety.
This application is related to patent applications: PCT/US2011/028320, published as WO 2011/1158.92; and U.S. Ser, No. 14/1 18,1 16, published as US-2014-0187554; which are incorporated by reference herein in their entireties.
STATEMENT OF GOVERNMENT SUPPORT
This invention was made with government support under 1 R01 MH 108173 awarded by the National Institutes of Health. The government has certain rights in the invention.
BACKGROUND
Orphan retinoic acid receptors (RORs) are ke members of the nuclear receptor (N'R) family. The RORs subfamily is composed of three members RORa, ROR$ and RORy also known as NRF1-NRF3 and RORa-RORc respectively. Several studies have shown sterols as RORy modulators, but its endogenous Iigand is still unknown or controversial1"41 Two isoforms of RORy have been characterized, only differing by their N-terminai sequence and conserving the same iigand binding domain (LBD). RORyi is mainly expressed In liver, kidney, adipose tissue or also skeleta! muscle1'53 whereas RORyt is oniy found In lymphoid organs, like the thyrnus.161 In 2006, Liftman et ai. described RORyt as a key transcription factor involved in differentiation and function of CD4+/CD8+ into T helper 17 (Th17) cells, lnterleukin- (IL-17) is. a .major cytokine produced by Th17 ceils.*71 Several studies show IL-17 implication in autoimmune diseases, such as multiple sclerosis, rheumatoid arthritis, inflammatory bowel diseases and psoriasis.'-8"11] Initially, Th17 ceils are produced to defend the host organism against external agents like bacteria, fungi, viruses and protozoa. Numerous studies showed the presence of Th1 7 cells in tumor microenvironment.112, 31 Currently, it is unclear whether Th17 cells are induced or recruited by tumors. Th17 cells alone have .no cytotoxic effect which resulted in the reduction of -tumor proliferation,1131 but tumor progression was observed in IL-17 deficient mice and suppression of tumor growth was notified in overexpressed IL-17 tumor cells. [1 "17i Increased IL-17 production could lead to a new therapeutic strategy against cancer by boosting the immune system response.
Given the wide range of applications of RORy in the modulation of the immune system, this NR has become in the fast decade an .interesting target for curing various diseases. Interest was first focused on small compounds exhibiting inverse agonist activity on RQRy for treatment of autoimmune diseases.'18'"211 Various scaffolds were developed binding the RORy LSD such as SR22l1t2¾, indole 1{2¾, triazo!e 2m or 'biaryl amide 3l25i (Figure 1 ). Recent studies show that SR22.1 1 also represses tumor development in resistant prostate cancer model. i We can also highlight the development of allosieric ligands like RL871i27] (inverse agonist) or SR09871281
(agonist).
SUMMARY
The invention is directed, in various embodiments, to agonists of the nuclear receptor RORy. The invention can provide an RORy receptor agonist comprising a compound of formula ( I),
Figure imgf000004_0001
wherein
X-Y together is ~CH2~0-, -O-CHV, CH(R)-0-, -O-CH(R)-, -00-0-, -0-CO-, -CH2-NH-, - CH2- H(RK -NHCH{R)~, -NH-CO-, or -N(R)-CO;
the ring bonded to Y and B optionally further comprises 1 or 2 nitrogen atoms at an unsubstituted position thereof;
A-B together is -CR=CR- or ~CH(R)CH(RV,
each R is independently H or {C1-C6)alkyl, halo, ha!o(C1-C6)alkyl. aryL carboxyi, or carboxyaikyi;
R1 is halo, (C1 -C6)alkyl, (Cl -C6)alkoxy1, halo(Ct-C6)alkyl, halo(C1-C6)alkoxy, cyano, carboxy (C1-C6)alky! ' unsubstituted or substituted phenyl, or unsubstituted or substituted pyridyl; n1=0, 1 , 2, or 3;
wherein the ring bonded to X can optionally further comprise 1 or 2 nitrogen atoms;
R2.is halo, {C1-C6)alkyl, (Ci -C6)a!koxyi, .ha!o(C 1 -G6)aikyt, halo(C1-C6)alkoxy, cyano, carboxy (C1 -C6)a!kyi; unsubstituted or substituted phenyl, or unsubstituted or substituted pyridyl; n2~0, 1 , 2, or 3; wherein the ring bonded to R2 can optionally further comprise 1 or 2 nitrogen atoms; or a pharmaceutically acceptable salt there.
For example, the inventions can provide a compound of formula (I) wherein n1 ~2 and R is halo; or where n2~1 and R2 is trifiuoromethyl; or wherein each R is independently H or methyl; or X-Y is -CH2-.O-, or -O-CH2-; or any combination thereof.
For example, the in ula (I) of formula
Figure imgf000005_0001
wherein X, Y, A, B, R2, and nZ' , are as defined in claim 1 .
More specifically the fo
Figure imgf000005_0002
wherein
X, Y, A, B, and R, are as defined In claim 1 ;
or a pharmaceutically acceptable salt thereof.
In other embodiments, the invention provides a method of activating the nuclear receptor RORy, comprising contacting the RORy with an effective amou t or concentration of a compound of the invention; and a method of treating cancer in a patient, comprising
administering to the patient an effective dose of a compound of the invention.
BRIEF DESCRIPTION OF THE FIGURES
Figure 1 depicts the chemical structures of various scaffolds binding the RORy LBD.
Figure 2 shows relationships between the chemical structures of RORy inverse agonists (lefthand column) and related RORy agonists derived therefrom (nghthand column).
Figure 3 is a schematic diagram showing Blockage Immune checkpoint by RORyt agonist.
Figure 4 is a block diagram illustrating the efficacy of anti-PDI therapy depends largely on an initial strong endogenous anti-tumor immune response. In absence of such a response, a combination approach using a RORyt agonist to induce anti-tumor immunity coupled with use of anti-PDt therapy should provide improved tumor regression. DETAILED DESCRIPTION
During the development of RORy inverse agonists, minor changes on the structure such as removal of one carbon 4a-fotZ9i replacement of the amide by a benzyl alcohol 5a[30i to 5b,I31) or the methylation of the amide in compounds 6a-fof32) led to an opposite mechanism of action, RORy agonists (Figure 2). Based on previous studies performed on RORy inverse agonists by GiaxoSmithKiine5231 and Genentech'1333 it seems that N-arylsulfonyl indo(e is a good starting point for the development of new RORy agonists. The work presented herein was focused on the development of a new class of RORy agonists for its possible application In cancer treatment.
Herein we report modification on N~aryisu1fonyi indole and Indoiine, which led to potent compounds with various types of action on RORy determined by GAL4 assays. Differentia! hydrogen/deuterium exchange mass .spectrometry (HDX) shows different binding between two indolines with minor structural changes but opposite mechanisms of action. From this optimization effort, we identified RORy orthosteric agonists with acceptable metabolic stability.
For the N-aryisuifonyiindole, it appeared that the position of the 2-chloro~6~fiuorophenoxy part was crucial for the affinity of the synthetic compound to RORy. Introduction of this subsfituent in position 5 of the indole ring (18861) led to a compound with poor affinity in comparison with 18862 substituted in position 6. This starting N-ary!sulfonamide indole exhibit an affinity of 320 nfvl in binding assay, but a low activation of the NR was observed during the cell-based assay. Our initial goal was to develop potent agonists for RORy, which is why we attempted to improve cell activity. To better understand the interactions involved around the disubstituted pnenoxy group, we first Introduced variation on this phenyi ring (Table 1). Removal of both substituents or one by one as well as introducing the 4-pyrtdinyi moiety fed to a drastic loss of affinity. The same result was observed when introducing nitro or cyano group in position 2 of the pnenoxy ring. The 2-rnethylphenony derivate (18966) exhibited similar binding property as 18862, but it was unable to activate the nuclear receptor just like compound 18963.
Compounds carrying on the 2-meihpxy (18960) or the 2,6~dimethyi ( 8969) have similar properties as 18862, Ail the other analogues synfheiszed in this series have poor affinity for RORy (18965-18971 ).
Temporarily unsuccessful in replacing the 2-ch!oro-6-fluorophenoxy ring, we moved on to Investigate the N-ary!sulfonarnide part (Table 2). Clearly the N-arylsulfonamide is playing a key role for binding since its replacement by the corresponding N-aryiamide (19027) led to an inactive compound. Removing the 3-trifiuomethyl group or replacing it by other substituents resulted in poor agonist compounds (19033-19030). Substitution was not tolerated in position ortno or para, unless for the 4~f!uorophenyteulfonamide 19028.
Ta b fe 1 . S.AR of the Phenoxy j¾0 up
Figure imgf000007_0001
Crnpd Sb Ri ICso SPA3 ECKJ.GAL4*
i ίμΜ)
18861 5 2-C!-6~F-Ph 48%= n.t.
18882 6 2~Ci-6-F-Ph 0.32 2.7 (+2.8)
18984 6 Ph 60%= n.t.
18968 6 -Pyr 80%= n.t.
18981 6 2-C!-Ph 65%= n.t.
18982 6 2-F-Ph 70%= n.t.
18958 6 2-NOa-Ph 70%= n.t.
18959 6 2-C -Pb 65%= n.t.
18988 6 2-CH3-PI1 0.41 ■2.5 (+ .0.8)
18983 6 2-CFa-P 0.35 0.49 (+0.3)
18980 6 2-CMsO-Ph 0.36 3.6 (+2,9)
18989 6 2,6-{CH?)2-Ph 0.33 2.1 (+ 1 .5)
18985 6 2,3-C ^Ph 55%= n.t.
Figure imgf000007_0002
18970 6 1 -Naph 43%= n.t.
18971 6 2-Naph 35%= n.t.
8 Displacement of triliated T09 from human RORy LBD; b c % displacement of 3H-T09 at ΙΟμ .; n.t: not tested; n.a.; not active
Tabfe 2. SAR of N-Afylsuifonamide
Figure imgf000007_0003
Cmpd i Ra iCs;: SP/v" ECsa
am GAL.4!l
(μΜ)
18862 3-CF3PhS02 H 0.32 2.7 (+2.8)
19027 3-CFaPhCO H 35%e n.t.
19033 'PhS02 H 5Q%<- n.t
1 035 3-PyrS02 H 1.10 1.0 (+0.5)
19034 3-CH3-PhS02 H 0.46 1.9 (+1.7)
Figure imgf000008_0001
19036 3-N02-PhS02 H 0.33 1.0 (+0..8)
9026 2-CFj-PhSO;, H 48%c n.t
19032 2-Ci-P S02 H 54%c n.t.
19028 4-F-PhS02 ri 0,70 0.96 (+1 .2)
19037 4-CH3-PhS02 H 65%c n.f.
19030 4-.CF3-P S(¼ H 65%c n.t.
19158 3-CF;,PhS02 CH
0.28 2.7 (+2.7)
3
s Displacement of tritiated TO 9 from human RORy LBD; 6 c % displacement of 3H-T09.at 1Qp ; n.t: not tested; n.a.: not active
The N-arylsulfonamide and the phenoxy group showed low stability in protic/bas'ic and acidic conditions, which limited the synthetic exploration of the indole. We first chose to replace the spacer between the 2-chloro-8-fluorophenyl and the indole. Inversion on the ~0~CHs" conducted to compound 19257, which kept similar affinity for RORy as 18862. This property Is also observed with the alkane link 19081 , when the introduction of an alkene or a alkyne (19080-19079) led to inactive compounds. Surprisingly, reduction of the indole in indoiine conducted generally to more poteni compounds in cell- based assays without increasing binding affinity for RORy LBD (189S7«19453).
Modification of the linker gave us an interesting family of compounds with good affinity but a wide range of activity in the cell-based assay (Table 3). We noticed that the introduction of an amide link (19355) led to a full inverse agonist and that its metbylation (19379) allowed to recover the agonist function. These observations were consistent with previously published studies (see Figure 2)J32'33] Inverse amide as well as methylated inverse amide (19429-19435) showed no activity in the GAL4 assay. Replacement of the oxygen atom by secondary amine (1.93J 1 ) drove to a loss of activity, which was recovered by methylatson or ethylation (19382-19428). All these results suggested that the nature of the spacer plays a key r oie m the activation or the repression of RORy.
Table 3. From indole to indoline and spacer variatio
Figure imgf000009_0001
.SPA8 GAL4b
(μΜ) (MM)
Figure imgf000009_0002
19257 CHTQ CH=CH 0.35 1.9 (+2.8)
19081 CH2-CH2 CH=CH 0,29 3,4 (+2.6)
19080 .CH=CH CH.=CH 55%c n.l
19079 c=c C.H=CH 15%c n.i.
Figure imgf000009_0003
19269 CH(CH>)-0 CHz- 0,75
0.35
GHa (+1,5)
19404 co-o CH2- 1.1 (+4,1 }
0.29
CHa
19380 o-co CH2- 3,9 (+2.9)
0.24
CHa
19355 CO -NH CHz- 0.06 (-1 )
0,058
Figure imgf000009_0004
19435 N(CHa)-Q.Q GHs- n.a
0.1 1
CHz
19381 C!-fe-NH CHs- 0.4O
0.21
19382
19428
Figure imgf000010_0001
a Displacement of iritiated T09 from human ROR.y L8D, 5 c <¾ displacement7 of 3H-T09 at 10μΜ; n.t: not tested; n.a.: not active
The 'indoline scaffold looks like a more promising scaffold for our optimization, in an effort to further improve the activity of 19170, we investigated the N-arylsulfonamide part (Table 4). As on the indole scaffold, removal of the trifluoroethyl group or introduction of substituenls in orlho or para positions led to less potent compounds (19262-19261 ). We pursued our exploration around the meta position by introducing various substituents (19258-1 264), None of them were more active than the starting compound 19170. Introduction of a nitrogen atom on this aryl was tolerated but did not increase RORy activation (19344-19348).
We next considered modifications of the benzyloxy group of the indoline 19170 (Table 5). Different disubstituted benzyloxy groups in position -2 and 6 were introduced (19171-19174), Ali the compounds obtained exhibited similar properties as the starting compound 19170 in binding and eeil-based assays. The 2-methoxy derivative (19175) performs as well as disubstituted compounds when the 2-trifiuoromethoxy benzyloxy (19268) induced a loss in the cell-based assay. Starting from the indoline carrying the 2- methoxybenzyloxy (19175), we decided to explore the three other positions of this aromatic ring (19351-19353). The presence of the chlorine group was tolerated in position 5 but not in position 3 and 4. In general pyridine did not improve agonist activity (19266 - 19497), but allowed us to determine exposure in plasma (see table 8), Surprisingly, compound 19507 showed no binding for RORy.
Table 4, SAR of N-Arylsuifonamide
Figure imgf000010_0002
Cmpd EC's:)
ICso SPA3
GAL4b
(μΜ)
(μΜ)
19170 3-CF3-P 0~Ϊ2 0.26 (+3 3)
19262 Ph 0.80 n.t
19259 2-C!-Ph 75%a n.t
19261 4-F-Ph 0/50 n.t
19258 3-ChVPh 0.23 0.50 (+3.1 )
19263 S-CHsOPb 0.25 0.65 (+3.4)
19346 S-Q-P 0.37 2.3 (+5.4)
19347 3-Ph-Ph 0.25 7.8 (+2.8)
19264 3,5-Cla-Ph 0.34 0.38 (+0.5)
19344 3-CF3-2- 0.25 0.43 (+1 .9)
Pyr
19349 3-CF3-4- 0.23 1,6 (+4.6)
Pyr
19267 5-CFV-3- 0.29 0.47 (+2.8)
Pyr
19348 5-CF -Z- 0.19 0.33 {+3.1 )
Pyr
a Displacement of tritiated 109 from human RORy LBD; c % displacement of 3H-T09 at 10μΜ; n.t not tested; n.a.; not active
Table 5. SAR of the faenzyjoxy group
Figure imgf000011_0001
SPAS C3AL411
(μΜ) (μΜ)
19170 2-Cl-6-F-PhCH20 0.12 0.26 (+3,8)
19171 2.6-CI?-P CH_ 5 0.13 0. 7.(43,3)
19172 ■2-Br-6-CH3PhCH20 0.16 0.20 (+3.1 )
191 3 2,6"(CH3)2-PhCH2Q 0.23 0.29 (+2.2)
1917 2-CI-6-CF3-PhCH20 0.17 0.10 (+3.9)
19175 2-CH30-P CH20 0,20 0.62 (+2.6) 19268 2-CFaO-PhCHzO 0.29 1.2 (+3.3)
19351 2-CHsO-3-CI- 0,44 1.2 (+1 .9).
PhCHaO
19.360 2-CH.30-4-Ci- 0.35 1 .5 (+3.1 )
PhCHaO
19353 2-CHsp-5-CI« 0.17 0.49 (+3.4}
PhCHaO
19266 6-CHaO«2-PyrCHaQ 0.085 0.48 (+1 .3)
19352 2.6-C - 3-PyrCHaG 0 078 .63 (+3.2)
19265 2,6-C!K-4-PyrCH20 0.20 0.45 (+2.9)
19497 2-CI"6-F-4-PyrCH2G 0.27 0.76 (+2.1 )
9498 2-a-6-CF3~4- 0.19 0.60 (+4.0)
PyrCHiO
18957 2-q-6-F-PhOCHz 0.21 0.18 (+3.2)
19507 2,6-Cia-4-PyrOCH2. n.a n.a
8 Displacement of tritiated T09 from human RORy LBD; b G % displacement of 3H-T09 at l OgJVi; n.i: not tested; n.a.: not active
To finish our exploration of the indoline scaffold (Table 6), we decided to introduce a methyl in position F¾ and F¾. In both cases, binding affinity was retained but a clear toss of activation was observed in the GAL4 assay when the methyl group was introduced in position F¾ (19426). In an attempt to mimic the t ifluoromethyl carried on by T0 , we introduced this group in position R2. Resuits were as good as the reference compounds (compare 19170 to 19425).
To better understand how the changes on the spacer affected the binding mode of the ligands and resulted in a divergent mechanism of action, we used differential
hydrogen/deuterium exchange (HDX) mass spectrometry. Data showed a clear difference in binding between the agonist (18957) and the inverse agonist (19355) even if structural modification was Sow. HDX revealed that helix. 11 (H11 ) showed increased protection to .solvent exchange (stabilization) with both RO yt ligands tested, suggesting common sites of direct interaction for ligands within the ligand-binding pocket (L.BP) of RORy (data not shown). 18957 increased stabilization of helix 12, which probably induces the agonist activity. These data are consistent with published crystal structures of RORv-LBD in complex with synthetic ligands (PDB ID: 4WQP.. 4WPF, 4ΝΒ6). 29·3¾
Table 6. S.AR on the aipbatic part of the indoline
Figure imgf000013_0001
SPA GAL4b
a {μΜ)
Figure imgf000013_0002
19170 2-CI-6-F- H H 0.12 0.26
P CHaO (+3.8)
19426 2-CI-6-F- H OH 0.18 1 .8 {+4,1 )
PhCHaO 3
19425 2-CI-6-F- CH3 H 0.38 0.11
PhCHaO (+4.8)
19547 2-CI-6-F- CFs H 0.19 0.18
PhCHaO (+6.2)
19548 2-CI-6-F-4- CF3 H 0.29 0.15
PyrCHaO (+5,0)
19546 2,6-012-4- CFs H 0.15 0.12
PyrCHsO (+5.3)
a Displacement of tritiated TQ9 from human RGRy LBD; c % displacement of 3H-T09 at 1Qp ; n.t: not tested; n.a.; not active
In general, synthesized compounds were unstable in presence of human liver microsomes, but exhibited acceptable plasma exposure and stability (Table 7). N- ary!sulfonylarnide indolines were poorly ionized in mass spectrometry (MS). Compounds tested in plasma exposure assays have to carry an ionizable nitrogen atom. to be easily detectable by MS . Compounds were dosed in plasma at i = 2h and t = 4h after an intraperitoneal injection of 10mg/kg. We observed that the 2,8-dichloropyridin~4~ylniethanolindo!ine derivate (19265) had a better exposure and stability than the corresponding 2-ch[oro-6-fluorodichloropyridin-4- lmethanolindoline (19497). Reversion of the spacer (19507) led to a compound with higher exposure but less stability. Introduction of the nitrogen on the N-arylsuffonamide moiety reduced drastically the presence of the compound in plasma. The indoiine with the best features was the inverse agonist (19355). ethy!alion o inversion of the amide present in 9355 Induced a decrease of them plasma -concentration. We also noticed that the introduction of a withdrawing group (CF3) on the indoiine part significantly reduced the stability of the compound (19546). Table 7. In Vivo Exposures of selected indoiines
Plasma 2h Plasma 4h
Cmpcl ciogP
(pM)a (MM)a
19265 0.89 0.62 4.6
19497 0.41 0.21 4.1
19507 1.62 0.46 4.6
19349 0.29 0.12 4.3
19355 .21 0.66 4.5
19379 0.73 0.41 4.1
19429 0.74 0.36 4.4
19546 0 60 0.16 6.0
^average range over 3 mousses, IP, Omg/kg, formulation Img/mL, vehicle used 10/10/8.0
D SO/Tween8Q/water.
The T .cell specific nuclear receptor RORyt has been shown to be the key lineage- defining transcription factor to initiate the differentiation program of TH1 7 ceils making RORyt the master regulator for TH17 and TY17 differentiation, cells that have demonstrated anti-tumor efficacy, and RORyt controls gene programs that enhance immunity (including increased IL17 production) and decrease immune suppression. We have recently published results showing that activation of T cells using a synthetic agonist of RORyt (SR0987) [1] drives proliferation of TH1 pells and decreased expression of the immune checkpoint protein PD 1 (programmed ceil death protein 1 ), a mechanism that will enhance anti-tumor immunity while blunting tumor associated adaptive immune resistance [2], Interestingly, putative endogenous sterols drive proliferation of TH17 cells but do not repress PD-1 expression. Biophysical studies using HDX suggest that SR0987 occupies the recently described alfosteric site on RORyt. Combined these studies suggests that synthetic al!osteric agonists of RORyt will activate TC17/TH17 ceils (leading to a decrease in the population of Tregs), repress PD-1 , and produce 111 in situ (IL17 Is associated with good prognosis in cancer (3J) (see Figure 3). Enhanced immuniiy and blockage of immune checkpoints has transformed cancer treatment, thus such a molecule could provide a unique combination therapy with approved anti-PD-1 molecules for treatment of cancer {see Figure 4).
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All 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. Examples
The following examples of the compounds of the invention, further demonstrate features and aspects of specific embodiments of the invention. The parameters and characteristics of the compounds of the invention are set forth by the foregoing text.
Figure imgf000017_0001
Figure imgf000018_0001
1.6
Figure imgf000019_0001
i 7
Figure imgf000020_0001
Figure imgf000021_0001
Figure imgf000022_0001
Ge raf Procedures:
General Procedure A: Preparation of N-su!fonyl. To the soiuiion of N-B-indoie (1 eq.) in DCM (C: 0.5 mmol/mL) were added KOH (2 eq.) and TBAHS (0.15 eq.) at room temperature. The reaction mixture was stirred 20 min before addition of arySsuifonyi chloride (1 .5 eq.}. The reaction was stirred at the same temperature for 6-12h. The completion of the reaction was monitored by HPLC. Upon completion, l-½Q was added and the reaction mixture was extracted with DCM. The combined organic layers were washed with brine and dried over NaaSO-*.
Filtration and removal; of the solvent provided the crude product, which was purified by
Combifiash silica gel chromatography or preparative HPLC to afford the corresponding products.
General Procedure B* Reduction of methyl indole ester. To the solution of methyl N-sulfonyl indole ester f 1eq,) in anhydrous DCM (C: 0.2 mmol/mL) at -?8°C was added dropwise a soiuiion of PIBAL-H at 1M in. DCM (2 eq.). The reaction was stirred at -78CC for 2h. The completion of the reaction was monitored by HPLC. Upon completion, H2O was added and the reaction mixture was extracted with EtOAc. The combined organic layers were washed with saturated aqueous NaHCOa, brine and dried over NaaS.CH. Filtration and removal of the solvent provided the desired product, which was used without further purification.
General Procedure C: Mltsunobu reaction. To the solution of benzyl alcohol (1 eq.) in anhydrous DC (C: 0.1 mmol/mL) at room temperature were added the selected phenol or hydroxypyridtne {1.05 eq, ), PPha (1 2 eq.) and DIAD ( 1.2 eq,). The reaction was stirred at the same temperature for 1 -2h. The completion of the reaction was monitored by HPLC. Upon completion, the solvent was removed and the crude product was purified by preparative HPLC or Combif!ash silica gel ch omatography to afford the corresponding products.
'General Procedure Dii Reduction of benzaldehyde to benzyl alcohol. To the solution of benza!dehyde or pyrtdinecarboxaldehyde ( 1 eq.) in MeOH (C; 0.3 mmol) at 0 °C was added NaBH4 (1 eq.). The reaction was stirred at the same temperature for 1 ~2h. The completion of the reaction was monitored by HPLC. Upon completion, the solvent was removed, H2O was added and the crude mixture was extracted with EfOAc. The combined organic layers were washed with saturated aqueous NaHCOs, brine and dried over Na¾S04. Filtration and removal of the solvent provided the desired product, which was used without further purification.
General Procedure Da: Reduction of benzoic acid to benz l alcohol. To the solution of benzoic acid (1 eq.) in anhydrous THF (C; 0, 1 mmol) at 0 eC was added SH3THF 1 M in THF (3 •eq.). T e reaction was stirred overnight at room temperature. The completion of the reaction was monitored by HPLC. Upon completion, MeOH was added and the solvents were removed. H2O was added and the crude mixture was extracted with EtOAc. The combined organic layers were washed with saturated aqueous NaHCOa, brine and dried over NasSCH. Filtration and removal of the solvent provided the desired product, which was used without further purification. Genera! Procedure E: Formation of benzyl bromide, To the solution of benzyl alcohol or pyridinemethanol (1 eq.) in THF (G: 0.2 mmol) at 0 °C were added Ε¾Ν. (1 .5 eq.) and MsC.I (1 .2 eq,). The reaction was stirred at the same temperature for 1-2b. The completion of the reaction was monitored by HPLC. Upon completion, LIBr (5 eq.) was added and the reaction was stirred for another hour. The completion of the reaction was monitored by HPLC. Upon completion, H20 was added and the reaction mixture was extracted with EtOAc, The combined organic layers were washed with saturated aqueous NaHCOa, brine and dried over .NazS04. Filtration and removal of the solvent provided the desired product, which was used without further purification.
General Procedure F: ucleophsHc substitution of enzyl bromide by hydroxyindote. To the solution of hydroxylndoie (1 eq.) In D F {C: 0, 1 mmol) at room temperature were added K2CQ3 (3 eq .) and the selected benzyl bromide eq.). The reaction was stirred at the same temperature for 2-4b. The completion of the reaction was monitored by HPLC. Upon completion, H2O was added and the reaction mixture was extracted with EtOAc. The combined organic layers were washed with brine and dried ove NasSC-i. Filtration- and removal of the. solvent provided the crude product, which was purified by Combiflash silica gel chromatography o preparative HPLC to afford the corresponding products.
General Procedure 6; Reduction of indole in indolin-e. To the solution of indole (1 eq.) in AcOH (C; 0,5 rnmo!) at room temperature was added N38H3CN (3 eq.). The reaction was stirred at the same temperature for 2~4h, The completion of the reaction was monitored by HPLC. Upon completion, H2O was added and the reaction mixture was concentrated to dryness. H2O was added to the crude residue and the reaction mixture was extracted with EtOAc. The combined organic layers were washed with saturated aqueous NaHCCh, brine and dried over a^SQ^ Filtratio and removal of the solvent provided the desired product, which was used without further purification or purified by Combiflash silica gel chromatography to give the corresponding products.
General Procedure H: Preparation of -su fonyl indollne. To the solution of N-H-indoline (1 eq,) in DCM (C: 0.1 mmof/mL) were added Ets {3 eq.) and aryl/heteroarylsulfonyl chloride (1.5 eq,). The reaction was stirred at room temperature for 4-1 -2h. The completion of the reaction was monitored by HPLC, Upon completion, H2O was -added and the reaction mixture: was extracted with DCM. The combined organic layers were washed with saturated aqueous
W3HCO3, brine and dried over NaaSC Filtration and removal of the solvent provided the crude product, which was purified by Combiflash silica ge! chromatography or preparative HPLC to afford the corresponding products.
General Procedure I: Introduction of benzyl mercaptan. In a dried microwave (MW) flask under -Ar were 'introduced bromobenzene, bromopyridlne or chloropyridine (1 eq.), DIEA (2 eq.) and anhydrous dioxane (C: 0,2 mmol/mL). The flask was purged three times with Ar before the addition of Pd2(d a)3 {0.05 eq.), Xantphos (0.1 eq.) and benzyl mercaptan (1 ,5 eq.). The flask was sealed and the reaction mixture was stirred overnight at 100 °C. After removal of the solvent in vacuo, H2O was added -to the crude residue and the reaction mixture was extracted with EtOAc. The combined organic layers were washed with saturated aqueous NaHC03, brine and dried over NazSC Filtration and removal' of the solvent provided the crude product, which was purified by Combiflash silica gel chromatography to afford the corresponding products. General Procedure J: Formation of su fonyS chloride, To a solution of benzyl(phenyl)sulfane or (benzy!ihio)pyridine (1 eq.) in A0OH/H2O (3/1 , C; 0.1 mmol/mL) at room temperature was added NCS (6 eq.). The reaction was stirred at the same temperature for 3-6h. The completion of the reaction was monitored by HPLC. Upon completion, the solvent was removed π vacuo, and saturated aqueous NaHCChwas added and the reaction mixture was extracted with EtOAc. The combined organic layers were washed with brine and dried over NazSG... Filtration and removal of the solvent provided the crude product, which was purified by Combifiash silica gel chromatography or preparative HPLC to afford the corresponding products.
General Synthetic Pathway 1 :
Figure imgf000025_0001
2b: 6-C .jMS
i) 3-CF3PhS02C!, KOH, TBAHS, DCM, r.t; ii) DIBAL-H 1 in DC , DCM, -78°C; Hi) phenol, PPh3j DIAD, DCM, r.t.
Synthetic Example t ; 5"((2--ch ro--6-fl,uorophenoxy)me
(trifluoromethv0phenyl:)suifonyl)-1 H-indoie (SR18861 );
Figure imgf000025_0002
Synthesis of methyi 1 (3 trifiuorpmethyi)phenvi)suifonvi)-1.H
Figure imgf000025_0003
The title compound was prepared by the introduction of 3-(trifSuoromethyl)benzenesiilfqnyi chloride (137 L, 0.86 mmol) on the methyi indoie~5-carboxyiate (100 mg, 0.57 mmol) according to General Procedure A. The crude product was purified by Combifiash silica gel
chromatography (0-70% of EtOAc in hexane), which provided 210 mg (96%) of the title
compound as a colorless solid; H N R (400 MHz, GDCl3) δ '= 8.31 - 8.27 (m, 1 H), 8.17 (s, 1 H), 8,10 - 6.03 (m, 3 H), 7,83 (d, J ~ 7.9 Hz, 2 H), 7.64 (rf, - 3.7 Hz, 2 H), 6.79 (dd, J = 0.7, 3.7 Hz, 1 H)( 3,94 (s, 3 H),
Synthesis of (1-((3-(trifiuoromethyl)phenyl)su!fonyi)-1 H-indo!'5-vi)methanoi: TThhee ttiittllee c coommppoouunndd wwaass pprreeppaarreedd bbyy rreedduuccttiioonn ooff mmeetthhyyll 11--((((33--((ttrrilfflluuoorroommeetthhyy!l})pphheennyyll))ssuullffoonnyyll 11 HH--iinnddoollee--55--ccaarrbbooxxyllaattee ((8800 mmgg,, 00..2211 mmmmooli)) wwiitthh DDIIBBAALL--HH 1 iivvll iinn DDCCMM ((441177 ppLL,, 00..4422 mmmmooii)) aaccccoorrddiinngg ttoo GGeenneerraall PPrroocceedduurree BB.. TThhee eexxttraraccttiioonn p prroovviiddeedd 7744 mmgg ( (9999%%)) ooff aa tthhee ttiittllee ccoommppoouunndd aass aa ccoolloorrlleessss ooiill wwhhiicchh wwaass uusseedd wwiitthhoouutt ffuurtrthheerr ppuuririffiiccaattiioonn;; 11HH NNMMRR ((440000MMHHzz,, MeeOODD)) δδ ~~ 88..1166 ( (ss,, 11 HH)),, 88..1133 ( (dd,, JJ == 88..11 HHzz,, 11 HH)),, 77..9977 ( (dd,, J J''~~ 88..66 HHzz,, 11 HH)),, 77..8844 ((dd,, JJ ~~ 88..33 HHzz,, 11 HH)),, 77..6668 ((dd,, JJ == 33..77 HHzz,, 11 H H)),, 77..6666 -- 77..6611 ((mm,, 11 H H)),, 77,.5511 ( (dddd,, JJ "™ 00..77,, 11 ..55 HHzz,, 11 HH)),, 77..3355 ( (dddd,, -J J ~ = ..33,, 88..66 HHzz,, 11 HH)),, 66..7733 ((dddd,, JJ == 00..99,, 33..77 HHzz,, 11 H H)),, 44..6633 ((ss,, 22 H H))..
Figure imgf000026_0001
indole (SRI 8861 );
The title compound was prepared according to General Procedure C from (1-((3- (triiiuoromethyl)phenyl}sulfonyi)"1 H~indol~5"yi)meihanol (74mg, 0,21 mmoi) and 2-chloro-6- fluorophenoi (32 mg, 0.22 mmoi). The crude product was purified fay preparative HPLC (20- 100% CHsCN/MeOH (1 :1) in H20 (0.01% TFA)) which provided after lyophitization 82 mg (81 %) of the title compound as a colorless solid; Ή NMR (400 MHz, CDCfe) δ ~ 8.16 (s, 1 H), 8.07 - 7.98 (m, 2 H}, 7.80 (d, J = 7.8 Hz, 1 H), 7.71 (s, 1 H), 7.64 - 7.55 (m, 2 H), 7.51 (dd, J.~ 15, 8.6 Hz, 1 M), 7.20 ... 7, 13 (m, 1 H). 7.07 ~ 6.94 (m, 2 H), 8,73 (dd, J - 0.8, 3.5 Hz, 1 H), 5.18 (s, 2 H). Synthetic Example 2 r 8-((2-chiorp-6-fluorophenp^
Figure imgf000026_0002
The title, compound was prepared by the introduction of 3-(trifluoromethyl}ben enesulfonyi chloride (961 pL 6.00 mmoi) on methyl indole-6-carboxyiate (700 mg, 4.00 mmoi) according to General Procedure A. The crude product was purified by Combif!ash silica gel chromatography (0-70% of EtOAc in hexane), which provided 1 ,44 g (94%) of the title compound as a colorless solid; H NMR (400 MHz, CDCfe) δ = 8.68 (id, J - 0.7, 1.5 Hz, 1 H), 8.22 - 8.17 (m, 1 H), 8.13 - 8.06 (m, 1 H), 8.00 - 7.93 (in,. 1 H), 7.86 - 7.79 (m, 1 H), 7.72 (d, J = 3.7 Hz, 1 H), 7.65 - 7.58 (m, 2 H), 6.76 (dd, J - 0.9, 3.7 Hz, 1 H), 3.98 (s, 3 H). Synthesis of (1 -((3~(ihfl.uorome^
Figure imgf000027_0001
TThhee ttiittllee ccoommppoouunndd wwaass pprreeppaarreedd bbyy rreedduuccttiioonn ooff mmeetthhyyll 11--((((33--((ttrriiffliuuoorroommeeiihhyyll))pphheennyy!!))ssuu!lfofonnyyll))~~ 11 HH--iinnddoollee--66--ccaarrbQQxxyyllaattee (( 11..4433 gg,, 33..7733 mmmmooil)) wwiitthh DDIIBBAALL--HH 11 MM iinn DDCCMM ((77..4466 mmLL,, 77,,4466 mmmmooli)) aaccccoorrddiinngg ttoo GGeenneerraall PPrroocceedduurree BB.. TThhee eexxttrraaccttiioonn pprroovviiddeedd 11..2222 gg ((9922%%)) ooff tthhee ttiittllee ccoommppoouunndd aass a a ccoolloorrlleessss ooiill wwhhiicchh wwaass uusseedd wwiitthhoouutt ffuurtrthheerr ppuurriiffiiccaattiioonn;; 11HH NNMMRR ((440000 MMHHzz,, C CDDCCII33)). δδ -- 88..1166 ((ss,, 11 HH)),, 88..0044 ((dd,, JJ == 88..11 HHzz,, 11 HH)),, 88..0011 ((ss,, 11 HH)),, 77..7788 ((dd,, JJ -- 77..88 HHzz,, 11 HH)).,, 77..6600 -- 77..5544 ((mm,, 22 HH)),, 77,,5511 ((dd,, JJ == 88..11 HHzz,, 11 HH)),, 77,.2277 ((dddd,, JJ ~~ 11..55,, 88..11 HHzz,, 11 HH)),, 66..6699 .((dddd,, JJ -- 00..88,, 33,,55 HHzz,, 11 HH)),, 44..8800 ((ss,, 22 HH))..
SSyynntthheessiiss ooff 6€--f(((22--cchhiloorroo--66-filuuoorroopphh^ennooxxyy))mmeetthh^yi^)-1-((3-(trifluoromethyl)phen
iinnddoollee ((SSRRII 88886622))::
TThhee t tiittllee ccoommppoouunndd wwaass pprreeppaarreedd aaccccoorrddiinngg ttoo GGeenneerraall PPrroocceedduurree CC ffroromm ((11--((((33-- ((ttrriiffiiuuoorroommeetthhyyii))pphheennyyii))ssuuiifofonnyyl)""11 HH--iinnddoo!l--68--yy1i))mmeetthhaannoofl ((6655 romgg,, 00..1188 mmmmooll)) aanndd 22--cchhlloorroo~-66~- ffiiuuoorroopphheennooll ((2288 mmgg,, 00..1199 mmmmooii)).. TThhee ccrruuddee pprroodduucctt wwaass ppuurriiffiieedd bbyy pprreeppaarraattiivvee HHPPLLCC ((2200-- 110000%% CCHHssCCNN//MMeeOOHH ((11 ::11 )) IInn HH22OO ((00..0011 %% TTFFAA)))) wwhhiicchh pprroovviiddeedd aafftteerr iIyyoopphhjjllrrzzaattiioonn 6611 mmgg ((6699%%)) ooff tthhee t tiittllee ccoommppoouunndd aass aa ccoolloorrlleessss ssoolliidd;; 11HH NNMMRR ((440000MMHHzz ,, CCOOCCII33)) δδ ??== 88..2266 -- 88,,1155 ((mm,, 22 HH)),, 88..0077 ((dd,, JJ == 88,,11 HHzz,, 11 HH)),, 77..8800 ((dddd,, JJ ~~ 00..88,, 77..88 HHzz,, 11 HH)),, 77..6633 -- 77,,5522 ((mm::,, 33 HH)),, 77..4411 ((dddd,, JJ ~~ 11..55,, 88..11 HHzz,, 11 H H)),, 77..11..88 ((ttdd,, JJ == 11..99,, 77..66 HHzz,, 11 HH)),, 77..0088 ~~ 66..9955 ((mm,, 22 HH)),, 66..7722 ((dddd,, JJ ~~ 00..88,, 33..88 HHzz,, 11 HH)),, 55..2277 ((ss,, 22 HH)),,
SSyynntthheettiicc EExxaammppllee 33:: 66--¾¾''((22--cchhiioorroo--66--fflluuoorrQQpphheennooxxyy))mmeett..hhyyll))--11^^((((33----
Figure imgf000027_0002
The title compound was prepared according to General Procedure C from (1-((3- (trif uoromethyl)ph'enyl)su!fony!)-lH-inddl^-y])meihanpl (50 mg, 0.14 mmol) and phenol (14 mg, 0. 5 mmol). The crude product was purified by preparative HPLC (20-100% CHsCN/lvle-OH (1 :1 ) in H2O (0.01 % TFA)) which provided after lyophi!ization 43 mg (71 %) of the title compound as a colorless solid; 1H NMR (400 MHz, CDC!3) δ. ~ 8.16 (s, 1 H), 8.1 1 (s, 1 H), 7.96 (d, J = 8.1 Hz, 1 H), 7.78 (d, J = 7.2 Hz, 1 H), 7.60 - 7,54 (m, 2 H), 7.51 (t J - 7.9 Hz, 1 H), 7.39 - 7.28 (m, 3 H), 7.04 - 6.97 (m, 3 H), 6.72 (dd, J » 0,9, 3.7 Hz, 1 H), 5,21 (s, 2 HJ.
Figure imgf000028_0001
The title compound was. prepared according to General Procedure G from (1 -((3- (trifiuoromeihyf)phenyi)suifonyi)-1 H.-indoi-6-yi)met anoi (50 mg, 0.14 mmol) and 4- h yd ro pyridine (14 mg, 0.15 mmol). The crude product was purified by preparative HPLC (20- 100% CHsGN/MeOH (1 :1 ) in H20 (0.01 % TFA}) which provided after lyophilizaliqn 9 mg (15%) of the title compound as a .colorless solid as the TFA salt; H NMR (400 MHz, MeOD) δ = 8.36 (d, ,J = 6.1 Hz, 2 H), 8.1 (s, 1 H), 8.13 - 8,08 (m, 2 H), 7,92 (d, J ~ 7.8 Hz, 1 H), 7.73 (d, J - 3.5 Hz, 1 H), 7.67 (t, J = 8.0 Hz, 1 H),. 7.60 (d, J ~ 8.1 Hz, 1 H), 7.36 (dd, J 1.5, 8.1 Hz, 1 H), 7,11 - 7.06 (m, 2 H), 6.80 {dd, J ~ 0.8, 3.8 Hz. 1 H), 5.35 (s, 2 H).
Synthetic Example 5; 6-(l2-chlorophenoxy)methv))-1-({3-(trifluoromethyl)phenvl)suifonyi)-1 Hr. indole (SR18961 ):
Figure imgf000028_0002
The title compound was prepared according to General Procedure C from (1~((3~
{tntluoromethyl)phenyi)suifonyi)-1H-indo!-6-yl)methan0i {50 mg, 0.14 mmol) and 2-chlorophenol (19 mg, 0.15 mmol). The crude product was purified by preparative HPLC (20-100%
CHsGN/MeOH (1 : 1 ) in H20 {0.01 % TFA)) which provided afte lyophilizatiph 51 mg (78%) of the title compound as a colorless solid; 1H NMR (400 MHz, CDC!3) δ = 8.23 - 8.11 (m, 2 H), 8.07 (d, J = 8.1 Hz, 1 H), 7,81 - 7.73 (m, 1 H), 7.64 - 7,51 (m, 3 H), 7.46 - 7.32 (m, 2 H), 7,22 - 7.18 (m, 1 H), 6 99 (dd, = 1.4, 8.2 Hz, 1 H), 6.97 - 6.91 (m, 1 H), 6.71 (dd, - 0.8, 3.8 Hz, 1 H), 5.28 (s, 2 H).
Synthetic Example 6: 8"((2-fluorophenoxv)methy]i):i1 -({3-(tnfluoromethy()phenyl)sulfonyi)"1 H-
Figure imgf000028_0003
The title compound was prepared according to General Procedure- C from {ί~({3- (tn'fluoromethyl)phenyi)sulfonyl)- 1 H-s dQi-6-yl)methanol (50 mg, 0.14 mmol) and 2-fluorop enol (17 mg, 0.15 mmol). The crude product was purified by preparative HPLC (20-100% CH3CN/ eOH {1:1} in HzO (0.01% TFA}} which provided after lyophilization 41 mg (71%) of the title- compound as: a colorless solid; *H HUH (400 MHz, CDCb) δ = 8, 18 - 8.14 (m, 1 H). 8.14 - 8.10 (m, 1 H), 8.07 - 8.01 (m, H), 7.81 - 7,75 (rn, 1 H), 7.62 - 7.54 (m:s 3 H), 7.40 - 7.32 (m, 1 H), 7.17 - 7.09 (ffi, 1 H), 7.08 - 6.99 (m, 2 H), 6.98 - 6.89 (m, 1 H), 6.71 (dd, J = 0,9, 3.7 Hz, 1 H), 5.26 (s, 2 H).
Synthetic Example 7: 6-f{2-n-itrophenoxy¾methyi)~1-((3-(trifluQro-m^
Figure imgf000029_0001
The title compound was prepared according to Genera! Procedure C from { 1-((3- (triflu.oromeihyl}phenyi}sulfonyl)-†H-indol-6-yl)methanol (50 mg, 0.14 mmoi) and 2-niirophenoi (21 mg, 0.15 mmoi). The crude product was purified by preparative HPLC (20-100%
CH3CN/ eOH (1 :1 ) in H20 (0.01 % TFA)) which provided after lyophilization 50 mg (75%) of the title compound as a colorless solid; 1H N R (400 MHz, CDCb) δ· - 8.21 (d, J ~ 7.8 Hz, 1 H), 8.19 (s, 1 H), 8.15 (s, 1 H). 7.90 (dd, J = 1 .8, 8.1 Hz, 1 H), 7,80 {d, J - 7.8 Hz, 1 H), 7.68 (t, J - 8.0 Hz, 1 H), 7,60 (d, J *- 3.8 Hz, 1 H), 7.58 - 7.51 ,(m, 2 H), 7.34 (dd, J » 1 .5, 8.1 Hz, 1 H), 7.18 (dd, J = 0.9, 8,5 Hz, 1 H), 7.1 1 - 7.05 {m, 1 H), 6.72 (dd, J - 0.8, 3.5 Hz, 1 H), 5.34 (s, 2 H), Synthetic, Example 8: 2--( H 3: ^
yj)rnethoxy)benzonitriie (SRI 8959):
Figure imgf000029_0002
TThhee ttiittllee ccoommppoouunndd wwaass pprreeppaarreedd aaccccoorrddiinngg ttoo GGeenneerraall PPrroocceedduurree CC ffrroomm ((11--(({{33-- ((ttririff!!uuoorroommeetthhyyll))pphheennyyll))ssuullffoonnyyll))~~11 HH--iinnddooll--66--yyll))rrrriieetthhaannooll ((5500 mmgg,, 00,,1144 mmmmooii)) aanndd 22--ccyyaannoopphheennooll ((1188 mmgg,, 00..1155 mmmmooii)),, TThhee ccrruuddee pprroodduucctt wwaass p puurriiffiieedd bbyy pprreeppaarraattiivvee H HPPLLCC ((2200--110000%%
CCHHssCCNN//MMeeOOHH ((11 ::11 )) iinn HH2200 ((00..0011%% TTFFAA}})) wwhhiicchh pprroovviiddeedd aafftteerr llyyoopphhiilliizzaattiioonn 4488 mmgg ((7788%%)) ooff tthhee ttiittllee ccoommppoouunndd aass aa ccoolloorrlleessss ssoolliidd;; ΉΉ N NMMRR ((440000 MMHHzz..,, C CDDCCbb)) 55 == 88..2244 -- 88..1122 ( (mm,, 33 HH)),, 77,,7799 ( (dd,, JJ::~~ 77..88 HHzz,, 11 HH)),, 77..7711 -- 77..4499 ((mm,, 55 HH)),, 77..3366 ((dd,, JJ == 88..11 HHzz,, 11 HH)),, 77,, 11 -- 77..0000 ((mm.. ,,22 HH)),, 66..7722 ((dd,, JJ -- --33..55 HHzz,, 11 HH)),, 55..3311 ( ($s·., 22 HH))..
Figure imgf000029_0003
iinnddoollee ((SSRR1188996800))::
Figure imgf000030_0001
The title compound was prepared according to Genera! Procedure C from (1 -({3- (tnfluoromethyl)phenyl}su!fonyl)-iH-indo!-6-yl)me hanoi (50 mg, 0.14 rorrsoi) and guaiacol (18 mg, 0.15 mmoi). The crude product was purified by preparative HPLC (20-100% CHsCN/MeOH (1 :1 ) in HjiO (0.01 % TFA))■■which provided after lyophitization 40 mg (82%) of the title compound as a colorless solid; 1H N R (400 MHz, CDCI3) 5 = 8.10 - 8.15 (m, 2H), 7.94 - 7.99 (m, 1 Ή), 7.75 - 7.80 (m, 1H), 7.47 - 7.57 (m, 3H), 7.34 - 7,39 (m, 1 H)( 6.95 - 6.98 (m, 2H), 6.89 - 6.92 (m, 1H), 6.81 - 6.87 (m, 1 H), 6.69 (dd, J ~ 0.9, 3.7 Hz, 1 H), 5.29 (s, 2H), 3.94 (s, 3H).
Synthetic Example 10: 6~({2-(trifluoromethyl)phenoxy )rnethyi)~1 ~(f 3-
Figure imgf000030_0002
The title compound was prepared according to Genera! Procedure C from ( 1-((3- (triffuoromethyl)phenyl)suifonyl)-1H-in'doi-6-yl)methanol (50 mg, 0.14 mmol) and 2- (trifiuorpmethyl)phenol (24 mg, 0.15 mmol). The crude product was purified by preparative HPLC (20-100% CH3CN/MeOH (1 :1 ) in H2O (0.01% TFA)) which provided after lyophifea!ion 48 mg (68%) of the title compound as a colorless solid; 1H NMR (400 MHz, CDC%) δ - 8.19 (s, 1 H)s 8.15 (s, 1 H), 8, 10 (d, J ~ 8.1 Hz, 1 H), 7.79 (d, J - 7.8 Hz, 1 H), 7.65 {d, J - 7,6 Hz, 1 H, 1 H), 7.62 - 7.52 (m, 3 H), 7.52 - 7.45 (rrt, 1 H), 7.36 - 7.28 (m, 1 H), 7,12 - 7.02 (m, 2 H), 6.71 (dd, J - 0.8, 3.5 Hz, 1 H), 5.30 (s, 2 H)
Synthetic Example 1 : 6-{(o-toiyioxy)rnethyl)-1 -((3-(trifiuorometf )ph
Figure imgf000030_0003
T e title compound was prepared according to General Procedure C from (1-((3- (trifluoromethyl)pheny!)sulfonyl)-1 H-indoi-6-yi )methanol (50 mg, 0.14 mmol) and o-cresol (16 mg, 0.15 mmol). The crude product was purified by preparative HPLC (20-100% CHsCN/ eOH (1 :1) in H2Q (0.01 % TFA)) which provided after lyophitizaiion 32 mg (51 %) of the title compound as a colorless solid; 1 NMR (400 MHz, CDCb) δ = 8.14 (a, 2 H), 7.96 (d, J ~ 7.9 Hz, 1 H), 7,78 {<± J * 7.9 Hz, 1 H), 7.60 - 7.49 (m, 3 Ή), 7.35 (d, ~ 8.1 Hz, 1 H), 7.21 (d, J * 7.5 Hz, 1 H), 7.19 - 7.12 (m, 1 H), 6.95■■ 6.87 (in, 2 H), 6.72 (d, J = 3.7 Hz, 1 H), 5.23 (s, 2 H), 2.35 (s, 3 H),
Synthetic Example 12; 6-((2,6-dimethylphenoxy)methyi)- 1 -((3-ftri luorometM^
):
Figure imgf000031_0001
The title compound was prepared according to General Procedure C from (1-((3- {triftuoromethyi)phenyt)suifonyi)-1 H-ind.o!-6-yl)methanol (50 mg, 0.14 mmol) and 2,6- dsmethylphenoi (18 mg, 0.15 mmol). The crude product was purified by preparative HPLC {20- 100% .CH3CN/ eOH {1 :1 ) in H20 (0.01 % TFA)) which provided after iyophitization 27 mg (42%) of the title compound as a colorless solid; H NMR (400 MHz, CDC ) δ™ 8.19 (s, 1 H), 8.15 (s, 1 H), 8.05 (d, J = 8.1 Hz, 1 H), 7.81 (d, J = 7.9 Hz, 1 Ή), 7.63 - 7.55 (rn, 3 H), 7.40 (dd, = 1.3, 8.1 Hz, 1 H), 7.09 - 7.04 (m, 2 H), 7,01 - 6.95 (m, 1 H), 6.74 (dd, J = 0.9, 3.7 Hz, 1 H). 4 94 (s, 2 H ), 2.33 (s, 6 H).
Synthetic Example 3: 6-f{2,3-dichlorophenoxy methvi)-1 -((.3-(trifluQromethyl)phenvl)euifonvl)-
Figure imgf000031_0002
The title compound was prepared according to General Procedure C from (1-((3- (triflUoromethy phenyi)su fonyi)-1 H-indoi-6-yl)meihanol (50 mg, 0.14 mmol) and 2,3- dichiorophenol (24 mg, 0.15 mmol). The crude product was purified by preparative HPLC (20- 100% CHaC / eQH (1 :1 ) in H20 (0.01 % TFA)) which provided after lyophilizatipn 55 mg (78%) of the title compound as a colorless solid; H NMR (400 MHz, CDC!3) δ = 8.18 - 8.12 (m, 2 H), 8.08 (d, J » 7.5 Hz, 1 H), 7.79 (d, J 7.9 Hz, 1 H), 7,62 - 7.52 (ms 3 H), 7.40 - 7.31 (m, 1 H), 7.16 - 7.07 (m, 2 H), 6.90 {dd, J * 2.4, 7.2 Hz, 1 H), 6.72 (dd, J ~ 0,9, 3.7 Hz, 1 H), 5.28 (s, 2 H).
Figure imgf000031_0003
The title compound was prepared according to General Procedure C from (1 -{{3- (trifluoromethyl)phenyl)su!fonyi)-l H-indoi-6-yl)methanol (50 mg, 0.14 mmol) and 2,5- difluoropheno! (19 mg, 0.15 mmoi). The crude product was purified by preparative HPLC (20- 100% GHsCN/ eOH (1 :1 ) in H20 (0.01% TFA)) which provided after iyophilszation 55 mg (84%) of the title compound as a co!oriess solid; 1H NMR (400 MHz, CDCi3> δ = 8.14 (s, 1 H). 8.10 (s, 1 H), 8.05 (d. J - 8,1 Hz, H), 7.80 (d, J = 7.7 Hz, 1 H), 7,62 - 7.54 (m, 3 H), 7.3.7 - 7.32 (m, 1 H), 7.09 - 7.03 (m, H), 6.78 - 6.71 (m, 2 H), 6.65 - 6.57 (no, 1 H), 5.23 (s, 2 H),
Synthetic Example 15: 6-((naphthafenJ-yloxy methyj^^^
Figure imgf000032_0001
The title compound was prepared according to 'General Procedure C from (1'-((3- (trtfluoromethyl)phenyi)sUlfo yi)-1H~ir5doi~8~yi)met a'noi (50 mg, 0.14 mmoi) and -naphthoi (21 mg, 0.15 mmoi). The crude product was purified by preparative HPLC (20-100% CH3CN/MeOH (1 :1) in HjO (0.01% TFA)) which provided after lyophifization 37 mg (55%) of the title compound as a colorless solid; 1H NMR (400 MHz, CDCi3) 6 = 8.42 - 8.36 (m, 1 H), 8.20 (s, 1 H), 8.12 (s, 1 H), 7.92 (d, J = 8.1 Hz, 1 H), 7.88 - 7,82 (m, 1 H), 7.75 (d, J = 7.8 Hz, 1 H), 7.81 - 7.57 (m, 2 H), 7.55 - 7.51 (m, 2 H), 7.50 - 7.43 (m, 2 H), 7.40 - 7.34 (m, 2 H), 6.90 (d, J ~ 7.8 Hz, 1 H), 6.73 (dd, J = 0.8, 3.5 Hz, 1 H), 5.41 (s, 2 H).
Synthetic Example 16; 6-((naphthalen-2-vloxy)methyi)-1 -((3-(tri{luoromethyi)p: ;enyi)sulfonyi)-1 H- irtdole (S 18971 ):
Figure imgf000032_0002
The title compound was prepared according to General Procedure C from (1-((3- (tnfluoromethyl)phenyl)suifonyi)-1 H"indol-6~yl)melhanol (50 mg, 0.14 mmoi) and 2-naphthol (21 mg, 0.15 mmoi). The crude product was purified by preparative HPLC (20-100% CH3CN/MeOH (1 :1 ) in H2O (0.01% TFA)) which provided after lyophisizaiion 46 mg (68%) of the title compound as a colorless solid; 1H NMR (400 MHz, CDCis) 6 = 8.16 ·· 8.1 (m, 2 H), 7.84 (d, J ~ 8.1 Hz, 1 H), 7.83 - 7.78 (m, 2 H), 7.73 - 7.66 (m, 2 H), 7.60 - 7.56 (m, 2 H), 7.46 (dt, J - 1.3, 7.6 Hz, 1 H), 7.42 - 7.35 (m, 2 H')f 7.28 (dd, J » 2.6, 9.0 Hz, 1 H), 7.23 - 7.18 (m, 2 H), 6.72 (dd, J - 0.9, 3.7 Hz, 1 H), 5.35 (s, 2 H). Ge nera I Syn thetjc Pathway^ 2 :
Figure imgf000033_0001
i) DfBAL-H 1 M in DCM, DCM, -78C'C; ii) Phenol, PPh3, DIAD, DCM, r.t; sis) Aryisuifon i chloride, KOH, TBAHS, DCM, r.t; iv) 3-CF3PhCOCi, KOH, TBAHS, DCM, r.t.
Synthetic Example
trifjuoromethyj}phen.yi)m
Figure imgf000033_0002
Synthesis of (1 H-indoi-6-yi)methano!:
Figure imgf000033_0003
The title compound was prepared by reduction of methyl indole-.6-.carboxytate (700 mg, 4.00 mmol) with DIBAL-H iM in DCM (8,00 mi, 8.00 mmol) according to General Procedure B. The extraction provided 537 mg (91 %) of the title compound as a colorless oil which was used without further purification; H NMR (400 MHz, CD.Cfe) δ * 8.24 (br. s 1 H), 7.64 (d, J ~ 8.1 Hz, 1 H), 7.39 (s, 1 H), 7,22 (dd, J - 2,4, 3,2 Hz, 1 H), 7.13 (dd, J = 1.4, 8.2 Hz, 1 H), 6,5.6 (s, 1 H), 4.79 (s, 2 H).
Synthesis of. ;6^
Figure imgf000033_0004
The title compound was prepared according to General Procedure C from (1 H-indol~6- ■y1)methanol (530 mg, 3,60 mmol) and 2~chloro-6-fluorophenol (554 mg, 3.78 mmol). The crude product was purified by Combiilash silica gel chromatography (0-20% of EtOAc In hexane), which provided 300 mg (30%) of the title compound as a colorless solid; 1H NMR (400 MHz, CDC ) δ -.8.22 (s, 1 H), 7,65 (d, J - 8,1 Hz, 1 H), 7.58 (s, 1 H},. 7.26 - 7.23 (m, 1 H), 7.16 - 7,1 1 (m, 1 H), 7.05 - 6,95 (m, 2 H), 6.56 (dd, J = 1.4, 2.5 Hz,; 1 H), 5.26 (s, 2 H). Syntheis of (6-{(2-chiorQ-6-fiuQrophenoxy)methvi¾-1 H-indol- -vi)(3-
(trifiuoromethyDphenvDmethanone (SRI 9027):
To the solution of 6-({2-ch!o.ro-6-fluorophenoxy}methyl)-1 H-indGie (20 mg, 0.07 mmol) in 2 mL of DCM were added KOH (8 mg, 0.14 mmol) and TBAHS (4 mg, 0.01 rnmoi) at room temperature. The reaciiors mixture was stirred 20 min. before addition of 3-(trifluorornethyi)benzoyl chloride (16 μΐ, 0.1 mmo!). The reaction was stirred at the same temperature for 6- 12k The completion of the reaction was monitored by HPLC. Upon completion, H20 was added and the reaction mixture was extracted with DCM. The combined organic layers were washed with brine and dried over a2SP . Filtration and removal of the solvent provided the crude product, which was purified by preparative HPLC (20-100% CH3GN/MeOH (1 : 1 ) in HzO (0.01 % TFA)) which
provided after !yophilization 19 mg (58%) of the title compound as a colorless solid. TH NMR (400 MHz, CDC;;;) δ = 8.56 (s, 1 H), 8,06 - 8.02 (m, 1 H), 7.94 (d, J ~ 7.2 Hz, 1 H), 7.89 (d, J ~ 7,9 Hz, 1. H), 7.73■■ 7,66 (m, 1. H), 7.64 (d, J « 7.5 Hz, 1 H), 7.56 fdd, J = 1.5, 8.1 Hz, 1 H), 7.24 (d, J = 3.7 Hz, 1 H), 7.18 (id, J = 1.6, 7.9 Hz, 1 H), 7.08 - 6.95 (m, 2 H), 6.67 (dd, J = 0.7, 3.7 Hz, 1 H), 5.29 (s, 2 H).
Figure imgf000034_0001
i): l2, KOH, DMF, r.t; is) 3-CF3Ph$02CI, KOH, TBAHS, DCM, r.t; iii) DIBAL-H 1 M in DCM, DCM
78°C; iv) 2-chlora-6-ftuorophenol, PPhs, DIAD, DCM, r.t; v) MeB(OH)2, K3PO4,
Pd(dppf)Cl2.CH2CI2;, THF, 65 °C.
Figure imgf000034_0002
To the solution of methyl indoie-6-carboxyiate (1.50 g, 8.56 mmol) in 20 mL of DMF were added KOH (1.20 g, 21.4 mmol) and h {2.17 g, 8.56 mmol) at room temperature. The reaction was stirred at the same temperature for I n. The completion of the reaction was monitored by HPLC. Upon completion,- an aqueous solution of ^SaOa containing ice was added to the reaction. The white solid precipitate was■ filtered. The cake was washed with cold H2O and a minimal amount of hexane then dried under vaccum which provided 2.46 g (95%) of the title compound as a colorless solid; ' NMR (400 MHz, CQC ) δ = 8.68 (br. s., 1 H), 8.15 (dd, J - 0.7, 1.3 Hz, 1 H), 7.90 (dd, J = 1.4, 8.4 Hz, 1 H), 7.50 (td, J = 0.7, 8.4 Hz, 1 H), 7.46 (d, J = 2,4 Hz, 1 H), 3.96 (s, 3 H),
Figure imgf000035_0001
The title compound was prepared by .the introduction of 3:-(trifluorometh.y()benzenesulfQnyl chloride (1.96 mL, 12.25 mmol} on methyl 3-iOdo-1H-indoie-8-carboxylate (2.46 g, 8.17 mmol) according to Genera! Procedure A. The crude product was. purified by Gombiflash silica gel chromatography (0-30% of EtOAc in hexane), which provided 3.77 g .(91%) of the title compound as a colorless solid; 1H NMR (400 MHz, CDCI3) δ - 8,65 (dd, = 0.6, 1 ,4 Hz, 1 H), 8,24 {s, 1 H), 8.1 1 (d, J « 8.1 Hz, 1 H), 8.05 (dd, J = 1.5, 8.3 Hz, 1 H), 7.86 (d, J * 9.1 Hz, H), 7,84 (s, 1H), 7,69 - 7.63 ( , 1 H), 7.46 (dd, J ~ 0.5, 8.3 Hz, 1 H), 3.99 (s, 3 H).
Figure imgf000035_0002
The title compound was prepared by reduction of methyl 3-iodo~1-((3~
(tfjfluofomethyl)phenyl)suifooy[)-iH ndol©-6-carboxyla.ie (3.77 g, 7.40 mmol) with OfBAL-H 1 in DCM (14.8 mL, 14.8 mmol) according to General Procedure B, The extraction provided 3.00 g (84%) of the title compound as a colorless oil which was used without further purification; H NMR (400 MHz, CDCI3) δ = 8.24 - 8.17 (m, 1 H), 8.10 - 8.02 (m, 1 H), 8.02 - 7.95 (m, 1 H), 7.84 (td, J - 0.7, 7.9 Hz, 1 H), 7.69 (s, 1 H), 7.67 - 7.60 (m, 1 H), 7.39 ~ 7.35 (m, 2 H), 4.85 (s, 2 H). Synthesis of 6-((2-ohlpro-e-fluor6phenoxy)methvi 3 odo-1-((3-(trifluoromethyi)phenyl)suifonyl^ 1H-indaie;
Figure imgf000035_0003
The title compound was prepared according to General Procedure C from (3-iodo~1 ~((3- (frifluoromeihyl)pheny!)sulfonyi)-1H-indoW-yi)rnethanol (3.00 g, 6.23 mmoi) and 2-ehloro--6- fiuorophenol (959 mg, 6.54 mmoi). The crude product was purified by Combiflash silica gel chromatography {0- 10% of EtOAc in hexane), which provide 3.09 g (81 %) of the title compound as a colorless solid; H NMR (400 MHz, CDC ) δ = 8.24 - 8.20 (m, 1 H), 8.18 (dd, J « 0.7» 1.3 Hz, 1 H), 8.08 (dd, J™ 1 ,1, 8.1 Hz, 1 H), 7.86 - 7,80 (m, 1 H), 7.72 (s, 1 H), 7.66 - 7.59 (m, 1 H), 7.49 - 7.44 (m, 1 H), 7.39 (d, J « 8.1 Hz, 1 H), 7.21 - 7.15 (m, 1 H), 7,07 - 6.97 (m, 2 H), 5.29 (s, 2 H).
S.ynthesis of 6-((2-ch!oro^fl
(fnfjuororr¾eihvi')phenyl)sulfon jl)-1H"indoje (SRI 9158):
In a dried MW flask under Ar were introduced 6-((2-chloro-6-fluorophenoxy)methy]}-3-iodo-1-((3- (trifiuoromethyl)pheny!)suifonyl )-1 H-indoie ( 1 00 mg, 0.16 mmoi), methyfboronic. acid ( 3.9 mg,
0.65 mmol), K3PO4 (146 mg, 0.68 mmol) and 2 mL of anhydrous THF. The flask was purged three times with Ar before the addition of Pd(dppf)Cl2. CH2C ('13 mg, 0.016 mmol). The flask was sealed and the reaction mixture was stirred over night at 65 °C. After removal .of the solvent in vacuo, the crude product was purified by Combiflash silica, gel chromatography (0-10% of EtOAc in hexane), which provided 36 mg (44%) of the title compound as a colorless solid; 1H NMR. (400 MHz, CDC (3) 5 = 8.10 - 8.08 (m, 2 H), 7.94 (d, J - 8.1 Hz, 1 H), 7.68 (d, J = 7.9 Hz, 1 H), 7.50 - 7.45 (m, 1 H), 7.40 - 7.37 (m, 1 H), 7.35- 7.30 (m, 1 H), 7.24 - 7.23 (m, 1 H), 7.08 (td, J - 1.7, 7.8 Hz, 1 H), 6.98 - 6.85 (m:, 2 H), 5.18 (s, 2 H), 2,17 (d, J - 1.3 Hz, 3 H).
Synthetic .Example 19: 6-((2-chloro-6-f)uorophenoxy:)methyl)-1 -(pheny!suifonyl)-- H-indoie
Figure imgf000036_0001
The title compound was prepared by the introduction of benzenesuifony! chloride (14 ML, 0,11 mmol) on the 6-{(2-ehloro-6-flg.orophenoxy)methyl)-1H-indole (20 mg, 0.07 mmol) according to. General Procedure A. The crude product was purified by preparative HPLC (20-100%
CHsC /MeOH (1 :1 ) in H20 (0.01 % TP A)) which provided after !yophi!izaiion- 15 mg (50%) of the title compound as a colorless solid; .H NMR (400 MHz, CDCfe) δ - 8.18 (s, 1 H), 7.93 - 7.87 (m, 2 H), 7.61 - 7.50 (m, 3 H), 7.49 ~ 7.42 (m, 2 H), 7.39 (d, J * 8,1 Hz, 1 H), 7.20 - 7.15 (m, 1 H), 7.07 - 6.94 (m, 2 H), 6.67 (d, J = 3.5 Hz, 1 H), 5.27 (s, 2 H).
Synthetic Examp.te
(SR19035):
Figure imgf000037_0001
The title compound was prepared by the introduction of pyridine-3-sulfonyl chloride,
hydrochloride (23 mg, 0.11 mmol) on the 6-{(2-Ghloro-6 luorophenoxy)methy1}-1 H-indole (20 mg, 0,07 rrsrnol) according to General Procedure A- The crude product was purified by
preparative HPLC (20-100% CH3C /fv1eOH {1 :1} in H20 (0.01 % TFA)} which provided after lyophilization 8 mg (21 %) of the title compound as a colorless solid as the TFA salt; 1H N R (400 MHz, MeOD) δ = 9.06 (s, 1 H), 8.75 (d, J = 4.0 Hz, 1 H), 8,31 - 8,23 (m, 1 H), 8.18 s, 1 H), 7.72 (d, J - 3.8 Hz, 1 H), 7.58 - 7,50 (m, 2 H), 7.35 (dd, J « 1 .3, 8,1 Hz, 1 H), 7.21 (id, J ~ 1.6, 7.9 Hz, 1 H), 7.15 - 7.02 (m, 2 H), 6.79 (dd, J = 0,8, 3.8 Hz, 1 H), 5.2 (s, 2 H). MS (ESI*) mfe 416,75 [Μ÷ΗΊ
Synthetic Example 21 : 6-fC2-chlorO"6-fjuorophenoxY}meth^
Figure imgf000037_0002
The title compound was prepared by the introduction of m-toiuenesuifonyi chloride (16 p , 0.11 mmol) on the 6-({2-chioro-6-fiuorophenoxy)methyl)~1 H-indole (20 mg, 0.07 mmol) according to General Procedure A. The crude product was purified by preparative H PLC (20-100%
CHsCN/MeOH (1 :1 ) in H20 (0.01% TFA)) which provided after iyophiiizalio 21 mg (67%) of the title, compound as a colorless soiid; 1H NMR (400 MHz, CDCI3) δ = 8.18 (s, 1 H), 7,73 (s, 1 H), 7.71 - 7.67 (m, 1 H), 7.80 (d, J ~ 3.7 Hz, 1 H), 7.54 (d, J ~ 8.1 Hz, 1 H), 7,38 (dd, J = 1.3, 8.1 Hz, 1 H), 7.36 - 7.29 (m, 2 H), 7.17 (id, ,J = 1.8, 7.8 Hz, 1 H), 7.07 - 6,94 (m, 2 H), 8.67 (dd, J ~ 0.9, 3.7 Hz, 1 H), 5,26 (s, 2 H), 2,36 (s, 3 H).
Synthetjc Example 22: 6
Figure imgf000037_0003
The title compound was prepared by the introduction of 3-methoxybenzenesulfonyi chloride (15 μΙ_, 0.1 mmol) on the 6-((2-chloro-6-fJuorophenoxy)methyl)-1 H-indoie (20 mg, 0.07 mmol) according to General Procedure A. The crude product was purified by preparative HPLC (20- 100% CHsCN/MeOH (1 :1) in H20 (0.01 % TFA)) which provided after lyophilization 4 mg (43%) of the title compound as a colorless solid; 1H NMR (400 MHz, CDCi3) δ = 8,20 (s, 1 H), 7.58 (d, J = 3.8 Hz, 1 H), 7.54 (d. J - 8,1 Hz, 1 H), 7.46 (d, J = 6.8 Hz, 1 H), 7,42 - 7.37 (m, 2 H), 7.33 (t, J = 8.1 Hz, 1 H), 7.17 (td, J - 1.5, 7.8 Hz, 1 H), 7.08 - 6.95 (m, 3 H), 6.67 (d, J = 3.5 Hz, 1 H), 5.25 (s, 2 H), 3.79 (s, 3 H).
Synthetic Example .23: 6-((2-chioro*6- uorophenoxy)methvi)-i -((3-nitrophenyi)sulfonyl)-1 H-
Figure imgf000038_0001
TTThhheee tttiiitttllleee cccooommmpppooouuunnnddd wwwaaasss ppprrreeepppaaarrreeeddd bbbyyy ttthhheee iiinnntttrrroooddduuuccctttiiiooonnn ooofff 333---nnniiiiiirrrooobbbeeennnzzzeeennneeesssuuulllfffooonnnyyylll ccchhhlllooorrriiidddeee (((222444 mmmggg,,, 000...111 111 mmmrrnrnnooolll))) ooonnn tt thhheee 666---((((((222---ccchhhiiiooorrrooo«««666---fffllluuuooorrroooppphhheeennnoooxxxyyy)))mmmeeettthhhyyyiii)))---111;;HHH~~~iiinnndddooollleee (((222000 mmmggg,,, 000...000777 m mmmrnrnooolll))) aaaccccccooorrrdddiiinnnggg tttooo GGGeeennneeerrraaalll PPPrrroooccceeeddduuurrreee A AA... TTThhheee cccrrruuudddeee ppprrroooddduuucccttt ww waaasss pppuuuriririfffiiieeeddd bbbyyy ppprrreeepppaaarrraaatttiiivvveee HHHPPPLLLGGG (((222000--- 111000000%%% CCCHHH333CGGMNN/// eeeOOOHHH {((111 :::111 }}} iiinnn HHH222000 (((000,,,000111 %%% T TTFFFAAA))))}} ww whhhiiiccchhh ppprrrooovvviiidddeeeddd aaafffttteeerrr l llyyyoooppphhhiiiiiiiiizzzaaatttiiiooonnn 7 mmmggg ( ((222111 %%%))) ooofff ttthhheee tttiiitttllleee cccooommmpppooouuunnnddd aaasss aaa cccooolllooorrrllleeessssss sssooollliiiddd;;; HHH NNNMMMRRR (((444000000 MMMHHHzzz,,, C CCDDDCCCiIIsss))) δδδ === 888...777888 --- 888...666999 ( ( (mmm,,, 111 HHH))),,, 888...444222 ---.888...333888 (((mmm,,, 111 H))),,, 888...222444 --- 888...111666 <<<mmm,,, 222 HHH))),,, 777...777111 ~■■■■ 777...666444 (((mmm,,, 111 HHH))),,, 777...666111 (( (ddd,,, JJJ ~~~ 333...777 HHHzzz,,, 111 HHH))),,, 777...555555 (((ddd,,, JJJ === 777...999 HHHzzz,,, 111 HHH))),,, 777...444111 (((dddddd,,, JJJ ~~~ 111...333,,, 888...111 HHHzzz,,, 111 HHH))),,, 777,,,222000 --- 777...111555 (((mmm,,, 111 HHH))),,, 777...000888 --- 666...999666 (((mmm,,, 222 H H H))),,, 666...777444 (((dddddd,,, JJJ === 000...999,,, 333...777 HHHzzz,,, 111 HHH))),,, 555,,,222777 (((sss,,, 222 HHH)))...
Figure imgf000038_0002
The title: compound was prepared by .the introduction of 2-(trifiuoromethyl)benzenesulfonyl chloride (17 μΙ,; 0.1 1 mrnol) on the 6-((2-chioro-6-fluorophenoxy)rnethyi)-1 H-lndoie (20 mg, 0.07 mmo!) according to General Procedure A. The crude product was purified by preparative HPLC (20-100% CHsCN/ eOH. (1:1) In HaO (0.01% TFA)) which provided after lyophiiization 6 mg (17%) of the title compound as a. colorless solid; H N R (400 MHz, CDCI3) δ = 7.98 (s, 1 H), 7.91 (d, J = 7.8 Hz, 1 H), 7.69 (t, J « 7.6 Hz, 1 H), 7.66 - 7.55 (m, 3 H), 7.54 - 7.50 (m, 1 H), 7.43 (d, J =· 8.1 Hz, 1 H), 7.15 - 7.07 (m, 1 H), 7.04 - 6.90 (m, 2 H), 6.74 (d, J = 3.5 Hz, 1 H), 5.21 (s, 2 H).
Synthetic Example 25: 6-((2-chlorQ-6-fiuofophe{ oxy .methvi)'1--'((2-chiorophenyi)sulfonyl>1H-
Figure imgf000038_0003
The ."title compound was prepared by the introduction of 2-c'h'loroben.zer»e$uifonyl chloride (15 pi 0.1 1 mnrtof) on the 6-{{2.-chlorQ-6-fluorophenoxy)meihyi)-1 H^indole (20 mg, 0,07 mmol) according" to General Procedure A. The crude product was purified by preparative HPLC (20- 10.0%. GH3.CN/¾ eOH (1:1 ) in H20 (0.01 % TFA)) which provided after lyophiiization 13 mg (40%) of the title compound as a colorless solid; 1H NMR (400 MHz, CDCI3) δ - 8.20 (dd, J - 1.5, 8.3 Hz, 1 H), 7.87 (s, 1 H), 7,77 (d, J =■ 3,8 Hz, 1 H), 7.58 (d, J * 8.1 Hz, 1 H), 7.51 (d' = 1.6, 7.6 Hz, 1 H), 7.47 - 7.43 (m, 2 H), 7.38 (d, J « 8.1 Hz, 1 H), 7.18 - 7,11 (m, 1 H), 7.06 - 6.93 (m, 2 H}, 6.68 (d, J ~ 3,8 Hz, 1 H), 5.19 (s, 2 H).
Synthetic Example 26. 6-((2-chloro-6-:flup_rQp )suif6nyQ-1 H-
Figure imgf000039_0001
The title compound was prepared by the introduction of ' 4-f!uorobenzenesuifony! chloride (21 mg, 0.1 1 mmol) on the e-((2-chlpfo-6"fiuorop enoxy)methyl)-1 H-indoie .(20 mg, 0.07 mmol) according to General Procedure A, The crude product was purified by preparative HPLC (20- 100% CHsC / eOH (1 :1) in H2G (0,01 % TFA)) which provided after lyophiiization 21 mg (67%) Of the title compound as a colorless solid; H NMR (400 MHz, CDCI3) δ = 8.17 (s, 1 H), 7.95 - 7.89 (m, 2 H), 7.57 (d, J - 3.7 Hz, 1 H), 7.54 (d, J = 8.1 Hz, 1 H), 7.39 (dd, J = 1.4, 8.0 Hz, 1 H), 7.19 - 7.16 (m, 1 H), 7.14 - 7.08 ( n, 2 H), 7,07 - 6.96 (m, 2 H), 6.68 (del, J ~ 0.9, 3.7 Hz, 1 H), 5.27 (s, 2 H),
Synthetic Example 27;, 6-((2-cMorg-^ (SRI 9037):
Figure imgf000039_0002
The title compound was prepared by the introduction of p-toiuenesulfonyi chloride (21 mg, 0.1 1 mmol) o the 6~((2~chloro-6-fluorophenoxy)meihyl)-1 H-indoie (20 mg, 0.07 mmol) according to General Procedure A. The crude product was purified by preparative HPLC (20-100%
CHaCN/MeOH (1 :1) in H20 (0.01 % TFA)) which provided after .lyophiiization 10 mg (32%) of the title compound as a colorless solid; Ή NMR (400 MHz, CDCI3} δ ~ 8.17 (s, 1 H), 7.78 (d, J ~ 8.3 Hz, 2 H)„ 7.58 (d, J - 3,5 Hz, 1 H), 7.53 (d, J = 8.1 Hz, 1 H), 7,38 (dd, J ~ 1.3, 8.1 Hz, 1 H), 7.22 (d, - 8.3 Hz, 2 H), 7.17 (td, J * 1 ,8, 7.8 Hz, 1 H), 7.07 - 6.95 .(m, 2 H), 6.65 (d.d, J » 0.9, 3.7 Hz, 1 H), 5.26 (s, 2 H), 2.35 (s, 3 H).
Synthetic Example 28: 6-((2-chioro-6TluorophenQxy)methyf)-1~ {4- (frifluoromethyi phenvi)sulfonv -1 H-lndole (SR19030):
Figure imgf000040_0001
The title compound was prepared by the introduction of 4-(tnf1uoromet yi}benzenesuifonyl chloride {27 mg, 0.1 1 mmoi) :on. the 6-{(2-chlofo-6-fjuorop enoxy)rnethyi)-1 H-indote (20 mg, 0.07 mmoi) according to General Procedure A The crude product was purified by preparative HPLC (20-100% CHaCN/ eOH (1 :1 ) in H2.0 (0.01 % TFA)) which provided after lyophilization 10 mg (28%) of the title compound as a colorless solid; 1H NMR (400 MHz, CDCb) δ - 8.19 (s, 1 H), 8.01 (d, J = 8.1 Hz, 2 H), 7.71 (d, J = 8.1 Hz, 2 H), 7.57 (d, J = 3.7 Hz, 1 H), 7.55 (d, J = 7.9 Hz, 1 H), 7.40 (dd, J - 1.4, 8.0 Hz, 1 H), 7.19 - 7.16 (m, 1 H), 7,06 - 6.96 (m, 2 H), 6.71 (dd, J ~ 0.8, 3.6 Hz, 1 H}, 5.28 (s, 2 H).
Genera! Synthetic Pathway 3:
Figure imgf000040_0002
i) MaBH4, MeOH, r.t; if) sCt, Et3N, THF, then UBrs 0 °C; iii) 6-hydroxyindole, K2C03, D F, r.t; iv) 3-CF3PhS02CI, K.OH, TBAHS, DCM, r.t.
Synthetic Exam.p|e: 29: 6^
1-H-indole (SR 19257):
Figure imgf000040_0003
The title compound was prepared according to Genera! Procedure Di from 2~chlQro~8~ ffuorobenzaidehyde (1.3 g, 8.19 mmoi). The extraction provided 1.31 g (100%) of the title compound as a colorless solid which was used without further purification; H N R {400 MHz, CDCis) δ = 7.29 - 7.20 (m, 2 H), 7.07 - 7.00 (m, 1 H), 4.87 (d, J = 3,7 Hz, 2 H).
Synthesis of 2-(bronipmethy )
The title compound was prepared according to General Procedure E from (2-chioro-6- fiuorophenyljmethanoi. (500 mg, 3.1 1 mmoi). The extraction provided 615 mg (88%) of the title compound as a colorless oil whic was used without further purification;- 1H N R (400 MHz, CDCI3) δ = 7,31 - 7.20 (m, 2 H), 7 06 - 6.99 (m, 1 H), 4.64 (d, J - 1.8 Hz, 2 H).
Figure imgf000041_0001
The title compound was prepared according to General Procedure F from 6-hydroxylndole (400 mg, 3.00 rnrnol) and 2-(bromQmeihyl)-1-chlo 3-fluOrobenzene (738 mg, 3.1 1 mmol). The crude product was purified by Combiflash silica gel chromatography (0-20% of EiOAc in hexane), which provided 565 mg (68%) of the title compound as a colorless solid; Ή NMR (400 MHz, COCfe) δ = 8.09 (s, 1 H), 7.65 (d, J = 8.6 Hz, 1 H), 7.35 - 7.23 (m, 1 H), 7.15 (dd, J - 2.4, 3.3 Hz, 1 H), 7.10 ~ 7,03 (m, 2 H), 6.92 (dd, J ~ 2,2, 8.8 Hz, 1 H)f 6,54 ~ 6.51 (m, 1 H), 5.24 (d, J = 2.0 Hz, 2 H).
S n hg s o^
Figure imgf000041_0002
The title compound was prepared by the introduction of 3-(trifluoromethylbenzenesulfonyt chloride (15 μί., 0,09 mmol) .on 'the 6-((2-chioro-6-fluorobenzy])oxy)~1 H-indole 1455 (17 mg, 0.06 romol) according to Genera! Procedure A. The crude product was purified by preparative HPLC (20-100% -CHsCN/MeOH (1 :1 ) in H20 (0.01 % TFA)) which provided after jyophiiizatipn 20 mg (67%) of the title compound as a colorless solid; H NMR (400 MHz, CDC ) 5 - 8.19 (s, 1 H), 8.03 (d, J - 8.1 Hz, 1 H), 7.81 (d, J ~ 7.8 Hz, 1 H), 7,69 (d, J ~ 2.3 Hz, 1 H), 7.63 - 7.57 (m, 1 H), 7.47 (d, J = 3.8 Hz, 1 H), 7.43 (d, J = 8.6 Hz, 1 H), 7,37 - 7.28 (m, 2 H), 7.1 1 - 7.04 (m, 1 H), 6.98 (dd, J = 2,3, 8.6 Hz, 1 H), 6,65 (dd, J - 0.8, 3.8 Hz, 1 H), 5.26 (d, 1.8 Hz, 2 H).
Figure imgf000041_0003
I) Tf02l pyridine, DCM, D °C; ii) Trimethylsillylacetylene, E!3N, PdGI2(PPh3)2; CH3CN, 85 °C; iii) K2CO3, MeOH, r.t; Iv) Bis(pinacoiaio)diboron, CuCl, NaOtBu, Xantphos, MeOH, THF, r.t; v) N- sulfonyi-6-bromoindote, K3PO4, Pd(PPh3)4, dioxane, 100 °C; vi) N-sulfonyl-6-bromoinciole, Et3N, Pd(PPh3)CI2, Cui, PPh3, DMF, 90 °C; vii) H2, Pf02, EtOH, EtOAc, r.i.
Figure imgf000042_0001
Synthesis of 2-ch1pro-(Hiuoroph
Ψ O
| T Γ
To the solution of 2-chloro-6-fiuorophenol (800 mg, 5.46 mmoi) in 10 mL DCM at 0 "C was added pyridine (442 pL 5.48 mmoi) and frifluoromethanesulfonic acid anhydride (918 μΐ, 5.45 mmoi). The reaction was stirred at the same temperature for 3h. The completion of the reaction was monitored by HPLG. Upon completion, solvent was evaporated in vacuo, H2Q was added to the crude residue and the reaction mixture was extracted with EtOAc. The combined organic layers were washed with brine and dried over NazS04, Filtration and removal of the solvent provided 1 ,25 g of the title compound as a colorless solid, which was used without Further purification; 1H NMR (400 MHz, COCI3) δ = 7.34 ~ 7.31 (m, 2 H);, 7.24 - 7.18 (m, 1 H).
Synthesis of i(2-chjoro-8-fiuorophenyl )ethynvj)irimethyisiiane:
Figure imgf000042_0002
In a dried MW flask under Ar was introduced a solution of 2~chioro-6-f!uorpphenyl
infiuoro ethanesuifonaie (1 ,25 g) in 30 ml CH3C was added E¾N (1 .14 ml, 8.19 mmoi). The flask was purged three times with Ar before the addition of trimethyisil y!acetyiene (1 .16 mL, 8.19 mmoi) and P C^ s)? (192 mg, 0.27 mmoi). The flask was sealed: and the reaction mixture was stirred overnight at 85 °C. After removal of the solvent in vacuo, the crude product was purified by Comhif!ash silica gel chromatography (0-30% of EtOAc in hexane), which provided 1.02 g of the title compound as a colorless solid; 1H NMR (400 MHz, CDC ) δ ~ 7.23 - 7.18 (m, 2 H), 7.04 ~ 6.97 {m, 1 H), 0,30 (s, 9 H).
Synthesis of 1-chloro-2-ethynyi-3-fiuorobenzene: To the solution of ((2-chior -6-fluorophenyl)ethyny!}trinnethy!silarie in 30 mL eOH at room temeperature was added K2CO3 (1.10 g, 7.96 mmoi) The reaction- was stirred at the same temperature for 3h. The completion- of the reaction was monitored by TLC. Upon .completion, H2O was added and the reaciion mixture was extracted with EfcQ. The combined organic layers were washed with brine and dried over a2S04. Filtration and removal of the solvent provided 485 mg (57% yield over 3 steps) of the 'title compound as a colorless oil, which was used without further purification. Desired compound is highly yolatil; ΊΗ NMR (400 MHz, CDC ) δ - 7.32■· 7.20 (m, 2 H), 7,0? - 7,00 (m, 1 H), 3.62 (d, J ~ 0.9 Hz, 1 H),
Figure imgf000043_0001
TThhee ttiittllee ccoommppoouunndd wwaass pprreeppaarreedd bbyy tthhee iinnttrroodduuccttiioonn ooff 33--{(ttrriiflfluuoorroommeettbhyy.ri))bbeennzzeenneessuullffO0nnyyli cchhlloorriiddee ((661133 ppLL,, 33..8822 mmmmooll)) oonn 66--bbrroommooiinnddooiiee ((550000 mmggs, 22..5555 mmmmooll)) aaccccoorrddiinngg: ttoo GGeenneerraall PPrroocceedduurree AA,, TThhee ccrruuddee pprroodduucctt wwaass ppuurriiffiieedd bbyy C Coommbbiiflflaasshh ssiilliiccaa ggeell cchhrroommaattooggrraapphhyy ((00--1100%% ooff EEttOOAAcc iinn hheexxaannee)),, wwhhiicchh pprroovviiddeedd 889999 mmgg ((8877%%)) ooff tthhee ttiittllee ccoommppoouunndd aass aa ccoolloorrlleessss ssoolliidd;; HH N NMMRR ((440000 MMHHzz,, C CDDCCib3)) 55 == 88..1199 ( (ttdd,, JJ == 00..88,, 11 ,,55 HHzz,, 11 HH)),, 88,, 1155 ((ss,, 11 HH)),, 88..0066 ((dd,, JJ == 88..11 HHzz,, 11 HH)),, 77,,8844-- ((dd,, == 77,,77 HHzz,, 11 HH)),, 77,,6683 -- 77..6611 ((mm,, 11 HH)),, 77.,5544 ((dd,, JJ -- 33,,77 HHzz,, 11 HH)),, 77,,4455 -- 77.,3366 ((mm.. 22 HH)),, 66,,6699 ((dddd,, JJ == 00..88,, 33..66 HHzz,, 11 HH)),,
SSyynntthheessiiss ooff 66--CCC(22--cchiioorroo~~66~~ffiiuuoorroo..pphheennvvll))eetthhy^ny^
iinnddoollee ((SSRR1199007799))::
IInn aa ddrriieedd MMWW ffllaasskk uunnddeerr AArr wweerree, iinnttrroodduucceedd 66--bbffoommoo--11--((((33--((ttrriiffttuuoorrOOmmeetthhyyll))pphheennyyii))ssuu!!ffoonnyyii''))-- 11 HH--iinnddooIIee ((115500 mmgg,, 00..3377 mmmmooll)),, EE¾¾NN ((115555 ppLL,, 11.. 11 mmmmooll)) aanndd 22..44 mmLL ooff aannhhyyddrroouuss DDMMFF TThhee ffllaasskk wwaass ppuurrggeedd tthhrreeee ttiimmeess --wwiitthh AArr bbeeffoorree tthhee aaddddiittiioonn ooff 11--cchhiioorroo--22--eetthhyynnyy!!--..33--ffiiuuoorroobbeennzzeennee ((111155 mmgg,, 00..7744 mmmmooll)),, PPdd((PPPPhh33))CCii22 ((2266 mmgg,, 00,,0044 mmmmooll)),, CCuull ((1144 mmgg,, 0 Q..G077 mmmmooli)) aanndd PPPPhh33 ((1100 mmgg,, 00..0044 mmmmooli)).. TThhee ffllaasskk wwaass sseeaalleedd aanndd tthhee rreeaaccttiioonn mmiixxttuurree wwaass ssttiirrrreedd oovveerrnniigghhtt aatt 9900 °°CC,, AAfftteerr rreemmoovvaall ooff tthhee ssoollvveenntt .. iinn vvaaccuuoo,, tthhee ccrruuddee pprroodduucctt wwaass ppuurriiffiieedd bbyy CCoommbbiiffllaasshh ssiilliiccaa ggeell cchhrroommaattooggrraapphhyy ( (00--1155%% ooff EEttOOAAcc iinn hheexxaannee)),, wwhhiicchh pprroovviiddeedd 112277 mmgg ((7722%%)) ooff tthhee ttiittllee ccoommppoouunndd aass aa ccoolloorrlleessss ssoolliidd;; 11HH NNMMRR ((440000 MMHHzz,, CCDDCCbb)) δδ == 88..2233 ((ss,, 11 HH)),, 88,, 1188 ((ss,, 11 HH)),, 88..0099 ((dd,, JJ == 88..66 HHzz,, 11 HH)),, 77..8833 ((dd,, JJ -- 77,,88 HHzz,, 11 HH)),, 77..6677 -- 77,,6611 ((mm,, 22 HH)),, 77..5566 -- 77..4488 ((mm,, 22 HH)),, 77..3311 -- 77,,2222 ((mm,, 22 HH)),, 77..1111 ···· 77..0044 ((mm,, 11 HH>),, 66..7733 ((dddd,, JJ ~~ 00..88,, 33..88 HHzz,, 11 HH)),,
Figure imgf000043_0002
Figure imgf000044_0001
In a dried W flask under Ar were introduced CuCI (4 mg, 0.04 mmol), NaOi-Bu (11 mg, 0.12 mmol), Xanlphos (22 mg, 0.04 mmol} and 4 ml. of anhydrous THF. The flask was purged three times with Ar and then was stirred 30 min at room temperature before the addition of bis(pinaco!ato)diboron {361 mg, 1.42 mmol). The reaction mixture was stirred another 10 min. before the addition of 1-ch!QrQ-2-ethyri !-3-fluorob©nzene (200 mg, 1.30 mmol) and eOH (210 uL, 5.18 mmol). The flask was sealed and the reaction mixture was stirred overnight at room temperature. The reaction mixture was filtered over Ceiite®. The cake was washed with THF. After removal of the solvent in vacuo, the crude product was purified by Combif!ash silica gel chromatography (0-30% of EtGAc in hexane), which provided 142 mg (39%) of the title compound as a colorless solid; 1H NMR (400 MHz, CDC ) δ = 7.49 (d, J- 18.9 Hz, 1 H), 7.21 ~ 7.12 (m, 2 B), 7.04 - 6.9.6- (m, 1 H), 6.43 (d, J = 18.9 Hz, 1 H), 1.55 (s, 6 H).
Synthesis of (E)-6-(2-chioro-6-fiuorostyryl)-1;~((3-(trifiuorome¾hyl)phenyl)su!fonyl)-1 H"indoie
(SRI 9080):
In a dried M flask under Ar were introduced 6-bromoTl-((3-(trifluoromethyl)p.henyf}suifonyi)- 1 H-indole (80 mg, 0.20 mmol),■(E)-2-(2-chloro-6-fiuorostyry!)-4,4,5,5-teiramethyl-1 )3,2~ dtoxaboroiane (84 mg, 0.30 mmol), 3PO4 (126 mg, 0,59 mmol) and 2.5 m'L of anhydrous dloxaoe. The flask was purged three times with Ar before the addition of Pd(PPh3)4 (23 mg, 0.02 mmol). The flask was sealed and the reaction mixture was stirred overnight at 100 °C. After removal of the solvent in vacuo, the crude product was purified by preparative HPLC (20-100% CHsCN/ eOH (1:1 ) in H20 (0.01% TFA)) which provided after lyophiiization 46 mg (48%) of the title compound as a colorless solid; H NMR (400 MHz, CDCb) δ - 8.14 (s, 1 H), 8.05;■($, 1 H), 8.02 (d, J - 7.9 Hz, 1 H), 7.75 (d, J. - 7.9 Hz, 1 H), 7.58 - 7,55 (m, 1 Ή), 7.53 (d, J~ 3.7 Hz, 1 H), 7.50 - 7.48 (m, 1 H), 7.45 (d, J 16.7 Hz, 1 H), 7.25 (d, J - 16.7 Hz, 1 H), 7,22 - 7.15 (m, 2 H), 7.10 (dt, = 5.8, 8.2 Hz, 1 H), 7.04 - 6.97 (m, 1 H), 6.66 (dd, J = 0.7, 3.7 Hz, 1 H).
Synthetic Example 32: 6-(2-chtoro-6~f luorophenethyl)-1 -ff3 trlfiuoromethyl)pheny|)sui^ indole (SR19081 ):
Figure imgf000045_0001
To the solution of 6-({2-chioro-6-fluorophenyl)ethy^
indole (30 mg, 0.06 rrjmo!) in 5 ml EtOH and 5 mL EtOAc was added 8 mg PtG2. The reaction mixture was stirred under Ha overnight at room temperature. The completion of the reaction was monitored by HPLC. Upon completion, the reaction mixture was filtered over Celite®. The cake was washed with EtOH and EtOAo. Soivents were removed in vacuo and the crude product was purified by preparative HPLC (20-100% CH3CN/ eOH (1 : 1 ) in H20 (0,O1 % TF A)) which
provided -after lyophilization 12 mg (40%) of the title compound, as a colorless solid; H NMR (400 MHz, CDC la) δ = &1 {s, 1 H), 8.03 (d, J = 8,1 Hz, 1 H), 7.8.8 (s, 1 H), 7.80 (d, J = 7.9 Hz, 1 H), 7.6:3 - 7.57 (m, 1 H), 7,52 (d, J = 3.7 Hz, 1 H), 7.45 (dd, J ~ 0.5, 8.0 Hz, 1 H), 7.21 - 7, 10 (m, 3 H), 6,98 - 6.93 (m, 1 H), 6,72 - 6,66 (m, 1 H), 3.13 - 3.04 (m, 2 H), 3.04 - 2.95 (m, 2 H). -3e n eraj S nth etic Pathway 5 ;
Figure imgf000045_0002
i) aBHaCN, AcOH, ri; if) 3-CF3PhS02CI, EfeN, DCM, r ; iii) DIBAL-H 1 M in DCM, DCM, -78 X; iv) 2-chloFO-6-fluofOphenQl, PPh3i DIAD, DCM, r.t;- v) sCi, Et3N, THF, 0°C, then LiBr; vi) 3,5- dicKloropyridin-4-ol, K2CO3, D F, r.t.
Figure imgf000045_0003
(trifiuoromethylJp.heryi)su (SRI 8957):
Figure imgf000045_0004
Synthesis of methyl indoljne-S-carboxylate:
,QMe
The title compound was prepared according to General Procedure G from methyl indo!e~6- carboxylate (200 mg, 1.14 mmo!). The crude product was purified b Combifiash silica gel chromatography (0-30% of EtOAc in hexane), which provided 153 mg (76%) of the title compound as a colorless solid; Ή NMR (400 MHz, CD ¾) δ - 7.51 (dd, J = 1,5, 7.6 Hz, 1 H), 7.39 (d, J ~ 15 Hz, 1 H), 7.19 (d, J = 7.6 Hz, 1 H), 3.89 (s, 3 H), 3.67 (! , J = 8,5 Hz, 2 H), 3.12 (t, J *= 8,5 Hz, 2 H).
Synthesis of methyl 1--((3v(trsfiuorom:ethy1)phenyi)sy|fo.n
Figure imgf000046_0001
To the solution of methyl ind line~6-carboxyiate (150 mg, 0,85 mmoi) in 5 ml acetone were added K2CO3 (351 mg, 2.54 mmoi) and 3-(tr!i!uQromethyl)benzenesuifonyi chloride (271 μί,, 1.69 mmoi). The reaction mixture was stirred at room temperature overnight. The completion of the reaction was monitored by HPLC Upon completion, the solvent was removed in vacuo. The crude product was purified by Combiflash silica gel chromatography (0-20% of EtOAc in hexarse), which provided 277 mg (85%) of the title compound as a colorless solid; 1H NMR (400 MHz, CDCis) 5 = 8.25 (d, J - 1.5 Hz, 1 H), 8.12 (s, 1 H), 8.00 (d, J - 8.1 Hz, 1 H), 7.84 (d, J = 7.9 Hz, 1 H), 7,74 (d.d, J =· 1.4, 7.8 Hz, 1 H), 7.66 - 7.58 (m, 1 H), 7.17 (d, J - 7.9 Hz, 1 H), 4.01 (t, J - 8.6 Hz, 2 H), 3.95 (s, 3 H), 3.00 (t, J ~ 8.6 Hz, 2 H).
Figure imgf000046_0002
The title compound was prepared b reduction of methyl 1-((3-
(tr|fluoromethyl)phenyi)suifony!)indo!ine-6-carboxyiate (270 mg, 0.70 mmoi) with DfBAL-H 1 in
DCM (1 .40 ml, 1.40 mmoi) according to General Procedure B. The extraction provided 240 mg (98%) of the title compound as a colorless oil which was used without further purification;
NMR (400 MHz, CDC ) δ = 8:08 (s, 1 K), 7,98 (d, J = 8.1 Hz, 1 H)s 7,82 (d, J * 8.6 Hz, 1 H), 7.65 (s, 1 H), 7.64 - 7.58 (m, 1 H), 7.09 (d, J = 7.7 Hz, 1 H), 7.04 (d, J ~ 7.7 Hz, 1 H), 4.71 (s, 2 H), 3.96 (t, J ~ 8,4 Hz, 2 H), 2.91 (t, J = 8.4 Hz, 2 H).
Synthesis of .6-((2-chioro^-fiuorophenoxy)methy^
(SR18957):
The title compound was prepared according to General Procedure C from (1-({3- (trifluoromethyl)phenyi)suifonyl)indoiin-6-yl)methanol (50 mg, 0,14 mmoi) and 2-chioro-6- fluorophenol (22 mg, 0.15 mmoi). The crude product was purified by preparative HPLC (20- 100% CHaCN/MeOH (1 ; 1 ) in H20 {0,01 % TFA)} which provided after iyophiiizaiion 30 mg (44%) of the title compound as a coioriess solid; 1H NMR (400 MHz, CDG ) δ = 8.12 (ss 1 H)s 7.98 (d, J - 7.5 Hz, 1 H), 7.86 - 7.78 <m, 2 H), 7.63 - 7.56 {m, 1 H). 7.22 ~ 7.09 (m, 3 H), 7.08 - 6.96 {m, 2 H), 5.14 (s, 2 H), 3,97 (t, J - 8.4 Hz, 2 H>. 2,93 (t, = 8.4 Hz, 2 H).
Figure imgf000047_0001
i) aBHsC , AcOH, r.t; ii) 3-CF3PhS02Ct, pyridine, THF, 0 °C; iil) Bn'O s or BnBr, 2C03> DMF, r.t; !v) EQCi, D AP, Dfv E. 60 °CA
Synthetic Example 34: of 6-({2-chioro-6-fiuorobenzyi)oxy.)r1.- {3-
Figure imgf000047_0002
The titie compound was prepared according to Generai Procedure G from 6-hydro indole {400 mg, 3.00 mmof). The extraction provided 400 mg (99%) of the titie compound as a coioriess oil which was used without further purification; 1H MR (400 MHz, MeOD) δ = 6.86 {d, J - 8,3 Hz, 1 H), 6.18 {d, J= 1.8 Hz, 1 H), 6. 4 (dd, J - 1.8, 8.3 Hz, 1 H), 3,43 (t, J " 8.2 Hz, 2 H), 2.87 (t, J ~ 8.2 Hz, 2 H).
Figure imgf000047_0003
To the solution of indoiin-6-οί (240 mg, 1.78 mmof) in 15 ml THF at 0 °C were added pyridine (172 μΐ, 2. 3.mmol) and 'dropwise solution of 3-(trif!uoromethyl)behzenesulfony! chloride (285 μΐ», 1 ,78 mmol) in 5 ml. THF. The reaction mixture was stirred 4h at 0 °C. The completion of the reaction was monitored by HPLC. Upon completion, aqueous HCI 1 was added and the crude residue was extracted with EtOAc. The combined organic layers were washed with brine and dried over Na-^SC . Filtration and removal of the solvent provided the crude product, which was purified by Combiffash silica gel chromatography (0-30% of EtOAc in hexane), which provided 280 mg (46%) of the title compound as a yellow solid; 1 H NMR (400 MHz, CDC! -.) δ ~ 8,08 (s, 1 H), 8.00 - 7.98 (m, 1 H), 7.84 - 7.82 (m, 1 H), 7-67 ~ 7.56 (m, 1 H), 7.20 (d, .J = 2,4 Hz, 1 H), 6.94 (td, J-~ 0.9, 8, 1 Hz, 1 H), 6.51 (dd, J- - 2.4, 8.1 Hz, 1 H), 3.95 {t, J = 8.3 Hz, 2 H), 2.84 (t, J - 8.3 Hz, 2 H).
Synthesis of^
(SRI 9170):
The title compound was prepared according to General Procedure C from 1 -((3- (trifl.uorQmethyl}pheny!)suifonyS)indolin-6-oi (40 mg, 0,12 mmoi) and (2~ch!orQ»6-- f!uorophenyi}methanpi (20 mg, 0.12 mmo!). The crude product was purified by preparative HPLC (20-100% CHsCN/MeOH (1 : 1 ) in H20 (0.01 % TFA)) which provided after !yophiiization 21 mg (31 %) of the title compound as a colorless solid; 1 H NMR (400 MHz, CDC!3) δ - 8.10 (s, 1 H), 7.99 (d, J - 7.8 Hz, 1 H), 7,83 (d, J = 7.8 Hz, 1 H), 7.66 - 7.57 (m, 1 H), 7.37 (d, J = 2.3 Hz, 1 H), 7.3© - 7,25 (rn, 2 H), 7.12 ~ 7.04 (m, 1 H), 7.00 (d, J * 8.1 Hz, 1 H), 6.67 (dd, J = 2.4, 8.2 Hz, 1 H), 5.20 (d, J - 2.0 Hz, 2 H), 3,97 (t, J = 8.3 Hz, 2 H), 2.86 (t, J = 8.3 Hz, 2 H).
l gi?-L xQg?P!Q .35:. 6-(1-(2-ch'lorQ-g-fJuorQphenyi)ethoxy)-1 -((3-
Figure imgf000048_0001
To the solution of 2-cbioro~6~fluoroaGetophenone (150 mg, 0.87 mmol) in 10 mL eOH at 0 °C was added NaBB4 (33 mg, 0.87 mmoi). The reaction was stirred at 60 °C for 2h. The completion of the reaction was monitored by HPLC. Upon completion, the solvent was removed in vacuo, HaO was added to the crude residue and the reaction mixture was extracted with EtOAc. The combined organic layers were washed with saturated aqueous NaHCC¼, brine and dried over Ν¾230 Filtration and removal of the solvent in vacuo provided 1 -(.2-chloro-6- fluoropheny!)ethan-1 -ol, which was directl used without further purification for the next step. To the solution of the previously obtained oil i 8 mL of THF at 0 °C were added EhU (182 pL, 1 ,30 mmoi) and sG! (81 pL; 1.04 mmol). The reaction was stirred at the same temperature for 3h. The completion of the reaction was monitored by TLC. Upon completion, H2O was added and the reaction mixture was extracted with EtOAc. The combined organic layers were washed with saturated aqueous aHCOs, brine and dried over N82SO4. Filtration and removal of the solvent in. vacuo provided 220 mg (100%) of the title compound as a colorless oil, which was used without further purification; H fviR (400 MHz, C Cb) δ = 7.33 - 7.27 m, 1 H), 7.25 - 7.21 (m, 1 H), 7.09 - 7.03 (m, 1 H), 6.30 (dq, J = 1.1 , 6.8 Hz, 1 H), 2.89 (s, 3 H), 1 ,83 (d, J = 6,8 Hz, 3 H), Synthesis of 6 1 ~(2 chSorG"6Tluorophenyl)ethoxy)-1 ^^
(SRI 9269):
To the solution of 1-((3-(trifluoromethyt)phenyi)su}fonyi)fndoiin-6-ol (30 mg, 0.09 mmoi) in 0.8 mL of DMF at room temperature were added K2GQ3 (48 mg, 0.35 mmoi) and 1 -(2-ch!oro-6~ ffuoropheny|)ethyl methanesulfonate (44 mg, 0.17 mmoi). The reaction was stirred at 60 °C overnight. The completion of the reaction was monitored by HPLG. Upon completion, H2O was added and the reaction mixture was extracted with EtOAc. The combined organic layers were washed with brine and dried over
Figure imgf000049_0001
and removal of the solvent in vacuo provided the crude product, which was purified by preparative HPLG (20- 00% CHaCN/MeOH (1 :1 } in H2O (0,01 % TFA}) which provided after lyophilizatjon 38 mg (87%) of the title compound as a colorless solid; 1H NMR (400 MHz, CDCb) 6 8.01 (s, 1 H), 7.79 (d, J ~ 7.0 Hz, 1 H), 7.74 (d, J - 7.9 Hz, 1 H), 7.54 - 7.46 (m, 1 H), 7.24 (d, J = 2.4 Hz, 1 H), 7,21 - 7.17 (m, 2 H), 7.02 - 6,94 (m, H), 6.89 (d, J - 8.3 Hz, 1 H), 6.56 (dd, J = 2.3, 8.2 Hz, 1 H), 5.95 - 5.83 (m, 1 H), 3.89 (t J = 8.3 Hz, 2 H), 2.76 (t, = 8,3 Hz, 2 H), 1.79 (d, J ~ 6.8 Hz. 3 H).
Synthetic Example 36: 1-((3-(thfluoromethvi)phenyl)su!fonyl)indolin-6-vi 2-chioro-6- fiuorobenzoate (SRI 9404):
Figure imgf000049_0002
To the solution of 2-chloro-6-fluorobenzaidehyde {1 ,0 g, 6.31 mmoi) in 25 mL of THF and 10 ml of H2O was added 8H2PO4 (454 rng, 3.78 mmoi). The reaction was stirred 10 min at room temperature before introduction of NaCiC¾ (1.88 g, 20.8.1 mmoi) and 1 ,4 mL of H2O2 (30%wt ..in H2O), The reaction was stirred at room temperature 3h, Upon completion, the reaction mixture was extracted with EtOAc. The combined organic layers were washed with an aqueous solution of NaOH 1 .. The combined aqueous layers were acidified to pH-1 'with an aqueous solution of HG 1 and wer extracted with EtOAc. The combined organic layers were washed with brine and dried over ¾>SQ . Filtration and removal of the solven in. vacuo provided 1.10 g (99%) of the title compound as a colorless solid which was used without further purification; ¾H NMR (400 MHz, CDC ) δ - 7.44 - 7.37 (m, 1 H), 7.31 - 7.27 (m, 1 H), 7.1 - 7,07 (m, 1 H},
Synthesis of 1-({3-(trifiuorornethvi)phenvi)¾ulfonvQindoiiri-6-vi 2-chloro-8-fjuQrobenzoate
(SR19404):
To the solution of 1-{{3-(trifluoromethy!)phenyi)suifony!)indolin~6-ol (20 mg, 0.08 mmol) in 1 mL D E were added EDCI (61 mg, 0.29 mmol), 2-chlorq-6-fluorobenzo!G acid (51 mg, 0.29 mmol) and DMAP (36 mg, 0.29 mmol).. The reaction was stirred at 60 °C overnight. The completion of the reaction was monitored'. y HPLC. Upon completion, the solvent was removed In vacuo. The crude product was purified by preparative HPLC (20-100% CH3CN/MeOH (1 :1) in H20 (0.01 % TFA)] which provided after lyophiilzation 25 mg (86%) of the title compound as a colorless solid; 1H NMR {400 MHz, CDCb) δ ~ 8.13 (s, 1 H), 8.04 (d, J = 7.9 Hz, 1 H), 7.84 (d, J ~ 1.7 Hz, 1 H), 7.69 - 7.62 (m, 1 H), 7,58 (d, J ~ 2.0 Hz, 1 H), 7.44 (dt, J = 5.9, 8.2 Hz., 1 H), 7.32 (tti, J = 0.9, 8,3 Hz, 1 H), 7.16 (dt, J = 0.9, 8.7 Hz, 2 H), 6.92 (dd, J - 2.2, 8,1 Hz, 1 H), 4.01 (t, J * 8.4 Hz, 2 H), 2.97 :(t, J - 8,4 Hz, 2 H)„
G e n era I ; S y n thetic Pat hwav 7:
Figure imgf000050_0001
i) NaBHaC , AcOH, r.t; ft) 3-CF3PhS02CI, EfeN, DGM, r.t; iii) NH2BOC, Cs2CG3, Pd(OAc)2l Xantphos, tiioxane, 90 °C, then TFA/DCM, r.t; iv) .a: 2-chloro-6-f]uorobenzoic acid, EfeN, HATU, CHaCN, 60 °C, b: NaH, Mel D F, 0 °C to r.t; v) a: 2-chloro-6~fluorobenza^ehyde> NaBH(OAc)3, .AcOH, DCE, r.t, b: RGOH, NaBHsCN, AGDH, CH3CN, r.t.
Synthetic, Example 37: 2~chloro^6-fiuQro~N~(1~((3-(trifiu^
■vDbenzamide (SR19355):
Figure imgf000051_0001
TThhee ttiittllee ccoommppoouunndd wwaass pprreeppaarreedd aaccccoorrddiinngg ttoo GGeenneerraall PPrroocceedduurree GG ffrroomm 66--bbrroommooiinnddoollee ((220000 mmgg,, 11 ..0022 mmmmooii)).. TThhee eexxttrraaccttiioonn pprroovviiddeedd 220000 mmgg ((9999%%)) ooff tthhee ttiittllee ccoommppoouunndd aass aa ccoolloorrlleessss ooiill wwhhiicchh wwaass uusseedd wwiitthhoouutt ffuurrtthheerr ppuurriiffiiccaattiioonn;; ΉΉ NNMMRR ((440000 MMHHzz,, CCDDCCbb)) 55 ~~ 77..0033 -- 66,,9977 ((mm,, 11 HH)),, 66..9955 -- 66..8888 ((mm,, 22 HH)),, 33..6644 ((tt,, JJ -- 88,,33 HHzz,, 22 H H)),, 33,,0033 ((ii,, JJ == 88..33 HHzz,, 22 HH))..
Figure imgf000051_0002
The title compound was prepared according to Genera! Procedure H from 6-bromoindoiine (200 mg, 1.01 mmof) and 3-(trif!uorom«thy!}benzenesu!fonyi chloride (243 L, 1.52 mmpj). The crude product was purified by . Com bif lash silica gel chromatography (0-30% of EtOAc in hexane), which provided 380 mg (93%) of the title compound as a colorless solid; H NMR (400 MHz, CDCb) $ = 8.11 (s, 1 H), 8.00 (d„ J - 8.3 Hz, 1 H), 7.87 (d, J - 8.8 Hz, 1 H), 7.82 (s, 1 H), 7.70 - 7.64 (m, 1 H), 7, 16 (d, J~ 9.9 Hz, 1 H), 6.97 (s, 1 .H), 3.97 (t, J - 8.4 Hz, 2 H), 2.91. (t, J - 8.4 Hz, 2 H).
3-(trifiuoromethy[)phenyl)suifonyi)indofin-6-arnine:
Figure imgf000051_0003
tn a dried IvlW flask under Ar were introduced 6-bromo-1-((3-
(tnf!uorometh:yl)phenyi)suifonyr)indo!ine (420 mg, 1 .03 mmoi), CS2CG3 (1.01 g, 3.10 mmoi), 1- butyl carbamate (240 mg, 2.0 mmoi) and 10 mi of anhydrous dioxane. The flask was purged three times with Ar before the addition of Pd(OAc)a (12 mg, 0.05 mmoi) and Xantphos (60 mg, 0.10 mmoi). The flask was sealed and the reaction mixture was stirred overnight at 90 °C After removal of the solvent in vacuo, the crude product was purified by Combifiash silica gel chromatography (0-20% of EtOAc in hexane) to afford tert-but l (1-((3- (trifluoromethy!)pheny!)sulfonyl)indoiin-6~yi)carbamate as a yellow solid; *H NMR (400 MHz, CDCIs) δ = 8.13 (s, 1 H), 8,02 (d, J - 7,8 Hz, 1 H), 7.82 (d, J = 8, 1 Hz, 1 H), 7.65 - 7,57 (m, 2 H), 7.10 (d, J ~ 9.1 Hz, 1 H), 7.0Θ (d, J = 8.3 Hz, 1 H), 6.56 (s, 1 H), 3.9 (t, J - 8.3 Hz, 2 H), 2.87 (t, J ~ 8.3 Hz, 2 H). To the solution of the previously obtained solid in 10 ml. DC was added 5 mi TFA. The completion of the reaction was monitored fay HPLC. Upon completion, the solvent was removed in vacuo, which provided 400 rrsg (85% yield over 2 steps) of the title compound as a ye!!ow solid as the TFA salt.
Synthesis of 2-Ghioro^-fluo^
{S i 55};
To the soiution of 2-ch!oro-6-fluorobef z<3ic acid (52 mg, 0.30 mmol) in 3 mL CH3CN were added E¾N (110 L, 0.79 mmol), HATU (105 mg, 0.2.8 mmol). The reaction was stirred 10 mi at room temperature before the addition of 1-((3-(trifSuoromethyl)pheny!)sulfonyt)indoJi''n-6-amine (90 mg, 0.20 mmol). The reaction was stirred at 60 °C overnight. The completion of the reaction was monitored by HPLC. Upon completion, the solvent was removed in vacuo. The crude product was purified by preparative HPLC (20-100% CH3CN/ eOH (1 :1) in H2O (0.01 % TFA)) which provided after lyophiiizaiion 50 mg (51%) of the title compound as a colorless solid; 1H NMR (400 MHz, CDCI3) δ * 8.13 (s, 1 H), 8.08 (d, J - 7.8 Hz, 1 H), 7,84 (&, J = 7.8 Hz, 1 H), 7.75 (d, J * 1 .8 Hz, 1 H)( 7.68 - 7.62 (m, 1 H), 7.57 ($ 1 H), 7.51 (dd, J - 2,0, 8.1 Hz, 1 H), 7.39 (dt, J - 5.9, 8.3 Hz, 1 H), 7.31 - 7.27 (m, 1 H), 7.14 - 7.10 (m, 2 H), 3,97 (t, J= 8.3 Hz, 2 H), 2.95 (f, J = 8.3 Hz, 2 H). MS (ES!+) m/z: 499.10 i'M+H"]
Figure imgf000052_0001
To the solution of 2-chloro-6-f!uoro-N-(1-((3-(trifiuoromethyl)phenyl)sulforsyl)indoiin-6- yl)benzamide (10 rng, 0.02 mmol) in 0.2 mL anhydrous DMF at 0 was added aH 80%wt in oil (2 mg, 0.06 mmol). The reaction was stirred .30 min at 0 °C before the addition of methyl iodide (5 L, 0.08 mmol). The reaction was stirred at room temperature for 1 h. The completion of the reaction was monitored by HPLC. Upon completion, H2O was added and the reaction mixture was extracted with EtOAc. The combined organic layers were washed with brine and dried over Na?SG4. Filtration and removal of the solvent in vacuo provided the crude product, which was purified by preparative HPLC (20-100% CHsCN/MeOH (1 :1) in H20 (0.01% TFA)) to afford after Syoph lization 8 mg (78%) of the title compound as a colorless solid; H NMR (400 MHz, CDCI3) δ = 7.95 (s, 1 H), 7.78 (d, J =■ 7.9 Hz, 1 H), 7.74 (d, J = 7.9 Hz, 1 H), 7.56 - 7.50 (m, 1 H), 7.46 (d, J ~ 1.8 Hz, 1 H), 7.05 (dt, J - 5.9, 8.2 Hz, 1 H), 7.00 - 6.96 (m, 1 H). 6.85 (d, J
SO = 7.9 Hz, 1 H), 6.82 - 6,78 (m, 1 H), 6.74 (dt, J = 1.1 , 8.3 Hz, 1 H), 3.83 (t, J = -8.4 Hz, 2 H), 3.43 (s, 3 H), 2.74 (t, J - 8,4 Hz, 2 H). MS (Ε8Γ) m/z: 5 3,13 [ +H+]
Synthetic Example 39: -(2-chloro--8 to
):
Figure imgf000053_0001
To the solution of 1-({3-{trifluoromethyi}phenyl)sulfony!)indolin-6-am!ne 100 mg, 0.29 mmo!) in 3 mL of DCE were added 2~chloro-6-fluorabenza;.dehyde (51 mg, 0.32 mmoi), AcOH (18μΙ, 0,32 mmoi) and NaBH(OAc)3 (93 mg, 0,44 mmo!). The reaction was stirred overnight at room temperature. The completion of the reaction was monitored by HPLC. Upon completion, 2O was added and the reaction mixture was extracted with EiQAc, The combined organic layers were washed with brine and dried over N92SO4. Filtration and removal of the solvent in vacuo provided the crude product, which was purified by preparative HPLC (20-100% CHsCN/ eOH (1 :1 ) in H2O (0.01 % IF A)) to afford after iyophiiization 90 mg (51 %) of the title compound as a colorless solid as the TFA salt; 1H N R {400 MHz, CDC¾) 5 " 8.08 (s, 1 H), 7,94 (d, J = 7.9 Hz, 1 H)( 7,80 (d, J = 7.9 Hz, 1 H), 7,60 ·· 7.53 (tn, 1 H), 7.26 - 7.18 (m, 2 H), 7.11 (d. J * 2.2 Hz, 1 H), 7.07 - 6.98 (m, 1 H), 6.89 (d, J - 8,1 Hz, 1 H), 6.43 (dd, J ~ 2.2, 8.1 Hz, 1 H), 4.53 (d, J - 1.5 Hz, 2 H), 3.91 (t. J - 8.3 Hz, 2 H), 2,77 (t, J = 8.3 Hz, 2 H). MS (EST) m/z: 484.81 [ +H*j
Synthetic Example .40;„ -(2-ch?oro-6-fluofQbenzyl)-N-met y|r1 -((3-
Figure imgf000053_0002
To the■.solution of N"(2-chloro»6-fiuoro enzy!)-1~((3"(trifluoromethy!)phenyi)sulfonyl)indoiin-6~ amine (20 mg, 0.03 mmoS) in 0.5 mL of CH3CN were added formaldehyde 37%wt in H¾0 (28 pL, 0.33 mmoi), AcOH (38uL, 0.66 mmoi) and NaBH3C'N (6 mg, 0.10 mmoi). The reaction was stirred at room temperature for l h. The completion of the reaction was monitored by HPLC. Upon completion, H?0 was added and the reaction mixture was extracted with EtOAc. The combined organic layers were washed with brine and dried over NazSC^. Filtration and removal of the soivent provided the crude product, which was purified by preparative HPLC (20- 00% CHaCN/M.eOH (1 :1 ) in H20 (0.01 % TFA)) to afford after iyophiiization 5 mg (73%) of the title compound as a colorless solid as the TFA salt; -H NMR (400 MHz, CDCI3) δ = 8,09 (s, 1 H), 7.97 (d, J * 7.7 Hz, 1 H), 7,82 (d, J ~ 7.7 Hz, 1 H), 7.65 - 7.56 (m, 1 H), 7.34 (d, J = 2.4 Hz, 1 H), 7.32 ·■ 7.21 (m, 2 H), 7,08. - 6.96 (m, 2 H), 6.68 (dd, J ~ 2.2, 8.3 Hz, 1 H), 4.65 (d, J = 1.5 Hz, 2 H), 3.96 (t, J = 8.3 Hz, 2 H), 2.93 (d, J - 0.9 Hz, 3 H), 2.84 (t, J = 8.3 Hz, 2 H). MS (Ε8 ) m/z: 499.09 [M+H+]
Synth else Exa m pie 41 : N-(2-chJo rp-6-f i uorp be nzy l)- -ethy i - i -{ ( 3- (trif luo rom ethy I )pheny i ) su If o n !) i ndo! in-6 -amine:
Figure imgf000054_0001
To the solution of N~(2 ;hloro-6-fluorobenzyi)~1-(^
amine (20 mg, 0.03 mmoi) in 0.5 ml of Cf-feCN were added acetajdehyde (19 μΐ, 0.33 mmol), AcOH (38μΙ., 0.66 mmol) and NaBHjCN (6 mg, 0,10 mmol}. The reaction was stirred at room temperature for 1 h. The compleiion of the reaction was monitored by HPLC. Upon compietion, H2O was added and the reaction mixture was extracted with EtOAc. The combined organic layers were washed with brine and dried over aiSO*. Filtration and removal of the solvent provided the crude product, which was purified by preparative HPLC (20-100% CH3CN/MeOH (1 :1 ) in H20 (0.01 % TFA}} to afford after iyophilizafion 8 mg (38%) of the title compound as a colorless solid as the TFA salt; 1H NMR (400 MHz, CDC ) δ = 8.06 (s, 1 H), 7.98 (d, J = .8.1 Hz, 1 H), 7.83 (d, J - 7.7 Hz, 1 H), 7.64 - 7.58 (m, 1 H), 7.32 (d, J ~ 2.2 Hz, 1 H), 7.30 - 7.21 (m, 2 H), 7.07 - 7.03 (m, 1 H), 7.03 - 6.98 (m, 1 H), 6.7 (d, J * 7.2 Hz, 1 H), 4.67 (d, J - 1.5 Hz, 2 H), 3.97 (t, J = 8.3 Hz, 2 H), 3.46 (q, J - 6.9 Hz, 2 H), 2.86 (t, J - 8.3 Hz, 3 H), 1.12 (t, J ~ 6.9 Hz, 3 H>. MS (EST) m/z; 513.13 [ +H"J
General Synthetic Pathway 8:
Figure imgf000054_0002
I) UGH 1 M, THF, 40°C; ii) 2-chloro-6-fiuoroph.enol, EDCI, OMAR, DCE, 60 °C; fit) a; oxalyi chloride, D F, THF, 0eC-r.t, then 2-chloro-6-fl.UGroanllihe, THF, 55 °C, b: NaH, Mel, DMF, 0 °C to r.t.
Synthetic Example 42: 2-chloro-6-fluorophe yl 1-((3- triftugrorr^
carboxyjate (SRl 9380):
Figure imgf000055_0001
To the solution of methyl 1-((3-{trif!u0rornethyi)pbe^ ( 100 mg,
0.28 mmol) in 3 ml of THF was added 3 mL of an aqueous solution of LiOH 1 . The reaction was stirred overnight at 4Q °C. The completion of the reaction was monitored by HPLC. Upon completion, the reaction mixture was acidified with HCi 1 until pH~1 and extracted with EtOAc. The combined organic layers were washed with brine and dried over Na2S0 . Filtration and removal of the solvent provided 90 mg (93%) of the title compound, which was used without further purification; 1H NMR (400 MHz, CDCb) 5 * 8.32 (s, 1 H), 8.1-3 (s, 1 H), 8.04 (d, J = 7.9 Hz, 1 H), 7.85 (d, J = 7.9 Hz, 1 H), 7.80 (dd, J - 1.4, 7.8 Hz, 1 H), 7.68 - 7.61 (m, 1 H), 7.22 (d, J 7.9 Hz, 1 H)„ 4.03 (t, J ~ 8.4 Hz, 2 H), 3.04 (t, J = 8.4 Hz, 3 H).
To the solution of 1-({3^irrfluoromethyl)phenyl)suifonyl)indoline-6-carboxyHc acid (20 mg, 0.05 mmoi) in 0,4 ml of DCE were added EDCI (15 mg, 0.08 mmoi), 2~chloro-6-fiuorophe.noi (39 mg, 0.27 mmol) and DMAP (7 mg, 0,05 mmol). The reaction was stirred overnight at 60 °C. The completion of the reaction was monitored by HPLC, Upon completion, the solvent was removed in vacuo. The crude product was purified by preparative HPLC (20-100% CHaCN/MeOH (1 :1 ) in H2O (0.01% TFA)) which provided after lyophiiization 18 mg (67%) of the title compound as a colorless solid; 1H NMR (400 MHz, CDCb) δ ~ 8.45 (s, 1 H), 8.15 (s, 1 H), 8.07 (d, J ~ 7.8 Hz, 1 H), 7.91 (d, J = 7.8 Hz, 1 H), 7.86 (d, J = 7,8 Hz, 1 H), 7.69 - 7.62 (m, 1 H), 7.34 - 7.13 (m, 4 H), 4.05 (t, J = 8.5 Hz, 2 H), 3.08 (t, J ~ 8.5 Hz, 2 H).
Figure imgf000055_0002
To the solution of H(3-(trifiuoFomethyl phenyf)sulfonyl)indolirte-6-carboxyiic acid (50 mg, 0.13 mmol): in 1 mi of anhydrous THF at 0 °C were added oxa!yl chloride (23 pL, 0.27 mmol) and a drop of DMF. The reaction was stirred at room temperature for l b. The completion of the reaction was monitored by HPLC, Upon completion, the solvent was removed in vacuo. To the crude residue was added 1 mL of anhydrous THF and 2~chloro-6-fiuoroaniline (78 mg, 0.54 mmol). The reaction was stirred at 55 °C for 2h. The completion of the reaction was monitored by HPLC. Upon completion, the solvent was removed in vacuo. The crude product was purified by preparative HPLC (20-100% CH3CN/MeOH (1 :1 ) in H20 (0.01% TFA)) which provided after lyophilization 40 mg (60%) of the title compound as a colorless -solid; 1H NMR (400 MHz, CDCi3) 6 - 8 14 (d, J = 1.3 Hz, 1 H), 8.12 (s, 1 H), 8.02 {d, J - 7.8 Hz, 1 H), 7.85 (d, J ~ 7.1 Hz, 1 H), 7.67 - 7.61 (m, 2 H), 7.59 (s, 1 H), 7.32 - 7,21 (m, 3 H), 7.18 - 7.10 (m, 1 H), 4.02 (1, J - 8,5 Hz, 2 H), 3.03 (1, J = 8.5 Hz, 2 H). MS (Ε5Γ) m/z; 499,02 [M+H+]
Synthetic Example 44: N-i2-chioro-6-fluorophenyi)--N-niethyl-1-((3-
Figure imgf000056_0001
To the solution of N^2~chloro-6 iuorophenyl)-1-((3-(trifiuorom:ethyl)phenyl)su fony[)indo[ine-6- carboxamide (15 mg, 0 03 mmol) in 0,3 ml of anhydrous DMF at 0 °C was added NaH 60%wt i oil (4 mg, 0.09 mmol). The reaction was stirred 30 min at 0 °C before the addition of methyl iodide (8 pL, 0.12 mmol). The reaction was stirred at room temperature for 1h. The completion of the reaction was monitored by HPLC. Upon completion, HzO was added and the reaction mixture was extracted with EtOAc. The combined organic layers were washed with brine and dried over a2SQ4. Filtration and removal of the solvent in vacuo provided the crude product, which was purified by preparative HPLC (20-100% CH3CN/MeOH (1 :1 ) in H2G (0,01% TFA)) to afford after iyophilization 14 mg (91 %) of the title compound as a colorless solid; H NMR (400 MHz, CDCb) δ - 7.98 (s, 1 H), 7.82 (d, J - 7.8 Hz, 1 H), 7.78 (d, J ~ 8.1 Hz, 1 H), 7,61 (s, 1 H), 7.60 - 7.54 (m, H), 7.22 - 7.15 (m, 2 H), 7.13 (dd. J* 1.4, 7.7 Hz, 1 H), 7.0 - 6,96 (m, 1 H), 6,95 (d. J ~ 7,8 Hz, 1 H), 3.86 (t, J 8.6 Hz, 2 H 2 H), 3.38 (s, 3 H), 2.80 (t, J = 8.6 Hz, 2 H). MS (ESP) m/z: 513.15 [M+H1
(SRI 9262):
Figure imgf000056_0002
Figure imgf000057_0001
The title compound was prepared according to General Procedure G from 6-((2-chioro~6- fluorobenzyi.)oxy)-1 H-indole (200 mg, 0.72 mmol). The extraction provided 200 mg (100%) of the title compound as a coloriess solid which was used without further purification; H NMR (400 MHz, CDC ) δ = 7.33 - 7.17 (m, 3 B), 7,08 - 7,00 (m, 2 H), 6.37 (dd, J » 2.2, 8.3 Hz, 1 H), 5.12 (d, J = 2.0 Hz, 2 H), 3.56 (t J ~ 8.3 Hz, 2 H), 2.98 (t, J ~ 8,3 Hz, 2 H).
Figure imgf000057_0002
The title compound was prepared according to General Procedure H from 6-({2-chloro.~6~ ftuorobenzyf)oxy)indoiine (20 mg, 0.0.7 mmoi) and benzenesulfonyl chloride (14 μΐ, 0.11 mmol). The crude product was purified by preparative HPLC (20-100% CH3CN/MeOH (1 :1 ) in H20
(0.01% TFA)) which provided after iyophiiizaiion 20 mg (66%) of the title compound as a colorless solid; 1H NMR (400 Hz, CDCb) δ 7.86■· 7.79 (m, 2 H), 7.60 - 7.54 (m, 1 H), 7.49 - 7.43 (m, 2 H), 7.39 (d, J~ 2.4 Hz, 1 H), 7.35 - 7.25 (m, 2 H), 7.10 - 7.06 (m, 1 H), 6.99 - 6.96 (m, 1 H), 6.64 (dd, J ~ 2.4, 8.1 Hz, 1 H), 5,20 (d, J - 1.8 Hz, 2 H), 3.94 (t, J = 8.4 Hz, 2 H), 2.83 (t, J - 8.4 Hz, 2 H),
Synthetic Example 46: 6-((2-chloro-6-fluorobenzy1)ox )- --((2-chlorophenyl^
Figure imgf000057_0003
The title compound was prepared according to General Procedure H from 6-((2-chloro-6- fluorobenzyl)oxy)indoline (20 mg, 0.07 mmol) and 2-chlorobenzenesulfonyl chloride (15 pi, 0.11 mmol). The crude product was purified by preparative HPLC (20-100% CHaGN/MeOH (1 : 1) in H2O (0.01 TFA)) which provided after Iyophiiizaiion 18 mg (55%) of the title compound as a colorless solid; H NMR (400 MHz, CDCb) δ - 8.21 - 8.10 (m, 1 H), 7.52 - 7.45 (m, 2 H), 7,44 - 7,37 (m, 1 H), 7,33 - 7.23 (m, 2 H), 7.07 - 7,01 (m:, 2 H), 6.97 (d, J = 2.4 Hz, 1 H), 6.60 (dd, J - 2,3, 8.2 Hz, 1 H), 5.Q9 (d, J= 2.0 Hz, 2 H), 4.28 (t, J « 8.2 Hz, 2 H), 3.06 (t, J ~ 8.2 Hz, 2 H).
Synthetic Example 47: 6-{{2-chloro- ^
Figure imgf000057_0004
The title compound was prepared according to General Procedure H from 6- (2~chloro-6- fluorobenzyi)oxy)indoline (20 mg, 0.07 mmol) and 4~fiuorobenzenesoifonyS chloride (21 mg, 0.1 1 mmol). The crude product was purified by preparative HPLC (20-100% CHsCN/MeOH (1 :1 ) in HaO (0.01 % TFA)) which provided after lyophjlization 19 mg (61 %) of the title compound as a colorless solid; 1H NMR (400 MHz, CDC ) δ -= 7.78 - 7.70 (m, 2 H), 7.30 - 7.20 (m, 3 H), 7.09 - 6.94 (m, 3 H), 6,92 (d, J = 8.3 Hz, 1 H), 6,58 (dd, J = 2.3, 8.2 Hz, 1 H), 5,12 (d, J = 2,0 Hz, 2 H), 3.85 (t, J = 8.3 Hz, 2 H), 2.77 (t, J = 8.3 Hz, 2 H).
Synthetic Example„48„ i2-chjorQ-6rfl (S .9258):
Figure imgf000058_0001
The title compound was prepared according to Genera! Procedure H from 6-({2-chlorQ-6- fluorob:enzyS)oxy)indoline (20 mg, 0.07-mmol) and m-toluenesulfonyl chloride (16 pL, 0.11 mmoi). The crude product was purified by preparative HPLC {20-100% CH3CN/MeOH (1 : 1 ) in H2O (0,01 % TFA)) which provided after iyoph.iiization 16 mg (51%) of the title compound as a colorless solid; Ή MR (400 MHz, CDC!?,) δ = 7.65 (s, 1 H), 7.61 (d, J « 7.8 Hz, 1 H), 7.39 (d, J = 2.5 Hz, 1 H), 7.37 - 7.26 (m, 4 H), 7.10 - 7.05 (m, 1 H), 6.98 (d, J - 8.1 Hz, 1 H), 6,63 (dd, J ~ 2,4, 8.2 Hz, 1 H), 5,20 .{d, J = 1.8 Hz, 2 H), 3,95 (i, J = 8.5 Hz, 2 H), 2.91 - 2.81 (m, 2 Hj, 2.38 (s, 3 H).
Synthetic Example 49: 6-((2-chioro~6 iuorabenzyl)oxy)~t-^
Figure imgf000058_0002
The title compound was prepared according to. General Procedure H from 6-((2-chloro-6- fluorober¾zyi}oxy)indoline (20 mg, 0.07 mmol) and 3-methoxybenzenesulfonyl chloride (15 ,μΐ, 0.1 1 mmoi). The crude product was purified by preparative HPLC (20-100% CH3CN/ eOH (1 :1 ) in H2O (0.01 % TFA)) which, provided after lyophi!szation 17 mg (53%) of the title compound as a colorless solid; 1H NMR (400 MHz, CDCb) δ - 7.42 - 7,38 (m, 2 H), 7.37 (d, J - 8, 1 Hz, 1 H), 7,32 (dd, J = 2.3, 8.2 Hz, 1 H), 7.30 - 7.27 (m, 2 H), 7.10 ~ 7.08 (m, 1 H), 7.08 - 7.06 (m, 1 H), 6.99 (d.« J = 8.1 Hz, 1 H), 6.65 (dd, J ~ 2,4, 8, 1 Hz, 1 H), 5.19 (d, J - 2,0 Hz, 2 H), 3.94 (dd, J - 8.0, 8.9 Hz, 2 H), 3.75 (s, 3 H), 2.84 (t, J = 8.4 Hz, 2 H).
Synthetic Example 50: 6~((2>chloro-6"fluorDbenz
(SR 19346):
Figure imgf000059_0001
The title compound was prepared according to Genera! Procedure H from 6~((2~chloro~6- fluorobenzyi)oxy)indoline (25 mg, 0.09 mmol) and 3-chlorobenzenesuffGny! chloride (19 μΐ, 0.13 mmol). The crude product was purified by preparative HPLC (20-100% CH3CN/ eOH (1 :1 ) n HzO (0.01 % TFA}) which provided after tyophilization 35 mg (88%) of the title compound as a colorless solid; 1H NMR (400 MHz, C.DCia) δ = 7.83 (t, J = 1.9 Hz, 1 H), 7.70 - 7.67 (m, 1 H), 7.56 - 7.52 (m, 1 H), 7.40 (t, J ~ 7.9 Hz, 1 H), 7.37 - 7.35 {m, 1 H), 7,34 - 7.26 (m, 2 H), 7,07 (dt, J ~ 1.5, 8.6 Hz, 1 H), 7.Q1 (d, J = 8, 1 Hz, 1 H), 6.66 (dd, J ~ 2.4, 8.1 Hz, 1 H), 5.21 (d, J - 2.0 Hz, 2 H), 3.96 (t, J = 8.4 Hz, 2 H), 2,88 (t, J - 8.3 Hz, 2 H).
Syn fo^cjSx^^^
Figure imgf000059_0002
Synthesis of 3-brpmo-lJ.'-bjphen^
Figure imgf000059_0003
in a dried MW flask under Ar were introduced 1-iodo-3-bromobenzene (451 μ[_, 3.54 mmol), NazCOs (749 mg, 7.07 mmo ), pheny!boronic acid (388 mg, 3.18 mmol), 1:5 ml of toluene, 3 mi of EtQH and 3 ml of HsO. The flask was purged three times with Ar before the addition of
Pd(PPh3)4 (204 mg, 0.18 mmol). The flask was sealed and the reaction mixture was stirred at 90 °C for 2h. After removal of the solvent in vacuo, the crude product was purified by Com b'if lash silica gel chromatography (0-10% of EtOAc in hexane).,. which provided 402 mg (54%) of the title compound as a colorless oil; H NMR (400 MHz, CDC ) .5 = 7.76 - 7.74 (m, 1 H), 7.59 - 7,56 (m, 2 H), 7.55 - 7.51 (m, 1 H), 7.50 - 7.44 (m, 3 H), 7.41 - 7.36 (tn, 1 Ή), 7.35 - 7,29 (m, 1 H),
Figure imgf000059_0004
The titl compound was prepared according to Genera! Procedure 1 from 3-bromo-1 ,1 '-bipheny! (390 mg, 1 .67 mmol). The crude product was purified by Comhif!ash silica gel chromatography (0-40% of EtOAc in hexane), which provided 450 mg (97%) of the title compound as a yellow oil; Ή NMR (400 MHz, CDCb) δ - 7.54 - 7.50 (m, 3 H), 7.47 - 7.40 (m, 3 H), 7.38 - 7.27 (m, 8 H), 4.18 (8, 2 H).
Figure imgf000060_0001
The title compound was prepared according to General Procedure J from [1 ,1'-biphenyi]-3- yl(benzyl)s.ulfane (450 mg, 1.63 mmoS). The crude product was purified by Gombiflash silica gel chromatography ( 00% hexane), which provided 250 mg (5.9%) of the title compound as a. colorless solid; *H NMR (400 MHz, CDCb) δ = 8.28 - 8,24 (m, 1 H), 8.05 - 8.01 (m, 1 H), 7,98 - 7.95 (m, H), 7.74 - 7.68 (m, 1 H), 7.66 - 7.61 (m, 2 H), 7,56 - 7.49 (m, 2 H), 7.49 - 7.43 {m, 1 H).
Synthesis of 1 -([1 , 1 ' ^henyn-3-yisuifonyl)-6-C(2-chio^ (SR19347);
The title compound was prepared according to Genera! Procedure H from 6-((2-chloro-6- fluorobenzyl )oxy)indoline (25 mg, 0.09 mmoi) and [1 , 1'-biphenyl]-3-sulfonyi chloride (34 mg, 0.13 mmo ). The crude product was purified by preparative HPLC (20-100% CH3CN/MeOH (1 :1 ) in H2O (0.01% TF.A)) which provided after lyophilization 28 mg (63%) of the title. compound as a colorless solid; 1H NMR (400 MHz, CDCb) 5 ~ 8.03 {t, J = 1.8 Hz, 1 H), 7.82 ~ 7.74 (m, 2 H), 7.58 - 7.36 (m, 7 H), 7.36 - 7.22 (m, 2 H), 7.11 - 7.03 (m, 1 H), 7.00 (d, J - A Hz, 1 H), 8.66 (dd, J ~ 2.4, 8.3 Hz, 1 H), 5.21 (d, J = 1.8 Hz, 2 H), 3.99 (t, J - 8.3 Hz, 2 H), 2.85 (t, J => 8.3 Hz, 2 H).
Synthetic .Example.52: 6-((2-ch{oro-6-fiuorobenzyi)oxy)-1-((3 5 ilehiorophenyi)su}foriyI)mdQline
Figure imgf000060_0002
The title compound was prepared according to General Procedure H from 8-({2~chioro-6- f1uorobenzyJ)oxy)indoline (20 mg, 0.07 mmoi) and 3,.5-dichtorobenzenesuifonyl chloride (27 mg, 0.1 1 mmol). The crude product was purified by preparative HPLC (20-100% CHaC /Me.OH (1:1 ) in HsO (0.01 % TFA)) which provided after lypphiiization 14 mg (40%) of the title compound as a coioriess solid; H NMR (400 MHz, CDCb) δ = 7.70 (d, J = 1.8 Hz, 2 H), 7.54 (t, J ~ 1.9 Hz, 1 Ή), 7.36 - 7.27 (m, 3 H), 7.11 - 7.02 (m. 2 H), 6.69 (dd, J ~ 2.4, 8.3 Hz, 1 H), 5.21 (d, J = 2.0 Hz, 2 H), 3.98 (t, J * 8.3 Hz, 2 H), 2.93 (t, J « 8.4 Hz, 2 .H).
Synthetic Example 53: 6-((2-chloro-6-^
yl)sulfonyl)indoiine (SR19344):
Figure imgf000061_0001
Synthesis of 2-(benzylthto)-6-<trifl,uofpmet yi)pyndine
Figure imgf000061_0002
TThhee ttiittllee ccoommppoouunndd wwaass pprreeppaarreedd aaccccoorrddiinngg ttoo G Geenneerraa!l PPrroocceedduurree I I ffrroomm 22--cchhlloorroo--66-- ((ttririffliuuoorroommeetthhyyll))ppyyrrsiddsinnee ((330000 mmgg,, 11 ,,6655..mmmmooii)).. TThhee ccrruuddee pprroodduucctt wwaass ppuurriiffiieedd bbyy C Coommbbiiffllaasshh ssiilliiccaa ggeell cchhrroommaattooggrraapphhyy ((00--4400%% ooff EEttOOAAcc iinn h heexxaannee)),, wwhhiicchh pprroovviiddeedd 441100 mmgg ((9922%%)) ooff tthhee ttiittllee ccoommppoouunndd aass aa.. oorraannggee o oiill;; HH--ii NNMMRR ((440000 MMHHzz,, CCDDCCib3)) δδ ==77..6633 -- 77..5588 ((mm,, 11 H H)),, 77..4477■■ 77..4433 ((mm,, 22 HH)),, 77..3366 -- 77..2288 {{mm,, 44 HH)),, 77..2266 -- 77..2211 ((mm,, 11 HH)),, 44..4466 ((ss,, ..22 HH))..
Figure imgf000061_0003
The title compound was prepared according to General Procedure J from 2-{benzy!thio)-6- (tnfiuoromeihyl)pyridine (410 mg, 1.52 mmoi), The crude product was purified by Combiflash silica gel chromatography (0- 0% EtOAc in hexane), which provided 210 mg (56%) of the title compound as a colorless solid; 1H NMR (400 MHz, CDCb) δ - 8.34 - 8.26 (m, 3 H), 8.08 - 8.05 (m, 1 H).
Synthesis of 6-C(2-chloro-6 ]uorobenzyi)oxy)-H(6-(^
(SR19344):
The title compound was prepared according to General Procedure H from 6-((2-ch!oro-6- fiuoroben2yl)ox.y)indoline (25 mg, 0.09 mmoi) and 6~(trif!uororaethyl)pyridine-2-sulfonyl chioride (23 mg, 0.13 mmoi). The crude product was purified by preparative HPLC (20-100%
CH3CN/iVteGH (1 :1 ) in H?0 (0.01 % TFA)) which provided after !yophilization 32 mg (59%) of the title compound as. a colorless solid as the TFA salt; 1H NMR (400 MHz, CDCI3) δ - 8. 7 (d, J - 7.9 Hz, 1 H), 8,11 - 8.01 (m, 1 Ή), 7.80 (dd, J = 1.0, 7.8 Hz, 1 H), 7.34 - 7.22 (m, 2 H), 7, 15 (d, J ~ 2.2 Hz, 1 H), 7.07 - 6.99 (m, 2 H), 6.61 (dd, J ~ 2.4, 8.1 Hz, 1 H), 5,1 1 (d, J · 2.0 Hz, 2 H), 4.45 (1, J ~ 8.3 Hz, 2 H), 3.08 (t, J ~ 8.3 Hz, 2 H), MS (Ε8 ) m z: 486.68 [M+H+]
Figure imgf000061_0004
Figure imgf000062_0001
The title compound was prepared according to General Procedure I from 4~ebloro-2- (trifiuoromethyi)pyndine (150 mg, 0.82 mmo!). The crude product was purified by Combiflash silica gel chromatography (0-40% of EtGAc in hexane), which provided 130 mg (58%) of the title compound as a colorless oil; H NMR (400 MHz, CDC!s) δ - 8,48 (d, J ~ 5.3 Hz, 1 H), 7,51 (s, 1 H), 7.44 - 7.28 (m, 6 H), 4.28 (s, 2 H).
Figure imgf000062_0002
q, ^a
■I j o
The title compound was prepared according to General Procedure J from 4~( benzyl thio)~2~ (tnf!uoromethy!)pyridine (130 mg, 0,48 mmoi). The crude product was purified by Combiflash silica gel chromatography (0-10% of EfOAc in hexane), which provided 40 mg (34%) of the title compound as a colorless oil; Ή HMR (400 MHz, CDCfe) 5 = 9.14 (d, J - 5.1 Hz. 1 H). 8.25 (dd, J = 0,5, 1.8 Hz, 1 H), 8.20 - 8.03 (m, 1 H),
Synthesis of.e^(2^hioro^6. luoroben^
(SR19349):
The title compound was prepared according to General Procedure H from 6-((2-chloro-6- fiuorobenzyl)oxy)indoline (25 mg, 0.09 mmoi) and 2-(frifiuoromethyi)pyridine-4-sulfonyl chloride (27 mg, 0.1 1 rnmol). The crude product was purified by preparative HPLC (20-100%
CHsCN/MeOH (1 : 1 ) in H20 (0,01 % TFA)) which provided after lyophiKzation 25 mg (46%) of the title compound as a colorless solid as the TFA salt; 1H NMR (400 MHz, CDC¾) 6 = 8.82 (d, J - 4,8 Hz, 1 H), 7.95 (s. 1 H). 7.79 - 7.70 (m, 1 H), 7.29 - 7.21 (m, 3 H), 7.04 - 6.92 (m, 2 H), 6.64 (dd, J - 2.3, 8.2 Hz, 1 H), 5.1.3 (d, ~ 2.0 Hz, 2 H), 3,92 (t, J - 8.3 Hz, 2 H), 2,84 (t, J - 8.3 Hz, 2 H). MS (ESn m/z; 486.66 [ +'H*]
Figure imgf000062_0003
TThhee ttiittllee ccoommppoouunndd wwaass pprreeppaarreedd aaccccoorrddiinngg ttoo GGeenneerraall PPrroocceedduurree II ffrroomm 33--bbrroommoo----55-- ((ttrriifflluuoorroommeetthhyyii))ppyyrriiddiinnee ((11.0000 gg,, 44.,4422 'mmmmooll)).. TThhee ccrruuddee pprroodduucctt wwaass ppuurriiffiieedd bbyy CCoommbbiiffllaasshh ssiilliiccaa .g geell. cchhrroommaattooggrraapphh ((00--5500%% ooff EEttOOAAcc iinn hheexxaannee)),, wwhhiicchh pprroovviiddeedd ,, 1155 gg ((9977%%)) ooff tthhee ttiittllee ccoommppoouunndd aass aa yyeellllooww ooiill;; 11HH N NMMRR ((440000 MMHHzz,, CCDDCCbb)) δδ ** 88..7733 -- 88,.6655- ( (mm,, 22 HH)),, 77,,7744 -- 77..7733 ((mm,, 11 HH)),, 77,,3377 -- 77..2244 ((mm,, 55 HH)),, 44..1188 ((ss,, 22 HH))..
SSyynntthheessiiss ooff 55--(.(Wtrifif{uugprrpomm^^
■ ■ IITT¾¾
TThhee ttiittllee ccoommppoouunndd wwaass pprreeppaarreedd aaccccoorrddiinngg ttoo GGeenneerraall PPrroocceedduurere JJ ffrroomm 33--((bbeennzzyylltthhiioo))--55-- ( (ttrriifflluuoorroommeetthhyyli))ppyyrriiddiinnee ((550000 mmgg,, 118866 mmmmooll)).. TThhee ccrruuddee pprroodduucctt wwaass ppuurriiffiieedd bbyy GGoommbbiiffiiaasshh ssiilliiccaa ggeell c chhrroommaatotoggrraapphhyy ((00--1100%% ooff EEiiOOAAee iinn hheexxaannee)),, wwhhiicchh pprroovviiddeedd 330000 mmgg ( (.6666%%)) ooff tthhee ttiittllee ccoommppoouunndd aass aa ccoolloorrlleessss ooiill;; ΉΉ NNMMRR ((440000 MMHHzz,, C CDDCCib3)) δδ == 99..44..55 ((dd,, JJ ~~ 22..22 HHzz,, 11 H H)),, 99..2244 ((dd,, JJ == 1133 HHzz,, 11 HH))., 88..5588 -- 88..5522 ((mm,, 11 HH)),,
SSyynntthheessiiss ooff 66--((((22--Gchhiioorrop~-66~-ffttouoroben^
((SSRR11 QQ226677))::
TThhee ttiittllee ccoommppoouunndd wwaass pprreeppaarreedd a accccoorrddiinngg ttoo GGeenneerraall PPrroocceedduurree HH ffrroomm 66~~((((22~~cchh!!oorroo~~66~~ ffiiuuoorroobbeennzzyyll))ooxxyy))iinnddoolliinnee ((2200 mmgg,, 00,,0077 mmmmooll)) aanndd 55--((ttrriiffiiuuoorroommeeiihhyyii))ppyyrriiddiinnee--33~~ssuullffoonnyyll cchhlloorriiddee.. ((2277 mmgg,, 00..1111 mmmmooll)).. TThhee ccrruuddee pprroodduucctt wwaass ppuurriiffiieedd bbyy pprreeppaarraattiivvee HHPPLLCC ( (2200--110000%%
CCHHssCC //MMeeOOHH ((11 :: 11 )) iinn HH2200 ((00..0011 %% TTFFAA)))) wwhhiicchh pprroovviiddeedd aafftteerr llyyoopphh''iiiiiizzaattiioorrii 1199 mmgg ((4444%%)) ooff tthhee t tiittllee ccoommppoouunndd aass aa c coolloorrlleessss ssoolliidd aass tthhee TTFFAA ssaalltt;; HH NNMMRR ((440000 MMHHzz,, CCDDCCbb)) δδ ~~ 99..1199 ((dd,, JJ ~~ 22..33 H Hzz,, 11 H H)),, 99..0055 ( (dd,, JJ ~~ 1100 HHzz,, 11 HH)),, 88..3377 -- 88..2299 ((mm(( 11 HH)),, 77..3388 -- 77..2255 ( (mm,, 33 HH)),, 77..1100 -- 77,,0055 ((mm,, 11 HH)),, 77..0033 ((dd,, JJ == 88..33 HHzz 11 HH)),, 66..7711 ( (dddd,, JJ == 22..33,, 88..33 HHzz,, 11 HH)),, 55,,2200 ((dd,, JJ == 22..00 HHzz,, 22 HH)),, 44..0011 ((tt,, JJ -- 88..33 HHzz,, 22 HH)),, 22..9900 ((ii,, JJ-- 88..55 HHzz,, 22 HH)).. MMSS ((EESSTI")) m m//zz:: 448866..7777 [ [MM++BB++]]
SSyynntthheettiicc EExxaammppllee 6666:: ooff 66--(((f22^-cchhlloo.rroo--66--fflluuoorroobbeennzzyyli)ooxxyy))--11--((((44--fo(trifluoromethyl)pyri
Figure imgf000063_0001
The title compound was prepared according to General Procedure I from 2-chloro-4- (triiluoromethyl)pyridine (213 pL, 1.65 mmol). The crude product was purified by Combiflash silica gel chromatography {0-40% of EtOAc in hexane), which provided 440 mg (99%) of the title compound as an orange oil; 1H NMR (400 MHz, CDC ) δ » 8.58 - 8,51 (m, 1 H), 7.35 ~ 7,32 (rn, 2 H), 7.29 (id, J 0.8, 1.5 Hz, 1 H), 7.26 - 7.21 (m, 2 H), 7,21 - 7.17 (m , 1 H), 7.12 - 7.10 (m, 1 H), 4.40 (s, 2 H).
Figure imgf000064_0001
The title compound was prepared according to General Procedure. J 'from 2-(benzyithio)-4~
(trifluoromethyl)pyndine (440 mg, 1.63 mmol). The crude product was purified by Cpmbifi.ash silica gel chromatography {0-30% of EtOAc in hexane), which provided 200 mg (50%) of the title compound as a colorless oil; >H NMR (400 MHz, CDG ) 5■= 9.05 (d, J ~ 4.8 Hz, 1 H), 8.33 (dd,
J - 0.7, 1.5 Hz, 1 H), 8.01 - 7.85 (m, 1 H).
Synthesis of 6-({2-ehloro-6-fluofobenzyi)oxy)-†-((4-(trtf^
(SRT9348):
The title compound was prepared according to General Procedure H from 6~((2~ehioro-6- fluorober yl)oxy)indo!ine (20 mg, 0.07 mmo!) and 4-(trifiuoromethyJ)pyridtne-2-sulfonyl chloride (21 mg, 0.09 mmol). The crude product was purified by preparative HPLC (20-100%
CHsCN/MeOH ( 1 : 1 ) in H20 (0.01% TFA)} which provided after iyop ilization 20 mg (46%) of the title compound as a colorless solid as the TFA salt; Ή NMR (400 MHz, CDCb) δ = 8.83 (d, J ~ 4,8 Hz, 1 H), 8.22 (s, 1 H), 7.72 - 7.64 (m, 1 H), 7.34 - 7.22 (m, 2 H), 7. 9 (d, J =-2,4 Hz, 1 H), 7.08 - 6.99 {rn, 2 H), 6.62 (dd, J = 2.3, 8.2 Hz, 1 H), 5.13 (d, J = 2.0 Hz, 2 H), 4,38 (t, J = 8.4 Hz, 2 H), 3.05 (t, J = 8.3 Hz, 2 H). MS (ESI*), m/z: 486.60 [ +H+]
Synthetic Example 57: 6-C 2,6-dichloTObenzyi)oxv)-1-((3-^^
Figure imgf000064_0002
The title compound was prepared according to General Procedure Di from 2,6- dSchlorobenzaldehyde (200 mg, 1.14 mmol). The extraction provided 200 mg (99%) of the title compound as a colorless solid which was used without further purification; 1H NMR (400 MHz, CDCb) δ = 7.37 - 7.32 (m, 2 H), 7.23 - 7.16 (m, 1 H), 4,98 (s, 2 H). SSyynntthheessiiss ooff 66--((ii((22,,66--ddjiGchhlloorr^obeennzzyyll))ooxxvv))--11 ~~((((33~~ * uullffoonnyyppiinnddooiiiinnee ((SSRRII 9911711 ))::
TThhee t tiittllee ccoommppoouunndd wwaass pprreeppaarreedd aaccccoorrddiinngg ttoo GGeenneerraall PPrroocceedduurree CC ffrroomm 11 --((((33-- {(ttrriifflluuoorroommeetthhyy:ll))pphheennyySi})ssuu!!ffoonnyyll))iinnddooHiinn--66--oo!! ((4400 mmgg,, 00,,1122 mmmmooii)) aanndd ((22,,66-- d diicchhlloorroopphheennyyil))mmeetthhaannool! ((2222 mmgg,, 00..1122 mmmmooll)).. TThhee ccrruuddee pprroodduucctt wwaass ppuurriiffiieedd bbyy pprreeppaarraattiivvee HHPPLLCC ((2200--110000%% C CHH3aCCNN//MeeOOHH ((11 ::11 )) iinn HH2200 ..((00..0011%% TTFFAA)))) wwhhiicchh p prroovviiddeedd aafftteerr llyyoopphhiiiliizzaattsioonn 3300 mmgg ((5511%%)) ooff tthhee t tiittllee ccoommppoouunndd aass aa ccoolloorrlleessss ssoolliidd;; HH N N.MRR ((440000 MMHHzz,, G GODGCIIs3)) 55 -- 88.. 11 ((ss,, 11 HH)),, 88..0011 ((dd,, JJ = - 77..88 HHzz,, 11 HH)),, 77..8833 ((dd ,, JJ -- 77..11 HHzz,, 11 HH)),, 77..66S8 -- 77..5588 ((mm,, 11 HH)),, 77..4422 -- 77..3377 ((mm,, 33 HH)),, 77..2288 ((dddd,, J J ~~ 77..33,, 88..88 HHzz,, 11 HH)),, 77..0022 ((dd.. JJ = 88..33 HHzz,, 11 HH)),, 66,,6699 ((dddd,, J J ** 22,,44,, 88..22 HHzz,, 11 HH)),, 55,,3300 ((ss,, 22 HH)),, 33..9988 ((tt,, J3 -- 88..33 HHzz,, 22 HH)),, 22..8888 ((tt,, JJ == 88..33 HHzztt 22 HH))..
SSyynntthheettiicc EExxaammppllee 5588:: 66--((((22--bbrroommoo--66-- aallhhyy11bbeennzzyySS))ooXXyy 11 --((((33··
Figure imgf000065_0001
The title compound was prepared according io Genera! Procedure D2 from 2.-brorrto-6- methyibenzolc acid (200 rrig, 0.93 mmoi). The extraction provided 182 mg (97%) of the title compound as a colorless solid which was used without further purification; rH NMR (400 MHz, C.PCI3) 5 = 7.43 (d, 3 - 7.7 Hz, 1 H), 7.16 .(d, 3 » 7,7 Hz, 1 H), 7,07 (t, 3 - 7,7 Hz, 1 H), 4.88 (s, 2 H), 2.50 (s, 3 H).
Figure imgf000065_0002
(SR 9172):
The title compound was prepared according to General Procedure C from 1-((3- (trif!uoromethyl)phenyi)suifonyi)indolin~6-ol (40 mg, 0.12 mmol) and (2-bromo-6- methylpheny methanol (22 mg, 0,12 mmoi). The crude product was purified by preparative HPLC (20-100% CHaCN/fvteOH (1 :1 ) in HsO (0,01% TFA)) which provided after lyophilization 32 mg (52%) of the title compound as a colorless solid; 1H NMR (400 MHz, CDGI3) δ = 8. 0 (s, i H), 8.01 (d, J = 7.9 Hz, 1 H), 7.83 (d, 3 ~ 7,9 Hz, 1 H), 7.86 - 7.58 (m, 1 H), 7,50 (d, J * 7,9 Hz, 1 H), 7.37 (d, 3 - 2.4 Hz, 1 H), 7.21 (d, 3 = 7,0 Hz, 1 H), 7.14 (t, J = 7,8 Hz, 1 H), 7.02 (d, J - 8,3 Hz, 1 H), 6,68 (dd, J = 2.4, 8.3 Hz, 1 H), 5,23 (s, 2 H), 3,98 {t, J * 8.4 Hz, 2 H), 2.88 (t„ J = 8,4 Hz, 2 H), 2.48 (s, 3 H), Synthetic, Example .59: 6-((2,6-dimethvibeh¾vj)o^
Figure imgf000066_0001
pr
The title compound was prepared according to General Procedure D2 from 2,8-dsrnethylbenzo c acid (200 mg, 1.33 mmoi). The extraction provided 175 mg (96%) of the title compound as a colorless solid which was used without further purification; rH NMR (400 MHz, CDC ) δ - 7,15 - 7,10 (m, 1 H), 7,08 - 7.03 (m, 2 H), 4.77 (s, 2 H), 2.45 (s, 6 H).
Synthesis of 6-((2,6-dimethy^
(SR19173):
The title compound was prepared according to General Procedure G from 1 ~((3- (triiluoromethyl)pheny!)suifonyi)indoiin-6'Ol (40 mg, 0.12 mmoi) and (2,6- dimethylphenyl)methanoi (17 mg, 0.12 mmoi). The crude product was purified by preparative HPLC (20-100% GH3CN/MeOH (1 :1 ) in H20 (0.01 % TFA)) which provided after lyophilization 28 mg (52%) of the title compound as a colorless solid; ;1H NMR (400 MHz, CDCfe) δ ~ 8.10 (s, 1 H), 7.98 (d, J ~ 7.8 Hz, 1 H), 7.83 (d, J - 8.1 Hz, 1 H), 7.84 - 7.58 (m, 1 H), 7.37 (d, J = 2.3 Hz, 1 H), 7.23 - 7.17 (m, 1 H), 7,1 1 (d, J - 7,6 Hz, 2 H)„ 7.02 (d, J~ 8.1 Hz, 1 H), 6.67 (dd, J - 2.4, 8.2 Hz, 1 H), 5.07 (s, 2 H), 3,98 (t: J = 8.3 Hz, 2 H), 2.88 (i, J = 8.3 Hz, 2 H), 2.43 (s, 6 H).
Synthetic Exampje βΟ,, , Β
{ trif ! uoro methyl )phe ny I )su If o n yi )f nd o I in e (S R 19 74):
Figure imgf000066_0002
The title compound was prepared according to General Procedure D2 from 2-chfc>ro-6~
(trifluoromethyl)benzoic ac d (100 mg, 0.44 mmoi). The extraction provided 84 mg (90%) of the tit!e compound as a colorless oil which was used without further purification; 1H NMR (400 MHz CDCb) 6 = 7.66 - 7.62 (m, 2 H), 7.45 - 7.34 (m, 1 H), 4.94 (s, 2 H). Synthesis of e-((2-chloro-6-(trifiuofomet yl)benzyljp y)- ;-((3- { tr if iuoromethyl )phenyi )su If onyl ) ind ol ine (SR 9174);
The title compound was prepared according to General Procedure C from 1 ~((3- (irifluoromethyS)pheny!)sulfony!)inddlin-6-o! (40 mg, 0,12 mmoi) and (2-cbloro-6- {trifluoromethyl)phenyl)methanoi (26 mg, 0.12 mmo!). The crude product was purified by preparative HPLC (20-100% CH3CN/MeOH (1 : 1 ) in H20 (0,01% TFA)) which provided after lyophilization 35 mg (56%) of the title compound as a colorless solid; H NMR (400 MHz, CDCI3) δ = 8.10 (s1 1 H), 8,01 (d, J - 7.8 Hz, 1 H), 7.83 (d, J - 7.8 Hz, 1 H), 7.72 - 7.68 (m, 2 H), 7.62 (t, J * 7.8 Hz, 1 H), 7.52 - 7.42 (m, 1 H), 7.36 (d, J - 2.3 Hz, 1 H), 7.02 (d, J ~ 8.3 Hz, 1 H), 6.66 (dd, J = 2.4, 8.2 Hz, 1 H), 5.26 (s, 2 H), 3.98 (t, J = 8.5 Hz, 2 H), 2,88 (t, J = 8.3 Hz, 2 H).
Synthetic Exampie 6 : 6-{{2-methoxYbenz.y0oxy)-1 -((3-(trifluoromethy pheny1)sulfonyl)jndpjjne
Figure imgf000067_0001
TThhee ttiittllee ccoommppoouunndd wwaass pprreeppaarreedd aaccccoorrddiinngg ttoo GGeenneerraall PPrroocceedduurree DDzz ffrroomm 22--mmeeffhhooxxyy bbeennzzooiicc aacciidd ((220000 mmgg,, 11 ,,3311 mmmmooii)).. TThhee eexxttrraaccttiioonn pprroovviiddeedd 117755 mmgg ((9966%%)) ooff tthhee ttiittliee ccoommppoouunndd aass aa ccoolloorrileessss ooiill wwhhiicchh wwaass uusseedd wwiitthhoouutt ffuurrtthheerr ppuurriiffiiccaattiioonn;; 11HH NNMMRR ( (440000 MMHHzz,, CCDDCCbb)) δ5" ~~ 77..3322 -- 77..2277 ( (mm,, 22 HH)),, 77,,0022 -- 66,,8866 ((mm,, 22 HH)),, 44..7700 ((dd,, JJ ** 66,,66 HHzz,, 22 HH)),, 33..8888 ((ss,, 33 H H)).,
SSyynntthheessiiss ooff 66~~((((22~~mmeetthhooxxyvbbeennzzyy00ooxxYY))--HH^^
((SSRR1199117755))::
TThhee ttiittllee ccoommppoouunndd wwaass pprreeppaarreedd aaccccoorrddiinngg ttoo GGeenneerraall PPrroocceedduurree CC ffrroomm 11 --((((33-- ( (ttrirtfflluuoorroommeetthhyyll))pphheennyyl!))ssuui!ffoonnyyti))iinnddooiliinn--66--ooli' ((4400 ..mmgg,, 00,,1122 m mmmooii)) aanndd ((22--mmeetthhooxxyypphheennyyii))mmeetthhaannooli
((11 mmgg,, 00..1122 mmmmooii)).. TThhee ccrruuddee pprroodduucctt wwaass ppuurriiffiieedd bby pprreeppaarraattiivvee HHPPLLCC ((2200--110000%%
CCHHasCGNN//MMeeGOHH ((11 :: 11 )) iinn HH2200 ((00..0011 %% TTFFAA)))) wwhhiicchh pprroovviiddeedd aafftteerr llyyoopphhiilliizzaattiioonn 2288 mmgg ((5522%%)) ooff tthhee ttiittllee ccoommppoouunndd aass aa ccoolloorrlleessss ssoolliidd;; 11HH NNMMRR ((440000 MMHHzz,, CCDDCCbb)) 5& - ~ 88..QQ99 ((ss,, 11 HH)),, 77,,8822 -- 77..7777 ((mm,, 22 HH)),, 77..5588 -- 77,,5511 ((mm,, 11 HH)),, 77..4499 -- 77,,4466 ((mm,, 11 HH)),, 77,,3366 -- 77..3300 ((mm,, 22 HH)),, 77,,0044 -- 66..9933 ((mm,, 33 HH)),, 66..6666 ((dddd,, JJ == 22..44,, 88..22 HHzz,, 11 HH)),, 55..1177 ((ss,, 22 HH)),, 33..9988 -- 33..9900 ((mm,, 55 HH)),, 22..8833 ((tt,, JJ ** 88..33 HHzz,, 22 HH))..
Figure imgf000067_0002
(trjfluoromethyi)phenyOsujfo ■.nvDindoline . (SR19268);
Figure imgf000068_0001
Synthesis of f2~(irifiuprom |hp
The title compound was prepared according to General Procedure
Figure imgf000068_0002
from 2- (irifluoromethoxy)beozaldehyde (225 μΐ, 1 ,58 mmoi). The extraction provided the title compound' .as a colorless oil which was used without further purification; 1H R {400 MHz, CPCfa) 5 - 7.60 - 7,54 (m, 1 H), 7.38 - 7.30 (m, 2 H), 7.27 - 7.22 (m, 1 H), 4.80 (s, 2 H).
Synthesis of 1 -(bfomomethySj 2:^
,-··· . : . oor,,
The title compound was prepared according to General Procedure E from (2- {ttifiuoromethoxy)phenyl)methanoL The extraction provided 350 mg (87% yield over 2 steps) of the title compound as a yellow oil which was used without further purification; 1·Η NMR (400 MHz, CDCi3) 5 ~ 7.59 - 7.54 (m, 1 H), 7,38 - 7,29 {m, 2 H), 7,29 - 7.22 <m, 1 H), 4.80 (S, 2 H). Synthesis of 6-({2^.rifiuororoeth^
(SR 19268):
The title compound was prepared according to General Procedure F from 1 -((3- (trifluoromethy!)phenyi)suifonyl)indolin-8~oi (30 mg, 0,09 mmo!) and 1 -(bromomethyi)~2- (trifluoromethoxy)benzene (33 mg, 0.1 3 mmol). The crude product was purified by preparative HPLC (20-100% CH.3CN MeOH (1 : 1 ) in H20 (0,01 % TFA)} which provided after lyophilization 13 mg (29%) of the title compound as a colorless solid; 1 H NMR (400 MHz, CDC'b) δ = 8,08 (s, 1 H), 7.95 ·· 7,89 (m, 1 H), 7,85 - 7.7.8 (m, 1 H), 7,65 - 7.55 (m, 2 H), 7 44 ~ 7,29 (m, 4 H), 7,0 - 6,96 (m, 1 H), 6.62 (dd, J = 2,3, 8.2 Hz, 1 H), .5.1.7 (s, .2 H):> 3.96 (t, J ~ 8,4 Hz, 2 H), 2,85 (t, J - 8,4 Hz, 2 H).
Synthetic ExampJe.egi ^
Figure imgf000068_0003
Step 1 : To the solution of 3-ch!oro-2-methoxybenz.osc acid (150 mg, 0.80 mmol) in 5 ml of MeOH was added 0,5 ml. of H2SG4, The reaction was stirred overnight at 80 X·. The completion of the reaction was monitored by HRLC. Upon completion, solvent was removed ihen H2G was added to the crude residue and the reaction mixture was extracted with EiOAc. The combined organic layers were washed with saturated aqueous NaHCOs, brine and dried over agSCt. Filtration and removal of the solvent in vacuo provided methyl 3:~chloro~2~me!hoxybenzoaie> which was used without further purification; 1H MR (400 MHz, CDCI3) δ = 7.71 (dd, J = 1.8, 7.8 Hz, 1 H), 7.55 (dd, J - 1.8, 7.8 Hz, 1 H), 7.17 - 7.07 (m, 1 H), 3.95 {s, 3 H), 3.94 (s, 3 H).
Step 2: To the solution of methyl 3-cbiaro~2~methoxybenzoate in 5 mL of MeOH was added NaBH.4 (304 mg, 8.04 mmol). The reactio was stirred at 60 °C for 4h. The completion of the reaction was monitored by HPLC. Upo completion, the solvent was removed in vacuo, H2O was added to the crude residue and the reaction mixture was extracted with EtOAc. The combined organic layers were washed with saturated aqueous NaHCQ3, brine and dried over Na^SG*. Filtration and removal of the solvent in vacuo provided 75 rng (54% yield over 2 steps) of the title compound as a colorless oil, which was used without further purification; 1H NMR (400 MHz, CPCis) δ ~ 7.37 - 7.31 (m, 1 H), 7.31 - 7.28 (m, 1 H), 7.10 - 7.05 (m, 1 H), 4.75 (s, 2 H), 3.93 (s, 3 H).
Synthesis of■1-(brQmomethv1)-3.-chlorQ--2-methoxybenzeng:
ci
The title compound was prepared according to General Procedure E from (3~chloro~2- methoxyphenyljrnethanol (70 mg, 0.41 mmol). The extraction provided 90 mg (94%) of the title compound as. a colorless oil which was used' without further purification; 1H NMR (400 MHz,
CDCis) δ - 7.35 (dd, J - 1.6, 7.9 Hz, 1 H), 7.30 (dd, J - 1.6, 7.9 Hz, 1 H), 7.05 (t, J = 7.9 Hz, 1
H), 4.57 (s, 2 H). 4.01 (s, 3 H).
Figure imgf000069_0001
(SRI 9351 ):
The title compound was prepared according to General Procedure F from 1-((3~
(trifluoromethyl)phenyl)sulfonyl)sndol n-6-ol (25 mg, 0.07 mmol) and 1 ~(bromomethyl)-3-chloro-2- methoxybenzene (34 mg, 0.15 mmol). The crude product was purified by preparative HPLC (20- 100% CHsCN/MeOH (1 :1 ) in H20 (0.0.1% TFA)) which provided after lyophiiization 24 mg (66%) of the title compound as a colorless solid; 1H NMR (400 MHz, CDCI3) 5 ~ 8.07 (s, 1 H), 7.93 (d, J = 8.3 Hz, 1 H), 7.33 (d, J ~ 8.6 Hz, 1 H), 7.59 (t, J - 7.8 Hz, 1 H), 7.43 - 7.38 (m, 2 H), 7.34 (d, J - 2.3 Hz, 1 H), 7.15 - 7.09 (m, 1 H), 7.00 (d, J = 8.1 Hz, 1 H), 6.64 (dd, J = 2.3, 8.3 Hz, 1 H), 5.14 (s, 2 H), 4.02 - 3.9.2 ( , 5 H), 2 86 {!, J = 8-3 Hz, 2 H).
Synthetic Example 64; 6-?( -6hlor.o-2-mettiQxybenzvi)oxy)-1-(f.3-
Figure imgf000070_0001
Step 1 : To the solution of 4-chloro~2-methoxybenzoic acid (150 mg, 0.80 mmol} in 5 mL of MeOH was added 0.5 mL of H2SO4. The reaction was stirred overnight at 80 °C. The compleiion of the reaction was monitored by HPLC. Upon completion, the solvent was removed in vacuo, H.2O was added to the crude residue and the reaction mixture was extracted with EtOAc. The combined organic layers were washed with saturated aqueous NaHCOs, brine and dried over Na2$0 . Filtration and removal of the solvent in vacuo provided methyl 4~eh!oro~2~
methoxybenzoate, which was used without further purification; 1H NMR (400 MHz, CD.CI3). δ = 7.77 {d, J - 8.8 Hz, 1 H), 7.01 - 6.95 (m, 2 H), 3.92 (s, 3 H), 3.89 (s, 3 H).
Step 2; To the solution of meihyl 4-chioro-2-methoxybenzoate in 5 mL of MeOH was added aBH4 (304 mg, 8.04 mmol). The reaction was stirred at 60 °C for 4h. The completion of the reaction was monitored by HPLC. Upon completion, solvent was removed in vacuo, H2O was added to the crude residue and the reaction mixture was extracted with EtOAc. The combined organic layers were washed with saturated aqueous NaHC03, brine and dried over Na2$'04. Filtration and removal of the solvent provided 49 mg (35% overall yield) of the title compound as a colorless oil, which was used without further purification; . 1H N (400 MHz, CDC ) ~ 7.22 (d, J - 7.9 Hz, 1 H), 6.94 (dd, J = 2,0, 7.9 Hz, 1 H), 6.88 (d, J ~ 2.0 Hz, 1 H), 4.65 (s, 2 H), 3.87 (s, 3 H).
Figure imgf000070_0002
The title compound was prepared according to General Procedure E from (4-chloro-2- methoxyphenyl)methanoi (45 mg, 0.26 mmol). The extraction provided SO mg (81 %) of the title compound as a colorless oil which was used without further purification; 5H NMR (400 MHz, CDCb) δ 7.27 - 7,25 (3, 1 H), 6.92 (dd, J ~ 2.0, 8.1 Hz, 1 H), 6.88 (d, J ~ 2.0 Hz, 1 H), 4.52 (s, 2 H), 3.90 (s, 3 H). Synthesis of 6~((4-c^
(SR 19350):
The title compound was prepared according to 'General Procedure F from 1 -((3- (trif!uoromethyi)phenyl)sulfony!}indoiin-6-ol (25 mg, 0,07 rnmoi) and 1~(bromomethy1)-4-chloro-2~ methoxybenzene (34 mg, 0.15 rnmoi). The crude product was purified by preparative HPLC (20- 100% CH3CN/IV3eOH (1 ;1) in H20 (0.01 % TFA)} which provided after tybphilization 22 mg (61 %) of the title compound as a colorless solid; 1H N'M (400 MHz, CDCI3) δ = 8.07 (s, 1 H), 7.81 (d, J ~ 7.9 Hz, 1 H), 7.76 (d, J ~ 8.1 Hz, 1 H), 7.58 - 7,52 (m, 1 H), 7.38 (d, J~ 7.9 Hz, 1 H), 7,29 (d, J = 2.4 Hz, 1 H), 7,00 - 6.94 (m, 2 H), 6.92 (d, J = 2,0 Hz, 1 H), 6.62 (d.d, J ~ 2.3, 8.2 Hz, 1 H), 5.1 1 (s, 2 Ή), 4,02 - 3.86 (m, 5 H), 2.83 (t, J - 8.3 Hz, 2 H).
Synthetic Example 65: e-((5-Ghtoro-2-methoxybenzyi)oxy)-1-((3- ( trif lupromethyl )phe n yj )s u If onyi )ind 0 j in e (SR 19353):
Figure imgf000071_0001
Synthesis of (5-chloro-2-rnethpxyphesiy|)met
Figure imgf000071_0002
Step 1: The solution of 5-chloro-2-methoxybenzoic acid (150 mg, 0.80 mmol) in 5 mL of SOCI2 was stirred at 80 °C for 2h. The completion of the reaction was monitored by HPLC. Upon completion, removal of the solvent in vacuo provided the 5~cbior0"2-methoxybenzoyl chloride, which was used without further purification.
Step 2: To the solution of NaBH (61 mg, 1.61 rnmoi) in 5 ml H2O at 0 °G was added 5-chloro- 2-methoxybenzoyt chloride. The reaction was stirred at 60 °.C for 4h. The completion of the reaction was monitored by HPLC. Upon completion, brine was added and the reaction mixture was extracted with EfcQ. The combined organic layers were dried over MasSC^. Filtration and removal of the solvent in vacuo provided 100 mg (72% yield over 2 steps) of the title compound as a colorless oil, which was used: without further purification; 1H MR (40.0 MHz, CDC ) δ - 7,30 (d, J = 2.8 Hz, 1 H), 7.23 (dd, J~ 2.8, 8.6 Hz, 1 H , 6.81 (d, J ~ 8.6 Hz, 1 H), 4,66 (s, 2 H), 3.86 (s, 3 H .
Synthesis of 2-(bromomethyl)-4-chioro-1-methoxybenzene:
Figure imgf000071_0003
The .title compound was prepared according to General Procedure E from (4-chloro~2- methoxyphenyi)methanol (100 mg, 0,58 mmol). The extraction provided 75 mg (55%) of the title compound as a coiortess oil which was used without further purification; 1H NMR (400 MHz, CDCi3) δ - 7.32 (d, J » 2.6 Hz, 1 H), 7.25 (dd, J ~ 2.6, 8.8 Hz, 1 H), 6.82 (d, J= 8.8 Hz, 1 H), 4.50 (s, 2 H), 3.88 (s, 3 H).
Synthesis of 6-((S-chioro-2-methoxy enzyl>oxy)-1 -((3-(faifluorometh^)phenvi)sulfonyl)iridoiine
(SR19353):
The title compound was prepared according to General Procedure F from 1-{(3- (trif!uoroniethyl:}phenyi)sulfonyl}sndolin-6-ol (25 mg, 0,07 mmol} and 2~{brornomethy }-4-chioro-1~ methoxybenzene (34 mg, 0.15 mmol). The crude product was purified by preparative HPLC (20-100% CHsCN/ eOH (1:1) in H20 (0.01 % TFA}) which provided after iyophi!ization 23 mg (63%) of the title compound as a colorless solid; H NMR (400 MHz, CDCI3) δ = 8.08 (s, 1 H), 7.81 (d, J = 7,8 Hz, 1 H), 7.73 (d, - 7.8 Hz, 1 H), 7.56 (t, J ~ 7.8 Hz, 1 H), 7.46 (d, J = 2,8 Hz, 1 H), 7.30 - 7.24 (m, 2 H), 6.97 (d, J = 8.3 Hz, 1 H), 6.86 (d, J = 8,8 Hz, 1 H), 6.65 (dd, J - 2.4, 8.2 Hz, 1 H), 5.12 (s, 2 H), 3.93 (t, J * 8.3 Hz, 2 H), 3.89 (s, 3 H), 2.83 (t, J 8.3 Hz, 2 H).
Synthetic Example 66:■ 6 {{3 m.et Qxypy.rid^n-2-vi)rnethoxy)-1- (.3- (trif^ϋoromethyl¾' h■envi sliSfonyl^)indoiine (SR19266):
Figure imgf000072_0001
Synthesis of methyl 3-hydroxypicoi.inate:
Figure imgf000072_0002
TToo tthhee ssoolluuttiioonn ooff 33--hhyyddrrooxxyyppiiccoollitnniicc- aacciidd ((11..0000 gg,, 77..1199 m mmmoo!l)) i in 2200 mmLL ooff MMeeOOHH wwaass aaddddeedd 22 mmLL ooff H H22SSOO44.. TThhee rreeaaccttiioonn wwaass ssttiirrrreedd oovveerrnniigghhtt aatt 8800 °°GG,, TThhee ccoommpplleettiioonn ooff tthhee rreeaaccttiioonn wwaass mmoonniittoorreedd bbyy HHPPLLCC.. UUppoonn ccoommpplleettiioonn,, ssoollvveenntt wwaass rreemmoovveedd iinn vvaaccuuoo,, HH OO aanndd NNaa22CC(Q¾s wweerree aaddddeedd uunnttiill ppHH==66,, tthheenn tthhee rreeaaccttiioonn mmiixxttuurree wwaass eexxttrraacctteedd wwiitthh CC..HHCCii33.. TThhee ccoommbbiinneedd oorrggaanniicc llaayyeerrss wweerree wwaasshheedd wwiitthh bbrriinnee aanndd ddrriieedd oovveerr NNaazzSSCCXXfi.. FFiillttrraattiioonn aanndd rreemmoovvaall o off tthhee ssoollvveenntt iinn vvaaccuuoo pprroovviiddeedd 889911 mmgg ((8811 %%)) ooff tthhee ttiittllee ccoommppoouunndd aass aa ccoolloorrlleessss ssoolliidd,, wwhhiicchh wwaass uusseedd wwiitthhoouutt ffuurrtthheerr ppuurriiffiiccaattiioonn;; HH NNMMRR ((440000 MMHHzz,, CCDDCCbb)) δδ == 1100..6644 ((dd,, JJ -- 00..55 HHzz,, 11 H H)),, 88..2299 ((dddd,, J ~ = 11..66,, 44..22 HHzz,, 11 HH)),, 77..4477 -- 77..4411 ( (mm,, 11 HH)),, 77..4411 -- 77..3377 ((mm,, 11 HH)),, 44..0077 ((ss,, 33 HH))..
Figure imgf000072_0003
To the solution of methyl 3-hydroxypicoiinate (885 mg, 5.78 mmol) in 25 mL of DMF were added CS2CO3 (2.07 6.36 mmol) and. methyl iodide (396 uL, 6.36 mmoi). The reaction was stirred overnight at room temperature. The completion of the reaction was monitored by HPLC. Upon completion, solvent was removed in vacuo, H2O was added to the crude residue and the reaction mixture was extracted with QCfVL The combined organic layers were washed with saturated aqueous NaHC03, brine and dried over asSO^. Filtration and removal of the solvent provided 546 mg (57%) of the title compound as a light brown oil which was used without further purification; rH NMR (400 MHz, CDCI3) δ - 8.29 (dd, J = 1.3, 4Λ Hz, 1 H), 7.46 - 7.41 (m, 1 H), 7.37 (dd, J ~ 1 ,3, 8.8 Hz, 1 H), 3.98 (s, 3 H), 3.94 (s, 3 H).
Synthesis of (3-methoxypyridin-2-yi)methano
To the solution of methyl 3-methoxypieolinate (300 mg, 1 ,80 mmol) in 10 ml of fvleOH at 0eC was added NaBI-i? (304 mg, 8,04 mrnoi). The reaction was stirred overnight at room
temperature. The completion of the reaction was monitored by HPLC. Upon completion, solvent was removed in vacuo, H2O was added to the crude residue and the reaction mixture was extracted with DC . The combined organic layers were washed with saturated aqueous NaHCCh, brine and dried over NaaSC . Filtration and removal .of the solvent provided 210 mg (84%) of the title compound as a colorless oil, whic!rwas used without further purification; 1H NMR (400 MHz, CDCI3) δ - 8.16 (dd, J ~ 1.3, 4.8 Hz, 1 H), 7,24 - 7.18 (m, 1 H), 7.17 - 7.1 1 (m, 1 H), 4,75 (d, J = 4.5 Hz, 2 H), 4.30 (t, J = 4.5 Hz, 1 H), 3.87 (s, 3 H)
Figure imgf000073_0001
The title compound was prepared according to Genera! Procedure E from (3-methoxypyridin-2- yl)me!hanol (200 mg, 1.44 mrnoi). The extraction provided 260 mg (90%) of the title compound as a colorless solid which was used without further purification; H NMR (400 MHz, CDCI3) δ - 8.19 (dd, J = 1.5, 4.5 Hz, 1 H), 7.26 - 7,22 (m, 1 H), 7.22 - 7.19 (m, 1 H), 4.65 (s, 2 H), 3.93 (s, 3 H),
Synthesis^^
(SR 9266):
The title compound was prepared according to General Procedur F from 1 -((3- (trifluoromethyi)phenyi)sulfonyl)indo!in-6~ol (30 mg, 0.09 mmol) and '2-(bromomethy.l)-3- methoxypyridine (26 mg, 0.13 mrnoi). The crude product was purified by preparative HPLC (20- 100% CHaCN/ eGH (1 :1) in HzO (0.01 % TFA)} which provided after lyophilization 43 mg (85%) of the title compound as a colorless solid as the TFA salt; '1H NMR (400 MHz, CDO3) δ ~ 8.52 (d, J ~ 4.4 Hz, 1 H), 8.05 (s, 1 H , 7.88 (d, J ~ 7.9 Hz, 1 H),. 7.81 (d, J = 7,7 Hz, 1 H), 7.77 - 7.66 (m, 2 H), 7.84 - 7.57 (m, 1 H), 7.29 (d, J = 2.4 Hz, 1 H), 7.00 (d, J « 8.3 Hz, 1 H), 6.76 (dd, J -
2.2, 8.3 Hz, 1 H), 5,38 (s, 2 H), 4,07 (s, 3 H), 3.92 (f, J 8.3 Hz, 2 H), 2.82 (t, J = 8.3 Hz, 2 H).
MS (ESI*) m/z: 464.88 [M+H*]
Synthetic Example 67: 6-(.{2,4-dichlpropy^
(trifiuoromethv!jphen j)sulionyl)jndotine (SRI 9352):
Figure imgf000074_0001
Synthesis of . (2,4-dichloropyridin-3^
Figure imgf000074_0002
Step 1 : The solution of 2,4-d(.chiorppyridine-3-carboxyiio acid (150 mg, 0.78 mmor) in 5 mL of
SOCb was stirred at 60 UC for 2h. The completion of ihe reaction was monitored by HPLC. Upon compietion, remova of the solvent in vacuo provided 2,4-dichiorOnicotinGyf chloride, which was used without further purification.
Step 2: To the solution of NaBH4 (59 mg, 1.56 mmol) in 5 mL of H2O at 0 °C was added 2,4- dich!oronicGtinoyi chloride. The reaction was stirred at 60 "C for 4h. The completion of the reaction was monitored by HPLC. Upon compietion, brine was added and the reaction mixture was extracted with £¾0, The combined organic layers were dried ove NasSO,*. Filtration and removal of the solvent in vacuo provided 100 mg (72% yield over 2 steps) of the title compound as a colorless oil, which was used without further purification; H NMR (400 MHz, CDCI3) δ - 8.26 (d, J - 5.3 Hz, 1 H), 7.33 (d, J = 5.3 Hz, 1 H), 4.98 (s, 2 H),
Synthesis of 3-(broniomethyi. -2,4-dichlQfOpyridine:
Figure imgf000074_0003
The title compound was prepared according to Genera! Procedure E from (2,4-dichioropyridin-3-
■yS)methano! (100 mg, 0,56 mmoi). The extraction provided 120 mg (89%) of the title compound as a colorless solid which was used without further purification; NMR (400 MHz, CDC ) δ ~
8,28 (d, J « 5,3 Hz, 1 H), 7.34 (d, J 5.3 Hz, 1 H), 4.86 (s, 2 H).
-¾ Dl ©sis_o _6^
(SR 9352):
The title compound was prepared according to General Procedure F from 1-((3- (trif{uoromet y!).phenyl)su(fonyi)indoHn-6-oi (25 mg, 0.07 mmol) and 3-(bromomethyl)-2,4- dichiorop'yridirie (35 mg,: 0, 15 mmol). The crude product was purified by preparative HPLC (20- 100% CHaCN/MeOH (1 :1 ) in H20 (0.01 % TFA)) which provided after iyophilization 25 mg (56%) of the title compound as colorless solid as the TFA salt; 1H NMR (400 MHz, CDCb) δ = 8.35 (d, J~ 5,1 Hz, 1 H), 8.10 (s, 1 H), 8.00 (d, J - 8.1 Hz, 1 H), 7.84 (d, J = 7.3 Hz, 1 H), 7.66 - 7.60 (m, 1 H), 7.41 (d, J = 5.3 Hz, 1 H), 7.36 (d, J « 2.3 Hz, 1 H), 7.03 (d, J = 8.3 Hz, 1 H), 6.67 (dd, J ~ 2,4, 8.2 Hz, 1 H), 5.29 (s, 2 H), 3.98 (I, J « 8.5 Hz, 2 H), 2,88 (t, J = 8,5 Hz, 2 H), MS (Ε8Γ) m/z: 502.79 [M÷H+]
Synthetic Example 68: 6-((3,5-dichioropyridin-4-vi)metho,xy,)-1-((3- (trifiuoromethyi¾phenvi)suifonyl)indoline (SR19285):
Figure imgf000075_0001
Synthesis of (3,5-dichioropyridin-4-yl)methanoi:
The title compound was prepared according to General Procedure Di from 3,5-dichloro- - pyridinecarboxajdehyde (310 mg, 1.76 mmoi). The extraction provided 310 mg (99%) of the title compound as a light yefiow solid which was used without further purification; 1H NMR (400 MHz, CDCb) δ = 8.53 (s, 2 H), 4.96 (s, 2 H).
Synthesis of 4-{ bromoroethyl )-3, 5-dic.h ioropyrjd.i.ne;
'ί
The title compound was prepared according to General Procedure E from (3,5-diehiorapyridin-3- yi)MeOH (300 mg, 1 ,68 mmol). The extraction provided 310 mg (76%) of the title compound as a yellow oil which was used without further purification; 1H NMR (400 MHz, CDCb) δ ~ 8.52 (s, 2
H), 4.65 (s, 2 H)
Synthesis of 6"((3,5-dichioropy
(S T9265):
The title compound was prepared according to General Procedure F from t-((3- (trifluoromethyi)pheny!)stilfonyi)indolrn-6-ol (30 mg, 0.09 mmol) and 4~(foromomethyl)~3(5- dichioropyridine (32 mg, 0. 3 mmol). The crude product was purified by preparative HPLC (20- 100% CHsCN/MeOH (1 :1 ) in H20 (0,01% TFA)) which provided after Iyophtlization 33 mg (61%) of the si e compound as a colorless solid as the TFA salt; 1H NMR (400 MHz, CDCb} δ = 8.58 (s, 2 H), 8.09 (s, 1 H), 7,99 (d, J ~ 7.8 Hz, 1 H), 7.84 id, J = 7.8 Hz, 1 H), 7.68 - 7.58 (m, 1 H), 77..3366 ((dd,, JJ ~= 22..33 HHzz,, 11 HH)),, 77..0022 ((dd,, JJ == 88..11 HHzz,, 11 HH)),, 66..6666 ((dddd,, JJ -- 22,,44,, 88..22 HHzz,, 11 HH)),, 55..2277 ( (ss,, 22 HH)),, 33..9977 ((†t,, ~~ 88.,33 H Hzz,, 22 HH));; 22..8888 ( (tt,, JJ™™ 88..33 HHzz,, 22 HH)),, MMSS ((EESSTT)) m m//zz:: 550022,,7733 [[MM++HH**]]
SSyynntthheettiicc EExxaammppllee 6699:: 66--((((33--cchhlloorroo--55--flfluuoarrooppyyrriiddjinn--44--vyii))mmeetihooxxyy))-~11-~((C(33--
Figure imgf000076_0001
--^^
rr FF tt OO
TToo tthhee ssoolluuttiioonn ooff 33--cchhlloorroo--55--ffiluuoorrooppyyrrliddiinnee ((330000 m mgg,, 22..2288 mmmmooll)) iinn 55 mmLL ooff aannhhyyddrroouuss T THHFF aatt -- 7788 °°CC wwaass aaddddeedd LLDDAA 11 iinn T THHFF ((22..7744 mmll,, 22..7744 m mmmooll)).. T Thhee rreeaaccttiioonn wwaass ssttiirrrreedd aatt --7788 °°CC ffoorr 3300 mmiinn bbeeffoorree tthhee ddrrooppwwiissee aaddddiittiioonn ooff mmeetthhyyll ffoorrmmaattee ( (228822 ppLL,, 44..5588 mmmmooll)).. TThhee rreeaaccttiioonn wwaass ssttiirrrreedd aatt --7788 °°CC ffoorr aann aaddddiittiioonnaall hhoouurr.. SSaattuurraatteedd aaqquueeoouuss NNaaHHCCOOss wwaass aaddddeedd aanndd tthhee rreeaaccttiioonn mmiixxttuurree wwaass eexxttrraacctteedd w wiitthh EEttOOAAcc.. TThhee ccoommbbiinneedd oorrggaanniicc llaayyeerrss wweerree wwaasshheedd wwiitthh bbrriinnee a anndd ddririeedd oovveerr aaaaSSGG .. FFiillttrraattiioonn aanndd rreemmoovvaall ooff tthhee ssoollvveenntt pprroovviiddeedd tthhee ccrruuddee pprroodduucctt,, wwhhiicchh wwaass ppuurriiffiieedd bbyy CCoommbbiiff!!aasshh ssiilliiccaa ggeell cchhrroommaattooggrraapphhyy ((00--5500%% EEttOOAAcc iinn hheexxaannee)) ttoo aaffffoorrdd 114455 mmgg ((4400%%)) ooff tthhee ttiittllee ccoommppoouunndd aass aa yyeellllooww ooiill;; 11HH NMMRR ((440000 MMHHzz,, CCDDCCii33)) 66 == 1100,,3399 ( (ss,, 11 H H)),: 88..5544 ((ss,, 11 HH)),, 88..5522 ((ss,, 11 HH))..
Figure imgf000076_0002
The title compound was prepared according to General Procedure Di from 3-cWoro-5- fluoroisonicotinaldehyde (145 mg, 0.91 mmol). The extraction provided 1 15 rrrg (78%) of the title compound as a colorless oil which was used without further purification; H NMR (400 MHz, CDCU) δ = 8.40 (s, 1 H), 8.34 (s, 1 H), 4.84 (d, J = 1.2 Hz, 2 H).
Figure imgf000076_0003
The title compound was prepared according to General Procedure E from (3-chloro-5- fluoropynd.in-4-yl )methahol (50 mg, 0.31 mmol). The extraction provided 60 mg (87%) of the title compound as a colorless oil which was used without further purification; 1H NMR (40G MHz, CDCIs) δ - 8.44 (s, 1 H), 8,38 (s, 1 H), 4.52 (d, J ~ 1.5 Hz, 2 H).
Figure imgf000077_0001
(trsflUQrQmethv )phenv1)sulfonvi)indoiine (SR 9407):
The title compound was prepared according to Genera! Procedure F from 1-( 3- {Wfluoromethyl)phenyi)sulfonyl)indoitn-6-Ql (20 mg, 0,06 mmoi) and 4-(bromomeihyl)-3-chloro-5- fiuoropyridine (16 mg, 0,07 mmol). The crude product was purified by preparative HPLG (20- 100% CHaCN/MeOH (1 :1 ) in H20 (0.01 % TFA)) which provided after !yophiiization 24 mg (69%) of the .title compound as a colorless -solid as the TFA salt; !H NMR (40O M-Hz, CDC ) δ ~ 8.53 (s, 1 H), 8.47 (s, 1 H), 8.08 s, 1 H). 7.97 (d, J - 7.9 Hz, 1 H), 7.84 (d, J = 7.9 Hz, H), 7.66 - 7.57 (m, T H), 7.34 (d, J-* 2,4 Hz, 1 H), 7.01 (d, J * 8.3 Hz, 1 H), 6,64 (cfd, J - 2.4, 8.1 Hz, 1 H), 5.22 {d, J = 1.5 Hz, 2 H), 3.97 (i, J « 8.3 Hz, 2 H), 2.87 (t, J* 8.3 Hz, 2 H). MS (ESI*) m/z:
.486.90 [M+H+]
Synthetic Example 70: 6-((3-chioro~5-(trifjUOromethvl¾pyri^
(tnfluoromethyj)phenyi)sulfonvl)iodoHne (SRI 9498):
Figure imgf000077_0002
The title compound was prepared according to .General Procedure F from 1 -((3- (trifluoromethyl)phenyi)sulfonyl)indo[in-6-ol (20 mg, 0.06 mmoi) and 4-(bromomeihy1)-3-chloro-5- (trifluoromethyi)pyridine (18 mg, 0,07 mmoi, obtained by the same synthetic pathway than 4- {bromomethyi)-3-ch!oro-5-f1uo'ropyridine). The crude product was purified by preparative HPLC (20-100% GHaC /MeOH (1 :1 ) in H?G (0.01% TFA)) which provided after lyophilization 22 mg (65%) of the title compound as a colorless solid as the TFA salt; ''H NMR (400 MHz, CDC¾) δ - 8.91 (s, 1 H): 8.90 (s, 1 H), 8.0.8 (s, 1 H), 8.00 (d, J * 7.8 Hz, 1 H), 7.84 (d, J = 7.8 Hz, 1 H), 7.69 - 7.59 (m, 1 H), 7.33 (d, J = 2.5 Hz, 1 H), 7,03 (d, J ~ 8.3 Hz, 1 H}„ 6.64 (dd, J = 2.3, 8.3 Hz, 1 H), 5.24 (s, 2 H), 3.98 (t, J ~ 8,3 Hz, 2 H), .2.89 (t, J * 8.1 Hz, 2 H). MS (ESI") m/z: 536.81
[M+H+]
Synthetic. Example 71.: 6-f(f3,5-dic oropyridin-4-yl)o^
Figure imgf000077_0003
Synthesis of 6-(brornpmethyl)-1 -
Figure imgf000078_0001
The title compound was prepared according to General Procedure E from (l -((3- (trifluofome iyi)p enyi)sulfonyi)indo}in-6-yl)methan0! {40 mg, 1.88 mmol). The extraction provided 45 mg (96%) of the title compound as a colorless solid which was used without further purification; Ή HMR (400 MHz, CDCb) δ ~ 8.03 (s, 1 H), 8.01 (d, J ~ 7.9 Hz, 1 H}, 7.83 (d, J = 7.9 Hz, 1 H), 7.70 (s, 1 H), 7,68 - 7.56 (m, 1 H), 7.1 1 - 6.97 (m, 2 H), 4.51 (s, 2 H), 3.96 (t, J - 8.4 Hz, 2 H), 2.93 (t, J .= 8.4 Hz, 2 H).
Synthesis of 6-f((3;5-dichiorq^ -((3- {trifiuorornethy )phenyj)sulfonyl)indoiine (SRI 9507):
The title compound was prepared according to General Procedure F from 6-(bromomethyl)-1- (3-(triffuofomethyl.)phe:ny!)suifonyl)indoline (45 mg, 0.1 1 mmol) and ' 3„5-dichlpro~4- hydroxypyridine (21 mg, 0.13 mmol). The crude product was purified by preparative HPLC (20- 00% CHsC /MeOH (1 :1 ) in H20 (0.01% TFA)) which provided after lyophilization 41 mg (62%) of the title compound as a colorless solid as the TFA salt; 1H NMR (40G MHz, CDCb) δ·= 8.04 (s, 1 H), 7,86 (d, J - 7.9 Hz, 1 H), 7.89 (d, J - 7.9 Hz, 1 H), 7.67 (s, 2 H), 7.65 - 7.60 (m, 1 H), 7.51 (s, 1 H), 7.19 (d, J * 7.5 Hz, 1 H), 6.87 (d, J » 7.5 Hz, 1 H), 5.00 (s, 2 H), 4,01 (t, J = 8,6 Hz, 2 H), 3.01 (t, J - 8.6 Hz, 2 H). MS (ESf+) m/z: 502.78 [ +H*]
General Synthetic Pathway 9:
Figure imgf000078_0002
i) POC , DMF, 65 °C; ii) UAIH4, THF, 65 °C; iit) NaBHaCN, AcOH, r.t; iv) 3-CF3PHSp2Ci. Et3N, DCiVi r.t.
Synthetic Example 72: 6-(|2-chioro-6-fluorobenzyl.)Qxy^3-methyl-1 -((3- (trif!uoromethyi)phenyl)sulfoo 9426 ):
Figure imgf000078_0003
Synthesis of 6-((2-chloro-6-fiuoroberizyl);oxy)~1 H-indoj&^
Figure imgf000079_0001
To the solution of 6-((2-chioro~8-fluorophenox )meth l)-1 H-indofe (200 mg, 0.72 mmoi) fn 5 ml of DMF at 0°C was added POCI3 (81 μί_, 0.87 mmol).. The reaction was stirred at 65 °C for 3h. The compietion of the reaction was monitored by HPLC. Upon compietion, solvent was removed in vacuo, H2O was added to the crude residue and the reaction mixture was extracted with EtOAc. The combined organic layers were washed, with saturated aqueous NaHCOa, brine and dried over aaSCk Filtration and removal of the solvent provided 210 mg (95%) of the title compound as a colorless oil, which was used without further purification; 1H NMR (400 MHz, CDCIs) 5 = 10.01 (s, 1 H), 9.10 (br. s, 1 H)( 8,21 (d, J = 8.6 Hz, 1 H), 7.77 (d, J = 3,1 Hz, 1 H), 7.35 - 7.23 (m, 2 H), 7.09 - 7.02 (m, 3 H), 5.22 (d, J ~ 2.0 Hz, 2 H).
Synthesis of 6-((2-chioro-6-fluorobenzyl: oxy)-3-methyl-1 H-indole:
Figure imgf000079_0002
To the solution of 6-((2-ehiora-6-fluorobenzyf)oxy)->1 HHndole-3-carbaldehyde -(210 mg, 0,89 mmoi) in 4 mL of anhydrous THF was added Li'ASH4;{79 nig, 2.07 mmoi). The reaction was stirred at 65 °G for 3h. The completion of the reaction was monitored by HPLC. Upon completion, were added 200 pL Η20, 200 pL NaOH 1 M in H2O and finally 650 μί. Η.,Ο. After 30 min, the solid was removed by filtration. Solvent was removed in vacuo, H2O was added to. the crude residue and the reaction mixture was extracted with EtOAc. The combined organic layers were washed with NaOH 1 M, brine and dried over asSG^ Filtration and removal of the solvent provided 150 mg (75%) of the title compound as a colorless solid, which was used without further purification; Ή NMR (400 MHz, CDCb) δ = 7,42 - 7.36 (m, 1 H), 7.24 - 7.15 (m, 2 H), 7.00 - 6.94 (m, 1 H), 6.94 - 6.91 (m, 1 H), 8.88 - 6.77 (m, 2 H), 5.14 (d, J - 2,0 Hz, 2 H), 2.2 (d, d, J - 1.1 Hz, 3 H).
Figure imgf000079_0003
The title compound was prepared according to General Procedure G from 6-{(2-chlorOr6~ fiuorobenzyl)oxy)-3"methyi:-1 H" ndoie (150 mg, 0,52 mmoi). The extraction provided 130 mg (85%) of the title compound as a colorless oil which was used without further purification; Ή NMR (400 MHz, CDCb) δ « 7.34 - 7.23 (m, 2 H), 7.09 - 6.99 (m, 2 H), 6.50 (dd, J = 2,1, 8.2 Hz, 1 H), 6.46 - 6.41 (m, 1 H), 5.13 (d, J ~ 2.0 Hz, 2 H), 3.77 (I, J - 8.8 Hz, 1 H), 3.40 - 3.30 (m, 1 H), 3.17 (t, J = 8.7 Hz, 1 H), 1.32 (d, J = 6.8 Hz, 3 H).
Synthesis of 6-({2-chloro-6-fluorobenzyl)oxy)-3-rnethyl-1 -((3- {trifluoromethyj}p.heny0s
The title compound was prepared according to General Procedure H from 6-((2-chforo-6- fiuorobenzyl)oxy)-3-methyHndoline (25 mg, 0.09 mmol) and 3-(trifluQromethyl)benzenesuifonyl chloride (27 pL, 0,17 mmol), The crude product was purified by preparative HPLC (20-100% CHaCN/MeOH (1 :1) in H20 (0.01 % IF A)} which provided after iyophilization 1 1 mg (26%) of the title compound as a colorless solid; TH NMR (400 MHz, GDCfe) δ = 8.03 (s, 1 H), 7.93 - 7.89 (m, 1 H), 7.77 - 7.73 (m, 1 H), 7.57 - 7.51 (m, 1 H), 7.28 (d, J ~ 2.4 Hz, 1 H), 7.26 - 7.20 (m, 2 H), 7.03 - 6.97 (m, 1 H), 6.90 (dd, J ~ 0.8, 8.2 Hz, 1 H), 6.61 (dd, J = 2.3, 8.2 Hz, 1 H), 5.12 (d, = 2.0 Hz, 2 H), 4.05 (dd, J = 9.0, 10.5 Hz, 1 H), 3.39 (dd, J = 6.8, 10.5 Hz, 1 H), 3.15 - 3,04 {rn, 1 H), 1.01 (d, J = 6.8 Hz, 3 H).
Figure imgf000080_0001
!) 2-c oro-6~fluorobenzylbromide, K2C03, DMF, r.t.; ii) NH4CI, Fe, EtOH HaO, '80 °C; iii) tBtiOCI. methyl ihio-2-prqpanorte, Et3N, DCM, -78 °C-r.t; then Raney-Ni, EtOH/H20, r.t; iv) Na8H3CN, Ae'OH, r.t; v) 3-CF3PhS02C!1 EtsN, DCM, r.t.
Synthetic Example 73: 6-(f2-chloro--6-fluQrQben
Figure imgf000080_0002
Synthesis of 1 -chloro-3-fiuoFO-2-(('3-nitrophenoxy)rriethyl)benzene:
Figure imgf000080_0003
To the solution of 3-nitrophenoi (1.50 g, 10.78 mmol) in 70 ml of DMF were added K2C03(4.47 g, 32.35 mmol) and 2-(bromomethyi)-1-chioro~3~fluorobenzene (2,65 g, 1 1.86 mmol). The reaction was stirred overnight at room temperature. The completion of the reaction was
monitored by HPLC. Upon completion, solvent was- removed in vacuo, H2.O was added to the crude residue and the reaction mixture was extracted with EtOAc. The combined organic layers were washed with brine and dried over N32SO . Filtration and removal of the -solvent provided the title compound as a colorless solid, which was used without further purification; 1H NMR (400 MHz, CDCI3) δ ~ 7.92 - 7,85 (ffi, 2 H), 7.50 - 7.42 (m, 1 H), 7.39 - 7.27 (m, 3 H), 7.11 - 7.06 (m, 1 H), 5.27 (d, J ~ 1.8 Hz, 2 H).
Synthesis of 3-((2-chloro-6-fluorobenzyi)oxy)aniline:
Figure imgf000081_0001
To the solution of 1 -chloro--3-fluoro-2-((3-nitrophenoxy)methyl)benzene in 30 mL of EtOH and 30 mL of H2O were added NhUCI (5.2 g, 97.05 mmoi) and Fe (1.81 g, 32.35 mmol}. The reaction was stirred at 80 °C for 2h, The completion of the reaction was monitored by HPLC. Upon completion, the reaction mixture was filtered over Ceiite®. The cake was washed with MeOH and the filtrated was concentrated in vacuo, To the crude residue was added H2O and the reaction mixture was extracted with EtOAc. The combined organic layers were washed with brine and dried over Ν¾3θ4. Filtration and removal of the solvent provided 2.66 g (98% yield over 2 steps) of the title compound as a light yellow oil, which was used without further
purification; H NMR (400 MHz., CDC ) δ' - 7.34 - 7.23 {m, 2 H), 7.12 (t, J = 7.9 Hz, 1 H), 7.07 - 7.02 (m, 1 H),.6.53 - 6.47 (m, 1 H), 6,45 - 6.38 (m, 2 H), 5.15 (d, J = 1.8 Hz, 2 H).
Synthesis of 6-;'(2:-chloro-6-f luQrobenzy!¾oxy)-2-methyl-1 H-indole:
Figure imgf000081_0002
Step 1: To a vigorously stirred solution of 3-({2-chioro-6-fluord'benzyl)pxy}aniiine (1 .00 g, 3.97 mmol) in 20 mL of DCM at -78 °C was added dropwise a solution of tert-butyl hypochlorite (447 pL, 3.97 mmol) in 4 mL of the same solvent. After 10 min, a solution of methylthio-2-propanone {407 3.97 mmol) in DCM (4 ml.) was added slowly over 10 min. After stirring for another hour at -78 °C, a solution of EtsN (554 pL, 3.97 mmol) In 4 mL of DCM was added slowly over 5 min. After an .additional' 10 min at -78 °C, the cooling bath, was removed and the reaction, was allowed to warm to room temperature. A 20 mL portion of HzO was added under vigorous stirring, and the organic layer was separated, dried over NasSOd, filtered, and concentrated in vacuo to give a 2: 1 mixture of the desired 6-{(2-chloro~6-fiuorobenzy!)oxy)-2-methy)-3- (methylthk>)-1 H-indole and the corresponding 4-benzy!oxy isomer as an orange oil. The crude product was used In the next step without further purification. MS (EST) m/z: 336.12 {M†H*j Step 2: To the -solution of the crude product formed in step 1 in 50 mL of ethane! was added 5 mL of Raney-Ni suspended in H2O. The reaction was stirred at room temperature for 1 h. The completion of the reaction was monitored by HPLG. Upon completion, The Raney Rickel was removed by filtration through Celste® and washed with ethanoi, The combined ethartoiic solutions were concentrated in vacuo. The crude product was purified by Combiflash silica gel chromatography {0-10% EiOAc in hexane) which provided 490 mg (43%) of the title compound as a colorless .oil; 1H NMR (400 MHz, CDC!a) δ = 7,41 (d, J * 8.6; Hz, 1 H), 7.34 - 7.25 (m, 3 H), 7.09 ~ 7.03 (m, 1 H), 7,00 (s, 1 H), 8,87 (d, J * 10.7 Hz, 1 H), 5.23 id, J ~ 2.0 Hz, 2 H), 2.46 {s, 3 H).
Synthesis of 6^
Figure imgf000082_0001
The title■compound was prepared according to General Procedure G from 6~{(2-chloro-6- f!uorobenzyl)oxy)-2-methyl-1H-jridole {200 mg, 0.69 mmol). The extraction provided 180 mg (89%) of the title compound as a colorless oil which was used without further purification; 1H NMR {400 MHz, CDCls) δ * 7.34 - 7.21 (m, 2 H), 7, 0 - 6,98 (m, 2 H), 6.43 (dd, J ~ .8, 8, 1 Hz,
1 H), 6.38 (s, 1 H), 5.12 (d, J ~ 2.0 Hz, 2 H), 4.09 - 3.99 (m, 1 H), 3.12 (dd, J - 8.4, 15.2 Hz, 1 H). 2.61 (dd, J - 7,6, 15.2 Hz, 2 H), 1.32 {d, J - 6.1 Hz, 3 H).
Synthesis of 6-((2-Ghloro-8-f1uorobenzyi oxy)-2-methyi-1 -((3- (trr luoromethvl phenvi)sulfonvt)indoiirie (SRI 9425):
The title compound was prepared according to General Procedure H from 6-{(2-chloro-6~ fluprobe'n2yl)axy)-2-methy)tndolirie (25 mg, 0.09 mmol) and '3-(trinuorofTiethyl)benzen'esulfony chloride (27 μΙ_, 0.17 mmol). The crude product was purified by preparative HPLC ' (20-100% O-feCN/MeOH (1 :1 ) in H20 {0.01 % TFA).) which provided after tyop ilizatjon 38 mg (89%) of the title compound as a colorless solid; 1H NMR (400 MHz, CDC ) δ = 8.02 (s, 1 H), 7.86. (d, J - 7.9 Hz, 1 H), 7.79 (d, J - 7,2 Hz, 1 H), 7.58 - 7.52 (m, 1 H), 7.39 (d, J * 2,2 Hz, 1 H), 7,36 - 7.27 (m,
2 H), 7.11 ~ 7.05 (rn, 1 H), 6.97 (d, J = 8,3 Hz, 1 H), 6.71 (dd, J ~ 2,3, 0.2 Hz, 1 H), 5,21 (d, J - 1.8 Hz, 2 H), 4,44 - 4.34 (m, 1 H), 2.84 (dd, J = 9.3, 5.7 Hz, 1 H), 2.42 (dd, J = 2.7, 15,7 Hz, 1 H), 1.46 (d, J ~ 6.4 Hz, 3 H).
General Synthetic Pathway 1 1 :
Figure imgf000082_0002
i) NH4CI, Fe, EtOH/H20, 80 °C; ii) (CFaGQjsQ, DCM. r.t; lis) Br2> H2O2 50%wt, DCM/HaO, 50 °C; iv) PPh¾ -toluene, 90 °C; y) DMF, 2O0°C, W; vi) NaBHsC'N, TFA, 4 °C; vii) 3-CF3PhS02CI, D AP, pyridine, 90 °C; viii) bis(pinacolato)diboron, AcOK, Pd(dppf)CI2.CH2Cl2S dioxane, 80 °C, then isiaOH, H202 5G%wt, H20, r.t; ix) BnBr, 2CC¾, DMF, r.t.
Synthetic Example 74: 6-ff2-ehloro-6-fiuo.iOben2yl)oxy)-^-(trifiuoromethyl)--1 -((3-
Figure imgf000083_0001
Synthesis of N-(5-bromo-2-mefhy1phenyl )-2, 2,2 -trifiuoroaceiamicie:
. F}C- A K ,'Χ Br
H
Step 1 : To the solution of 4-bromo-2-riitrotoiuene (8.00 g, 37.03mmol) in 100 mL of ethanol and 100 mL of H20 were added NhUCi (19.8 g, 370.3 mmol) and Fe (14.4 g, 259.2 mmol). The reaction was stirred at 80 "C for 2h. The completion of the reaction was monitored by HPLC. Upon completion, the reaction mixture was filtered over Celite®. The cake was washed with MeOH and the filtrated was concentrated in vacuo. To the crude residue was added H2O and the reaction mixture was extracted with EtOAc. The combined organic layers were washed with saturated aqueous aHCOs, brine and dried over ajSO . Filtration and removal of the solvent in vacuo provided 5-brorno-2-rnethyfanil.ine as a light yellow oil, which was used without further purification; 1H NMR (400 MHz, CDCia) δ = 6-99 - 6,82 (m, 3 H), 4.47 (br. s., 2 H), 2, 15 (s, 3 H). Step 2: To the solution of 5-bromo-2-methyianiii.ne in 200 ml of DCM was added trifiuoroacetic anhydride (6,18 mL, 44.43 mmol). The reaction was stirred at room tem erature for in. The completion of the reaction was monitored by HPLC. Upon completion, removal of volatile in vacuo provided 9.30g (89% yield over 2 steps) of the title compound as a light yellow solid, which was used without further purification; H NMR (400 MHz, CDCI3) δ = 7.99 (s, 1 H), 7.76 (br. s.s 1 H), 7,33 (dd, J - 2.0, 8,1 Hz, 1 H), 7.12 (d, J™ 8.1 Hz, 1 H), 2.25 (s, 3 H).
Figure imgf000083_0002
To the solution of N-(5-bromo-2~methylphenyl)-2,2,2~trifluoroacetamide (4.00 g, 14,20 mmol} in 40 mL of DC /H2O: 7/3 was added Bi¾- (880 JJL, 17.04 mmol). The reaction was stirred at 50 °C, followed by the dropwise addition over in of H2O2■ 50wt% in H.2O (965 pL, 14.20 mmol). The reaction was stirred at 50 °C for 4h. The maximum conversion of the starting material was observed after 4h by HPLC. At room temperature, an aqueous solution of agSjOa was added and the reaction mixture was extracted with EtOAc. The combined organic layers were washed with brine and dried over a2SG4. Filtration and removal of the solvent in vacuo provided a yellow oil as an inseparable mixture of the starting material and the title compound {4/6), which was used without further purification; H NMR (400 MHz, CDCIs) δ - 8,36 (br, s., 1 H), 8.15 (d, J =? 2.0 Hz, 1 H), 7,41 (dd, J = 2.0, 8.1 Hz, 1 H), 7.25 (d, J - 8.1 Hz, 3 H), 4.46 (s, 2 H),
Figure imgf000084_0001
The solution of crude N-(5-bromo-2~(bromomethyi)p^ in 20 mL of toluene was added 145 mg of PPha. The reaction solution was stirred at 90 °C for h. The completion of the reaction was monitored by HPLC. Upon completion, the precipitate was filtered and washed with toluene to provide 3,98 g (45% yield over 2 steps) of the title compound as a colorless solid, which was used without further purification; H NMR (400 MHz, DMSO) δ * 10.93 (s, 1 H), 7,90 (t J ~ 7.3 Hz, 3 H), 7.77 -7.72 (m, 7 H), 7.59 - 7.56 (m, 6 H), 7,42 (d, J = 7.7 Hz, 1 H), 6.98 (dd, J = 2.5, 8.4 Hz, 1 H), 5.20 (d, J - 15.3 Hz, 2 H).
Synthesis of §-bromo-2-(trifluoromethyi)- 1 H-indoie:
Figure imgf000084_0002
The solution of {4~bromo-2-(2,2t2 nfluoroacetamido)benzyl)triphenyiphosphonium bromide (2.00 g, 3.28 mmoi) in 12 mL of DMF was stirred at 200 °C for 15min under MW irradiation. The completion of the reaction was monitored by HPLC. Upon completion, solvent was removed, HzO was added to the crude residue and the reaction mixture was extracted with EtOAc. The combined organic layers were washed with brine and dried over Na!jSC . Filtration and removal of the solvent provided the crude product, which was purified by Combifiash silica gel chromatography (0-10% EtOAc in hexane) to afford 795 mg (94%) of the title compound as a colorless solid; 'H NMR (400 MHz, CQCfe) 6 = 8.46 (or. s., 1 H), 7.61 (s, 1 H), 7.56 (d, J = 8.6 Hz, 1 H), 7.32 (dd, J = 1.4, 8.6 Hz, 1 H), 6.92 (td, J = 1.4, 2.3 Hz, 1 H).
Figure imgf000084_0003
To the solution of 6-bromo-2-(trifiuoromethyl)-1 H-indoie (500 mg, 1.89 mmoi) in 7 mL of TFA at 4 °C was added NaBHsC (120 mg, 1 ,89 mmoi). The reaction was stirred at the same temperature for 15 min. The completion of the reaction was monitored by H PLC, Upon ccoommpplleettiioonn,, HH22OO wwaass aaddddeedd aanndd tthhee rreeaaccttiioonn mmiixxttuurree wwaass ccoonncceennttrraatteedd ttoo ddrryynneessss.. HH22OO wwaass aaddddeedd ttoo tthhee ccrruuddee rreessiidduuee aanndd tthhee rreeaaccttiioonn mmiixxttuurree wwaass eexxttrraacctteedd wwiitthh EEttOOAAcc.. TThhee ccoommbbiinneedd oorrggaanniicc llaayyeerrss wweerree wwaasshheedd wwiitthh ssaattuurraatteedd aaqquueeoouuss NNaaHHCCOOss,, bbrriinnee aanndd ddrriieedd oovveerr aaaSSCQ^. FFiillttrraattiioonn aanndd r reemmoovvaall ooff tthhee s soollvveenntt, iinn vvaaccuuao pprroovviiddeedd tthhee ccrruuddee pprroodduucctt,, wwhhiicchh w waass ppuurriiffiieedd bbyy CCoommbbiiffiiaasshh ssiilliiccaa ggeeil cchhrroommaattooggrraapphhyy ((00--5500%% E EttOOAAcc iinn hheexxaannee)) toto aaffffoorrdd 445500 mmgg ( (9900%%)) ooff tthhee ttiittllee ccoommppoouunndd aass aa ccoolloorrlleessss ooiiii;; HH NNMMRR ( (440000 MMHHzz,, CCDDCCII33)) δδ == 66..9986 ((dd,, JJ *« 77,,88 HHzz,, 11 H H)),, 66..8888 ( (dddd,, JJ = ~ 11..88,, 77,,88 HHzz,, 11 H H)),, 44,,3355 ((qquuiinndd,, JJ== 66..99,, 1100,,33 HHzz,, 11 HH)),, 33,,2299 ((dddd,, J*~ 1100..22,, 1166..55 HHzz,, 11 HH)),, 33,, 1144 ((dddd,, J J - - 66,.88,, 1166..77 HHzz,, 11 HH))..
Figure imgf000085_0001
To the solution of e-bromo-2-(trifluoromethyi)indoline (90 mg, 0,34 mmol) in 0.4 mL of pyridine were added 3-(trifiUoromethyl}benzenesuifonyi chloride (108 pL, 0.88 mmol) and D AP (4 mg, 0.03 mmol), The reaction was stirred overnight at 90 °C. The completion of the reaction was monitored by HPLC, Upon completion, aqueous solution of HCi I was added and the mixture was extracted with EtOAc. The combined organic layers were washed with saturated aqueous NaHCOs, brine and dried over Na2SQ4. Filtration and removal of the solvent in vacuo provided the crude product, which was purified by Combifiash silica gei chromatography (0-20% EtOAc in hexane) to afford 120 mg (75%) of the title compound as a colorless solid; 1H N R (400 MHz,
CDCI3) δ 7.87 (s, 1 H), 7.80 - 7.76 (m, 2 Ή), 7.72 (s, 1 H), 7.58 - 7.51 (m, 1 H), 7.18 (d, J - 8.6 Hz, 1 H), 6.90 (d, J * 7.9 Hz, 1 H), 4.76 - 4.62 (m, 1 H), 2,88 (dd, J * 1.8, 1 .3 Hz, 1 H), 2.76
Figure imgf000085_0002
in a dried MW flask under Ar were introduced 6~bromo-2-(trifluoromethyl)-1-((3- (trifluoromethyl)phenyl)sLfifonyl)indoline (120 mg, 0,25 mmol), AeOK (75 mg, 0.78 mmol), bis(pinaeoialo)di boron (98 mg, 0.38 mmol) and 2.5 mL of anhydrous dioxane, The flask was purged three times with Ar before the addition of PdiappfjCb.GHjCb. (21 mg, 0,03 mmol). The flask was sealed and the reaction mixture was stirred at 80 °C for 6h. The completion of the reaction was monitored by HPLC (mixture 1/1 : corresponding boron ic ester/boronfc acid). The reaction mixture was cooled down to room temperature. To the reaction mixture were added 0,25 mL of H20, NaOH (30 mg, 0.76' 'mmol) and H2Q2 50%wt i H20 (52 L, 0.76 mmof). The reaction was stirred at room temperature for 1h. The completion of the reaction was monitored by HPLG. Upon completion, aqueous solution of HCi 1 N was added and the reaction mixture was extracted with EtOAc. The combined organic layers were washed with brine and dried over Na¾SO4. Filtration and removai of the solvent provided the crude product, which was purified by Combiflash silica gel chromatography (0-40% EtOAc in hexane) to afford 90 mg (88%) of the title compound as a colorless solid; 1M NMR (400 MHz, CDC|3) δ = 7.93 (s, 1 H), 7.88 - 7.81 (m, 2 H), 7.62 - 7.55 (m, 1 H), 7,19 (d, J « 2.2 Hz, 1 H), 6.94 (d, J « 8.3 Hz, 1 H), 6.63 (dd, J ~ 2,3, 8.2 Hz, 1 H), 4.77 - 4.70 (m, 1 H), 2.94 - 2.87 (m, 1 H), 2.81 - 2.72 (m, 1 H).
Synthesis of 6-((2-chJpro 6-fl^ -¾{3 -
(trifluorQmet yi)phenyi)suifonyl)jndoline (SR19547):
The title compound was prepared according to General Procedure F from 2-(trifJuoromethyi)-1- .((3r(trifluoromeih-yi)phenyl)suifon i)indo!fn-6-oi (20 mg, 0.05 mmol) and 2~(bromoniethyl)~1~ chloro-3-fiuorobenzene (22 mg, 0.10 mmol). The crude product was purified by preparative HPLG (20-100% CHsCN/MeOH (1:1 ) in H20 (0.01 % TFA)) which provided after Syophslization 26 mg (97%) .of the title compound as a colorless solid; 1H NMR (400 MHz, CDCI3) 6 ~ 7.93 (s, 1 H), 7.83 (t, J = 6.7 Hz, 2 H), 7.61 - 7.54 (m, 1 H), 7.37 - 7.27 (m, 3 H), 7.12 - 7.04 (m, 1 H), 6.99 (d, J = 8.3 Hz, 1 H), 6.76 (dd, J * 2,5, 8.3 Hz, 1 H), 5.20 <d, J = 1 .8 Hz, 2 H), 4.81 ~ 4.69 (m, 1 H), 2.9.3 (dd, * 1.9, 16.5 Hz, ί H), 2.80 (dd, J ~ 9.7, 16.5 Hz, 1 H).
Synthetic Example 75: .6r((3-chio.rp-^
(trifiuororhethyl)phenyl)sulfonyi)indoiine (SR 9548):
Figure imgf000086_0001
The title compound was prepared according to General Procedure F from 2»(trifiuorometbyi)-1- {(3-(trifiuororneihyl)phenyl}sulfonyl)indo!in-6-ol (20 mg, 0.05 mmol) and 4-(bromometh l)~3- chloro-5-fluoropyridine (22 mg, 0,10 mmol}. The crude product was purified by preparative HPLG {20-100% GHsCN/fvteOH (1 :1 ) in H:,0 (0.01 % TFA)) which provided after iyophiiization 12 mg (37%) of the title compound as a colorless solid, as the TFA salt; 1H NMR (400 MHz, CDC ) δ * 8.56 (s, 1 H), 8.49 (s, 1 H), 7.90 (s, 1 H), 7.84 (d, J = 8.1 Hz, 2 H), 7.64 - 7.55 (m, 1 H), 7.33 (d, J = 2.3 Hz, 1 H), 7.01 (d, 8.3 Hz, 1 H), 6.75 (dd, J = 2.3, 8,3 Hz, 1 H), 5.23 (d, J = 1.3 Hz, 2. H), 4.81 - 4.71 :(m, 1 H), 2.98 - 2.90 (m, 1 H), 2.87 * 2.76 (m, 1 H). MS (ESP) rn/z: 554.84
[M+H*] Synthetic Example 76: 6-{(S,5^1chioropyridin-4-yi T{ethQxv)-2-(trifluoromet
(trifluofomeihy].)phenyi)su!fonYl)indoiine (SR19546)
Figure imgf000087_0001
The title compound was prepared according to General Procedure F from 2-(tfifiuoromet yf)-1- {(3-(tnfluoroniethyS)phenyl)sulfony!)indoHn-e-ol (20 rng, 0.05 mmoi) and 4*(bromomethyl)«3.,5- dichioropyridine (23 rng, 0.10 mmoi). The crude product was purified by preparaiive HPLC (20- 100% CH3C / eOH (1 :1 ) in H20 (0,01 % TFA)} which provided after Jyophilization 16 mg (48%) of the title compound as a colorless solid, as the TFA salt; 1H N R (400 MHz,. GDCI3) δ = 8.80 (s, 2 H), 7,95 - 7.80 (m, 3 H), 7.65 - 7.56 (m, 1 H), 7.34 (d, J = 2,5 Hz, 1 H), 7.02 (d, J - 8.3 Hz, 1 H), 6.76 (dd, J = 2,3, 8,3 Hz, 1 H), 5.29 (s, 2 H), 4,86 - 4.72.(m, 1 H), 2.95 (dd, J - 1 ,8, 16,5 Hz, 1 H), 2,82 (dd, J ~ 9,7, 16.5 Hz, 1 H). MS (ES!+) m/z: 572.8.2 [ +H^J
Synthetic Example 77: (£>"3 ¾" (2-chlorO"6-f!uorophenoxy)methyi¾-1--((3--
Figure imgf000087_0002
jSynthesls.o^
Figure imgf000087_0003
In a dried MW flask under Ar were introduced CuCI (7 mg, 0.07 mmoi), NaOt-Bu (21 mg, 0.21 mmoi), Xantphos (41 mg, 0.21 mmoi) and 6 mL of anhydrous THF, The flask was purged three times with Ar and then was stirred 30 min at room temperature before the addition of
:bjs.(prnacolato')diboron (664 mg, 2.62 mmoi). The reaction mixture .was stirred another 10 min before the addition of tert-butyl propionate (326 pL, 2.38 mmoi) and !vleOH (385 yL, 9..S2 mmoi). The flask was sealed and the reaction mixture was stirred overnight at room
temperature. The reaction mixture was filtered over Ceiite®, The cake was washed with THF, After removal of the solvent in vacuo, the crude product was purified by Combiflash silica gel chromatography (0-30% of EiOAc in hexane), which provided 376 mg (62%) of the title compound as a colorless solid; H NMR (400 MHz, CDCI3) 6 ~ 6,69 (d, J - 18,2 Hz, 1 H), 6.57 (d, v/ = 18,2 Hz, 1 H), 1.48.(s, 9 H), 1.29 (s, 12 H). Synthesis; of (E)-3-{6-({2-chioro-6-fluorophenQxv)m^thyi)-1 ^^
1 H-indol-3-vj)acryllc acid (SR19Q78 :
In a dried MW flask under Ar were Introduced 6-{{2-chloro"6"fluorophenoxy)methylV3-iodo-1 -{{3- (trifluoromethyl)phen l)sulfony[)- 1 H-indoie. (80 mg., 0.13 mmol), tert-butyl (E)-3-(4t4,5,5- tetram:ethy!-1 ,3,2-dioxaborolan-2-yi5acrylate (43 mg, 0.17 mmol), CsF (40 mg, 0.28 mmol) and 0.5 mL of anhydrous DME. The flask was purged three times w th Ar before the addition of Pd(dba}'2 (4 mg, 0.007 mmol) and PPha (3 mg, 0.01 mmol). The flask was sealed and the reaction mixture was stirred overnight at 90 °C. After removal of the solvent in vacuo, the crude product was purified by Combiflash silica gel chromatogra hy (0-15% of EtOAc in hexane), which provided 53 mg (66%) of iert~butyl~(E)-3-(6-((2-chloro-6 luorophenoxy)me!hy!)-1-((3-- (trifluorornethyi)phenyi)sulfonyl)-1 H-indol-3"yt)aciyiaie as a colorless solid. The obtained compound was solubilized In 4 mL of a mixture DCM/TFA: 10/1 and stirred at room temperature for 1 h. After removal of the solvent in vacuo, the crude product was purified by preparative HPLC (20-100% CHsC /MeOH (1 : 1 ) in HaD (0.01% TFA)) which provided after lyophilization 25 mg (51 %) of the title compound as a colorless solid; H NM (400 MHz, CDCI3) δ - 8.25 (s, 2 H), 8.12 (d, J = 8.1 Hz, 1 H), 7.92 - 7.82 (m, 4 H), 7.69 - 7.62 (m( 1 H), 7.50 (dd, J * 1 ,4, 8.2 Hz, 1 H), 7.22 - 7.15 (m, 1 H), 7.10 - 6.97 (m, 2 H), 6.56 (d, J = 16,7 Hz, 1 Ή), 5.29 (s, 2 H). MS (ES(-) m/z: 552.28 [ -H+J
Synthetic Example 78: 3-(6~((2-chloro-6-fiuorophenoxy)methyl 1~((3- (trifluof ethyl)phenvOsulfon^ (SR19085):
Figure imgf000088_0001
Synthetic of tert-butyl 3-(6-{:(2-chloro-6-fluorQphenoxy)methyl)- -((3-
Figure imgf000088_0002
In a dried W flask under Ar were introduced 6-((2-chloro-8-fluorophenoxy)meihyl)-8-iodo-1 -((3-- (triiluoromethyi)ph^ny!)su!fpnyi)-1 H-indoie (80 mg, 0.13 mmol), K2CO3 (36 mg, 0.26 mmol) and 0.5 mL of anhydrous DME. The flask was purged three times with Ar before the addition of tert- butyl propionate (108 μΙ_, 0.79 mmol), PdC tPPhaJs (5 mg, 0.00? mmol ) and Cu! (2 mg, 0.013 mmol). The flask was sealed and the reaction mixture was stirred overnight at 70 °C. After removal of the solvent in vacuo, the crude product was purified by Combifia.sh silica gel chromatography (0-15% of EtOAc in hexane), which provided 73 mg (92%) of the title compound as a colorless solid; 1H UMR (400 MHz, CDCfe) δ·= 8.23 (s, 1 H), 8.21 (s, 1 H), 8.10 (d., J ~ 7.9 Hz, 1 H), 7.95 (s, T H), 7.86 (d, J « 7.9 Hz, A H), 7.72 (d, J ~ 8.1 Hz, 1 H), 7.65 ( , J * 8.0 Hz, 1 H), 7.46 (d, J = 6.8 Hz, 1 H), 7.21 - 7.16 (m. 1 H), 7.08 - 6.96 (m, 2 H), 5.28 (s, 2 H), 1.57 (s, 9 H).
Synthesis of 3-(6 (2-oiiioro-6.-fluorophenoxy)m
indol-8-yl)propioNc acid (SR19Q85):
To a solution of tert-butyi 3-(6-{{2-chloro~6~f!uorophenoxy)methyl)-1-((3~
(trifluoromethy1)phenyl}sulfony!)-1 H-indoi-3-y[)propiolate (24 mg, 0.04 mmol) in 0.5 mL of
CH3CN were added CeC(3.7H;,0 (22 mg, 0.06 mmol) and ai (8 mg, 0.05 mmol). The reaction mixture was stirred overnight at 80 °C. The completion of the reaction was monitored by HPLC. Upon completion, aqueous solutio of HO1 1 was added and the reaction mixture was extracted with EfOAc. The combined organic layers were washed with brine and dried over Na?S0 . Filtration and removal of the solvent in vacuo provided the crude product, which was purified by preparative HPLC (20 -100% CHaCN/MeOH (1 :1.) in H.2O (0.01 % TFA)) to afford after iyophi!ization 7 mg (32%) of the title compound as a colorless solid; 1H NMR (400 MHz., CDCb) 5 * 8.24 (s, 1 H), 8.21 (s, 1 H), 8.1 1 (d, J - 7.9 Hz, 1 H), 7.99 (s, 1 H), 7,87 (d, J ~ 7.9 Hz, 1 H), 7.73 (d, J. =? 8.1 Hz, 1 H), 7.70 - 7,62 (m, 1 H), 7.47 (dd, J™ 1 .3, 8.1 Hz, 1 H), 7.21 - 7.16 (m, 1 H), 7.09 - 6.96 (m, 2 H), 5.28 (s, 2 H), MS (ESI ) m/z: 550.64 [M-H+].
Synthetic Example 79: 3-{6-((2--chioro-6-fluorophenoxy)methyl -1-((3- (trifjuQrornethvDphenvDsuifonvO-l H-indoi-3~yl)propanoic.acid (SR19082):
Figure imgf000089_0001
To a solution of tert-butyi 3-'(6-((;2-chloro-6-flu.orophenoxy.)methyl)-1 -({3- {trif]uoromethyl)phenyl)su}fonyl)-1 H-indoi-*3-yl)propiolate (30 mg, 0.04 mmol) in 5 ml of EtOH and 5 mL of EtOAc was added 6 mg Pt(¼, The reaction mixture was stirred under Ha at room temperature for 2h, The completion of the reaction was monitored by HPLC. Upon completion, the reaction mixture was filtered over Celiie®. The cake was washed with EtOH and EtOAc. Solvents were removed in vacuo and the crude product was directly used for the next step without further purification. To a solution of th crude compound in 0.5 mL of CH3CN were added CeCbJHzQ (28 mg, 0.07 mmoi) and Nal (10 nig, 0.06 mmoi).. The reaction mixture was stirred overnight at 80 °C. The completion of the reaction was monitored by HPLC, Upon completion, aqueous solution of HQ I was added and the reaction mixture was extracted with EtOAc. The combined organic layers were washed with brine and dried over NazSO^ Filtration and removal of the solvent in vacuo provided the crude product, which was purified by preparative HPLC (20-100% CH3C /MeOH (1 :1 ) in H20 {0.01 % TFA)> to afford after lyophiiization 9 mg .{33%} of the title compound as a colorless solid; 1H N R (400 MHz, CDCI3) 5 = 8.17 (S, 1 H), 8,16 ($, 1 H), 8.03 (d, J = 7.9 Hz, 1 H), 7.78 (d, J = 7.2 Hz, 1 H), 7,59 (s, 1 H), 7.54 - 7.50 (m, 1 H), 7.45 - 7.39 (m, 2 Ή), 7.20 - 7.16 (m, 1 H], 7,08 - 6.95 (m, 2 H), 5,26 (s, 2 H), 3,03 (t, J = 7.7 Hz, 2 H), 2.77 (f, J ~ 7.7 Hz, 2 H). MS (ESI ) m/z: 554.19 [ -H fj.
gynihetjg,Examp.je 80; .4-(6-(.(2-chloro-6-fluorophenoxy)methvQ-i -((3-
Figure imgf000090_0001
In a dried W flask under Ar were introduced 6-{{2-chloro--6--fiuorophenoxy)methyl)-3-iodo-1-((3~ (trifluorometh l)pheny!)sulfonyl)-1 H-lndole (100 mg, 0.16 mmoi), 4-(tert-butoxycarbo)phenyl boronic acid (47 mg, 0.21 mmoi), Cs.F (50 mg, 0.33 mmoi} and 0,7 mL of anhydrous DME. The flask was purged three times with Ar before the addition of Pd(dba}2 (5 mg, 0.008 mmoi) and PPI 3 (4 mg, 0.016 mmoi). The flask was sealed and the reaction mixture was stirred overnight at 90 °C. After removal of the solvent in vacuo, the crude product was purified by Combiflash silica gel chromatography (0- 5% of EtOAc in hexane), which provided 96 mg (89%) of the teri- butyl 4-(6-((2-chioro-6-fluarophenoxy)methy^
yl)benzoate as a colorless solid. To a solution of the obtained compound (30 mg, 0.05 mmoi) in 0.5 mL of CH3G.N were added CeC!3.7H20 (25 mg, 0,07 mmoi) and Nal (9 mg, 0.06 mmoi). The reaction mixture was stirred overnight at 80 °C. The completion of the reaction was monitored by HPLC. Upon completion, aqueous solution of HCI N was added and the reaction mixture was extracted with EtOAc. The combined organic layers were washed with brine and dried over 82SQ . Filtration and removal of the solvent in vacuo provided the crude product, which was purified by preparative HPLC (20-100% CH3C /MeOH (1 :1 ) 'in H20 (0.01 % TFA}} to afford after Iyophilization 19 mg (69%) of the. title compound as a colorless solid; NMR (400 MHz, CDC ) δ - 8.29 (s, 1 H), .8.27 (s, 1 H), 8.25 - 8.19 (m, J ~ 8.5 Hz, 2 H), 8.14 (d, J = 7.9 Hz, 1 H}: 7.87 - 7.79 .(m, 3 H), 7.76 - 7.71 (m, J ~ 8.6 Hz, 2 H), 7.68 - 7.60 (m, 1 H), 7.50 dd, J = 1.3, 8.3 Hz, 1 H), 7.20 (td, J = 1.7, 7.8 Hz, 1 H), 7,10 - 6.97 (m., 2 H), 5.31 (s, 2 H). MS (ESI") m/z; 602,33 [ - ΗΊ-
Synthetic Example 81 : 3>-(6-ii(2-chloro-6-f uofOphenoxy)methylV1-{0-
Figure imgf000091_0001
in a dried iVfW flask under Ar were introduced 6-((2-ch ro-8-fSuorophenoxy)methy!)-3-iodo-1-((3~ {trifluoromethy phenyi)su!fony[)-1 H-indole (80 mg, 0.13 mmol), 3-{tert~hutoxycarbo)phenyl boronic acid (38 rng, 0.17 mmol), CsF (40 mg, 0.26 mmol) and 0.5 mL of anhydrous DME. The flask was purged three times with Ar before the addition of Pd(dba)2 (4 mg, 0.007 mmol} and PPhs {3 mg, 0.013 mmol). The flask was sealed and the reaction mixture was stirred overnight at 90 *C. After removal of the solvent in vacuo, the crude product was purified by Combifiash silica gel chromatography (0-15% of E OAc in hexane), which provided 52 mg (60%) of tert- buty! 3~(6-((2~ch!oro-6 luorophenoxy)m^
yi}benzoate as a colorless solid. To a solution of the obtained compound {25 mg, 0.04 mmol) in 0.5 mL of CH3CN were added CeCl3.7H2G (21 mg, 0.06 mmol) and Nal (7 mg, 0.05 mmol). The reaction mixture was stirred overnight at 80 °C. The completion of the reaction was monitored by HPLC, Upon completion, aqueous solution of HCi H was added and the reaction mixture was extracted with EtOAc The combined organic layers were washed with brine and dried over Na2$04. Filtration and removal of the solvent in vacuo provided the crude product, which was purified by preparative. HPLC (20-100% CH3CN/ eOH (1 :1 ) in H20 (0.01% TFA}.) to afford after Iyophilization 19 mg (83%) of the title compound as a colorless . solid; 1 H NMR (400 MHz, CDCb) δ ~ 8.35 (t, J ~ 1 ,5 Hz, 1 H), 8.29 :(s, 1 H), 8.27 (s, 1 H), 8,17 - 8.09 ( n, 2 H), 7.90 - 7.77 (m, 4 H), 7.69 - 7,57 m, 2 H), 7.49 (dd, J = 1.4, 8.2 Hz, 1 H), 7.19 (td, J - 1.8, 7.6 Hz, 1 H), 7.10 - 6.97 (m, 2 H), 5.31 (s, 2 H). MS (ESI') m/z: 602.46 [ -hTj.
Synthetic; Exampie 8¾
(trifiuoromethyl)phenvj sulfonyl)-1 H"indol-3"V
Figure imgf000092_0001
In a dried MW flask under Ar were introduced 8-((2-chioro-6-fiuorQphenoxy)methyl)-3-iodo-1»{(3- ^rff!uoromethyl)phenyl)sulfonyl)-1H-indoie {80 mg, 0.13 mmoi),. (4-tert- buiylcarbpnylmethy!phenyi)borpnic acid pirsacol ester (54 mg, 0,17 mmoi), CsF (40 mg, 0.26 mmoi} and 0.5 ml of anhydrous D E. The fiask was purged three times with Ar before the addition of Pd(dba)2 (4 mg, 0,007 mmoi) and P ha (3 mg, 0.013 mmoi). The flask was sealed and the reaction mixture was stirred overnight at 90 °C. After removal of the solvent in vacuo, the crude product was purified by Combifiash siiica gel chromatography (0-15% of EtOAc in hexane), which provided 68 mg (77%) of tert-buty! 2-(4-(8-((2-chloro-6-fluorophenoxy)mefhyi}-1- ({3-(tnfiuoromethyl)phenyt)sulfony!)-1 H-indo{-3-yS)phenyi)acetate as a colorless solid. To a solution of the obtained compound (27 mg, 0.04 mmoi) in 0.5 mL of CH3CN were added
CeGi3>7HzO (22 mg, D.06 mmoi) and Nal (8 mg, 0,05 mmoi), The reaction mixture was stirred overnight at 80 °C. The completion of the reaction was monitored b HPLC. Upon completion, aqueous solution of HGI I was added and the reaction mixture was extracted with EtOAc. The combined organic layers were washed with brine and dried over aaSC . Filtration and removal of the solvent in vacuo provided the crude product, which was purified by preparative HPLC (20- 100% CHsCN/MeOH (1 :1) in H20 (0.01 % TFA)) to afford after !yophiiization 19 mg (77%) of the title compound as a colorless solid; H NMR (400 MHz, CDC ) δ = 8.28 (s, 1 H), 8.23 (s, 1 H), 8.10 (d, J 7,9 Hz, 1 H), 7.82 (d, J ~ 7.9 Hz, 1 H), 7.78 (d, J = 8.1 Hz, 1 H), 7.70 (8, 1 H), 7.64 - 7,55 (m, 3 H), 7.46 (dd, J ~ 1 .5, 8.3 Hz, 1 H), 7.41 (d, J - 8.3 Hz, 2 H), 7.19 (td, J - 1.8, 7.8 Hz, 1 H), 7.09 - 6.97 (m, 2 H), 5.29 (s, 2 H), 3J4 (s, 2 H), MS (ESI") m/z: 617.20 M-H*].
Synthetic, Example ^
(trif uoromethyi)pheriy[)suifony0-1H-indoi-3-yl)phenyi)acetfc! acid (SR 9087):
Figure imgf000092_0002
in a dried MW flask under Ar were introduced 6-((2-ch!oro-6-f!uorophenoxy)methyi:)-3-iodo-1-((3- (trifiuoromelhy!)p eny!)su!fony!)-1H-indple (80 mg, 0.13 mmoi), (3~tert- buiyicarbonyimeihy!phenyi)boronic acid pinacoi ester {54 mg, 0.17 mmol), CsF (40 mg, 0.26 mmo!) and 0.5 ml of anhydrous DME. The flask was purged three times with Ar before the addition of Pd(dba)2 (4 mg, 0.007 mmol) and PPh3 (3 mg., 0.013 mmol). The flask was seated and the reaction mixture was stirred overnight at 90 °C. After removal of the solvent in vacuo, the crude product was purified by Combif!ash silica gel chromatography (0-15% of EtOAc in hexahe), which provided 82 mg (93%) of teri-butyl-2-(3-(6-((2-chloro~6-f1uo!OphenGxy)methyi)-1- {(3-(trifluoromethyi)p.henyl)sulfonyi)-1 H-indoi-3-yi)phenyi)acetate as a colorless solid. To a solution of the obtained compound (27 mg, 0.04 mmol) in 0.5 mL of CH3CN were added
CeCt3.7H20 (22 mg, 0.08 mmol) and Nal (8 mg, 0.05 mmol). The reaction mixture was stirred overnight at 80 °C, The completion of the reaction was monitored by HPLC. Upon completion, aqueous solution of HC1 1 N was added and the reaction mixture was extracted with EtOAc. The combined organic layers were washed with brine and dried over Na2SG4. Filtration and removal of the solvent in vacuo provided the crude product., which was purified by preparative HPLC (20- 100% CH3CN/MeOH (1 :1 ) in H20 (0.01 % TFA)) to afford after lyophilization 18 mg (73%) of the title compound as a colorless solid; H NMR (400 MHz, CDCI3) δ = 8.25 £d, J ~ 5.0 Hz, 2 H), 8.10 (d., .J = 8.1 Hz, 1 H), 7,84 - 7.75 (m, 2 H), 7.71 (s, 1 H), 7.61 (I, J ~ 7.9 Hz, 1 H), 7.53 (d, J * 2.0 Hz, 2 H), 7.49 - 7,42 (m, 2 H), 7.33 (d, J = 7.5 Hz, 1 H), 7.18 (d, J » 7.7 Hz, 1 H), 7.09 - 6.95 (m, 2 H), 5.29 (s, 2 H), 3.75 (s, 2 H). MS (ESI ) m/z: 81 .99 [M-H*].
Synthetic Example 84: N-{4-(6-((2-chloro-6--fluorophenoxy)methvl)-1-((3-
Figure imgf000093_0001
in a dried M flask under Ar were introduced 6-((2-chloro-6-fluorophenoxy)rnethy!)-3-iodo-1-((3-
(trifiuQromefhyl)phenyl)su!fonyi)-1 H~!ndoie (300 mg 0.49 mmol), 4-acetamidophenylboronic acid (123 mg, 0.69 mmol), CsF (149 mg, 0.98 mmol) and 2.5 ml of anhydrous DME. The flask was purged three times with Ar before the addition of Pd(dba)2 (14 mg, 0.025 mmol) and PPhs (13 mg, 0.05 mmol}.. The flask was sealed and the reaction mixture was stirred overnight at 90 °C. After removal of the solvent in vacuo, the crude product was purified by Combiflash silica gel chromatography (0-50% of EtOAc in hexane), which provided 220 mg (72%) of the title
compound as a colorless solid: 1H NMR (400 MHz, D SO) δ = 10.07 (s, 1 H), 8.41 (s, 1 H), 8.35 (d, J = 8.3 Hz, 1 H), 8.23 (s, 1 H), 8.20 (s, 1 H), 8.1 1 (d, J = 7.9 Hz, 1 H), 7,88 - 7.82 (m, 2 H), 7.74 - 7.64 (m, 4 H), 7.44 (dd, J ~ 1.4, 8.2 Hz, 1 H), 7.3.7 - 7.27 (m, 2 H), 7,20 - 7.13 (m, 1 H), 5.31 (s, 2 H), 2.07 (s, 3 H). MS (Ε3 ) m/z: 617.96 +j,
Synthetic Example 85: 4-(6-((2-chiQro-6-fluorophenoxy)rn^thyi¾-1-f(3- ( il1uorornethvl)phenyi)sulfonyt 1H ndo{-3-yl)benzamide:
Figure imgf000094_0001
In a dried MW flask under Ar were introduced 6-((2-chlofo-6-fluorophenoxy)rriethyl.}-3-iod.o-1~{{3- (trifluorornethyi)'phenyl)sulfonyl)-1 H-in to!e. (80 mg, 0.13 rrimol}, 4-aminocarbonylpheny!boronic acid (39 rrtg, 0.24 mmol), K2C03 (54 mg, 0.39 mmol) and 1 ml. of anhydrous THF. The flask was purged three times with Ar before the addition of Pd(PPba)4 (1 5 mg, 0.013 mmol). The flask was sealed and the reaction mixture was stirred overnight .at 90 °C. The completion of the reaction was monitored by HPLC. Upon completion, saturated aqueous NaHCOg was added and Ihe reaction mixture was extracted with EtOAc. The combined organic layers were washed with brine and dried over K^SC ,, Filtratio and removal of the solvent in vacuo provided the crude product, which was purified by preparative HPLC (20-100% CHeCN/MeOH (1 :1) in H20 (0.01% TFA)} to afford after lyophilization 9 mg (1 1%) of the title compound as a colorless solid; H R (400 MHz, GDG ) δ - 8.28 (s, 1 H), 8.28 (s, 1 H), 8.13 (d, J = 8.3 Hz, 1 H), 7.96 - 7.92 (m, 2 H), 7.84 (d, J = 7.3 Hz, 1 H), 7.81 - 7.77 (m, 2 H), 7.73 - 7.68 (m, 2 H), 7.66 - 7.61 (m, 1 H), 7.48 (dd, J - 1.4, 8.2 Hz, 1 H), 7.19 (Id, J - .8, 7.7 Hz, 1 H), 7.09 - 6.97 (m, 2 H), 6.03 (br. s., 1 H), 5.30 (s, 2 H). MS (EST) m/z; 603.01 [M+H+].
Synthetic
{irifluoromethyi)phenyl)suifonylH H-indoie (SR19 59):
Figure imgf000094_0002
in a dried .MW flask under Ar were introduced 6-((2-chloro-6-fluorophenoxy)meihyl)-3-iodo-1-((3- (trif!uoromethyl)phenyl)su!fony!)-1.H-indOie {80 mg, 0,13 mmol), -chlorQp.henylboronjo acid (29 mg, 0.18 mmol), CsF (40 mg, 0.26 mmol) and 0.6 mL of anhydrous DME. The flask was purged three times with Ar before the addition of Pd(dba)2 (4 mg, 0.007 mmol) and PPh3 (3 mg, 0.013 mmol). The flask was sealed and the reaction mixture was stirred overnight at 90 *C> After removal of the solvent in vacuo, the .crude product was purified by Combifiash .silica- gel
chromatography (0-20% of EtOAc in hexane), which provided 43 mg (55%) of the title compound as a colorless solid; Ή NMR (400 MHz, CDCfe) 5 = 8.27 (s, 1 H), 8.25 (s, 1 H), 8.12 (d, J 8.1 Hz, 1 H), 7.83 (d, J = 7.8 Hz, 1 H), 7.74 (d. J - 8.3 Hz, 1 H), 7.70 (s, 1 H), 7.67 - 7.59 (m, 1 H], 7.57 - 7.51 (m, 2 H), 7.50 ·· 7.42 (m, 3 H), 7.19- (td, J e 1.7, 7.6 Hz, i H), 7,09 - 6.95 (m, 2 H), 5.30 (s, 2 H).
Syptheti:ci:Example 87: 4-(6-((2-chloro-6-fluorophenoxy)methyl)-1-((3- (trifluoromethyl)phenyj)suifo^
Figure imgf000095_0001
in a dried W flask under Ar were introduced 6r((2-chjoro-6-fluoropbenoxy:}methyl)~3-(odo-1-((3- {trifkjoromethy!)phenyl)suifonyl)-1 H-indo!e (80 mg, 0.13 mmol), 4-(dimethyiamino)phenylborontc acid (39 mg, 0.24 mmol), K2CO3 (54 mg, 0.39 mmol) and 1.5 mL of anhydrous DMF. The flask was purged three times with Ar before the addition of Pd(PPh-3)4 (1.5 mg, 0.013 mmol). The flask was sealed and the reaction mixture was stirred overnight at 90 °G. The completion of the reaction was monitored by HPLC. Upon completion, saturated aqueous NaHCOs was added and the reaction mixture was extracted with EtOAc. The combined organic layers were washed with brine and dried over aaSC Filtration and removal of the solvent in vacuo provided the crude product, which was purified by preparative HPLC (20-1-00% CH3CN/ 0OH (1 :1 ) in H2.O (0.01 % 'f FA)) to afford after iyophilization 34 mg (38%) of the title compound as a colorless solid, as the TFA salt; Ή NMR (400 MHz, CDCI3) δ = 8.27 (s, 1 H), 8.24 (s, 1 H), 8.11 (d, J = 8.1 Hz, 1 H), 7.82 (d, J = 7.9 Hz, 1 H), 7.75 (d, J * 8,3 Hz, 1 H), 7.67 (s, 1 H), 7,64 - 7.58 (m, 3 H), 7.46 (dd, J 5= 14, 8.2 Hz, 1 H), 7.26 (d, J = 8.8 Hz, 2 H), 7.19 (td. J = 1.7, 7.7 Hz, 1 H , 7.09 - 8.96 (m, 2 H), 5.29 (s, 2 H), 3.13 (s, 6 H). MS (EST) m/'z: 602.89 [M*].
Synthetic Example 88; 4-(6-((2-chloro-6-fluorophe.i oxy)methyl)-1-((3- (tnfluoromethyl)phe:nyl)sulfonyl)-1 H-indol-3-yl)benzon
Figure imgf000096_0001
In a dried MW fiask under Ar were introduced 8-((2-ch!oro-6 luorophenGxy)methyl)-3--iodo-1'-{{3- (irifiuorom.eihyl}phenyi)sulfonyl}-1 H-indqle (80 mg, 0.13 mmoi), 4-cyanophenyl oronic acid (25 mg, 0, 17 mmo!), CsF (40 mg, 0,26 mmoi) and 1 mL of anhydrous D E. The fiask was purged three limes with Ar before the addition of Pd{dba)2 (4 mg, 0.007 mmoi) and PPi¾ (3 mg, 0.013 mmoi). The flask was sealed and the reaction mixture was stirred overnight .at -90 °C. After removal of the solvent in vacuo, the crude product was purified by Combiflash silica gel chromatography (0-20% of EtOAc in hexane), which provided 46 mg (80%) of the title compound as a colorless solid; 1H NM.R (400 MHz, GDCfe) δ = 8.29 {s, 1 H), 8.26 (s, 1 H), 8.15 (d, J - 8:1 Hz, 1 H), 7.87 - 7.62 :{m, 8 H), 7.49 fdd, = 1.4, 8.2 Hz, 1 H), 7.22 - 7.16 (m, 1 H), 7. 0 - 8.98 (m, 2 H), 5,30 s, 2 H).
Synthetic Example J¾ -.((2-chiotO;^
{trifluoromethvnphenviisuifonyl)-1 H-indote (SR19162);
Figure imgf000096_0002
In a dried MW flask under Ar were introduced 6-((2-chloro~6-fluorophenoxy)methyi)-3-iodo.-1-((3- (trifluorpmethyl)phenyl}sulfPfiyi)-1 H-indo!e (80 mg, 0.13 mmoi), -methoxyphenyiboronic acid (26 mg, 0.17 mmoi), CsF (40 mg, 0.26 mmoi) and 1 mL of anhydrous D E. The fiask was purged three times with Ar before the addition of Pd(dba)2 (4 mg, 0.007 mmoi) and PPhg (3 mg, 0.013 mmq!). The flask was sealed and the reaction mixture was stirred overnight at .90 °C. After removal of the solvent In vacuo, the crude product was purified b Combiffash silica gel chromatography (0-20% of EtOAc in hexane), which provided 70 mg (90%) of the title compound as a colorless solid; *H MR' {400 MHz, GDCfe) δ ~ 8.28 (s, 1 H), 8.24 (s, 1 H}, 8.10 (d, J - 9.2 Hz, 1 H), 7.84 - 7.80 (rn, 1 H), 7.76 (d, J ~ 8.1 Hz, 1 H), 7.64 {s, 1 H), 7.60 (t, J - 7.9 Hz, 1 H}, 7.55 - 7.50 (m, 2 H), 7.45 (dd, J = 15, 8.1 Hz, 1 H), 7.21 - 7.16 (m, 1 H), 7.08 - 8,97 (m, 4 H), 5.29 (s, 2 H), 3.88 (s, 3 Ή).
Synthetic Example, 90; 3-(4-(tert^butyl)phenyj)-6-(:(2
(ti1fiuofomethy pheny! suj,fo.nyl)-1 H-indole (SR19163);
Figure imgf000097_0001
In a dried MW flask under Ar were introduced 6-((2-diioro-6-fluorophenoxy}methyj)-3~iodo-1-{(3- (irifluoromethyl)phenyi)suifonyi)-1H-indde (80 mg, 0.13 mol), 4-tert-butylphenylboronic acid (33 mg. 0.18 mrnol), CsF (40 mg, 0.26 mmol) and 1 ml of anhydrous DME. The flask was purged three times with Ar before the addition of Pd(dba)2 (4 mg, 0,00? mmol) and PPhs (3 mg, 0.013· mmol). The flask was sealed and the reaction mixture was stirred overnight at 90 °C. After removal of the solvent in vacuo, the crude product was purified by Corobifiash silica gel chromatography (0-20% of EtOAc in hexane), which provided 52 mg (64%) of the title compound as a colorless solid; 1H NMR (400 MHz, CDCI3) δ ~ 8.27 (s, 1 H), 8.24 (s, 1. H), 8.10 (d, J ~ 8.1 Hz, 1 H), 7.84 - 7.79 (m, 2 H), 7.70 (s, 1 M), 7.66 - 7.42 (m, 6 H), 7.22 - 7.17 (m, 1 H), 7,0 - 6.97 (m, 2 H), 5.30 (s, 2 H), 1.39 (s, 9 H),
Synthetic Example 91 : 4-{4--(6-{(2-chioro-6-fluorophenoxy)methyl)-1-i(3--
Figure imgf000097_0002
In a dried MW flask under Ar were introduced 6-((2-chlOiO-6-fluoropheRoxy)methyi)-3-iodo-1 -((3- (irifluoromethy!)phenyi)$ulfonyl)-1H-indole (8.0 mg, 0.13 mmol), 4 ( orpho nyl)phenylboronic acid (49 mg, 0.24 mmol), 2CO3 (54 mg, 0.39 mmol) and 1.5 ml of anhydrous D F, The flask was purged three times with Ar before the: addition of Pd(PPha)4 (15 mg, 0.013 mmol). The flask was sealed and the reaction mixture was stirred overnight at 90 X. The completion of the reaction was monitored by HPLC, Upon completion, saturated aqueous NaHCOa was added and the reaction mixture was extracted with EtOAc. The combined organic layers were washed with brine and dried over NaaS04. Filtration and removal of the solvent in vacuo provided the crude product, which was purified by preparative HPLC (20-100% C.HsCN/MeOH (1 :1 ) in H2O (0,01 % TFA)) to afford after lyophilization 37 mg (37%) of the title compound as a colorless solid, as the TFA .salt; 1H NMR (400 MHz, CDCb) 5 = 8.26 (s, 1 H), 8.24 (s, 1 H), 8.12 - 8.08 (m, 1 H),. 7.81 (d, J = 7.9 Hz, 1 H), 7.77 (d, ~ 8,1 Hz, 1 H), 7.65 (s, 1 H), 7.60 (f, J = 8.0 Hz, 1 H), 7.57 - 7.52 (m, 2 H), 7.46 (dd, J ~ 1.5, 8.1 Hz, 1 H), 7.20 - 7.16 (m, 1 H), 7.1 1 - 7.06 (m, 2 H), 7.06 - 6.96 (m, 2 H), 5.29 (s, 2 H), 3.9.9 - 3.90 {m, 4 H), 3.42 - 3 22 (m, 4 H). MS (ESf+) .m/z: 645.02 [M +].
Synthetic Example 92: 6--f f2-chloro-6-fluOrobenzyi)oxy)-1 -((3-(trifiuoromethyi)phenyi)suifonyl)-
Figure imgf000098_0001
Step 1: To a solution of 6-chloro~1-H-pyrrota[2,3-b]pyridine (200 mg, 1 .31 mmol) in 1 mi of DM.E and 2 ml. of TFA was added Et3S!H {2.1 mL, 13.1 mmol). The reaction mixture was stirred overnight at 70 eC. The completion of the reaction was monitored by HPLC. Upon completion, solvents were removed in vacuo. To the crude residue was added saturated aqueous NaHGOa and the reaction mixture was extracted with EtOAc. The combined organic layers were washed with brine and dried over 'Na2S04. Fiitration and removal of the solvent in vacuo provided 6- chloro-2,3-dihyd-ro-1 H-pyrrolo[2,3-b}pyridine, which was used without further purification.
Step 2; To a solution of 6--chlQro-2!3~d!hydro-1 H-pynOio[2,3--b|pyridine in 5 ml of acetone were added K2CO3 (725 mg, 5,24 mmol) and 3-{trifiuoromethyl)benzenesulfonyl chloride (420 pL, 2.62 mmol). The reaction mixture was stirred overnight at room temperature. The completion .of the reaction was monitored by HPLC. Upon completion, solvents were removed in vacuo, To the crude residue was added saturated aqueous NaHCC¾ and the reaction mixture was extracted with EtOAc. The combined organic layers were washed with brine and dried over a2S04. Filtration and removal of the solvent in vacuo provided the crude product which was purified by Combiffasb silica gel chromatography (0-50% of EtOAc in hexane), to afford 150 mg (32% yield over 2 steps) of 6-chloro-1~((3~(trifiuoromethyi)phenyl)sulfonyl)-2,3~dihydro-1 H- pyrro [2,3-b]pyridine as a yellow solid; H R (400 MHz, CDCI3) δ - 8.51 (s, 1 H), 8.37 (d, J - 6.8 Hz, 1 H), 7.88 (d, J = 7.2 Hz, 1 H), 7.73 ~ 7.65 (m, 1 H), 7.31 (id, J - 13, 7.8 Hz, 1 H), 6.86 (d, J ~ 7.7 Hz, 1 H), 4.1 S (t, J. - 8.4 Hz, 2 H), 3.07 (dt, J = 11, 8.4 Hz, 2 H).
Step 3* In a dried W flask under Ar were introduced 6-chloro-1 -({3- .{trif)uorome†hyl)phenyi)sylfo^ mg, 0,14mol), (2- chtorQ-6-f!uoropheny methanoi (29 mg, 0.18 mmol), CS2CO3 (90 mg, Q.28 mmol) and 1 ,2 mL of anhydrous toluene. The flask was purged three times with Ar before the addition of Pd{OAc)2 (2 mg, G.G07 mmoi) and Xantphos (8 mg, 0.014 nrtmol). The flask was sealed and the reaction mixture was stirred overnight at 100 °C. The compietion of the reaction was monitored by HPLC. Upon completion, saturated aqueous aHCOa was added and the reaction mixture was extracted with EtOAc, The combined organic layers were washed with brine and dried over NazSO Filtration and removal of the solvent in vacuo provided the crude product, which was purified by preparative HPLC (20-100% CH3CN/ e.OH (1 : 1 ) in H2Q (0.01% TFA)) to afford after lyophiiization 1 1 mg (16%) of the title compound as a colorless solid, as the TFA salt; 1H NMR (400 MHz, CDC ) δ = 8.43 (s, 1 H), 8.36 (d, J = 7.2 Hz, 1 H), 7.86 (d, J « 7.9 Hz, 1 H), 7.68 (t, J = 7.9 Hz, 1 H), 7.36 - 7.23 (m, 3 H), 7.10 - 7.03 .(m, 1 H), 6.33 (d, J ~ 8.1 Hz, 1 H), 5,45 (d, J - 2.0 Hz, 2 H), 4:18 (t, J ~ 8,4 Hz, 2 H), 3.04 (t, J ~ 8.4 Hz, 2 H). MS (ESI+) m/z: 486.90 [H÷],
Synthetic Example 93: 6-f(2-chioro-6 luorobenzyl)oxy)-1 -((3-(irifluoromethvi)phenyj)suifonyn-
Figure imgf000099_0001
Step 1 : To a solution of 6-chloro-5-azaindoie (200 mg, 1.31 mmoi) in 3.3 mL of THF was added BHs-Slvle (622 pL, 6.55 mmoi). The reaction mixture was stirred overnight at 70 °G. The completion of the reaction was monitored by HPLC, Upon completion, methanol was added and solvents were removed in vacuo. To the crude residue was added saturated aqueous NaHC(¼ and extracted with EiOAc. The combined organic layers were washed with brine and dried over a2.S04. Filtration and removal of the solvent provided 6-ch Qro-2,3-dihydro-1 H-pyrrolo[3,:2~ c]pyridine, which was used without further purification.
Step 2: To a solution of 6-chioro-2,3-dihydro-1H-pyrro!o[3,2-c3pyrid)ne in 5 mL of acetone were added K2CO3 (725 mg, 5.24 mmo!) and 3-(trifluoromethyl)benzenesuifonyj chloride (420 μΐ, 2,62 mmoi). The reaction mixture was stirred overnight at room temperature. The completion of the reaction was monitored by HPLC. Upon completion, solvents were removed in vacuo. To the crude residue was added saturated aqueous hiaHCQa and extracted with EtOAc. The combined organic layers were washed with brine and dried over 'NasSG*. Filtration and removal of the solvent in vacuo provided 'the. crude product which was purified by Combifiash silica gel chromatography (0-50% of EtOAc in hexane), to afford 131 .mg (28% yield over 2 steps) of 6- chioro~1~((3"(trifluQromethyl)phenyi)sulf'ony!)~2,3~dihydro-1 H-pyrroio|3!2"C]pyrldine as a yellow solid product; 1H N R (400 MHz, CDCfe) δ = 8.15 (s, 1 H), 8.09 - 8.02 (m, 2 H), 7.93 (d, J ~ 7.9 Hz, 1 H), 7.78 - 7.70 (m, 1 H), 7.52 (s, 1 H), 4.02 (t, J = 8.1 Hz, 2 H), 3.09 (t, J ~ 8.4 Hz, 2 H).
Step 3: In a dried MW flask under Ar were introduced 6~chioro-1~((3- (trifluorome.thy!)phen l)su!fonyi)-2,3-dihydro-1H-pyfro.io{3,^ (50 mg, .0.14moi), (2- ehioro-6-iiUGrophenyi)methanoS (66 mg, 0.41 mmoi), GsgC(¾ (180 mg, 0.55 mmoi) and 1.2 mL of anhydrous toluene. The flask was purged three times with Ar before the addition of Pd(OAc)2 (2 mg, 0,007 rnmoi) and Xantphos (8 mg, 0.014 mmoi). The flask was sealed and the reaction mixture was stirred overnight at 100 °C. The completion of the reaction was monitored by HPLC. Upon completion, saturated aqueous !MaHC03 was added and the reaction mixture, was extracted with EtOAc. The combined organic layers were washed with brine and dried over a2St> . Filtration and removal of the solvent provided the crude product, which was purified by preparative HPLC (20-100% CHaCN/MeGH {1 : 1 } in H2O (0.01% TFA)) to afford after
iyophilizaiion 11 mg (16%) of the title compound as a colorless solid, as the TFA salt; H NMR (400 MHz, CDC ) δ * 8.16 (s, 1 H), 8.10 - 8.04 (m, 2. H), 7.95 (d, J = 7.2 Hz, 1 H), 7.77 - 7.71 (m, 1 H), 7.37 (dt, - 5.9, 8,2 Hz, 1 H), 7.30 (dd, J 1.0, 8.0 Hz, 1 H), 7.14 - 7.07 (m, 2 H), 5.53 (d, J - 1.8 Hz, 2 H), 4.07 (t, J = 8.1 Hz, 2 H), 3.12 (t, J - 8.1 Hz, 2 H). MS (ESI4) m/z: 487.87 [M+H+J.
Figure imgf000100_0001
ii)) mmeetthhyyll 44--bbrroommppbbeennzzooaattee,, KK22CCOO33,, BBnnBBuussNNCCII,, PPdd((OOAAcc}}¾¾ ttoolluueennee,, 9900 °°CC;; iiss)) EEfcfcSSiiHH,, TTFFAA,, DDMMEE,, 5500 °°..CC,, tthheenn 33--CCFF33PPhhSS0022CC!!,, EEii33NN,, DDCCMM,, rr..tt.. ;; i iiiii)) LLiiOOHH 11MM,, TTHHFF,, r r..tt;; iiyy)) NNHH44GGSS oorr HHNNMMeegg..HHCCll,, HHAATTUU,, DD!!EEAA,, DDMMFF,, rr..tt..
S Syynntthheettiicc EExxaammppll 9944:: m meetthhyyll 44--((ee--((((22--cchhiioorroo--66--ffiiuuoorrQQbbeennzzyyll))ooxxyy))--11--((((33--
Figure imgf000100_0002
Figure imgf000101_0001
Step 1: In a dried W flask under Ar were introduced 8-{{2-chloro-6-fiuoro enzyi)oxy)~1 H~indole (200 mg, 0,73 .mmoi), K2CO3 (301 mg, 2.18 mmol) and 2.5 mL of anhydrous toluene. The flask was purged three limes with Ar before the addition of methyl 4-bromcbenzoate (199 mg, 0.87 mmoi), Br¾BLi3 Ci {45 mg, 0.14 mmoi) and Pd{OAc)s (8 mg, 0,04 mmoi) The flask was sealed and the reaction mixture was stirred overnight at 90 °C. After removal of the solvent in vacuo, the crude product was purified by Cornblfiash silica gel chromatography (0-40% of EtOAc in hexane), which provided 175 mg (59%) of methyl 4-(6-((2 Chloro-6-fluoroben2yl)oxy)-1 H-indoi-3- y!)benzoate as a yellow oil product; 1H N (400 MHz, CDCI3) δ = 8.13 - 8.08 (m, 2 H), 7.86 (d, J = 8.8 Hz, 1 H), 7.75 - 7.67 (ra, 2 H), 7.37 (d, J = 2,4 Hz, 1 H), 7.32 - 7.22 (m, 2 Hj. 7.08 - 7.03 (m, 1 H), 7.03 - 6.93 (m, 1 H), 5.22 (d, J = 2.0 Hz, 2 H), 3.95 (s, 3 H)..
Step 2: To a solution of methyl 4-(6~((2~chipro-6-fluoiObenzy!)oxy)-1 H~indol-3-y!)benzoate { 5 mg, 0.43 mmol) in 1 mL of DME and 2 mL of TFA was added Et3SiH (1 .0 ml, 6.41 mmol) The flask was sealed and the reaction mixture was stirred overnight at 50 °C, After removal of solvents in vacuo, the crude product was purified by preparative HPLC (20-100% CH3CN/MeOH (1 :1 ) in H2O (0.01 % TFA)) which provided methyl 4~(6-((2-chjoro-6-fSuorobenzyi)oxy)indol!i>3- yl)benzoate.
Step 3: To a solution of methyi 4~(6-((2-chloro-6~fiuorobenzyl)oxy)indolin-3-y1)benzoate in 2 mL of DC. were added Et^ (298 pL, 2.14 mmoi) and -3-(trifiuoromethyl)benzenesuifony.i chloride (137 uL, 0.85 mmoi). The. solution was stirred 2h at room temperature, After removal of the solvent in vacuo, the crude product, was purified by preparative HPLC (20-100% CH3CN/MeOH (1 :1 ) in HaO (0.01 % TFA)) which- provided after lyophilizaiion 35 mg (13% yield over 2 steps) of the title compound as a colorless solid; 1H NMR (400 MHz, CDC ) 5 = 8.06 fa, 1 H), 7.97 (d, J = 8.1 Hz, 1 H), 7.88 - 7.82 (m, 3 H), 7.53 - 7.5 .(m, 1 H), 7.47 (d, ,/ * -2,4 Hz, 1 H), 7,38 - 7.27 {m, 2 H), 7.13 - 7,05 (m, 1 H), 8.95 - 6.88 (m, 2 H), 6.8-1 (d, J * 8.3 Hz, 1 H), 6,68 (dd, J - 2.4, 8,3 Hz, 1 H), 5,24 (d, J = 1.8 Hz, 2 H), 4.46 - 4.34 (m, 2 H), 3.91 (s, 3 H), 3,85 (dd, 4.9, 9.8 Hz, 1 H). Synthetic Example 95; 4-{6-({2-chloro-6-fiuoroben:^
1 H-»ndol-3-yl)benzojc acid (SRI 9341 ):
Figure imgf000102_0001
To a solution of methyl 4'{6-((2-chlb'ro-6-fluofobenzyl)oxy)-1 -((3-
(trifl.uoromethylipheny suifonyi iH-'indoS-S-ylJbenzoate {30 mg, 0.05 mmol) in 1 m l of THF was added 100 μΐ of aqueous LiOH 1 M. The reaction was stirred overnight at room temperature. The completion of the reaction was monitored by HPLC. Upon completion, aqueous HQ 1 N was added and the reaction mixture was extracted with EtOAe. The combined organic layers were washed with, brine and dried over aaS04. Filtration and removal of the solvent in vacuo provided the title compound as a light yellow solid, which was used without further purification; 1H NMR (400 MHz, CDGL3) δ = 8 07 (s, 1 H), 7,98 (d, J = 7.9 Hz, 1. H), 7.93 - 7.88 (m, 2 H), 7.85 (d, J = 8.5 Hz, 1 H), 7.60 (t, J = 7.9 Hz, 1 H), 7.47 (d, J ~ 2.4 Hz, 1 H), 7.38 - 7,28 (m, 2 H), 7.13 - 7.05 (m, 1 H), 6.97 - 6.91 (m, 2 H), 6.83 (d, J = 8.3 Hz, 1 H), 6.70 (del, J 2.4, 8.3 Hz, 1 H), 5.24 (d, J = 1 ,3 Hz, 2 H), 4.47 - 4.35 (m, 2 H), 3.87 (dd, J = 4.2, 9.2 Hz, 1 H), MS .(ESI") m/z: 604.15 [M-Hl
Synthetic Example 96: 4-(6-{(2-chloro~6~f iuorobenzyQoxy)- -((3 (tri<luoromethyt}phenyl.¾sulfonyl)- - j n d o ί-3-yl) enza m i de (S R 19342):
Figure imgf000102_0002
To a solution 4-(6-((2-chloro-6-fluorobenzyl)o^^
3-yl)benzoic acid .{8 mg, 0.013 mmol) in 0.2 ml. of D F were added HATU (8 mg, 0.02 mmo!),
DIEA (9 pi, 0.05 mmol) and NH4C! (1 mg, 0.03 mmd!). The reaction was stirred overnight at room temperature. After removal of the solvent in vacuo, the crude product was purified by preparative HPLC (20-100% CH3CN/ eOH (1 :1 ) in H20 (0.01% TFA}) which provided after lyophrlization 7 mg (88%) of the title compound as a colorless solid; 1H NMR (400 MHz, CDC ) δ = 8.08 {s, 1 H), 7.99 (d, J - 7.9 Hz, 1 H), 7.85 (d, J * 7.9 Hz, 1 H), 7.67 - 7,58 (rn, 3 H), 7.48 (d, J = 2.2 Hz, 1 H), 7.39 - 7.27 (m, 2 H), 7.13 - 7.08 (m, 1 H), 6.97 (d, J - 8.3 Hz, 2 H), 6.81 (d, JJ -- 88..33 HHzz,, 11 HH)),, 66..6699 ((dddd,, JJ == 22..44,, 88..33 HHz,, 11 HH)),, 66..0000 ((bbrr.. ss..,, 22 HH)),, 55..2233 ((dd.. JJ = = 22..00 HHzz.,, 22 HH)),, 44,,4444 -- 44..3344. ((mrn,, 22 HH)),, 33..9911 -- 33 8811 ((rnn,, 11 HH)).. MMSS ((EΕS8IΓ+)) mm//zz:: 660044..8833 [[MMll..
Figure imgf000103_0001
imethylbenzamide (SR19343):
Figure imgf000103_0002
To a solution 4-(6-((2~chloro-6-fiuorobenzy!)oxy)-1 -((3-(trifiuoromethyl)phenyl)su!fonyl)-1 H-indol- 3~yi)benzoic acid (8 mg, 0.Q13 mmol} in 0.2 mL of DMF were added HATU (8 mg, 0.02 mmo!), DIEA {9 μΐ_, 0.05 mmol) and dimethyiamine hydrochloride (2 mg, 0,03 mmol). The reaction was stirred overnight at room temperature. After removal of the solvent in vacuo, the crude product was purified by preparative HPLC (20-100% CH3CN/!y†eOH (1:1) in H20 (0.01% TFA)) which provided after lyophilization 6 mg (72%) of the title compound as a colorless solid; 1H NMR (400 MHz, CDCIs) δ = 8,11 (s, 1 H), 8.00 (d, J * 7,9 Hz, 1 H), 7.86 (d, J = 7.9 Hz, 1 H), 7.68 - 7.60 (m, 1 H), 7,45 (d, J - 2.4 Hz, 1 H), 7.38 - 7.28 (m, 2 H), 7.28 - 7.24 (m, 2 H), 7.12 - 7.06 (m, 1 H), 6.92 (d, J = 8.1 Hz, 2 H), 6.80 (dd, J = 0.7, 8.3 Hz, 1 H), 6,68 (dd, J ~ 2.3, 8.4 Hz, 1 H), 5.23 (d, J - 18 Hz, 2 H), 4.44 - 4,31 (m, 2 H), 3.87 - 3.82 (m, 1 H). MS (ESr) m/z: 632.96: [M*J.

Claims

What is claimed is:
An RORy receptor agonist comprising a compound of formula ( I),
Figure imgf000104_0001
wherein
X-Y together is -CH2-0-, -O-CH,-, CH(R)-G-, -O-CH(R)-, ~CG~0-, -G-GG-, -CH2-NH-. - CH2-NH(R)-, -NHC.H(R)-, -NH-CO-, or - (R)-CO;
the ring bonded to Y and B optionally further comprises 1 or 2 nitrogen atoms atari unsubstituted position thereof;
A-B together s -CR~CR- or™CH(R)CH(R)-, wherein each R is independently H or (C1 - C6)alkyi,. halo, haio(Cl~C6}aikyi. aryi, carboxyi, or carboxyalky!;
R1 is halo, (C1-C6)aikyl, (C1-C6)aikoxyi, halo{ei-C6)alkyi, ha!o(C1 -G6)alkoxy, cyano, carboxy (C1 ~C6)aiky1; unsubstituted or substituied phenyl, or unsubstituted or substituted pyridyl; n1 =0, 1 , 2, or 3;
wherein the ring bonded to X can optionally further comprise 1 or 2 nitrogen atoms;
R2 is halo, (C1~C6)alkyi, {C1-C6)alkoxyi, halo(C1-C.6)alkyl( halo(C1-C6)alkoxy, cyano, carboxy (C1-C8)aikyl; unsubstituted or substituted phenyl, or unsubstituted or substituted pyridyl; n2~0, 1 , 2, or 3;
wherein the ring bonded to R2 can optionally further comprise 1 or 2 nitrogen atoms; or a pharmaceutically acceptable salt there,
2. The compound of claim 1 , wherein n1~2 and R1 is halo; or where n2~1 and R2 Is trifiuprornethyi; or wherein each R is independently H or methyl; or X-Y is -CH2-O-, or -O-CM2-; or any combination thereof.
The compound of claim 1 of formula
Figure imgf000104_0002
wherein X, Y, A, B, R2, and n2, are as defined in claim 1 .
4. The compound of claim 1 , wherein the compound of formula (I) is
Figure imgf000105_0001
wherein
X, Y, A, B, and R, are as defined in claim 1 ;
or a pharmaceutically acceptable salt thereof.
5. A method of activating the nuclear receptor RORv, comprising contacting the RO y with an effective amount or concentration of a compound of claim 1,
6. A method of treating cancer in a patient, comprising administering to the patient an effective dose of a compound of claim 1 ,
PCT/US2017/051178 2016-09-13 2017-09-12 RORγ MODULATORS WO2018052903A1 (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140088094A1 (en) * 2010-11-08 2014-03-27 Merck Sharp & Dohme Corp. N-SULFONYLATED TETRAHYDROQUINOLINES AND RELATED BICYCLIC COMPOUNDS FOR INHIBITION OF RORgamma ACTIVITY AND THE TREATMENT OF DISEASE
US20150111877A1 (en) * 2012-05-08 2015-04-23 Merck Sharp & Dohme Corp. TETRAHYDRONAPHTHYRIDINE AND RELATED BICYCLIC COMPOUNDS FOR INHIBITION OF RORgamma ACTIVITY AND THE TREATMENT OF DISEASE

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140088094A1 (en) * 2010-11-08 2014-03-27 Merck Sharp & Dohme Corp. N-SULFONYLATED TETRAHYDROQUINOLINES AND RELATED BICYCLIC COMPOUNDS FOR INHIBITION OF RORgamma ACTIVITY AND THE TREATMENT OF DISEASE
US20150111877A1 (en) * 2012-05-08 2015-04-23 Merck Sharp & Dohme Corp. TETRAHYDRONAPHTHYRIDINE AND RELATED BICYCLIC COMPOUNDS FOR INHIBITION OF RORgamma ACTIVITY AND THE TREATMENT OF DISEASE

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Title
FAUBER ET AL.: "Modulators of the Nuclear Receptor Retinoic Acid Receptor-Related Orphan Receptor- (ROR or RORc)", J. MED. CHEM., vol. 57, no. 14, 2014, pages 5871 - 5892, XP055242989 *
FAUBER ET AL.: "Structure-based design of substituted hexafluoroisopropanol-arylsulfonamides as modulators of RORc", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 23, 2013, pages 6604 - 6609, XP028788052 *

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