|HAO WAKAT I MARIAUS009937186B2 DEL CON AT MALAMAN NAT (12 ) United States Patent (10 ) Patent No. : US 9 , 937 , 186 B2 Ohlmeyer et al. (45 ) Date of Patent: Apr. 10 , 2018 (54 ) SULFONAMIDES DERIVED FROM USPC ...... 514 / 217 TRICYCLYL - 2 - AMINOCYCLOALKANOLS See application file for complete search history . AS ANTICANCER AGENTS ( 71 ) Applicant: ICAHN SCHOOL OF MEDICINE ( 56 ) References Cited AT MOUNT SINAI, New York , NY U . S . PATENT DOCUMENTS (US ) 4 ,634 ,766 A 1 / 1987 Atkinson et al. (72 ) Inventors : Michael Ohlmeyer , Plainsboro , NJ 4 ,668 ,671 A 5 / 1987 Gribble et al . (US ); David Kastrinsky , Fair Lawn, NJ 4 , 882 , 351A 11/ 1989 Oshima et al. 6 ,583 , 138 B1 6 /2003 Miyamoto et al . (US ) 9 , 540 , 358 B2 1 / 2017 Ohlmeyer et al. 2002/ 0103189 A18 / 2002 Miyamoto et al. @(73 ) Assignee : ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI, New York , NY 2008/ 0275023 Al 11/ 2008 Guidi et al . (US ) (Continued ) ( * ) Notice : Subject to any disclaimer , the term of this FOREIGN PATENT DOCUMENTS patent is extended or adjusted under 35 CN 102942562 A 2/ 2013 U . S .C . 154 (b ) by 0 days . EP 0679641 A1 11/ 1995 (21 ) Appl. No. : 15 /124 , 891 (Continued ) ( 22 ) PCT Filed : Mar. 10 , 2015 OTHER PUBLICATIONS Zhang et al, “ Akt, FoxO and regulation of apoptosis, ” Biochimica ( 86 ) PCT No .: PCT/ US2015 / 019770 et Biophysica Acta , 2011, vol. 1813, pp . 1978 -1986 .* $ 371 (c )( 1 ), (Continued ) ( 2 ) Date : Sep . 9 , 2016 (87 ) PCT Pub . No. : WO2015 /138500 Primary Examiner — Kathrien A Cruz Assistant Examiner — Janet L . Coppins PCT Pub . Date : Sep . 17 , 2015 (74 ) Attorney, Agent, or Firm — Heslin Rothenberg (65 ) Prior Publication Data Farley & Mesiti P . C . US 2017 /0015625 A1 Jan . 19 , 2017 ( 57 ) ABSTRACT Related U .S . Application Data A genus of arylsulfonamide derivatives of aminocycloal ( 60 ) Provisional application No . 61/ 951 , 237 , filed on Mar . kanols is disclosed . The compounds are of the following 11 , 2014 . genus : (51 ) Int. Ci. A61K 31/ 517 ( 2006 .01 ) R 3 A61K 31/ 55 ( 2006 .01 ) A61K 31 / 18 ( 2006 .01 ) UR4 C07C 311 /29 ( 2006 .01 ) CO7D 243 /38 ( 2006 .01 ) OH 025 C070 471/ 04 ( 2006 .01 ) CO7D 265 / 38 ( 2006 . 01 ) NH CO7D 267 / 18 ( 2006 .01 ) CO7D 495 /04 ( 2006 .01 ) R2 - + IT C07D 209 /86 ( 2006 .01 ) ( CH2) CO7D 487/ 04 ( 2006 .01 ) (52 ) U . S . CI. CPC ...... A61K 31 /55 ( 2013 .01 ); A61K 31/ 18 (2013 . 01 ) ; A61K 31/ 517 ( 2013 . 01) ; C07C 311/ 29 ( 2013 .01 ) ; C07D 209 /86 (2013 .01 ) ; The compounds induce FOXO1 transcription factor trans C07D 243 /38 (2013 . 01 ) ; C07D 265 / 38 location to the nucleus by modulating PP2A and , as a ( 2013 .01 ); C07D 267 / 18 (2013 . 01 ) ; C07D consequence , exhibit anti- proliferative effects . They are 471/ 04 (2013 . 01 ) ; C07D 487 /04 ( 2013 .01 ) ; useful in the treatment of a variety of disorders , including as C07D 495 /04 (2013 .01 ) ; C07C 2601/ 08 a monotherapy in cancer treatment, or used in combination (2017 . 05 ); C07C 2601/ 14 (2017 . 05 ); C07C with other drugs to restore sensitivity to chemotherapy 2603 /18 (2017 .05 ) where resistance has developed . (58 ) Field of Classification Search CPC ...... A61K 31/ 18 ; A61K 31/ 517 ; A61K 31/ 55 19 Claims, No Drawings US 9, 937 , 186 B2 Page 2

( 56 ) References Cited carbon bonds, " Chemical Communications, 2011 ( published on Web : Jun . 22, 2011) , vol. 47 , No . 29 , pp . 8343 - 8345 . U . S . PATENT DOCUMENTS Azuine et al. , “ Cancer chemopreventive effect of phenothiazines and related tri- heterocyclic analogues in the 12 - 0 2015 /0376191 Al 12 /2015 Ohlmeyer et al . tetradecanoylphorbol - 13 -acetate promoted Epstein - Barr virus early 2017 /0015630 A11 / 2017 Ohlmeyer et al. antigen activation and the mouse skin two - stage carcinogenes is models ,” Pharmacological Research , 2004 , vol. 49 , No . 2 , pp . FOREIGN PATENT DOCUMENTS 161- 169 . EP 0881220 A112 / 1998 Ohshima, et al ., “ Non - Prostanoid Thromboxane A , Receptor WO 2004052847 A2 6 / 2004 Antagonists with a Dibenzoxepin Ring System . 2 " J . Med . Chem , wo 2006116157 A2 11 /2006 1992 , 35 , 3402 - 3413 . WO 2006117183 A1 11/ 2006 Morak -Mlodawska et al. , “ Acyl and Sulfonyl Derivatives of WO 2013025882 A2 2 / 2013 10 - Aminoalkyl- 2 , 7 - Diazaphenothiazines# , Hetrocycles” , vol . 78 , WO WO2013025882 A2 * 2 / 2013 . . . C07D 417 /04 No . 5 , 2009 . WO 2014031986 Al 2 / 2014 WO 2014130534 Al 8 / 2014 Alfonso et al. , “ Synthesis of a Cu Spiropiperdino derivative of WO 2015138496 A1 9 / 2015 8 - Chloro - 6 , 11 -dihydro 5H - Benzo [ 5 , 6 ] cyclohepta [ 1 , 2 WO 2017 /024229 A1 2 / 2017 b ]pyridine ” , Tetrahedron Letters 39 , 1998 , 7661 -7664 . WO 2017 /044567 A1 3 /2017 Kau et al ., A chemical genetic screen identifies inhibitors of regu WO 2017 /044569 A1 3 / 2017 lated nuclear export of a Forkhead transcription factor in PTEN WO 2017 / 044571 AL 3 / 2017 deficient tumor cells , Cancer Cell, XP008037524 , Dec . 2003 . 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N - acylphenothiazines” International Journal of Antimicrobial International Search Report for PCT/ US2014 /017127 dated May Agents, 2000 , pp . 203 - 207, vol. 14 . 20 , 2014 Database PubChemCompound , “ N - [4 -methoxy -3 -( 3 -phenothiazin Alfredsson et al. , “ Mass Fragmentographic Analysis of Clomip 10 - ylpropylsulfamoyl) phenyl ]acetamide ," URL : http : / /pubchem . ramine and Its Mono - Demethylated Metabolite in Human Plasma” ncbi. nlm .nih . gov / search .cgi , 2005 - 2009 . Psychopharmacology , 52, 25 -30 ( 1977) . International Search Report for PCT/ US2015 /019764 dated May 8 , Midgley et al. , " Synthesis of [ 13C2] - Amitriptyline , Nortriptyline 2015 . and Desmethynortriptyline” Journal of Labelled Compounds and International Search Report for PCT/ US2016 /050685 dated Oct. 18 , Radiopharmaceuticals , vol . XV , pp . 511 -521 ( 1978 ). 2016 . Hadrich et al ., “ Synthesis and Characterization of Fluorescent International Search Report for PCT/ US2016 /050688 dated Oct . 18 , Ligands for the Norepinephrine Transporter : Potential 2016 . Neuroblastoma Imaging Agents” , J . Med . Chem . , 1999, (published International Search Report for PCT/ US2016 /045779 dated Sep . 30 , on web Jul. 16 , 1999 ) . 2016 . Runyon et al . , “ Influence of Chain Length and N - Alkylation on the International Search Report for PCT/ US2016 / 050690 dated Oct. 18 , Selective Serotonin Receptor Ligand 9 - (Aminomethyl ) - 9 , 10 2016 . dihydroanthracene” , Bioorganic & Medicinal Chemistry Letters 11 International Search Report for PCT /US2016 /050696 dated Oct. 18 , (2001 ) , 655 -658 . 2016 . Van Dort et al. , Synthesis of 11 C - Labeled Desipramine and its International Search Report for PCT/ US2016 /050692 dated Oct. 18 , Metabolite 2 -Hydroxydesipramine : Potential Radiotracers for PET 2016 . Studies of the Norepinephrine Transporter , Nuclear Medicine & O ' Brien et al ., “ cis - and trans -Stereoselective Epoxidation of N -pro Biology, vol. 24 , pp . 707 - 711 , 1997. tected 2 - Cyclohexen -1 - ylamines ,” Organic Letters , 2003 , 14 ( 23 ), Ilies et al. , “ Protease Inhibitors : Synthesis of Bacterial Collagenase 6012 -6015 . and Matrix Metalloproteinase Inhibitors Incorporating International Search Report & Written Opinion issued in PCT/ Arylsulfonylureido and 5 -Dibenzo - suberenyl / suberyl Moieties" , US2015 /019770 , dated May 8 , 2015 . Bioorganic & Medicinal Chemistry , 11 (2003 ) 2227 -2239 . RN 1350122 - 38 - 1 CAS Registry , entered STN : Dec. 7 , 2011 . Yang et al. , “ Catalytic decarboxylative alkylationof B -keto acids with sulfonamides via the cleavage of carbon - nitrogen and carbon * cited by examiner US 9 , 937 , 186 B2 SULFONAMIDES DERIVED FROM proapoptotic protein BIM . In addition , PP2A directly regu TRICYCLYL - 2 - AMINOCYCLOALKANOLS lates FOXO3 a subcellular localization and transcriptional AS ANTICANCER AGENTS activation . Without wishing to be held to any particular theory , it may be that the compounds described herein CROSS REFERENCE TO RELATED 5 promote apoptosis by acting on FOXO transcription factors APPLICATIONS via activation of PP2A . This application is a U . S . National Phase filing under 35 Prostate cancer is the second leading cause of cancer U . S . C . $ 371 of International Application PCT/ US2015 / death in men in America , behind lung cancer. According to 019770 , filed Mar . 10 , 2015 , and published as WO 2015 / 10 the American Cancer Society , approximately 1 man in 36 138500 on Sep . 17 , 2015 . PCT/ US2015 /019770 claims will die of prostate cancer. Male hormones, specifically priority of U . S . provisional application 61 / 951 ,237 , filed testosterone , fuel the growth of prostate cancer. By reducing Mar. 11 , 2014 . The entire contents of each of the prior the amount and activity of testosterone, the growth of applications are incorporated herein by reference . advanced prostate cancer is slowed . Endocrine therapy , 15 known as androgen ablation , is the first line of treatment for FIELD OF THE INVENTION metastatic prostate cancer. Androgen deprivation therapy for metastatic prostate cancer results in tumor regression and The invention relates to the use of tricyclic chemical symptomatic improvement in the majority of patients . How modulators of PP2A , comprising 2 - sulfonamido - tricyclyl- ever, metastatic prostate cancer inevitably progresses cycloalkanols to treat diseases such as cancer, neurodegen - 20 despite castrate levels of serum testosterone . Several new erative disease and other disorders . therapies have been approved for patients with castration resistant prostate cancer (CRPC ) ; however, none are cura BACKGROUND tive and tumors ultimately develop resistance . To combat The FOXO (Forkhead transcription factors , Class O ) 25 CRPC new approaches and novel therapies are required . proteins are a group of transcription factors involved in Breast cancer can affect both men and women . Breast control of a variety of physiological, metabolic and devel cancer is the most prevalent cancer in women , after skin opmental pathways. They are downstream effectors in a cancers , with about 1 in every 8 women expected to develop number of signaling pathways including insulin and growth invasive breast cancer at some point. One subset of breast factor signaling ; they are also regulated by oxidative stress 30 cancer expresses the androgen receptor (AR ) , which has and nutrient deprivation . Cellular processes affected by been implicated as a therapeutic target in that subset. About FOXO activity include cell cycle control, differentiation , 10 - 20 % of breast cancers — more than one out of every proliferation and apoptosis . Disregulation of FOXO medi- 10 are found to be triple - negative . “ Triple negative breast ated processes has been implicated in a number of patholo - cancer ” refers to a breast cancer that does not contain gies including tumorigenesis , inflammation , diabetes and 35 estrogen receptors , progesterone receptors , or human epi neurodegenerative conditions amongst others . Activity of FOXO transcription factors are controlled in part by their dermal growth factor receptor 2 (HER2 ). This means that the sub - cellular localization , in particular their localization to growth of the cancer is not supported by the hormones the nucleus from the cytosol , and their subsequent transcrip estrogen and progesterone, nor by the presence of too many tional activation . HER2 receptors. Therefore , triple - negative breast cancer Four FOXO proteins designated FOXO1, FOXO3a , does not respond to hormonal therapy (such as tamoxifen or FOX04 and FOXO6 are present in human cells and their aromatase inhibitors ) or therapies that target HER2 recep activity is controlled by a variety of mechanisms including tors, such as Herceptin ( chemical name: trastuzumab ) . stability (proteolytic cleavage ) , sub - cellular localization and While these tumors are often treatable , the chemotherapy is transcriptional activation . Activity of the first three members 45450 not targeted , and response durations are short. For doctors of the family is controlled by cytosolic - nuclear transloca and researchers, there is intense interest in finding new tion . medications that can treat breast cancer. FOXO1 regulates expression of a number of genes that The compounds described herein , which are based on a play critical roles in cell cycle and apoptosis . A pivotal 2 -aminocycloalkanol scaffold , exhibit anti -proliferative regulatory mechanism of FOXO is reversible phosphory - 50 effects and are useful as monotherapy in cancer treatment. lation , catalyzed by kinases and phosphatases . Phosphory . Additionally , they can be used in combination with other lation of FOX01 is associated with 14 - 3 - 3 binding and drugs to restore sensitivity to chemotherapy where resis cytosolic localization , whereas dephosphorylated FOXO1 tance has developed . translocates to the nucleus and is transcriptionally active . Protein phosphatase 2A is one of the four major serine 55 threonine phosphatases and is implicated in the negative SUMMARY OF THE INVENTION control of cell growth and division . Protein phosphatase 2A holoenzymes are heterotrimeric proteins composed of a A genus of arylsulfonamide derivatives of aminocycloal structural subunit A , a catalytic subunit C , and a regulatory kanols has now been found that induce FOXO1 transcription subunit B . The PP2A heterotrimeric protein phosphatasehosphatase isis 60 factor translocation to the nucleus by modulating PP2A . The a ubiquitous and conserved phosphatase with broad sub compounds described herein exhibit anti -proliferative strate specificity and diverse cellular functions . Among the effects , and are useful in the treatment of a variety of targets of PP2A are proteins of oncogenic signaling cas disorders, including as a monotherapy in cancer treatment, cades , such as Raf , MEK , and AKT. or used in combination with other drugs to restore sensitivity PP2A interacts directly with FOX01 and dephosphory - 65 to chemotherapy where resistance has developed . lates FOX01. Inhibition of PP2A phosphatases rescues In a first aspect the invention relates to compounds of FOXO1- mediated cell death by regulating the level of the formula ( I ) : US 9 ,937 , 186 B2

R3 pur U + R4 R4 . - U R4 OH OS OH 028 22 NH NH 10 R2 + T R + T (CH2 ) RI 15 wherein : as described above . B is selected from the group consisting of: direct bond , In some embodiments , the invention relates to compounds - 0 % , (CH2 – 0 ) - , - ( 0 – CH2) - , -C O N of formula (II ) : (CH3 ) - and — N ( CH2) C ( 0 ) ; 20 A is selected from N and CH ; T is a benzene ring or a five or six membered heteroaromatic II ring ; U is a benzene ring or a five or six membered heteroaromatic ring; 2525 U R4 n is zero , 1 or 2 ; R ' , R2, R3 and R + are chosen independently from H , OH , halogen , cyano , nitro , ( C1- C3 ) alkylamino , (C ,- C3) dialky Y HO028 6 lamino , (C , - CZ )acylamino , ( C , -CZ Jalkylsulfonyl, (C , -CZ ) alkylthio , ( C , - CZ) alkyl, ( C , -C3 ) haloalkyl, ( C , - C3) ha - 30 11101 loalkoxy, - CC ( O ) (CZ -Cz ) alkyl, and ( C , -CZ ) alkoxy ; R27 T R and Rºare chosen independently from H , halogen , cyano , nitro , azido, (C , -Cz ) haloalkyl , (C ,- Cz) haloalkoxy , and (C2 - C3) haloalkylthio . In a second aspect, the invention relates to methods and 35 uses of the above - described compounds in medicine , par ticularly for the treatment of a disease chosen from : ( a ) In some embodiments , the invention relates to compounds cancer; ( b ) diabetes; (c ) autoimmune disease ; ( d ) age onset of formula ( IIIa ) or IIIb : proteotoxic disease ; ( e ) mood disorder ; ( f ) acne vulgaris ; ( g ) IIIa solid organ transplant rejection ; ( h ) graft vs . host disease ; ( i ) 40 cardiac hypertrophy ; (j ) viral infection ; (k ) parasitic infec tion ; ( 1 ) autism ; ( m ) schizophrenia and ( n ) psychostimulant abuse . These methods include administering to a patient a R4 therapeutically effective amount of a compound described R6 above . 45 In a third aspect, the invention relates to a method for OH restoring sensitivity to one or more chemotherapeutic agents in the treatment of cancer. The method includes administer ing an effective amount of a compound described above . In a fourth aspect, the invention relates to a method for 50 R2 + T treating a disease or disorder in a patient where the disease ata (CH2 ) ME or or disorder involves the dysregulation of PP2A influenced signaling cascades such as the PI3K - AKT, MAP kinase and IIIb mTOR pathways . These methods include administering to a patient a therapeutically effective amount of a compound 55 to described above . U + R4 In a fifth aspect , the invention relates to pharmaceutical R6 compositions comprising the above -described compounds . M2 OH DETAILED DESCRIPTION OF THE 60 III. INVENTION Substituents are generally defined when introduced and R2 + T retain that definition throughout the specification and in all H2n independent claims. 65 In a composition aspect, the invention relates to com pounds of formula ( I) : US 9 ,937 , 186 B2 In the embodiments described below , the compound may be of formula I , II, IIIa or IIIb , unless otherwise indicated . In some embodiments , n is one . These compounds may be envisioned as N -arylsulfonyl derivatives of 2 - aminocyclo 5 UR4 hexanol: D6

??

10 Inn U R2 - 4 T (CH2 ) M

15 In this trans : trans subgroup , compounds can be either R2 + T single enantiomers IIIa and IIIb or a mixture of the two . If a mixture , the mixture will most commonly be racemic , but it need not be . Substantially pure single enantiomers of biologically active compounds such as those described herein often exhibit advantages over their racemic mixture . In some embodiments , n is zero . These compounds may be envisioned as N - arylsulfonyl derivatives of 2 - aminocy - 25 ??a clopentanol: R3 UR4 30 R4 OH R6 OH ou - RS. RR27 T 3535 (CH2 ) n T R2 of IIIb Tu 40 to R4 In some embodiments , n is two . These compounds may be envisioned as N -arylsulfonyl derivatives of 2 - aminocyclo - 45 OH heptanol: III N . R27 T (CH2 )n 50 U B R4 In any of the foregoing subgenera (cyclohexanol , cyclo pentanol or cycloheptanol) , A may be N or CH . In both the 55 N - series and the CH series , B may be a direct bond , O - , - (CH2 – 0 ) — , - 0 _ CH2) — , - C ( O ) N (CH3 ) - or ou - N (CH2 )C10 ) . In some embodiments , at least one of T and U is a heterocycle such as pyridine , pyrimidine , diazine , thio 60 phene , thiazole , oxazole , imidazole , pyrrole , or furan . In some embodiments , one of T and U is a benzene ring , and the other of T and U is selected from pyridine, pyrimidine, and thiophene . In other embodiments , T and U are both In any of the foregoing subgenera (cyclohexanol , cyclo - benzene rings . pentanol or cycloheptanol) , preferred cycloalkanols are 65 When B is a direct bond , T and U are benzene rings and those in which the relative configurations are such that the A is N , a subgenus of cycloalkanols in which the tricyclic amine and the tricycle are both trans to the alcohol: substituent is a carbazole results : 15US 959 ,937 , , 186 186 12B2 R3 22 R4

OH H3C - N ZI LR5 and R2 10 (CH2 ) n (CH2 ) When B is 04 , T and U are benzene rings and A is N , HzC FR4 a subgenus of cycloalkanols in which the tricycle is a , dibenzooxazine results : 15 N R2D 20 R6 ( CH2) , OH FR$ When B is a direct bond , T and U are benzene rings and A is CH , a subgenus of cycloalkanols in which the tricyclic TheSon 25 substituent is a fluorene results :

(CH ) R3 30 R* When B is ( CH20 - or - ( 0 _ CH _) , T and U are R6 benzene rings and A is N , two subgenera of cycloalkanols in OH which the tricyclic substituent is a dibenzooxazepine result: R ? s 3535 R4 ( CH2 ), In some embodiments , R2 and R * are H , and R and R3 are OH 40 chosen independently from H , OH , F , C1, Br, CN , CO CHz, - RS and CH3, CF3, OCF3, and OCHz. In some embodiments , all of R1, R2, R3 and R4 are H . In some embodiments , at the least ou one of R1, R2, R3 and R4 is located at a carbon two positions away from a bridgehead carbon . In some embodiments , RS (CH2 ) 45 is H , and Ris chosen from H , F , C1, CF3, OCFz , SCFZ , NZ and CN . Often Ró is in the para position . In summary , the invention relates to : [ 1 ]. A compound of formula I , II , IIIa or IIIb . [ 2 ] . A compound according to [ 1 ] above wherein n is one. 50 [ 3 ] . A compound according to [ 1 ] above wherein n is two . [4 ]. A compound according to [ 1] above wherein n is three . R6 [ 5 ] . A compound according to any of [ 1 ] through [ 4 ] OH above wherein B is a direct bond . - 55 [ 6 ]. A compound according to any of [ 1 ] through [ 4 ] - R above wherein B is 0 [7 ]. A compound according to any of [ 1 ] through [4 ] above wherein B is – (CH2 - 0 ) - or - 0 ( CH ) — [ 8 ]. A compound according to any of [ 1 ] through [ 4 ] ( CH2 ) 60 above wherein B is CEO) N ( CH3) or — N (CH3 ) C 90 [ 9 ]. A compound according to any of [ 1 ] through [ 8 ] above wherein A is N . When B is — CEO) N (CH3 ) or — N (CH3 ) C ( O ) - , [ 10 ]. A compound according to any of [1 ] through [ 8 ] T and U are benzene rings and A is N , two subgenera of 65 above wherein A is CH . cycloalkanols in which the tricyclic substituent is a diben - [ 11 ]. A compound according to any of [ 1 ] through [10 ] zodiazepine result : above wherein T and U are both benzene rings . US 9 ,937 , 186 B2 10 [ 12 ] . A compound according to any of [ 1 ] through [ 10 ] indicates either, or both , of the two trans: trans enantiomers : above wherein at least one of T and U is chosen from pyridine , pyrimidine , diazine , thiophene , thiazole , oxazole , imidazole , pyrrole , and furan . [ 13 ]. A compound according to any of [ 1 ] through [ 10 ] or 5 [ 12 ] above, wherein one of T and U is a benzene ring, and R* the other of T and U is selected from pyridine, pyrimidine , R6 and thiophene . [ 14 ] . A compound according to any of [ 1 ] through [ 13 ] above, wherein R2 and R4 are H , and Rl and R3 are chosen *1111 independently from H , OH , F , C1, Br, CN , CO , CHz, CH3, CF3, OCF3, and OCHZ. R2 - 4 T 106 [ 15 ]. A compound according to any of [ 1 ] through [14 ] above, wherein all of R2, R3 and R4 are H . 15 [16 ]. A compound according to any of [ 1 ] through [ 15 ] above, wherein at least one of R², R3 and R4 is located at a carbon two positions away from a bridgehead carbon . U R4 [17 ] . A compound according to any of [ 1 ] through [ 16 ] R6 above , wherein R is H , and R? is chosen from H , F , C1, CF3, 20 SCF3, OCF3, N , and CN . 51 pus [ 18 ] . A compound according to any of [ 1 ] through [ 17 ] above , wherein Rº is in the para position . ? The compounds described herein contain three or more R2 + T asymmetric centers and may thus give rise to enantiomers , 25 (CH2 ) , diastereomers, and other stereoisomeric forms which may be defined in terms of absolute stereochemistry as (R )- or (S ) -. R1 The present invention is meant to include all such possible diastereomers as well as their racemic and optically pure in any ratio , from pure enantiomers to racemates . The forms. Optically active ( R ) - and ( S ) - isomers may be pre - 30 graphic represent pared using homo- chiral synthons or homo -chiral reagents, or optically resolved using conventional techniques. When the compounds described herein contain olefinic double R3 bonds or other centers of geometric asymmetry , and unless of specified otherwise, it is intended to include both ( E ) - and UR ( Z ) - geometric isomers . Likewise , all tautomeric forms are R6 intended to be included . The graphic representations of racemic , ambiscalemic and scalemic or enantiomerically pure compounds used herein 40 are a modified version of the denotations taken from Maehr R2 - 7 T J . Chem . Ed . 62 , 114 - 120 ( 1985 ) : simple lines provide no information about stereochemistry and convey only connec CH ) tivity ; solid and broken wedges are used to denote the RY absolute configuration of a chiral element; solid and broken 45 bold lines are geometric descriptors indicating the relative indicates a single enantiomer of unknown absolute stereo configuration shown but not necessarily denoting racemic chemistry , i. e . it could be either of the two preceding character ; and wedge outlines and dotted or broken lines structures, as a substantially pure single enantiomer. And , denote enantiomerically pure compounds of indeterminate finally , the representation : absolute configuration . For example, the graphic represen - 30 tation ?? w 55 ma U R4 we HO indicates a pure ( 1R ,2R ,6S ) - 2 -amino - 6 - ( C -attached tricycle ) 60 cyclohexanol. For the purpose of the present disclosure , a Inn 11111 " pure ” or “ substantially pure ” enantiomer is intended to mean that the enantiomer is at least 95 % of the configuration R27 T shown and 5 % or less of other enantiomers . Similarly , a " pure " or " substantially pure ” diastereomer is intended to 65 mean that the diastereomer is at least 95 % of the relative configuration shown and 5 % or less of other diastereomers. In the text describing the stereochemistry of the examples, US 9 ,937 , 186 B2 the convention of Chemical Abstracts is used . Thus “ 1R , The formulations include those suitable for oral , parent 2R ,6S ) - rel- ” indicates that the three chiral centers are in that eral ( including subcutaneous, intradermal, intramuscular, relative relationship , which would be depicted in a structural intravenous and intraarticular ) , rectal and topical ( including diagram by solid bold and dashed lines, whereas " (1R , 2R , dermal, buccal, sublingual and intraocular ) administration . 6S ) " without the " rel” indicates a single enantiomer of that 5 The most suitable route may depend upon the condition and absolute configuration , which would be depicted in a struc disorder of the recipient. The formulations may conve tural diagram by solid and broken wedges . niently be presented in unit dosage form and may be All the members of the genus described above exhibit prepared by any of the methods well known in the art of biological activity in screens that are predictive of utility. pharmacy. All methods include the step of bringing into However, it may be found upon examination that certain 10 association a compound of formula I or a pharmaceutically species and genera are not patentable to the inventors in this acceptable salt thereof (" active ingredient ” ) with the carrier application . In this case , the exclusion of species and genera which constitutes one or more accessory ingredients . In in applicants ' claims are to be considered artifacts of patent general, the formulations are prepared by uniformly and prosecution and not reflective of the inventors' concept or intimately bringing into association the active ingredient description of their invention , which encompasses all mem - 15 with liquid carriers or finely divided solid carriers or both bers of the genus I that are not in the public ' s possession and then , if necessary, shaping the product into the desired As used herein , and as would be understood by the person formulation . of skill in the art, the recitation of “ a compound” — unless Formulations of the present invention suitable for oral expressly further limited — is intended to include salts of that administration may be presented as discrete units such as compound . In a particular embodiment, the term " compound 20 capsules , cachets or tablets each containing a predetermined of formula ” refers to the compound or a pharmaceutically amount of the active ingredient; as a powder or granules; as acceptable salt thereof . a solution or a suspension in an aqueous liquid or a non The term “ pharmaceutically acceptable salt” refers to salts aqueous liquid ; or as an oil - in -water liquid emulsion or a prepared from pharmaceutically acceptable non - toxic acids water- in - oil liquid emulsion . The active ingredient may also or bases including inorganic acids and bases and organic 25 be presented as a bolus , electuary or paste . acids and bases. When the compounds of the present inven A tabletmay be made by compression or molding , option tion are basic , salts may be prepared from pharmaceutically ally with one or more accessory ingredients . Compressed acceptable non - toxic acids including inorganic and organic tablets may be prepared by compressing in a suitable acids . Suitable pharmaceutically acceptable acid addition machine the active ingredient in a free - flowing form such as salts for the compounds of the present invention include 30 a powder or granules, optionally mixed with a binder , acetic, adipic , alginic , ascorbic , aspartic , benzenesulfonic lubricant, inert diluent, lubricating , surface active or dis (besylate ), benzoic , boric , butyric , camphoric , camphorsul- persing agent. Molded tablets may be made by molding in fonic , carbonic , citric , ethanedisulfonic , ethanesulfonic , eth - a suitable machine a mixture of the powdered compound ylenediaminetetraacetic , formic , fumaric , glucoheptonic , moistened with an inert liquid diluent. The tablets may gluconic , glutamic , hydrobromic , hydrochloric , hydroiodic , 35 optionally be coated or scored and may be formulated so as hydroxynaphthoic , isethionic , lactic , lactobionic , laurylsul - to provide sustained , delayed or controlled release of the fonic , maleic , malic , mandelic , methanesulfonic , mucic , active ingredient therein . naphthylenesulfonic , nitric , oleic , pamoic , pantothenic , Formulations for parenteral administration include aque phosphoric , pivalic , polygalacturonic, salicylic , stearic , suc o us and non -aqueous sterile injection solutions which may cinic , sulfuric , tannic , tartaric acid , teoclatic , p - toluenesul- 40 contain anti -oxidants , buffers , bacteriostats and solutes fonic , and the like . When the compounds contain an acidic which render the formulation isotonic with the blood of the side chain , suitable pharmaceutically acceptable base addi- intended recipient. Formulations for parenteral administra tion salts for the compounds of the present invention tion also include aqueous and non - aqueous sterile suspen include , but are not limited to , metallic salts made from sions , which may include suspending agents and thickening aluminum , calcium , lithium , magnesium , potassium , sodium 45 agents . The formulations may be presented in unit- dose of and zinc or organic salts made from lysine , arginine , N , N - multi - dose containers , for example sealed ampoules and dibenzylethylenediamine , chloroprocaine , choline , dietha - vials , and may be stored in a freeze - dried (lyophilized ) nolamine , ethylenediamine , meglumine ( N -methylglu - condition requiring only the addition of a sterile liquid camine) and procaine . Further pharmaceutically acceptable carrier, for example saline , phosphate -buffered saline (PBS ) salts include , when appropriate , nontoxic ammonium cat - 50 or the like , immediately prior to use . Extemporaneous ions and carboxylate , sulfonate and phosphonate anions injection solutions and suspensions may be prepared from attached to alkyl having from 1 to 20 carbon atoms. sterile powders , granules and tablets of the kind previously Also provided herein is a pharmaceutical composition described . comprising a compound disclosed above , or a pharmaceu It will be recognized that the compounds of this invention tically acceptable salt form thereof, and a pharmaceutically 55 can exist in radiolabeled form , i . e ., the compounds may acceptable carrier or diluent. contain one or more atoms containing an atomic mass or While it may be possible for the compounds of formula I mass number different from the atomic mass or mass number to be administered as the raw chemical , it is preferable to usually found in nature . Radioisotopes of hydrogen , carbon , present them as a pharmaceutical composition . According to phosphorous, fluorine , and chlorine include 2H , PH , 13C , a further aspect, the present invention provides a pharma - 60 14C , 15N , 35S , 18F , and 3C1, respectively . Compounds that ceutical composition comprising a compound of formula I or contain those radioisotopes and /or other radioisotopes of a pharmaceutically acceptable salt thereof , together with one other atoms are within the scope of this invention . Tritiated , or more pharmaceutically carriers thereof and optionally one i. e. ' H , and carbon - 14 , i. e. , 14C , radioisotopes are particu or more other therapeutic ingredients . The carrier ( s ) must be larly preferred for their ease in preparation and detectability . " acceptable ” in the sense of being compatible with the other 65 Compounds that contain isotopes 11C , 13N , 150 and 18F are ingredients of the formulation and not deleterious to the well suited for positron emission tomography. Radiolabeled recipient thereof. compounds of formula I of this invention and prodrugs US 9 ,937 , 186 B2 13 14 thereof can generally be prepared by methods well known to riocarcinoma, sarcoma, interstitial cell carcinoma, those skilled in the art . Conveniently , such radiolabeled fibroma, fibroadenoma, adenomatoid tumors, and compounds can be prepared by carrying out the procedures lipoma ; disclosed in the Examples and Schemes by substituting a liver cancers, including , for example , hepatoma , e . g . , readily available radiolabeled reagent for a non - radiolabeled 5 hepatocellular carcinoma ; cholangiocarcinoma; hepa reagent. toblastoma; angio sarcoma ; hepatocellular adenoma ; The compounds provided herein can be used for treating and hemangioma ; cancer in a patient, the method comprising administering to bone cancers , including , for example , osteogenic sarcoma the patient a therapeutically effective amount of a compound (osteosarcoma ), fibrosarcoma, malignant fibrous histio of formula I . In some embodiments , the cancer is charac - 10 cytoma, chondrosarcoma, Ewing ' s sarcoma, malignant terized by dysregulation of the PI3K -AKT - FOXO signaling lymphoma ( reticulum cell sarcoma ) , multiple pathway. For example , the cancer can be selected from the myeloma , malignant giant cell tumor chordoma, group consisting of: ovarian , pancreatic , renal cell , breast, osteochrondroma (osteocartilaginous exostoses ) , prostate , lung , hepatocellular carcinoma, glioma, leukemia , 15 benign chondroma , chondroblastoma, chondromyxofi lymphoma, colorectal cancers, and sarcomas . broma, osteoid osteoma and giant cell tumors ; In some embodiments , the method further comprises nervous system cancers , including , for example, cancers administering one or more additional cancer chemothera of the skull , e . g ., osteoma , hemangioma , granuloma , peutic agents . In some embodiments , the one or more xanthoma , and osteitis deformans; cancers of the additional cancer chemotherapeutic agents are EGFR inhibi- 20 meninges, e . g . , meningioma, meningiosarcoma, and tors. Non - limiting examples of the additional chemothera gliomatosis ; cancers of the brain , e .g ., astrocytoma, peutic agent include erlotinib and gefitinib . medulloblastoma , glioma, ependymoma, germinoma In some embodiments , the cancer is chemotherapy resis (pinealoma ) , glioblastoma multiform , oligodendro tant cancer. In some embodiments , the method further glioma , schwannoma, retinoblastoma , and congenital comprises administering one or more cancer chemothera - 25 tumors ; and cancers of the spinal cord , e . g . , neurofi peutic agents . In some embodiments , the one or more cancer broma, meningioma, glioma, and sarcoma ; chemotherapeutic agents are EGFR inhibitors . For example , gynecological cancers , including, for example , cancers of the chemotherapeutic agent is erlotinib or gefitinib . the uterus, e. g . , endometrial carcinoma; cancers of the cervix , e . g . , cervical carcinoma, and pre tumor cervical In some embodiments , administration of a compound of dysplasia ; cancers of the ovaries , e . g ., ovarian carci formula I can restore sensitivity to one or more chemothera - 30 noma, including serous cystadenocarcinoma, mucinous peutic agents in a patient wherein the patient has developed cystadenocarcinoma, unclassified carcinoma, granu a resistance to the one or more chemotherapeutic agents . losa thecal cell tumors , Sertoli Leydig cell tumors , More particularly , cancers that may be treated by the com dysgerminoma, and malignant teratoma; cancers of the pounds, compositions and methods described herein 25 vulva , e . g ., squamous cell carcinoma , intraepithelial include, but are not limited to , the following: carcinoma, adenocarcinoma, fibrosarcoma, and mela cardiac cancers , including , for example sarcoma, e . g. , noma; cancers of the vagina, e . g ., clear cell carcinoma, angiosarcoma, fibrosarcoma, rhabdomyosarcoma, and squamous cell carcinoma, botryoid sarcoma, and liposarcoma; myxoma; rhabdomyoma; fibroma; lipoma embryonal rhabdomyosarcoma; and cancers of the fal and teratoma; 40 lopian tubes , e . g . , carcinoma; lung cancers , including , for example , bronchogenic car hematologic cancers , including , for example , cancers of cinoma , e . g ., squamous cell , undifferentiated small cell, the blood , e . g . , acute myeloid leukemia , chronic undifferentiated large cell , and adenocarcinoma; alveo myeloid leukemia , acute lymphoblastic leukemia , lar and bronchiolar carcinoma; bronchial adenoma; chronic lymphocytic leukemia , myeloproliferative dis sarcoma ; lymphoma; chondromatous hamartoma ; and 45 eases , multiple myeloma, and myelodysplastic syn mesothelioma ; drome, Hodgkin ' s lymphoma, non Hodgkin ' s lym gastrointestinal cancer, including , for example , cancers of phoma (malignant lymphoma ) and Waldenstrom ' s the esophagus , e . g ., squamous cell carcinoma, adeno macroglobulinemia ; carcinoma, leiomyosarcoma, and lymphoma; cancers skin cancers , including , for example , malignant mela of the stomach , e . g . , carcinoma , lymphoma, and leio - 50 noma, basal cell carcinoma , squamous cell carcinoma, myosarcoma; cancers of the pancreas , e . g ., ductal Kaposi ' s sarcoma , moles dysplastic nevi, lipoma, adenocarcinoma , insulinoma, glucagonoma, gastri angioma , dermatofibroma, keloids, psoriasis ; and noma , carcinoid tumors , and vipoma; cancers of the adrenal gland cancers , including , for example , neuroblas small bowel , e . g . , adenocarcinoma, lymphoma, carci toma. noid tumors, Kaposi' s sarcoma, leiomyoma, heman - 55 Cancers may be solid tumors that may or may not be gioma, lipoma, neurofibroma, and fibroma ; cancers of metastatic . Cancers may also occur, as in leukemia , as a the large bowel, e . g ., adenocarcinoma tubular diffuse tissue . adenoma , villous adenoma, hamartoma, and leio The compounds described herein can also be administered myoma; in combination with existing methods of treating cancers , genitourinary tract cancers, including, for example , can - 60 for example by chemotherapy, irradiation , or surgery . Thus , cers of the kidney , e . g ., adenocarcinoma, Wilm ' s tumor there is further provided a method of treating cancer com ( nephroblastoma) , lymphoma, and leukemia ; cancers prising administering an effective amount of a compound of the bladder and urethra , e . g . , squamous cell carci - according to formula I to a patient, wherein a therapeutically noma, transitional cell carcinoma, and adenocarci- effective amount of one or more additional cancer chemo noma; cancers of the prostate , e . g ., adenocarcinoma, 65 therapeutic agents are administered to the patient. Examples and sarcoma ; cancer of the testis , e . g . , seminoma, of suitable chemotherapeutic agents include EGFR inhibi teratoma, embryonal carcinoma , teratocarcinoma, cho - tors such as erlotinib or gefitinib . US 9 ,937 , 186 B2 16 Also provided herein is a method for treating diabetes in used for treating a disease or disorder in a patient wherein a patient, the method comprising administering to the patient the disease or disorder involves excessive or unregulated a therapeutically effective amountof a compound of formula cellular proliferation , the method comprising administering to the patient a therapeutically effective amount of a com Further provided herein is a method for treating an 5 pound of formula (I ) . Also provided herein is a method for autoimmune disease in a patient, the method comprising treating a disease or disorder in a patient where the disease administering to the patient a therapeutically effective or disorder involves the dysregulation of the pi3K -AKT amount of a compound of formula I. The autoimmune disease can be, for example , inflammatory bowel disease FOXO signaling pathway, the method comprising adminis ( IBD ). Immune responses are constantly and tightly regu - 10 tering to the patient a therapeutically effective amount of a lated and one important cellular component in maintaining 10 compound of formula I. self tolerance ( i. e ., prevention of autoimmunity ) and toler Further provided herein is a method for treating a disease ance of benign commensal gut flora are regulatory T cells in a patient wherein the disease is characterized by proteot ( Treg ) . Treg can be subdivided into multiple phenotypes, but oxicity , including age onset proteotoxicity leading to neu the most common are CD4 + CD25 + T cells that express the 15 rodegeneration , the method comprising administering to the transcription factor Foxp3 . Foxp3 is a direct transcriptional patient a therapeutically effective amount of a compound of target of FOXO proteins , particularly FOX01 and FOX03 . formula I . Hyperphosphorylated Tau has been implicated as Thus activation of FOXO proteins in naïve T -cells promotes the pathogenic protein in several neurodegenerative diseases and directs differentiation to maintain a population of Treg and furthermore PP2A has been shown to be an important cells . 20 phosphatase in reversing aberrant phosphorylation of Tau ; Acute immune mediated rejection and chronic immune see for example Ludovic Martin et al ., Tau protein phos mediated rejection are key obstacles to successful solid phatases in Alzheimer ' s disease : The leading role of PP2A organ transplantation . It is believed that these forms of in Ageing Research Reviews 12 ( 2013 ) 39 -49 ; Miguel rejection can be prevented /overcome by amplifying Treg Medina and Jesus Avila , Further understanding of tau phos number and or function . Similarly , a common and morbid 25 phorylation : implications for therapy in Expert Rev . Neuro complication of allogeneic hematopoietic cell transplants therapy , 15 ( 1 ) , 115 - 112 ( 2015 ) and Michael Voronkov et al ., ( Allo -HCT ) used to treat various malignant and non -malig - Phosphoprotein phosphatase 2A : a novel druggable target nant conditions , is graft versus host disease , in which the for Alzheimer ' s disease in Future Med Chem . 2011 May . transplanted immune cells from the donor damage multiple 3 ( 7 ) 821 -833 . Hyperphosphorylated alpha - Synuclein is a organs in the recipient (most notably skin , gut, and liver ) . 30 Increasing experimental and clinical data indicate that Tregs second exemplar of a toxic protein , and again PP2A has been can be harnessed to prevent and or treat this disease process . shown to reverse its aberrantly phosphorylated state ; see for Thus compounds of the present invention are useful in example Kang - Woo Lee et al. , Enhanced Phosphatase Activ treatment of autoimmune and related diseases , by activating ity Attenuates alpha -Synucleinopathy in a Mouse Model in FOXO proteins and inducing T cell differentiation to Tregs . 2535 Neurobiology of Disease , May 11 , 2011 , 31 ( 19 ) 6963 -6971 . Compoundsmay be administered therapeutically to subjects In some embodiments , the disease is selected from the group directly , or alternatively . T cells may be collected from a consisting of: Alzheimer ' s disease , Parkinson ' s disease , subject and differentiated ex vivo to Tregs as described by Huntington ' s disease , amyotrophic lateral sclerosis , fronto Taylor et al. [ Blood 99 , 3493 - 3499 ( 2002) . Compounds of temporal dementia , progressive supranuclear palsy, cortico the present invention may be used alone or in combination 40 basal degeneration and Pick 's disease . with conventional immunosuppressive drugs such as The compounds provided herein may further be used in a cyclosporine , FK506 or rapamycin and its analogs . In addi - method for treating a mood disorder in a patient by admin tion compounds of the present invention may be co - admin - istering to the patient a therapeutically effective amount of istered with histone deacetylase inhibitors (HDACi ) which a compound of formula I . In some embodiments , the mood have been shown to enhance Treg function by maintaining 45 disorder is stress - induced depression . Foxp3 acetylation and activity . Also provided herein is a method for treating acne vul Aspects of the invention include methods for treatment of garis in a patient by administering to the patient a therapeu autoimmune disease characterized by deficiency in Treg t ically effective amount of a compound of formula I . function comprising administering a therapeutically useful Further provided herein is a method for treating cardiac amount of compound of Formula I , optionally in combina - 50 hypertrophy in a patient by administering to the patient a tion with an HDAC inhibitor. The method can also include therapeutically effective amount of a compound of formula extraction of naïve T -cells from a patient, differentiation of I. In some embodiments , the cardiac hypertrophy is associ T -cells to Tregs ex vivo by treatment with a compound of ated with a disease selected from hypertension , myocardial Formula I , optionally supplemented with an HDACI, fol- infarction , and valvular heart disease . lowed by administration of Tregs to patient with optional 55 The compounds provided herein may further be used in a separation of compound of Formula I from Tregs prior to method for treating a viral infection in a patient by admin their administration . As stated above , autoimmune diseases istering to the patient a therapeutically effective amount of that can be so treated include IBD , solid organ transplant a compound of formula I . Examples of viruses that may rejection , and GVHD in allo -HCT cause viral infections to be treated include , but are not In some embodiments , the compounds can be adminis - 60 limited to : a polyomavirus , such as John Cunningham Virus tered to a patient to treat an autoimmune disorder, for ( ICV ) , Simian virus 40 (SV40 ) , or BK Virus (BKV ) ; influ example , Addison ' s disease , Amyotrophic Lateral Sclerosis , enza , Human Immunodeficiency Virus type 1 (HIV - 1 ) , celiac disease , Crohn ' s disease, diabetes , eosinophilic fas - Human Papilloma Virus (HPV ) , adenovirus , Epstein - Barr ciitis , Guillain -Barré syndrome (GBS ) , Graves ' disease , Virus (EBV ) , Hepatitis C Virus (HCV ) , Molluscum conta Lupus erythematosus, Miller - Fisher syndrome , psoriasis , 65 giosum virus (MCV ) ; Human T - lymphotropic virus type 1 rheumatoid arthritis , ulcerative colitis , and vasculitis . In HTLV - 1 ) , Herpes Simplex Virus type 1 (HSV - 1 ) , cytomega some embodiments , the compound provided herein can be lovirus ( CMV) , hepatitis B virus, Bovine papillomavirus US 9 ,937 , 186 B2 17 18 (BPV - 1 ), human T -cell lymphotropic virus type 1, Japanese the stated features, integers , steps or components but do not encephalitis virus, respiratory syncytial virus (RSV ) , and preclude the addition of one or more additional features , West Nile virus. integers , steps, components or groups thereof. This term Further provided herein is a method for treating a parasitic encompasses the terms " consisting of” and “ consisting infection in a patient by administering to the patient a 5 essentially of” . therapeutically effective amount of a compound of formula The phrase " consisting essentially of” or grammatical I. Examples of parasites that may cause parasitic infections variants thereof when used herein are to be taken as speci to be treated include, but are not limited to , Plasmodium and fying the stated features , integers , steps or components but Theileria . PP2A enzymes are involved in the regulation of cell 10 do not preclude the addition of one or more additional transcription , cell cycle , and viral transformation . Many features, integers , steps , components or groups thereof, but viruses , including cytomegalovirus , parainfluenza , DNA only if the additional features, integers , steps, components or tumor viruses , and HIV - 1 , utilize different approaches to groups thereof do not materially alter the basic and novel exploit PPA2 in order to modify , control, or inactivate characteristics of the claimed composition or method . cellular activities of the host Garcia et al . Microbes and 15 A “ patient, ” as used herein , includes both humans and Infection , 2 , 2000 , 401 - 407 ] . Therefore , the compounds other animals , particularly mammals . Thus the methods are provided herein may further be used in a method for treating applicable to both human therapy and veterinary applica a viral infection in a patient by administering to the patient tions . In some embodiments , the patient is a mammal, for a therapeutically effective amount of a compound of formula example , a primate . In some embodiments , the patient is a ( I) . Examples of viruses that may cause viral infections to be 20 human . treated include , but are not limited to : a polyomavirus , such Treatment can involve administering a compound as John Cunningham Virus ( JCV ) , Simian virus 40 (SV40 ) , described herein to a patient diagnosed with a disease , and or BK Virus (BKV ) ; influenza , Human Immunodeficiency may involve administering the compound to a patient who Virus type 1 (HIV - 1 ), Human Papilloma Virus (HPV ) , does not have active symptoms. Conversely , treatment may adenovirus, Epstein -Barr Virus ( EBV ) , Hepatitis C Virus 25 involve administering the compositions to a patient at risk of (HCV ) , Molluscum contagiosum virus (MCV ); Human developing a particular disease , or to a patient reporting one T - lymphotropic virus type 1 HTLV - 1 ) , Herpes Simplex or more of the physiological symptoms of a disease, even Virus type 1 (HSV - 1 ), cytomegalovirus ( CMV ) , hepatitis B though a diagnosis of this disease may not have been made . virus, Bovine papillomavirus (BPV - 1 ) , human T - cell lym - The terms “ administer” , “ administering ” or “ administra photropic virus type 1 , Japanese encephalitis virus, respira - 30 tion ” in reference to a dosage form of the invention refers to tory syncytial virus (RSV ) , and West Nile virus . the act of introducing the dosage form into the system of Serine / Threonine phosphatases, including PP2A are subject in need of treatment. When a dosage form of the involved in modulation of synaptic plasticity ( D . G . Winder invention is given in combination with one or more other and J . D . Sweatt, Nature Reviews Neuroscience , vol 2 , July active agents in their respective dosage forms) , " adminis 2001 , pages 461- 474 ) . Persistently decreased PP2A activity 35 tration ” and its variants are each understood to include is associated with maintenance of Long Term Potentiation concurrent and /or sequential introduction ofthe dosage form (LTP ) of synapses , thus treatment PP2A activators such as and the other active agents . Administration of any of the those described here may reverse synaptic LTP . Psycho - described dosage forms includes parallel administration , stimulant drugs of abuse such as cocaine and methamphet- co -administration or sequential administration . In some situ amine are associated with deleterious synaptic LTP ( L . Mao 40 ations , the therapies are administered at approximately the et al, Neuron 67 , Sep . 9 , 2010 and A . Stipanovich et al, same time, e . g . , within about a few seconds to a few hours Nature vol 453 , 2008, pages 879 - 884 ) , which may underlie of one another . the pathology of addiction and relapse therefore PP2A A " therapeutically effective” amount of the compounds activators described here may be useful as treatments for described herein is typically one which is sufficient to psychostimulant abuse . 45 achieve the desired effect and may vary according to the Abnormalities in synaptic structure and signaling are nature and severity of the disease condition , and the potency linked to autistic spectrum disorder , see for example, Y Chen of the compound . It will be appreciated that different con et al. , CTTNBP2 , but not CTTNBP2NL , regulates dendritic centrations may be employed for prophylaxis than for treat spinogenesis and synaptic distribution of the striatin — PP2A ment of an active disease . A therapeutic benefit is achieved complex , Molecular Biology of the Cell, 23 , Nov . 15 , 2012 , 50 with the amelioration of one or more of the physiological 4383 -4392 . PP2A has been shown to be important in normal symptoms associated with the underlying disorder such that development of dendritic spines , and treatment with com - an improvement is observed in the patient, notwithstanding pounds of the present invention may ameliorate or reverse that the patient may still be afflicted with the underlying autistic spectrum disorder. disorder. Unless defined otherwise , all technical and scientific 55 The term " modulate ” with respect to a FOXO transcrip terms used herein have the same meaning as is commonly tion factor protein refers to activation of the FOXO tran understood by one of ordinary skill in the art to which this scription factor protein and its biological activities associ disclosure belongs . A comprehensive list of abbreviations ated with the FOXO pathway. Modulation of FOXO utilized by organic chemists ( i. e . persons of ordinary skill in transcription factor proteins includes up - regulation (i . e ., the art ) appears in the first issue of each volume of the 60 agonizing , activation or stimulation ) . The mode of action of Journal of Organic Chemistry . The list , which is typically a FOXO modulator can be direct , e .g ., through binding to the presented in a table entitled “ Standard List of Abbrevia - FOXO transcription factor protein as a ligand . The modu tions” is incorporated herein by reference. In the event that lation can also be indirect , e . g. , through binding to and /or there is a plurality of definitions for terms cited herein , those modifying another molecule which otherwise binds to and in this section prevail unless otherwise stated . 65 activates the FOXO transcription factor protein . As used herein , the terms " comprising ” and “ including Throughout this specification the terms and substituents or grammatical variants thereof are to be taken as specifying retain their definitions . US 9 ,937 , 186 B2 19 20 C , to C20 hydrocarbon includes alkyl, cycloalkyl, poly - to 6 carbon atoms of a straight or branched configuration cycloalkyl, alkenyl, alkynyl , aryl and combinations thereof. attached to the parent structure through an oxygen . Examples include benzyl, phenethyl, cyclohexylmethyl, Examples include methoxy, ethoxy, propoxy , isopropoxy adamantyl, camphoryl and naphthylethyl. Hydrocarbyl 5 and the like . Lower -alkoxy refers to groups containing one refers to any substituent comprised of hydrogen and carbon to four carbons. For the purpose of this application , alkoxy as the only elemental constituents . Aliphatic hydrocarbons and lower alkoxy include methylenedioxy and ethylenedi are hydrocarbons that are not aromatic ; they may be satu oxy. rated or unsaturated , cyclic , linear or branched . Examples of aliphatic hydrocarbons include isopropyl , 2 -butenyl , 2- bu 10 The term “ halogen ” means fluorine, chlorine, bromine or tynyl, cyclopentyl, norbornyl, etc . Aromatic hydrocarbons iodine atoms. In one embodiment, halogen may be a fluorine include benzene (phenyl ), naphthalene (naphthyl ) , anthra or chlorine atom . cene , etc . Unless otherwise specified , acyl refers to formyl and to Unless otherwise specified , alkyl ( or alkylene) is intended 15 groups of 1 , 2 , 3 , 4 , 5 , 6 , 7 and 8 carbon atoms of a straight, to include linear or branched saturated hydrocarbon struc - branched , cyclic configuration , saturated, unsaturated and tures and combinations thereof. Alkyl refers to alkyl groups aromatic and combinations thereof, attached to the parent from 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms, structure through a carbonyl functionality . Examples include more preferably 1 to 6 carbon atoms. Examples of alkyl 20 acetyl, benzoyl, propionyl , isobutyryl and the like . Lower groups include methyl, ethyl, propyl, isopropyl, n -butyl , acyl refers to groups containing one to four carbons. The s -butyl , t - butyl and the like . double bonded oxygen , when referred to as a substituent Cycloalkyl is a subset of hydrocarbon and includes cyclic itself is called “ oxo ” . hydrocarbon groups of from 3 to 8 carbon atoms. Examples 25 As used herein , the term " optionally substituted ” may be of cycloalkyl groups include cy -propyl , cy -butyl , cy- pentyl , used interchangeably with " unsubstituted or substituted ” . norbornyl and the like. The term " substituted ” refers to the replacement of one or Unless otherwise specified , the term " carbocycle ” is more hydrogen atoms in a specified group with a specified intended to include ring systems in which the ring atoms are 30 radical. For example , substituted alkyl , aryl, cycloalkyl, all carbon but of any oxidation state . Thus (C3 -C10 ) carbo - heterocyclyl etc . refer to alkyl, aryl, cycloalkyl, or hetero cycle refers to both non -aromatic and aromatic systems, cyclyl wherein one or more H atoms in each residue are replaced with halogen , haloalkyl, alkyl, acyl, alkoxyalkyl, including such systems as cyclopropane , benzene and cyclo hydroxy lower alkyl, carbonyl, phenyl, heteroaryl, benze hexene ; (C8 - C12 ) carbopolycycle refers to such systems as 35 nesulfonyl , hydroxy , lower alkoxy, haloalkoxy, oxaalkyl , norbornane, decalin , indane and naphthalene . Carbocycle , if carboxy , alkoxycarbonyl [/ C (= O )O - alkyl] , alkoxycarbo not otherwise limited , refers to monocycles , bicycles and nylamino (HNC ( O ) O - alkyl] , aminocarbonyl ( also known polycycles. as carboxamido ) [ / CEO) NH2 ) , alkylaminocarbonyl [4C Heterocycle means an aliphatic or aromatic carbocycle FO) NH - alkyl] , cyano , acetoxy , nitro , amino , alkylamino , residue in which from one to four carbons is replaced by a tu dialkylamino , ( alkyl) ( aryl ) aminoalkyl , alkylaminoalkyl ( in cluding cycloalkylaminoalkyl) , dialkylaminoalkyl, dialky heteroatom selected from the group consisting of N , O , and laminoalkoxy, heterocyclylalkoxy , mercapto , alkylthio , sul S . The nitrogen and sulfur heteroatomsmay optionally be foxide , sulfone, sulfonylamino , alkylsulfinyl, alkylsulfonyl, oxidized , and the nitrogen heteroatom may optionally be is acylaminoalkyl, acylaminoalkoxy, acylamino , amidino , quaternized. Unless otherwise specified , a heterocycle may 45 aryl, benzyl , heterocyclyl, heterocyclylalkyl, phenoxy, ben be non - aromatic (heteroaliphatic ) or aromatic (heteroaryl ) . zyloxy, heteroaryloxy , hydroxyimino , alkoxyimino , Examples of heterocycles include pyrrolidine , pyrazole , oxaalkyl, aminosulfonyl, trityl, amidino , guanidino , ureido , pyrrole , indole , quinoline, isoquinoline , tetrahydroisoquino - benzyloxyphenyl, and benzyloxy . “Oxo ” is also included line . benzofuran . benzodioxan . benzodioxole ( commonly 50 among the substituents referred to in “ optionally substi tuted ” ; it will be appreciated by persons of skill in the art referred to as methylenedioxyphenyl, when occurring as a that , because oxo is a divalent radical , there are circum substituent) , tetrazole , morpholine, thiazole , pyridine , stances in which it will not be appropriate as a substituent pyridazine , pyrimidine , thiophene , furan , oxazole , oxazo ( e .g . on phenyl) . In one embodiment, 1, 2 , or 3 hydrogen line , isoxazole , dioxane , tetrahydrofuran and the like. 55 atoms are replaced with a specified radical. In the case of Examples of heterocyclyl residues include piperazinyl, pip alkyl and cycloalkyl, more than three hydrogen atoms can be eridinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazo - replaced by fluorine ; indeed , all available hydrogen atoms could be replaced by fluorine . In preferred embodiments , lidinyl, pyrazinyl, oxazolidinyl, isoxazolidinyl, thiazolidi substituents are halogen , haloalkyl , alkyl, acyl, hydroxy nyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, 600 alkyl, hydroxy, alkoxy, haloalkoxy , aminocarbonyl oxaalkyl, benzimidazolyl, thiadiazolyl , benzopyranyl, benzothiazolyl, carboxý cyano , acetoxy , nitro , amino. alkylamino . dialky tetrahydrofuryl , tetrahydropyranyl, thienyl (also historically lamino , alkylthio , alkylsulfinyl , alkylsulfonyl , alkylsulfo called thiophenyl) , benzothienyl, thiamorpholinyl , oxadiaz - nylamino arylsulfonyl, arylsulfonylamino , and benzyloxy. olyl, triazolyl and tetrahydroquinolinyl. 55 Substituents R ” are generally defined when introduced Alkoxy or alkoxyl refers to groups of from 1 to 20 carbon and retain that definition throughout the specification and in atoms, preferably 1 to 10 carbon atoms, more preferably 1 all independent claims . US 9 ,937 , 186 B2 21 EXAMPLES

Example No . Structure H1650 G150 Notes 5 M Racemic Single diastereoisomer

1111Z ON

OCF3 5 M Peak 1 of chromatographic resolution [ a ] ] = + 19 ( c = 1 . 0 MeOH ) 1R , 2R , 3S ZITIR OH absolute sterochemistry

OCF3

1b 5 UM Peak 2 of chromatographic resolution [ a ] p = - 23 ( c = 1 . 0 MeOH ) 15 , 2S ,3R absolute nosterochemistry

OCF3 2 20 M Racemic

TITUT 0 0 NH

OCF3 3 10 M Racemic . Single diastereoisomer

INIZ ON

OCF3 US 9 ,937 , 186 B2 23 24 - continued Example No . Structure H1650 G150 Notes ?? 10 M Peak 1 of chromatographic resolution 1R 2R , 35 absolute ZITII sterochemistry ??

tillNH COCF3 3b 10 um Peak 2 of chromatographic resolution 19 , 2S ,3R absolute sterochemistry . 11110D

OCF3

15 UM

tillll

.240 20 UM TITILIZ

CN

20 M IZ

OMe US 9 ,937 , 186 B2 25 26 25 -continued Example No . Structure H1650 G150 Notes ? 25 UM

INIZ OH

>111111 IZ

Me 15 UM

>ILTIZ

OCF3

Me 25 um

>IZ 0 0 >Ull NH

10

RaoOCF3 US 9 , 937 , 186 B2 28 27 -continued Example No . Structure H1650 G150 Notes 12

ZILI ON

>111111 N OCF3

13

>UTZ ON

IUNI

0CF3

14 ZIMIT

OCF3

15

MITIME

OCF3 16 10 UM Racemic ZI111

SCF3 US 9 , 937 , 186 B2 29 30 - continued Example No. Structure H1650 G150 Notes 15 UM Racemic ZINC 0 C1

>0ll

OCF3 18 15 UM Racemic

UZ ON

>110IIN CH2CF3 19 10 M Racemic ZIMIT MIIOS CF2CF3 20 25 M Racemic TIIMIZ

1110N

OCHF , 15 UM Racemic

ZITI ON

. eeOCF3 US 9 , 937 , 186 B2 31 - continued Example ExampleNo . Structure H1650 G150 Notes 22 CM 5 UM Racemic

ZH ??

111lll

OCF3 2323 CI 5 M Racemic

INIZ ? .

ci 24 Br Br 5 M Racemic ZITTO

OCF3

25 Br Br 15 uM Racemic

ZIMITI 50

26 NC Weak Racemic

ZITII OH

11111

OCF3 US 9 , 937 , 186 B2 33 34 -continued Example No . Structure H1650 G150 Notes 27 Br CN 5 UM Racemic

ZILNIC OH

OCF3

28 CN 10 UM Racemic

IZ ON 0 0 >ININ

OCF3 29 CO2Me 15 MM Racemic ZITTO 0 0

'OCF3 30 5 UM Racemic

ILITZ OH 0 0

IZ ' OCF3 31a 5 M Chiral 18 , 25 , 3R

titlON

OCF3 US 9 , 937 , 186 B2 35 36 -continued Example No . Structure H1650 G150 Notes 31b F 5 M Chiral Dom1R ,2R , 3S

OCF3 32a F . 5 M Chiral 15 , 2S ,3R

sillON

OCF3 32632b F F 5 M Chiral 1R , 2R , 35 11111Z OH

' OCF3 34 F

ULIZ ??

OCF3 35 va Zum F OH

NH OCF3 US 9 ,937 , 186 B2 38 37 -continued Example No . Structure H1650 G150 Notes

36

UZ OH

OCF3

37 IZ N OCF3

38 F

ZILI OH 0

12

OCF3

39

TON

OCF3 US 9 , 937 , 186 B2 39 40 -continued Example No. Structure H1650 G150 Notes 40 s

1111110 NH TOCF3 41

11111

OCF3

30 Preparation of compounds can involve the protection and - continued deprotection of various chemical groups . The need for protection and deprotection , and the selection of appropriate protecting groups, can be readily determined by one skilled 35 UR4 in the art. Suitable groups for that purpose are discussed in standard textbooks in the field of chemistry , such as Protec tive Groups in Organic Synthesis by T . W . Greene and P . G . M . Wuts [John Wiley & Sons, New York , 1999 ], in Pro T tecting Group Chemistry , 1st Ed. , Oxford University Press , 40 R2 + 2000 ; and in March 's Advanced Organic chemistry : Reac tions, Mechanisms, and Structure , 5th Ed ., Wiley -Inter science Publication , 2001 . In general, compounds of formula I can be prepared as 45 shown in Schemes 1 , 2 and 3 . The first step is attachment of the tricycle to the cycloalkene that will become the amino cycloalkanol. When A is N , the first step is as follows:

Scheme 1

U + R4 Br ht NH U + RAR4 R2 + T

A R2 - F min NaH / DMF r . t. 4 hours US 9 , 937 , 186 B2

When A is CH , the first step is as follows : - continued

U R4

Scheme 2

R3 10 R2 + T UR4 RI AcO

LU + R4 R2 + T man Pd catalyst; 20 ??? DMF The remaining steps are the same:

Scheme 3 ??

O OH OsO4, NMMO 11111 t -BuOH /H20 (CH2 ) n r . t . 34 hours (CH2 ) n

MsCi pyridine r . t . 16 hours

N3 OH OH NaN3/ DMF O OMs O mun O Que11100 110111Nz NaN3/ DMF QUI10 110° C . 14 hours ( CH2) , (CH2 ) , microwave (CH2 ) n minor major OH OH Q 111111 111A PPh3, H20 QUI NH2 THF r . t . 17 hours (CH2 ) n (CH2 ) n Et3N DMF r . t . 4 hours CISO2

OH O munu 111111A

(CH2 ) n US 9 ,937 , 186 B2 43 44 The foregoing scheme produces sulfonamide products of the (1H , m ), 1 . 96 -1 . 89 (1H , m ), 1. 83 - 1. 81 (1H , m ), 1. 72 - 1. 66 ( 18 ,25 ,3R )- rel configuration . When products of other rela - (2H , m ), 1. 51 - 1 .43 (2H , m ) ; 13C NMR ( 150 MHz, DMSO tive configurations are desired , the cycloalkene may be dº) d 148 .2 , 136 .1 , 124 .2 , 121 .9 , 117 . 4 , 115 .7 , 71. 3 , 70 .5 , oxidized with reagents , such as meta - chloroperbenzoic acid 62 . 0 , 31 . 4 , 29 . 4 , 19 . 7 ; LCMS m / z 298 .2582 ( [ M + H + 1 , and others well -known to persons of skill in the art , and the 5 C18H20NO3 requires 298 . 3558 ) . resulting epoxide opened in a trans sense . 2 -hydroxy - 3 - ( 10H - phenoxazin - 10 - yl) cyclohexyl meth anesulfonate . To a solution of 3 -( 10H -phenoxazin - 10 -yl ) Exemplary syntheses are presented below : cyclohexane - 1 ,2 - diol ( 1. 09 g, 3 .67 mmol) in pyridine (2 .8 Example 1 mL ) under argon , at 0° C . , was added methane sulfonyl 10 chloride . The mixture was stirred for 2 . 5 h at RT. 1 N HC1 was added to the reaction mixture, and extracted with DCM . Organic layer was washed with brine , concentrated , to obtain a residue which was purified by flash chromatography (SiO2 , 75 % - 100 % dichloromethane- hexanes ) to afford 2 -hy droxy - 3 - ( 10H -phenoxazin - 10 - yl) cyclohexyl methanesul OCF3 fonate ( 0 . 668 g , 48 % ) . ' H NMR (600 MHz, CDC13) S OH 6 . 93 - 6 . 80 ( 8H , m ) , 5 . 15 ( 1H , d , J = 10 . 8 Hz ) , 4 .51 ( 1H , bs ) , 4 .23 ( 1H , bs) , 3 . 18 ( 1H , s ) , 2 .88 (3H , s ) , 2 . 13 - 1 .82 (4H , m ) , 1 .62 - 1 . 55 (2H , m ); 13C NMR ( 150 MHz, CDC13 ) 8 149 . 1 , 20 134 . 9 , 124 . 1 , 123 . 2 , 117 . 7 , 116 . 3 , 84 .081 . 7 , 70 . 0 , 61. 3 , 38 . 9 , 30 .6 , 18. 7 ; LCMS m /z 376 .2399 ([ M + H + ], C19H22NOZS requires 376 .4461 ) . 2 - amino - 6 - ( 10H -phenoxazin - 10 - yl) cyclohexanol. A solu The synthesis begins with alkylation of commercially tion of 2- hydroxy -3 - (10H -phenoxazin - 10 -yl ) cyclohexyl available 10H -phenoxazine with commercially available 25 methanesulfonate ( 0 . 417 g , 1 . 11 mmol) in DMF ( 2 mL ) was 3 -bromocyclohex -1 - ene to afford 10 -( cyclohex - 2 -en - 1 -yl ) - treated with sodium azide (0 .144 g , 2 .22 mmol) . Themixture 10H -phenoxazine in 77 % yield . An osmium tetroxide cata - was heated at 110° C . for 28 h in a Biotage Initiator® lyzed dihydroxylation afforded diol in 44 % yield . Treatment microwave reactor, sat . aq . ammonium chloride was added , of diol with methanesulfonyl choride furnished mesylate in mixture was extracted in dichloromethane , and concentrated 48 % yield . A sodium azide - induced azide displacement 30 in vacuo . The residue obtained was purified by flash chro afforded crude azide , which was taken to the next step matography (SiO2 , 10 % - 50 % ethylacetate -hexanes ) to without further purification . Amine was synthesized from afford crude 2 -azido -6 - ( 10H - phenoxazin - 10 - yl) cyclohexa azide via a Staudinger reaction ; the overall yield of amine nol ( 0 . 112 g , 31 % ) which was taken to the next step without from mesylate was 8 % . Treating the amine with commer - further purification . cially available 4 - ( trifluoromethoxy )benzene - 1 - sulfonyl 35 A solution of 2 - azido - 6 - ( 10H -phenoxazin - 10 - yl ) cyclo chloride afforded target sulfonamide Example 1 in a yield of hexanol ( 0 . 127 g ) in THF ( 1 . 4 mL ) was cooled to 0° C . , 42 % . treated with PPh , ( 0 . 114 g , 0 . 433 mmol) , H , O ( 0 . 043 g , 2 .36 10 - (cyclohex - 2 -en - 1 - yl) - 10H - phenoxazine . To a solution mmol) , and stirred for 17 h at RT. The solution was con of 10H -phenoxazine ( 2 .00 g , 10 . 9 mmol) in DMF ( 11 mL ) centrated to dryness, dissolved in a minimal amount of at RT, was added NaH ( 0 .480 g , 11. 9 mmol, 60 % dispersion 40 CH , C1, and purified by flash chromatography ( SiO2, 100 % in mineral oil ) . The mixture was stirred at RT for 1 h . hexanes , 50 % ethyl acetate - hexanes , 5 % , methanol - dichlo 3 -bromocyclohex - 1 - ene ( 3 .51 g , 21 .8 mmol) was added to rmethane , 17 : 2 : 1 dichloromethane :methanol : 35 % ammo the above solution , and the reaction mixture was stirred at nium hydroxide ) to afford ( 2 -amino -6 -( 10H -phenoxazin - 10 RT for 3 h , neutralized with sat. aq . NH _ C1, extracted with yl) cyclohexanol (0 .029 g , 8 % over two steps) . ' H NMR (600 dichloromethane, concentrated in vacuo to give a residue 45 MHz, CDC13 ) 8 6 .99 -6 .77 ( 8H , m ), 4 . 67 ( 1H , m ), 3 .66 ( 1H , which was purified by flash chromatography (SiO2 , 100 % t , J = 18 .6 Hz) , 3 . 36 - 3 .32 ( 1H , m ), 2 .94 - 2 .70 ( 3H , m ) , 1 . 95 hexanes ) to afford 10 - ( cyclohex - 2 -en - 1 - yl) - 10H -phenox - 1 . 93 ( 1H , m ) , 1 . 82 - 1 . 80 ( 1H , m ), 1 .72 - 1 .65 (2H , m ) , 1 . 36 azine ( 2 .21 g , 77 % ). ' H NMR (600 MHz , CDC13 ) d 6 . 84 - 1 . 27 ( 1H , m ), 1 .21 - 1 . 15 ( 1H , m ) ; 13C NMR ( 150 MHz , 6 .71 ( 7H , m ) , 5 . 94 - 5 . 92 ( 1H , m ) , 5 . 94 - 5 . 92 ( 1H , m ) , 5 .84 CDC13 ) 150 .0 , 135 . 0 , 123 . 8 , 123. 5 , 119 . 7 , 116 . 2 , 74 . 8 , 5 . 82 ( 1H , m ), 4 .58 ( 1H , bs ), 2 . 23 - 2 . 15 ( 3H , m ) , 2 .07 - 1 . 99 50 70 . 5 , 56 . 2 , 33 . 1 , 28 . 1 , 23 . 0 ; LCMS m / z 297 . 2937 ( [ M + H + 1 , (2H , m ) , 1 . 84 - 1 .77 ( 1H , m ); 13C NMR (150 MHz, CDC1z ) C18H2 N20 , requires 297 .3710 ) . 8 147 . 4 , 134 . 8 , 130 .1 , 129 . 8 , 123 . 5 , 121 . 2 , 115 . 8 , 114 .4 , N -( 2 -hydroxy - 3 -( 10H -phenoxazin - 10 -yl ) cyclohexyl ) - 4 55 .3 , 24 .8 , 24 .6 , 22. 4 ; LCMS m /z 264 . 1354 ([ M + H + ], (trifluoromethoxy )- benzenesulfonamide . A solution of C , H , NO requires 264 . 3411 ) . 2 -amino - 6 - ( 10H -phenoxazin - 10 -yl )cyclohexanol ( 0 .029 g , 3 - ( 10H -phenoxazin - 10 - yl) cyclohexane - 1 , 2 -diol . A solu - 55 0 .098 mmol ) in DMF (0 . 5 mL ) was cooled to 0° C ., treated tion of 10 - ( cyclohex - 2 -en - 1 - yl) - 10H -phenoxazine ( 2 .21 g , with EtzN (0 .055 mL , 0 .392 mmol) , and 4 - ( trifluo 8 . 39 mmol) , 4 -methylmorpholine N - oxide ( 0 . 098 g , 0 . 838 romethoxy )benzene - 1 - sulfonyl chloride ( 0 .018 g , 0 . 108 mmol) , and osmium tetroxide ( 0 . 080 mL , 0 .008 mmol, 2 . 5 % mmol) . The mixture was warmed to RT, and stirred for 17 h . in tert- butanol ) in tert- butanol ( 11 . 6 mL ) and water ( 2 . 3 mL ) , The mixture was partitioned between water ( 10 mL ) and was stirred at RT for 12 h . The reaction mixture was treated 60 CH , C1, ( 10 mL ) . The organic layer was washed with satu with sat. aq . sodium bisulfite solution , extracted with dichlo - rated aqueous NaCl (30 mLx5 ) to remove DMF, and con romethane , concentrated , and purified by flash chromatog - centrated in vacuo . The residue was dissolved in a minimal raphy (SiO2 , 0 % -70 % ethyl acetate -hexanes ) to afford amount of CH2Cl2 and purified by flash chromatography 3 - ( 10H - phenoxazin - 10 - yl) cyclohexane - 1 , 2 - diol ( 1 .09 g (SiO2 , 0 % - 50 % ethylacetate - hexanes ) to afford N - ( 2 - hy 44 % ). ' H NMR (600 MHz, DMSO - dº) 8 6 . 96 -6 .94 (2H , m ), 65 droxy - 3 -( 10H -phenoxazin - 10 -yl ) cyclohexyl) - 4 - ( trifluo 6 . 86 -6 .84 (2H , m ) , 6 . 73 - 6 .69 (4H , m ) , 4 .76 ( 1H , d , J = 5 . 4 romethoxy )benzenesulfonamide Example 1 ( 0 .021 g , 42 % ) . Hz ) , 4 .52 ( 1H , d , J = 2 . 4 Hz) , 4 . 00 - 3 . 95 ( 2H , m ), 3 . 92 - 3 . 87 H NMR (600 MHz, MeOD ) d 8 .02 ( 2H , d , J = 8 . 4 Hz) , 7 . 44 US 9 ,937 , 186 B2 45 46 (2H , d , J = 8 . 4 Hz) , 6 . 95 - 6 . 94 ( 2H , m ) , 6 . 88 ( 2H , dt, J = 1 . 4 , -continued 7 . 7 , 7 . 8 Hz) , 6 . 80 (2H , t , J = 7 . 8 Hz ), 6 .74 - 6 .72 (2H , m ) , 3 .83 ( 1H , dd , J = 9 .6 , 10 .2 Hz ), 3 .40 ( 1H , ddd , J = 4 .2 , 10 . 8 , 12 .0 F3C0 - S - C1 Hz) , 3 . 11 ( 1H , ddd , J = 4 . 2 , 9 . 6 , 11 . 4 Hz ) , 1 . 94 - 1 . 92 ( 1H , m ) , 1 .80 - 1 .74 ( 2H , m ), 1 .68 - 1 . 66 (1H , m ), 1 .35 - 1 .25 ( 2H , m ) ; 5 13C NMR ( 150 MHz, MeOD ) 8 151. 7 , 149 .6 , 141. 0 , 135 . 3 , Et3N 129 . 2 , 123 . 3 , 122 . 5 , 120 . 8 , 118 . 6 , 115 . 4 , 73 . 0 , 69 . 2 , 59 . 3 , DMF, RT , 24 h 32 .3 , 28 . 5 , 22. 3 ; LCMS m / z 521 . 2955 ([ M + H + ] , C25H24F3N2O5S requires 521. 5281 ) . 10 Gram - Scale Synthesis of Example 1 NH2 0007016 Scheme 4

Br OH NaH , DMF, RT, 4 h oso on jä NHNH OsO4, NMMO OCF3 t - butanol- H20 , RT , 38 h Example 1 30 All reactions were done in multiple batches (see experi > mental ). The synthesis was commenced by alkylation of ~ commercially available 10H -phenoxazine 1 with commer cially available 3 -bromocyclohex - 1 - ene to afford 10 - ( cyclo hex - 2 - en - 1 - yl ) - 10H -phenoxazine 2 in crude 109 % yield . An osmium tetroxide catalyzed dihydroxylation of 2 afforded diol 3 in 67 % yield . Treatment of diol 3 with thionyl chloride SEO furnished crude sulfide 4 ( 91 % yield ) . A sodium azide induced azide displacement of 4 afforded crude azide 5 (69 % OH Et3N , DCM yield ), which was taken to the next step without further RT, 2 h purification . Amine 6 was synthesized from 5 via a Staudinger reaction in 79 % yield . Treating 6 with commer cially available 4 - ( trifluoromethoxy )benzene - 1 - sulfonyl OH chloride afforded target sulfonamide Example 1 in a yield of 3 97 % . 45 Experimental

Br NaN3 50 DMF, 110° C . , 16 h NaH , DMF , (microwave ) N R?, 4 h

55

PPh3, H20 60 OH THF RT , 40 h 10 - cyclohex - 2 -en - 1- yl) - 10H -phenoxazine N3 65 5 The reaction was done on 40 .0 g of 10H - phenoxazine (5 reactions of 8 .00 g each ). US 9 ,937 , 186 B2 47 Typical Procedure : To a solution of 10H -phenoxazine (8 .00 g , 43. 7 mmol) in DMF (44 . 0 mL ) at RT, was added NaH ( 1 . 91 g , 48 . 1 mmol, 60 % dispersion in mineral oil ) . The mixture was stirred at = ( RT for 1 h . 3 -bromocyclohex - l - ene ( 14 . 1 g , 87 .4 mmol ) was 5 added to the above solution , and the reaction mixture was OH EtzN , DCM stirred at RT for 4 h . RT , 2 h To the above five reactions cold water was added , precipitate was filtered , and dried over pump to afford crude 10 - (cyclohex - 2 - en - 1 - yl) - 10H -phenoxazine (62 . 5 g , 109 % ). 10 OH ' H NMR (600 MHz, CDC13 ) 8 6 .84 - 6 .71 (7H , m ), 5 .94 - 5 .92 ( 1H , m ), 5 . 94 - 5 .92 ( 1H , m ), 5 . 84 - 5 .82 ( 1H , m ), 4 . 58 ( 1H , bs ) , 2 . 23 - 2 . 15 ( 3H , m ), 2 .07 - 1 .99 (2H , m ) , 1 . 84 - 1 . 77 (1H , m ) ; 13C NMR ( 150 MHz, CDC12 ) d 147 . 4 , 134 . 8 , 130 . 1 , 15 129 . 8 , 123 . 5 , 121. 2 , 115 . 8 , 114 . 4 , 55 . 3 , 24 . 8 , 24 . 6 , 22 . 4 ; LCMS m / z 264 .1354 ([ M + H + ], C18H , NO requires 264 . 3411 ) .

20 4 - (10H - phenoxazin - 10 - yl) hexahydrobenzo [d ][ 1 ,3 , 2 ] dioxathiole 2 -oxide OsO4, NMMO The reaction was done on 28 . 0 g of 3 - ( 10H - phenoxazin t - butanol- H20 , 25 10 -yl ) cyclohexane - 1, 2 -diol (4 reactions of 7 .00 g each ). RT, 38 h Typical Procedure: A solution of 3 - ( 10H - phenoxazin - 10 - yl) cyclohexane- 1 , 2 diol ( 7 .00 g , 13 . 5 mmol) in dichloromethane ( 100 . 0 mL ) under argon was cooled to 0° C . , and treated with triethyl 30 amine ( 14 . 9 mL , 107 mmol) . Following this thionyl chloride ( 2 .93 mL , 40 . 4 mmol) was added very slowly over 20 min . The reaction mixture was warmed to RT, stirred for 2 h . The above four reactions were partitioned between OH dichloromethane and water , concentrated to obtain a residue 35 which was purified in multiple batches by flash chromatog raphy (SiO , 10 % - 50 % ethylacetate -hexanes ) to afford solid product, which was triturated with 1 : 10 ethyl acetate OH?? hexanes to afford 4 - 10H -phenoxazin - 10 - yl ) hexahyd robenzo [ d ] [ 1 , 3 , 2 ] dioxathiole 2 -oxide (29 . 4 g , crude 91 % ) as 40 an off -white powder which was taken to the next step 3 -( 10H -phenoxazin - 10 - yl) cyclohexane - 1, 2 - diol without further purification . The reaction was done on 50 . 0 g of 10 - (cyclohex -2 -en 1 - yl) - 10H -phenoxazine (5 reactions of 10 . 0 g each ) . Typical Procedure : 45 A solution of 10 -( cyclohex -2 -en -1 -yl ) - 10H -phenoxazine ( 10 . 0 g , 37 . 9 mmol) , 4 -methylmorpholine N -oxide ( 4 .89 g , NaN3 41. 7 mmol) , and osmium tetroxide ( 3 . 84 mL , 0 . 379 mmol, DMF, 2 . 5 % in tert - butanol) in tert -butanol ( 50 . 0 mL ) and water 110° C ., 16 h ( 10 . 0 mL ) , was stirred at RT for 38 h . 50 O (microwave ) To the above five reactions — solid sodium bisulfite was added ( - 3 .00 g per reaction ) , the mixture was stirred for 1 h , all mixtures were combined and made into a slurry of silica gel and dichloromethane . The dichloromethane was removed in vacuo to make a silica gel plug. Purification was 55 done in multiple batches by flash chromatography (SiO2 , 0 % -70 % ethyl acetate -hexanes ) to afford solid product , © which was triturated with 1 : 4 ethyl acetate -hexanes to afford 3 - ( 10H -phenoxazin - 10 - yl )cyclohexane - 1 , 2 - diol ( 37 .7 g , 67 % ) as a white powder. ' H NMR (600 MHz, DMSO - d ' ) & 60 6 . 96 -6 . 94 (2H , m ), 6 . 86 -6 .84 (2H , m ), 6 .73 -6 .69 (4H , m ), 4 . 76 ( 1H , d , J = 5 . 4 Hz ), 4 . 52 ( 1H , d , J = 2 . 4 Hz ) , 4 . 00 - 3 . 95 ( 2H , m ), 3 . 92 - 3 . 87 ( 1H , m ) , 1. 96 - 1 . 89 ( 1H , m ), 1. 83 - 1 . 81 2 - azido -6 - ( 10H - phenoxazin - 10 - yl ) cyclohexanol ( 1H , m ) , 1 .72 - 1 . 66 ( 2H , m ) , 1 .51 - 1 .43 ( 2H , m ) ; 13C NMR ( 150 MHz, DMSO - d ) 8 148 . 2 , 136 . 1 , 124 . 2 , 121. 9 , 117 . 4 , 65 The reaction was done on 28 . 0 g of 4 - ( 10H -phenoxazin 115 .7 , 71. 3 , 70 .5 , 62 .0 , 31. 4 , 29 .4 , 19. 7 ; LCMS m /z 10 -yl ) hexahydrobenzo [d ] [1 , 3 ,2 ]dioxathiole 2 -oxide (7 reac 298 . 2582 ( [ M + H + ] , C18H2NO3 requires 298 . 3558 ). tions of 4 .00 g each ) . US 9 ,937 , 186 B2 49 50 Typical Procedure: A solution of 4 - ( 10H -phenoxazin - 10 -yl ) hexahydrobenzo [ d ][ 1, 3 ,2 ]dioxathiole 2 -oxide ( 4 .00 g , 11. 6 mmol ) in DMF ( 8 . 0 mL ) was treated with sodium azide ( 2 . 27 g , 34 . 9 mmol) . - C1 The mixture was heated at 110° C . for 4 h in a sealed 20 mL 5 OSUR vial in a Biotage Initiator microwave . Pressure was Et3N released by puncturing the vial cap with a needle , cap was DMF, RT , 24 h replaced and mixture was heated at 110° C . for 12 h more in OH the same microwave . To the above seven reactions — brine (around 400 mL ) 10 was added and the mixture was stirred for 3 h . The super " NH2 natent aqueous layer was extracted with dichloromethane . The chunky dark precipitate at the bottom was combined with the above dichloromethane layer , silica was added , and 1 solvent was removed in vacuo to make a dry plug . Purifi cation was done in multiple batches by flash chromatogra phy ( SiO2, 6 % - 10 % ethylacetate -hexanes ) to afford crude 2 - azido -6 - ( 10H - phenoxazin - 10 - yl ) cyclohexanol ( 18 . 1 g , crude 69 % ) . 20 0 j= O=

25 PPh3, H2O OCF3 THF RT , 40 h Example 1 : N - ( 2 -hydroxy - 3 -( 10H - phenoxazin - 10 30 yl) cyclohexyl ) - 4 - (trifluoromethoxy )benzenesulfona mide The reaction was done on 15 .0 g of 2 -amino - 6 -( 10H phenoxazin - 10 - yl) cyclohexanol ( 3 reactions of 5 . 00 g each ) . 3s theTypical Procedure: OH A solution of 2 - amino - 6 - ( 10H -phenoxazin - 10 - yl) cyclo hexanol ( 5 . 00 g , 16 . 9 mmol) in DCM ( 55 . 0 mL ), and DMF ( 11 . 0 mL ) was cooled to 0° C . , treated with EtZN ( 9 .42 mL , " NH10 67 . 6 mmol) , and 4 - ( trifluoromethoxy )benzene - 1 - sulfonyl chloride ( 3 . 00 mL , 17 . 7 mmol) . The mixture was warmed to RT, and stirred for 24 h . 2 -amino -6 - ( 10H -phenoxazin - 10 - yl) cyclohexanol The above three reactions were partitioned between water and CH , C1, . The organic layer was washed with saturated The reaction was done on 18 . 0 g of 2 - azido - 6 - ( 10H - 45 aqueous NaCl ( 100 mLx5 ) to remove DMF, and concen phenoxazin - 10 - yl) cyclohexanol (6 reactions of 3 .00 g each ) . trated in vacuo . The residue was dissolved in dichlorometh ane , silica was added , and solvent was removed in vacuo to Typical Procedure : make a dry plug . Purification was done in multiple batches A solution of 2 - azido - 6 - ( 10H -phenoxazin - 10 - yl) cyclo by flash chromatography ( SiO , , 0 % - 20 % ethylacetate hexanol (3 .00 g , 9 .31 mmol ) in THF (32 .0 mL ) was cooled 50 hexanes ) to afford white solid , which was triturated with 9 : 1 to 0° C ., treated with PPhz ( 2 .68 g , 10 .2 mmol) , H2O (0 .042 ether -hexanes , filtered , and dried to afford N - ( 2 - hydroxy - 3 g , 2 . 32 mmol) , and stirred for 40 h at RT. ( 10H -phenoxazin - 10 - yl ) cyclohexyl) - 4 - ( trifluoromethoxy ) The above six reactions — were concentrated to dryness, benzenesulfonamide Example 1 (25 .38 g , 97 % ) as a white dissolved in dichloromethane , silica was added , and solvent powder. ' H NMR (600 MHz, MeOD ) 8 . 02 ( 2H , d , J = 8 . 4 was removed in vacuo to make a dry plug . Purification was 55 Hz ), 7 . 44 ( 2H , d . J = 8 . 4 Hz) , 6 . 95 - 6 . 94 ( 2H , m ) , 6 .88 (2H , dt, done in multiple batches by flash chromatography ( SiO2, J = 1 . 4 . 7 . 7 . 7 . 8 Hz) , 6 . 80 (2H . t . J = 7 . 8 Hz) , 6 . 74 - 6 .72 ( 2H . 100 % hexanes, 50 % ethyl acetate -hexanes , 3 % , methanol - m ), 3 .83 ( 1H , dd , J = 9. 6 , 10 .2 Hz) , 3 . 40 ( 1H , ddd , J = 4 . 2 , dichloromethane , 17 : 2 : 1 dichloromethane :methanol : 35 % 10 . 8 . 12 . 0 Hz ), 3 . 11 ( 1H , ddd . J = 4 . 2 . 9 .6 . 11 . 4 Hz ), 1 . 94 ammonium hydroxide ) to afford 2 -amino -6 - ( 10H -phenox - 1 .92 ( 1H , m ), 1. 80 - 1 .74 (2H , m ), 1. 68 - 1. 66 ( 1H , m ), 1 .35 azin - 10 - yl ) cyclohexanol ( 13 . 1 g , 79 % ). ' H NMR (600 MHz , 60 1 . 25 ( 2H , m ) ; 13C NMR ( 150 MHz, MeOD ) 8 151. 7 , 149 .6 , CDC1 ) d 6 .99 -6 .77 (8H , m ), 4 .67 ( 1H , m ), 3 .66 ( 1H , t, 141 .0 , 135 .3 , 129. 2 , 123. 3 , 122 .5 , 120 .8 , 118 .6 , 115. 4 , 73 .0 , J = 18 . 6 Hz ), 3 . 36 - 3 . 32 ( 1H , m ) , 2 . 94 - 2 . 70 ( 3H , m ), 1 . 95 - 1 . 93 69. 2 , 59 . 3 , 32 . 3 , 28 . 5 , 22 . 3 ; LCMS m / z 521 . 2955 ( M + H + ] , ( 1H , m ), 1 . 82 - 1 . 80 ( 1H , m ), 1 . 72 - 1 .65 ( 2H , m ) , 1 . 36 - 1 . 27 C25H24F3N20 S requires 521. 5281 ) . ( 1H , m ), 1. 21 - 1. 15 (1H , m ) ; 13C NMR ( 150 MHz, CDC13 ) Chiral preparative HPLC with CHIRALCEL® OZ - H 150 .0 , 135 .0 , 123 . 8 , 123 . 5 , 119 . 7 , 116 .2 , 74 . 8 , 70 . 5 , 56 .2 , 65 eluting with 70 : 30 hexane :ethanol was used to resolve 33 . 1, 28 .1 , 23 .0 ; LCMS m /z 297. 2937 ([ M + H + ], Example 1 into its enantiomers . Peak 1 (retention time 5 C18H2 N20 , requires 297. 3710 ) . min ) was Example 2 > 99 % ee; [ a ] d = - 3 ( c = 1 . 0 , CH2Cl2) ; US 9 ,937 , 186 B2 51 52 [ a ] = + 19 ( c = 1 . 0 , CH3OH ) and Peak 2 ( retention time 9 min ) was, Example 3 > 99 % ee ; [ a ] ) = + 3 ( c = 1 . 0 , CH , C1, ) ; Scheme 4B [ a ] d = - 23 ( c = 1 . 0 , CH3OH ) . Analytical chiral HPLC was also performed using CHIRALPAK® OZ - H stationary Scheme 4B phase column and 1 . 0 mL /min 70 : 30 hexane: ethanol. 5 Stereoselective Synthesis of Example 1b The compounds of formula I may also be synthesized by utilizing a known chiral starting material in a stereoselective route , removing the necessity of chiral separation of the .. 1000 enantiomers after synthesis of the racemate ( or other mix - 10 NaNH ture ) . The synthesis shown below employs a chiral allylic Toluene alcohol that can then be epoxidized and the chiral epoxide MOBI 100° C . , 19 h opened with the anion of a tricyclic moiety . This method also allows the absolute stereochemistry of Example la and 1 Example 1b to be assigned . 15 To establish the absolute configuration of these com pounds, an asymmetric synthesis was carried out (Scheme 4B ) . Chiral starting material ( 18 , 2R ,6S ) - 2 - (benzyloxy ) - 7 10 % Pd / C oxabicyclo [ 4 . 1 . 0 ]heptane 1 was prepared from the known THF :MeOH R - ( + ) -cyclohexen - 2 - ol by literature methods as shown in 20 MON RT , 15 h Scheme 4A t11111IOBA Scheme 4A 25 O OCO2Me Pd2dba3CHC13 (2 mol% ) (S . S )- DACH -phenyl Trost Ligand ( 8 % ) SEO CH2Cl2: H20 9 :1 ON Et3N , DCM RT, 2 h OH UPLO VO (acac ) . TBHP OH CH2Cl2 3

( R ) - ( + ) -cyclohex - 2 - en - 1 - ol lit. [ a ] ] = +42 ( c = 1 .0 . CHC13) R absolute configuration NaN3 OH OBnOBA 40 DMF, •10110 100° C ., 14 h NaH , BnBr (microwave ) THF *

Starting 45 1 material 1

The starting material methyl cyclohex - 2 - enecarboxylate PPh3 , H2O was synthesized according to methods detailed in the sup - 50 THF porting information of the following reference : Timothy R . 11111ON RT , 17 h Ramadhar, Jun - ichi Kawakami, Alan J . Lough , and Robert A . Batey , Org . Lett. , 2010 , 12 ( 20 ), pp 4446 -4449 . This material ( 1 ) was deracemized according to procedures described in Bernhard J . Lussem and Hans - Joachim Gais . J . 55 5 Am . Chem . Soc . 2003 , 125 , 6066 -6067 to provide the chiral ( R )- cyclohex - 2 - enol ( 2 ) . Literature lit . [a ] ) = + 42 ( c = 1 .0 , = CHC13 ) . The epoxidation of ( R ) - cyclohex - 2 - enol ( 2 ) was - S - C1 performed according to procedures in Toshio Sato , Yoshi F3C0 — hiko Gotoh , Makoto Watanabe , and Tamotsu Fujisawa 60 07 Chemistry Letters, 1983 , 1533 - 1536 to provide the chiral EtzN epoxide ( 1R 2R , 3S ) - cis - 2 , 3 - epoxycyclohexan - 1 -ol ( 3 ) . Ben 11ON DMF, RT , 16 h zylation of ( 1R ,2R , 3S ) - cis - 2 , 3 - epoxycyclohexan - 1 -ol was performed using procedures in Federico Calvani, Paolo Crotti , Cristina Gardelli , Mauro Pineschi. Tetrahedron , 65 V NH2 1994 , 50 ( 45 ), 12999 - 13022 to provide starting material 1 shown in Scheme 4B . US 9 ,937 , 186 B2 53 54 - continued ( 1R ,28 , 3R ) - 3 - ( 10H -phenoxazin - 10 - yl) cyclohexane 1 , 2 - diol 3 A solution of 10H -phenoxazine (0 .323 g , 1 .76 mmol) in toluene ( 1 . 0 mL ) was treated with sodium amide (50 % wt . suspension in toluene, 0 . 274 g , 3 . 52 mmol ) . ( 18 , 2R , 6S ) - 2 (benzyloxy ) - 7 - oxabicyclo [ 4 . 1 . 0 ]heptane 1 (0 . 300 g , 1 .47 mmol ) in toluene (1 . 6 mL ) was added and the mixture NH heated to 100° C . for 19 h . The mixture was cooled to 25° NH , C . and poured over a solution of saturated aqueous ammo nium chloride ( 100 mL ) . The organic layer was separated and the aqueous layer was extracted with ethylacetate ( 3x100 mL ) . The organic layers were combined , dried 15 (Na , SO2) , and concentrated in vacuo . The residue was OCFz dissolved in a minimal amount of dichloromethane and Example 1B purified by flash chromatography (SiO2 , 25 g , 0 % - 20 ethyl acetate -hexanes ) to afford crude ( 18 , 2R , 6R ) - 2 - ( benzyloxy ) The synthesis was commenced by epoxide opening of 6 -( 10H - phenoxazin - 10 - yl) cyclohexanol 2 ( 0 . 422 g , crude previously synthesized ( 15 , 2R ,6S ) - 2 - ( benzyloxy ) - 7 -oxabi -- 2040 62 % ) which was taken to the next step without further cyclo [ 4 . 1 . Ojheptane 1 with commercially available 10H - purification . phenoxazine to afford 2 . Compound 2 was deprotected using A solution of ( 19 , 2R , 6R ) - 2 - ( benzyloxy ) - 6 - ( 10H - phenox 10 % Pd / C under hydrogen to afford diol 3 in an over- all azin - 10 - yl) cyclohexanol 2 (0 .422 g , 1 .09 mmol) in THF : yield of 41 % from 1 . Treatment of diol 3 with thionyl MEOH ( 1 : 1, 4 . 6 mL ) was treated with 10 % Pd / C ( 0 . 110 g , chloride furnished crude sulfide 4 . A sodium azide induced 0 . 110 mmol ) and then placed under an atmosphere of H2 ( g ) . azide displacement of 4 in a microwave reactor afforded The mixture was stirred for 15 h at 25° C . then filtered crude azide 5 , which was taken to the next step without through a celite pad , washed with hot methanol and ethyl further purification . Amine 6 was synthesized from 5 via a acetate , and concentrated in vacuo . The residue was dis Staudinger reaction ; the overall yield of 6 from 3 was 49 % . 30 solved in a minimal amount of dichloromethane and purified Treating 6 with commercially available 4 -( trifluo by flash chromatography (SiO2 , 10 % - 50 % ethyl acetate romethoxy )benzene - 1 - sulfonyl chloride afforded target sul hexanes ) to afford ( 1R , 2S , 3R ) - 3 - ( 10H - phenoxazin - 10 - yl ) fonamide Example 1b in a yield of 22 % . cyclohexane - 1 , 2 - diol 3 (0 .201 g , 41 % over two steps ) . ' H Experimental NMR (600 MHz, MeOD ) 8 7 . 00 (2H , dd , J = 7 . 2 , 0 . 6 Hz ) , 35 6 .89 - 6 . 86 (2H , m ) , 6 .80 -6 .78 (2H , m ), 6 .72 ( 2H , dd , J = 7 . 8 , 1 . 2 Hz) , 4 . 13 (1H , br s ) , 4 .03 ( 1H , dd , J = 10 . 8 , 2 . 4 Hz ), 3 . 90 ( 1H , td , J = 11 . 4 , 3 . 6 Hz ), 1 . 94 - 1 . 92 ( 1H , m ) , 1 . 85 - 1 .73 (3H , m ) , 1 . 53 - 1 .48 ( 2H , m ) ; ESI- HRMS calcd for C18H2NO3 [ M + H - ] 298 . 1438 , found 298 . 1439. NH 40 NaNH2 Toluene "110B 100° C . , 19 h 1 s = 0 . til EtzN , DCM RT, 2 h 10 % Pd / C THF MOH: VOH ON RT, 15 h

MOBI 2

60 111ONOH NaN3 DMF = O 100° C ., 14 h po" OH open(microwave ) 4 US 9 , 937 , 186 B2 55 56 - continued 1 .73 - 1. 71 ( 1H , m ), 1. 40 - 1. 37 (1H , m ), 1. 22 -1 .19 ( 1H , m ); ESI- HRMS calcd for C18H2 N202 [ M + H + ] 297 . 1598 , found 297 . 1597 .

PPh3, H2O 11110N THF RT, 17 h o=n F3C0 oN 10 ZIMIT UH a Et3N DMF, RT, 16 h

15 6 11110OH NH, 20 6 111ON

( 1R ,2S ,6R ) - 2 - amino - 6 - ( 10H -phenoxazin - 10 -yl ) cy clohexanol 6 25 A solution of ( 1R , 28 ,3R ) - 3 - ( 10H -phenoxazin - 10 - yl) cy clohexane - 1 , 2 - diol 3 ( 0 . 201 g , 0 .675 mmol) in dichlo romethane ( 2 mL ) under argon was cooled to 0° C ., and 30 OCF3 treated with triethylamine ( 0 . 147 mL , 2 . 03 mmol) . Follow Example 1b ing this thionyl chloride (0 . 748 mL , 5 .40 mmol) was added over 20 min . The reaction mixture was warmed to RT, stirred for 2 h , partitioned between dichloromethane and water , concentrated to obtain a residue which was purified by flash 35 N - ( ( 15 ,2S , 3R )- 2 - hydroxy - 3 - ( 10H - phenoxazin - 10 - yl) chromatography (SiO2 , 10 % -50 % ethylacetate -hexanes ) to cyclohexyl) - 4 - ( trifluoromethoxy ) benzenesulfona afford crude ( 3aS ,4R , 7aR ) - 4 - ( 10H - phenoxazin - 10 - yl) hexa mide ( Example 1b ) hydrobenzo [ d ] [ 1 , 3 , 2 ]dioxathiole 2 -oxide 4 ( 0 . 146 g , crude A solution of ( 1R , 28 , 6R ) - 2 - amino -6 - ( 10H -phenoxazin 63 % ). 40 10 - yl) cyclohexanol 6 ( 0 . 076 g , 0 . 256 mmol) in DMF ( 1 . 0 A solution of ( 3aS, 4R , 7aR ) - 4 - ( 10H -phenoxazin - 10 - yl) 40 mL ) was cooled to 0° C . , treated with triethylamine ( 0 .143 hexahydrobenzo [ d ][ 1, 3 ,2 ]dioxathiole 2 -oxide 4 (0 . 146 g , mL , 1 . 03 mmol) , and 4 - ( trifluoromethoxy ) benzene - 1 - sulfo 0 .425 mmol ) in DMF ( 2 . 5 mL ) was treated with sodium nyl chloride (0 .048 mL , 0 . 282 mmol) . The mixture was azide (0 .099 g , 1 .53 mmol) . The mixture was heated at 100 warmed to RT, and stirred for 16 h . The mixture was C . for 14 h in a Biotage Initiator® microwave reactor, sat*. 45 partitioned between water ( 10 mL ) and dichloromethane ( 10 aq. ammonium chloride was added ,mixture was extracted in mL ). The organic layer was washed with saturated aqueous dichloromethane , washed with brine , and concentrated in NaCl ( 30 mLx5 ) to remove DMF, and concentrated in vacuo . The residue obtained was purified by flash chroma vacuo . The residue was dissolved in a minimal amount of tography (SiO2 , 6 % - 13 % ethylacetate -hexanes ) to afford dichloromethane and purified by flash chromatography crude ( 15 .2S ,6R ) - 2 -azido - 6 - ( 10H - phenoxazin - 10 -yl ) cyclo - 50 (SiO . . 9 % - 50 % ethylacetate -hexanes to afford N - ( ( 15 , 2S , hexanol 5 ( 0 . 106 g, crude 77 % ) which was taken to the next 3R ) - 2 -hydroxy - 3 - ( 10H -phenoxazin - 10 - yl) cyclohexyl) - 4 step without further purification . ( trifluoromethoxy )benzenesulfonamide ( Example 1b ) A solution of (15 , 2S ,6R ) - 2 -azido - 6 - ( 10H -phenoxazin - 10 - (0 . 029 g , 22 % ) . ' H NMR (600 MHz, MeOD ) 8 8 .02 (2H , d , yl) cyclohexanol 5 ( 0 . 106 g , 0 . 329 mmol) in THF ( 1 . 20 mL ) J = 8 . 4 Hz ), 7 . 44 (2H , d , J = 8 . 4 Hz ) , 6 . 95 -6 . 94 (2H , m ) , 6 .88 was cooled to 0° C ., treated with PPhz ( 0 .094 g , 0 . 362 55 (2H , dt, J= 1. 4, 7. 7 , 7 .8 Hz ), 6 .80 (2H , t, J= 7. 8 Hz ), 6 .74 -6 .72 mmol) , H20 (0 .001 mL , 0 .056 mmol) , and stirred for 17 h (2H , m ), 3 .85 - 3 .82 (1H , m ) , 3 .42 -3 .37 ( 1H , m ), 3 . 12 - 3 .09 at RT. The solution was concentrated to dryness , dissolved ( 1H , m ), 1 . 93 - 1 . 91 ( 1H , m ) , 1 . 78 - 1 .74 (2H , m ) , 1 .67 - 1 .66 in a minimal amount of dichloromethane and purified by (1H , m ) , 1 . 35 - 1 .27 ( 2H , m ); 13C NMR ( 150 MHz , MeOD ) flash chromatography ( SiO2, 100 % hexanes , 50 % ethyl S 151. 7 , 149 .6 , 141 . 0 , 135 . 3 , 129 . 2 , 123 . 3 , 122 . 5 , 120 . 8 , acetate -hexanes , 3 % , methanol- dichloromethane , 17 : 2 : 1 60 118 . 6 , 115 . 4 , 72 . 9 , 69 . 2 , 59 . 3 , 32 . 3 , 28 . 5 , 22 . 3 ; ESI- HRMS dichloromethane: methanol : 35 % ammonium hydroxide ) to calcd for C25H24F2N2O3S [ M + H + ] 521 . 1353 , found afford ( 1R , 28 ,6R ) - 2 -amino - 6 - ( 10H -phenoxazin - 10 - yl) cy - 521 . 1349 ; [ a ] ) = + 13 ( c = 1 . 0 , CH , C1, ); [ a ] ) = - 11 ( c = 1 . 0 , clohexanol 6 ( 0 .076 g , 49 % over two steps ) . ' H NMR (600 C H ,OH ) ; MHz, MeOD ) d 6 . 96 (2H , dd , J = 7 . 8 , 0 . 6 Hz) , 6 .85 ( 2H , td , The enantiomeric identity and purity was also confirmed J = 7 . 2 , 1. 2 Hz ) , 6 .77 ( 2H , td , J = 7 .8 , 1 . 2 Hz ) , 6 .70 ( 2H , dd , 65 by analytical chiral HPLC > 98 % (CHIRALPAK® OZ - H J = 8 . 4 , 1 . 8 Hz ), 3 .73 - 3 .70 (1H , m ) , 3 . 42 - 3 . 38 ( 1H , m ) , column , 70 : 30 hexanes - EtOH , 1 mL /min , retention times : 9 2 .61 - 2 .57 (1H , m ), 1 . 92 - 1 . 90 (1H , m ), 1 .86 - 1 .82 ( 2H , m ) , min . Thus the material produced by this route is the same as US 9 ,937 , 186 B2 57 58 that from Peak 2 of the chromatographic resolution of 10H -phenoxazine employing chiral catalysis maybe Example 1 , that is Example 1b , and furthermore its absolute performed to control the first stereogenic center, followed by steochemistry is established as : diastereoselective osmlation to give optically enriched 3 -( 10H - phenoxazin -10 -yl ) cyclohexane -1 , 2 -diol as 5 described below . Asymmetric synthesis of ( 1R , 28 ,3R ) - 3 - ( 10H - phenox azin - 10 - yl) cyclohexane - 1 , 2 - diol.

10 ON Scheme 5 OBoc =O = ?

5 mol % Pd2dba3 , CHCl3 15 mol % ( S , S ) -DACH OCF3 phenyl Trost ligand o DCM , RT , 10 days N - ( ( 15 ,2S , 3R ) - 2 -hydroxy - 3 - ( 10H - phenoxazin - 10 -yl ) cyclohexyl) -4 -( trifluoromethoxy )benzenesulfona mide 25 In addition the absolute configuration of Example la is established as : OsO4, NMMO t -butanol - H20 , posto RT, 34 h 1111117

R (S ) WOH

( R ) OH

OCF3 ( 1R ,2S ,3R ) -3 - ( 10H -phenoxazin - 10 - yl) cyclohexane 45 1 ,2 - diol N - ( ( 1R , 2R ,3S ) - 2 -hydroxy - 3 - ( 10H - phenoxazin - 10 A 20 mL Biotage® microwave reaction vial was charged yl) - 4 - ( trifluoroxy ) benzenesulfonamide with Pd2 . dbaz. CHC1z ( 0 . 052 g , 0 .05 mmol) , and ( S , S ) DACH -phenyl Trost ligand ( 0 . 104 g , 0 . 15 mmol) . The vial Syntheses of optically enriched Examples la and 1b , 50 was sealed , evacuated and backfilled with argon three times . described above , employ chromatographic separation of Dry degassed dichloromethane ( 2 . 5 mL) was added to this racemic Example 1 by chiral HPLC or stereoselective syn - vial, and the mixture was stirred at room temperature for 30 thesis from optically enriched cyclohexen - 2 - ol of known min . Racemic tert -butyl cyclohex - 2 - en - 1 - yl carbonate configuration . In addition intermediates in the synthesis of ( 0 . 238 g , 1 . 20 mmol) was added to the vial and the contents Example 1 may be resolved , then optically enriched material 55 were transferred to a separate 20 mL Biotage® microwave carried forward to to give Example la or Example 1b . For reaction vial containing 10H -phenoxazine ( 0 . 183 g , 1 . 00 example , racemic 3 - ( 10H -phenoxazin - 10 - yl) cyclohexane- 1 , mmol) in dry degassed dichloromethane ( 3 . 0 mL ) . The 2 - diol ( intermediate 3 in Scheme 4B ) may be resolved by reaction mixture was stirred at room temperature for 10 chiral HPLC using CHIRALPAK® IF - 3 analytical column days . At this point, the reaction mixture was evaporated onto ( 4 . 6 mm diameterx150 mm length , 3 micron particle size ), 60 silica gel and subjected to column chromatography (SiO ; 70 :30 hexanes - EtOH , 1 mL /min to give enantiomers eluting 100 % hexanes ) to afford pure ( R ) - 10 - cyclohex - 2 -en - 1 - yl) with retention times 3 . 7 (Peakl ) and 4 . 7 ( Peak2 ) min 10H - phenoxazine ( 0 . 114 g , 43 % ) . HRMS m / z 264 . 1383 respectively. ( [ M + H + ] , C18H18NO requires 264. 1379 ) . In Scheme 4 , the first stereogenic center is introduced on A solution of ( R ) - 10 - ( cyclohex - 2 - en - 1 - yl ) - 10H - phenox alkylation of 10H -phenoxazine with 3 - bromocyclohex - 1 - 65 azine (0 . 114 g , 0 .432 mmol) , 4 -methylmorpholine N -oxide ene to yield racemic 10 - (cyclohex - 2 - en - 1 - yl) - 10H - phenox - monohydrate ( 0 .056 g , 0 .476 mmol) , and osmium tetroxide azine . An asymmetic synthesis of 10 -( cyclohex -2 - en -1 -yl ) - (0 .040 mL, 0 .004 mmol, 2 .5 % in tert- butanol ) in tert -butanol US 9 ,937 , 186 B2 59 60 ( 1 . 30 mL ) and water (0 . 30 mL ) , was stirred at RT for 34 h . solution at RT , and the reaction mixture was stirred for 3 h , The reaction mixture was treated with solid sodium bisulfite neutralized with sat. aq . NH _ C1, extracted with dichlo solution , stirred for 1 h , evaporated on to silica and purified romethane, concentrated in vacuo to give a residue which by flash chromatography (SiO2 , 0 % - 70 % ethyl acetate was purified by flash chromatography (SiO2 , 0 % - 5 % ethy hexanes ) to afford ( 1R .28 . 3R ) - 3 - ( 10H - phenoxazin - 10 - vl) 5 lacetate in hexanes ) to afford 5 - (cyclohex - 2 - en - 1 - yl) - 5 , 11 cyclohexane - 1, 2 - diol ( 0 . 101 g , 79 % ) . ' H NMR (600 MHz , dihydrodibenzo [ b , e ][ 1 , 4 ] oxazepine ( 5 . 08 g , 83 % ). ' H NMR M OD ) 8 7 .01 - 7 .00 ( 2H , m ) , 6 . 88 (2H , bs ), 6 . 80 (2H , m ) , (600 MHz, CDC12 ) 8 7 . 26 - 7 . 23 ( 1H , m ) , 7 . 17 - 7 . 14 ( 3H , m ) , 6 .73 - 6 .72 (2H , m ) , 4 . 14 ( 1H , m ), 4 .04 - 4 .03 ( 1H , m ), 3 . 90 7 . 06 - 7 .04 ( 1H , m ), 6 . 97 - 6 . 94 ( 1H , m ), 6 .89 -6 .87 ( 1H , m ), 6 .77 -6 .74 ( 1H , m ), 5 .99 - 5 .98 ( 1H , m ), 5 .71 ( 1H , d , J= 10 .2 ( 1H , bs ) , 1 . 93 ( 1H , bs ) , 1 . 84 - 1 . 74 (3H , m ) , 1 . 53 - 1 . 52 ( 2H , 10 Hz ) , 4 .58 (1H , d , J= 14 .4 Hz ) , 4 . 35 -4 . 32 (2H , m ), 2. 16 - 2 . 06 m ); 13C NMR ( 150 MHz, MeOD ) d 123. 3 , 122. 3 , 118. 7 , (2H , m ), 1 .97 - 1. 86 ( 2H , m ), 1 .70 - 1 .65 (2H , m ); 13C NMR 115 . 3 , 72 . 2 , 70 . 6 , 64 . 3 , 30 . 8 , 28 . 7 , 19 . 1 ; HRMS m / z ( 150 MHz, CDC12 ) 8 157 . 8 , 147 . 5 , 141. 0 , 131 . 9 , 131. 2 , 298 . 1437 ([ M + H * ], C18H20NOZ requires 298 . 1438 ). Mate 129 . 7 , 128 . 7 , 128 . 1 , 124 . 4 , 123 . 7 , 122 . 1 , 120 . 1 , 119. 6 , rial produced in this fashion exhibited (alp = + 0 . 03 ( c = 1 . 0 , 118 . 2 . 56 . 9 . 48 . 6 . 26 . 9 . 25 . 2 . 21. 6 : LCMS m / z 278 .3577 CH , C , 2 ). The enantiomeric purity was confirmed by ana - 15 ( M + H - 1. C . H . NO requires 278 3677 ) . lytical chiral HPLC > 99 % (CHIRALPAK® IF - 3 column, ( 15 , 2R , 3S ) - rel- 3 - ( dibenzo [ b , e ] [ 1 , 4 ]oxazepin - 5 ( 11H ) - yl) 70 : 30 hexanes- EtOH , 1 . 5 mL /min , retention time: 4 . 7 min . cyclohexane - 1 , 2 - diol. A solution of 5 - ( cyclohex - 2 - en - 1 - yl) This material co -elutes with 4 .7 min , peak 2 of the racemate . 5 , 11 -dihydrodibenzo [b ,e ][ 1, 4 ]oxazepine (5 .08 g , 18 .3 In addition ( 10H - phenoxazin - 10 - yl) cyclohexane - 1 , 2 -diol mmol) , osmium tetroxide ( 1 . 84 mL , 0 . 183 mmol, 2 . 5 % in produced by the method of Scheme 1B , i . e . from ( R ) - ( + ) - 20 tert - butanol) , and N -Methylmorpholine N -oxide ( 2 . 35 g , cyclohex - 2 - enol, has retention time 4 . 7 min by the same 20 . 1 mmol) in tert - butanol: water ( 25 mL : 5 mL ) was stirred chiral HPLC analysis , which confirms the absolute stereo at RT for 34 h . The reaction mixture was treated with solid chemistry of the product from the asymmetric catalysis as sodium bisulfite for 1 h , concentrated , and purified by flash that shown above , i . e . ( R ) - 10 - ( cyclohex - 2 -en - 1 -yl ) - 10H - chromatography (SiO , 0 % - 70 % ethyl acetate - hexanes ) to phenoxazine and (1R , 28 ,3R )- 3 - (10H -phenoxazin - 10 - yl) cy - 25 afford Rac -( 18 ,2R ,3S )- 3 - (dibenzo [b , e ][ 1, 4 ]oxazepin - 5 clohexane - 1 , 2 -diol . The other enantiomeric series may be ( 11H ) - yl cyclohexane - 1 . 2 - diol. ( 2 .30 g . 40 % ) . IH NMR accessed by the same method but employing the opposite (600 MHz, DMSO - d ) 8 7 .31 ( 1H , dd , J = 7 . 2 , 1 . 2 Hz ) , 7 .24 enantiomer of the chiral ligand , i. e . ( R , R ) -DACH -phenyl ( 1H , td , J = 7 . 8 , 1 . 8 Hz) , 7 . 11 - 7 . 10 ( 1H , m ), 7 .07 - 7 .05 ( 1H , Trost ligand in the asymmetric allylation step . m ) , 7 .00 - 6 . 97 ( 2H , m ) , 6 . 88 ( 1H , td , J = 7 . 8 , 1 . 8 Hz ) , 6 .62 30 6 .60 ( 1H , m ), 4 . 59 ( 1H , d , J= 14 .4 Hz ), 4 . 43 ( 1H , d , J = 3 .6 Example 2 Hz) , 4 . 39 ( 1H , d , J = 5 . 4 Hz ), 4 . 28 ( 1H , d , J = 14 . 4 Hz) , 3 . 97 ( 1H , bs ) , 3 .81 ( 1H , td , J = 4 . 8 , 10 . 2 Hz ), 3 .65 ( 1H , td , J = 3 . 0 , 6 .0 Hz) , 1. 67 - 1. 65 ( 1H , m ) , 1 .59 - 1 .46 (3H , m ), 1. 42 - 1. 35 ( 2H , m ) ; 13C NMR ( 150 MHz, CDC12 ) 8 150 . 6 , 129 . 0 , 2 35 128 . 5 , 124 . 4 , 123 . 6 , 123 . 1 , 122 . 0 , 120 . 4 , 72 . 5 , 69 . 0 , 62 . 0 , 49 . 9 , 29. 9, 27 .5 , 19 .6 ; LCMS m /z 312 .3229 ([ M + H + ], LOCF3 C19H22NO , requires 312 . 3823 ) . OH (18 ,2R , 3S ) - rel - 3 - (dibenzo [ b , e ] [ 1 , 4 ]oxazepin - 5 ( 11H ) - yl) 2 -hydroxycyclohexyl methanesulfonate . To a solution of N 40 Rac - ( 18 ,2R , 3S ) - 3 - ( dibenzo [ b , e ] [ 1 , 4 ] oxazepin - 5 ( 11H ) -yl ) ou cyclohexane - 1 , 2 - diol ( 2 . 30 g , 7 . 39 mmol ) in pyridine ( 16 . 0 mL) under argon , at 0° C . , was added methane sulfonyl chloride (0 .572 mL , 7. 39 mmol) . The mixture was stirred for 16 h at RT. The reaction mixture was treated with 1 N HC1, The synthesis begins with alkylation of commercially 45 extracted with DCM , organic layer was washed with brine , available 5 , 11- dihydrodibenzo [be ] [ 1 , 4 ]oxazepine with concentrated , to obtain a residue which was purified by flash commercially available 3 -bromocyclohex - l -ene to afford chromatography ( SiO2, 90 % dichloromethane -hexanes ) to 5 - ( cyclohex - 2 - en - 1 -yl ) - 5 , 11 - dihydrodibenzo [be ] [ 1 , 4 ]ox afford Rac - ( 18 ,2R ,3S ) - 3 - (dibenzo [ b , e ] [ 1 , 4 ]oxazepin - 5 azepine in 83 % yield . An osmium tetroxide catalyzed dihy ( 11H ) - yl) - 2 - hydroxycyclohexyl methanesulfonate ( 0 . 301 g , droxylation of the alkene afforded diol in 40 % yield . Treat - 50 10 % ). ' H NMR (600 MHz , CD ,OD ) 8 7 .29 - 7 . 28 ( 1H , m ) , ment of diol with methanesulfonyl choride furnished 7 .25 - 7 .23 ( 1H , m ) , 7 . 11 -7 .09 (2H , m ), 7 .06 -7 .04 ( 2H , m ), mesylate in 10 % yield . A sodium azide induced azide 6 . 97 - 6 . 94 ( 1H , m ), 6 .81 - 6 . 79 ( 1H , m ), 4 . 89 - 4 .87 ( 1H , m ) , displacement of the mesylate afforded regioisomeric azides : 4 .45 ( 2H , s ), 4. 38 - 4. 37 (1H , m ), 4 .06 ( 1H , td , J = 10 .2 , 3 .6 the 2 - azido - 6 - tricyclylcyclohexanol in 29 % yield and the Hz ) , 2 . 94 ( 3H , s ) , 1 . 85 - 1 . 82 ( 1H , m ) , 1 . 72 - 1 .58 ( 4H , m ) , 2 -azido - 3 - tricyclylcyclohexanol in 17 % yield . The 2 - amino - 55 1 .51 - 1 .49 ( 1H , m ) ; 13C NMR ( 150 MHz, CD ,OD ) 8 157 . 9 , 6 - tricyclylcyclohexanol was synthesized from the 2 -azido - 149. 6 , 141. 0 , 130 .7 , 128 . 7, 128 .6 , 124 .1 , 123 .4 , 121. 9 , 6 -tricyclylcyclohexanol via a Staudinger reaction in 80 % 121. 4 , 121 . 1 , 119 .4 , 83. 2 , 69. 1 , 59. 3 , 48 . 8 , 37 . 5 , 30 . 7 , 29 .0 , yield . Treating 2 -amino -6 -tricyclylcyclohexanol with com - 18 .6 ; LCMS m /z 390 .3659 ( [M + H + ], C20H24NO S requires mercially available 4 - ( trifluoromethoxy )benzene - 1 - sulfonyl 390 . 4727 ) . chloride afforded target sulfonamide Example 2 in a yield of 60 (1R ,2R ,6S ) - rel - 2 -azido - 6 - ( dibenzo [ b , e ] [ 1 , 4 ]oxazepin - 5 53 % . ( 11H ) -yl ) cyclohexanol. A solution of ( 15 ,2R , 3S ) - rel- 3 5 - (cyclohex - 2 - en - 1 - yl) - 5 , 11 -dihydrodibenzo [ b , e ] [ 1, 4 ] ox - ( dibenzo [ b , e ][ 1 ,4 ]oxazepin - 5 ( 11H ) - yl) - 2 - hydroxycyclo azepine . To a solution of 5 ,11 - dihydrodibenzo [b , e ][ 1 ,4 ]ox - hexyl methanesulfonate ( 0 .301 g, 0 .773 mmol) in DMF ( 1 azepine ( 4 .37 g , 22 . 1 mmol) in DMF (22 mL ) at RT, was mL ) was treated with sodium azide (0 .075 g, 1. 16 mmol) . added NaH ( 0 . 975 g , 24 . 4 mmol, 60 % dispersion in mineral 65 The mixture was heated at 110° C . for 14 h in a Biotage oil ) . The mixture was stirred at RT for 20 min . 3 - bromocy - Initiator® microwave reactor, sat. aq . ammonium chloride clohex - l - ene ( 7 . 12 g , 44 . 2 mmol) was added to the above was added , mixture was extracted in dichloromethane , and US 9 ,937 , 186 B2 62 concentrated in vacuo . The residue obtained was purified by J = 14 . 4 Hz) , 3 .83 ( 1H , dd , J = 10 . 2 , 4 . 8 Hz) , 3 .47 (1H , dd , flash chromatography (SiO2 , 10 % ethylacetate -hexanes ) to J = 10 .2 , 3. 6 Hz ) , 3 .29 (1H , dd , J= 10 . 2 , 10 . 2 Hz) , 2 . 06 - 2 . 00 afford the major product — 1R ,2R ,6S )- rel -2 -azido -6 (2H , m ), 1 .69 - 1 .68 ( 1H , m ), 1 .41 - 1 . 28 (3H , m ); 13C NMR ( dibenzo [ b , e ][ 1 , 4 ] oxazepin - 5 ( 11H ) - yl) cyclohexanol ( 0 .075 ( 150 MHz, CD ,OD ) 8 158 . 2 , 151 . 5 , 148 . 9 , 142 . 6 , 140 . 2 , g , 29 % ), and the minor product — ( 1R 2R ,6S ) - rel- 2 - azido - 3 - 5 130 . 2 . 128 . 9 . 128 . 6 . 124 . 5 . 123 . 9 . 121 . 3 . 120 . 7 . 120 . 5 . ( dibenzo [ b , e ][ 1 , 4 ] oxazepin - 5 ( 11H ) - yl) cyclohexanol ( 0 .044 119 . 9 . 119 . 5 . 71 . 3 . 69 . 3 , 53 . 4 . 33 . 9 . 33 . 2 , 20 . 8 ; LCMS m / z g , 17 % ) . ' H NMR (600 MHz, CD ,OD ) 8 7 .28 (1H , dd , J = 7 . 2 , 1 . 2 Hz ) , 7 .23 ( 1H , td , J = 7 . 8 , 1 . 2 Hz ), 7 . 12 - 7 . 11 (2H , 535 . 2464 ([ M + H + ], C26H27F3N2O S requires 536 . 5621 ) . d ) , 7 . 06 - 7 .03 ( 2H , m ), 6 . 92 - 6 . 89 ( 1H , m ) , 6 .72 -6 .69 ( 1H , m ) , Examples 3 , 4 , 5 , 6 and 7 4 .65 ( 1H , d , J = 14 . 4 Hz ), 4 .42 ( 1H , d , J = 14 . 4 Hz ) , 3 . 83 ( 1H , 10 td , J = 10 . 2 , 4 .8 Hz) , 3. 63 ( 1H , td , J= 10 . 8 , 4 .8 Hz ), 3. 35 - 3 .32 ( 1H , m ), 2 . 05 - 2 .01 (2H , m ) , 1. 75 - 1 . 73 ( 1H , m ), 1 . 43 - 1 .31 ( 3H , m ) ; 13C NMR ( 150 MHz, CD , OD ) 8 158 . 8 , 148 . 4 , 142 . 1 , 131. 1 , 128 . 8 , 128 . 2 , 123 . 9 , 123 . 6 , 121. 4 , 120 . 5 , 119 . 8 , 119 . 4 , 71 . 9 , 69 . 2 , 60 . 8 , 46 . 9 , 33 . 6 , 31 . 3 , 20 . 7 : LCMS 15 m / z 337 .2954 ( [ M + H + ], C1, H2 , N20 , requires 337 . 3951 ) . ' H NMR (600 MHz, CD2OD ) 8 7 . 25 - 7 . 21 ( 2H , m ) , 7 . 12 7 .02 (4H , m ), 6 .95 -6 .92 ( 1H , m ) , 6 .79 -6 .77 ( 1H , m ), 4 .42 IZ (2H , s ), 4 . 21 ( 1H , d , J = 1 .2 Hz ), 3 . 98 ( 1H , td , J = 11 .4 , 3 .6 Hz) , 3 .61 - 3 .60 ( 1H , dd , J = 10 . 8 , 3 . 0 Hz) , 1. 79 - 1 .77 ( 1H , m ) , 20 1 . 66 - 1 .61 ( 2H , m ) , 1 .55 - 1 . 46 (3H , m ) ; 13C NMR ( 150 MHz, CD , OD ) 158 . 0 , 149 . 3 , 140 . 6 , 131 . 1 , 128 . 6 , 128 . 3 , 123 . 9 , 123 .3 , 121. 4 , 121. 0 , 120 .8 , 119 . 4 , 69. 4 , 65 .4 , 59 .2 , 46 . 91 , R = OCFz ( Ex . 3 ) , RS = C1 ( Ex . 4 ), RS = CN ( Ex . 5 ), RS = OCHZ 31. 2 , 29. 0 , 19. 0 ; LCMS m / z 337 . 3301 ( [ M + H + ] , (Ex . 6 ) , RP = H ( Ex . 7 ) . C19H2 N40 , requires 337 .3951 ) . 25 First route to racemic Example 3 : (15 , 2R ,6S )- rel- 2 -amino -6 -( dibenzo [b ,e ][ 1 , 4 ]oxazepin -5 9 - (cyclohex - 2 -en - 1 - yl) -9H -carbazole . A solution of car ( 11H ) - yl) cyclohexanol. A solution of ( 1R , 2R ,6S ) -rel - 2 - bazole ( 4 . 00 g , 23 . 9 mmol ) in DMF ( 40 mL ) was cooled to azido - 6 - (dibenzo [b , e ][ 1, 4 ]oxazepin - 5 (11H )- yl ) cyclohexa - 0° C ., treated with NaH (60 % dispersion in mineral oil, 1. 00 nol (0 .075 g, 0 .223 mmol) in THF (0 . 8 mL ) was cooled to g , 25 .1 ,mmol ) , stirred for 0 . 5 h , then treated with 3 -bromo 0° C . , treated with PPh , (0 .064 g , 0 .245 mmol) , H , O ( 0 .001 30 cyclohex - 1 -ene ( 3 . 03 mL , 26 . 3 mmol) . The mixture was mL , 0 .056 mmol ), and stirred for 17 h at RT. The solution warmed to 25° C ., and stirred for 14 h . The mixture was was concentrated to dryness , dissolved in a minimal amount partitioned between saturated aqueous NaCl ( 100 mL ) , and of CH _ C12 and purified by flash chromatography (SiO2 , CH C12 ( 300 mL ) . The organic layer was washed with 100 % hexanes , 50 % ethyl acetate - hexanes , 5 % , methanol- saturated aqueous NaCl ( 3x100 mL ) , dried (Na , SO2 ), and dichloromethane , 17 : 2 : 1 dichloromethane :methanol : 35 % 35 concentrated in vacuo . The residue was dissolved in a ammonium hydroxide ) to afford ( 18 , 2R , 6S ) - rel- 2 - amino - 6 - minimal amount of CH , C1, and purified by flash chroma ( dibenzo [b , e ][ 1 , 4 ] oxazepin - 5 ( 11H ) - yl) cyclohexanol ( 0 .055 tography (SiO2 , 100 % hexanes ) . The purified fractions were g , 80 % ) . ' H NMR (600 MHz, CD2OD ) 87 .29 - 7 . 25 ( 3H , m ) , combined , dissolved in a minimal amount of methanol and 7 .61 - 7 . 15 ( 1H , m ), 7 .08 - 7 .04 ( 2H , m ), 6 .93 ( 1H , td , J = 7 . 8 , stirred until a white solid precipitated affording the title 1. 8 Hz ) , 6 .75 -6 . 72 ( 1H , m ), 4 . 73 ( 1H , d , J = 15 . 0 Hz ), 4 .42 40 compound as a white solid (5 .41 g , 91 % ) . ' H NMR (600 ( 1H , d , J = 15 Hz) , 3 . 86 ( 1H , td , J = 10 . 2 , 4 . 8 Hz ), 3 .25 (1H , MHz, CDC1z ) 8 8 . 12 (2H , d , J = 7 . 8 Hz ), 7 . 56 (2H , d , J = 7 . 8 dd , J = 10 . 2 , 10 . 2 Hz ), 2 . 92 ( 1H , td , J = 10 . 8 , 4 . 2 Hz ) , 2 . 10 - Hz ) , 7 .43 ( 2H , t , J = 7 . 2 Hz ), 7 .23 ( 2H , t , J = 7 . 2 Hz ), 6 . 11 - 6 . 14 2 .09 ( 1H , m ) , 1 . 93 - 1 .91 ( 1H , m ), 1. 76 - 1 .74 ( 1H , m ) , 1 .49 - (1H , m ), 5 . 94 ( 1H , d , J = 10 . 2 Hz) , 5 . 33 - 5 . 38 ( 1H , m ), 1 .41 ( 2H , m ) , 1 .24 - 1 . 18 ( 1H , m ) ; 13C NMR ( 150 MHz, 2 . 33 - 2 . 36 ( 1H , m ) , 2 . 22 - 2 .28 (2H , m ) , 2 . 09 - 2 . 12 ( 1H , m ) , CD , OD ) 8 157 . 8 , 148 . 4 , 143 . 1 , 131 . 1 , 128 . 7 , 127 . 9 , 124 . 2 , 45 2 . 02 - 2 .05 ( 1H , m ), 1 . 89 - 1 . 92 ( 1H , m ) ; 13C NMR ( 150 MHz, 123 . 8 , 121. 2 , 120 . 9 , 120 . 0 , 119 . 8 , 73 . 4 , 69 . 1 , 51. 1 , 46 . 5 , CDC12 ) d 140 . 1 , 131. 0 , 129 . 1 , 125 . 5 , 123 . 5 , 123 . 4 , 120 . 4 , 34 . 3 , 32 . 8 , 21 . 3 ; LCMS m / z 311 . 2788 ( M + H + ) , 118. 9 , 52 . 0 , 27 . 7 , 25 . 0 , 22 . 2 ; C19H23N202 requires 311 .3976 ). ( 1R ,28 , 3R ) - rel- 3 - ( 9H -carbazol - 9 -yl ) cyclohexane - 1 , 2 N - ( ( 1R , 2R , 3S ) -rel - 3 - (dibenzo [ b , e ][ 1 , 4 ]oxazepin - 5 (11H ) - diol. A solution of 9 - ( cyclohex - 2 - en - 1 -yl ) - 9H - carbazole yl) - 2 -hydroxycyclohexyl ) - 4 -( trifluoromethoxy )benzenesul - 50 ( 4 .00 g , 16 . 2 mmol) in t -BuOH - H20 5 : 1 ( 20 .0 mL ) at 25° C . fonamide. A solution of ( 15 , 2R ,6S ) - rel- 2 -amino - 6 - (dibenzo was treated with OsO4 ( 2 . 5 wt. % solution in t - BuOH , 2 .02 [ b , e ][ 1 , 4 ]oxazepin - 5 ( 11H ) - yl) cyclohexanol ( 0 .055 g , 0 . 177 mL , 0 . 162 mmol) and N -methyl morpholine N -oxide ( 2 . 08 mmol) in DMF ( 1. 5 mL ) was cooled to 0° C ., treated with g , 17 .8 mmol) . The mixture was stirred for 14 h at 25° C ., Et N ( 0 .030 mL , 0 . 212 mmol) , and 4 - (trifluoromethoxy ) treated with a saturated aqueous solution of sodium hydro benzene - 1 -sulfonyl chloride ( 0 .033 mL , 0 . 195 mmol) . The 55 sulfite ( 5 mL ) and stirred for an additional 1 h . The mixture mixture was warmed to RT, and stirred for 4 h . The mixture was concentrated in vacuo and the residue was taken up in was partitioned between water ( 10 mL ) and CH , C , , ( 10 a minimal amount of CH , C1 , and purified by flash chroma mL ) . The organic layer was washed with saturated aqueous tography ( SiO2, 0 - 35 % ethyl acetate - hexanes ) to afford the NaCl (30 mLx3 ) to remove DMF, and concentrated in title compound as a clear foam ( 4 . 86 g , 99 % ) . ' H NMR (600 vacuo . The residue was dissolved in a minimal amount of 60 MHz, CDC1z ) 8 8 . 10 ( 2H , br s ), 7 . 44 ( 2H , br s ) , 7 . 32 ( 1H , CH , C1, and purified by flash chromatography (SiO2 , 25 % - brs ), 7 .24 (3H , brs ), 4 .65 (1H , td , J= 14 . 4 , 4 .2 Hz ), 4 .65 ( 1H , 50 % ethylacetate - hexanes ) to afford N - ( ( 1R , 2R , 3S ) - rel- 3 - td , J = 10 . 2 Hz ) , 3 . 75 ( 1H , s ) , 2 .92 ( 2H , br s ), 2 . 27 ( 1H , qd , ( dibenzo [ b , e ] [ 1 , 4 ] oxazepin - 5 ( 11H ) - yl ) - 2 -hydroxycyclo - J = 14 . 4 , 5 . 4 Hz ), 1 . 86 - 1 . 94 ( 3H , m ) , 1 .62 - 1 .64 ( 1H , m ), 1 . 43 hexyl) - 4 - ( trifluoromethoxy )benzenesulfonamide (0 .050 g , ( 1H , t , J = 14 .4 Hz ); LCMS m / z 282. 1503 ( [ M + H + ] , 53 % ) . H NMR (600 MHz, CD , OD ) 8 7 . 74 - 7 .72 ( 2H , m ), 65 C , H , NO , requires 282 . 1489 ) . 7 .26 -7 .24 (1H , m ), 7 . 18 - 6 . 90 (7H , m ), 6 . 93 -6 . 90 ( 1H , m ), (1R ,28 ,3R ) - rel - 3 -( 9H -carbazol - 9 - yl ) - 2 -hydroxycyclo 6 .73 -6 .70 ( 1H , m ) , 4 . 31 ( 1H , d , J = 14 . 4 Hz) , 4 . 23 ( 1H , d , hexyl methanesulfonate . A solution of ( 1R , 28 , 3R ) -rel - 3 US 9 ,937 , 186 B2 63 64 (9H -carbazol - 9 - yl) cyclohexane - 1, 2 -diol (4 . 86 g , 15. 7 Second Route to Racemic Example 3 and Single Enantiom mmol) in pyridine (5 .0 mL ) was cooled to 0° C . and treated ers Examples 3a and 3b dropwise with methanesulfonyl chloride (1 .22 mL, 15. 7 mmol ). The mixture was warmed to 25° C ., stirred for 3 h , and then concentrated in vacuo . The residue was suspended 5 in CH , C1 , ( 200 mL ) and the organic phase was washed with 1 M HC1 (3x100 mL ) , dried (Na2SO4 ) , and concentrated in vacuo . The residue was dissolved in a minimal amount of Q CH _ C12 and purified by flash chromatography (SiO2 , 0 - 35 % ethyl acetate - hexanes ) to afford the title compound as a 10 white solid (6 . 12 g , 99 % ) . ' H NMR (600 MHz, CDC1z ) 8 8 .08 ( 2H , br s ) , 2H [ 7 .59 ( br s ) , 7 . 50 ( brs) ] , 7 .46 ( 2H , t , J = 7 . 2 Hz ), 7 .24 ( 2H , t , J = 7 . 2 Hz) , 2 . 92 ( 1H , br s ), 5 . 40 (1H , d , J = 10 . 2 Hz ) , 5 . 14 ( 1H , td , J = 12 . 0 , 4 . 2 Hz ) , 4 .51 ( 1H , br s ) , je 2 .29 ( 1H , qd, J = 13 . 2 , 3 . 6 Hz ), 2 . 16 - 2 . 18 ( 1H , m ), 2 . 10 - 2 . 11 9 - (cyclohex - 2 - en - 1 -yl ) - 9H - carbazole ( 1H , m ), 2 .02 -2 . 06 (1H , m ), 1 .76 (2H , t, J= 12 .0 Hz ), 1. 54 A solution of carbazole ( 4 .00 g , 23 . 9 mmol) in DMF ( 40 ( 3H , s) ; LCMS m /z 360 . 1267 ([ M + H +] , C19H2 NOAS mL ) was cooled to 0° C ., treated with NaH (60 % dispersion requires 360 . 1264) . in mineral oil , 1 .00 g , 25 . 1 , mmol) , stirred for 0 . 5 h , then ( 1R ,28 ,6R ) - rel- 2 - azido - 6 - ( 9H - carbazol- 9 - yl) cyclohexa- 20 treated with 3 - bromo- cyclohex - l - ene ( 3 . 03 mL , 26 . 3 nol A solution of ( 1R . 2S ,3R ) - rel- 3 - ( 9H - carbazol- 9 - yl) - 2 - mmol) . The mixture was warmed to 25° C ., and stirred for hydroxycyclohexylmethanesulfonate (6 . 12 g , 17 .0 mmol) in 2 h . The mixture was quenched with saturated aqueous DMF ( 10 . 0 mL) was treated with NaNZ ( 1 .66 g , 25 . 5 mmol) NH . CI ( 100 mL ) . On larger scales, the mixture could be and heated to 70° C . for 14 h . The mixture was cooled to 25° treated with H , O ( 100 mL ) , CH , OH ( 200 mL ) , and then the C . and partitioned between saturated aqueous NaCl ( 100 25 white solid that had formed was collected by filtration . mL ) and CH , C1, ( 300 mL ) . The organic layer was washed Alternatively, the mixture was extracted with CH , C1 , hexanes (50 : 50 mixture , 3x200 mL ) . The organic layer was with saturated aqueous NaCl ( 3x100 mL ) , dried (Na2SO4 ) , washed with saturated aqueous NaCl ( 100 mL ) , dried and concentrated in vacuo . The residue was taken up in a (Na , SO2 ) , and concentrated in vacuo . The residue was minimal amount of CH2Cl2 and purified by flash chroma dissolved in a minimal amount of CH2Cl2 and purified by tography (SiO2 , 0 - 20 % ethyl acetate - hexanes) to afford the 30 flash chromatography ( SiO2, 100 % hexanes ) . The purified title compound as a beige oil ( 0 .792 g , 15 % ), with the fractions were combined , dissolved in a minimal amount of remainder as unreacted starting material . ' H NMR (600 methanol and stirred until a white solid precipitated afford MHz , CDC1z ) 0 (as a mixture of rotamers ) 2H [ 8 .13 (t , J= 8 . 4 ing the title compound as a white solid (5 .41 g , 91 % ). ' H Hz ), 8 . 09 ( t, J = 7 . 8 Hz ) , 7 .57 ( 1H , t, J = 9 . 6 Hz ) , 7 .45 - 7 .51 - NMR (600 MHz, CDC12 ) 8 8 . 12 (2H , d , J = 7 . 8 Hz ) , 7 .56 ( 2H , ( 2H , m ) , 7 .43 ( 1H , t , J = 6 . 0 Hz ) , 2H [ 7 . 30 ( t , J = 7 . 8 Hz ) , d , E7. 8 Hz) , 7 . 43 ( 2H , t , J = 7 . 2 Hz ) , 7 .23 (2H , t , J = 7 . 2 Hz ) , 7 . 26 - 7 . 28 ( m ) ] , 5 . 32 ( 1H , t , J = 9 .6 Hz) , 1H [ 4 .64 ( td , J = 4 . 2 6 . 11 -6 . 14 ( 1H , m ), 5 .94 ( 1H , d , J= 10 .2 Hz ) , 5 . 33 - 5 . 38 ( 1H , Hz ), 4 .40 -4 .48 ( m ) ], 1H [3 .67 (ddd , J = 12 .6 , 9 .6 , 4 .2 Hz ), m ) , 2 .33 - 2 . 36 ( 1H , m ), 2 .22 - 2 . 28 (2H , m ), 2 .09 - 2 . 12 ( 1H , 3 .53 -3 .57 ( m ) ], 1H [ 2 .60 , qd , J = 13 .2 , 3 .6 Hz ), 2 .45 ( qd m ) , 2 . 02 - 2 . 05 ( 1H , m ), 1 . 89 - 1 . 92 ( 1H , m ) ; 13C NMR ( 150 J= 12. 0 , 3 .6 Hz) ] , 1H [2 .34 - 2 .37 ( m ), 2 . 25 (br s) ], 2 .17 ( 1H , 40 MHz120 , CDC13 ) d 140 . 1 , 131. 0 , 129 .1 , 125 .5 , 123. 5 , 123 . 4 , m ), 3H [2 .03 -2 .06 (m ), 2 .02 (s ) , 1. 93 - 2 .00 ( m )] , 2H [ 1. 74 ( qdH , 40 120 . 4 , 118. 9 , 52 .0 , 27 . 7 , 25 . 0 , 22. 2 . J = 13 . 8 , 3 .6 Hz) , 1. 53 - 1 .65 ( m ) ]; LCMS m / z 307 . 1559 ( [ M + H + ], C20H24N20 requires 307. 1553 ). ( 1R , 28 ,6R ) -rel - 2 - amino -6 - ( 9H - carbazol- 9 - yl) cyclohexa nol. A solution of ( 1R , 2S ,6R ) - rel - 2 - azido -6 - ( 9H -carbazol - 9 - 45 yl) cyclohexanol . (0 .792 g , mmol) in DMF ( 10 .0 mL ) was treated with PPhz ( 4 .71 g , 18 . 0 mmol) , H , O ( 0 . 5 mL ), and stirred for 14 h at 25° C . The mixture was concentrated in vacuo , taken up in a minimal amount of CH , Cl, and purified unON by flash chromatography (SiO2 , 0 - 50 % ethyl acetate - 50 hexanes to remove nonpolar impurities , followed by 0 - 3 % Iman MeOH - CH2Cl2 to remove triphenylphosphine oxide, fol lowed by 17 : 2 : 1 CH2Cl2 :MeOH : NH , OH to elute the prod uct ). The purified fractions were combined , dried azeotro (1R , 28 ,3R ) - rel - 3 - ( 9H - carbazol- 9 - yl) cyclohexane - 1 , pically with toluene to afford the title compound as a beige 55 2 - diol oil ( 0 . 238 g , 39 % ) . ' H NMR (600 MHz, CDC13 ) 8 8 . 13 ( 1H , d , J = 7 .8 Hz ), 8 .08 ( 1H , d , J = 7. 8 Hz ), 7 .58 ( 1H , d , J = 8 .4 Hz) , solution of 9 -( cyclohex -2 - en - 1 -yl ) - 9H - carbazole ( 4. 00 7 .45 (1H , d , J = 4 . 2 Hz ) , 7 .40 (1H , t , J = 7 . 8 Hz) , 7 . 19 - 7 . 26 g , 16 . 2 mmol) in t -BuOH - H , O 5 : 1 ( 20 . 0 mL ) at 25° C . was ( 2H , m ) , 7 .08 ( 1H , t , J = 6 . 6 Hz) , 4 . 33 - 4 . 37 ( 1H , ddd , J = 12 . 6 , treated with OsO . ( 2 . 5 wt. % solution in t - BuOH , 2 .02 mL , 9 .6 , 6 . 0 Hz) , 4 .03 ( 1H , t , J = 9 .6 Hz) , 2 .65 - 2 .69 ( 1H , ddd , 60 0 . 162 mmol) and N -methyl morpholine N -oxide ( 2 . 08 g , J = 12 . 0 , 9 . 0 , 3 .6 Hz) , 2 .40 ( 1H , qd , J = 13. 2 , 4 . 2 Hz) , 1 . 88 - 17. 8 mmol) . The mixture was stirred for 14 h at 25° C ., 1 . 90 ( 1H , m ) , 1 . 84 ( 1H , dt, J = 10 . 8 , 3 . 0 Hz ) , 1 . 77 - 1 .79 ( 1H , treated with a saturated aqueous solution of sodium hydro m ) , 1 . 51 ( 1H , qt, J = 13 .8 , 3 . 0 Hz) , 1 . 25 ( 1H , qd, J = 13 . 8 , 3 . 6 sulfite ( 5 mL ) and stirred for an additional 1 h . The mixture Hz ) ; 13C NMR ( 150 MHz, CDC13 ) S 141 . 9 , 138 .7 , 132 .3 , was concentrated in vacuo and the residue was taken up in 126 . 1 , 125 . 5 , 124. 3 , 120 . 8 , 120 . 2 , 119. 21 , 119 . 15 , 111. 7 , 65 a minimal amount of CH C12 and purified by flash chroma 109 . 3 , 75 . 7 , 60 . 2 , 56 . 0 , 33 . 3 , 28 . 9 , 23. 4 ; LCMS m / z tography ( SiO2, 0 - 50 % ethyl acetate -hexanes ). The pure 281. 1851 ([ M + H +] , C18H2N2O requires 281 . 1648 ) . fractions were combined , concentrated in vacuo , and then US 9 ,937 , 186 B2 65 66 resuspended in a minimal amount of ethyl acetate and 100 . 8 mmol) and heated to 100° C . for 72 h . The mixture precipitated with the addition of hexanes to afford the title was cooled to 25° C . and partitioned between saturated compound as a white solid ( 4 . 86 g , 99 % ). IH NMR (600 aqueous NaCl ( 100 mL ) and CH2C12 ( 300 mL ). The organic MHz, CDC1 . ) 8 8 . 10 (2H . br s ). 7 . 44 (2H . br s ) . 7 .32 ( H . layer was washed with saturated aqueous NaCl ( 3x100 mL ) , brs ) , 7 . 24 (3H , brs ), 4 .65 ( 1H , td , J = 14 .4 . 4 . 2 Hz ), 4 .65 ( 1H . 5 dried (Na2SO4 ) , and concentrated in vacuo . The material could be purified by flash chromatography (SiO2 , 0 - 10 % td , J = 10 . 2 Hz ), 3 . 75 ( 1H , s ) , 2 . 92 (2H , br s ), 2 .27 (1H , qd , ethyl acetate - hexanes ) to afford the title compound as a J = 14 .4 , 5 . 4 Hz) , 1 . 86 - 1 . 94 ( 3H , m ) , 1 .62 - 1 .64 ( 1H , m ), 1 .43 beige oil. ' H NMR (600 MHz , CDC12 ) d ( as a mixture of ( 1H , t, J= 14 .4 Hz ); LCMS m / z 282. 1503 ([ M + H + ], rotamers ) 2H [ 8 . 13 (t , J = 8 . 4 Hz) , 8 .09 ( t , J = 7 . 8 Hz) ], 7 . 57 C18H / 9NO , requires 282 . 1489 ). (1H , t, J = 9 .6 Hz) , 7 .45 - 7 .51 ( 2H , m ) , 7 . 43 (1H , t , J = 6 . 0 Hz) , 10 2H [ 7 . 30 ( t , J = 7 . 8 Hz ) , 7 . 26 - 7 .28 ( m ) ] , 5 .32 ( 1H , t , J = 9 . 6 Hz ), 1H 4 .64 ( td , J = 4 . 2 Hz ), 4 . 40 - 4 .48 ( m ) ] , 1H [ 3 .67 ( ddd , J = 12 . 6 , 9 .6 , 4 . 2 Hz) , 3 .53 - 3 . 57 (m ) ], 1H [ 2 .60 , qd , J = 13 . 2 , 3 . 6 Hz ) , 2 . 45 ( qd , J = 12 . 0 , 3 . 6 Hz ) ] , 1H [ 2 . 34 - 2 . 37 ( m ) , 2 . 25 (br s ) ] , 2 . 17 ( 1H , m ), 3H [ 2 . 03 - 2 .06 ( m ) , 2 .02 ( s ), 1. 93 - 2 . 00 15 (m )] , 2H [ 1 .74 ( qd , J = 13 .8 , 3. 6 Hz ) , 1. 53 - 1. 65 (m )] ; LCMS m / z 307. 1559 ( [ M + H + ], C20H24N20 requires 307 . 1553 ) . 111111

OH 20

(3aS , 4R , 7aR ) -rel - 4 - (9H - carbazol- 9 -yl ) hexahyd OH robenzo [ d ] [ 1, 3 ,2 ]dioxathiole 2 -oxide 2525 1111111 A solution of rac -( 1R ,28 ,3R )- 3 -( 9H -carbazol - 9 -yl ) cyclo hexane - 1 , 2 - diol ( 5 .34 g , 19. 0 mmol) in CH C12 (50 .0 mL ) NH2 was cooled to 0° C . and treated dropwise with triethylamine (21 . 1 mL , 152 . 0 mmol) , and SOC12 (slowly , over 30 min utes) ( 4 . 14 mL , 57 . 0 mmol) . The mixture was warmed to 25° rac - (18 , 2S ,6R ) -rel - 2 - amino -6 -( 9H -carbazol - 9 - yl) C ., stirred for 2 h , poured over a solution of saturated cyclohexanol aqueous sodium chloride (100 mL ) , and then extracted into CH _C12 (3x100 mL ). The combined organic layers were From the previous step , the crude residue was suspended washed with water ( 2x100 mL ) , saturated aqueous sodium in THF (50 mL ) treated with PPhz ( 13 . 2 g , 50 . 4 mmol) , H2O chloride (100 mL ) , dried (Na2SO4 ) , and concentrated in » ( 1 .0 mL ) , and stirred for 14 h at 25° C . The mixture was vacuo. The residue was dissolved in a minimal amount of concentrated in vacuo , taken up in a minimal amount of CH ,C1 , and purified by flash chromatography (SiO ,, 0 - 10 % CH2Cl2 and purified by flash chromatography (SiO2 , 0 -50 % ethyl acetate -hexanes ) to afford the title compound as an ethyl acetate -hexanes to remove nonpolar impurities , fol orange solid ( 7 . 13 g , 99 % ) . ' H NMR (600 MHz, CDC12 ) 8 lowed by 0 - 3 % MeOH - CH2Cl2 to remove triphenylphos m 40 phine oxide , followed by 17 :2 : 1 CH2C12: MeOH : NH ,OH to (as a mixture of sulfite diastereomers) 8 . 06 -8 . 18 (2H , m ), * elute the product) . The purified fractions were combined , 4H [ 7 .66 (br s ), 7 .33 - 7 . 47 ( m ) , 7 . 23 - 7 .27 ( 2H , m ), 1H [ 5 .51 dried azeotropically with toluene to afford the title com ( dd , J = 9 . 6 , 4 . 8 Hz ) ] , 1H 5 . 42 (ddd , J = 14 . 4 , 9 . 6 , 4 . 8 Hz ) , 4 . 50 pound as a beige solid ( 6 . 11 g , 65 % ) . ' H NMR (600 MHz, ( ddd , J = 14 . 4 , 9 . 6 , 4 . 8 Hz) ] , 1H [ 5 . 34 - 5 . 37 ( m ) , 4 . 90 - 4 . 92 CDC1, ) 8 . 13 ( 1H , d , J = 7 . 8 Hz ), 8 . 08 ( 1H , d , J = 7 .8 Hz) , ( m ) ] , 2 .55 - 2 .58 ( 1H , m ), 2 .45 ( 1H , qd , J = 13 . 8 , 3 . 6 Hz2 ), 45 7 .58 ( 1H , d , J= 8 .4 Hz ), 7. 45 ( 1H , d , J= 4 .2 Hz) , 7 .40 ( 1H , t , 2 .10 - 2 . 16 ( 1H , m ) , 1 . 98 - 2 .08 ( 1H , m ) , 1 . 90 - 1 .97 ( 1H , m ) , J = 7 . 8 Hz ), 7 . 19 - 7 .26 ( 2H , m ) , 7 .08 ( 1H , t , J = 6 . 6 Hz) , 1 . 90 (1H , qt, J = 13 . 8 , 3 .6 Hz) ; LCMS m / z 328 . 0997 ( [ M + 4 . 33 - 4 . 37 ( 1H , dd, J = 12 . 6 , 9 .6 , 6 . 0 Hz ) , 4 .03 ( 1H , t , J = 9 .6 H *] , C18H , 7NO2S requires 328 .1002 ) . Hz ) , 2 .65 -2 .69 ( 1H , ddd , J= 12 . 0 , 9 .0 , 3 .6 Hz ), 2 .40 (1H , qd , J = 13 . 2 , 4 . 2 Hz) , 1 .88 - 1 . 90 ( 1H , m ) , 1 .84 ( 1H , dt, J = 10 . 8 , 3 . 0 50 Hz) , 1 .77 - 1 .79 ( 1H , m ), 1 .51 ( 1H , qt , J = 13 . 8 , 3 . 0 Hz) , 1 . 25 ( 1H , qd , J = 13 . 8 , 3 . 6 Hz ) ; 13C NMR ( 150 MHz, CDC1 , ) 141. 9 , 138 . 7 , 132 . 3 , 126 . 1 , 125 . 5 , 124 . 3 , 120 . 8 , 120 . 2 , 119 .21 , 119 . 15 , 111 . 7 , 109 . 3 , 75 . 7 , 60 . 2 , 56 . 0 , 33 . 3 , 28 . 9 , 23 . 4 ; LCMS m / z 281. 1851 ( [ M + H + ], C13H2N2O requires 4 55 281. 1648 ). 511110 11111 = 0 ** * lll D o ( 18, 28 ,6R )- rel -2 - azido -6 -( 9H -carbazol - 9 -yl ) cyclo osestadounidensyon hexanol A solution of rac - ( 3aS ,4R ,7aR ) - 4 - ( 9H - carbazol- 9 - yl) 65 hexahydrobenzo [ d ] [ 1 , 3 , 2 ] dioxathiole 2 -oxide (11 . 0 g , 33 . 6 . mmol) in DMF ( 40 . 0 mL ) was treated with NaNZ (6 .56 g , US 9 ,937 , 186 B2 67 68 - continued N - ( ( 1R , 2R ,3S ) - 3 - ( 9H - carbazol- 9 - yl ) - 2 -hydroxycy clohexyl) - 4 - ( trifluoromethoxy )benzenesulfonamide N - (( 1R ,2R ,3S )- 3 -( 9H -carbazol - 9 -yl ) - 2 -hydroxycyclo hexyl) - 4 - ( trifluoromethoxy ) benzenesulfonamide; tr = 4 . 4 minutes ; white solid , mp. 107 - 109° C . ( from IPA -hexanes ) : 1110ll [a ]) = - 7 ( 1. 0 in CH ,C12 ), [ q ]D = - 5 ( 1. 0 in CH ,OH ) . Peak 2 : Example 3b N o=0 - OCF3 10 Example 3b

( 18, 29 ,3R ) - rel -N -( 3 -( 9H -carbazol - 9 -yl ) -2 -hydroxy 15 cyclohexyl) - 4 -( trifluoromethoxy )benzenesulfona mide A solution of rac - (18 ,28 ,6R )- 2 -amino -6 - ( 9H -carbazol - 9 - 20 yl) cyclohexanol ( 7 . 11 g , 25 . 4 mmol) in DMF ( 50 .0 mL ) was NH cooled to 0° C . , treated with EtzN ( 3 .52 mL , 25 . 4 mmol) , and 4 - trifluoromethoxybenzenesulfonyl chloride ( 4 . 30 mL , OCF3 25 . 4 mmol) . The mixture was warmed to 25° C ., and stirred for 2 h . The mixture was partitioned between saturated aqueous NaCl (200 mL ), and CH C12 (300 mL ). The aque ous layer was extracted with CH C12 (3x200 mL ). The N -( ( 15 ,2S ,3R )- 3 -( 9H - carbazol- 9- yl ) -2 -hydroxycy combined organic layers were washed with saturated aque clohexyl) -4 -( trifluoromethoxy )benzenesulfonamide ous NaCl (4x200 mL ), dried (Na2SO4 ) , and concentrated in vacuo . The residue was dissolved in a minimalmal amount of 30 N - ( ( 18 ,25 , 3R ) - 3 - ( 9H -carbazol - 9 -yl ) - 2 -hydroxycyclo CH , C1, and purified by flash chromatography (SiO , , 0 - 25 % hexyl) - 4 - ( trifluoromethoxy )benzenesulfonamide ; tr = 6 . 7 ethyl acetate - hexanes ). The purified fractions were com - minutes ; white solid , mp . 107 - 109° C . ( from IPA - hexanes ) : bined , dissolved in a minimal amount of ethyl acetate , and [a ] d = + 7 (1 . 0 in CH2Cl2 ), [ a ]D = - 5 ( 1. 0 in CH3OH ) . were precipitated with the addition of hexanes to afford the 35 Absolute configuration of Examples 3a and 3b may be title compound as a white solid (11 . 9 g, 88 % ) . ' H NMR (600 assigned in a manner exactly analogous to that used for the MHz, CDC1z ) (as a mixture of rotamers) 2H [8 .11 ( d , J = 7 .2 phenoxazine Examples la and 1b , that is by stereoselective Hz) , 8 . 06 ( d , J = 7 . 8 Hz) ] , 2H [ 7 . 93 ( d , J = 9 . 0 Hz ), 7 . 86 (d . synthesis from chiral stating materials of known absolute J = 9 .0 Hz )] , 7 .52 (1H , d , J = 7 .8 Hz )] , 7. 38 - 7. 45 (2H , m ), 7 . 36 configuration (see Scheme 4A ) ( 1H , d , J = 8 . 4 Hz ) , 7 .30 ( 1H , d , J = 8 . 4 Hz ), 7 . 22 - 7 .27 ( 3H , m ), 5 . 76 (1H , t, J = 10 .2 Hz ), 1H [ 5 . 19 (d , J= 4 . 8 Hz ), 5 .09 ( d , J = 8 . 4 Hz ) ] , 2H [ 4 . 56 ( td , J = 12 . 0 , 4 . 2 Hz ), 4 . 29 - 4 . 38 ( m ) ] , 11 [ 3 .60 - 3 .66 ( m ), 3 . 23 - 3 .27 ( m ) ] , 1H [ 2 .49 (qd , J = 13 . 2 , 3 . 6 Hz) , 2 .41 ( qd , J = 11 . 1 , 1 . 8 Hz) ] , 1H [ 2 . 24 - 2 . 25 ( m ) , 2 . 19 ( m ) ] , 2H [ 1 . 97 ( t , J = 15 . 0 Hz ) , 1 . 90 ( d , J = 10 . 8 Hz ) ] , 2H [ 1 . 59 - 1 .66 ( m ), 1. 47 - 1. 55 (m )] ; LCMS m / z 505 .1415 ([ M + H + ], C25H23F3N204S requires 505 . 1403) . Pure Enantiomers of Example 3 were obtained from Chiralcel OD - H resolution , preparative scale eluting with 1111* 100 % MeO H . 50 Peak 1 : Example 3a

Example 3a 55

ZI .. til

*1* 11110

COCF3 US 9 ,937 , 186 B2 69 70 ( 18 ,2R ,6R ) - 2 - (benzyloxy ) -6 - (9H -carbazol - 9 -yl ) cy s ) , 2 .28 ( 1H , sextet , J = 7 . 8 Hz ), 1 . 93 (1H , sextet, J= 6 . 0 Hz) , clohexanol 1 .74 ( 1H , sextet, J = 7 . 2 Hz ), 1. 54 (1H , sextet , J = 7 .8 Hz ); LCMS m / z 282 .1482 ( M + H + ], C13H2. NO , requires A solution of 9H - carbazole ( 0 . 500 g , 3 . 00 mmol) in 282 . 1489) . toluene (8 . 0 mL ) was treated with sodium hydride (60 % 5 The optically pure diol was carried forward by the same dispersion in mineral oil ( 0 . 240 g , 6 .00 mmol) and ( 18 , 2R , series of conversions depicted above for Example 3 to arrive 6S ) - 2 - (benzyloxy ) -7 -oxabicyclo [ 4 . 1. 0 ]heptane ( 0 .582 g , at the final product . Example 3b . N - ( ( 15 .28 . 3R ) - 3 - (9H 2 .85 mmol) at 25° C . stirred for 0 . 5 h . The vessel was then carbazol - 9 - yl) - 2 -hydroxycyclohexyl ) - 4 - ( trifluoromethoxy ) sealed and the mixture heated to 90° C . for 14 h . The vessel benzenesulfonamide. Example 3b , produced from the opti was cooled , treated with a solution of saturated ammonium 10 chloride (50 mL ) , and then extracted with toluene (2x100 cally active ( 19 , 2R , 6S ) - 2 - ( benzyloxy ) - 7 - oxabicyclo [ 4 . 1 . 0 ] mL ) . The combined organic layers were washed with satu heptane coeluted with peak 2 by chiral analytical HPLC rated aqueous NaCl ( 100 mL ) , dried (Na , SO2 ) , and concen analysis (Chiralcel OD - H 20 % IPA -Hexanes , peak 1 : tx = 7 . 5 trated in vacuo . The residue was dissolved in a minimal minutes, peak 2 : tr = 25 .1 minutes) and this establishes the amount of CHCl, and purified by flash chromatography 15 absolute stereochemistry of Example 3b as 18 ,25 , 3R . In ( SiO , 0 - 10 % ethyl acetate -hexanes ) to afford the title com addition the absolute stereochemistry of the enantiomer , pound as a clear oil ( 0 . 371 g , 33 % ) . ' H NMR (600 MHz, N - ( ( 1R ,2R , 3S ) - 3 - ( 9H - carbazol- 9 -yl ) - 2 - hydroxycyclo CDC12 ) 8 8 . 13 ( 2H , d , J = 7 . 8 Hz ) , 7 .48 - 7 .60 ( 1H , br m ) , hexyl) - 4 - ( trifluoromethoxy )benzenesulfonamide , Example 7 .43 - 7 . 46 (6H , m ), 7 .37 ( 2H , t . J = 7 . 2 Hz) , 7 . 24 ( 2H , d . J = 7 . 8 3a , Peak - 1 of the preparative and analytical HPLC methods Hz ) , 4 .89 ( 1H , ddd , J = 12 .6 , 11 . 4 , 4 . 8 Hz ) , 4 . 80 ( 1H , d , 201820 is established as 1R ,2R , 3S . J = 11. 4 Hz ) , 4 .66 ( 1H , d , J = 11. 4 Hz ) , 4 .52 ( 1H , ddd , J = 11. 4 , Asymmetric synthesis of the intermediates in the synthe 9 . 0 , 3 . 0 Hz ) , 4 . 11 - 4 . 14 ( 1H , m ) , 2 .45 ( 1H , qd , J = 13 . 2 , 4 . 2 ses of Examples 3a or 3b may be carried out in a manner Hz ), 2 . 25 - 2 .31 ( 1H , m ), 2 . 16 ( 1H , d , J = 8 .4 Hz ), 1 . 99 - 2 .05 exactly analogous to that for Examples la and lb . Thus ( 1H , m ) , 1 .94 ( 1H , qt, J = 13 . 8 , 3 . 6 Hz) , 1 .72 - 1 .78 ( 1H , m ), synthesis of ( 1R , 2S , 3R ) - 3 - ( 9H - carbazol - 9 - yl) cyclohexane 1. 56 - 1. 63 (1H , m ); LCMS m / z 372. 2047 ([ M + H + ], 2535 1 , 4 2 - diol is carried out as described below . C25H25NO , requires 372 .1958 ).

30

uitlON 1111ON 35 **

**11111 ( 1R , 2S , 3R ) - 3 - (9H -carbazol - 9 - yl) cyclohexane - 1 , 2 40 diol A 20 mL Biotager microwave reaction vial was charged with Pd2 .dbaz . CHCl3 ( 0 .052 g , 0 .05 mmol) , and ( S , S ) DACH -phenyl Trost ligand ( 0 . 104 g , 0 . 15 mmol) . The vial 45 was sealed , evacuated and backfilled with argon three times . Dry degassed dichloromethane ( 2 . 5 mL ) was added to this vial, and the mixture was stirred at room temperature for 30 stillo min . Racemic tert -butyl cyclohex - 2 - en - 1 - yl carbonate ( 0 .238 g , 1 . 2 mmol) was added to the vial and the contents 50 were transferred to a separate 20 mL Biotage® microwave ** ULOH reaction vial containing 9H -carbazole ( 0 . 167 g , 1 .00 mmol ) in dry degassed dichloromethane ( 3 . 0 mL ) . The reaction mixture was stirred at room temperature for 10 days. At this (1R ,28 ,3R ) - 3 - ( 9H -carbazol - 9 - yl) cyclohexane - 1 , 2 point , the reaction mixture was evaporated onto silica gel diol and subjected to column chromatography ( SiO . ; 100 % hexanes ) to afford pure ( R ) - 9 - ( cyclohex - 2 - en - 1 - yl) - 9H - car A solution of ( 19 , 2R , 6R ) - 2 - ( benzyloxy ) -6 - ( 9H - carbazol - bazole (0 .082 g , 33 % ) . ' H NMR ( 600 MHz , MeOD ) S 9 -yl ) cyclohexanol ( 0 . 100 g , 0 .269 mmol) in THF :MeOH 8 . 05 - 8 . 04 ( 2H , m ), 7 . 55 ( 2H , bs ), 7 . 36 ( 2H , bs) , 7 .15 (2H , ( 1 : 1 , 8 . 0 mL ) was treated with 10 % Pd / C ( 0 .030 g ) , placed bs ), 6 . 08 ( 1H , bs ) , 5 .86 ( 1H , bs ) , 5 . 39 ( 1H , bs ), 2 .31 - 2 . 17 under an atmosphere of H , ( g ), and stirred for 6 h at 25° C . 60 (3H , m ), 1 .99 - 1 . 92 ( 3H , m ); 13C NMR ( 150 MHz, MeOD ) The mixture was filtered thru Celite and concentrated in S 140. 0 , 130 . 5 , 128 . 8 , 125 . 1 , 123 . 2 , 119 . 7 , 118 . 5 , 109 . 9 , vacuo to afford the title compound as a beige foam ( 0 . 035 g , 51 . 7 , 27 . 2 , 24 . 5 , 21. 8 ; HRMS m / z 248 . 1434 ( [ M + H + ) , 47 % ) . [ a ] s = + 0 .41 ( c = 1 . 0 , CH , C1, ) . ' H NMR (600 MHz, C , H , N requires 248 . 1436 ) . CDC1z ) 8 7 .13 (2H , t, J= 7 . 2 Hz ) , 7 . 10 (2H , d , J = 7 .2 Hz ), A solution of (R )- 9 -( cyclohex -2 -en -1 - yl) -9H -carbazole 7 . 05 - 7 . 31 ( 2H , br s ), 6 . 96 (2H , t, J = 7 . 2 Hz ) , 4 .47 ( 1H , ddd , 65 ( 0 . 035 g , 0 . 142 mmol) , 4 -methylmorpholine N -oxide mono J = 7 . 8 , 5 . 4 , 3 .6 Hz ), 4 . 16 ( 1H , q , J = 6 . 0 Hz ), 3 .98 ( 1H , t , J = 3 . 6 hydrate ( 0 .018 g , 0 . 156 mmol) , and osmium tetroxide ( 0 .016 Hz) , 3 . 30 - 3 .60 ( 2H , br s ), 2 .60 - 2 . 90 ( 2H , br s ) , 2 .44 ( 1H , br mL , 0 .001 mmol, 2 .5 % in tert- butanol) in tert -butanol ( 1 . 00 US 9 ,937 , 186 B2 71 72 mL ) and water ( 0 . 10 mL ) , was stirred at RT for 60 h . The 4 . 23 ( 1H , d , J = 1 . 8 Hz) , 2 .51 - 2 .44 ( 1H , m ) , 2 .11 - 1 . 92 ( 2H , reaction mixture was treated with solid sodium bisulfite m ) , 1 . 88 - 1 . 72 ( 3H , m ) , 1 . 70 - 1 . 67 ( 1H , m ) ; 13C NMR ( 150 solution , stirred for 1 h , evaporated on to silica and purified MHz, MeOD ) 8 125 . 1 , 119. 7 , 118 . 3 , 109 . 1 , 71. 0 , 70 . 5 , 55 . 3 , by flash chromatography (SiO2 , 0 % -70 % ethyl acetate - 31. 1 , 28 . 8 , 19 . 1 ; HRMS m / z 282 . 1482 ( [ M + H + ] , hexanes ) to afford ( 1R ,28 , 3R ) - 3 - ( 9H -carbazol - 9 - yl ) cyclo - 5 C18H2NO , requires 282 . 1489) . Material produced in this hexane - 1 , 2 - diol ( 0 .037 g , 95 % ) . H NMR (600 MHz, fashion exhibited [ a ] d = + 0 .41 ( c = 1 . 0 , CH , C12) . The enantio MOD ) 8 8 .07 (2H , d , J = 6 .6 Hz ), 7 .65 - 7 .63 (2H , m ), 7 .40 meric identity and purity was also confirmed by analytical ( 2H , d, J= 7 .2 Hz ), 7 . 16 (2H , d , J = 7. 8 Hz ) , 4 .55 (1H , dd , chiral HPLC > 99 % (CHIRALPAK® IF - 3 column, 70 : 30 J = 10 . 8, 3 Hz ), 4 .23 ( 1H , d , J = 2 . 4 Hz ), 2 .51 -2 .44 ( 1H , m ), hexanes - EtOH , 1 . 5 mL /min , retention times : 5 . 2 min . This 2 . 03 - 1 . 96 ( 2H , m ) , 1 . 88 - 1 .77 ( 3H , m ), 1 . 70 - 1 .67 ( 1H , mmt ) ; 10 confirms the absolute stereochemistry of thematerial arising 13C NMR ( 150 MHz, MeOD ) 125. 1 , 119 .7 , 118 .3 , 71. 0 , from the catalytic process mediated by ( S , S ) -DACH -phenyl 70 . 5 , 55 . 3 , 31. 1 , 28 . 8 , 19 . 1 ; LCMS m / z 282 .2184 ([ M + H + ] , Trost ligand as that shown above , i . e. yielding ( R ) - 9 - ( cy C18H2. NO2 requires 282. 1489 ). Material produced in this clohex - 2 - en - 1 - yl) - 9H -carbazole in the first step to create the fashion exhibited [ a ] = + 0 .43 ( c = 1 . 0 , CH , C1, ) . The enantio - , stereogenic center. As in Example 1 the other enantiomeric meric identity and purity was also confirmed by analytical 15 series may be accessed by the same method but employing chiral HPLC > 99 % ( CHIRALPAK® IF - 3 column , 70 : 30 the opposite enantiomer of the chiral ligand , i. e . ( R , R ) hexanes - EtOH , 1 . 5 mL /min , retention times : 5 . 2 min DACH - phenyl Trost ligand in the asymmetric allylation Alternative synthesis of ( 1R , 2S , 3R ) - 3 - ( 9H -carbazol - 9 - yl) step . cyclohexane - 1 , 2 -diol : 20 Examples 4 - 7 N - ( 18 , 2S , 3R ) - rel - 3 - ( 9H - carbazol- 9 - yl ) - 2 -hydroxycyclo hexyl) - 4 -chlorobenzenesulfonamide Example 4 . A solution of ( 1R , 28 , 6R ) - rel - 2 - amino - 6 - ( 9H - carbazol- 9 - yl ) cyclohexa 25 nol (0 .059 g , 0 .210 mmol ) in DMF ( 1 . 0 mL ) was cooled to 0° C . , treated with EtzN (29 . 0 ul , 0 .210 mmol) , and 4 -chlorobenzenesulfonyl chloride ( 0 . 044 g , 0 . 210 mmol) . utilON The mixture was warmed to 25° C . and stirred for 2 h . The mixture was partitioned between saturated aqueous NaCl 30 (50 mL ) , and CH , C1, (100 mL ) . The organic layer was washed with saturated aqueous NaCl ( 3x50 mL ), dried ( Na2SO4) , and concentrated in vacuo . The residue was A solution of 9H -carbazole (0 .500 g, 3 .00 mmol) in dissolved in a minimal amount of CH C1, and purified by toluene ( 8 . 0 mL ) was treated with sodium hydride (60 % wt. flash chromatography (SiO2 , 0 - 20 % ethyl acetate -hexanes ) . dispersion in mineral oil, 0 . 240 g , 6 . 00 mmol) . ( 15, 2R ,6S ) - 35 The purified fractions were combined , dissolved in a mini 2 - ( benzyloxy ) - 7 - oxabicyclo [ 4 . 1 . 0 ]heptane ( 0 . 582 g , 2 .85 mal amount of ethyl acetate , and were precipitated with the mmol) was added and the mixture heated to 100° C . for 24 addition of hexanes to afford Example 4 as a white solid h . The mixture was cooled to 25° C . and poured over a (0 .500 g , 52 % ) . ' H NMR (600 MHz , CDC13 ) 8 (as a mixture solution of saturated aqueous ammonium chloride ( 100 mL ) . of rotamers ) 8 . 11 ( 1H , dd , J = 2 . 4 Hz) , 8 . 06 ( 1H , d , J = 7 . 8 Hz ) , The organic layer was separated and the aqueous layer was 40 7 . 83 ( 2H , d , J = 8 . 4 Hz) , 7 .51 ( 1H , d , J = 8 . 4 Hz) , 7 . 46 ( 2H , d , extracted with ethylacetate ( 3x100 mL ) . The organic layers J = 6 . 6 Hz) , 7 .42 (2H , t, J = 7 . 8 Hz ), 7 .37 - 7 . 40 (1H , m ) , 7 . 24 were combined , dried (Na , SO2 ), and concentrated in vacuo . ( 2H , dt, J = 15 . 0 , 7 . 2 Hz ) , 5 . 14 ( 1H , d , J = 3 .6 Hz ) , 4 .29 - 4 . 37 The residue was dissolved in a minimal amount of dichlo - (2H , m ), 3. 20 - 3 .25 (1H , m ), 2 . 38 - 2. 45 ( 1H , m ), 2. 23 - 2 .27 romethane and purified by flash chromatography ( SiO (1H , m ) , 2 .09 ( 1H , br s ) , 1 . 89 - 1 . 92 (2H , m ) , 1 .48 - 1 . 54 ( 2H , 0 % - 20 ethyl acetate - hexanes ) to afford ( 15 , 2R ,5R ) - 2 -( ben - 45 m ) ; 13C NMR (600 MHz , CDC12 ) d 141. 6 , 138 . 3 , 129. 6 , zyloxy ) -6 - ( 9H - carbazol- 9 - yl) cyclohexanol ( 0 . 125 g , 82 % ). 128 . 9 , 126 . 2 , 125 . 7 , 120 . 1 , 119 . 7 , 111. 4 , 109 . 1 , 73 . 0 , 60 . 1 , 1H NMR (600 MHz, CDC1 ) 8 . 12 ( 1H , d , J = 7 . 8 Hz ), 7 .53 59 . 0 , 31 .7 , 28 . 3 , 22 . 9 ; LCMS m / z 455 . 1202 ( [ M + H + ] , ( 2H , bs ), 7 . 46 - 7 .41 (6H , m ) , 7 . 36 ( 1H , t, J = 7 . 2 Hz) , 7 .23 C24H23C N202S requires 455 . 1191) . (2H , t, J = 7 . 8 Hz ), 4 . 91 - 4 .87 ( 1H , m ), 4 . 80 - 4 .79 ( 1H , m ), N - (( 18 , 25 ,3R ) - rel - 3 - (9H - carbazol- 9 - yl) - 2 -hydroxycyclo 4 .66 - 4 .64 ( 1H , m ) , 4 .53 - 4 .49 ( 1H , m ) , 4 . 13 - 4 . 12 ( 1H , m ) , 50 hexyl ) - 4 -cyanobenzenesulfonamide Example 5 . A solution 2 .45 ( 1H , ddd , J = 26 .4 , 13 . 2 , 4 . 2 Hz ), 2 . 28 - 2 . 25 (2H , m ), of ( 1R , 28 ,6R )- rel - 2 - amino - 6 - ( 9H - carbazol- 9 - yl) cyclohexa 2 . 16 - 2 . 15 ( 1H , m ), 2 .02 - 1. 90 ( 2H , m ) , 1 . 75 - 1 .73 ( 1H , m ) , nol (0 .078 g , 0 . 276 mmol) in DMF ( 1 . 0 mL ) was cooled to 1 .62 - 1 . 56 (1H , m ); LCMS m /z 372 .2057 ([ M + H + ], 0° C ., treated with EtzN ( 38 0 .276 mmol) , and 4 - cyanoben C25H26NO , requires 372 .1959 ) . zenesulfonyl chloride ( 0 . 056 g , 0 . 276 mmol) . The mixture A solution of ( 15 , 2R ,6R )- 2 - ( benzyloxy ) - 6 -( 9H -carbazol - 55 was warmed to 25° C . and stirred for 2 h . The mixture was 9 -yl ) cyclohexanol (0 . 100 g , 0 . 269 mmol) in THF: MEOH partitioned between saturated aqueous NaCl (50 mL ), and ( 1: 1 , 1. 10 mL ) was treated with 10 % Pd / C (0 .030 g , 0 .029 CH C12 (100 mL ). The organic layer was washed with mmol) and then placed under an atmosphere of H2 ( g ) . The saturated aqueous NaCl (3x50 mL ) , dried (Na2SO4 ) , and mixture was stirred for 24 h at 25° C . then filtered through concentrated in vacuo . The residue was dissolved in a a celite pad , washed with hotmethanol and ethylacetate , and 60 minimal amount of CH ,C1 , and purified by flash chroma concentrated in vacuo . The residue was dissolved in a tography (SiO2 , 0 - 20 % ethyl acetate- hexanes ) . The purified minimal amount of dichloromethane and purified by flash fractions were combined , dissolved in a minimal amount of chromatography (SiO2 , 10 % - 50 % ethyl acetate -hexanes ) to ethyl ether, and were precipitated with the addition of afford ( 1R , 28 , 3R ) - 3 - ( 9H - carbazol- 9 - yl) cyclohexane - 1 , 2 hexanes to afford Example 5 as a white solid ( 0 .0434 g , diol ( 0 .035 g, 47 % ) . ' H NMR (600 MHz, MeOD ) S 8 .07 65 35 % ). H NMR (600 MHz, CDC1z ) (as a mixture of ( 2H , d , J = 6 . 6 Hz) , 7 .65 - 7 . 62 ( 2H , bs ), 7 . 39 (2H , d , J = 7 . 2 rotamers ) 8 . 11 ( 1H , d , J = 7 . 8 Hz) , 8 .05 ( 1H , d , J = 7 . 2 Hz) , Hz ), 7 . 16 ( 2H , d , J = 7 . 2 Hz) , 4 .55 ( 1H , dd, J = 10 . 8 , 3 Hz) , 2H [ 7 . 91 ( d , J = 8 . 4 Hz) , 7 . 87 ( d , J = 8 . 4 Hz ) ], 7 .69 (2H , d , US 9 ,937 , 186 B2 73 74 J= 8. 4 Hz) , 7. 51 (1H , d , J= 8 .4 Hz ), 2H [7 .44 (t , J= 7 . 2 Hz) , 120 .3 , 119. 5 , 111. 5, 109. 2 , 73 .0 , 59. 9 , 59 . 1, 31. 6 , 28 .4 , 22 .9 ; 7 .40 ( t, J = 7 . 8 Hz) ], 1H [ 7 . 36 ( d , J = 8 . 4 Hz) , 7 .33 ( d , J = 8 . 4 LCMS m / z 421 .1618 ( [ M + H + ], C24H24N2O2S requires Hz) , 7 .24 (2H , dt, J = 20 . 4 , 7 . 2 Hz ), 5 .73 ( 1H , t , J = 10 . 2 Hz) , 421. 1580 ) . 1H [ 5 .29 ( d , J = 9 . 0 Hz ) , 5 . 19 ( d , J = 6 . 0 Hz ) ] , 1H [ 4 . 55 ( ddd , J = 13 . 8 , 12 . 6 . 4 . 2 Hz ) , 4 .31 (ddd , J = 13 . 8 , 10 . 2 . 4 . 2 Hz ) ) , 4 . 24 5 Examples 8 and 9 ( 1H , t , J = 9 .6 Hz) , 1H [ 3 . 56 - 3 .65 ( m ) , 3 .21 - 3 .28 ( m ) ] , 1H [ 2 .48 - 2 . 51 ( m ), 2 . 35 - 2 .42 ( m ) ], 2 . 16 - 2 . 20 ( 2H , m ) , 1 . 86 1 . 90 (2H , m ) , 1 .47 ( 2H , t , J = 10 . 8 Hz) ; 13C NMR (600 MHz, CDC13 ) d 145 .1 , 141. 6 , 138 .3 , 133. 0 , 127. 9 , 127 .7 , 126 . 3 , 125 . 6 , 124 . 6 , 122 . 9 , 121. 0 , 120 . 4 , 119 . 7 , 117 . 6 , 116 . 4 , 111. 4 , 10 109 . 1 , 72 . 9 , 60 . 1 , 59 . 1 , 32 . 1 , 28 . 5 , 22 . 9 ; LCMS m / z 446 . 1546 ( [ M + H + ] , C25H23N302S requires 446 . 1533 ) . H3CN OH N - ( ( 18 ,2S , 3R ) - rel - 3 - ( 9H - carbazol- 9 -yl ) - 2 -hydroxycyclo hexyl) - 4 -methoxybenzenesulfonamide Example 6 . A solu tion of ( 1R , 28 ,6R )- rel - 2 - amino -6 - ( 9H - carbazol - 9 - yl) cyclo - 15 hexanol ( 0 .0786 g , 0 . 280 mmol) in DMF ( 1 . 0 mL ) was cooled to 0° C . , treated with Et2N ( 39 . 0 uL , 0 . 280 mmol) , and 4 -methoxybenzenesulfonyl chloride ( 0 . 0580 g , 0 .280 mmol) . The mixture was warmed to 25° C ., and stirred for REOCF3 (Ex . 8 ), RS = C1 ( Ex . 9 ) 2 h . The mixture was partitioned between saturated aqueous 20 10 -Methyl - 5H -dibenzo [b , e ][ 1, 4 ]diazepin - 11 ( 10H ) -one . NaCl (50 mL ) , and CH C12 ( 100 mL ) . The organic layer was A solution of 5H -dibenzo [ b ,e ][ 1, 4 ]diazepin - 11 ( 10H )- one washed with saturated aqueous NaC ; (3x50 mL ) , dried ( 11 .00 g , 4 . 1076 mmolm ) in DMF ( 5 .0 mL ) was cooled to 0° C . (Na SO . ) , and concentrated in vacuo . The residue was and treated with NaH (60 % dispersion in mineral oil, 0 . 200 dissolved in a minimal amount of CH ,C1 , and purified by g , 5 .00 mmol) and methyl iodide ( 0 .33 mL , 5 . 24 mmol ) . The flash chromatography ( SiO . , 0 - 20 % ethyl acetate - hexanes ) . 25 solution was warmed to 25° C . and stirred for 14 h . The The purified fractions were combined , dissolved in a mini mixture was poured over saturated aqueous NaCl (100 mL ) mal amount of ethyl acetate , and were precipitated with the and extracted with CH , C12 ( 3x100 mL ) . The combined addition of hexanes to afford Example 6 as a white solid organic layers were washed with saturated aqueous NaCl ( 0 . 0521 g , 41 % ) . ' H NMR (600 MHz, CDC1z) ( as a (3x100 mL ) , dried (Na2SO4 ) , concentrated in vacuo , and the mixture of rotamers ) 8. 11 (1H , d , J = 7 .2 Hz) , 8 .04 (1H , d , 30 residue was purified by flash chromatography (SiO2 , 0 - 20 % J = 7 . 8 Hz) , 7 .81 (2H , dd , J = 7 . 2 , 1 . 8 Hz) , 7 .52 ( 1H , d , J = 8 . 4 ethyl acetate -hexanes ) to afford the title compound as a Hz) , 7 . 38 ( 2H , t , J = 6 . 6 Hz ) , 7 .34 ( 1H , t , J = 8 . 4 Hz ) , 7 .21 (2H , white solid ( 0 . 886 g , 83 % ) . ' H NMR (600 MHz, CDC12 ) 8 dt, J = 13. 2 , 7 . 8 Hz ), 6 .91 (2H , d , J = 9 . 0 Hz) , 5 . 36 ( 1H , d . 7 .90 ( 1H , dd , J = 7 .8 , 1. 8 Hz) , 7 . 30 ( 1H , td , J = 7 .8 , 1 . 8 Hz ), J = 6 . 0 Hz ) , 4 .28 - 4 . 34 ( 2H , m ) , 3 . 82 ( 3H , s ) , 3 . 15 - 3 . 20 ( 1H , 7 . 19 ( 1H , dd , J = 7 . 8 , 1 . 2 Hz ) , 7 .11 ( 1H , td , J = 7 . 2 , 1 . 8 Hz ) , m ) , 2 . 49 ( 1H , brs) , 2 . 36 ( 1H , qd , J = 13 . 2 , 3 . 6 Hz ) , 2 . 05 - 2 .09 35 7 .07 ( 1H , td , J = 7 . 8 , 1 . 8 Hz ), 7 .02 ( 1H , td , J = 7 . 8 , 1 . 2 Hz) , ( 1H , m ) , 1 .82 (2H , t, J = 12 .6 Hz ), 1. 40 - 1. 50 (2H , m ); 13C 6 . 92 (1H , dd , J= 7 .8 , 1 .2 Hz ), 6 .81 (1H , d , J = 8 .4 Hz ), 5 .46 NMR (600 MHz, CDC1 , ) & 163 . 0 , 141 . 6 , 138 . 4 , 132 . 1 , ( 1H , s ) , 3 . 55 ( 3H , s ) ; 13C NMR ( 150 MHz, CDC12 ) 8 168 . 8 , 129 .5 , 126 . 0 , 125 .5 , 124 .4 , 122 .8 , 120 . 8 , 120 .2 , 119 .34 , 150 . 8 , 143. 4 , 135 .8 , 133 .1 , 132 .7 , 125 .9 , 125 . 0 , 124 .5 , 119 .27 , 117 . 6 , 114 . 4 , 111 . 5 , 109. 2 , 72 . 9 , 59 . 8 , 59 . 0 , 55 . 7 , 123 . 4 , 122 . 8 , 120 . 4 , 118 . 7 , 38 . 3 ; LCMS m / z 225 . 1040 31 . 5 , 28 . 4 , 23 . 0 ; LCMS m / z 451. 1887 ([ M + H + ], 40 ( [ M + H + ] , C4H2N2O requires 225 . 1022 ) . C25H26N204S requires 451. 1686 ). Rac- 5 - ( cyclohex - 2 - en - 1 - yl) - 10 -methyl - 5H - dibenzo [ b , e ] N - ( ( 15 , 2S ,3R ) - rel - 3 - (9H - carbazol - 9 - yl ) - 2 -hydroxycyclo - [ 1 , 4 ] diazepin - 11 ( 10H ) - one . A solution of 10 -methyl - 5H hexyl) benzenesulfonamide Example 7 . A solution of (1R , dibenzo [ b , e ] [ 1 , 4 ] diazepin -11 (10H ) -one ( 0 .622 g , 2 .77 2S ,6R ) - rel- 2 -amino - 6 - (9H - carbazol- 9 -yl ) cyclohexanol mmol) in CHC1z (5 . 0 mL ) was treated with EtzN ( 1 . 15 g , ( 0 .0791 g , 0 . 282 mmol) in DMF ( 1 . 0 mL ) was cooled to 0° 45 8 . 32 mmol) and 3 - bromocyclohex - 1 - ene ( 0 . 38 mL , 3 . 32 C ., treated with Et N ( 39 . 0 0 .282 mmol) , and benzenesul- mmol) . The solution was warmed to 50° C . and stirred for fonyl chloride ( 36 . 0 UL , 0 . 282 mmol) . The mixture was 2 h . The mixture was concentrated in vacuo , taken up in a warmed to 25° C ., and stirred for 2 h . The mixture was minimal amount of CH2Cl2 and purified by flash chroma partitioned between saturated aqueous NaCl (50 mL ) , and tography ( SiO . , 0 -20 % ethyl acetate -hexanes ) to afford the CH , C1, ( 100 mL ) . The organic layer was washed with 50 title compound as a clear foam ( 0 .836 g , 99 % ) . ' H NMR saturated aqueous NaCl ( 3x50 mL ) , dried (Na , SO2) , and (600 MHz, CDC1z ) & ( as a mixture of conformers ) 1H [ 7 . 78 concentrated in vacuo . The residue was dissolved in a (d , J = 6 .6 Hz ), 7 .62 ( td , J= 6 . 0 , 1. 2 Hz )] , 7 . 19 - 7. 25 ( 1H , m ), minimal amount of CH2Cl2 and purified by flash chroma- 7 . 04 - 7 . 12 ( 2H , m ), 6 .98 - 7 . 03 ( 2H , m ) , 6 . 93 -6 . 97 ( 1H , m ) , tography (SiO2 , 0 - 20 % ethyl acetate - hexanes ) to afford 1H [ 6 .86 - 6 .89 ( m ) , 6 .75 (d , J = 7 . 8 Hz ), 1H [ 5 .91 - 5 .94 ( m ) , Example 7 as a white solid ( 0 .0454 g , 38 % ) . ' H NMR (600 55 5 . 89 - 5 . 90 ( m ) ] , 1H [ 5 .68 - 5 . 69 ( m ) , 5 .63 - 5 .64 (m ) ], 4 .45 ( 1H , MHz, CDC1z ) & ( as a mixture of rotamers ) 8 . 11 ( 1H , d , J = 7 . 8 br s ) , 3H [ 3 .47 ( s ) , 3 .45 ( s ) ] , 1 . 90 ( 2H , br s ) , 1 .80 - 1 .84 ( 1H , Hz) , 8 . 05 ( 1H , q , J = 5 . 4 Hz ), 2H [ 7 .92 ( d , J = 7 . 8 Hz ) , 7 . 83 ( d , m ) , 1 .67 - 1 .70 ( 1H , m ) , 1 . 48 - 1 .65 ( 1H , m ), 1 .43 - 1 .48 ( 1H , J = 7 . 2 Hz ) ], 7 .56 ( 1H , 9 , J = 7 . 2 Hz) , 7 . 49 - 7 . 53 (3H , m ), 7 .43 m ) ; LCMS m /z 305 . 1690 ([ M + H + 1, C2H2N , O requires ( 1H , t, J = 7 . 8 Hz) , 7 . 37 - 7 .41 (1H , m ) , 7 .36 (1H , t , J = 7 . 8 Hz) , 305 . 1648 ) . 7 .22 (2H , dt, J = 12 . 6 , 7 . 8 Hz) , 5 .77 ( 1H , t , J = 10 . 2 Hz ), 60 5 - ( ( 1R , 28 ,3R ) - rel - 2 , 3 - dihydroxycyclohexyl) - 10 -methyl 1H [ 5 .30 ( d , J = 4 . 8 Hz) , 5 . 13 ( d , J = 9 . 0 Hz) ], 2H [ 4 . 56 ( td , 5H - dibenzo [ b , e ] [ 1 , 4 ]diazepin - 11 ( 10H ) -one . A solution of J = 12 . 6 , 4 . 2 Hz) , 4 . 29 - 4 . 37 ( m ) ] , 1H [ 3 .60 - 3 . 66 ( m ) , 3 . 22 - rac - 5 - ( cyclohex - 2 - en - 1 - yl) - 10 -methyl - 5H - dibenzofbel[ 1 , 4 ] 3 . 26 ( m ) ] , 1H [ 2 . 48 ( qd , J = 13 . 2 , 3 . 6 Hz ) , 2 . 41 ( ad , J = 12 . 6 , diazepin - 11 ( 10H ) - one ( 0 .826 g , 2 . 71 mmol) in t - BuOH - H , O 3 .6 Hz) ] , 2 .29 (1H , br s ), 2 . 15 - 2. 18 (1H , br s ), 2H [ 1. 91 - 1. 96 5 :1 (5 . 0 mL ) at 25° C . was treated with OsO4 (2 .5 wt. % ( m ), 1. 84 - 1 . 87 ( m ) ], 2H | ( 1 . 54 - 1 .63 ( m ), 1 .42 - 1. 52 ( m ) ]; 13C 65 solution in t -BuOH , 0 . 34 mL , 0 .027 mmol) and N -methyl NMR (600 MHz, CDC13 ) 141. 6 , 140 . 6 , 138 . 4 , 132 . 9 , morpholine N -oxide monohydrate ( 0 . 403 g , 2 . 98 mmol) . 129 .3 , 127 .3 , 127 . 1 , 126 .1 , 125 .6 , 124 .5 , 122 . 9 , 120 . 9 , The mixture was stirred for 14 h at 25° C ., treated with a US 9 , 937 , 186 B2 75 76 saturated aqueous solution of sodium hydrosulfite ( 5 mL ) g , 1 . 17 mmol) in THF ( 5 mL ) was treated with PPhz (0 .337 and stirred for an additional 1 h . The mixture was concen - g, 1 .28 mmol) , H2O (0 . 3 mL ), and stirred for 14 h at 25° C . trated in vacuo and the residue was taken up in a minimal The mixture was concentrated in vacuo , taken up in a amount of CH C12 and purified by flash chromatography minimal amount of CH2Cl2 and purified by flash chroma ( SiO2, 0 - 50 % ethyl acetate -hexanes ) to afford the title com - 5 tography (SiO , 0 - 50 % ethyl acetate -hexanes to remove pound as a clear film ( 0 . 754 g , 82 % ) . ' H NMR (600 MHz , nonpolar impurities, followed by 0 - 3 % MeOH - CH , C1 , to CDC1z ) ( as a mixture of conformers ) 1H [ 7 .74 ( t , J = 1 . 8 remove triphenylphosphine oxide , followed by 17 : 2 : 1 Hz ), 7 .72 ( t, J = 1 .8 Hz )] , 7 .37 ( 1H , tt, J= 7 .8 , 1 . 8 Hz) , 7. 30 CH _ C12 :MeOH :NH ,OH to elute the product ). The purified ( 1H , dd , J = 7 . 8 , 1 . 8 Hz ) , 7 .22 - 7 . 25 ( 2H , m ) , 7 . 12 - 7 . 15 (3H , fractions were combined , dried azeotropically with toluene m ) , 7 . 10 ( 1H , t, J = 6 . 6 Hz ), 4 . 21 ( 1H , br s ) , 2H [ 3 . 94 - 3 . 95 10 to afford the title compound as a clear film ( 0 . 393 g , 99 % ) . ( m ), 3 .89 -3 .91 (m ), 3 .82 -3 .87 (m )] , 3H [3 .58 ( s ), 3 .57 (s ) ], 'H NMR (600 MHz, CDC1z ) & 1H [7 .83 (dd , J= 7 . 8 , 1. 8 Hz ), 2 .08 - 2 . 11 ( 1H , m ) , 1 .91 - 1 . 93 ( 1H , m ) , 1 . 83 - 1 . 86 ( 1H , m ), 7 .78 ( d , J = 8 . 4 Hz ) ], 7 . 37 - 7 .41 ( 2H , m ) , 7 . 22 - 7 .25 ( 1H , m ) , 1 .69 - 1 .74 ( 1H , m ), 1 .65 - 1 .69 ( 1H , m ), 1 .43 - 1 .46 ( 1H , m ) ; 7 .20 - 7 .22 (2H , m ) , 2H [ 7 . 15 - 7 . 19 ( m ) , 7 . 11 - 7 . 15 ( m ) ] , LCMS m / z 339 . 1747 ( M + H + ], C2H , , N , O , requires 3H [ 3 . 56 ( s ) , 3 .54 ( s ) ], 1H [ 3 .40 - 3 . 45 ( m ) , 3 . 35 - 3 .39 ( m )] , 339 . 1703 ) . 15 1H [ 3 .20 (t , J = 9 . 6 Hz ) , 3 . 06 ( t , J = 9 . 0 Hz ) ] , 2 .61 - 2 .66 ( 1H , (1R ,28 ,3R ) - rel - 2 -hydroxy - 3 - ( 10 -methyl - 11 -oxo - 10 ,11 - m ) , 2H [ 2 .23 - 2 .26 ( m ) , 1 . 99 ( m ) ] , 1 . 76 - 1 .83 ( 2H , m ) , 1 .67 dihydro - 5H - dibenzo [ b , e ] [ 1 , 4 ] diazepin - 5 - yl) cyclohexyl 1 . 74 ( 1H , m ) , 1 .63 ( 1H , dt, J = 13 . 8 , 3 . 0 Hz) , 1 . 25 - 1 . 38 ( 2H , methanesulfonate . A solution of 5 -( ( 1R , 2S , 3R )- rel -2 , 3 -dihy - m ), 1 .08 (1H , sextet of d , J = 13 .2 , 3 .6 Hz ); LCMS m / z droxycyclohexyl) - 10 -methyl -5H -dibenzo [b , e ] [ 1 , 4 ]diaz 338 .2148 ( [ M + H + 1, C2H , N20 , requires 338 . 1863) . epin - 11 ( 10H ) -one ( 0 .734 g , 2 . 17 mmol) in pyridine ( 5 . 0 mL ) 20 4 - Trifluoromethoxy - N - ( ( 15 , 2S ,3R ) - rel- 2 - hydroxy - 3 - ( 10 was cooled to 0° C . and treated dropwise with methanesul methyl- 11 - oxo - 10 , 11 - dihydro - 5H - dibenzo [ b , e ] [ 1 , 4 ]diaz fonyl chloride ( 168 uL , 2 . 17 mmol) . The mixture was epin - 5 - yl) cyclohexyl) benzenesulfonamide Example 8 . A warmed to 25° C . , stirred for 3 h , and then concentrated in solution of 5 - (( 1R , 2R ,3S ) - rel - 3 - amino - 2 -hydroxy cy clo vacuo . The residue was suspended in CH , C1 , ( 200 mL ) and hexyl ) - 10 -methyl - 5H - dibenzo [be ] [ 1 , 4 ] diazepin - 11 ( 10H ) the organic phase was washed with 1 M HCl ( 3x100 mL ) , 25 one ( 0 .0800 g , 0 . 238 mmol ) in DMF ( 1 .0 mL ) was cooled to dried (Na2SO4 ) , and concentrated in vacuo . The residue was 0° C ., treated with EtzN (33 . 0 ul , 0 . 238 mmol ) , and dissolved in a minimal amount of CH , C1, and purified by 4 - trifluoromethoxybenzenesulfonyl chloride (40 . 0 uL , 0 . 238 flash chromatography (SiO2 , 0 - 50 % ethyl acetate -hexanes ) mmol) . The mixture was warmed to 25° C . , and stirred for to afford the title compound as a white solid ( 0 .761 g , 84 % ). 2 h . The mixture was partitioned between saturated aqueous IH NMR (600 MHz, CDC1z ) 8 ( as a mixture of conformers ) 30 NaCl (50 mL ) , and CH , C1, ( 100 mL ) . The organic layer was 1H [ 7 .77 (dd , J= 7 .8 , 1. 2 Hz ), 7 .73 (dd , J= 7 . 8 , 1. 2 Hz ) ], washed with saturated aqueous NaCl ( 3x50 mL ), dried 1H ( 7 . 42 ( td , J= 9 .0 , 1. 2 Hz ), 7 . 38 (td , J = 7 . 8 , 1 . 2 Hz ) ] , (Na , SO . ) , and concentrated in vacuo . The residue was 7 .25 - 7 . 30 (2H , m ), 7 . 18 - 7 . 34 ( 2H , m ), 7 . 12 - 7 . 17 ( 2H , m ) , dissolved in a minimal amount of CH2Cl, and purified by 4 . 80 - 4 . 84 ( 1H , m ) , 2H | 4 . 31 - 4 .34 ( m ), 4 .22 (br s ) , 4 .07 (br flash chromatography ( SiO , , 0 -50 % ethyl acetate -hexanes ) . s ) , 3H [3 .65 ( s ) , 3 .60 ( s ) , 3H [ 2 . 89 ( s ) , 2 . 82 ( s ) , 2 . 14 - 2 . 16 35 The purified fractions were combined , dissolved in a mini ( 1H , m ), 2 . 00 - 2 . 08 (1H , m ), 1 . 89 - 1 . 98 (1H , m ), 1 .85 - 1 . 89 mal amount of ethyl acetate , and precipitated with the ( 1H , m ) , 1 .69 - 1 . 76 ( 1H , m ), 1 .55 - 1 .62 ( 1H , m ), 1 . 44 - 1 .48 addition of hexanes to afford Example 8 as a white solid ( 1H , m ) ; LCMS m /z 417 .1498 ([ M + H +] , C2 H24N20 S (0 . 100 g , 75 % ) ; ' H NMR (600 MHz, CDC13 ) 8 7 .94 (2H , t, requires 417 . 1479 ) . J = 7 .2 Hz ) , 7 . 76 ( 1H , dd , J = 7 . 8 , 1 . 8 Hz) , 7 . 38 ( 1H , td , J = 7 . 8 , 5 - (( 1R , 2S , 3S ) - rel - 3 - azido - 2 -hydroxycyclohexyl ) - 10 - 40 1 . 8 Hz ), 7 . 33 ( 2H , d , J = 8 . 4 Hz ), 7 . 28 ( 2H , d , J = 7 .2 Hz ), methyl- 5H - dibenzo [ b , e ][ 1 , 4 ] diazepin - 11 ( 10H ) - one . A solu - 7 .23 - 7 . 24 (2H , m ) , 7 . 12 - 7 . 16 ( 2H , m ) , 5 . 27 ( 1H , d , J = 6 . 6 tion of ( 1R ,28 , 3R ) -rel - 2 -hydroxy - 3 -( 10 -methyl - 11 -oxo - 10 , Hz ) , 3 .53 (3H , s ) , 3 . 35 - 3 .37 ( 2H , m ) , 3 . 34 ( 1H , s ), 3 .08 - 3 . 10 11 - dihydro -5H -dibenzo [b ,e ] [ 1, 4 ]diazepin - 5 -yl ) cyclohexyl (1H , m ), 1. 99 - 2 .01 (1H , m ), 1 .83 - 1. 85 ( 1H , m ), 1. 60 - 1. 63 methanesulfonate ( 0 .614 g , 1 .47 mmol ) in DMF ( 3 . 0 mL ) ( 1H , m ), 1 . 32 - 1 .38 ( 1H , m ), 1 . 12 - 1 . 18 ( 2H , m ) ; LCMS m / z was treated with NaN ; (0 .144 g , 2 .21 mmol) and heated to 45 562 .1625 ([ M + H + ], C27H26F3N30 S requires 562 . 1618 ). 100° C . for 2 h under microwave radiation . The mixture was 4 - Chloro - N - ( ( 15 , 2S , 3R ) -rel - 2 - hydroxy - 3 - ( 10 -methyl - 11 cooled to 25° C . and partitioned between saturated aqueous oxo - 10 , 11 - dihydro - 5H - dibenzo [ b , e ] [ 1 , 4 ]diazepin - 5 - yl) cy NaCl ( 100 mL ) and CH C12 ( 300 mL ). The organic layer clohexyl) benzenesulfonamide Example 9 . A solution of was washed with saturated aqueous NaCl ( 3x100 mL ) , dried 5 - ( ( 1R , 2R , 3S ) -rel - 3 - amino - 2 - hydroxycyclohexyl ) - 10 (Na2SO4 ) , and concentrated in vacuo . The residue was 50 methyl -5H - dibenzo [b , e ] [ 1 ,4 ] diazepin - 11( 10H ) - one (0 . 0800 dissolved in a minimal amount of CH , C1 , and purified by g , 0 .238 mmol) in DMF ( 1 . 0 mL ) was cooled to 0° C . , flash chromatography ( SiO , , 0 - 20 % ethyl acetate -hexanes ) treated with Et N ( 33 . 0 uL , 0 . 238 mmol) , and 4 -chloroben to afford the title compound as a white solid (0 .444 g, 83 % ) . zenesulfonyl chloride ( 0 .050 g , 0 .238 mmol) . The mixture IH NMR (600 MHz, CDC1z ) & 1H [ 7 .85 (dd , J = 7 . 8 , 1 . 2 Hz ) , was warmed to 25° C . and stirred for 2 h . The mixture was 7 .81 (dd , J = 7 . 8 , 1 . 8 Hz) , 7 .40 ( 1H , tt, J = 7 . 8 , 1 . 8 Hz ) , 55 partitioned between saturated aqueous NaCl (50 mL ) , and 2H [ 7 .37 ( d , J = 7 . 8 Hz) , ( t, J = 7 . 8 Hz) ] , 7 .24 - 7 .26 ( 2H , m ), CH , C1, ( 100 mL ) . The organic layer was washed with 7 . 14 - 7 .21 (2H , m ) , 3H [ 3 .57 ( s ) , 3 . 54 ( s ) , 3 . 42 - 3 . 45 ( 1H , m ) , saturated aqueous NaCl ( 3x50 mL ) , dried (Na , SO2) , and 3 . 33 - 3 . 38 (1H , m ) , 3 . 31 - 3 . 32 ( 1H , m ) , 2 .23 - 2 . 25 ( 0 . 5H , m ), concentrated in vacuo . The residue was dissolved in a 1 . 95 - 2 .01 ( 2H , m ) , 1 . 83 ( 0 .5H , doublet of quintets , J = 10 . 2 , minimal amount of CH ,C1 , and purified by flash chroma 3 .6 Hz) , 1H [ 1. 75 (brs ) , 1 .70 - 1. 75 (m )] , 1 .67 (0 . 5H , qd , 60 tography (SiO2 , 0 -50 % ethyl acetate -hexanes ). The purified J = 12 .6 , 4 .2 Hz )] , 1. 37 (0 .5H , qt, J = 13 . 2 , 3. 6 Hz) , 1. 24 - 1. 30 fractions were combined , dissolved in a minimal amount of (2H , m ); LCMS m / z 364 . 1814 ( [M + H + ], C20H2 N 02 ethyl acetate , and precipitated with the addition of hexanes requires 364 . 1768) . to afford Example 9 as a white solid ( 0 . 0958 g , 79 % ) . ' H 5 - ( ( 1R 2R ,3S ) - rel - 3 -amino - 2 -hydroxycyclohexyl ) - 10 NMR (600 MHz, CDC1z ) 8 2H [ 7 .81 ( d , J = 8 .4 Hz) , 7 .78 ( d , methyl- 5H - dibenzo [ b , e ] [ 1 , 4 ]diazepin - 11 ( 10H ) -one . A solu - 65 J = 7 . 2 Hz ) ] , 2H [ 7 .47 ( d , J = 8 . 4 Hz ) , 7 .44 ( d , J = 8 . 4 Hz) ] , tion of 5 - (( 1R , 2S ,3S ) -rel - 3 -azido - 2- hydroxycyclohexyl ) - 10 7 .33 -7 . 38 (1H , m ), 7 .30 -7 . 33 (2H , m ) 7 . 21 - 7 .23 (2H , m ), methyl- 5H - dibenzo [ b , e ][ 1 , 4 ] diazepin - 11 ( 10H ) - one (0 .424 7 .11 - 7 . 14 ( 2H , m ) , 1H [ 5 .39 ( d , J = 6 . 6 Hz) , 5 .32 ( d , J = 4 . 8 US 9 ,937 , 186 B2 77 78 Hz ) ] , 3 .52 (3H , s ) , 2H [ 3 .41 ( s ) , 3 . 35 - 3 . 37 ( m ) , 3 .29 ( s ), 3 . 19 - continued ( t, J = 9 . 6 Hz) ] , 1H [ 3 .03 - 3 .08 ( m ) , 2 .95 ( septet, J = 4 . 8 Hz) ] , 1H [ 2 .20 - 2 .22 ( m ) , 1 .98 ( m ) ] , 2H [ 1 .75 - 1 .79 ( m ) , 1 .65 - 1 .70 III ( m ), 1 . 56 - 1 .60 (m ) ], 1. 29 - 1. 34 (1H , m ), 1 .13 - 1 .17 (2H , m ); LCMS m /z 512 .1409 ([ M + H +] , C26H26C1N2O4S requires 5 512 . 1405 ) . HO OH Example 10 10

111110> LOCF3 15 OH ?? TTTTTTT >TIT

20

( U + R4 The synthesis is begun by a palladium -catalyzed C -ally - Q = lation of commercially available 9H - fluorene 1 with cyclo hex - 2 - en - 1 - yl acetate to afford alkene (Zhurnal Organ - 23 R2 + I um icheskoi Khimii, 1986 , 22 ( 7 ) , 1565- 6 ) . An osmium tetroxide catalyzed dihydroxylation will afford diol . Treatment of diol with methanesulfonyl choride will furnish mesylate . A a : The protected diastereomeric epoxide is reacted with the nitrogen tricycle in the presence of a strong base , such as NaH . The protecting group may be , for example , sodium azide induced azide displacement will afforded benzyl or t -butyldimethylsilyl . b : The protecting group is removed with an appropriate reagent, e . g . catalytic azide . The amine may be synthesized via a Staudinger hydrogenation for benzyl or tetrabutylammonium fluoride for t- butyldimethylsilyl . reaction . Treating the amine with commercially available c : The diol is treated with thionyl chloride in the presence of a base , such as 4 -( trifluoromethoxy )benzene -1 -sulfonyl chloride will afford triethylamine. d : The sulfite ester is ring- opened with an azide, such as sodium azide. target sulfonamide Example 10 . e : The azide is reduced to the amine with phosphine , such as triphenylphosphine . f : (not shown ) The amine is acylated as described in many examples above with the Examples 12 , 13 and 14 may be synthesized by the route 35 appropriate phenylsulfonyl choloride . shown in Scheme 6 :

Scheme 6 40 Example 12

( U + R4 U B R? LOCF3 ca OH NH 01 - RA 45 R2 + 1 ) Vli RI N111111 OPG shop HO OPG 50 loco

55 Example 13 1111 ?60 LOCF3 ?? OH OPG 111111 16 65 lever US 9 ,937 , 186 B2 79 80 -continued tography ( SiO2, 0 - 10 % ethyl acetate - hexanes ) to afford the Example 14 title compound as a beige foam ( 1. 38 g , 66 % ) and minor amount of the other regioisomer ( 0 . 229 g , 11 % ) . ' H NMR 5 (600 MHz, CDC13 ) 8 8 .05 ( 1H , d , J = 7 . 2 Hz) , 7 . 75 ( 1H , d , LOCF3 OH J = 7 . 2 Hz) , 7 .41 - 7 .47 (7H , m ), 7 . 36 (1H , tt , J = 6 . 0 , 1 . 8 Hz) , OHL 7 .22 ( 1H , t, J= 7 .8 Hz) , 7. 17 ( 1H , t , J= 8 . 4 Hz) , 4 .80 -4 .84 ( 1H , 111111 S m ) , 4 .79 ( 1H , d , J = 12 . 0 Hz) , 4 .61 (1H , d , J = 11. 4 Hz ), 10 4 . 43 - 4 . 48 ( 1H , m ), 4 . 11 - 4 . 13 ( 1H , m ) , 2 .37 - 2 .44 ( 1H , m ) , Segons2 . 28 ( 1H , doublet of quintets , J = 14 . 4 , 3 . 0 Hz) , 2 . 18 ( 1H , d , J = 9 . 6 Hz) , 1 . 98 - 2 . 03 ( 1H , m ) , 1 .91 ( 1H , qt, J = 13. 8 , 3 . 6 Hz) , Example 15 is synthesized in a fashion analogous to that 1 .73 - 1 .76 ( 1H , m ), 1 . 55 - 1 .61 (1H , m ); LCMS m /z 390 .1855 shown above in Example 10 by a palladium -catalyzed 15 ([ M + H + ] , C25H24FNO , requires 390 . 1864 ) . C - allylation with cyclopent- 2 - en - 1 - yl acetate .

Example 15

LOCF3. ?? ILON TON luongo111111 1111111 25 _ 90 “ tion OH Chiral materials . Method analogous to stereoselective synthesis of 3 -optically active staring materials tive 30 ( 1R ,28 ,3R )- 3 -( 3 - fluoro -9H -carbazol - 9 - yl )cyclo hexane - 1 , 2 - diol OBn 35 A solution of ( 18 , 2R ,6R )- 2 -( benzyloxy ) -6 - ( 3 - fluoro - 9H F carbazol- 9 -yl )cyclohexanol ( 1. 36 g, 3. 49 mmol ) in THF : MeOH ( 1: 1 , 10 .0 mL ) was treated with 10 % Pd /C (0 . 370 g ), placed under an atmosphere of H2 ( g ), and stirred for 48 h IZ 40 at 25° C . The mixture was filtered thru Celite and concen F trated in vacuo . The residue was dissolved in a minimal amount of CH2Cl2 and purified by flash chromatography (SiO2 , 0 -50 % ethyl acetate - hexanes) to afford the title com 45 pound as a white solid 0 .926 g , 89 % ) . ' H NMR (600 MHz, CDC13 ) 8 8 .05 (1H , br s) , 7 . 76 (1H , br s ), 7 .41 - 7 .60 ( 3H , br HOH m ) , 7 . 25 ( 1H , t , J = 7 . 8 Hz) , 7 . 15 - 7 .24 ( 1H , br s ) , 5 .31 ( 1H , s ) , 4 .85 ( 1H , br s ) , 4 .49 ( 1H , br s ) , 4 .31 - 4 . 32 (1H , m ), 2 . 56 50 (1H , br s ), 2 .38 ( 1H , br s ), 2 .12 -2 .17 ( 1H , m ), 2 .00 (1H , qt , BU J= 13 .2 , 3. 6 Hz ), 1. 96 (1H , d, J = 3. 0 Hz ) , 1. 93 -1 . 96 (1H , m ), 1 .65 - 1 . 76 ( 2H , m ); LCMS m / z 300 . 1393 ( [ M + H + ], (15 ,2R ,6R ) - 2 - (benzyloxy )- 6 -( 3 - fluoro - 9H -carbazol C13H 3FNO , requires 300 .1394 ) . 9 - yl) cyclohexanol 55 A solution of 3 - fluoro - 9H -carbazole ( 1 . 00 g , 5 . 40 mmol ) F in toluene ( 10 mL ) at 0° C . was treated with NaH (60 % dispersion in mineral oil ( 0 . 431 g , 10 . 8 mmol) , and ( 15 , 2R , 6S ) - 2 -( benzyloxy ) -7 -oxabicyclo [ 4 .1 . 0 ]heptane (1 . 10 g , 5 .40 60 mmol) . The mixture was warmed to 100° C . and stirred for 14 h . The mixture was cooled to 25° C . , treated with UZ saturated aqueous NH4C1 ( 50 mL ) , and extracted with ON toluene (3x50 mL ) . The organic layer was washed with saturated aqueous NaCl ( 3x50 mL ) , dried (Na , SO2 ) , and 65 concentrated in vacuo . The residue was dissolved in a * 100 minimal amount of toluene and purified by flash chroma US 9 ,937 , 186 B2 87 82 -continued 3 .36 mmol) in DMF ( 10 .0 ml) was treated with sodium azide ( 0 .656 g , 10 . 1 mmol) , and heated to 110° C . for 14 h under microwave irradiation . The mixture was diluted with CH _ C12 ( 200 mL ) and this organic layer was washed with saturated aqueous NaCl (3x100 mL ) , dried (Na2SO4 ) , and concentrated in vacuo . The residue was dissolved in a minimal amount of CH2Cl2 and purified by flash chroma $1111 tography (SiO2 , 0 - 10 % ethyl acetate -hexanes ) to afford the sc0 10 title compound as a clear oil ( 0 . 775 g , 71 % ) . ' H NMR (600 MHz, CDC13 ) & 1H [8 .05 (d , J= 7 . 2 Hz ) , 8 .04 (d , J = 7. 8 Hz ) ], 1H [ 7 .78 ( dd , = 9 .0 , 3 . 0 Hz ) , 7 .78 (dd , J = 8 . 4 , 2 . 4 Hz ) , 1H [ 7 . 55 ( d , J = 8 . 4 Hz ), 7 .38 (dd , J = 9 . 0 , 3 . 6 Hz ) ] , 7 . 43 - 7 . 52 ( 3aS ,4R ,7aR ) - 4 - ( 3 - fluoro - 9H - carbazol- 9 - yl) hexahy 15 (2H , m ), 7 . 22 - 7 . 26 ( 1H , m ), 1H?7 . 21 (td , J = 9 . 0 , 3 . 0 Hz ) , drobenzo [ d ] [ 1, 3 , 2 ] dioxathiole 2 -oxide 7 .17 ( td , J = 8 . 4 , 2 . 4 Hz ) ], 4 . 35 - 4 .47 ( 2H , m ), 3 .54 - 3 .61 ( 1H , A solution of ( 1R .28 3R ) - 3 - ( 3 - fluoro - 9H - carbazol- 9 - yl ) m ) , 2 . 38 - 2 .50 ( 1H , m ) , 2 . 18 - 2 .24 ( 1H , m ) , 2 . 14 - 2 . 19 ( 1H , cyclohexane - 1 , 2 -diol ( 0 . 906 g , 3 .03 mmol) in CH , C1, ( 10 . 0 m ), 2 .00 - 2 .04 ( 1H , m ) , 1 . 94 - 1 . 98 ( 1H , m ) , 1 .55 - 1 .64 ( 2H , mL ) at 0° C . was treated dropwise with triethylamine (3 . 36 m ); LCMS m / z 325 .1455 ( [M + H * ] , C18H17FN4O requires mL , 24 . 2 mmol) , and SOCI, ( 0 . 66 mL , 9 . 08 mmol) . The - 325 . 1459 ) . mixture was warmed to 25° C . , stirred for 2 h , poured over a solution of saturated aqueous sodium chloride ( 100 mL ) , and then extracted CH C12 (3x100 mL ) . The combined F organic layers were washed with water (2x100 mL ) , satu - 75 rated aqueous sodium chloride ( 100 mL ) , dried (Na2SO4 ) , and concentrated in vacuo . The residue was dissolved in a minimal amount of CH C12 and purified by flash chroma tography (SiO2 , 0 - 10 % ethyl acetate -hexanes ) to afford the title compound as an orange oil ( 1 . 16 g , 99 % ) . ' H NMR (600 3030 OH MHz , CDC1z ) d (as a mixture of sulfite diastereomers ) 8 .07 illo ( 1H , br s ), 1H [ 7 .78 (brs ) , 7 . 73 ( br s ) , 7 .67 (brs ), 7 .60 (br s ) ] , 2H [ 7 . 40 - 7 .54 ( m ) , 7 . 35 (brs ) ] , 7 .27 ( 2H , t , J = 6 . 0 Hz ) , 7 . 19 ( 1H , br s ), 1H [ 5 .48 ( brs ) , 5 .27 ( m ) ] , 5 .34 - 5 . 44 (1H , m ) , NH2 1H [ 4 .93 - 4 . 95 ( m ) , 4 .47 (brs ) ] , 2 . 57 - 2 .61 ( 1H , m ) , 2 . 36 - 2 .55 25 (1H , m ), 2 . 16 ( 1H , tt, J = 16 . 8 , 4 . 2 Hz) , 2 .00 - 2 .08 ( 2H , m ) , 1 .82 - 2 .00 ( 1H , m ), 1 .88 ( 1H , qt, J = 13 . 8 , 3 . 0 Hz ); LCMS m / z ( 1R ,2S ,6R ) - 2 - amino -6 - ( 3 - fluoro - 9H -carbazol - 9 - yl) 346 .0912 ([ M + H * ], C13H16FNOŽS requires 346 .0908 ) . cyclohexanol 40 A solution of ( 15, 2S ,6R )- 2 -azido - 6 -( 3 - fluoro - 9H - carba zol - 9 - yl ) cyclohexanol ( 0 .755 g , 2 .33 mmol ) in THF ( 10 . 0 mL ) was cooled to 0° C ., treated with PPhz ( 0 . 794 g , 3 . 03 mmol) , H20 (0 . 5 mL ), and stirred for 14 h at 25° C . The 45 solution was concentrated to dryness, dissolved in a minimal 11110 amount of CH2Cl2 and purified by flash chromatography = O (SiO2 , 0 -50 % ethyl acetate -hexanes to remove nonpolar ** 11110 impurities followed by 3 % MeOH - CH2Cl2 to remove F 50 triphenylphospine oxide and 17 :2 : 1 CH2C12 :MeOH :NH OH to elute the product ). The combined fractions of pure prod uct were concentrated , dried azeotropically with toluene to 55 afford the title compound as a white solid ( 0 .648 g , 93 % ). ' H NMR (600 MHz, CDC13 ) d 1H [ 8 .06 ( d , J = 7 . 8 Hz) , 8 .01 ( d , 11ON J = 8 . 4 Hz) ] , 1H [ 7 . 77 ( dd , v = 9 . 0 , 2 .4 Hz) , 8 . 01 ( d , J = 9 . 0 , 2 . 4 Hz ) ] , 2H [ 7 .60 ( 1H , d , J = 8 . 4 Hz ), 7 . 41 - 7 .44 ( m ) ] , 1H [ 7 . 50 N3 (dd , J= 9 .0 , 3 .6 Hz ), 7 .34 (dd , J = 9 .0 , 4 . 2 Hz ) ], 2H [7 .24 (t , J = 7 .8 Hz) , 7 .13 - 7 .21 ( m ) ], 1H [4 . 35 (ddd , J= 12 .6 , 10 .2 , 4 .2 Hz ) , 4 .29 (ddd , J = 12 .6 , 10 . 2 , 4 .2 Hz )] , 3 .97 -4 .04 ( 1H , m ), ( 15 ,2S ,6R ) - 2 - azido - 6 - ( 3 - fluoro - 9H - carbazol- 9 - yl) cyclohexanol 2 .66 - 2 . 73 ( 1H , m ) , 1H [ 2 .41 (qd , 7 .34 ( dd , J = 13 . 2 , 3 .6 Hz) , 65 2 .. 37 37 ( qd , J = 13. 2 , 4 . 2 Hz) ] , 1 . 83 - 1 . 94 (6H , m ), 1. 48 - 1 . 56 A solution of (3aS ,4R ,7aR )- 4 -( 3 - fluoro - 9H -carbazol - 9 . (1H , m ) , 1 . 30 (1H , qt , J = 13 . 2 , 3 .6 Hz) ; LCMS m / z 299. 1556 yl) hexahydrobenzo [ d ] [ 1, 3 ,2 ]dioxathiole 2 -oxide (1 .16 g , ([ M + H +] , C18H , FN O requires 299 .1554 ). US 9 ,937 , 186 B2 83 84 Example 31a 1597. Example 31b 55 OBnOBn

steps as above

.. til T]

1111Z

0

11110 IZ DEO SOCF3. NH 31b OCF3 Enantiomer as above starting from ( 1R , 2S ,6R ) - 2 - benzy 31a loxy) - 7 - oxabicyclo [ 4 . 1 . 0 ]heptane to yield Example 31b : N - ( ( 15 , 2S ,3R ) - 3 - ( 3 - fluoro -9H - carbazol- 9 - yl) - 2 -hydroxycy clohexyl) -4 -( trifluoromethoxy )benzenesulfonamide . [ a ] d = - 3 ( 1 .0 in CH2Cl2) . N -( ( 18 ,25 , 3R )- 3 -( 3 - fluoro -9H -carbazol - 9 -yl ) - 2- hy droxycyclohexyl) - 4 -( trifluoromethoxy )benzenesulfo 30 Examples 32a and 32b namide Chiral materials . Method analogous to stereoselective A solution of ( 1R , 28 ,6R ) - 2 - amino - 6 - ( 3 - fluoro - 9H - carba synthesis of 3 -optically active staring materials zol- 9 -yl ) cyclohexanol (0 .220 g, 0 .737 mmol ) in CH C12 (2 . 0 35 mL) was cooled to 0° C ., treated with Et3N ( 107 uL , 0 .774 OBn mmol) , and 4 - trifluoromethoxybenzenesulfonyl chloride ( 131 UL , 0 . 774 mmol) . The mixture was warmed to 25° C . , and stirred for 2 h . The mixture was partitioned between 40 saturated aqueous NaCl ( 50 mL ) and CH C12 ( 100 mL ). The organic layer was washed with saturated aqueous NaCl (3x50 mL ), dried (Na2SO4 ) , and concentrated in vacuo . The N residue was dissolved in a minimal amount of CH , C1, and 45 purified by flash chromatography (SiO2 , 0 - 35 % ethyl acetate -hexanes ). The pure fractions were combined , con centrated , and the residue was dissolved in a minimal amount of ethyl acetate and precipitated with the addition of 50 hexanes to afford the title compound as a white solid ( 0 . 269 stilo g , 70 % ). [ a ] y = + 3 ( 1 . 0 in CH2Cl2 ), ' H NMR (600 MHz , CDC13 ) S 1H [ 8. 02 (d , J = 7 .8 Hz ), 7 .97 ( d , J = 7. 8 Hz ) ], ** *11110 Bn 2H [ 7 .94 (d , J = 1 . 8 Hz ), 7 .93 (d , J = 1 .8 Hz )] , 1H [7 .74 (dd , 55 J = 8 . 4 , 2 . 4 Hz) , 7 .65 ( d , J = 8 . 4 , 2 . 4 Hz ) ] , 1H [ 7 .53 ( d , J = 7 . 8 Hz) , 7 .29 ( d, J = 8 .4 Hz ), 1H [7 .45 (dd , J= 9 .0 , 3 .6 Hz ), 7 . 16 (15 , 2R ,6R )- 2 -( benzyloxy )- 6 -( 3, 6 -difluoro -9H - carba (dd , J = 9 . 0 , 4 . 2 Hz) , ], 7 . 40 ( 1H , dt, J = 7 . 8 Hz) , 7 .31 (2H , dd , zol- 9 -yl ) cyclohexanol J = 8 .4 , 2 . 4 Hz ), 1H?7 .23 (t , J= 7 .2 Hz) , 7 . 19 (t , J = 7 . 2 Hz )] , 60 A solution of 3 ,6 -difluoro - 9H -carbazole ( 1 .00 g , 4 .92 1H [ 7 .13 (td , J= 9 .0 , 2 .4 Hz) , 7 . 06 ( td , J = 8 . 4 , 2 .4 Hz ) ], mmol) in toluene (10 mL ) at 0° C . was treated with NaH 1H [5 .32 (d , J= 5. 4 Hz) , 5. 26 ( d, J = 4 .8 Hz) ], 4. 18 -4 .32 (2H , (60 % dispersion in mineral oil (0 .393 g, 9 .84 mmol) , and ( 15 ,2R ,6S ) - 2 - (benzyloxy ) - 7 -oxabicyclo [ 4 . 1 . 0 ]heptane m ), 3 .21 -3 .24 ( 1H , m ), 2H [2 .35 - 2 .41 (m ), 2. 28 - 2. 35 ( m ) ], ( 1 .00 g , 4 . 92 mmol) . The mixture was warmed to 100° C . 2 . 13 - 2 . 16 ( 1H , m ) , 1 . 85 - 1 .89 ( 2H , m ), 1. 41 - 1 . 54 (411 2H ,, m )); 65 and stirred for 14 h . The mixture was cooled to 25° C . , LCMS m /z 523. 1313 ([ M + H + ], C25H22F _N204S requires treated with saturated aqueous NH _ C1 (50 mL ) , and 523 . 1309 ) . extracted with toluene (3x50 mL ) . The organic layer was US 9 ,937 , 186 B2 85 washed with saturated aqueous NaCl (3x50 mL ) , dried (Na2SO4 ) , and concentrated in vacuo . The residue was F. dissolved in a minimal amount of toluene and purified by flash chromatography (SiO2 , 0 - 10 % ethyl acetate -hexanes ) 5 to afford the title compound as a beige foam ( 1 . 78 g , 89 % ) . ' H NMR (600 MHz, CDC13 ) 8 7 .66 - 7 .69 (2H , m ), 7 .39 - 7 .45 (5H , m ), 2H [ 7 . 35 - 7 .39 ( m ), 7 .31 ( dd , J = 9 . 0 , 4 . 2 Hz ) ] , 11110 7 . 15 - 7 . 21 ( 2H , m ), 4 .79 ( 1H , d , J = 12 . 0 Hz ), 4 .77 ( 1H , ddd , 10 * J = 12 .6 , 10 . 8 , 4 . 2 Hz ) , 4 .59 ( 1H , d , J= 12. 0 Hz ), 4 . 41 ( 1H , H ddd, J = 12 .0 , 10 . 2 , 3 .0 Hz ), 4 . 10 -4 . 11 (1H , m ), 2 .37 ( 1H , qd , J = 13 . 2, 4 .2 Hz) , 2 .29 ( 1H , doublet of quintets , J = 14 .4 , 2 .4 Hz) , 2 . 20 ( 1H , d , J = 9. 0 Hz) , 1. 98 - 2 .02 (1H , m ), 1. 91 (1H , qt , 15 J= 13. 8 , 3 .6 Hz) , 1. 72 - 1. 77 (1H , m ) , 1 .52 - 1. 60 (1H , m ); LCMS m /z 408 .1770 ([ M + H * ], C25H23F2NO , requires 408. 1770 ). ** * 1110 20 = O

25 (3aS , 4R ,7aR ) -4 -( 3, 6 -difluoro -9H -carbazol - 9 - yl ) hexahydrobenzo [ d ][ 1, 3 ,2 ] dioxathiole 2 -oxide 11111ON A solution of (1R ,28 , 3R )- 3 -( 3 ,6 -difluoro - 9H -carbazol - 9 30 yl) cyclohexane - 1 , 2 - diol ( 1 . 26 g , 3 . 97 mmol) in CH2Cl2 viden ( 20 .0 mL ) at 0° C . was treated dropwise with triethylamine F F ( 4 .40 mL , 31. 8 mmol ), and SOCI, (0 . 86 mL , 11. 9 mmol) . The mixture was warmed to 25° C ., stirred for 2 h , poured 35 over a solution of saturated aqueous sodium chloride ( 100 mL ), and then extracted CH C12 ( 3x100 mL ) . The combined organic layers were washed with water (2x100 mL ), satu 11110 rated aqueous sodium chloride ( 100 mL ) , dried (Na2SO4 ) , and concentrated in vacuo . The residue was dissolved in a * 40 H minimal amount of CH C1, and purified by flash chroma tography (SiO2 , 0 - 10 % ethyl acetate -hexanes ) to afford the title compound as an orange solid ( 1 .29 g , 89 % ). ' H NMR ( 1R ,2S , 3R ) -3 - ( 3 ,6 - difluoro - 9H -carbazol - 9 - yl) cyclo - 45 (600 MHz, CDC13 ) d (as a mixture of sulfite diastereomers ) hexane - 1, 2 - diol 2H [ 7. 71 (br s ), 7 .66 (brs ) , 7 .60 (br s) ], 7 .34 (2H , br s ), 7 . 15 -7 .25 (2H , br s ), 1H [ 5 .43 (dd , J = 9. 6 , 4 .8 Hz ), 5 . 22 (dd , A solution of (19 ,2R ,6R )- 2 -( benzyloxy )- 6 -( 3 ,6 -difluoro J = 10 . 2, 5 .4 Hz )] , 1H [ 5 .37 - 5 .39 ( m ), 4 .93 -4 .95 ( m ) ], 4. 24 9H -carbazol - 9 -yl ) cyclohexanol (1 .77 g , 4. 34 mmol) in THF: ( 1H , ddd , J = 13. 2, 9. 0 , 4 .2 Hz) , 2 . 56 - 2. 63 ( 1H , m ), 2 .39 ( 1H , MeOH ( 1 : 1 , 10. 0 mL) was treated with 10 % Pd / C ( 0 .923 g ) , qd , J= 13 .2 , 3. 0 Hz ) , 2 . 16 ( 1H , tt, J = 9 .6 , 4 .2 Hz ), 2. 00 - 2. 07 placed under an atmosphere of H2 ( g ), and stirred for 48 h (2H , m ) , 1. 94 - 2 .00 (1H , m ), 1 .86 ( 1H , qt, J = 13 .8 , 3 .0 Hz ); at 25° C . The mixture was filtered thru Celite and concen LCMS m /z 364. 0797 ([ M + H + ], C18H15F2NO3S requires trated in vacuo . The residue was dissolved in a minimal 364 .0813 ) . amount of CH2Cl2 and purified by flash chromatography (SiO2 , 0 -50 % ethyl acetate -hexanes ) to afford the title com - F pound as a beige foam ( 1. 14 g , 82 % ) with additional recovered starting material ( 0 . 41 g , 23 % ). ' H NMR ( 600 MHz , CDC13 ) d 7 .68 ( 2H , br s ), 7 .45 ( 2H , br s ), 7 . 20 ( 2H , br s ), 4 .79 ( 1H , ddd , J= 13 . 2 , 10 . 8 , 4 . 2 Hz ), 4 .40 ( 1H , dd , J = 10 .2 , 3 .0 Hz ), 2 .64 ( 1H , br s ), 2 . 32 (1H , qd , J = 12 .2 , 3. 6 Hz ) , 2 .07 -2 .13 ( 1H , m ), 2 . 10 -2 . 17 ( 1H , br m ), 1. 91 - 2 .01 65a S = 0 He(2H , 207m ) , 1 .2469 - 1 .1 74 ( 1Hm , m ),1017 1 .62 - 1 . 68 ( H(1H x, m mm) ; LCMS 1220 m / z = 318. 1302 ([ M + H + ], C18H F2NO , requires 318 .1300 ). US 9 ,937 , 186 B2 87 88 ( 1R ,28 ,6R )- 2 - amino - 6 - ( 3 , 6 - difluoro - 9H - carbazol- 9 -continued yl) cyclohexanol A solution of ( 19 ,2S ,6R ) - 2 - azido - 6 - ( 3 , 6 - difluoro - 9H - car 5 bazol- 9 - yl) cyclohexanol ( 0 . 901 g , 2 .63 mmol) in THF ( 10 . 0 mL ) was cooled to 0° C ., treated with PPhz ( 1 . 04 g , 3 . 95 mmol) , H , O ( 0 . 5 mL ) , and stirred for 14 h at 25° C . The 11lUM solution was concentrated to dryness , dissolved in a minimal amount of CH , C1, and purified by flash chromatography 10 (SiO , , 0 -50 % ethyl acetate -hexanes to remove nonpolar impurities followed by 3 % MeOH - CH2Cl2 to remove triphenylphospine oxide and 17 : 2 : 1 CH , C1, :MeOH :NH OH to elute the product) . The combined fractions of pure prod uct were concentrated , dried azeotropically with toluene to ( 15 . 2S ,6R ) - 2 - azido - 6 - ( 3 , 6 - difluoro - 9H - carbazol- 9 - 15 afford the title compound as a white solid ( 0 . 790 g , 95 % ) . ' H yl) cyclohexanol NMR (600 MHz , CDC13 ) 8 7 .70 (1H , dd , J= 8 .4 , 2 .4 Hz ), 7 .66 ( 1H , dd , J = 8 . 4 , 2 . 4 Hz ) , 7 . 47 ( 1H , dd , J = 9 . 0 , 3 . 6 Hz ) , 7 . 36 ( 1H , dd , J = 9 .0 , 3 .6 Hz ), 7 . 21 ( 1H , td , J= 9. 0 , 3 .0 Hz ), A solution of (3aS ,4R ,7aR ) -4 - ( 3, 6 -difluoro - 9H -carbazol 7 . 16 ( 1H , td , J= 9 . 0 , 2 . 4 Hz) , 4 . 31 ( 1H , ddd , J= 13 . 2 , 10 .2 , 3 .6 9 - yl) hexahydrobenzo [ d ] [ 1 , 3 , 2 ]dioxathiole 2 -oxide ( 1 .27 g , 20 Hz ), 4 . 02 ( 1H , t . J = 9 . 0 Hz ) , 2 .74 ( 1H , ddd , J = 12 . 0 , 9 . 0 , 3 . 6 3 .50 mmol) in DMF (8 . 0 ml) was treated with sodium azide Hz ), 2. 37 (1H , qd , J= 13 . 2 , 3 .6 Hz ), 1. 75 - 2. 05 (3H , m ), 1. 55 ( 0 .684 g , 10 .5 mmol) , and heated to 110° C . for 14 h under ( 1H , qt, J = 13 .2 , 3 .6 Hz ), 1. 35 (1H , qd , J= 13. 8, 4 .2 Hz ); microwave irradiation . The mixture was diluted with LCMS m / z 317 . 1459 ( [ M + H + 1 , C , H , F , N , O requires CH _ C12 ( 200 mL ) and this organic layer was washed with 317 . 1460 ) . saturated aqueous NaCl ( 3x100 mL ) , dried (Na2SO4 ) , and 25 concentrated in vacuo . The residue was dissolved in a minimal amount of CH2Cl2 and purified by flash chroma F tography (SiO2 , 0 - 10 % ethyl acetate -hexanes ) to afford the title compound as a beige oil ( 0 . 921 g , 77 % ). ' H NMR (600 MHz , CDC1z ) 8 7 .71 ( 1H , dd , J = 8 . 4 , 2 . 4 Hz) , 7 .67 ( 1H , dd , 30 J = 8 . 4 , 2 . 4 Hz ), 7 .47 ( 1H , dd , J = 9 . 0 , 4 . 2 Hz) , 7 . 38 ( 1H , dd , J = 9 . 0 , 1 . 8 Hz) , 7 . 23 ( 1H , td , J = 8 . 4 , 2 . 4 Hz) , 7 . 18 ( 1H , td , utilo J = 9 .0 , 2 . 4 Hz ), 4 .40 ( 1H , td , J = 10 . 2 , 4 .2 Hz ), 4 .33 ( 1H , t, J = 10 . 2 Hz) , 3 .56 ( 1H , ddd , J= 10 .8 , 9. 0 , 4 .2 Hz ), 2 .40 ( 1H , qd , J= 12 .6 , 3. 6 Hz ) , 2 . 20 - 2 .22 ( 2H , m ), 2 .01 -2 .03 ( 1H , m ), 35 NH2 1 . 95 - 1 . 98 ( 1H , m ) , 1 . 55 - 1 .65 (2H , m ) ; ' ' C NMR ( 150 MHz, CDC12 ) 158 . 1 ( d , J= 54 Hz) , 156 .6 ( d , J = 60 Hz ), 139 .0 , 135 . 6 , 124 . 6 (dd , J = 36 , 18 Hz ), 122 .9 ( dd , J = 36 , 18 Hz ), 114 .6 ( d , J = 102 Hz ) , 114 . 1 ( d , J = 96 Hz) , 112 . 1 ( d , J = 36 Hz) , 10 110 . 1 ( d , J = 36 Hz ), 106 . 8 ( d , J = 90 Hz ) , 106 . 1 ( d , J = 96 Hz) , ullO 74 . 5 , 65 . 8 , 60 . 1 , 30 . 3 , 28 . 5 , 22 . 8 ; LCMS m / z 343 . 1374 ( [M + H + ], C18H16F2N40 requires 343. 1365) .

45 'OCF3 32a

50 N -( (15 ,2S ,3R )- 3 -( 3, 6 -difluoro -9H - carbazol- 9 - yl ) -2 110H hydroxycyclohexyl ) - 4 - ( trifluoromethoxy )benzene sulfonamide 55 A solution of ( 1R , 28 ,6R ) -2 -amino - 6 - (3 ,6 -difluoro - 9H F carbazol- 9- yl ) cyclohexanol (0 . 200 g , 0 .664 mmol) in CH _ C12 ( 2 .0 mL ) was cooled to 0° C ., treated with EtzN ( 97 . 0 uL , 0 .697 mmol) , and 4 - trifluoromethoxybenzenesul fonyl chloride (118 ul , 0 .697 mmol) . The mixture was 60 warmed to 25° C ., and stirred for 2 h . The mixture was partitioned between saturated aqueous NaCl (50 mL ) and sille CH , C1 , ( 100 mL ). The organic layer was washed with saturated aqueous NaCl (3x50 mL ) , dried ( Na2SO4) , and concentrated in vacuo . The residue was dissolved in a NH2 65 minimal amount of CH C12 and purified by flash chroma tography (SiO2 , 0 - 35 % ethyl acetate -hexanes ). The pure fractions were combined , concentrated , and the residue was US 9 ,937 , 186 B2 89 90 dissolved in a minimal amount of ethyl acetate and precipi tated with the addition of hexanes to afford the title com Scheme 7 pound Example 32a as a white solid (0 . 347 g , 97 % ). OH [ a ] = + 4 ( 1 . 0 in CH2Cl2 ) . ' H NMR ( 600 MHz , CDC13 ) d 5 K2CO3 7 . 94 ( 2H , d , J = 8 .4 Hz ), 7. 57 ( 1H , dd, J= 8 .4 , 2 .4 Hz ), 7. 48 DMSO (1H , dd , v= 9. 0 , 4. 2 Hz) , 7. 45 (1H , dd , J = 9. 0 , 2 .4 Hz ), 7 .31 ON F 100° C . , 8 - 15 h (2H , d , J = 9 . 0 Hz ), 7 . 11 ( 1H , td , J = 9 . 0 , 2 . 4 Hz) , 5 . 93 (1H , d , J = 6 . 6 Hz) , 4 . 27 ( 1H , t , J = 9 . 6 , 3 . 0 Hz) , 3 . 98 ( 1H , ddd , J = 13 . 2 , 10 Sn( II ) C12•2H20 10 . 2 , 4 . 2 Hz ) , 3 . 17 - 3 .23 ( 1H , m ) , 3 .03 ( 1H , d , J = 3 . 0 Hz) , Ethyl acetate , RT , 18 h 2 .22 (1H , qd , J= 13 . 2 , 4 .8 Hz ), 1. 80 - 1. 82 (1H , m ), 1. 73 - 1. 77 ( 2H , m ), 1. 41 ( 1H , td , J = 12. 2 , 3 .6 Hz ) , 1 .22 - 1 . 30 ( 1H , m ); 13C NMR ( 150 MHz, CDC12 ) 8 157 . 9 ( d , J = 24 Hz ), 156 . 3 15 ( d , J= 18 Hz ), 152. 3 , 139. 7 , 138 .7 , 135 .4 , 129. 2, 124 .3 (dd , Acetic anhydride J = 36 , 18 Hz) , 122 . 5 (dd , J = 36 , 18 Hz) , 121. 1 , 120 . 4 ( q , RT, overnight J = 1032 Hz ) , 114 . 4 ( d , J = 102 Hz ), 113 . 9 ( d, J = 36 Hz ), 112 .3 84 % yield H2N v F ( d, J= 36 Hz) , 110 . 1 (d , J= 36 Hz ), 106 .4 (d , J = 96 Hz ) , 105 .8 20 ( d , J = 96 Hz) , 72. 4 , 60 . 1 , 59. 1 , 31. 4 , 28 . 3 , 22. 7 ; LCMS m / z ( 75 % yield over two steps ) 541. 1223 ([ M + H + ], C25H2/ F3N204S requires 541 .1215 ) . NHMe *01012 NHMe Example 32b 25

HN -- F K2CO3 Toluene OBn 135° C ., 24 h 0 CH3 84 % yield Base hydrolysis , steps asas aboveabove for example : NaoMe F ------MeOH , reflux

ZI 0 CHZ OH 0 0

NH 2 - fluoro - 10H -phenoxazine - OCF3. 45 32b ? A related copper mediated method has been used to access 3 ,7 Art -difluoro - 10H -phenoxazine as shown in Scheme 8 : Enantiomer as above starting from ( 1R ,28 ,6R ) - 2 - (benzy loxy ) - 7 -oxabicyclo [ 4 . 1 . 0 ]heptane to yield Example 32b , Scheme 8 that is N4( 1R , 2R , 3S ) - 3 - ( 3 ,6 - difluoro - 9H - carbazol - 9 - yl) - 2 50 hydroxycyclohexyl) - 4 -( trifluoromethoxy )benzenesulfona F mide . [ a ] d = - 4 ( 1 . 0 in CH2C12 ) . K2CO3, DMSO Substituted Phenoxazines F Substituted phenoxazines and heterocyclic analogs of the 55 Br phenoxazine system are known and these may be incorpo rated into active compounds disclosed in the present inven O2N tion by methods used for the synthesis of Examples 1 , la and 100° C ., 5 h 1b or variants thereof . The syntheses outlined in I . Thome and Carsten Bolm , Org . Lett. , Vol. 14 . No . 7 , 2012, pages 60 1892 - 1895 provide ready access to several relevant reagents , for example 2 - fluoro - 10H -phenoxazine , 3 - fluoro - 10H - phe Fe noxazine , 2 -( trifluoromethyl) - 10H -phenoxazine and F MOH :H20 (2 : 1 ) 8 - fluoro - 10H -benzo [b ]pyrido [ 2 ,3 -e ] [ 1, 4 ]oxazine . As an 2 h example the literature synthesis of 2 - fluoro - 10H - phenox - 65 ST ya azine with the additional hydrolytic removal of the N - pro ON tecting group is shown in Scheme 7 . US 9 ,937 , 186 B2 91 92 -continued - continued I 17 - 0 . aq NaOH , p -xylene F Formic acid 170 - 200° C . 150° C . , 2 h 14 h 0 H Br H?N 2. 78 g ( crude 70 % , 4 . 96 g scale ) 10 NH 0 . 167 g ( 8 % over 3 steps from A K2CO3, 2 .78 g scale ) Cu (OH ) 2 p -xylene 170 -200°C . Compounds from the present invention may be synthe 2 h sized by methods outlined for Examples 1 , la and 1b , as HN shown in Schemes 9A and 9B using N - 3 - ( 2 - fluoro - 10H 20 phenoxazin - 10 - yl )- 2 -hydroxycyclohexyl ) -4 -( trifluo 0 H romethoxy )benzenesulfonamide and its enantiomers as exemplars .

Scheme 9A

1 . Alkylation with 3 -bromocyclohex - l -ene 2 . Osmium mediated dihydroxylation Z F I- ZULO

1. Cyclic sulfite formation

2 . Azide displacement and reduction to amine

3 . Reaction with aryl sulfonyl chloride , for example 4 (trifluoromethoxy )benzenesulfonyl chloride

UZ

OCF3

resolution by preparative chiral HPLC or SCF or other method US 9 ,937 , 186 B2 93 94 - continued

V F 11111Z F 111ON OH NH OCF3 OCF3. 18 ,2S ,3R absolute stereochemistry 1R , 2R ,3S absolute stereochemistry

Thus 2- fluoro - 10H -phenoxazine is alkylated with a cyclic -continued allylic electrophile such as 3 - bromocyclohex - 1 - ene and the product is cis - dihydroxylated with osmium tetroxide , potas sium osmate or other reagent and an appropriate co -oxidant 20 such as N -methylmorpholine N -oxide in the case of osmium based reagents . This yields racemic 3 - ( 2 - fluoro - 10H -phe noxazin - 10 - yl) cyclohexane - 1 , 2 -diol : this maybe resolved by L ( S) JOH Steps as above preparative chiral HPLC or other method to give single enantiomers and these , or the racemic material, maybe carried forward as described in Example 1. As before , the (R ) OH diol is reacted to form a cyclic sulfite which is displaced with azide and reduced to an amino group which is subsequently reacted with an aryl sulfonyl chloride, in Scheme 9A , , 4 -( trifluoromethoxy )benzenesulfonyl chloride to give the 30 target example , racemic N - 3 - ( 2 - fluoro - 10H -phenoxazin - 10 yl) - 2 -hydroxycyclohexyl ) - 4 - ( trifluoromethoxy )benzenesul fonamide . This maybe resolved into its enantiomers by preparative chiral HPLC or other methods to give the single os enantiomers of the target compound , N - ( ( 1R 2R , 3S ) - 3 - ( 2 35 fluoro - 10H - phenoxazin - 10 - yl) - 2 -hydroxycyclohexyl ) - 4 ( trifluoromethoxy ) benzenesulfonamide and N - ( 18 ,25 , 3R ) 111ON 3 - ( 2 - fluoro - 10H - phenoxazin - 10 -yl ) - 2 - hydroxycyclohexyl) 4 - trifluoromethoxybenzenesulfonamide . Alternatively , Pd mediated asymmetric allylation maybe 40 carried out on relevant substituted phenoxazines , as shown in Scheme 3B with 3 ,7 - difluoro - 10H -phenoxazine as an OCH ; example , to yield single enantiomers without resorting to resolutions. 45 Thus a chiral catalyst is formed from Pd2. dbaz . CHC12 and (S , S ) -DACH -phenyl Trost ligand as described in Example 1 . Scheme 9B This is added to a mixture of 3 , 7 - difluoro - 10H - phenoxazine and tert - butyl cyclohex - 2 - en - 1 - yl carbonate and the reaction 50 is allowed to proceed at room temperature . The product is ( R ) - 10 - ( cyclohex - 2 - en - 1 -yl ) - 3 , 7 - difluoro - 10H - phenoxazine 5 mol % Pd2dba3 , CHCl3 15 mol % (S , S )- DACH which is isolated and cis - dihydroxylated to give ( 1R , 28 , 3R ) phenyl Trost ligand 3 -( 3 , 7 -difluoro - 10H -phenoxazin - 10 -yl ) cyclohexane - 1, 2 DCM , diol. This material is carried forward to the target, N - ( ( 1S , RT, 10 days 2S ,3R ) - 3 - ( 3 , 7 - difluoro - 10H -phenoxazin - 10 - yl) - 2 MOBoc hydroxycyclohexyl) -4 -methoxybenzenesulfonamide as described above . The other enantiomer, N - (( 1R ,2R ,3S )- 3 ( 3 ,7 - difluoro - 10H - phenoxazin - 10 -yl ) - 2 - hydroxycyclo hexyl) - 4 -methoxybenzenesulfonamide , is synthesized using a catalyst formed from ( R , R )- DACH -phenyl Trost ligand . OsO4, NMMO A third route circumventing the cis - dihydroxylation step t -butanol - H , O , RT, 34 h is expoxide opening of 2- (benzyloxy ) -7 -oxabicyclo [ 4 .1 . 0 ] heptane, either enantiomer of which may be accessed from 65 optically pure cyclohex - 2 - en - 1 -ol as described in Example 1 . This route is shown in Scheme 10 using 8 - fluoro - 10H benzo [ b ] pyrido [ 2 , 3 - e ] [ 1 ,4 ] oxazine as an example . US 9 ,937 , 186 B2 95 96 Scheme 10 Example 34

NaNH ZMIT + Toluene 100° C ., 19 h

" Bn OCF3 Example 35

F 10 % Pd / C VF THFMOH: >UMUZ OH 11ONT RT, 15 h 0 0 >DIN *11111 “Ron NH OCF3 Example 36

N F 11ON Steps as above IZ OH " OH 0 0 >Un NH OCF3 N Example 37 TlONT

NH F IZ> OCF3 >iiul Thus the appropriately substituted phenoxazine or het- 50 eroaromatic variant, for example 8 - fluoro - 10H -benzo [ b ] pyrido [ 2 , 3 - e ] [ 1 , 4 ]oxazine in Scheme 4 , is reacted with (1S , OCF3 2R ,6S ) - 2 - (benzyloxy ) - 7 - oxabicyclo [ 4 . 1 . 0 ] heptane under Example 38 basic conditions to yield ( 18 , 2R ,6R ) - 2 - ( benzyloxy ) -6 - ( 8 fluoro - 10H -benzo [b ]pyrido [ 2 ,3 - e ][ 1, 4 ]oxazin - 10 -yl ) cyclo - 55 hexan - 1 - ol. The benzyloxy moiety is cleaved using mild hydrogenolysis or other appropriate deprotection method to yield ( 1R ,28 ,3R ) - 3 - ( 8 - fluoro - 10H -benzo [ b ]pyrido [ 2 , 3 - e ] [ 1 , 4 ]oxazin -10 -yl ) cyclohexane -1 , 2 -diol . This diol is carried TUTTO OH forward to N - (( 18 ,25 , 3R )- 3 -( 8 - fluoro - 10H -benzo [b ]pyrido 60 [ 2, 3 - e ][ 1 ,4 ] oxazin - 10 -yl ) -2 -hydroxycyclohexyl ) - 4 - (trifluo 111111 romethoxy )benzenesulfonamide using the steps shown above . Using the methods described above , or related variants , 65 OCF3 racemic compounds, or either of their enantiomers , shown below may be synthesized . US 9 , 937 , 186 B2 97 98 Heterocyclic Analogs of Carbazoles -continued Heterocyclic analogs of the carbazole system are known and these may be incorporated into active compounds dis closed in the present invention by methods outlined below . 5 Examples of heterocyclic systems include, but are not lim ZI OsO4, NMMO ited to , 9H -pyrimido [ 4 , 5 - b ] indole , 4H - thieno [ 3 , 2 - b ] indole tBuOH — H2O and 9H -pyrido [3 , 4 -b ]indole which may be incorporated into cis -Dihydroxylation examples shown below :

Example 39 SN ? SOC12 , Et3N 11111Z CH2Cl2 ul OH Cyclic sulfite formation 20 OH - OCF3 Example 40 240 25 ZI NaHz DMF Azide displacement

- 1111111 30

35 OCF3 Example 41 PPh3 ZIT THF OH Azide reductionto amine EN 40 uulu 45

ArSO2C1, EtzN ZIT Formation of OCF3 OH sulfonamide 50 Methods to incorporate 9H -pyrimido [ 4 , 5 - b ] indole are " NH2 shown in Schemes 11A and 11B :

55 Scheme 11A

11.

NaH DMF Alkylation Br 65 Steps in Scheme 11A are analogous to those used in Example 1. An alternate synthetic route is shown in Scheme 11B : US 9 ,937 , 186 B2 99 100

Scheme 11B Scheme 12

.Z NaH NaH + toluene toluene Alkylation Alkylation

Bn N TBSOL

Pd (OH )2 1? MeOH Deprotection Bu NF, THF ?? Deprotection NBn2 OTBS 11111Z ArS02C1, EtzN OH Formation of sulfonamide SOCl2 , Et3N CH2Cl2 ?? lic sulfite formation

N

| ??

Ar NaHz 111111Z DMF Azide displacement Steps in Scheme 11B are alkylation of 9H -pyrimido [ 4 , 5 = b ] indole with (19 ,2R ,6R ) N , N - dibenzyl- 7 -oxabicyclo 45 [ 4 . 1 .O ]heptan - 2 - amine, deprotection and reaction with aryl sulfonamide to yield the active compound . As shown in Scheme 1B the epoxide may be optically active and either enantiomer may be accessed for the methods described in Aciro , Caroline ; Davies, Stephen G .; Roberts , Paul M . ; so Russell , Angela J .; Smith , Andrew D . ; Thomson , James E . , PPhz Organic & Biomolecular Chemistry ( 2008 ), 6 ( 20 ) , 3762 3770 and Davies, Stephen G . ; Long , Marcus J . C . ; Smith , OH THF Andrew D ., ChemicalCommunications (Cambridge , United Azide reduction Kingdom ) ( 2005 ) , ( 36 ) , 4536 - 4538 . 9H -pyrido [ 3 , 4 -blindole may be incorporated into N - 2 - 55 hydroxy - 3 - ( 9H - pyrido [ 3 , 4 - b ]indol - 9 - yl) cyclohexyl) - 4 - ( trif luoromethoxy ) benzenesulfonamide , or either of its enantiomers by the methods in Schemes 11A and 11B , or related variants thereof. 4H - thieno [ 3 , 2 - b ] indole may be incorporated into target 60 structures by the methods shown in Scheme 2 . The method is analogous to that used in Example 1 except that a silyl 11111Z ArSO2C1, Et3N ether protecting group is employed in place of a benzyl on OH Aryl sulfonamide formation the epoxide alkylating agent, (( ( 15 ,2R ,6S )- 7 -oxabicyclo [ 4 . 1. 0 ]heptan - 2 -yl ) oxy ) (tert -butyl )dimethylsilane , in the 65 first step . The epoxide may be chiral , as shown , and either enantiomer used . 888888888888 US 9 , 937 , 186 B2 101 102 - continued aspirated from each well and the cells are washed twice with ice -cold PBS, then plates are allowed to dry at room temperature for 4 hours . Cells are fixed for one hour in a fixing solution consisting of 10 % methanol and 10 % glacial 5 acetic acid in distilled water, then stained overnight in 1 % 11111z ( w / v ) crystal violet dissolved in methanol. The next day , staining solution is aspirated from the wells and plates are Ar washed gently with distilled water to remove excess stain before colony counting . Colonies are imaged on a Chemi 10 Doc XRS + (Bio -Rad ) and images are exported as 8 - bit TIFF files. Colonies are counted using the Colony Counter plugin in Image ) , with colony size defined as between 4 and 400 Cell Viability Assays ( IC50 Determination ) square pixels , and minimum circularity set at 0 . 6 . Duplicate Cell viability assays were performed according to Den - wells are averaged to obtain a single value for each condi izot, F . and R . Lang, Journal of Immunological Methods, 15 tion . Results (number of colonies ) for A549 luc cells and 1986 . 89 ( 22 ) : p . 271 - 277 . H1650 lung cancer cells were results ( number of colonies ) for H1650 cells may be ana plated at 150 ,000 cells per well in a 12 well plate . Twenty lyzed separately . G150 for colony formation for selected four hours after plating , cells were treated as described with examples are shown in the table below . increasing concentrations of drug and control. Forty -eight hours after drug treatment, cells were treated with 100 uL of 20 3 -( 4 ,5 -Dimethylthiazol - 2 -yl ) - 2 ,5 - diphenyltetrazolium bro G150 (colony formation ) mide (MTT ) and incubated for 2 hours at 37 C . The MTT solution was subsequently replaced with 300 uL of n - propyl Compound H1650 A549 alcohol and re - aliquoted to a 96 well plate . Spectrophoto Example 3 5 MM 7 . 5 M Example 3a 5 M 7 . 5 MM metric analysis of each solution was performed using a 96 25 Example 3b 7 . 5 M 10 UM well plate reader at 600 nm in triplicate . Results are shown Example 1 5 uM 7 . 5 M in Table 1 : Example la 5 M 7 . 5 UM Example 1b 5 UM 7 . 5 M TABLE 1 30 In Vivo Cancer Model Cell Viability Data To assess the in vivo effects of the compounds, subcuta Example # IC50 (UM ) neous xenograft of lung cancer cell line H441 was gener ated . Cells (5x10 ) were injected into the right flank of 6 - to 20 35 8 - week - old male BALB / c nu /nu mice (Charles River , Wilm 10 ington , Mass . ) . Tumor volumewas assessed twice a week by 15 caliper measurement. Mice were randomized to treatment 20 groups based on initial tumor volume average of 100 mm OvauAWNA per group . Mice were dosed by oral gavage with 15 mg/ kg Example la QD , 15 mg/ kg Example la BID , 50 mg/ kg 25 40 Example la QD , or 50 mg/ kg Example 3a QD . Mouse 20 tumors were measured twice a week for the duration of the study . Mouse body weights were recorded weekly and Colony Formation Assay percentage of mice body weights during treatment was Protocol for clonogenic assay follows Sangodkar et al. , J . calculated as: weight at each time point/ initial weightx100 . Clin Invest 2012 ; 122 :2637 -51 . Animals were observed for signs of toxicity (mucous diar Cell culture and staining : For both A549luc and H1650 rhea , abdominal stiffness and weight loss ) and no adverse cells , 500 cells are seeded into each well of a 6 -well plate signs were observed . Mice underwent treatment for 30 days and allowed to attach for 24 hours before drug treatment and were sacrificed 2 hours after the last dose . Tumors were The following day , cells are treated with either the appro - then excised and cut for both formalin - fixation and snap priate dose of drug or an equivalent volume of DMSO (two frozen in liquid nitrogen . Compounds showed statistically replicates were treated for each condition ) . For each condi significant, dose dependant, inhibition of tumor ( T ) growth tion , depleted media was replaced with fresh media con versus vehicle control ( C ) as shown in the Table A below . No taining the equivalent drug dose four days after initial statistically significant toxicity was observed as judged from treatment. Cells are harvested either 7 (A549 luc ) or 8 animal body weights of compound treated groups versus (H1650 ) days after initial treatment. Briefly , medium is vehicle control group as shown in Table B below . TABLE A Compound ; dose ; Mean Tumor Median Tumor Standard Student ' s frequency Volume( T ) % T/ C Volume( T ) % T / C error t test Vehicle Contol ( C ) 1209 .23100 . 00 1002. 74 100. 00 309. 23 DMA : solutol: water ( 10 : 10 : 80 ) Example la ; 50 mg/ kg ; 441 . 37 36 . 50 338 .69 33. 78 106 . 96 0 .02 QD US 9 ,937 , 186 B2 103 104 TABLE A - continued Compound ; dose ; Mean Tumor Median Tumor Standard Student ' s frequency Volume( T) % T / C Volume( T ) % T / C error t test Example 1a ; 15 mg/ kg ; 742 . 80 61. 43 608 .58 60 .69 196 .79 0 . 15 QD Example 1a; 15 mg/ kg ; 315 . 40 26 .08 274 .43 27 . 37 74 . 24 0 . 01 ExampleBID 3a ; 50 mg /kg ; QD 388. 47 32. 13 377. 21 37. 62 44 .66 0. 01

TABLE B Compound ; dose; Mean body Median body Standard Student 's frequency weight g % T / C weight/ g % T/ C error ttest Vehicle Control( C ) 34. 85 100. 00 35 .60 100 .00 1. 24 DMA : solutol: water ( 10 : 10 :80 ) Example 1a ; 50 mg/ kg ; 35 . 06 100 .59 35 . 50 99 .72 1 . 23 0 .90 QD Example 1a ; 15 mg/kg ; 33 . 20 95 .27 33 . 35 93 .68 1 .55 0 . 35 QD Example 1a ; 15 mg/kg ; 33 . 20 95 . 27 35 .45 99 . 58 1 .65 0. 39 BID Example 3a; 50 mg/ kg ; 32 . 74 93 . 96 33 . 00 92 . 70 1 . 31 0 . 21 QD

30 While typical embodiments have been set forth for the (C2 -C3 ) alkylthio , (C1 - C3) alkyl , (C2 - C3) haloalkyl , (C1 purpose of illustration , the foregoing descriptions and Cz) haloalkoxy , - CC ( = O ) 0 ( C1 -C3 ) alkyl, and ( C , -C3 ) examples should not be deemed to be a limitation on the alkoxy; scope of the invention . Accordingly , various modifications, 26 R and R are chosen independently from H , halogen , adaptations, and alternatives may occur to one skilled in the cyano , nitro , azido , ( C , -CZ ) haloalkyl , (C , - CZ) ha art without departing from the spirit and scope of the present loalkoxyen , nogand (eenC , -C3 ) anderenhaloalkylthio . beiden invention . 2 . A compound according to claim 1 of formula ( II ) : We claim : 1 . A compound of formula ( I ) : 40 RI

R3 UR4 45 HO U + R4 Po OH R2 + T N R2 + T ) ou 50 (CH ) (CH2 ) n 3 . A substantially pure single enantiomer according to claim 2 of formula IIIa or IIIb : wherein : 55 B is selected from the group consisting of: direct bond , IIIa < 0 > , <( CH , O ) , (O CH2) 2 , C ( = OÀN R3 (CH3 ) - and — N (CH3 ) CEO ) — ; A is selected from N and CH ; T is a benzene ring or a five or six membered heteroaro - 60 U + R4 RO matic ring ; Y OH U is a benzene ring or a five or six membered heteroaro -RS matic ring ; n is zero , 1 or 2 ; R2 + T R1, R2, R3 and R * are chosen independently from H , OH , 65 halogen , cyano , nitro , (C1 - C3 ) alkylamino , ( C , - C3 )di (CH2 ) n alkylamino , ( C , -CZ ) acylamino , ( C . -C3 ) alkylsulfonyl, US 9 ,937 , 186 B2 105 106 -continued 105 - continued continued IIIb Example † No. Structure UR4 5 la OH III R2 + 11lllZ COM 10 OH

( CH2) n1 4 . A compound according to claim 1 wherein n is one . 5 . A compound according to claim 1 wherein n is zero . 15 6 . A compound according to claim 1 , wherein B is a direct OCF3 bond . 7 . A compound according to claim 1 , wherein B is O — . 1b16 8 . A compound according to claim 1, wherein B is - (CH20 ) or ( 0 CH ) . 20 9 . A compound according to claim 1 , wherein B is C ( = O ) N (CH3 ) or - N (CH3 ) CEO) — . . 10 . A compound according to claim 1 , wherein A is N . till 11 . A compound according to claim 1 , wherein Ais — CH . 25 12 . A compound according to claim 1 , wherein T and U are both benzene rings. 13. A compound according to claim 1 , wherein one of T and U is a benzene ring , and the other of T and U is selected COCF3 from pyridine, pyrimidine , and thiophene . 14 . A compound according to claim 1 ,wherein R2 and R4 302 are H , and R ' and Rare chosen independently from H , OH , F , C1, Br, CN , CO2CH3, CH3, CF3, OCF3, and OCHZ. 15 . A compound according to claim 1 , wherein R5 is H , and R is chosen from H , F , C1, CFz , OCF2 , SCF , N , and 35 INIZ OH CN . 16 . A compound according to claim 15 wherein Ro is in the para position . MIN 17 . A method for treating a disease in a patient chosen from : 40 breast cancer, prostate cancer, leukemia , lung cancer , and OCF3 glioblastoma; 3 the method comprising administering to the patient a thera peutically effective amount of a compound according to claim 1 . 45 18 . A pharmaceutical composition comprising a pharma ceutically acceptable carrier and a compound according to LIITE ?? claim 1 . 19 . A compound according to claim 1 selected from : 50 N Example No . Structure SOCF3 55 3a3a

III ZIT OH l10 NH OCF3 65 OCF3 US 9 ,937 , 186 B2 107 108 -continued -continued Example Example No . Structure No . Structure

3b Me

.111110N o >ITUZ

Mill OCF3 ' OCF3

HITZ ??

11111 NH

>HTML

111111 TIIMIZ 0 0

10 CN 40

IIIIIIII OH 45

UZ OH 0 0

50 OCF3

OMe

12 55 12

ZIMIT OH OH MZ 0 0 111111 NH OCF3 US 9 ,937 , 186 B2 109 110 - continued - continued Example Example ExampleNo. Structure No . Structure 13 5 18

ITTITIZ OH TITIZ OH

>IIIIIN tilllyEZ OCF , CHCF3 14 |2223 19 UTILITZ ????IIIIITZ OH N

OCF3 CFCF3

15 303 ) 20)

IIIIIIIT IllulZ 10 ? -| 0 0 MAY OCF, 40 NOCHE, 16 | 21

? IIIIII IIIIUIZ OH - iiiiii • illnN SCF OCF1 22 55 C1

|1Z R IlllllZ 60) littlu

OCF365 0CF3 US 9 ,937 , 186 B2 111 112 - continued - continued Example Example No. Structure No . Structure 5 23 28 CN

10 > ZI11 OH IZ

IZ N 15 OCF3 24 Br Br 29 CO2Me

20

ZITTO ?? ZIMI

> 25 NH OCF3 'OCF3

25 Br 30 30 QaBr 30 30

ZIMIT ILLZ OH O >111111 N ci 40 OCF3 2626 NC . 31a

TITIZ OLT stillo O 0 O NH NH SOCF3 OCF3

27 Br 5555 31b316

ZI ZIIIIII OH su 11111 NH NH OCF3 65 OCF3 US 9 ,937 , 186 B2 113 114 - continued - continued Example Example ExampleNo . Structure No . Structure 32a F

10 UZ OH >ilili NH 15 OCF3 OCF3 32b326 F 3838 F .

20 ZI | OH

N 25 OCF3 OCF3 39 34 30 39

' N

35 >111011 NH OCFz 40 OCF3 35 40

45

OH HOH

IZ IZ 50 'OCF3 OCF3 41 36 41 55

CF3CF3 NOT ON 3

COCF3. OCF3 65 * * * * *