US 20200079745A1 INI (19 ) United States (12 ) Patent Application Publication ( 10) Pub . No .: US 2020/0079745 A1 Kruegel et al. (43 ) Pub . Date : Mar. 12 , 2020

(54 ) CARBOXYLIC DIARYTHIAZEPINEAMINES Publication Classification AS MIXED MU - AND DELTA -OPIOID (51 ) Int. Ci. RECEPTOR AGONISTS C07D 281/02 ( 2006.01 ) (71 ) Applicants :Andrew Kruegel, New York , NY (US ) ; (52 ) U.S. CI. Dalibor Sames , New York , NY (US ); CPC CO7D 281/02 (2013.01 ); A61K 45/06 Jonathan A. Javitch , Dobbs Ferry, NY (2013.01 ) (US ) (57 ) ABSTRACT ( 72 ) Inventors : Andrew Kruegel , New York , NY (US ) ; The present invention provides a compound having the Dalibor Sames , New York , NY (US ); structure : Jonathan A. Javitch , Dobbs Ferry , NY (US ) Rg Ri (73 ) Assignee : The Trustees of Columbia University in the City of New York , New York , Ro R4 NY (US ) -R5, (21 ) Appl. No .: 16 /493,992 R10 ( 22) PCT Filed : Mar. 15 , 2018 R11 N R2 R7 Ro ( 86 ) PCT No .: PCT/ US2018 /022650 R3 $ 371 ( c ) ( 1 ) , or a pharmaceutically acceptable salt or ester thereof , and a (2 ) Date : Sep. 13 , 2019 method of treating a subject afflicted with a pain , a depres sive disorder , a mood disorder, an anxiety disorder , border Related U.S. Application Data line personality disorder, opioid addiction , or opioid with (60 ) Provisional application No.62 /471,745 , filed on Mar. drawal symptoms by administering the compound to the 15 , 2017 subject . hDOR + GOB - Luc + B1 + y2 - Venus 150 DPDPE

100

GProteinActivation(%) Www Wewe

os des . 9c IT Most 12 DI -50 Log (drug ] (M ) Patent Application Publication Mar. 12 , 2020 Sheet 1 of 2 US 2020/0079745 A1

Fig . 1

hDOR + GOB -Luc + B1 + y2 - Venus 150 DPDPE

GProteinActivation(%) 50 9c

.L DI 3 -2 HH Log ( drug ] ( M ) 50 Patent Application Publication Mar. 12 , 2020 Sheet 2 of 2 US 2020/0079745 A1

Fig . 2

30 TW

25-1 Tianeptine (15 min ) ED50 = 15 mg/ kg Latency(s) 9b ( 15 min ) 20 ED50 = 5.1 mg/ kg 9k ( 15 min ) ED50 1.7 mg/ kg 15

10

0.1 1 10 Baseline Drug (mg /kg ) US 2020/0079745 A1 Mar. 12 , 2020 1

CARBOXYLIC DIARYTHIAZEPINEAMINES [0006 ] Long -acting prescription opioidsmay also be used AS MIXED MU - AND DELTA -OPIOID as maintenance ( replacement ) therapies in the treatment of RECEPTOR AGONISTS opioid addiction . In this case , a prescription opioid is provided to the patient chronically and under medical super [ 0001 ] This application claims priority of U.S. Provisional vision to substitute for the use of illicit opioids (e.g. heroin ), Application No. 62/ 471,745 , filed Mar. 15 , 2017 , the con thus reducing cravings for , and abuse of, the illicit drug . tents of each of which are hereby incorporated by reference. Opioid maintenance therapy is considered a standard [ 0002 ] Throughout this application , certain publications method of care for opioid addiction and is more successful are referenced in parentheses. Full citations for these pub than behavioral or antagonist interventions (Bart , G. 2012 ) . lications may be found immediately preceding the claims. The disclosures of these publications in their entireties are SUMMARY OF THE INVENTION hereby incorporated by reference into this application in order to describe more fully the state of the art to which this [0007 ] The present invention provides a compound having invention relates . the structure :

BACKGROUND OF THE INVENTION Rg [0003 ] The mu opioid receptor (MOR ) has been the major molecular target for treatment of pain for several decades . R9 R4 However, the vast majority of MOR agonists used clinically today are structurally related to or derived from morphine -R5, ( and other poppy alkaloids ). These compounds suffer from R10 many serious problems, including development of tolerance Ril ( increased dosing is required to achieve the same analgesic R7 Ro effects ) , high addiction liability , and other side effects (e.g. R? R3 respiratory depression , nausea , and constipation ) (Williams , J. T. et al. 2013) . Therefore , there is a continuing interest in the development of new pain medications , including new [0008 ] wherein MOR agonists with improved therapeutic profile ( Corbett , [0009 ] Riis1 -H or - (alkyl ) ; A. D. et al. 2006 ) . [0010 ] R2 is (Cz - C20 alkyl) -CO2H or — (C3 -C20 alkyl) [ 0004 ] There is also both historical and growing interest in CO2- alkyl) ; the use of MOR agonists as medicaments for depression . [0011 ] R , is - H or -alkyl) ; Prior to the adoption of tricyclic antidepressants and elec [ 0012 ] R4 , R5, R. and R , are each independently —H , troshock therapy as favored treatments for depression , opi Ci, —Br, -F , -1, CN , CF3, — OCF3, - (alkyl ) , oids were among the only options available , with the “ opium -( alkenyl) , -( alkynyl ), -( aryl ) , -NH2, -NH-( alkyl) , -NH cure " being an accepted treatment modality in the early 20th (alkenyl ) , -NH-( alkynyl) -NH - Caryl) , -NH-(heteroaryl ) , century (Berrocoso , E. et al. 2009 ) . More recently , studies in OH , OAc , O C ( O ) ( alkyl) , O - alkyl) , O - alky both rodents (Besson , A. et al. 1996 ) and humans (Bodkin , laryl) , O-( alkenyl) , O-( alkynyl ), O -Caryl ) , O-( het J. A. et al. 1995 ) have suggested that MOR activation may eroaryl) , S-( alkyl ), —S- (alkenyl ) , —S-( alkynyl ) , S lead to antidepressant and / or anxiolytic effects . The antide ( aryl ), S-( heteroaryl ) , -SS ( O )- ( alkyl )) , S ( O )-aryl ) , pressant tianeptine has also been reported to act as a full S ( O ) - (heteroaryl ) , SO2- (alkyl ), -SO2- (aryl ) , or agonist of the MOR (Gassaway , M.M. et al. 2014 ). On the -SO-(heteroaryl ) ; molecular level , MORs are extensively expressed in the hippocampus and have been shown to exert a variety of [0013 ] Ry, Ry, Rio and Rui are each independently —H , indirectmodulatory effects on glutamatergic neurons in this C1, —Br, —F, —I, CN , CF39 OCF3, - ( alkyl) , brain region ( Xie , C. W. et al . 1997 ; Svoboda, K. R. et al. -aryl ), -( heteroaryl) - (alkenyl ) , - (alkynyl ), -NH2, -NH 1999 ) . Normalization and modulation of glutamate signaling ( alkyl) , NH-( alkenyl) , -NH-( alkynyl ) -NH -Caryl ) , has been strongly associated with the actions of antidepres NH-( heteroaryl ) , OH , -OA , 0_C (O )( alkyl ) , sants (Paul , I. A. and Skolnick , P. 2003 ) and indeed , the O - alkyl) , O-( alkenyl ) , O-( alkynyl ) , O - aryl ), NMDA receptor antagonist ketamine , shows rapid and effi O-( heteroaryl ) , S - alkyl) , -S- alkenyl) , -S - alkynyl) , cacious antidepressant activity in human clinical trials S - aryl) , S-( heteroaryl ) , -S ( O ) - (alkyl ) , -S ( O ) - (aryl ) , ( Zarate , C. A. Jr et al. 2006 ) . Further , agonists of the related S ( O )- (heteroaryl ) , SO2- ( alkyl) , -SO2- ( aryl) , or delta opioid receptor ( DOR ) have been demonstrated to SOZ- (heteroaryl ) ; show robust antidepressant efficacy in animals ( Jutkiewicz , [0014 ] wherein when R , is (C3-6 alkyl) -CO H , then E. M. 2006 ). one of Rs or Ro is - ( alkynyl) or S-( alkyl ) , or R , and [0005 ] Opioid receptor dysfunction may also be associ Ro are each independently — Cl, —Br, —F, or —I, ated with borderline personality disorder (BPD ). Patients [0015 ] wherein when R , is – (C3-6 alkyl) -CO2- (alkyl ), afflicted with BPD exhibit alterations in both basal MOR then one of R , or Rois - ( alkynyl ) , or R , and Roare each binding potential and endogenous opioid responses to nega independently C1, -Br, —F, or —I, tive stimuli (Prossin , A. R. et al. 2010 ) . There is also a high 10016 ] wherein when R , is CH , Rz, R4 , R., Rz, Rg, prevalence of BPD among patients seeking buprenorphine R9, R10 and Ru1 are each H , and R , is Cl, then R2 is treatment for opioid addiction (Sansone , R. A. et al . 2008 ) . other than ( CH2) , CO H , ( CH2) 1.CO2H , CH Accordingly , MOR modulators may be useful medicaments (CH ) ( CH2) CO , H or ( CH2) 2CH (CH3 ) ( CH2) for BPD . 3CO2H , and US 2020/0079745 A1 Mar. 12 , 2020 2

[0017 ] wherein when R , is CH3, R3 , R4, R6 R7, R8, R9, other than ( CH ) CO2H , (CH2 ) 1.CO H , CH R10 and Rui are each -H , and R , is SCH3, then R2 is other (CH ) (CH ) COZH or - ( CH2) 2CH (CH3 ) (CH2 ) than ( CH2) .CO , H , 3CO , H , and [ 0018 ] or a pharmaceutically acceptable salt or ester [0031 ] wherein when R , is CH3, R3, R4, R6, R7, Rg, thereof . R9, R10 and R11 are each — H , and R , is SCHz, then R2 is other than (CH ).CO , H , BRIEF DESCRIPTION OF THE FIGURES [0032 ] or a pharmaceutically acceptable salt or ester [ 0019 ] FIG . 1 : Compound 9c activates DOR to a lesser thereof. Emax than the control agonist DPDPE . [0033 ] In some embodiments , a compound having the [0020 ] FIG . 2 : Dose- response curves of analgesic activity structure : of tianeptine, 9b and 9k in the hot plate assay. DETAILED DESCRIPTION OF THE Rg R1 INVENTION R9 R4 [0021 ] The present invention provides a compound having the structure : R5, Rió Rg Ri R11 R2 R Ro Ro Lo R4 R3

.R5, [ 0034 ] wherein Rio (0035 ] Ri is -H or - ( alkyl) ; Ru1 [0036 ] R2 is (Co - C20 alkyl) -CO H or (Co - C20 R7 R6 R R3 alkyl) -C02- (alkyl ) ; [0037 ] Rz is -H or - ( alkyl) ; [0038 ] R4, R5, R. and R , are each independently —H , [0022 ] wherein C1, —Br, —F, — I , -CN , –CF3, -OCF3, - (alkyl ) , [0023 ] R1 is H or - ( alkyl) ; - (alkenyl ) , -( alkynyl ) , -( aryl ) , —NH2, —NH - alkyl) , [0024 ] R2 is – (Cz - C20 alkyl) -CO , H or —Cz- C20 NH-( alkenyl) , -NH-( alkynyl) -NH - Caryl) , -NH alkyl) -CO2-( alkyl ) ; ( heteroaryl) , OH , OA , O C ( O ) (alkyl ) , O [0025 ] Rz is –H or - (alkyl ) ; ( alkyl) , O - alkylaryl) , O - alkenyl) , O - alkynyl) , [0026 ] R4, R5, R. and R , are each independently —H , O-( aryl ) , O-( heteroaryl ) , S-( alkyl ) , S-( alk Cl, Br, -F, -I, - CN , CF3, OCF3, - ( alkyl) , enyl) . -S-( alkynyl ) , S -Caryl aryl) , S-( heteroaryl ) , - ( alkenyl) , -alkynyl) , -aryl) , -NH2, -NH - alkyl) , S ( O )-alkyl ) , -S ( O )-aryl ) , -S( O ) - (heteroaryl ) , NH-( alkenyl ), NH - alkynyl) -NH -Caryl ) , -NH SO2- ( alkyl) , SO2- (aryl ) , or -SO2- (heteroaryl ) ; (heteroaryl ) , —OHOH , —OAcOAc, OC( O )( alkyl ) , O [0039 ] Rg, R9 , R1o and R11 are each independently - H , ( alkyl ), O - alkylaryl) , O - alkenyl) , O - alkynyl ), CI, -Br, —F, —1, CN , CF3, OCF3, -alkyl) , O-( aryl ) , O-( heteroaryl ) , S-( alkyl) , S-( alk -( aryl ) , -( heteroaryl ) -( alkenyl ) , -( alkynyl ), NH2, enyl) , S - alkynyl) , S - aryl) , S-( heteroaryl ) , -NH-( alkyl ) , NH-( alkenyl) , -NH - alkynyl) S ( O ) - ( alkyl) , S ( O ) - ( aryl) , -S ( O ) - (heteroaryl ) , -NH-( aryl) , -NH-( heteroaryl ) , OH , OAc, SO2- ( alkyl ) , SO2- ( aryl) , or SO2- ( heteroaryl) ; 0 - C ( O ) (alkyl ), O - alkyl) , -O-( alkenyl ) , O [ 0027 ] R8, R9, R10 and R11 are each independently —H , (alkynyl ) , O - Caryl) , O-( heteroaryl ) , S-( alkyl ) , Cl, Br, —F, —I, CN , CF3, OCF3, - (alkyl ) , -S-( alkenyl ) , S-( alkynyl) , S - Caryl) , S- (het -aryl) , -( heteroaryl ) -( alkenyl ) , -alkynyl) , NH , eroaryl) , -S ( O ) - ( alkyl) , -S ( O ) - ( aryl) , S ( O ) - ( het -NH - alkyl) , -NH-( alkenyl ) , -NH - alkynyl) eroaryl) , -S02- alkyl) , SO2 - aryl) , or -SO2- het -NH - Caryl) , NH-( heteroaryl ) , -??, OAc , 0 C (O ) (alkyl ) , O - alkyl) , O-( alkenyl ) , 0 eroaryl) ; ( alkynyl) , O-( aryl ) , O-( heteroaryl ) , S-( alkyl ) , [ 0040 ] wherein when R2 is – (C6 alkyl) -CO2H , then S-( alkenyl) , S-( alkynyl) , S - aryl) , S - het one of R , or Ro is - (alkynyl ) or S - alkyl) , or R , and eroaryl) , -S( O )-alkyl ) , -S ( O ) -aryl) , -S( O ) - (het R , are each independently Cl, Br, -F , or -I , eroaryl) , SO2- (alkyl ) , _Soz- Caryl ), or SO2- het [0041 ] wherein when R , is CH3, R3 , R4 , R6 , R7 , Rg , eroaryl) ; R9, R10 and Rui are each -H , and R , is Cl, then R2 is [ 0028 ] wherein when R , is – (C3-6 alkyl ) -CO , H , then other than (CH2 ) ,CO2H , (CH2 ) 1.CO H , CH one of Rs or Rois - (alkynyl ) or S - alkyl) , or Rs and (CH3 ) (CH2 ) , CO2H or ( CH2) 2CH (CH3 ) ( CH2) Ro are each independently Cl, Br, -F, or —I, 2CO , H , and [ 0029 ] wherein when R2 is ( C3-6 alkyl )-C02- ( alkyl) , [0042 ] wherein when R , is CH3, R3 , R4, R6 , R7, Rg , then one of R , or R is -( alkynyl ) , or R , and R. are each R9, R10 and R11 are each - H , and R , is SCHz, then R , independently —C1, -Br, -F , or -I, and is other than (CH ).CO , H , (0030 ) wherein when R , is CH3, R3, R4, R6, R7, Rg, [ 0043 ] or a pharmaceutically acceptable salt or ester R9, R10 and R11 are each H , and R , is C1, then R , is thereof. US 2020/0079745 A1 Mar. 12 , 2020 3

[0044 ] In some embodiments , a compound having the [0061 ] In some embodiments , the compound having the structure : structure :

R8 Ri Rg Ri R. Lo R4 R $ R4

R5, -R5 R10 Rio Ru Rii R7 R6 R7 Ro Ra R3 R R3 [ 0062] wherein [0045 ] wherein [ 0063] Ri isH or - ( alkyl) ; [0046 ] R ,1 is H or - ( alkyl) ; [0064 ] R , is – (C7 - C20 alkyl) -CO ,H or —C7- C20 [0047 ] R2 is (Co - C20 alkyl )-CO2H or (Co -C20 alkyl) -C02- ( alkyl ) ; alkyl) -C02 - alkyl) ; [0065 ] Rz is H or -( alkyl ) ; [0048 ] Rz is H or -( alkyl ) ; [ 0066 ] R4, R5, Ro and R , are each independently —H , CI, -Br, -F, -I , CN , CF3, OCF3, - (alkyl ) , [0049 ] R4, R3, R. and R , are each independently —H , - ( alkenyl ) , - ( alkynyl) , - ( aryl ) , -NH2 -NH-( alkyl) , C1, -Br, F , I , CN , CF3 , OCF3, - ( alkyl) , -NH - alkenyl) , NH - alkynyl) -NH - aryl) , -NH - ( alkenyl) , - ( alkynyl) , - ( aryl) , -NH2, -NH - alkyl) , (heteroaryl ), OH , OAc, O C (O ) (alkyl ) , O NH - alkenyl) , NH - alkynyl ) -NH - Caryl ), -NH ( alkyl) , -O-( alkylaryl ) , -O-( alkenyl ) , O - alkynyl) , (heteroaryl ) , OH , OAc , O C (O )( alkyl ) , 0 O-( aryl ) , O-( heteroaryl) , S-( alkyl) , S-( alk (alkyl ), O - alkylaryl) , O - alkenyl) , O - alkynyl ), enyl ) , -S-( alkynyl) , S -Caryl ) , S-( heteroaryl) , -O - aryl) , O-( heteroaryl heteroaryl ) , S-( alkyl ) , S-( alk S ( O ) -( alkyl) , -S (O )- ( aryl) , -S ( O )- ( heteroaryl ) , enyl ) , S-( alkynyl ) , S - aryl) , S-( heteroaryl ) , SO2- (alkyl ) , SO2- (aryl ) , or SO2- (heteroaryl ) ; S ( O )- (alkyl ) , -S( O ) - ( aryl) , -S ( O ) - (heteroaryl ) , [0067 ] R8, R9, R10 and Ru are each independently - H , SO2- ( alkyl ) , SO2- ( aryl) , or SO2- (heteroaryl ) ; Ci, Br, -F, -I, CN , CF3, OCF3, - ( alkyl) , [0050 ] Rg, R9, R10 and Rui are each independently —H , -Caryl) , - (heteroaryl ) -alkenyl) , -( alkynyl) , -NH2, NH - alkyl) , -NH - alkenyl) , -NH-( alkynyl ) Cl, Br, F , I , CN , CF3, OCF3, - ( alkyl) , -NH -Caryl ) , -NH-( heteroaryl ) , OH , OA , -Caryl ), -( heteroaryl ) -( alkenyl) , -( alkynyl) , -NH2, 0_C (O ) (alkyl ) , O-( alkyl ) , O-( alkenyl ) , O -NH - alkyl) , -NH - alkenyl) , -NH - alkynyl) (alkynyl ) , O-( aryl ) , O-( heteroaryl ) , S-( alkyl ) , -NH - aryl ) , NH-( heteroaryl ) , OH , OA , S-( alkenyl ) , S-( alkynyl ) , S-( aryl) , S-( het 0 C ( O ) (alkyl ) , O-( alkyl ) , O-( alkenyl) , O eroaryl) , -S ( O )- ( alkyl) , S (O )- ( aryl ) , S ( O )- ( het ( alkynyl ), O - aryl) , O-( heteroaryl ) , S - alkyl) , eroaryl ) , SO2- (alkyl ) , SO2- ( aryl) , or SO - het S-( alkenyl) , S - alkynyl) , S - Caryl) , S-( het eroaryl) ; eroaryl) , -S( O ) - (alkyl ) , -S ( O )-aryl ) , S ( O ) -chet [0068 ] wherein when R , is - CH3, R3, R4, R6, R7, Rg, eroaryl ), SO2- alkyl) , SO2- aryl ), or -SO2- (het R9, R10 and Ru1 are each H , and R , is C1, then R2 is eroaryl) ; other than (CH2 ) CO , H , (CH2 ) .CO , H , CH [ 0051 ] wherein when R , is – (C6 alkyl) -CO , H , then (CH3 ) (CH ) CO2H or (CH2 ) 2CH (CH3 ) (CH2 ) one of R , or Rois -( alkynyl) or S - alkyl) , or R , and 2CO H , and Ro are each independently Cl, Br, F , or —I, [0069 ] or a pharmaceutically acceptable salt or ester thereof . [0052 ] wherein when R2 is (C. alkyl ) -CO2- ( alkyl) , [0070 ] In some embodiments , the compound wherein then one of Rs or Rg is - (alkynyl ) , or Rs and Ro are each [0071 ] R2 is (Co - C20 alkyl) -CO2H or (C8 - C20 independently —C1, Br, -F , or -1, and alkyl )-C02 - alkyl) [ 0053 ] wherein when R , is CH3, R3, R4 , R6, R7, Rg , [0072 ] In some embodiments , the compound wherein R9, R10 and Ru1 are each H , and R , is C1, then R2 is [ 0073 ] R2 is – (C2 - C20 alkyl) -CO2H or — (C2 -C20 other than (CH2 ) , CO2H or — ( CH2) 1.CO2H , alkyl ) -CO2- ( alkyl) [0054 ] or a pharmaceutically acceptable salt or ester [0074 ] In some embodiments , the compound wherein thereof. [0075 ] R2 is (C8 -C20 alkyl) -CO2H or (C8 -C20 alkyl) -CO CHz. [ 0055 ] In some embodiments , the compound wherein [0076 ] In some embodiments , the compound wherein [0056 ] R2 is (Co alkyl) -CO , H ) ; and [0077 ] R2 is – (C2 - C30 alkyl) -CO2H or (C2 -C20 [0057 ] one of R , or R is - ( alkynyl) or S - alkyl) and alkyl) -CO_CH_CHz. the other is H , or R , and R. are each independently [0078 ] In some embodiments , the compound wherein C1, —Br, -F , or —I. [0079 ] R? is Br , -F , -1, CN , CF3, OCF3 , -alkyl) , -( alkenyl ) , -alkynyl) , -aryl) , -NH ,, -NH [0058 ] In some embodiments , the compound wherein (alkyl ) , -NH-( alkenyl) , -NH - alkynyl ) -NH - Caryl) , [0059 ] R , is (C. alkyl) -CO2 - alkyl) ; and NH-( heteroaryl ) , OH , OAC , 0 C ( O ) (alkyl ) , [0060 ] one of R , or Ro is - (alkynyl ) and the other is 0 - alkyl) . O - alkylaryl) , O-( alkenyl ) , O H , or R , and Ro are each independently Cl, Br, (alkynyl ) , O-( aryl ) , O-( heteroaryl ) , S - alkyl) , -F, or -1. S-( alkenyl ) , S-(( alkynyl alkynyl ), S - Caryl) , S-( het US 2020/0079745 A1 Mar. 12 , 2020 4

eroaryl ), -S( O ) - ( alkyl) , S (O )-aryl ), -S ( O )- ( het -continued eroaryl) , SO2- ( alkyl) , SO2- ( aryl) , or - S02- het RS Ri eroaryl) Ro R4 [ 0080 ] In some embodiments , the compound wherein [0081 ] R , is —Br, -I, - (alkenyl ) , - (alkynyl ) or —S (alkyl ) . Rio [0082 ] In some embodiments, the compound wherein R11 R7 RO [0083 ] R? is -Br, -I, - (C2 alkenyl ), (C2 alkynyl ) Ra R3 or or S CHz. Rg Ri [ 0084 ] In some embodiments , the compound wherein R9 R4 [0085 ] one of Rs orRis -alkynyl) . [0086 ] In some embodiments , the compound wherein Rió SMe, [0087 ] one of R , or Ro is -S-( alkyl) RU N Ro [0088 ] In some embodiments , the compound wherein Rz R3 R7 [ 0089 ] Rs and R , are each independently —C1, -Br, -F , or -1. [0090 ] In some embodiments , the compound wherein [ 0097] wherein [0091 ] R , and R. are each independently - Br, F , or [ 0098 ] R , is H or - ( alkyl) ; [0099 ] R2 is – (C7 - C20 alkyl) -CO H or — (C7 - C20 -1. alkyl) -CO2 - alkyl) ; [ 0092 ] In some embodiments , the compound wherein [0100 ] Rz is -H or - (alkyl ); [ 0093 ] R , and R. are each independently —Br, Cl, or -1. [0101 ] R4, R6 and R , are each independently - H , C1, BI. F , I, CN , CF3, OCF3 , - (alkyl ) , - (alk [0094 ] In some embodiments , the compound wherein enyl) , -( alkynyl ) , -( aryl ) , -NH2, -NH-( alkyl ) , -NH (alkenyl ) , —NH-( alkynyl ) -NH-( aryl ), –NH- het [0095 ] R , and R. are each independently - Br or —I. eroaryl) , OH , OA , 0 C (O )( alkyl ) , 0 [ 0096 ] In some embodiments , the compound having the (alkyl ) , O - alkylaryl ), O-( alkenyl ), O - alkynyl) , structure O-( aryl ) , O-( heteroaryl ) , S-( alkyl) , S-( alk enyl) , S-( alkynyl ) , S-S - ( aryl ) , S-( heteroaryl ) , S ( O ) - ( alkyl) , S ( O ) - ( aryl) , -S( O ) -( heteroaryl ) , R $ Ri SO2- ( alkyl) , SO2- (aryl ) , or SO2- (heteroaryl ) ; . Rg, R9, R10 and Ru1 are each independently - H , C1, R. R4 -Br, F , -1, CN , CF3, OCF3, - (alkyl ) , -aryl) , - (heteroaryl ) -( alkenyl ) , -alkynyl) , NH , Br, -NH - alkyl) , -NH-( alkenyl) , -NH - alkynyl) Rio -NH -Caryl ) , -NH-( heteroaryl ) , OH , OAc , Ru1 0 C ( O ) (alkyl ) , 0-( alkyl ) , O-( alkenyl ) , 0 R6 (alkynyl ) , O-( aryl ) , O- (heteroaryl ) , S-( alkyl ) , R? R7 S- ( alkenyl) , S- ( alkynyl) , S - Caryl ) , S-( het Rg eroaryl) , -S( O )-alkyl ) , -S ( O ) -Caryl) , -S ( O ) - (het O eroaryl) , —S02- ( alkyl) , -SO2- (aryl ) , or —S02- ( het RO R4 eroaryl) . [0102 ] In some embodiments , the compound having the Rio I, structure R11 R7 Ro Rz R3 Rg Ri Rg R1 Ro . RA RO RA Rio Br Rio Ru Ru N R R3 R7 R7 Ro R? R3 US 2020/0079745 A1 Mar. 12 , 2020 5

[0103 ] wherein -continued [0104 ] R 1 is –H or -( alkyl ) ; [0105 ] R2 is – (C7 - C20 alkyl) -CO2H or (C2 - C20 // alkyl) -C02- alkyl) ; [0106 ] Rz is H or -( alkyl ) ; [0107 ] R4 and R , are each independently -H , CI, Br, -F, -1, -CN , CF3, OCF3, -( alkyl ) , -( alk enyl) , -( alkynyl ) , -( aryl ) , -NH2, -NH - alkyl) , -NH (alkenyl ) , -NH-( alkynyl ) -NH - Caryl) , -NH - het NH eroaryl) , OH , OAc , 0 C ( O ) (alkyl ), O R2 or (alkyl ) , -O-( alkylaryl ) , -O-( alkenyl) , -O-( alkynyl) , O-( aryl ) , O-( heteroaryl ), S - alkyl) , S - alk enyl ) , S- (alkynyl ) , S -Caryl ) , S-( heteroaryl ) , -S (O ) -( alkyl ) , S ( O ) - ( aryl) , S ( O ) - ( heteroaryl) , SO2- ( alkyl) , SO2- (aryl ) , or — SO2- (heteroaryl ) ; Br, [0108 ] R8, R9, R10 and Ru1 are each independently —H , Cl, Br, -F, -I, -CN , CF3, OCF3, - ( alkyl) , NH -( aryl ) , - (heteroaryl ) - ( alkenyl ) , - ( alkynyl) , —NH2, F -NH - alkyl) , -NH - alkenyl) , -NH - alkynyl) R? -NH - Caryl) , NH-( heteroaryl ) , OH , OAc , O C ( O ) (alkyl ) , O - alkylalkyl)) , O - alkenyl) , _O (alkynyl ) , O - aryl) , O-( heteroaryl ) , S - alkyl) , [ 0110 ] wherein S-( alkenyl ) , S-( alkynyl ) , S - aryl) , S - het [0111 ] R2 is (C7 - C20 alkyl )-CO H or — (C7 -C20 eroaryl) , -S ( O ) - ( alkyl) , S ( O )- ( aryl) , -S (O ) -( het alkyl) -CO2 - alkyl) , eroaryl) , SO2- alkyl) , SOZ- aryl) , or SO ,-het [0112 ] or a pharmaceutically acceptable salt or ester eroaryl) . thereof. [ 0109 ] In some embodiments , the compound having the [0113 ] In some embodiments , the compound having the structure structure

NH NH R2 R

NH NH

Rz 2 Rz

www

-SCH3, -SCH3,

NH NH R R2

O

Br, Br,

NH NH R2 R? US 2020/0079745 A1 Mar. 12 , 2020 6

-continued -continued //

NH NH R2 or Rz or

Br,

NH F. Rz Br,

[0114 ] wherein NH [0115 ] R2 is (Co - C20 alkyl) -CO2H or (C8 -C20 alkyl) -C02 - alkyl) , R2 [0116 ] or a pharmaceutically acceptable salt or ester thereof. [ 0117 ] In some embodiments , the compound having the structure [ 0118 ] wherein [0119 ] R2 is ( C , -C20 alkyl) -CO H or - ( C , -C20 alkyl) -CO2- ( alkyl) , [0120 ] or a pharmaceutically acceptable salt or ester thereof. [ 0121 ] In some embodiments , the compound having the structure NH R Ri

-R5,

N NH R6 R R R3

[0122 ] wherein [0123 ] R , is H or - (alkyl ) ; -SCH3, (0124 ] R2 is – (C7 -C20 alkyl) -CO2H or— (C2 -C20 alkyl) -CO2- ( alkyl) ; NH [0125 ] R3 is H or -( alkyl) ; R [ 0126 ] R , is -Br, -I, -( alkenyl) - ( alkynyl) or S (alkyl ) , and [0127 ] Riis - H , [0128 ] or Rs and Rg are each independently Cl, Br, Br, -F , or LI; [0129 ] or a pharmaceutically acceptable salt or ester NH thereof. R2 [0130 ] In some embodiments , the compound having the structure US 2020/0079745 A1 Mar. 12 , 2020 7

-continued Se

-Br, I ,

HN HN

MeO2C

EtO2C

www

-I, HN HN

MeO2C

CO2Et,

-Br, HN HN

CO2Et HO2C US 2020/0079745 A1 Mar. 12 , 2020 8

-continued -continued

HN HN

HO2C

CO2H , [0131 ] or a pharmaceutically acceptable salt or ester thereof. HN [0132 ] In some embodiments , the compound having the structure

Br ,

H2N

COH

HO2C

or lo HN 0101H?N

HO2C HO2C US 2020/0079745 A1 Mar. 12 , 2020 9

-continued [0134 ] In some embodiments , the compound having the structure :

Rg Ri RO 0 R4 H?N . R10 CI, R11 R7 Ci R R3 Rg R1 R9 R4

R10 CO2H Ru

Rz or Rg RO RA

H2N Rio R11 R7 R R3

[ 0135 ] wherein [0136 ] R , is H or -( alkyl ) ; [0137 ] R2 is – (CZ - C2 alkyl) -CO ,Hor— ( C2 - C20 alkyl) -CO2- (alkyl ) ; [0138 ] Rz is -H or - (alkyl ) ; HO2C or (0139 ] RA and R , are each independently - H , CI, Br, F , I , CN , CF3, OCF3, - (alkyl ) , - ( alk ILO enyl) , -alkynyl) , -Caryl) , -NH2, -NH - alkyl) , -NH (alkenyl ) , NH-( alkynyl ) -NH-( aryl ) , –NH-( het -1, eroaryl) , OH , OA , O C ( O ) (alkyl ) , O ( alkyl) , O - alkylaryl ), O-(alkenyl ) , O - alkynyl ), HN O - aryl) , O-( heteroaryl) , S - alkyl) , S-( alk c/o enyl) , S - alkynyl) , S - aryl) , S-( heteroaryl ) , -S ( O ) - ( alkyl ) , -S ( O ) - ( aryl ) , -S ( O ) -( heteroaryl ) , SO2- (alkyl ) , SO2- (aryl ) , or SO2- (heteroaryl ) ; [0140 ] Ry, Ry, R10 and R 11 are each independently —H , CI, Br, -F, -1, CN , CF3, OCF3 , -alkyl) , -aryl) , - (heteroaryl ) - (alkenyl ) , -alkynyl) , NH , -NH - alkyl) . —NH - alkenyl) , -NH - alkynyl) -NH - Caryl ), -NH-(heteroaryl ) , OH , OAc , 0_C (O )( alkyl) , O - alkyl) , O-( alkenyl ) , O (alkynyl ) , O-( aryl ) , O-( heteroaryl ) , —S-( alkyl) , S - alkenyl) , S - alkynyl) , S - Caryl ) , S -chet CO2H eroaryl) , -S( O ) - (alkyl ) , -S ( O ) - ( aryl) , -S ( O ) - (het eroaryl ), -SO2- (alkyl ) , Soz- Caryl ) , or - Soz- het [ 0133 ] or an ester thereof. eroaryl) . US 2020/0079745 A1 Mar. 12 , 2020 10

[0141 ] In some embodiments , the compound having the - ( alkenyl ) , -alkynyl) , -aryl) , -NH2, -NH - alkyl) , structure : -NH-( alkenyl) , -NH-( alkynyl) -NH - Caryl) , -NH (heteroaryl ) , OH , OAc, 0_C (O )( alkyl) , O ( alkyl) , -O-( alkylaryl ) , -O-( alkenyl) , -O-( alkynyl) , O - Caryl) , O-( heteroaryl ) , S-S - (alkyl ) , S-( alk // enyl) , -S-( alkynyl) , S - Caryl) , S-( heteroaryl ) , -S ( O ) - (alkyl ) , S (O )- ( aryl) , -S ( O ) -( heteroaryl ) , SO2- (alkyl ) , SO2- ( aryl) , or -SO2- (heteroaryl ) ; -CI, [0155 ] R8, R9, R10 and R11 are each independently - H , NH C1, -Br, -F, -1, —CN , CF3, -OCF3, -alkyl) , CI -Caryl) , -( heteroaryl ) -( alkenyl ) , -( alkynyl ) , —NH2, R -NH - alkyl) , -NH-(alkenyl ) , -NH-( alkynyl) NH-( aryl ) , -NH-( heteroaryl ) , OH , OAc , 0_C (O )( alkyl ) , O - alkyl ), O - alkenyl) , O (alkynyl ) , O-( aryl ) , O-( heteroaryl ), S-( alkyl) , S- ( alkenyl ), S-( alkynyl) ), S - Carylaryl) , , S - het CI eroaryl ) , -S ( O ) - (alkyl ) , -S( O ) - ( aryl) , S ( O ) - (het NH eroaryl) , SO2- alkyl) , SO2-( aryl ) , or -SOZ-( het F eroaryl) ; R2 or (0156 ] wherein one of Rs or Ro is -( alkynyl ) or S ( alkyl ) , or R , and Ro are each independently CI, Br, F , or - I , wherein when R ,1 is CH3, R3, R4, R6, R7, R8, R9 , R10 and Ru1 are each -H , and R , is -I , SCHz, then R2 is other than (CH2 ).CO , H , [0157 ] or a pharmaceutically acceptable salt or ester NH F thereof. R2 [0158 ] In some embodiments , the compound having the structure : [0142 ] wherein [0143 ] R , is- (C2 - C20 alkyl) -CO , H or -C7-20 alkyl ) CO2- alkyl) , Rg R1 [0144 ] or a pharmaceutically acceptable salt or ester thereof. R9 R4 [0145 ] In some embodiments , wherein R , is (Co - C20 alkyl) -CO2H or (C8 - C20 alkyl ) -CO2- (alkyl ) , Br [0146 ] or a pharmaceutically acceptable salt or ester Rio thereof. R11 [0147 ] In some embodiments , wherein R , is (C2 - C20 R7 alkyl) -CO , H or (Cy - C20 alkyl) -CO2- ( alkyl) , Rz R3 [ 0148 ] or a pharmaceutically acceptable salt or ester thereof. [ 0149 ] In some embodiments , the compound having the [0159 ] wherein structure : [0160 ] R1 is -H or - ( alkyl ) ; [0161 ] R , is - C . alkyl) -CO ,H ; Rg Ri [ 0162 ] Rz is H or -( alkyl) ; RO Ru [0163 ] R4 and R , are each independently —H , CI , -Br, -F, -I, CN , –CF3, OCF3, - (alkyl ), - (alk enyl) , - ( alkynyl) , - (aryl ), -NH2, - NH - alkyl) , -NH Rio -R5 (alkenyl ) . -NH-( alkynyl ) -NH-( aryl ) , NH-( het R11 eroaryl) , -?? , OA , 0 C (O )( alkyl ) , 0 RO (alkyl ) , O - alkylaryl) , -O-( alkenyl ) , O - alkynyl ), Ra R3 R7 O - aryl) , O-( heteroaryl ) , S-( alkyl) , S-( alk enyl) , -S-( alkynyl) , S - Caryl) , S-( heteroaryl ) , S ( O )-alkyl ) , S ( O )-aryl ) , -S ( O ) - (heteroaryl ) , [0150 ] wherein -SO2- (alkyl ) , -SO2- (aryl ) , or SO2- (heteroaryl ) ; [0151 ] R ,1 is —H or - ( alkyl) ; [0152 ] R , is (Coalkyl ) -CO , H ; [0164 ] R8, R9, R10 and Ru are each independently —H , [0153 ] Rz is H or - (alkyl ) ; CI, -Br, —F, —1, CN , — CF3, OCF3, -alkyl) , [0154 ] R4, R5, R. and R , are each independently —H , -aryl) , - (heteroaryl ) -( alkenyl ), - (alkynyl ) , NH2, Cl, Br, -F, -I, CN , CF3, OCF3, - (alkyl ) , -NH-( alkyl ) , -NH-( alkenyl ) , -NH-( alkynyl ) US 2020/0079745 A1 Mar. 12 , 2020 11

-NH - Caryl ) , -NH-( heteroaryl ) , ?? , OA , [0174 ] In some embodiments , the compound having the O - C ( O ) ( alkyl) , -O-( alkyl) , -O-( alkenyl ) , O structure : ( alkynyl) , O - aryl ), O - heteroaryl) , S - alkyl) , -S-( alkenyl) , S-( alkynyl ) , S - aryl) , S (het eroaryl) , -S( O ) - (alkyl ) , -S ( O ) - ( aryl) , -S( O ) - (het R1 eroaryl ), SO2- ( alkyl) , SO2- ( aryl) , or —SO2- (het eroaryl) , [0165 ] or a pharmaceutically acceptable salt or ester thereof. -R5, [ 0166 ] In some embodiments , the compound having the R6 structure : R? R3

R $ Ri [0175 ] wherein R. R4 [ 0176 ] Rj is -H or - ( alkyl) ; [0177 ] R2 is ( C6 alkyl) -CO2H ; Rio [ 0178 ] Rz is -H or - ( alkyl) ; Ril R7 R6 [0179 ] Rs is - (alkynyl ) or -S - alkyl) and R , is H , or R? R3 or [0180 ] R , and Ro are each independently Cl, Br, R8 Ri -F, or —I, Ro RA [0181 ] or a pharmaceutically acceptable salt or ester thereof. -SMe R 10 [0182 ] In some embodiments , the compound having the structure : Ru RO R2 R3 R7

[0167 ] wherein

[0168 ] R ,1 is - H or - (alkyl ) ;

[0169 ] R2 is (Co alkyl ) -CO2H ; NH [0170 ] Rz is -H or - (alkyl ) ; R [0171 ] R4, R. and R , are each independently - H , CI , Br, -F, -I, CN , CF3, OCF3, - (alkyl ) , -( alk enyl) , -( alkynyl ) , -( aryl ) , -NH2, -NH-( alkyl ) , -NH ( alkenyl) , NH-( alkynyl) -NH-( aryl ) , NH-( het eroaryl) , OH , OAc, O C ( O ) ( alkyl) , -O -SCH ; ( alkyl) , O - alkylaryl) , O - alkenyl ) , O - alkynyl) , O-( aryl) , O-( heteroaryl ) , S-( alkyl ) , S- (alk NH enyl) , S-( alkynyl) , S-( aryl) , S-( heteroaryl ) , S ( O ) - (alkyl ) , S ( O ) - (aryl ) , S ( O ) -( heteroaryl ) , R or SO2- ( alkyl) , SO2-( aryl ) , or SO2- (heteroaryl ) ; [0172 ] R3, R .,, Rio and Ry are each independently —H , Cl, Br, -F, -I, -CN , CF3, OCF3, - ( alkyl) , -Caryl) , - (heteroaryl ) - ( alkenyl) , - ( alkynyl ) , -NH2, Br, -NH - alkyl) , -NH - alkenyl) , -NH - alkynyl) -NH - Caryl) , -NH-( heteroaryl ) , OH , OA , NH 0_C ( O ) ( alkyl) , O - alkyl) , O-( alkenyl ) , O F (alkynyl ) , O-( aryl ) , O-( heteroaryl ) , S-( alkyl) , R -S-( alkenyl ) , S-( alkynyl ) , S - Carylaryl) , S - het eroaryl) , -S (O )- (alkyl ) , -S( O )- (aryl ) , -S( O )- ( het eroaryl) , SO2- (alkyl ) , _Soz- Caryl) , or - Soz- het [0183 ] wherein eroaryl) , [0184 ] R2 is (Co alkyl) -CO , H . [0173 ] or a pharmaceutically acceptable salt or ester [0185 ] or a pharmaceutically acceptable salt or ester thereof. thereof. US 2020/0079745 A1 Mar. 12 , 2020 12

[0186 ] In some embodiments , the compound having the -continued structure : Lo LIO Br or HN or F

HN

CO2H Lo CO2H SMe,

HN Br,

HN

CO2H

[0189 ] or an ester thereof. CO2H [0190 ] In some embodiments , the compound having the structure [ 0187 ] or a pharmaceutically acceptable salt or ester thereof. Rg Ri [0188 ] In some embodiments , the compound having the Ro R4 structure : CI, Rió Ri1 N R7 C1 R R3

HN Rg Ri R. RA

CI or Rio Rul R7 CO2H R R3 US 2020/0079745 A1 Mar. 12 , 2020 13

-continued -continued Rg Ri Rg R4

-I, Rio R11 N NH R7 F F Ra R3 R2

[0191 ] wherein [0192 ] Riis H or - ( alkyl) ; [0193 ] R2 is ( C6 alkyl) -CO2H ; [ 0199 ] wherein [0194 ] Rz is H or -alkyl) ; [0200 ] R2 is (Co alkyl) -CO , H , [0195 ] RA and R , are each independently - H , CI, [0201 ] or a pharmaceutically acceptable salt or ester -Br, F , -I , -CN , CF3, OCF3, - ( alkyl) , - (alk thereof . enyl) , - (alkynyl ) , -( aryl ) , -NH2, NH - alkyl) , -NH ( alkenyl) , NH - alkynyl) -NH-( aryl ) , –NH-( het [ 0202 ] In some embodiments , the compound having the eroaryl) , OH , OAc , OC( O ) (alkyl ) , O structure : (alkyl ), -O-( alkylaryl ) , -O-( alkenyl ) , O-( alkynyl ) , -O - aryl) , O-( heteroaryl ) , S-( alkyl) , S-( alk enyl) , S-( alkynyl ) , S - aryl) , S-( heteroaryl ) , S ( O ) - ( alkyl) , S ( O ) - (aryl ) , S ( O )- ( heteroaryl ) , SO2- alkyl) , SO2-SO2- (aryl aryl ) , , oror SO2- (heteroaryl ) ; [0196 ] Rg, R9, R10 and R11 are each independently —H , CI, Cl, Br, -F, -I, CN , CF3, OCF3, -alkyl) , - ( aryl) , - (heteroaryl ) - ( alkenyl ) , - ( alkynyl) , -NH2, HN -NH - alkyl) , -NH - alkenyl) , -NH - alkynyl) CI -NH - Caryl) , -NH-( heteroaryl ) , ?? , OAc, OC( O ) ( alkyl) , O - alkyl) , O-( alkenyl) , O ( alkynyl) , O-( aryl ) , O-(heteroaryl ) , S - alkyl) , S-( alkenyl ) , S- (alkynyl ) , S - Caryl) , S-( het eroaryl ), -S ( O ) - ( alkyl) , -S( O ) - ( aryl ) , -S( O ) - (het eroaryl) , SO2- ( alkyl) , SO2- ( aryl) , or - S02- het eroaryl) [0197 ] or a pharmaceutically acceptable salt or ester CO2H thereof. [0198 ] In some embodiments , the compound having the structure :

S

CI or CI,

HN NH F R2 CI

CI or

NH R2 F CO2H US 2020/0079745 A1 Mar. 12 , 2020 14

-continued -continued

N

I , -I,

HN H2N F

CO2H CO2H [ 0205 ] or an ester thereof. [0203 ] or an ester thereof. [0206 ] In some embodiments , the compound having the [0204 ] In some embodiments , the compound having the structure : structure : Rg R1 lo Ro RA Rs CI, Rio R11 R7 R6 H2N Rz R3 CI [ 0207 ] wherein [0208 ] Rj is H or -alkyl) ; [ 0209 ] R , is -( Ca alkyl )-CO , - ( alkyl) ; [0210 ] R2 is H or - ( alkyl) ; [0211 ] R4, R3, R. and R , are each independently H , C1, —Br, —F, —I, CN , CF3, -OCF3, -alkyl) , -alkenyl) , - (alkynyl ) , -aryl ) , -NH ,, -NH - alkyl) , CO2H -NH - alkenyl) , NH - alkynyl) -NH - aryl) , -NH (heteroaryl ) , OH , OA , O C (O )( alkyl ) , O (alkyl ) , -O-( alkylaryl ), O-( alkenyl ) , O - alkynyl) , O-( aryl) , O-( heteroaryl ) , S - alkyl) , S - alk enyl) , S - alkynyl) , S - aryl) , S-( heteroaryl ) , -S( O ) - ( alkyl) , -S ( O ) - ( aryl ), -S ( O ) - (heteroaryl ) , SO2- (alkyl ) , SO2-( aryl ) , or -SO2-( heteroaryl ) ; [ 0212 ] R3, R9, R10 and Rui are each independently -H , C1, Br, -F, -I, CN , CF3, OCF3 , -( alkyl ) , CI or -aryl) , - (heteroaryl ) -( alkenyl) , -alkynyl) , -NH2, NH - alkyl) , -NH - alkenyl) , -NH-( alkynyl ) NH - aryl) , -NH-( heteroaryl ) , OH , OAc, H2N F 0_C ( O ) ( alkyl) , 0-(alkyl ) , O-( alkenyl ) , O (alkynyl ) , O-( aryl ) , O-( heteroaryl ) , -S-( alkyl ) , S- ( alkenyl ) , S- (alkynyl ) , S-( aryl ) , S - het eroaryl ) , S ( O ) - (alkyl ) , -S( O ) - (aryl ) , S ( O ) - (het eroaryl ), SO -( alkyl ) , SO -( aryl) , or SO - het eroaryl) ; [ 0213 ] wherein one of R , or Ro is -( alkynyl ) or —S (alkyl ) , or Rs and R. are each independently C1, -Br, —F, or -I, and CO2H [0214 ] or a pharmaceutically acceptable salt or ester thereof. US 2020/0079745 A1 Mar. 12 , 2020 15

[0215 ] In some embodiments , the compound having the enyl ), - (alkynyl ) , -aryl) , -NH2, -NH - alkyl ) , -NH structure : (alkenyl ) , NH-( alkynyl) NH-( aryl) , NH- ( het eroaryl) , OH , OAc , 0 - C ( O ) (alkyl ) , O ( alkyl) , O - alkylaryl ), O-( alkenyl ), O - alkynyl) , Rs Ri O-( aryl) , O-( heteroaryl) , -S-( alkyl ) , S-( alk enyl) , -S- ( alkynyl ) , —S- Caryl) , S-( heteroaryl ) , R. Lo R4 S ( O ) -( alkyl) , S ( O )- (aryl ) , S ( O ) - (heteroaryl ), SO2- (alkyl ) , SO2- (aryl ) , or SO2- (heteroaryl ) ; R5 [ 0230 ] R3, R9, R10 and Rui are each independently —H , Rio Cl, Br, -F, -I, CN , CF3, OCF3, -alkyl ), R11 -Caryl) , -( heteroaryl ) -( alkenyl ) , -( alkynyl ) , —NH2, . R7 R6 -NH-( alkyl) , -NH-( alkenyl) , NH - alkynyl) Rz R3 -NH - Caryl) , -NH-( heteroaryl ) , OH , OA , 0 C ( O ) ( alkyl) , O-( alkyl ) , O-( alkenyl ) , O (alkynyl ) , 0O - Carylaryl) , O-( heteroaryl ) , -S - alkyl) , [0216 ] wherein -S- alkenyl) , S-( alkynyl ) , S-( aryl ) , S - het [0217 ] Riis1 H or - (alkyl ) ; [0218 ] R , is (Coalkyl ) -C02 - alkyl) ; eroaryl) , -S( O ) - ( alkyl) , -S ( O )-aryl ) , -S ( O ) - ( het [0219 ] R2 is H or -( alkyl ) ; eroaryl) , -SO2- alkyl) , SO2-( aryl) , or -SO2- het [0220 ] R4, Rs, Ro and R , are each independently —H , eroaryl ), Cl, Br, -F, -I, CN , CF3, OCF3, - (alkyl ), [0231 ] or a pharmaceutically acceptable salt or ester -alkenyl) , -alkynyl) , -aryl ), -NH2, -NH - alkyl) , thereof. -NH-( alkenyl ) , -NH-( alkynyl ) -NH -Caryl ) , -NH [ 0232 ] In some embodiments , the compound having the (heteroaryl ) , OH , OAc, 0_C ( O ) (alkyl ) , -O structure : (alkyl ), O - alkylaryl) , O - alkenyl) , O - alkynyl ), O - aryl) , O-( heteroaryl ), S - alkyl) , S- (alk enyl) , S- (alkynyl ) , S-( aryl) , S-( heteroaryl ) , R8 Ri S ( O ) - ( alkyl ), S ( O ) - ( aryl) , -S ( O ) -( heteroaryl ) , SO2- (alkyl ) , SO2- (aryl ) , or SO2-( heteroaryl ) ; R9 RA [ 0221 ] R3, Ry, R10 and R11 are each independently —H , Cl, Br, -F, -I, -CN , CF3, OCF3, -( alkyl) , -aryl) , - (heteroaryl ) -( alkenyl) , -alkynyl) , -NH2, R10 NH - alkyl) , -NH - alkenyl) , -NH - alkynyl) Rul -NH - Caryl) , -NH-( heteroaryl ) , OH , OA , R7 R6 O C (O ) (alkyl ) , O-( alkyl ) , O- (alkenyl ) , O Rz R3 (alkynyl ) , O - aryl) , O - heteroaryl) , S - alkyl) , S- (alkenyl ) , S-( alkynyl ) , S - Caryl) , S - het eroaryl) , -S( O ) - (alkyl ) , -SS ( O ) - ( aryl ) , -S( O ) - (het [0233 ] wherein eroaryl) , SO2- ( alkyl) , SO2- ( aryl ), or -SO2- (het [0234 ] Riis H or -alkyl ) ; eroaryl ); [ 0235 ] R2 is – (Co alkyl) -CO2- ( alkyl) ; [0222 ] wherein one of R , or Ro is - ( alkynyl) , or R , and [0236 ] Rz is H or - (alkyl ) ; Ro are each independently Cl, Br, -F, or —I, and [0237 ] R4 , R and R , are each independently - H , C1, [0223 ] or a pharmaceutically acceptable salt or ester -Br, —F, —1, CN , CF3, OCF3, - ( alkyl) , - ( alk thereof. enyl) , - (alkynyl ) , -( aryl ) , -NH2, -NH - alkyl) , -NH [ 0224 ] In some embodiments , the compound having the (alkenyl ) , -NH-( alkynyl) NH-( aryl) , NH-( het structure : eroaryl) , OH , OAc, 0 C ( O ) (alkyl ) , 0 (alkyl ), O - alkylaryl) , O-( alkenyl ) , O - alkynyl ), -O - aryl) , O-( heteroaryl ) , S-( alkyl) , S-( alk Re Ri enyl) , -S-( alkynyl) , S - aryl) , S-( heteroaryl ) , S (O )- ( alkyl) , S (O ) -( aryl ) , S (O ) - (heteroaryl ) , R9 R4 SO2- ( alkyl) , SO2- ( aryl) , or SO2- (heteroaryl ) ; [ 0238 ] R3, R9, R10 and R11 are each independently —H , Br Ci, -Br, —F, —1, CN , CF3, OCF3, -( alkyl ) , R10 -aryl ), -( heteroaryl ) -( alkenyl ), -( alkynyl ) , NH , Ru1 -NH-( alkyl ) , -NH-( alkenyl ) , -NH - alkynyl) . R7 F -NH - aryl) , -NH-( heteroaryl ) , OH , OAc, Ra R3 O - C (O ) (alkyl ) , 0-( alkyl ) , O-( alkenyl ) , O (alkynyl ) , O - arvl) . O-( heteroaryl ) , S-( alkyl ) , [0225 ] wherein -S - alkenyl) , SS- -( alkynylalkynyl)) , SS - Carylaryl)) , S - het [0226 ] Riis -H or -( alkyl) ; eroaryl) , -S( O ) - ( alkyl) , -S( O ) - (aryl ) , -S ( O ) - (het [0227 ] R2 is (C. alkyl) -CO2- ( alkyl) ; eroaryl) , -S02- ( alkyl) , SO2- aryl ) , or -SO2- (het [0228 ] Rz is H or -( alkyl ) ; eroaryl) , [0229 ] R4 and R , are each independently H , CI , [0239 ] or a pharmaceutically acceptable salt or ester -Br, -F , -I, CN , –CF3, OCF3 , - (alkyl ), - (alk thereof. US 2020/0079745 A1 Mar. 12 , 2020 16

[ 0240 ] In some embodiments , the compound having the -continued structure :

N Ri Br,

R5, NH R2 F

Ro R? R3 [0253 ] wherein [0254 ] R , is - Co alkyl) -CO , CH , CHz. [0241 ] wherein [0255 ] or a pharmaceutically acceptable salt or ester [0242 ] R , is –H or -( alkyl ) ; thereof. [0243 ] R2 is (C. alkyl) -CO2- ( alkyl ) ; [0256 ] In some embodiments , the compound having the [0244 ] Rz is H or - ( alkyl) ; structure : [0245 ] R , is - ( alkynyl) and Ro is H , or [0246 ] Rs and Ro are each independently Cl, Br, -F , or — I , [0247 ] or a pharmaceutically acceptable salt or ester thereof . [0248 ] In some embodiments , the compound having the or structure :

NH Rz

or Br, NH Rz NH R2 F

[0257 ] wherein Br, [0258 ] R2 is (C. alkyl) -CO , CHz. NH [0259 ] In some embodiments , the compound having the R2 F structure : [0249 ] wherein [0250 ] R2 is (C. alkyl) -CO2- (alkyl ) . [ 0251 ] or a pharmaceutically acceptable salt or ester thereof. [ 0252 ] In some embodiments , the compound having the or structure : HN

or

NH R2 CO2Et US 2020/0079745 A1 Mar. 12 , 2020 17

-continued [0262 ] wherein [0263 ] R , is H or -( alkyl ) ; [0264 ] R2 is (Co alkyl) -C02- (alkyl ) ; [0265 ] Rz is H or - ( alkyl) ; Br, [0266 ] R4 and R , are each independently H , CI, Br, F , I , CN , –CF3, OCF3, - (alkyl ) , - (alk HN enyl) , - (alkynyl ) , -Caryl ) , -NH2, -NH - alkyl) , -NH F (alkenyl ) , -NH - alkynyl) -NH-( aryl) , NH-( het eroaryl) , OH , OA , 0 C (O )( alkyl ) , 0 ( alkyl) , O - alkylaryl ), - O-(alkenyl ) , O-( alkynyl ), O - Caryl) , O-( heteroaryl ), S-( alkyl ) , S- (alk enyl) , -S-( alkynyl) , S -Caryl aryl) , S-( heteroaryl ) , S ( O ) - (alkyl ) , -S( O ) - ( aryl) , -S ( O ) - ( heteroaryl) , SO2-( alkyl ) , SO2-( aryl ) , or SO2- (heteroaryl ) ; [0267 ] R3, R9, R10 and R11 are each independently –H , CO2Et Cl, Br, -F, -I, CN , CF3, OCF3, -alkyl) , -aryl ) , - (heteroaryl ) - (alkenyl ) , -alkynyl) , —NH , -NH- (alkyl ), -NH-( alkenyl) , -NH-( alkynyl) [0260 ] or a pharmaceutically acceptable salt or ester NH-( aryl ) , -NH-( heteroaryl ) , OH , OA , thereof. 0 C ( O ) (alkyl ) , - alkyl ), O - alkenyl) , 40 (alkynyl ) , O - aryl) , O-0-( heteroaryl heteroaryl) , S-( alkyl) , [ 0261] In some embodiments , the compound having the -S-( alkenyl ) , S-( alkynyl ) , S -Caryl ) , S - het structure : eroaryl) , -S( O )- (alkyl ), -S( O ) -( aryl ), -S( O ) -( het eroaryl) , -SO2- alkyl) , Soz- Caryl ) , or S02-( het Rg Ri eroaryl) , I [0268 ] or a pharmaceutically acceptable salt or ester Ro R4 thereof. [0269 ] In some embodiments , the compound having the structure : Rió CI, R11 R7 R2 R3

CI,

Rg Ri NH R2 RO R4

CI or Rio Ril CI or R2 R7 R3 NH R2

Rg Ri I, RO R4 NH R2 F Rio Ru R7 F [ 0270 ] wherein R3 [0271 ] R2 is ( C. alkyl) -CO , CH3, [ 0272 ] or a pharmaceutically acceptable salt or ester thereof. US 2020/0079745 A1 Mar. 12 , 2020 18

[0273 ] In some embodiments , the compound having the [0276 ] wherein structure : [ 0277 ] Rj is H or - ( alkyl ) ; [0278 ] R , is ( C3-5 alkyl) -CO H or- (C3-5 alkyl) -CO , (alkyl ) ; [ 0279 ] Rz is H or - (alkyl ) ; -CI, [0280 ] R4, R5, R. and R , are each independently —H , C1, -Br, -F , -I , CN , CF , OCF , -alkyl) , HN - ( alkenyl) , -alkynyl ), -aryl ), -NH2, -NH - alkyl) , CI -NH-( alkenyl ) , -NH - alkynyl) -NH - Caryl) , -NH (heteroaryl ) , OH , OAc, 0_C ( O ) (alkyl ) , -O ( alkyl) , O - alkylaryl) , 0-( alkenyl ) , O - alkynyl) , O- (aryl ), O-( heteroaryl) , S-( alkyl) , S-( alk enyl) , S-( alkynyl) , S - Caryl) , S-( heteroaryl ) , S ( O ) - (alkyl ) , S (O ) -( aryl ), S (O ) - ( heteroaryl) , SO2- (alkyl ) , SO2- (aryl ) , or SO2- (heteroaryl ) ; [0281 ] Rg , R9, R10 and R11 are each independently —H , CO Et -Br, -F, -1, CN , CF3 , OCF3, - (alkyl ) , -arylcl, ) , - (heteroaryl ) -( alkenyl ) , -alkynyl) , NH , -NH-( alkyl ) , -NH-( alkenyl ) , NH - alkynyl) NH-( aryl) , NH-( heteroaryl ), OH , OA , O C ( O ) (alkyl ) , O-( alkyl ) , O-( alkenyl) , O CI or (alkynyl ) , O - aryl) , O-0- (heteroaryl heteroaryl )) , , —S-( alkyl) , S - alkenyl) , S - alkynyl) , S - aryl) , S - het HN eroaryl) , -S( O )- ( alkyl) , -S (O )-aryl ) , S ( O )- ( het F eroaryl) , -SO2- alkyl) , SO2- Caryl ) , or SO2-( het eroaryl) ; [0282 ] wherein Rs and R , are each independently Cl, Br, —F, or —I, [0283 ] or a pharmaceutically acceptable salt or ester thereof . [0284 ] In some embodiments , the compound having the CO2Et structure :

Rg R1 Rg R4 I ,

HN Br, F R10 R11 N R2 R7 CI R3 Rs R1

6 R4

CO2Et Rio CI, [ 0274 ] or a pharmaceutically acceptable salt thereof. [ 0275 ] In some embodiments , the compound having the Rul R2 R7 structure : R3 Rg R1 Rg Ri . R. R4 R9 R4

-R5 CI or R10 R10 R11 R11 R7 Ro R R7 R2 R3 R3 US 2020/0079745 A1 Mar. 12 , 2020 19

-continued [0299 ] In some embodiments , wherein R , is ( C4 alkyl) Rg Ri O CO , H , or (C4 alkyl) -CO , CH ; or alkyl) CO , CH , CHz, or a pharmaceutically acceptable( C4salt or ester Ro R4 thereof. [0300 ] In some embodiments , the compound having the Rió structure : Ru1 R2 R7 F R3 Br, [0285 ] wherein [0286 ] R is - H or - (alkyl ) ; H N. [ 0287 ] R , is - Cz- s alkyl )-CO ,Hor - Cz- s alkyl) -CO2 ( alkyl) ; [0288 ] R3 is H or - (alkyl ) ; [0289 ] R4 and R , are each independently - H , CI, -Br, -F, -1, CN , CF3, OCF3, -( alkyl ) , - (alk enyl) , - (alkynyl ) , -( aryl ) , -NH2, NH - alkyl) , -NH CO2H ( alkenyl) , -NH - alkynyl ) -NH - Caryl) , -NH-( het eroaryl) , OH , OA , O C ( O ) (alkyl ) , O (alkyl ) , O - alkylaryl) , -O-( alkenyl) , O-( alkynyl) , www. -O - aryl) , O-( heteroaryl ) , S - alkyl) , S - alk enyl ) , S-( alkynyl) , S - aryl ) , S-( heteroaryl ) , S ( O ) - (alkyl ) , S (O )-aryl ) , S ( O ) - (heteroaryl ) , -CI, SO2- ( alkyl) , -SO2- ( aryl) , or -SO2- ( heteroaryl) ; [0290 ] Rg, R9, R10 and R11 are each independently - H , HN Cl, Br, -F, -I, CN , CF3, OCF3, -( alkyl ) , CI -Caryl) , - (heteroaryl ) -( alkenyl) , - ( alkynyl) , NH , NH-( alkyl ) , -NH-( alkenyl) , -NH-( alkynyl) -NH - aryl) , -NH- (heteroaryl ) , OH , OAc , 0 - C (O ) (alkyl ), -O-( alkyl ) , -O-( alkenyl ) , O (alkynyl ) , O- (aryl ) , O-( heteroaryl ) , S - alkyl) , CO2H S - alkenyl) , S-( alkynyl) , S - Carylaryl)) , , S - het eroaryl) , -S ( O )-alkyl ) , -S( O ) -Caryl) , S (O )-chet eroaryl ), SO2- ( alkyl) , SO2- ( aryl) , or —SO2- (het eroaryl ), [0291 ] or a pharmaceutically acceptable salt or ester CI or thereof. [0292 ] In some embodiments , the compound having the H?N structure : F

Ri

Www CO2H -R5,

RO R R3 H2N [0293 ] wherein [0294 ] R is -H or - ( alkyl) ; [ 0295 ] R is – ( C3-5 alkyl ) -CO Hor— (C3-5 alkyl) -CO2 (alkyl ) ; [0296 ] Rz is H or - (alkyl ) ; and [0297 ] Rs and Ro are each independently Cl, Br, CO2H -F , or -1, [0298 ] or a pharmaceutically acceptable salt or ester thereof. or an ester thereof. US 2020/0079745 A1 Mar. 12 , 2020 20

[ 0301 ] In some embodiments , the compound having the [ 0303 ] In some embodiments , the compound having the structure : structure :

Br, Br,

HN HN F

CO2H CO2Me

CI, -CI, HN . HN ci CI

CO2Me CO2H

CI or CI or HN F HN F

CO2Me CO2H

-I,

HN HN F

CO2Me CO2H [0304 ] or a pharmaceutically acceptable salt thereof. [0305 ] The present invention provides a pharmaceutical [0302 ] or a pharmaceutically acceptable salt or ester composition comprising the compound of the present inven thereof. tion and a pharmaceutically acceptable carrier. US 2020/0079745 A1 Mar. 12 , 2020 21

[0306 ] In some embodiments , a pharmaceutical composi [0315 ] In some embodiments , a method of treating a tion comprising the compound the present invention , an subject afflicted with pain , a depressive disorder , a mood NMDA receptor antagonist, an NMDA receptor partial ago disorder , an anxiety disorder , or borderline personality dis nist, a neurokinin 1 receptor antagonist, a neurokinin 2 order, comprising administering to the subject an effective receptor antagonist , a neurokinin 3 receptor antagonist , a amount of naloxone or methylnaltrexone and an effective DOR agonist , naloxone or methylnaltrexone, and a pharma amount of the compound of the present invention so as to ceutically acceptable carrier. thereby treat the subject afflicted with pain , the depressive [0307 ] In some embodiments , a method of activating a disorder , the mood disorder , the anxiety disorder , or border mu- opioid receptor or delta -opioid receptor comprising con line personality disorder . tacting the mu -opioid receptor or delta -opioid receptor with [0316 ] In some embodiments, a pharmaceutical composi the compound of the present invention . tion comprising the compound of the present invention , a [0308 ] In some embodiments , a method of treating a selective serotonin reuptake inhibitor or a serotonin -norepi subject afflicted with a depressive disorder or a mood nephrine reuptake inhibitor, and a pharmaceutically accept disorder comprising administering an effective amount of able carrier. the compound of the present invention to the subject so as [0317 ] In some embodiments , a method of treating a to treat the subject afflicted with the depressive disorder or subject afflicted with a depressive disorder, a mood disorder, the mood disorder . an anxiety disorder, or borderline personality disorder , com [0309 ] In some embodiments , a method of treating a prising administering to the subject an effective amount of a subject afflicted with pain , an anxiety disorder , or borderline selective serotonin reuptake inhibitor or a serotonin -norepi personality disorder , comprising administering an effective nephrine reuptake inhibitor and an effective amount of the amount of the compound of the present invention to the compound of the present invention so as to thereby treat the subject so as to treat the subject afflicted with pain , the subject afflicted with the depressive disorder, mood disorder, anxiety disorder, or borderline personality disorder anxiety disorder , or borderline personality disorder. [0310 ] In some embodiments , a method of treating a mu[ 0318- opioid ] In receptorsome embodiments comprising , contactinga method ofthe activatingmu- opioid a subject afflicted with opioid addiction or opioid withdrawal receptor with the compound of the present invention . symptoms comprising administering an effective amount of [0319 ] In some embodiments , a method of activating a the compound of the present invention to the subject so as delta -opioid receptor comprising contacting the delta -opioid to treat the subject afflicted with the opioid addiction or receptor with the compound of the present invention . opioid withdrawal symptoms. [0320 ] In some embodiments , a method of activating a [ 0311 ] In some embodiments , a method of treating a mu -opioid receptor and delta -opioid receptor comprising subject afflicted with , a depressive disorder or a mood contacting the mu- opioid receptor and delta -opioid receptor disorder comprising administering to the subject an effective with the compound of the present invention . amount of an NMDA receptor antagonist , an NMDA recep [0321 ] In some embodiments , a method of treating a tor partial agonist , a neurokinin 1 receptor antagonist, a subject afflicted with pain comprising administering an neurokinin 2 receptor antagonist, a neurokinin 3 receptor effective amount of the compound of the present invention antagonist or a DOR agonist and an effective amount of the to the subject so as to treat the subject afflicted with pain . compound of the present invention so as to thereby treat the [0322 ] In some embodiments , a method of treating a subject afflicted with the depressive disorder or the mood subject afflicted with a depressive disorder comprising disorder. administering an effective amount of the compound of the [ 0312 ] In some embodiments , a method of treating a present invention to the subject so as to treat the subject subject afflicted with pain , an anxiety disorder, or borderline afflicted with the depressive disorder . personality disorder comprising administering to the subject [0323 ] In some embodiments , a method of treating a an effective amount of an NMDA receptor antagonist, an subject afflicted with a mood disorder comprising adminis NMDA receptor partial agonist , a neurokinin 1 receptor tering an effective amount of the compound of the present antagonist , or a DOR agonist and an effective amount of the invention to the subject so as to treat the subject afflicted compound of the present invention so as to thereby treat the with the mood disorder . subject afflicted with pain , the anxiety disorder , or borderline [ 0324 ] In some embodiments , a method of treating a personality disorder . subject afflicted with an anxiety disorder comprising admin [0313 ] In some embodiments , a method of treating a istering an effective amount of the compound of the present subject afflicted with opioid addiction or opioid withdrawal invention to the subject so as to treat the subject afflicted symptoms comprising administering to the subject an effec with the anxiety disorder . tive amount of an NMDA receptor antagonist , an NMDA [0325 ] In some embodiments , a method of treating a receptor partial agonist or a neurokinin 1 receptor antagonist subject afflicted with borderline personality disorder com and an effective amount of the compound of the present prising administering an effective amount of the compound invention so as to thereby treat the subject afflicted with the of the present invention to the subject so as to treat the opioid addiction or opioid withdrawal symptoms. subject afflicted with borderline personality disorder. [0314 ] In some embodiments , a method of treating a [0326 ] In some embodiments , a method of treating a subject afflicted with opioid addiction or opioid withdrawal subject afflicted with opioid addiction comprising adminis symptoms comprising administering to the subject an effec tering an effective amount of the compound of the present tive amount of naloxone or methylnaltrexone and an effec invention to the subject so as to treat the subject afflicted tive amount of the compound of the present invention so as with the opioid addiction . to thereby treat the subject afflicted with the opioid addiction [ 0327 ] In some embodiments , a method of treating a or opioid withdrawal symptoms. subject afflicted with opioid withdrawal symptoms compris US 2020/0079745 A1 Mar. 12 , 2020 22

ing administering an effective amount of the compound of tive amount of a compound of the present invention or a salt the present invention to the subject so as to treat the subject or ester thereof, so as to thereby treat the subject afflicted afflicted with the opioid withdrawal symptoms. with the opioid addiction or opioid withdrawal symptoms. [ 0328 ] In some embodiments , a method of treating a [0336 ] In some embodiments , a method of treating a subject afflicted with a pain comprising administering to the subject afflicted with pain , a depressive disorder , a mood subject an effective amount of an NMDA receptor antago disorder, an anxiety disorder or borderline personality dis nist, an NMDA receptor partial agonist, a neurokinin 1 order comprising administering to the subject an effective receptor antagonist or a DOR agonist and an effective amount of naloxone or methylnaltrexone and an effective amount of the compound of the present invention so as to amount of the compound of the present invention or a salt or thereby treat the subject afflicted with pain . ester thereof, so as to thereby treat the subject afflicted with [0329 ] In some embodiments , a method of treating a pain , the depressive disorder, themood disorder, the anxiety subject afflicted with a depressive disorder comprising disorder or borderline personality disorder . administering to the subject an effective amount of a NMDA receptor antagonist, an NMDA receptor partial agonist , a [0337 ] In one embodiment of any of the compounds neurokinin 1 receptor antagonist, a neurokinin 2 receptor disclosed herein R , is ( C7-20 alkyl) -CO2H or any combi antagonist , a neurokinin 3 receptor antagonist or a DOR nation or range within the C7-20 alkyl. The C7-20 alkyl may agonist and an effective amount of the compound of the be linear or branched . present invention so as to thereby treat the subject afflicted [0338 ] In one embodiment of any of the compounds with the depressive disorder. disclosed herein R , is ( C7-20 alkyl) -C02 - alkyl ) or any [0330 ] In some embodiments , a method of treating a combination or range within the C7-20 alkyl . The C7-20 alkyl subject afflicted with a mood disorder comprising adminis may be linear or branched . tering to the subject an effective amount of a NMDA [0339 ] In one embodiment of any of the compounds receptor antagonist , an NMDA receptor partial agonist , a disclosed herein R2 is (C7-20 alkyl) -CO2H or any combi neurokinin 1 receptor antagonist , a neurokinin 2 receptor nation of any of C , alkyl) -CO H , (C , alkyl) -CO H , antagonist, a neurokinin 3 receptor antagonist or a DOR (C , alkyl) -CO ,H , (Cho alkyl) -CO , H , - (Cu alkyl) agonist and an effective amount of the compound of the CO H , (C12 alkyl )-CO , H , (C , alkyl) -CO H , (C13 present invention so as to thereby treat the subject afflicted alkyl) -CO , H , (C14 alkyl) -CO , H , ( C , alkyl) -CO , H , with the mood disorder . (C15 alkyl) -CO2H , (C16 alkyl) -CO , H , (C17 alkyl) [0331 ] In some embodiments , a method of treating a CO2H , – (C18 alkyl) -CO , H , - (C19 alkyl) -CO2H or — (C20 subject afflicted with an anxiety disorder comprising admin alkyl) -CO , H . istering to the subject an effective amount of an NMDA [0340 ] In one embodiment of any of the compounds receptor antagonist , an NMDA receptor partial agonist , a disclosed herein R2 is (C7-20 alkyl) -CO2- ( alkyl) or any neurokinin 1 receptor antagonist, or a DOR agonist and an combination of any of ( C , alkyl) -C02 - alkyl) , ( C , effective amount of the compound of the present invention alkyl) -CO2- (alkyl ) , ( C , alkyl) -CO2- ( alkyl) , (C10 alkyl ) or a salt or ester thereof, so as to thereby treat the subject CO2- alkyl) , Cu alkyl) -CO2- alkyl) , C12 alkyl) -CO2 afflicted with the anxiety disorder. (alkyl ) , (C , alkyl ) -CO2- ( alkyl) , (C13 alkyl) -CO2 (0332 ] In some embodiments , a method of treating a ( alkyl) , (C14 alkyl) -C02- (alkyl ) , ( C , alkyl) -CO2 subject : afflicted with borderline personality disorder com ( alkyl) , Cis alkyl )-C02- ( alkyl) , (C16 alkyl) -C02 prising administering to the subject an effective amount of ( alkyl) , (C17 alkyl) -C02- ( alkyl ), (Cs alkyl) -CO2 an NMDA receptor antagonist, an NMDA receptor partial ( alkyl) , (C19 alkyl) -CO2- ( alkyl) or (C20 alkyl) -CO2 agonist, a neurokinin 1 receptor antagonist or a DOR agonist (alkyl ) . and an effective amount of the compound of the present [0341 ] In one embodiment of any of the compounds invention or a salt or ester thereof, so as to thereby treat the disclosed herein , R , is other than Cl, or other than SCHz. subject afflicted with borderline personality disorder. [0342 ] The present invention provides a pharmaceutical [0333 ] In some embodiments , a method of treating a composition comprising the compound of the present inven subject afflicted with opioid addiction comprising adminis tion and a pharmaceutically acceptable carrier . tering to the subject an effective amount of an NMDA receptor antagonist , an NMDA receptor partial agonist or a [ 0343 ] The present invention provides a pharmaceutical neurokinin 1 receptor antagonist and an effective amount of composition comprising the compound of the present inven the compound of the present invention or a salt or ester tion and an NMDA receptor antagonist , an NMDA receptor thereof, so as to thereby treat the subject afflicted with the partial agonist, a neurokinin 1 receptor antagonist, a neuro opioid addiction . kinin 2 receptor antagonist , a neurokinin 3 receptor antago [0334 ] In some embodiments , a method of treating a nist , a DOR agonist , naloxone or methylnaltrexone and a subject afflicted with opioid withdrawal symptoms compris pharmaceutically acceptable carrier . ing administering to the subject an effective amount of an [0344 ] The present invention provides a method of acti NMDA receptor antagonist , an NMDA receptor partial ago vating the mu- opioid receptor comprising contacting the nist or a neurokinin 1 receptor antagonist and an effective mu- opioid receptor with the compound of the present inven amount of the compound of the present invention or a salt or tion . ester thereof , so as to thereby treat the subject afflicted with [0345 ] The present invention provides a method of acti the opioid withdrawal symptoms. vating the delta -opioid receptor comprising contacting the [0335 ] In some embodiments , a method of treating a delta - opioid receptor with the compound of the present subject afflicted with opioid addiction or opioid withdrawal invention . symptoms comprising administering to the subject an effec [0346 ] The present invention provides a method of treat tive amount of naloxone or methylnaltrexone and an effec ing a subject afflicted with depression comprising adminis US 2020/0079745 A1 Mar. 12 , 2020 23 tering an effective amount of the compound of the present 1 receptor antagonist, or a DOR agonist in treating a subject invention to the subject so as to treat the subject afflicted afflicted with an anxiety disorder . with the depression . [ 0359 ] The present invention also provides a compound of [0347 ] The present invention provides a method of treat the present invention , or a salt or ester thereof, for use as an ing a subject afflicted with pain comprising administering an add -on therapy or in combination with an NMDA receptor effective amount of the compound of the present invention antagonist , an NMDA receptor partial agonist, a neurokinin to the subject so as to treat the subject afflicted with pain . 1 receptor antagonist or a DOR agonist in treating a subject [0348 ] The present invention provides a method of treat afflicted with borderline personality disorder. ing a subject afflicted with an anxiety disorder comprising [0360 ] The present invention also provides a compound of administering an effective amount of the compound of the the present invention , or a salt or ester thereof, for use as an present invention to the subject so as to treat the subject add - on therapy or in combination with an NMDA receptor afflicted with the anxiety disorder . antagonist , an NMDA receptor partial agonist or a neuroki [0349 ] The present invention provides a method of treat nin 1 receptor antagonist in treating a subject afflicted with ing a subject afflicted with borderline personality disorder opioid addiction or opioid withdrawal symptoms. comprising administering an effective amount of the com [ 0361 ] The present invention further provides a pharma pound of the present invention to the subject so as to treat the ceutical composition comprising an amount of a compound subject afflicted with borderline personality disorder . of the present invention , or a salt or ester thereof, and an [0350 ] The present invention provides a method of treat amount of a NMDA receptor antagonist , an NMDA receptor ing a subject afflicted with a depressive disorder comprising partial agonist , a neurokinin 1 receptor antagonist, a neuro administering an effective amount of the compound of the kinin 2 receptor antagonist , a neurokinin 3 receptor antago present invention to the subject so as to treat the subject nist , or a DOR agonist for use in treating a subject afflicted afflicted with the depressive disorder. with depression . [ 0351] The present invention provides a method of treat [0362 ] The present invention further provides a pharma ing a subject afflicted with a mood disorder comprising ceutical composition comprising an amount of a compound administering an effective amount of the compound of the of the present invention , or a salt or ester thereof, and an present invention to the subject so as to treat the subject amount of a NMDA receptor antagonist , an NMDA receptor afflicted with the mood disorder . partial agonist, a neurokinin 1 receptor antagonist or a DOR [0352 ] The present invention provides a method of treat agonist for use in treating a subject afflicted with pain . ing a subject afflicted with opioid addiction comprising [0363 ] The present invention further provides a pharma administering an effective amount of the compound of the ceutical composition comprising an amount of a compound present invention to the subject so as to treat the subject of the present invention , or a salt or ester thereof, and an afflicted with the opioid addiction . amountof a NMDA receptor antagonist , an NMDA receptor [0353 ] The present invention provides a method of treat partial agonist , a neurokinin 1 receptor antagonist , a neuro ing a subject afflicted with opioid withdrawal symptoms kinin 2 receptor antagonist, a neurokinin 3 receptor antago comprising administering an effective amount of the com nist, or a DOR agonist for use in treating a subject afflicted pound of the present invention to the subject so as to treat the with a depressive disorder or mood disorder. subject afflicted with the opioid withdrawal symptoms. [ 0364 ] The present invention further provides a pharma [0354 ] In some embodiments , the mu- opioid receptors or ceutical composition comprising an amount of a compound delta -opioid receptors are in a human subject. of the present invention , or a salt or ester thereof, and an [0355 ] The present invention also provides a compound of amount of a NMDA receptor antagonist, an NMDA receptor the present invention , or a salt or ester thereof, for use as an partial agonist, a neurokinin 1 receptor antagonist, or a DOR add -on therapy or in combination with an NMDA receptor agonist for use in treating a subject afflicted with an anxiety antagonist , an NMDA receptor partial agonist, a neurokinin disorder. 1 receptor antagonist , a neurokinin 2 receptor antagonist , a [0365 ] The present invention further provides a pharma neurokinin 3 receptor antagonist , or a DOR agonist in ceutical composition comprising an amount of a compound treating a subject afflicted with depression . of the present invention , or a salt or ester thereof, and an [0356 ] The present invention also provides a compound of amount of a NMDA receptor antagonist, an NMDA receptor the present invention , or a salt or ester thereof, for use as an partial agonist , a neurokinin 1 receptor antagonist or a DOR add - on therapy or in combination with an NMDA receptor agonist in treating a subject afflicted with borderline per antagonist, an NMDA receptor partial agonist, a neurokinin sonality disorder. 1 receptor antagonist or a DOR agonist in treating a subject [ 0366 ] The present invention further provides a pharma afflicted with pain . ceutical composition comprising an amount of a compound [ 0357 ] The present invention also provides a compound of of the present invention , or a salt or ester thereof, and an the present invention , or a salt or ester thereof , for use as an amount of an NMDA receptor antagonist, an NMDA recep add - on therapy or in combination with an NMDA receptor tor partial agonist or a neurokinin 1 receptor antagonist in antagonist , an NMDA receptor partial agonist, a neurokinin treating a subject afflicted with opioid addiction or opioid 1 receptor antagonist, a neurokinin 2 receptor antagonist, a withdrawal symptoms. neurokinin 3 receptor antagonist , or a DOR agonist in [ 0367 ] The present invention also provides a compound of treating a subject afflicted with a depressive disorder or the present invention , or a salt or ester thereof, for use as an mood disorder. add -on therapy or in combination with an SSRI or an SNRI [0358 ] The present invention also provides a compound of in treating a subject afflicted with a depressive disorder, a the present invention , or a salt or ester thereof, for use as an mood disorder, or borderline personality disorder. add - on therapy or in combination with an NMDA receptor [ 0368 ] The present invention also provides a compound of antagonist, an NMDA receptor partial agonist, a neurokinin the present invention , or a salt or ester thereof, for use as an US 2020/0079745 A1 Mar. 12 , 2020 24 add -on therapy or in combination with an SSRI or an SNRI receptor partial agonist, a neurokinin 1 receptor antago in treating a subject afflicted with an anxiety disorder. nist or a DOR agonist and a pharmaceutically accept [0369 ] The present invention also provides a compound of able carrier; the present invention , or a salt or ester thereof, and an [ 0389 ] b ) a second pharmaceutical composition com amount of an SSRI or an SNRI in treating a subject afflicted prising an amount of any compound of the present with a depressive disorder , a mood disorder , or borderline invention , or a salt or ester thereof; and personality disorder. [0390 ] c) instructions for use of the first and second [0370 ] The present invention also provides compound of pharmaceutical compositions together to treat a subject the present invention , or a salt or ester thereof, and an afflicted with borderline personality disorder. amount of an SSRI or an SNRI in treating a subject afflicted [0391 ] In some embodiments , a package comprising: with an anxiety disorder. [0392 ] a ) a first pharmaceutical composition comprising [0371 ] In some embodiments , a package comprising : an amount of an NMDA receptor antagonist , an NMDA [0372 ] a ) a first pharmaceutical composition comprising receptor partial agonist or a neurokinin 1 receptor an amount of an NMDA receptor antagonist , an NMDA antagonist and a pharmaceutically acceptable carrier; receptor partial agonist , a neurokinin 1 receptor antago [0393 ] b ) a second pharmaceutical composition com nist or a DOR agonist and a pharmaceutically accept prising an amount of any compound of the present able carrier ; invention , or a salt or ester thereof; and [0373 ] b ) a second pharmaceutical composition com [0394 ] c ) instructions for use of the first and second prising an amount of any compound of the present pharmaceutical compositions together to treat a subject invention , or a salt or ester thereof; and afflicted with opioid addiction or opioid withdrawal [0374 ] c ) instructions for use of the first and second pharmaceutical compositions together to treat a subject symptoms. afflicted with pain . [0395 ] The therapeutic package of the above embodiment, [0375 ] In some embodiments , a package comprising: wherein the respective amounts of said compound and said [0376 ] a ) a first pharmaceutical composition comprising agonist or antagonist in said unit dose when taken together an amount of an NMDA receptor antagonist , an NMDA is more effective to treat the subject than when compared to receptor partial agonist , a neurokinin 1 receptor antago the administration of said compound in the absence of said nist, a neurokinin 2 receptor antagonist, a neurokinin 3 agonist or antagonist or the administration of said agonist or receptor antagonist or a DOR agonist and a pharma antagonist in the absence of said compound . ceutically acceptable carrier ; [0396 ] In some embodiments , a therapeutic package for [0377 ] b ) a second pharmaceutical composition com dispensing to , or for use in dispensing to , a subject afflicted prising an amount of any compound of the present with pain , which comprises : invention , or a salt or ester thereof; and [ 0397 ] a ) one or more unit doses , each such unit dose [0378 ] c ) instructions for use of the first and second comprising : pharmaceutical compositions together to treat a subject [0398 ] (i ) an amount of any compound of the present afflicted with depression . invention , or a salt or ester thereof; and [ 0379 ] In some embodiments , a package comprising: [0399 ] ( ii ) an amount of an NMDA receptor antagonist , [0380 ] a ) a first pharmaceutical composition comprising an NMDA receptor partial agonist , a neurokinin 1 an amount of an NMDA receptor antagonist, an NMDA receptor antagonist or a DOR agonist , receptor partial agonist , a neurokinin 1 receptor antago [ 0400 ] wherein the respective amounts of said com nist , a neurokinin 2 receptor antagonist , a neurokinin 3 pound and said agonist or antagonist in said unit dose receptor antagonist, or a DOR agonist and a pharma are effective, upon concomitant administration to said ceutically acceptable carrier ; subject , to treat the subject, and [0381 ] b ) a second pharmaceutical composition com [0401 ] (b ) a finished pharmaceutical container therefor, prising an amount of any compound of the present said container containing said unit dose or unit doses , said invention , or a salt or ester thereof ; and container further containing or comprising labeling directing [0382 ] c ) instructions for use of the first and second the use of said package in the treatment of said subject . pharmaceutical compositions together to treat a subject [ 0402 ] In some embodiments , a therapeutic package for afflicted with a depressive disorder or mood disorder. dispensing to , or for use in dispensing to , a subject afflicted [ 0383] In some embodiments , a package comprising: with depression , which comprises : [0384 ] a ) a first pharmaceutical composition comprising [0403 ] a ) one or more unit doses, each such unit dose an amount of an NMDA receptor antagonist , an NMDA comprising : receptor partial agonist , a neurokinin 1 receptor antago [0404 ] (i ) an amount of any compound of the present nist or a DOR agonist and a pharmaceutically accept invention , or a salt or ester thereof; and able carrier ; [0405 ] (ii ) an amount of an NMDA receptor antagonist, [0385 ] b ) a second pharmaceutical composition com an NMDA receptor partial agonist , a neurokinin 1 prising an amount of any compound of the present receptor antagonist, a neurokinin 2 receptor antagonist, invention , or a salt or ester thereof; and a neurokinin 3 receptor antagonist, or a DOR agonist , [0386 ] c ) instructions for use of the first and second [0406 ] wherein the respective amounts of said com pharmaceutical compositions together to treat a subject pound and said agonist or antagonist in said unit dose afflicted with an anxiety disorder . are effective, upon concomitant administration to said [0387 ] In some embodiments , a package comprising: subject , to treat the subject, and [0388 ] a ) a first pharmaceutical composition comprising [ 0407 ] ( b ) a finished pharmaceutical container therefor, an amount of an NMDA receptor antagonist , an NMDA said container containing said unit dose or unit doses , said US 2020/0079745 A1 Mar. 12 , 2020 25

container further containing or comprising labeling directing [0427 ] a ) one or more unit doses, each such unit dose the use of said package in the treatment of said subject . comprising: [ 0408 ] In some embodiments , a therapeutic package for [0428 ] ( i) an amount of any compound of the present dispensing to , or for use in dispensing to , a subject afflicted invention , or a salt or ester thereof; and with a depressive disorder or mood disorder, which com [0429 ] (ii ) an amount of an NMDA receptor antagonist, prises : an NMDA receptor partial agonist or a neurokinin 1 [0409 ] a ) one or more unit doses, each such unit dose receptor antagonist, comprising : [ 0430 ] wherein the respective amounts of said com [ 0410 ] (i ) an amount of any compound of the present pound and said agonist or antagonist in said unit dose are effective, upon concomitant administration to said invention , or a salt or ester thereof; and subject , to treat the subject, and [0411 ] (ii ) an amount of an NMDA receptor antagonist , [0431 ] (b ) a finished pharmaceutical container therefor , an NMDA receptor partial agonist , a neurokinin 1 said container containing said unit dose or unit doses , said receptor antagonist , a neurokinin 2 receptor antagonist , container further containing or comprising labeling directing a neurokinin 3 receptor antagonist, or a DOR agonist , the use of said package in the treatment of said subject . [0412 ] wherein the respective amounts of said com [ 0432 ] The therapeutic package of the above embodiment, pound and said agonist or antagonist in said unit dose wherein the respective amounts of said compound and said are effective , upon concomitant administration to said agonist or antagonist in said unit dose when taken together subject, to treat the subject, and is more effective to treat the subject than when compared to [ 0413 ] (b ) a finished pharmaceutical container therefor, the administration of said compound in the absence of said said container containing said unit dose unit doses, said agonist or antagonist or the administration of said agonist or container further containing or comprising labeling directing antagonist in the absence of said compound . the use of said package in the treatment of said subject . [0433 ] [A1 ] [0414 ] In some embodiments , a therapeutic package for [0434 ] Apharmaceutical composition in unit dosage form , dispensing to , or for use in dispensing to , a subject afflicted useful in treating a subject afflicted with pain , which com with an anxiety disorder , which comprises : prises: [ 0415 ] a ) one or more unit doses, each such unit dose [ 0435 ] (i ) an amount of any compound of the present comprising: invention , or a salt or ester thereof; and [0416 ] ( i) an amount of any compound of the present [0436 ] (ii ) an amount of an NMDA receptor antagonist, invention , or a salt or ester thereof; and an NMDA receptor partial agonist, a neurokinin 1 [0417 ] ( ii ) an amount of an NMDA receptor antagonist , receptor antagonist, or a DOR agonist , an NMDA receptor partial agonist , a neurokinin 1 [ 0437 ] wherein the respective amounts of said com receptor antagonist , or a DOR agonist , pound and said agonist or antagonist in said composi [0418 ] wherein the respective amounts of said com tion are effective , upon concomitant administration to pound and said agonist or antagonist in said unit dose said subject of one or more of said unit dosage forms are effective, upon concomitant administration to said of said composition , to treat the subject . subject , to treat the subject, and [0438 ] A pharmaceutical composition in unit dosage form , [0419 ] ( b ) a finished pharmaceutical container therefor , useful in treating a subject afflicted with depression , which said container containing said unit dose or unit doses, said comprises : container further containing or comprising labeling directing [ 0439 ] ( i) an amount of any compound of the present the use of said package in the treatment of said subject . invention , or a salt or ester thereof; and [0440 ] (ii ) an amount of an NMDA receptor antagonist, [0420 ] In some embodiments , a therapeutic package for an NMDA receptor partial agonist, a neurokinin 1 dispensing to , or for use in dispensing to , a subject afflicted receptor antagonist, a neurokinin 2 receptor antagonist, with borderline personality disorder, which comprises : a neurokinin 3 receptor antagonist , or a DOR agonist , [0421 ] a ) one or more unit doses, each such unit dose [ 0441 ] wherein the respective amounts of said com comprising: pound and said agonist or antagonist in said composi [0422 ] (i ) an amount of any compound of the present tion are effective , upon concomitant administration to invention , or a salt or ester thereof; and said subject of one or more of said unit dosage forms [0423 ] ( ii ) an amount of an NMDA receptor antagonist , of said composition , to treat the subject . an NMDA receptor partial agonist, a neurokinin 1 [0442 ] A pharmaceutical composition in unit dosage form , receptor antagonist or a DOR agonist useful in treating a subject afflicted with a depressive dis [0424 ] wherein the respective amounts of said com order or mood disorder, which comprises : pound and said agonist or antagonist in said unit dose [0443 ] (i ) an amount of any compound of the present are effective, upon concomitant administration to said invention , or a salt or ester thereof; and subject , to treat the subject, and [0444 ] (ii ) an amount of an NMDA receptor antagonist, [0425 ] (b ) a finished pharmaceutical container therefor , an NMDA receptor partial agonist, a neurokinin 1 said container containing said unit dose or unit doses, said receptor antagonist, a neurokinin 2 receptor antagonist, container further containing or comprising labeling directing a neurokinin 3 receptor antagonist, or a DOR agonist , the use of said package in the treatment of said subject . [0445 ] wherein the respective amounts of said com [0426 ] In some embodiments , a therapeutic package for pound and said agonist or antagonist in said composi dispensing to , or for use in dispensing to , a subject afflicted tion are effective , upon concomitant administration to with opioid addiction or opioid withdrawal symptoms, said subject of one or more of said unit dosage forms which comprises: of said composition , to treat the subject. US 2020/0079745 A1 Mar. 12 , 2020 26

[0446 ] A pharmaceutical composition in unit dosage form , treating a subject afflicted with pain , a depressive disorder, useful in treating a subject afflicted with an anxiety disorder , a mood disorder , or borderline personality disorder . which comprises : [0447 ] (i ) an amount of any compound of the present [0462 ] The present invention further provides a pharma invention , or a salt or ester thereof; and ceutical composition comprising an amount of any of the [0448 ] ( ii) an amount of an NMDA receptor antagonist, compounds of the present invention , or a salt or ester an NMDA receptor partial agonist, a neurokinin 1 thereof, and an amount of an SSRI or an SNRI for use in receptor antagonist , or a DOR agonist , treating a subject afflicted with an anxiety disorder. [0449 ] wherein the respective amounts of said com [0463 ] The present invention also provides a method of pound and said agonist or antagonist in said composi treating a subject afflicted with a depressive disorder or tion are effective, upon concomitant administration to mood disorder comprising administering to the subject an said subject of one or more of said unit dosage forms effective amount of an NMDA receptor antagonist and an of said composition , to treat the subject . effective amount of any compound of the present invention , [0450 ] A pharmaceutical composition in unit dosage form , or a salt or ester thereof, so as to thereby treat the subject . useful in treating a subject afflicted with borderline person [ 0464 ] The present invention also provides a compound of ality disorder , which comprises : the present invention or a salt or ester thereof, for use as an [0451 ] (i ) an amount of any compound of the present add -on therapy or in combination with an NMDA receptor invention , or a salt or ester thereof; and antagonist , in treating a subject afflicted with a depressive [0452 ] ( ii ) an amount of an NMDA receptor antagonist , disorder or mood disorder. an NMDA receptor partial agonist, a neurokinin 1 receptor antagonist or a DOR agonist, [0465 ] The present invention further provides a pharma [0453 ] wherein the respective amounts of said com ceutical composition comprising an amount of any of the pound and said agonist or antagonist in said composi compounds of the present invention , or a salt or ester tion are effective , upon concomitant administration to thereof, and an amount of an NMDA receptor antagonist, for said subject of one or more of said unit dosage forms use in treating a subject afflicted with a depressive disorder of said composition , to treat the subject . or mood disorder. [0454 ] A pharmaceutical composition in unit dosage form , [0466 ] The present invention also provides a method of useful in treating a subject afflicted with opioid addiction or treating a subject afflicted with a depressive disorder or opioid withdrawal symptoms, which comprises : mood disorder comprising administering to the subject an [ 0455 ] ( i ) an amount of any compound of the present effective amount of an NMDA receptor partial agonist , and invention , or a salt or ester thereof; and an effective amount of any compound of the present inven [0456 ] ( ii) an amount of an NMDA receptor antagonist, tion , or a salt or ester thereof, so as to thereby treat the an NMDA receptor partial agonist or a neurokinin 1 subject. receptor antagonist , [0467 ] The present invention also provides a compound of [0457 ] wherein the respective amounts of said com the present invention or a salt or ester thereof, for use as an pound and said agonist or antagonist in said composi add -on therapy or in combination with an NMDA receptor tion are effective , upon concomitant administration to partial agonist in treating a subject afflicted with a depres said subject of one or more of said unit dosage forms of said composition , to treat the subject . sive disorder or mood disorder. [0458 ] The pharmaceutical composition of the above [0468 ] The present invention further provides a pharma embodiment, wherein the respective amounts of said com ceutical composition comprising an amount of any of the pound and said agonist or antagonist in said unit dose when compounds of the present invention , or a salt or ester taken together is more effective to treat the subject than thereof, and an amount of an NMDA receptor partial ago when compared to the administration of said compound in nist, for use in treating a subject afflicted with a depressive the absence of said agonist or antagonist or the administra disorder or mood disorder . tion of said agonist or antagonist in the absence of said [0469 ] The present invention also provides a method of compound. treating a subject afflicted with a depressive disorder or [0459 ] The present invention also provides a method of mood disorder comprising administering to the subject an treating a subject afflicted with pain , a depressive disorder, effective amount of a neurokinin 1 receptor antagonist and a mood disorder, or borderline personality disorder com an effective amount of any compound of the present inven prising administering to the subject an effective amount of tion , or a salt or ester thereof, so as to thereby treat the an SSRI or an SNRI and an effective amount of any subject. compound of the present invention , or a salt or ester thereof, so as to thereby treat the subject . [ 0470 ] The present invention also provides a compound of [0460 ] The present invention also provides a method of the present invention or a salt or ester thereof, for use as an treating a subject afflicted with an anxiety disorder compris add -on therapy or in combination with a neurokinin 1 ing administering to the subject an effective amount of an receptor antagonist in treating a subject afflicted with a SSRI or an SNRI and an effective amount of any compound depressive disorder or mood disorder . of the present invention , or a salt or ester thereof, so as to [ 0471] The present invention further provides a pharma thereby treat the subject . ceutical composition comprising an amount of any of the [0461 ] The present invention further provides a pharma compounds of the present invention , or a salt or ester ceutical composition comprising an amount of any of the thereof, and an amount of a neurokinin 1 receptor antagonist compounds of the present invention , or a salt or ester for use in treating a subject afflicted with a depressive thereof, and an amount of an SSRI or an SNRI for use in disorder or mood disorder. US 2020/0079745 A1 Mar. 12 , 2020 27

[0472 ] The present invention also provides a method of [0483 ] The present invention further provides a pharma treating subject afflicted with a depressive disorder or ceutical composition comprising an amount of any of the mood disorder comprising administering to the subject an compounds of the present invention , or a salt or ester effective amount of a neurokinin 2 receptor antagonist and thereof, and an amount of an NMDA receptor antagonist , for an effective amount of any compound of the present inven use in treating a subject afflicted with pain . tion , or a salt or ester thereof, so as to thereby treat the subject . [0484 ] The present invention also provides a method of [0473 ] The present invention also provides a compound of treating a subject afflicted with pain comprising administer the present invention or a salt or ester thereof, for use as an ing to the subject an effective amount of an NMDA receptor add - on therapy or in combination with a neurokinin 2 partial agonist , and an effective amount of any compound of receptor antagonist in treating a subject afflicted with a the present invention , or a salt or ester thereof, so as to depressive disorder or mood disorder. thereby treat the subject. [ 0474 ] The present invention further provides a pharma [0485 ] The present invention also provides a compound of ceutical composition comprising an amount of any of the compounds of the present invention , or a salt or ester the present invention or a salt or ester thereof, for use as an thereof, and an amount of a neurokinin 2 receptor antagonist add -on therapy or in combination with an NMDA receptor for use in treating a subject afflicted with a depressive partial agonist in treating a subject afflicted with pain . disorder or mood disorder. [ 0486 ] The present invention further provides a pharma [ 0475 ] The present invention also provides a method of ceutical composition comprising an amount of any of the treating a subject afflicted with a depressive disorder or compounds of the present invention , or a salt or ester mood disorder comprising administering to the subject an thereof, and an amount of an NMDA receptor partial ago effective amount of a neurokinin 3 receptor antagonist and nist , for use in treating a subject afflicted with pain . an effective amount of any compound of the present inven tion , or a salt or ester thereof, so as to thereby treat the [0487 ] The present invention also provides a method of subject. treating a subject afflicted with pain comprising administer [0476 ] The present invention also provides a compound of ing to the subject an effective amount of a neurokinin 1 the present invention or a salt or ester thereof, for use as an receptor antagonist and an effective amount of any com add - on therapy or in combination with a neurokinin 3 pound of the present invention , or a salt or ester thereof, so receptor antagonist in treating a subject afflicted with a as to thereby treat the subject. depressive disorder or mood disorder . [ 0488 ] The present invention also provides a compound of [0477 ] The present invention further provides a pharma the present invention or a salt or ester thereof, for use as an ceutical composition comprising an amount of any of the add -on therapy or in combination with a neurokinin 1 compounds of the present invention , or a salt or ester receptor antagonist in treating a subject afflicted with pain . thereof, and an amount of a neurokinin 3 receptor antagonist [0489 ] The present invention further provides a pharma for use in treating a subject afflicted with a depressive ceutical composition comprising an amount of any of the disorder or mood disorder. compounds of the present invention , or a salt or ester [ 0478 ] The present invention also provides a method of thereof, and an amount of a neurokinin 1 receptor antagonist treating a subject afflicted with a depressive disorder or for use in treating a subject afflicted with pain . mood disorder comprising administering to the subject an effective amount of a DOR agonist and an effective amount [0490 ] The present invention also provides a method of of any compound of the present invention , or a salt or ester treating a subject afflicted with pain comprising administer thereof, so as to thereby treat the subject . ing to the subject an effective amount of a DOR agonist and [0479 ] The present invention also provides a compound of an effective amount of any compound of the present inven the present invention or a salt or ester thereof, for use as an tion , or a salt or ester thereof, so as to thereby treat the add - on therapy or in combination with a DOR agonist in subject . treating a subject afflicted with a depressive disorder or [0491 ] The present invention also provides a compound of mood disorder. the present invention or a salt or ester thereof, for use as an [0480 ] The present invention further provides a pharma add - on therapy or in combination with a DOR agonist in ceutical composition comprising an amount of any of the treating a subject afflicted with pain . compounds of the present invention , or a salt or ester [ 0492 ] The present invention further provides a pharma thereof, and an amount of a DOR agonist for use in treating ceutical composition comprising an amount of any of the a subject afflicted with a depressive disorder or mood compounds of the present invention , or a salt or ester disorder. thereof, and an amount of a DOR agonist for use in treating [0481 ] The present invention also provides a method of treating a subject afflicted with pain comprising administer a subject afflicted with pain . ing to the subject an effective amount of an NMDA receptor [ 0493] In any of the embodiments of the present method , antagonist and an effective amount of any compound of the compound , package, use or pharmaceutical composition the present invention , or a salt or ester thereof, so as to thereby subject is afflicted with pain , depression , a depressive or treat the subject. mood disorder , an anxiety disorder , borderline personality [0482 ] The present invention also provides a compound of disorder , opioid addiction or opioid withdrawal symptoms. the present invention or a salt or ester thereof, for use as an [0494 ] In some embodiments of the present method , com add - on therapy or in combination with an NMDA receptor pound , package , use or pharmaceutical composition , the antagonist , in treating a subject afflicted with pain . compound has the structure : US 2020/0079745 A1 Mar. 12 , 2020 28

-continued 0

Br,

HN HN

MEO2C

EtO2C

HN HN

MEO2C

CO2Et

O

I, Br, HN HN

CO2Et HO2C US 2020/0079745 A1 Mar. 12 , 2020 29

-continued -continued

www

-I,

HN HN

HO2C 0

COH -I,

HN

HN

CO2H

CO2H

1,

HN

Br,

HN F

HO2C CO2H US 2020/0079745 A1 Mar. 12 , 2020 30

-continued -continued O

SMe, -SMe,

HN HN

CO2H CO2Et

Br,

HN F

CO2H HN

CI,

HN CI

CO2Et

CO2H

Br ,

HN CI,

HN F

CO2Et CO2H US 2020/0079745 A1 Mar. 12 , 2020 31

-continued -continued

I,

HN HN F

CO2H CO2Me

- Br, CI,

HN HN F

CO2Me

CO2H

.

CI, -CI, HN HN F CI

CO2Me CO2H

HN -CI, F

HN F

CO2Me CO2H US 2020/0079745 A1 Mar. 12. 2020 32

-continued

www .

CI, -Br,

HN H2N CI CI

CO2Et HO2C

CI I, HN F H2N

CO2Et or

HO2C

HN F I ,

H2N

CO2Et [0495 ] or a pharmaceutically acceptable salt or ester thereof . [0496 ] In some embodiments of the presentmethod , com pound , package , use or pharmaceutical composition , the CO2H compound has the structure : US 2020/0079745 A1 Mar. 12 , 2020 33

-continued -continued

O

Br,

H2N H2N F

CO2H

HO2C -SMe,

H2N -I,

H2N

CO2H

Br,

H2N CO2H

CO2H

O

CI, H2N HN

CO2H CO2H US 2020/0079745 A1 Mar. 12 , 2020 34

-continued -continued

CI, I, H2N H2N F F

CO2H O 0 CO2H

[0497 ] or an ester thereof. I , [0498 ] In some embodiments , a pharmaceutically accept able salt of any of the above compounds of the present H2N F invention . [ 0499 ] In some embodiments , a salt of the compound of the present invention is used in any of the above methods , uses, packages or compositions. [0500 ] In some embodiments, a pharmaceutically accept able salt of the compound of the present invention is used in CO2H any of the above methods, uses , packages or compositions . ( 0501 ] In some embodiments , an ester of the compound of the present invention is used in any of the above methods, uses, packages or compositions . [ 0502 ] Any of the above compounds may be used in any -CI , of the disclosed methods, uses, packages or pharmaceutical compositions. HÖN + CI [0503 ] Any of the compounds used in the disclosed meth ods, uses , packages or pharmaceutical compositionsmay be C1 replaced with any other compound disclosed in the present invention . [0504 ] Any of the above generic compounds may be used in any of the disclosed methods, uses , packages or compo sitions . [0505 ] In some embodiments , the methods, uses , packages CO2H or pharmaceutical compositions of the present invention wherein the depressive disorder includes, but is not limited to , depression , major depression , dysthymia , postpartum depression , seasonal affective disorder , atypical depression , psychotic depression , bipolar disorder , premenstrual dys phoric disorder, situational depression or adjustment disor Ci or der with depressed mood . Depressive disorders can also include other mood disorders and is not limited to the above H2N list . F [ 0506 ] In some embodiments , themethods , uses , packages or pharmaceutical compositions of the present invention wherein the depressive disorder is cyclothymia . [ 0507 ] In some embodiments , the methods, uses, packages or pharmaceutical compositions of the present invention wherein the anxiety disorder includes, but is not limited to , anxiety , post -traumatic stress disorder (PTSD ), acute stress disorder , generalized anxiety disorder (GAD ) , obsessive CO2H compulsive disorder (OCD ), panic disorder , social phobia or social anxiety disorder . US 2020/0079745 A1 Mar. 12 , 2020 35

( 0508 ] In some embodiments , themethods , uses , packages [0518 ] The term “ MOR agonist” is intended to mean any or pharmaceutical compositions of the present invention compound or substance that activates the mu- opioid receptor wherein the pain includes , but is not limited to , chronic pain (MOR ). The agonist may be a partial, full or super agonist. or acute pain . [ 0519 ] The term “ DOR agonist ” is intended to mean any [0509 ] In some embodiments , the methods, uses, packages compound or substance that activates the delta -opioid recep or pharmaceutical compositions wherein the opioid addic tor (DOR ). The agonist may be a partial, full or super tion includes, but is not limited to , addiction to codeine , agonist . hydrocodone , morphine, oxycodone, hydromorphone , oxy [0520 ] The term “ super agonist” is intended to mean a morphone, fentanyl or heroin . compound or substance that activates a receptor with a [ 0510 ] In some embodiments , the methods, uses , packages greater maximal response (higher Emax ) than said receptor's or pharmaceutical compositions wherein the opioid with primary endogenous ligand . drawal symptoms include, but are not limited to , agitation , [0521 ] In some embodiments , the compound is prepared anxiety , muscle aches , increased tearing, insomnia , runny by the following process: nose , sweating , yawning , abdominal cramping , diarrhea , dilated pupils , goose bumps, nausea or vomiting . [ 0511 ] In some embodiments , the NMDA receptor antago Ri nist is an arylcyclohexylamine , dextromorphinan or ada mantane . H2N CO2R [ 0512 ] In some embodiments , the NMDA receptor antago nist is dextromethorphan , dextrorphan , dextrallorphan , R3 Base memantine , amantadine , rimantadine, nitromemantine Suitable Solvent (YQW - 36 ) , ketamine ( and its analogs , e.g. tiletamine ), phen CI Heat cyclidine (and its analogs, e.g. tenocyclidine , eticyclidine , rolicyclidine ), methoxetamine ( and its analogs) , gacyclidine R1 (GK - 11) , neramexane, lanicemine (AZD6765 ) , diphenidine , dizocilpine (MK - 801) , 8a -phenyldecahydroquinoline (8A X , PDHQ ), remacemide, ifenprodil , traxoprodil ( CP - 101,606 ), eliprodil (SL -82.0715 ) , etoxadrol (CL - 1848C ) , dexoxadrol, WMS- 2539 , NEFA , delucemine (NPS - 1506 ) , aptiganel ( Cerestat ; CNS -1102 ) , midafotel (CPPene ; SDZ EAA 494 ) , R3N dexanabinol (HU - 211 or ETS2101 ), selfotel (CGS - 19755 ) , ) 7 -chlorokynurenic acid ( 7 - CKA ) , 5,7 - dichlorokynurenic acid (5,7 -DCKA ) , L -683344 , L -689560 , L - 701324 , ROC GV150526A , GV196771A , CERC - 301 ( formerly MK - 0657 ) , atomoxetine , LY - 235959 , CGP 61594 , CGP [0522 ] wherein R is -( alkyl ) ; R , is -H or - ( alkyl ) ; Rz is 37849 , CGP 40116 ( active enantiomer of CG 37849) , Hor - ( alkyl ) ; X = Br, I, —SMe, CH = CH2, or LY -233536 , PEAQX (NVP -AAM077 ), ibogaine , noribo C = CH ; and n = 7-20 . gaine, Ro 25-6981, GW468816 , EVT - 101 , indantadol, per [ 0523 ] In some embodiments , the compound is prepared zinfotel (EAA -090 ) , SSR240600 , 2- MDP (U - 23807A ) or by the following process : AP - 7 . [0513 ] In some embodiments , the NMDA receptor partial agonist is NRX - 1074 or rapastinel (GLYX - 13 ). R1 [0514 ] In some embodiments , the neurokinin 1 receptor antagonist is aprepitant, fosaprepitant, casopitant, maropi H2N CO2R tant, vestipitant, vofopitant, lanepitant, orvepitant, ezlopi X tant, netupitant, rolapitant, L -733060 , L - 703606 , L - 759274 , R3 L -822429 , L - 760735 , L -741671 , L -742694 , L - 732138 , EtzN CP - 122721 , RPR - 100893, CP - 96345 , CP - 99994 , TAK - 637 , CI MeNO2, 60 ° C. T - 2328 , CJ - 11974 , RP 67580 , NKP608 , VPD -737 , GR R1 205171 , LY686017 , AV608 , SR140333B , SSR240600C , FK 888 or GR 82334 . [ 0515 ] In some embodiments , the neurokinin 2 receptor X , antagonist is saredutant, ibodutant, nepadutant, GR -159897 or MEN - 10376 . [0516 ] In some embodiments , the neurokinin 3 receptor RŽN antagonist is osanetant, talnetant, SB - 222200 or SB - 218795 . ) [0517 ] In some embodiments , the DOR agonist is tianep tine, (+ )BW373U86 , SNC - 80 , SNC - 121, SNC - 162, DPI RO2C 287 , DPI- 3290 , DPI- 221 , TAN -67 , KN - 127 , AZD2327 , JNJ 20788560 , NIH11082 , RWJ- 394674 , ADL5747 , ADL5859 , [0524 ] wherein R is - (alkyl ) ; R1 is H or -( alkyl ) ; R3 is UFP -512 , AR -M100390 , SB -235863 or 7 - spiroindanyloxy H or - (alkyl ) ; X = Br, I , SMe, CH = CH2, or morphone. C = CH ; and n = 7-20 . US 2020/0079745 A1 Mar. 12 , 2020 36

[ 0525 ] In some embodiments , the compound is prepared [0530 ] In some embodiments , the compound is prepared by the following process: by the following process:

R1 R1 R3H2N CI ) n X Acid RO2C Heat Base Y Suitable Solvent R3N Heat Y2 RO2C R1 Ri

X Y R3N HR3N Y2 )n HO2C RO2C [0531 ] wherein R is -( alkyl ) ; R is H or -( alkyl ) ; Rz is [0526 ] wherein R is - (alkyl ) ; R1 is H or - ( alkyl) ; Rz is -H or - (alkyl ) ; Y1 = C1, Br or I ; Y = F , C1, Br or I ; and H or - (alkyl ) ; X = Br, I , SMe, CH = CH2, or n = 7-20 . C = CH ; and n = 7-20 . [0532 ] In some embodiments , the compound is prepared [0527 ] In one embodiment of the above process , the acid by the following process : is aqueous acid . [0528 ] In some embodiments , the compound is prepared by the following process : # R1 R3H2N In R1 RO2C EtzN X Y1 MeNO2 0.5M aq . HCI 60 ° C. 80 ° C. Y2 R3N 20

ROC R ]

Ri Y 1,

X R3N Y2 RO2C HR3N

HO2C

[ 0529 ] wherein R is - (alkyl ) ; R1 is -H or - (alkyl ) ; Rz is [0533 ] wherein R is - (alkyl ) ; R1 is H or -( alkyl ) ; R3 is H or ( alkyl) ; X = Br, I, SMe, CH = CH2, or H or - ( alkyl ) ; Y = Cl, Br or I ; Y = F , C1, Br or 1 ; and C = CH ; and n = 7-20 . n = 7-20 . US 2020/0079745 A1 Mar. 12 , 2020 37

[0534 ] In some embodiments , the compound is prepared [0541 ] In some embodiments , the compound having the by the following process: structure ,

R1 0 O

Y1 Acid ·Rs Heat NH R3N R2 In ROC [0542 ] wherein [0543 ] R , is Cl, Br, I, SMe or CECH , [ 0544 ] R2 is (C3-5 alkyl) -CO2H or (C3-5 alkyl) -CO2 ( alkyl) , Y1 [0545 ] wherein the F is 18F . R3HN [ 0546 ] In some embodiments , the compound having the Y2 structure , HO2C [ 0535 ] wherein R is -( alkyl ) ; R1 is H or -( alkyl ) ; Rz is H or - ( alkyl) ; Y = Cl, Br or I ; Y = F , C1, Br or I ; and n = 7-20 . R5 [0536 ] In one embodiment of the above process, the acid is aqueous acid . NH [ 0537 ) In some embodiments , the compound is prepared R2 F by the following process :

Ri 0 0 [0547 ] wherein -Y1 0.5M aq . HCI [ 0548 ] R , is Cl, Br, I, SMe or C = CH, 80 ° C. [ 0549 ] R2 is (C. alkyl )-CO , H or C alkyl )-CO2 R3N (alkyl ) , Y2 In [0550 ] wherein the F is 18F . ROC [ 0551 ] In some embodiments , the compound having the Ri structure ,

S

-Y R3HN Y2 R5

NH HO2C R2 F [0538 ] wherein R is -( alkyl ) ; Ry is -H or - (alkyl ) ; Rz is -H or -( alkyl ) ; Y1 = Cl, Br or I; Y = F, C1, Br or I ; and [0552 ] wherein n = 7-20 . [ 0553 ] R , is Cl, Br, I, SMe or C = CH, [0539 ] In one embodiment, wherein when F is present in the compound , the F is 18F . [0554 ] R , is (C7-10 alkyl) -CO ,H or - C7-10 alkyl) -CO2 [0540 ] In one embodiment, wherein when F is present in (alkyl ) , the compound at Ro , the F is 18F . [0555 ] wherein the F is 18F . US 2020/0079745 A1 Mar. 12 , 2020 38

[ 0556 ] In some embodiments , the compound having the -continued structure , O

CI,

H?N Br, F

HN F

CO2H

CO2H

www

I, Br , HN

H2N F

CO2H CO2H

-CI, H2N HN F F

CO2H CO2H US 2020/0079745 A1 Mar. 12 , 2020 39

-continued -continued

Br, Br,

HN H2N F CLO

CO2H

CO2Et -CI,

HN . F

-CI, CO2H

HN F

-I,

H2N . F CO2Et

CO2H

HN F Br,

HN

CO2Et CO2H US 2020/0079745 A1 Mar. 12 , 2020 40

-continued -continued

-CI, I ,

HN HN F F

CO2H CO2Me 0 [0557 ] wherein the F is 18F . [0558 ] In some embodiments , a pharmaceutical composi tion comprising the compound of the present invention containing an 18F and a pharmaceutically acceptable carrier . HN [0559 ] In some embodiments , a pharmaceutical composi F tion comprising the compound of the present invention containing an F , the same compound of the present invention containing an 18F, and a pharmaceutically acceptable carrier. [ 0560] In some embodiments , a method of detecting the presence of mu -opioid receptors in the brain of a subject which comprises determining if an amount of the compound CO2H of the present invention containing an 18F is present in the brain of the subject at a period of time after administration of the compound or salt thereof to the subject, thereby detecting the presence of the mu- opioid receptors based on the amount of the compound determined to be present in the brain of the subject. [ 0561 ] In some embodiments , a method of detecting the Br , location of mu- opioid receptors in the brain of a subject which comprises determining where an amount of the com HN pound of the present invention containing an 18F is present in the subject at a period of time after administration of the compound or salt thereof to the subject, thereby detecting the location of themu - opioid receptors based on the location of the compound determined to be present in the subject . [0562 ] In some embodiments , a method of quantifying the CO2Me occupancy of mu- opioid receptors by a compound of the present invention or another compound binding to mu opioid receptors in the brain of a subject , which comprises determining the binding competition between said com pound and a second compound of the present invention containing an 18F at a period of time after administration of the compounds or salts thereof to the subject , thereby detecting the occupancy of the mu- opioid receptors based on the displacement of the compound containing 18F by the CI or other compound . [ 0563] In some embodiments , a method of quantifying the HN occupancy of mu -opioid receptors by endogenous opioid F peptides in the brain of a subject, which comprises deter mining the binding competition between said endogenous opioid peptides and a compound of the present invention containing an 18F at a period of time after administration of the compound to the subject, thereby detecting the occu pancy of the mu- opioid receptors based on the displacement CO2Me of the compound containing 18F by the endogenous opioid peptides. US 2020/0079745 A1 Mar. 12 , 2020 41

[ 0564 ] In some embodiments , the method wherein the [ 0575 ] It will be noted that any notation of a carbon in compound binding to mu- opioid receptors in the brain of a structures throughout this application , when used without subject is the compound of the present invention . further notation , are intended to represent all isotopes of [ 0565] In some embodiments , the method wherein the carbon , such as 12C , 13C , or 14C . Furthermore , any com compound binding to mu -opioid receptors in the brain of a pounds containing 13C or 14C may specifically have the subject is the compound of the present invention containing structure of any of the compounds disclosed herein . an 18F . [0576 ] It will also be noted that any notation of a hydrogen [0566 ] In some embodiments , the method further com in structures throughout this application , when used without prising quantifying the amount of the compound containing further notation , are intended to represent all isotopes of 18F in the subject and comparing the quantity to a prede hydrogen , such as ' H , 2H , or ’ H. Furthermore , any com termined control. pounds containing ? H or H may specifically have the structure of any of the compounds disclosed herein . [0567 ] In some embodiments , the method wherein the [0577 ] Isotopically - labeled compounds can generally be determining is performed by a Positron Emission Tomog prepared by conventional techniques known to those skilled raphy (PET ) device . in the art using appropriate isotopically - labeled reagents in [0568 ] In some embodiments , the method further com place of the non - labeled reagents employed . prising determining whether the subject is afflicted with a [0578 ] In the compounds used in the method of the present disease associated with dysregulation , up -regulation or invention , the substituents may be substituted or unsubsti down - regulation ofmu - opioid receptor based on the amount tuted , unless specifically defined otherwise . of the compound containing 18F in the subject or its location [ 0579 ] In the compounds used in themethod of the present in the subject. invention , alkyl , heteroalkyl, monocycle , bicycle , aryl, het [0569 ] In some embodiments, the method further com eroaryl and heterocycle groups can be further substituted by prising determining whether the subject is afflicted with a replacing one or more hydrogen atoms with alternative disease associated with dysregulation , up - regulation or non -hydrogen groups . These include, but are not limited to , down- regulation of release of endogenous opioid peptides halo , hydroxy, mercapto , amino , carboxy, cyano and car based on displacement of the compound containing 18F from bamoyl. mu- opioid receptors in the subject . [0580 ] It is understood that substituents and substitution [0570 ] In some embodiments , the method further com patterns on the compounds used in the method of the present prising determining whether the subject is afflicted with a invention can be selected by one of ordinary skill in the art disease associated with dysregulation , up - regulation or to provide compounds that are chemically stable and that down- regulation of release of endogenous opioid peptides can be readily synthesized by techniques known in the art based on displacement of the compound containing 18F from from readily available starting materials . If a substituent is mu -opioid receptors in the subject. itself substituted with more than one group , it is understood [ 0571 ] In some embodiments , the method wherein the that these multiple groups may be on the same carbon or on disease is a depressive disorder , a mood disorder, pain , an different carbons, so long as a stable structure results . anxiety disorder or borderline personality disorder. [0581 ] In choosing the compounds used in the method of [ 0572 ] Additional synthetic methods for preparation of the the present invention , one of ordinary skill in the art will disclosed compounds are found in PCT International Appli recognize that the various substituents , i.e. R1, R2, etc. are to cation No. PCT/ US2015 /020273 , filed Mar. 12 , 2015 , the be chosen in conformity with well -known principles of contents of which are hereby incorporated by reference . chemical structure connectivity . [ 0573 ] Except where otherwise specified , the structure of [0582 ] As used herein , “ alkyl” is intended to include both a compound of this invention includes an asymmetric carbon branched and straight- chain saturated aliphatic hydrocarbon atom , it is understood that the compound occurs as a groups having the specified number of carbon atoms. Thus , racemate , racemic mixture , and isolated single enantiomer . CZ - C as in “ C -Cn alkyl” is defined to include groups All such isomeric forms of these compounds are expressly having 1, 2 ... , n - 1 or n carbons in a linear or branched included in this invention . Except where otherwise specified , arrangement, and specifically includes methyl, ethyl, propyl, each stereogenic carbon may be of the Ror S configuration . butyl , pentyl, hexyl, heptyl, isopropyl, isobutyl , sec -butyl It is to be understood accordingly that the isomers arising and so on . An embodiment can be C - C12 alkyl, C2 -C12 from such asymmetry ( e.g. , all enantiomers and diastereom alkyl, Cz -C12 alkyl, C4- C12 alkyl and so on . An embodiment ers ) are included within the scope of this invention , unless can be C , -C , alkyl, C2- C , alkyl, C3- C , alkyl, C4 - C , alkyl indicated otherwise . Such isomers can be obtained in sub and so on . “ Alkoxy ” represents an alkyl group as described stantially pure form by classical separation techniques and above attached through an oxygen bridge . by stereochemically controlled synthesis , such as those [0583 ] The term “ alkenyl” refers to a non - aromatic hydro described in “ Enantiomers , Racemates and Resolutions” by carbon radical, straight or branched , containing at least 1 J. Jacques, A. Collet and S. Wilen , Pub . John Wiley & Sons, carbon to carbon double bond , and up to the maximum N Y , 1981. For example , the resolution may be carried out possible number of non - aromatic carbon - carbon double by preparative chromatography on a chiral column. bonds may be present. Thus, C2 -Cn alkenyl is defined to [ 0574 ] The subject invention is also intended to include all include groups having 1 , 2 ... n - 1 or n carbons. For isotopes of atoms occurring on the compounds disclosed example , “ C2- C6 alkenyl ” means an alkenyl radical having herein . Isotopes include those atomshaving the same atomic 2 , 3 , 4 , 5 , or 6 carbon atoms, and at least 1 carbon - carbon number but different mass numbers . By way of general double bond , and up to , for example , 3 carbon - carbon example and without limitation , isotopes of hydrogen double bonds in the case of a Co alkenyl, respectively . include tritium and deuterium . Isotopes of carbon include Alkenyl groups include ethenyl, propenyl, butenyl and C - 13 and C - 14 . cyclohexenyl. As described above with respect to alkyl, the US 2020/0079745 A1 Mar. 12 , 2020 42 straight, branched or cyclic portion of the alkenyl group may contains from 1 to 4 heteroatoms selected from the group contain double bonds and may be substituted if a substituted consisting of O , N and S. Bicyclic aromatic heteroaryl alkenyl group is indicated . An embodiment can be C2- C12 groups include phenyl, pyridine , pyrimidine or pyridazine alkenyl or C2- Cg alkenyl. rings that are (a ) fused to a 6 -membered aromatic (unsatu [ 0584 ] The term “ alkynyl ” refers to a hydrocarbon radical rated ) heterocyclic ring having one nitrogen atom ; ( b ) fused straight or branched , containing at least 1 carbon to carbon to a 5- or 6 -membered aromatic ( unsaturated ) heterocyclic triple bond , and up to the maximum possible number of ring having two nitrogen atoms; ( c) fused to a 5 -membered non - aromatic carbon -carbon triple bonds may be present. aromatic (unsaturated ) heterocyclic ring having one nitrogen Thus, C2 -Cn alkynyl is defined to include groups having 1 , atom together with either one oxygen or one sulfur atom ; or 2 n - 1 or n carbons. For example , " C2- C , alkynyl ” ( d ) fused to a 5 -membered aromatic (unsaturated ) hetero means an alkynyl radical having 2 or 3 carbon atoms, and 1 cyclic ring having one heteroatom selected from 0 , N or S. carbon -carbon triple bond , or having 4 or 5 carbon atoms, Heteroaryl groups within the scope of this definition include and up to 2 carbon - carbon triple bonds , or having 6 carbon but are not limited to : benzoimidazolyl, benzofuranyl, ben atoms, and up to 3 carbon - carbon triple bonds. Alkynyl zofurazanyl , benzopyrazolyl , benzotriazolyl, benzothiophe groups include ethynyl, propynyl and butynyl. As described nyl, benzoxazolyl , carbazolyl , carbolinyl, cinnolinyl, fura above with respect to alkyl, the straight or branched portion nyl, indolinyl, indolyl, indolazinyl, indazolyl, of the alkynyl group may contain triple bonds and may be isobenzofuranyl , isoindolyl , isoquinolyl, isothiazolyl, isox substituted if a substituted alkynyl group is indicated . An azolyl, naphthpyridinyl, oxadiazolyl, oxazolyl , oxazoline , embodiment can be a C2- Cn alkynyl. An embodiment can be isoxazoline , oxetanyl, pyranyl , pyrazinyl, pyrazolyl , C2 -C12 alkynyl or Cz - C , alkynyl. pyridazinyl, pyridopyridinyl , pyridazinyl, pyridyl , pyrim [ 0585 ] As used herein , “ hydroxyalkyl” includes alkyl idyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl , tetra groups as described above wherein one or more bonds to zolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl , thienyl, triaz hydrogen contained therein are replaced by a bond to an olyl, azetidinyl, aziridinyl, 1,4 -dioxanyl , OH group . In some embodiments , C , -C12 hydroxyalkyl or hexahydroazepinyl, dihydrobenzoimidazolyl , dihydroben C1 -C5 hydroxyalkyl . C , -Cn as in “ C7- C , alkyl” is defined to zofuranyl , dihydrobenzothiophenyl , dihydrobenzoxazolyl, include groups having 1, 2 , ... , n - 1 or n carbons in a linear dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihy or branched arrangement ( e.g. C. - C , hydroxyalkyl, C , -CZ droisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl , hydroxyalkyl, C , -C4 hydroxyalkyl, C -C5 hydroxyalkyl , or dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl , dihy C - Cg hydroxyalkyl) For example , C.-C., as in “ C - C6 dropyridinyl, dihydropyrimidinyl, dihydropyrrolyl , dihydro hydroxyalkyl” is defined to include groups having 1 , 2 , 3 , 4 , quinolinyl , dihydrotetrazolyl, dihydrothiadiazolyl, dihy 5 , or 6 carbons in a linear or branched alkyl arrangement drothiazolyl, dihydrothienyl, dihydrotriazolyl, wherein a hydrogen contained therein is replaced by a bond dihydroazetidinyl, methylenedioxybenzoyl, tetrahydrofura to an OH group nyl , tetrahydrothienyl, acridinyl, carbazolyl , cinnolinyl, qui [ 0586 ] As used herein , " heteroalkyl ” includes both noxalinyl, pyrrazolyl, indolyl, benzotriazolyl, benzothiaz branched and straight- chain saturated aliphatic hydrocarbon olyl, benzoxazolyl, isoxazolyl, isothiazolyl, furanyl , thienyl , groups having the specified number of carbon atoms and at benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl, least 1 heteroatom within the chain or branch . oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridi [0587 ] As used herein , “monocycle ” includes any stable nyl , pyrimidinyl, pyrrolyl, tetra -hydroquinoline . In cases polyatomic carbon ring of up to 10 atoms and may be where the heteroaryl substituent is bicyclic and one ring is unsubstituted or substituted . Examples of such non - aromatic non - aromatic or contains no heteroatoms, it is understood monocycle elements include but are not limited to : cyclobu that attachment is via the aromatic ring or via the heteroatom tyl, cyclopentyl, cyclohexyl, and cycloheptyl. Examples of containing ring, respectively . If the heteroaryl contains nitro such aromatic monocycle elements include but are not gen atoms, it is understood that the corresponding N -oxides limited to : phenyl. thereof are also encompassed by this definition . [0588 ] As used herein , “ bicycle ” includes any stable poly [0591 ] The term “ heterocycle ” , “ heterocyclyl” or “ hetero atomic carbon ring of up to 10 atoms that is fused to a cyclic ” refers to a mono- or poly - cyclic ring system which polyatomic carbon ring of up to 10 atoms with each ring can be saturated or contains one or more degrees of unsatu being independently unsubstituted or substituted . Examples ration and contains one or more heteroatoms. Preferred of such non -aromatic bicycle elements include but are not heteroatoms include N , O , and / or S , including N - oxides , limited to : decahydronaphthalene . Examples of such aro sulfur oxides, and dioxides . Preferably the ring is three to matic bicycle elements include but are not limited to : ten -membered and is either saturated or has one or more naphthalene . degrees of unsaturation . The heterocycle may be unsubsti [0589 ] As used herein , “ aryl” is intended to mean any tuted or substituted , with multiple degrees of substitution stable monocyclic , bicyclic or polycyclic carbon ring of up being allowed . Such rings may be optionally fused to one or to 10 atoms in each ring , wherein at least one ring is more of another “ heterocyclic ” ring( s ), heteroaryl ring (s ) , aromatic , and may be unsubstituted or substituted . Examples aryl ring ( s ) , or cycloalkyl ring ( s ). Examples of heterocycles of such aryl elements include but are not limited to : phenyl, include , but are not limited to , tetrahydrofuran , pyran , p - toluenyl ( 4 -methylphenyl ) , naphthyl, tetrahydro -naphthyl , 1,4 - dioxane , 1,3 - dioxane, piperidine , piperazine , pyrroli indanyl, phenanthryl , anthryl or acenaphthyl . In cases where dine , morpholine , thiomorpholine , tetrahydrothiopyran , tet the aryl substituent is bicyclic and one ring is non -aromatic , rahydrothiophene , 1,3 -oxathiolane , and the like . it is understood that attachment is via the aromatic ring . [0592 ] The term “ ester ” is intended to a mean an organic [0590 ] The term " heteroaryl” , as used herein , represents a compound containing the R_0_0_R ' group . stable monocyclic , bicyclic or polycyclic ring of up to 10 [0593 ] The term “ substitution ” , “ substituted ” and “ sub atoms in each ring , wherein at least one ring is aromatic and stituent” refers to a functional group as described above in US 2020/0079745 A1 Mar. 12 , 2020 43 which one or more bonds to a hydrogen atom contained 2010 ), which are hereby incorporated by reference. Phar therein are replaced by a bond to non -hydrogen or non maceutically active agents which have pendant carboxylic carbon atoms, provided that normal valencies are main acid groups may be modified in accordance with the present tained and that the substitution results in a stable compound . invention using standard esterification reactions and meth Substituted groups also include groups in which one ormore ods readily available and known to those having ordinary bonds to a carbon ( s ) or hydrogen ( s ) atom are replaced by skill in the art of chemical synthesis . Where a pharmaceu one or more bonds, including double or triple bonds, to a tically active agent does not possess a carboxylic acid group , heteroatom . Examples of substituent groups include the the ordinarily skilled artisan will be able to design and functional groups described above, and halogens ( i.e., F, CI, incorporate a carboxylic acid group into the pharmaceuti Br, and I) ; alkyl groups, such as methyl, ethyl , n -propyl , cally active agent where esterification may subsequently be isopropryl, n - butyl, tert - butyl, and trifluoromethyl ; carried out so long as the modification does not interfere hydroxyl; alkoxy groups , such as methoxy, ethoxy, with the pharmaceutically active agent's biological activity n -propoxy , and isopropoxy ; aryloxy groups, such as phe or effect. noxy ; arylalkyloxy, such as benzyloxy (phenylmethoxy ) and [ 0599 ] The compounds used in the method of the present p - trifluoromethylbenzyloxy ( 4 -trifluoromethylphenyl invention may be in a salt form . As used herein , a “ salt” is methoxy ) ; heteroaryloxy groups ; sulfonyl groups , such as a salt of the instant compounds which has been modified by trifluoromethanesulfonyl, methanesulfonyl, and p -toluene making acid or base salts of the compounds. In the case of sulfonyl ; nitro , nitrosyl ; mercapto ; sulfanyl groups , such as compounds used to treat an infection or disease caused by a methylsulfanyl , ethylsulfanyl and propylsulfanyl; cyano ; pathogen , the salt is pharmaceutically acceptable . Examples amino groups, such as amino ,methylamino , dimethylamino , of pharmaceutically acceptable salts include, but are not ethylamino , and diethylamino ; and carboxyl. Where mul limited to , mineral or organic acid salts of basic residues tiple substituent moieties are disclosed or claimed , the such as amines; alkali or organic salts of acidic residues such substituted compound can be independently substituted by as phenols ; alkali or organic salts of acidic residues such as one ormore of the disclosed or claimed substituent moieties , carboxylic acids. The salts can be made using an organic or singly or plurally . By independently substituted , it is meant inorganic acid . Such acid salts are chlorides, bromides, that the (two or more ) substituents can be the same or sulfates, nitrates, phosphates , sulfonates, formates , tartrates, different . maleates , malates, citrates , benzoates , salicylates , ascor [ 0594 ] The compounds used in the method of the present bates, and the like . Phenolate salts are the alkali metal salts , invention may be prepared by techniques well known in sodium , potassium or lithium . The salts can be made using organic synthesis and familiar to a practitioner ordinarily an organic or inorganic base. Such basic salts are alkali skilled in the art. However, these may not be the only means metal salts , such as sodium , potassium or lithium and by which to synthesize or obtain the desired compounds . alkaline earth metal salts , such as magnesium and calcium . [0595 ] The compounds used in the method of the present [ 0600 ] The term “ pharmaceutically acceptable salt” in this invention may be prepared by techniques described in respect, refers to the relatively non - toxic , inorganic and Vogel's Textbook of Practical Organic Chemistry, A. I. organic acid or base addition salts of compounds of the Vogel , A. R. Tatchell , B. S. Furnis , A. J. Hannaford , P. W.G. present invention . These salts can be prepared in situ during Smith , ( Prentice Hall) 5th Edition (1996 ), March’s Advanced the final isolation and purification of the compounds of the Organic Chemistry : Reactions, Mechanisms, and Structure , invention , or by separately reacting a purified compound of Michael B. Smith , Jerry March , (Wiley - Interscience ) 5th the invention in its free base or free acid form with a suitable Edition (2007 ), and references therein , which are incorpo organic or inorganic acid or base, and isolating the salt thus rated by reference herein . However, these may not be the formed . Representative salts include the hydrobromide , only means by which to synthesize or obtain the desired hydrochloride, sulfate , bisulfate , phosphate , nitrate , acetate , compounds. valerate , oleate , palmitate , stearate , laurate , benzoate , lac [ 0596 ] The various R groups attached to the aromatic rings tate , phosphate , tosylate , citrate , maleate , fumarate , succi of the compounds disclosed herein may be added to the rings nate , tartrate , napthylate , mesylate , glucoheptonate, lactobi by standard procedures, for example those set forth in onate , and laurylsulphonate salts and the like . Advanced Organic Chemistry : Part B : Reactions and Syn Representative salts also include the sodium , potassium , thesis, Francis Carey and Richard Sundberg , (Springer ) 5th lithium , magnesium and calcium salts and the like. (See , ed . Edition . ( 2007 ), the content of which is hereby incor e.g., Berge et al . ( 1977 ) “ Pharmaceutical Salts ” , J. Pharm . porated by reference . Sci. 66 : 1-19 ). [ 0597 ] Another aspect of the invention comprises a com [0601 ] As used herein , “ treating” means preventing , slow pound used in the method of the present invention as a ing, halting , or reversing the progression of a disease or pharmaceutical composition . infection . Treating may also mean improving one or more [0598 ] As used herein , the term “ pharmaceutically active symptoms of a disease or infection . agent” means any substance or compound suitable for [ 0602 ] The compounds used in the method of the present administration to a subject and furnishes biological activity invention may be administered in various forms, including or other direct effect in the treatment, cure , mitigation , those detailed herein . The treatment with the compound may diagnosis, or prevention of disease , or affects the structure or be a component of a combination therapy or an adjunct any function of the subject. Pharmaceutically active agents therapy , i.e. the subject or patient in need of the drug is include , but are not limited to , substances and compounds treated or given another drug for the disease in conjunction described in the Physicians' Desk Reference ( PDR Network , with one or more of the instant compounds . This combina LLC ; 64th edition ; Nov. 15, 2009 ) and “ Approved Drug tion therapy can be sequential therapy where the patient is Products with Therapeutic Equivalence Evaluations ” (U.S. treated first with one drug and then the other or the two drugs Department of Health And Human Services, 30th edition , are given simultaneously . These can be administered inde US 2020/0079745 A1 Mar. 12 , 2020 44

pendently by the same route or by two or more different formsmay also includeminerals and other materials to make routes of administration depending on the dosage forms them compatible with the type of injection or delivery employed . system chosen . [0603 ] As used herein , a “ pharmaceutically acceptable [ 0607 ] Techniques and compositions for making dosage carrier" is a pharmaceutically acceptable solvent, suspend forms useful in the present invention are described in the ing agent or vehicle , for delivering the instant compounds to following references : 7 Modern Pharmaceutics, Chapters 9 the animal or human . The carrier may be liquid or solid and and 10 (Banker & Rhodes , Editors, 1979 ) ; Pharmaceutical is selected with the planned manner of administration in Dosage Forms : Tablets (Lieberman et al. , 1981) ; Ansel , mind . Liposomes are also a pharmaceutically acceptable Introduction to Pharmaceutical Dosage Forms 2nd Edition ( 1976 ) ; Remington's Pharmaceutical Sciences, 17th ed . carrier . (Mack Publishing Company, Easton , Pa. , 1985 ) ; Advances [ 0604 ] The dosage of the compounds administered in in Pharmaceutical Sciences (David Ganderton , Trevor treatment will vary depending upon factors such as the Jones, Eds. , 1992 ) ; Advances in Pharmaceutical Sciences pharmacodynamic characteristics of a specific chemothera Vol. 7. (David Ganderton , Trevor Jones, James McGinity , peutic agent and its mode and route of administration ; the Eds ., 1995) ; Aqueous Polymeric Coatings for Pharmaceuti age , sex , metabolic rate , absorptive efficiency, health and cal Dosage Forms (Drugs and the Pharmaceutical Sciences , weight of the recipient; the nature and extent of the symp Series 36 ( James McGinity , Ed . , 1989 ) ; Pharmaceutical toms; the kind of concurrent treatment being administered ; Particulate Carriers : Therapeutic Applications: Drugs and the frequency of treatment with ; and the desired therapeutic the Pharmaceutical Sciences, Vol 61 ( Alain Rolland , Ed ., effect . 1993 ); Drug Delivery to the Gastrointestinal Tract (Ellis [0605 ] A dosage unit of the compounds used in the method Horwood Books in the Biological Sciences. Series in Phar of the present inventioni may comprise a single compound or maceutical Technology ; J. G. Hardy , S. S. Davis , Clive G. mixtures thereof with additional antibacterial agents . The Wilson , Eds. ) ; Modem Pharmaceutics Drugs and the Phar compounds can be administered in oral dosage forms as maceutical Sciences , Vol 40 (Gilbert S. Banker , Christopher tablets, capsules , pills, powders , granules, elixirs , tinctures , T. Rhodes, Eds. ) . All of the aforementioned publications are suspensions, syrups, and emulsions. The compounds may incorporated by reference herein . also be administered in intravenous (bolus or infusion ), [0608 ] Tablets may contain suitable binders , lubricants , intraperitoneal, subcutaneous , or intramuscular form , or disintegrating agents , coloring agents , flavoring agents, introduced directly , e.g. by injection , topical application , or flow - inducing agents , and melting agents . For instance, for other methods, into or onto a site of infection , all using oral administration in the dosage unit form of a tablet or dosage forms well known to those of ordinary skill in the capsule , the active drug component can be combined with an pharmaceutical arts . oral , non - toxic , pharmaceutically acceptable , inert carrier [0606 ] The compounds used in the method of the present such as lactose, gelatin , agar, starch , sucrose , glucose , invention can be administered in admixture with suitable methyl cellulose, magnesium stearate , dicalcium phosphate , pharmaceutical diluents , extenders , excipients , or carriers calcium sulfate , mannitol, sorbitol and the like . Suitable ( collectively referred to herein as a pharmaceutically accept binders include starch , gelatin , natural sugars such as glu able carrier ) suitably selected with respect to the intended cose or beta - lactose , corn sweeteners , natural and synthetic form of administration and as consistent with conventional gums such as acacia , tragacanth , or sodium alginate , car pharmaceutical practices . The unit will be in a form suitable boxymethylcellulose, polyethylene glycol, waxes, and the for oral, rectal , topical, intravenous or direct injection or like . Lubricants used in these dosage forms include sodium parenteral administration . The compounds can be adminis oleate , sodium stearate , magnesium stearate , sodium benzo tered alone or mixed with a pharmaceutically acceptable ate , sodium acetate, sodium chloride , and the like. Disinte carrier . This carrier can be a solid or liquid , and the type of grators include , without limitation , starch , methyl cellulose , carrier is generally chosen based on the type of administra agar, bentonite , Xanthan gum , and the like . tion being used . The active agent can be co - administered in [ 0609 ] The compounds used in the method of the present the form of a tablet or capsule , liposome, as an agglomerated invention may also be administered in the form of liposome powder or in a liquid form . Examples of suitable solid delivery systems, such as small unilamellar vesicles , large carriers include lactose , sucrose , gelatin and agar . Capsule or unilamallar vesicles, and multilamellar vesicles. Liposomes tablets can be easily formulated and can be made easy to can be formed from a variety of phospholipids , such as swallow or chew ; other solid forms include granules, and cholesterol, stearylamine , or phosphatidylcholines. The bulk powders . Tablets may contain suitable binders , lubri compounds may be administered as components of tissue cants , diluents , disintegrating agents , coloring agents , fla targeted emulsions . voring agents , flow - inducing agents , and melting agents . [0610 ] The compounds used in the method of the present Examples of suitable liquid dosage forms include solutions invention may also be coupled to soluble polymers as or suspensions in water, pharmaceutically acceptable fats targetable drug carriers or as a prodrug . Such polymers and oils , alcohols or other organic solvents , including esters, include polyvinylpyrrolidone , pyran copolymer, polyhy emulsions, syrups or elixirs , suspensions , solutions and / or droxylpropylmethacrylamide - phenol, polyhydroxyethylas suspensions reconstituted from non - effervescent granules parta -midephenol , or polyethyleneoxide- polylysine substi and effervescent preparations reconstituted from efferves tuted with palmitoyl residues. Furthermore , the compounds cent granules . Such liquid dosage forms may contain , for may be coupled to a class of biodegradable polymers useful example , suitable solvents , preservatives , emulsifying in achieving controlled release of a drug, for example , agents , suspending agents , diluents , sweeteners , thickeners , polylactic acid , polyglycolic acid , copolymers of polylactic and melting agents . Oral dosage forms optionally contain and polyglycolic acid , polyepsilon caprolactone, polyhy flavorants and coloring agents . Parenteral and intravenous droxy butyric acid , polyorthoesters , polyacetals , polydihy US 2020/0079745 A1 Mar. 12 , 2020 45

dropyrans, polycyanoacylates, and crosslinked or amphip throughout the dosage regimen . Parenteral and intravenous athic block copolymers of hydrogels . forms may also includeminerals and other materials to make [0611 ] Gelatin capsules may contain the active ingredient them compatible with the type of injection or delivery compounds and powdered carriers, such as lactose , starch , system chosen . cellulose derivatives, magnesium stearate , stearic acid , and [ 0615 ] Each embodiment disclosed herein is contemplated the like . Similar diluents can be used to make compressed as being applicable to each of the other disclosed embodi tablets . Both tablets and capsules can be manufactured as ments . Thus, all combinations of the various elements immediate release products or as sustained release products described herein are within the scope of the invention . to provide for continuous release of medication over a period of hours . Compressed tablets can be sugar coated or [ 0616 ] This invention will be better understood by refer film coated to mask any unpleasant taste and protect the ence to the Experimental Details which follow , but those tablet from the atmosphere, or enteric coated for selective skilled in the art will readily appreciate that the specific disintegration in the gastrointestinal tract . experiments detailed are only illustrative of the invention as [ 0612 ] For oral administration in liquid dosage form , the described more fully in the claims which follow thereafter. oral drug components are combined with any oral , non toxic, pharmaceutically acceptable inert carrier such as EXPERIMENTAL DETAILS ethanol, glycerol , water , and the like. Examples of suitable liquid dosage forms include solutions or suspensions in Example 1. Preparation of Compounds water , pharmaceutically acceptable fats and oils , alcohols or [0617 ] General Considerations . other organic solvents , including esters , emulsions, syrups [ 0618 ] Reagents and solvents were obtained from com or elixirs , suspensions, solutions and /or suspensions recon mercial sources and were used without further purification stituted from non - effervescent granules and effervescent unless otherwise stated . All compounds were prepared in preparations reconstituted from effervescent granules . Such racemic form . All reactions were performed in flame- dried liquid dosage forms may contain , for example , suitable glassware under an argon atmosphere unless otherwise solvents , preservatives , emulsifying agents , suspending stated , and monitored by TLC using solvent mixtures appro agents , diluents , sweeteners , thickeners , and melting agents . priate to each reaction . All column chromatography was [ 0613 ] Liquid dosage forms for oral administration can performed on silica gel ( 40-63 um ). Preparative TLC was contain coloring and flavoring to increase patient accep conducted on 20x20 cm plates coated with a 1 mm silica tance. In general, water , a suitable oil, saline , aqueous layer. Nuclear magnetic resonance spectra were recorded on dextrose ( glucose ) , and related sugar solutions and glycols Bruker 400 or 500 MHz instruments as indicated . Chemical such as propylene glycol or polyethylene glycols are suitable shifts are reported as d values in ppm referenced to CDC13 carriers for parenteral solutions . Solutions for parenteral (' H NMR = 7.26 and 13C NMR = 77.16 ), MeOD (' H NMR = 3 . administration preferably contain a water - soluble salt of the 31 and 13C NMR = 49.00 ) , or DMSO -do (' H NMR = 2.50 and active ingredient, suitable stabilizing agents , and if neces 13C NMR = 39.52 ). Multiplicity is indicated as follows: s sary, buffer substances. Antioxidizing agents such as sodium (singlet ) ; d (doublet ); t (triplet ) ; q ( quartet) ; p (pentet ); dd bisulfite , sodium sulfite , or ascorbic acid , either alone or (doublet of doublets ); ddd ( doublet of doublet of doublets ) ; combined , are suitable stabilizing agents . Also used are dt (doublet of triplets ) ; td ( triplet ofdoublets ) ; m (multiplet ) ; citric acid and its salts and sodium EDTA . In addition , br ( broad ). All carbon peaks are rounded to one decimal parenteral solutions can contain preservatives , such as ben place unless such rounding would cause two close peaks to zalkonium chloride , methyl- or propyl- paraben , and chlo become identical ; in these cases , two decimal places are robutanol. Suitable pharmaceutical carriers are described in retained. Two carbon peaks joined by “ and ” in the peak list Remington's Pharmaceutical Sciences, Mack Publishing correspond to a single carbon atom but are split due to F - C Company, a standard reference text in this field . coupling . Low -resolution mass spectra were recorded on a [0614 ] The compounds used in the method of the present JEOL LCmate ( ionization mode: APCI + ) . For compounds 4 invention may also be administered in intranasal form via and 5 mass spectra are reported for carbocations correspond use of suitable intranasal vehicles, or via transdermal routes , ing to loss of OH or Cl respectively. using those forms of transdermal skin patches well known to those of ordinary skill in that art . To be administered in the Preparation of Diarylthiazepinones (3 ) form of a transdermal delivery system , the dosage admin istration will generally be continuous rather than intermittent [0619 ]

Scheme 1. Preparation of diarylthiazepinones. ZI H2N Br 1 ) NaNO2 Br aq . HCI, 0 ° C. 2 ) SO2, Cuci pyridine, MeO2C AcOH /H20 Me02C CH2Cl2 , R.T. 0 ° C. to R.T. 32 % la US 2020/0079745 A1 Mar. 12 , 2020 46

-continued

1. NaOH Br MeOH , H2O , reflux Br 2. SOC12 , CH2Cl2 , R.T. 3. AICI3 , CHCl3 , reflux CO2Me 68 % 62 % , 3 steps 2a 3a ON Br H?N Br 1 ) NaNO2 SnCl2 • 2H20 aq . HCI, 0 ° C. ETOAc/ CH2Cl2 2 ) SO2, Cuci MeO2C R.T. Me02C F AcOH /H20 96 % 0 ° C. to R.T.

N

Br Br

pyridine , Me02C F CH2Cl2 , R.T. F CO2Me 52 % 85 % 1b 2b 1. NaOH MeOH , H2O , reflux 2. SOC12 , CH2Cl2 , R.T. 3. AICI3 , CHCl3 , reflux

Br Br PhenoFluorMix toluene R.T. to 80 ° C. OH to 100 ° C. 54 % 22 % , 3 steps 3c 3b

= O Me Siz CI Pd2dba3 SiMe3 t - BuDavePhos ICI LiOAC CH2Cl2 DMF, H20 0 ° C. to R.T. 100 ° C. 3d 58 % 3e

55 % 3f US 2020/0079745 A1 Mar. 12. 2020 47

-continued

TIPS Pd2dba3 TIPS XPhos TBAF K2CO3, DMF THF 110 ° C. R.T.

3d 81 % 3g

76 % 3h

SMe NasMe DMF ago R.T. 3d 69 % 3i

Methyl 4 -bromo - 2 - chlorosulfonyl) benzoate ( la ) anhydrous pyridine ( 10.7 mL ) was added N -methylaniline [ 0620 ] A suspension of methyl 2 - amino -4 -bromobenzoate ( 1.71 mL , 1.68 g , 15.68 mmol) at room temperature , and the ( 10.35 g , 45.0 mmol) in 20 % aqueous HCI ( 29 mL ) was resulting mixture was stirred for 1 h . The reaction mixture sonicated for several minutes and warmed slightly until all was then diluted with CH C12 ( 100 mL ) and washed with 7 % clumps were broken up and the mixture was a uniform aqueous HCl ( 2x100 mL ) , brine ( 100 mL ), saturated aque suspension of fine particles . This mixture was cooled to 0 ° ous NaHCO3 (100 mL ), and brine again ( 100 mL ), dried C., and a solution of NaNO2 ( 3.11 g , 45.0 mmol) in water over Na S04, and concentrated to give a yellow - brown oil. ( 7.5 mL ) was added dropwise, maintaining the internal This material was purified by column chromatography ( 9 : 1 temperature below 5º C. The resulting mixture was then hexanes: EtOAc , 4 column volumes- > 8 : 2 hexanes : EtOAc , 4 stirred for 2 h at 0 ° C. Simultaneously, a solution of SO2 column volumes) to provide pure sulfonamide 2a as a (23.1 g , 360 mmol) in AcOH ( 36.0 mL ) and water (3.75 mL ) yellow oil (3.71 g , 68 % ) ' H NMR (500 MHz, CDC13 ) 8 7.69 was prepared by bubbling the gas though the mixed solvents (dd , J = 8.2, 1.9 Hz , 1H ) , 7.52 ( d , J = 1.9 Hz , 1H ) , 7.38-7.29 at 0 ° C. until themass had increased by the required amount. ( m , 4H ), 7.21-7.17 (m , 2H ) , 3.82 ( s, 3H ), 3.30 (s , 3H ); 13C To this SO2 solution was then added CuCl ( 1.11 g , 11.25 NMR ( 126 MHz , CDC13 ) 167.7 , 141.0 , 137.1, 135.5 , mmol) followed by the diazonium salt solution portionwise 132.8 , 132.3 , 129.8 , 129.3 , 128.0 , 127.4 , 123.9 , 53.4 , 39.0 . over 30 minutes at 0 ° C. The resulting mixture was then 3 -Bromo - 6 -methyldibenzo [ c , f ] [ 1,2 ] thiazepin - 11 ( 6H ) -one stirred for 1 h at 0 ° C. and 1 h at room temperature, poured 5,5 -dioxide (3a ). To a solution of sulfonamide 2a ( 3.69 g , into ice water ( 150 mL ) , and extracted with CH C12 ( 3x50 9.60 mmol) in MeOH ( 24 mL ) was added water ( 12 mL ) and mL ). The combined organics were poured into saturated NaOH ( 1.15 g , 28.80 mmol) and the mixture was refluxed aqueous NaHCO3 (75 mL) , and solid NaHCO3 was added for 1 h . Most of the MeOH was then removed in vacuo and carefully until effervescence ceased . The organic phase was the resulting clumpy white mixture was diluted with water then separated , washed with brine ( 50 mL ) , dried over (30 mL ) , acidified with 10 % aqueous HCl (20 mL ), and Na2SO4, and concentrated to provide the crude sulfonyl extracted with CH C12 (50 mL , 2x20 mL ) . The combined chloride la as a waxy brown solid (6.11 g , 74 mass % organics were dried over Na2SO4 and concentrated to pro product by NMR , 32 % yield ). This material was used in the vide the carboxylic acid as a pale -pink glass (3.46 g) , which next step without further purification . was used in the next step without further purification . The carboxylic acid ( 3.43 g , 9.26 mmol) was dissolved in thionyl Methyl chloride ( 15 mL ) and the solution was stirred for 13 h at 4 -bromo - 2- ( N -methyl - N -phenylsulfamoyl ) benzoate room temperature . The volatiles were then removed to ( 2a ) provide the crude acyl chloride as a yellow -orange oil . This [0621 ] To a solution of crude methyl 4 -bromo - 2-( chloro material was dissolved in CHC13 (40 mL ), aluminum chlo sulfonyl) benzoate la (6.04 g , 74 % pure , 14.25 mmol) in ride ( 3.95 g , 29.63 mmol) was added , and the mixture was US 2020/0079745 A1 Mar. 12 , 2020 48 refluxed for 1 h . The reaction was then cooled to room Methyl 4 -bromo - 5 - fluoro - 2-( N -methyl - N - phenylsul temperature , quenched with ice water ( 150 mL ), and famoyl) benzoate ( 2b ) extracted with CH2C12 (3x50 mL ) . The combined organics were filtered through a silica plug , washing with additional [0624 ] To a solution of N -methylaniline ( 1.05 mL , 1.04 g 9.66 mmol) in anhydrous CH , C1, (8.5 mL ) at 0 ° C. was CH , Cl, until all of the product had passed through , and the added anhydrous pyridine ( 6.4 mL ) followed by a solution filtrate was concentrated to provide an off -white solid . This of crude methyl 4 -bromo -2- ( chlorosulfonyl ) -5 - fluorobenzo material was recrystallized from MeOH (250 mL ) to provide ate 1b (3.54 g, 82 % pure , 8.78 mmol) in anhydrous CH2Cl2 the pure ketone 3a as cream -colored needles (2.08 g, 62 % ( 8.5 mL ) over 3 minutes . The resulting bright orange solu over 3 steps) . 'H NMR (500 MHz, CDC13 ) d 8.30 (dd , J = 8.1 , tion was then allowed to warm to room temperature and 1.5 Hz , 1H ) , 8.11 ( t, J = 1.0 Hz, 1H ) , 7.84 ( d , J = 1.1 Hz , 2H ) , stirred for 1 h . The reaction mixture was then diluted with 7.68-7.62 ( m , 1H ) , 7.41-7.37 ( m , 1H ) , 7.35 (dd , J = 8.1 , 0.7 CH2C12 ( 100 mL) and washed with 3 % aqueous HCl ( 2x50 Hz, 1H ) , 3.36 (s , 3H ); 13C NMR (126 MHz, CDC13 ) & 189.8 , mL ), brine (50 mL ), saturated aqueous NaHCO3 ( 50 mL ) , 141.5 , 138.5 , 136.4 , 135.1, 135.0 , 133.4 , 132.3 , 131.0 , and brine again (50 mL ), dried over Na2SO4, and concen 128.4 , 126.9 , 126.4 , 124.8 , 39.2 ; LR -MS calcd . for trated to give a viscous orange oil. This material was purified C14H11BrNO3S [ M + H ]+ 351.96 , found 351.85 . by column chromatography (9 : 1 hexanes :EtOAc , 4 column Methyl 2 - amino -4 - bromo -5 - fluorobenzoate volumes-> 8 : 2 hexanes: EtOAc , 2 column volumes) to pro [ 0622 ] To a solution of methyl 4 - bromo - 5 - fluoro - 2 - ni vide sulfonamide 2b as a viscous, pale -yellow oil that slowly trobenzoate (2.50 g , 9.00 mmol) in EtoAc (67.5 mL ) and crystallized to off- white crystals ( 3.00 g , 85 % ). 'H NMR CH , C1 , (22.5 mL ) was added SnC1, * 2H20 (10.15 g , 45.00 ( 500 MHz, CDC13 ) 8 7.58 ( d , J = 6.3 Hz, 1H ) , 7.39-7.29 ( m , mmol) and the white suspension was stirred for 15 h . The 3H ), 7.25-7.16 (m , 3H ), 3.83 (s , 3H ), 3.30 (s , 3H ); 13C NMR reaction mixture was then poured into saturated aqueous ( 126 MHz, CDC1z ) d 166.28 and 166.26 , 161.9 and 159.9 , NaHCO3 (200 mL) , solid NaHCO3 was added with stirring 140.9 , 135.84 and 135.83 , 134.81 and 134.76 , 132.59 and until bubbling stopped , and the mixture was extracted with 132.55 , 129.4 , 128.1, 127.4 , 116.6 and 116.41, 111.1 and EtOAC (3x200 mL ) . The combined organics were washed 110.9 , 53.6 , 39.0 . with water ( 200 mL ) and brine (200 mL ) , dried over Na2SO4, and concentrated to provide methyl 2 -amino -4 3 - Bromo- 2 -hydroxy - 6 -methyldibenzo [ c , f ][ 1,2 ]thiaz bromo- 5 - fluorobenzoate as a pale - tan crystalline solid (2.14 epin - 116H ) -one 5,5 - dioxide (3b ) g , 96 % ) . ' H NMR (500 MHz , CDC1z ) 0 7.58 ( d , J = 9.4 Hz, [0625 ] To a solution of sulfonamide 2b (2.98 g , 7.41 1H ) , 6.88 ( d , J = 5.7 Hz , 1H ) , 5.62 (br s , 2H ), 3.87 ( s , 3H ) ; mmol) in MeOH (19 mL ) was added water (9.5 mL ) and 13C NMR (126 MHz, CDC13 ) 8 167.39 and 167.36 , 151.4 NaOH (889 mg, 22.23 mmol) and the mixture was refluxed and 149.5 , 147.41 and 147.39 , 120.7 , 117.4 and 117.2 , 116.5 for 50 minutes . The volatiles were removed in vacuo and the and 116.3 , 110.2 and 110.1 , 52.1 . resulting white mass was triturated with water (50 mL ) and 10 % aqueous HCl ( 20 mL ) and extracted with CH C12 (250 Methyl mL , 150 mL , 50 mL ; poor solubility ). The combined organ 4 -bromo - 2 - chlorosulfonyl) -5 - fluorobenzoate ( lb ) ics were dried over Na2SO4 and concentrated to provide the [0623 ] A suspension of methyl 2 - amino -4 -bromo - 5 - fluo carboxylic acid as a white solid (2.99 g ), in which the fluoro robenzoate (4.18 g , 16.85 mmol) in 20 % aqueous HCI ( 10.9 substituent had been replaced with a methoxy group via mL ) was sonicated for several minutes and warmed slightly nucleophilic aromatic substitution occurring concurrent with until all clumps were broken up and the mixture was a hydrolysis . This material was used in the next step without uniform suspension of fine particles . This mixture was further purification . To the methoxy carboxylic acid ( 2.95 g , cooled to -5 ° C., and a solution of NaNO2 ( 1.16 g , 16.85 7.37 mmol) was added thionyl chloride ( 11.9 mL ) and the mmol) in water ( 2.8 mL ) was added dropwise over 10 mixture was stirred for 2.5 h at room temperature (solids minutes , maintaining the internal temperature below 0 ° C. now dissolved ) . The volatiles were then removed to provide The resulting mixture was then stirred for 30 minutes at -5 ° the crude acyl chloride as a white solid . This material was C., during which time, most solids dissolved to leave a dissolved in anhydrous CHC13 (32 mL) , aluminum chloride cloudy yellow solution . Simultaneously , a solution of SO2 (3.14 g , 23.58 mmol ) was added , and the mixture was ( 8.65 g , 135 mmol) in AcOH ( 13.5 mL ) and water ( 1.4 mL ) refluxed for 1.25 h . The reaction was then cooled to room was prepared by bubbling the gas though the mixed solvents temperature , quenched with ice water (150 mL ), diluted with at 0 ° C. until the mass had increased by the required amount. CH2C12 (50 mL ) , and stirred until all black sludge had To this SO , solution was then added CuCl (417 mg, 4.21 broken up . The mixture was then extracted with CH2Cl2 mmol) followed by the diazonium salt solution portionwise (3x50 mL ) and the combined organics washed with water over 25 minutes at 0 ° C. The resulting mixture was then ( 100 mL ) , dried over Na2SO4, and concentrated to provide stirred for 1 h at 0 ° C. and 1 h at room temperature, poured an olive solid . This material was purified by column chro into ice water ( 75 mL ), and extracted with CH C12 ( 3x30 matography ( 20 : 1 CH2Cl2 : Et20 , 2 column volumes-> 10 : 1 mL ). The combined organics were poured into saturated CH_C12: Et20 , 2 column volumes ) to give a pale -yellow aqueous NaHCO3 ( 100 mL ) containing excess solid solid still containing impurities (0.78 g ). The crude product NaHCO3 and the mixture was stirred until effervescence was washed 2 times with small portions of CH2Cl2 , remov ceased . The organic phase was then separated , washed with ing the supernatant by pipet each time. It was then dissolved brine (30 mL ), dried over Na2SO4, and concentrated to in CH2Cl2 , boiled down until most of the solvent was provide the crude sulfonyl chloride 1b as a waxy tan solid removed and the product had partially crystallized , cooled to ( 3.57 g , 82 mass % product by NMR , 52 % yield ). This 0 ° C., and the supernatant was again removed by pipet to material was used in the next step without further purifica provide the phenolic ketone 3b ( 0 - demethylation occurs tion . concomitant to cyclization ) as a crystalline , pale - yellow US 2020/0079745 A1 Mar. 12 , 2020 49 solid (595 mg, 22 % over 3 steps ) . ' H NMR ( 500 MHz , 3 - Iodo -6 -methyldibenzo [c ,f ][ 1,2 ]thiazepin - 116H ) DMSO - d ) 8 11.92 (s , 1H ) , 8.12 (dd , J = 8.1, 1.7 Hz , 1H ), one 5,5 -dioxide ( 3 ) 7.96 ( s, 1H ), 7.79-7.73 (m , 1H ) , 7.58 (dd , J = 8.2 , 1.2 Hz, 1H ), [0629 ] To a solution of trimethylsilylketone 3e (108 mg, 7.44 (ddd , J = 8.3 , 7.2 , 1.2 Hz, 1H ), 7.38 ( s , 1H ) , 3.28 ( s , 3H ) ; 0.313 mmol) in anhydrous CH C12 (0.94 mL ) at 0 ° C.was 13C NMR (126 MHz, DMSO -do ) 8 190.2 , 158.9 , 141.7 , added a solution of iodine monochloride ( 173 mg, 1.06 136.8 , 135.3 , 131.1, 129.9 , 129.7 , 126.9, 125.9 , 125.4 , mmol) in anhydrous CH C12( 0.63 mL) dropwise over 3 min . 117.6 , 113.0 , 39.0 . The resulting dark brown solution was allowed to warm to room temperature , stirred for 35 min ( extended reaction 3 -Bromo - 2 - fluoro - 6 -methyldibenzo [ c , f ] [ 1,2 ]thiaz times produce polyiodinated byproducts ), and quenched epin - 11 (6H ) -one 5,5 - dioxide (3 ) with saturated aqueous Na2S2O3 ( 3 mL ) . The resulting [0626 ] PhenoFluorMix (230 mg; a mixture of N , N - 1,3 mixture was diluted with water (15 mL ) and extracted with bis ( 2,6 -diisopropylphenyl chloroimidazolium chloride and CH_C12 (2x15 mL ). The combined organics were washed CsF ; Fujimoto , T. and Ritter, T. 2015 ) was dried under high with water ( 15 mL ) , dried over Na S04, and concentrated to vacuum at 140 ° C. in a vial for 1.5 h . After cooling to room yield a yellow solid . This material was purified by column temperature , phenolic ketone 3b ( 38.7 mg, 0.105 mmol) was chromatography ( 1: 1 CH2Cl :hexanes ) to yield impure added followed by anhydrous toluene ( 1.0 mL ) and the product . This crude product was recrystallized from MeOH mixture was stirred for 30 minutes at room temperature , 10 and the resulting fine -white needles were dissolved in minutes at 80 ° C., and 45 minutes at 100 ° C. The supernatant CH , C1, and concentrated , causing a second crystallization to was then removed from residual solids by pipet, the solids occur once most of the solvent had been removed . The were washed 3 times with CH2Cl2, and the combined powdery white crystals thus obtained were washed with organics were concentrated to give a pale -yellow solid . This ice -cold MeOH and dried to yield the pure ketone 3f (68.4 material was purified by repeated preparative TLC (Plate 1 : mg, 55 % ). ' H NMR (400 MHz, CDC13 ) 8 8.32-8.27 ( m , 7 : 3 hexanes: EtOAc ; Plate 2 : CH2Cl2 ) to provide ketone 3c 2H ) , 8.06 (dd , J = 8.1, 1.7 Hz , 1H ) , 7.69-7.62 ( m , 2H ) , 7.38 as a white , crystalline solid (21 mg, 54 % ). 'H NMR (400 (ddd , J= 8.2 , 7.3 , 1.1 Hz , 1H ), 7.34 (dd , J = 8.1 , 0.9 Hz, 1H ), MHz, CDC13 ) 8 8.29 (dd , J = 8.1 , 1.7 Hz, 1H ), 8.19 (d , J = 6.2 3.35 ( s , 3H ) ; 13C NMR ( 101 MHz , CDC1z ) & 190.1 , 142.4 , Hz , 1H ), 7.73 ( d , J = 8.5 Hz, 1H ) , 7.67 (ddd , J = 8.1 , 7.2 , 1.7 141.5 , 138.1 , 135.6 , 135.1 , 133.9 , 133.1, 132.2 , 131.0 , Hz, 1H ) , 7.40 (ddd , J = 8.3 , 7.2 , 1.2 Hz, 1H ) , 7.35 (dd , J = 8.1 , 126.3 , 124.7 , 98.7 , 39.2 ; LR -MS calcd . for C 4H INOZS 1.2 Hz, 1H ) , 3.36 ( s , 3H ); 13C NMR ( 101 MHz, CDC13 ) 8 [ M + H ] * 399.95 , found 399.78 . 188.4 , 163.2 and 160.6 , 141.4 , 137.62 and 137.55 , 135.4 , 134.25 and 134.21 , 132.4 , 131.4 , 130.6 , 126.5 , 124.9 , 120.0 6 -Methyl - 3 -( ( trimethylsilyl) ethynyl) dibenzo [c , f] [ 1, and 119.8 , 114.0 and 113.8 , 39.2 . 2 ] thiazepin - 11 (6H ) -one 5,5 -dioxide (38 ) [ 0630 ] Pd dbaz ( 20.6 mg, 0.0225 mmol) , XPhos ( 21.5 mg, 3 -Chloro - 6 -methyldibenzo [cf ] [, 2 ]thiazepin - 11 (6H ) 0.0450 mmol) , and K2CO3 were combined in anhydrous one 5,5 -dioxide ( 3d ) DMF ( 3.0 mL ) and the dark brown mixture was stirred at [0627 ] Ketone 3d was purchased from Ark Pharm Inc. room temperature for 5 min . Ketone 3d (462 mg, 1.50 (Libertyville , Ill. ) and used without further purification . mmol) and ( trimethylsilyl) acetylene ( 505 uL , 2.25 mmol) were then added and the mixture was heated to 110 ° C. for 6 -Methyl - 3-( trimethylsilyl) dibenzo [ c , f ][ 1,2 ] thiaz 3 h . The mixture was then cooled to room temperature , epin - 116H ) -one 5,5 - dioxide ( 3e ) diluted with water ( 20 mL ) , and extracted with Et20 ( 3x30 mL ). The combined organics were washed with water (2x20 [ 0628 ] Ketone 3e was prepared from the aryl chloride mL ) and brine ( 20 mL ) , dried over Na2SO4, and concen utilizing the trimethylsilylation procedure of Buchwald trated to give an orange- brown solid . This material was (McNeill , E. et al. 2007) . Ketone 3d (462 mg , 1.50 mmol) , purified by column chromatography (6 : 4 hexanes: CH2Cl2 , 3 Pdtert -dbazbutylphosphino (20.6 mg, )0.0225-N , N -dimethylbiphenyl mmol) , t- BuDavePhos - 2 - amine (,2 '- 46.1( Di column volumes-> 1 : 1 hexanes: CH2Cl2 , 5 column volumes ) mg, 0.135 mmol) , and LiOA (495 mg, 7.50 mmol) were to provide pure ketone 3g as pale -yellow foam , which , on combined under argon . Anhydrous DMF ( 4.5 mL) , water ( 54 addition of a little Et O , formed powdery , pale- yellow UL , 3.00 mmol) , and hexamethyldisilane ( 369 UL , 1.80 crystals (553 mg, 81 % ). 'H NMR ( 400 MHz, CDC1z ) 8 8.31 mmol) were then added , and the resulting orange -brown (dd , J = 8.1 , 1.7 Hz, 1H ) , 8.01 ( d , J = 1.6 Hz, 1H ) , 7.91 ( d , mixture was heated to 100 ° C. for 33 h . After cooling to J = 8.0 Hz, 1H ) , 7.75 (dd , J = 8.0 , 1.6 Hz, 1H ) , 7.68-7.61 ( m , room temperature , the reaction mixture was diluted with 1H ) , 7.38 (ddd , J = 8.2 , 7.3 , 1.2 Hz, 1H ), 7.34 ( dd, J = 8.1 , 1.1 water ( 20 mL ) and extracted with Et20 (3x10 mL ) . The Hz, 1H ), 3.36 (s , 3H ), 1.21-1.10 (m , 21H ); 13C NMR ( 101 combined organics were washed with water ( 10 mL ), dried MHz , CDC13 ) 190.1 , 141.6 , 137.3 , 136.4 , 135.3 , 135.0 , over Na2SO4, and concentrated to yield a yellow crystalline 132.2 , 131.8 , 131.2 , 128.6 , 128.1 , 126.3 , 124.8 , 104.3 , 97.5 , solid . This crude material was recrystallized from MeOH to 39.2 , 18.8 , 11.4 . obtain pure ketone 3e as fine yellow needles (301 mg, 58 % ) . 'H NMR (500 MHz, CDC13 ) 8 8.30 (dd , J= 8.1 , 1.6 Hz, 1H ), 3 - Ethynyl- 6 -methyldibenzo [ c , f ][ 1,2 ] thiazepin - 11 8.04 ( d , J = 0.8 Hz , 1H ), 7.91 ( d, J= 7.5 Hz, 1H ), 7.85 (dd , (6H ) -one 5,5 -dioxide (3h ) J = 7.6 , 1.1 Hz , 1H ) , 7.63 (ddd , J = 8.1 , 7.3 , 1.7 Hz, 1H ) , [ 0631 ] To a solution of ketone 3g (531 mg, 1.17 mmol) in 7.41-7.29 ( m , 2H ) , 3.35 (s , 3H ), 0.36 ( s, 9H ) ; 13C NMR ( 126 anhydrous THF (5.0 mL ) was added a solution of tetrabu MHz, CDC1z ) 191.2 , 147.4 , 141.9 , 138.3 , 136.6 , 136.0 , tylammonium fluoride ( 1.0 Min THF , 2.34 mL , 2.34 mmol) 134.8 , 132.1 , 131.2 , 130.5 , 129.7 , 126.0 , 124.6 , 39.1 , -1.2 ; at room temperature and the resulting black solution was LR -MS calcd . for CH20NO , SSi [M + H ]* 346.09 , found stirred for 2 h . The reaction mixture was then diluted with 345.86 . CH C12 (50 mL ) , washed with water ( 2x20 mL ) and brine US 2020/0079745 A1 Mar. 12 , 2020 50

( 20 mL ) , dried over Na2SO4, and concentrated to give a -continued brown solid . This material was purified by column chroma tography ( 1 : 1 hexanes : CH2Cl2, 3 column volumes - CH2Cl2 , 3 column volumes ) to provide the prod uct contaminated with residual silane . This material was .Ri washed 2x with small portions of hexanes and dried to give pure ketone 3h as powdery , off -white crystals (265 mg, 76 % ). ' H NMR (400 MHz, CDC13 ) 8 8.30 (dd , J = 8.1 , 1.7 R2 Hz, 1H ), 8.05 ( d , J = 1.6 Hz, 1H ), 7.92 ( d , J = 8.0 Hz, 1H ), 7.78 CI (dd , J = 8.0 , 1.6 Hz, 1H ) , 7.68-7.62 ( m , 1H ) , 7.38 (ddd , J = 8.2 , 5a , c , f , h , i 7.3 , 1.1 Hz, 1H ) , 7.34 (dd , J = 8.1 , 1.1 Hz, 1H ), 3.36 ( s , 1H ) , 3.35 ( s , 3H ) ; 13C NMR ( 101 MHz, CDC13 ) d 190.2 , 141.7 , N 137.3 , 136.5 , 136.0 , 135.0 , 132.2 , 131.9 , 130.9 , 128.8 , Br Br 126.7, 126.2 , 124.7 , 82.2 , 81.3 , 39.1 . F 6 -Methyl - 3- ( methylthio )dibenzo [ c, f ][ , 2 ] thiazepin - 11 OH OH (6H ) -one 5,5 -dioxide ( 3i ) 99 % quantitative [ 0632 ] To a solution of sodium thiomethoxide ( 116 mg, 4a 4c 1.65 mmol) in anhydrous DMF (2.0 mL ) was added ketone 3d (462 mg, 1.50 mmol) and the resulting yellow suspension S S was stirred at room temperature for 1 h . Additional sodium I thiomethoxide ( 26.3 mg, 0.375 mmol) was then added and stirring continued for a further 15 min . The reaction was then quenched with water ( 10 mL ) and extracted with CH2C12 ( 10 OH OH mL , 2x5 mL ) . The combined organics were washed with 95 % 98 % water (20 mL ) , dried over Na2SO4, and concentrated to yield 4f 4h a yellow oil containing residual DMF. This crude was diluted with Et20 and chilled on ice causing the product to crystallize as pale -yellow needles . These crystals were washed with several small portions of ice- cold Et20 and SMe Br dried to give the pure ketone 3i (331 mg, 69 % ) . ' H NMR ( 500 [0633 ] MHz, CDC13 ) 8 8.31 (dd , J = 8.1 , 1.6 Hz, 1H ) , 7.92 OH ( d , J = 8.3 Hz, 1H ) , 7.73 ( d , J = 2.0 Hz, 1H ) , 7.62 (ddd , J = 8.0 , quantitative 99 % 7.4 , 1.7 Hz, 1H ) , 7.48 (dd , J = 8.3 , 2.0 Hz, 1H ) , 7.40-7.33 ( m , 4i 5a 2H ) , 3.33 ( s , 3H ), 2.59 ( s , 3H ) ; 13C NMR ( 126 MHz, CDC13 ) 8 189.5 , 146.5 , 141.4 , 137.7 , 134.7 , 132.4 , 132.2 , 131.8 , 131.7 , 129.2 , 126.4 , 125.2 , 121.4 , 39.3 , 15.0 . LR -MS calcd . Br I for C5H4NO2S2[ M + H ]* 320.04 , found 320.75 .

Preparation of Diarylthiazepinyl Chlorides (5 ) CI quantitative 96 % [0634 ] 5c 5f

Scheme 2. Preparation of diarylthiazepinyl chlorides . S SMe

R1 CI CI NaBH4 quantitative 98 % MeOH Sh 5i R2 0 ° C. to R.T. [ 0635 ) General Procedure for Preparation of Diarylthiaz 3a , c , f , h , i epinyl Alcohols ( 4 ). [ 0636 ] Sodium borohydride ( 2 equivalents ) was added to an ice -cooled solution ( or suspension ) of the appropriate Ri ketone 3 ( 1 equivalent) in MeOH (0.05 M based on 3 ) and SOCI2 the mixture was allowed to warm to room temperature and H2Cl2 0 ° C. to R.T. stirred until TLC indicated the complete consumption of R2 starting material . The reaction was then quenched with OH saturated aqueous ammonium chloride (5 mL per mmol 3 ) 4a , c , f, h , i and saturated aqueous NaHCO3 (5 mL per mmol 3 ) . The MeOH was evaporated and the precipitate was filtered , US 2020/0079745 A1 Mar. 12 , 2020 51 washed with water , and dried ( alternatively , the residue was 11- Hydroxy -6 -methyl - 3- (methylthio ) -6,11- dihydrod extracted with EtoAc and the combined organic layers were ibenzo [cf ] [1,2 ]thiazepine 5,5 - dioxide (41 ) washed with water , dried over Na2SO4, filtered , and con centrated ). The resulting product 4 was used in the next step [0641 ] The product 4i was prepared according to the without further purification . general procedure and obtained as a pale - yellow crystalline solid (323 mg, quantitative ). ' H NMR (500 MHz, CDC13 ) d 3 -Bromo - 111 -hydroxy - 6 -methyl - 6,11 -dihydrod 7.75 ( d , J = 2.0 Hz, 1H ) , 7.57 (dd , J = 7.6 , 1.3 Hz , 1H ), 7.54 ( d , ibenzo [ c , f ] [ 1,2 ] thiazepine 5,5 - dioxide (4a ) J = 8.2 Hz, 1H ) , 7.37 (ddd , J = 9.2 , 7.9 , 1.9 Hz, 2H ) , 7.32-7.27 ( m , 2H ), 5.89 (d , J = 9.4 Hz, 1H ), 4.44 (d , J = 9.4 Hz, 1H ), 3.16 [ 0637 ] The product 4a was prepared according to the ( s , 3H ) , 2.51 (s , 3H ) ; 13C NMR (126 MHz, CDC13 ) d 140.8 , general procedure and obtained as a white solid ( 1.85 g, 138 137.4 , 136.0 , 134.0 , 131.2 , 130.4 , 30.3 , 129.7 , 99 % ). 'H NMR (500 MHz, CDC13 ) 8 8.11 (d , J = 2.0 Hz , 1H ), 127.7 , 127.0 , 124.8 , 75.9 , 39.2 , 15.4 ; LR -MS calcd . for 7.73 ( dd , J = 8.2 , 2.0 Hz, 1H ), 7.61 ( dd , J = 7.7 , 1.0 Hz, 1H ), C15H4NO2S2 [ M -OH ] * 304.05 , found 304.71. 7.57 (d , J= 8.2 Hz, 1H ) , 7.41 ( td , J = 7.6 , 1.5 Hz , 1H ), 7.37-7.30 (m , 2H ), 5.93 (d , J = 9.7 Hz , 1H ), 4.16 (d , J = 9.7 Hz , [0642 ] General Procedure for Preparation of Diarylthiaz 1H ) , 3.20 ( s, 3H ); 13C NMR (126 MHz, CDC13 ) 8 138.9 , epinyl Chlorides ( 5 ) . 138.8 , 136.9 , 136.4 , 135.3 , 131.8 , 131.5 , 131.0 , 130.1 , [0643 ] Thionyl chloride (6 equivalents ) was added drop 127.9 , 127.0 , 122.7 , 76.2 , 39.4 ; LR -MS calcd . for wise to a solution of the appropriate alcohol 4 ( 1 equivalent ) C4H , BrNO S [ M - OH ]+335.97 , found 335.89. in anhydrous CH2C12 ( 0.065 M based on 4 ) at 0 ° C. The reaction mixture was then warmed to room temperature , 3 - Bromo - 2 - fluoro - 11- hydroxy - 6 -methyl -6,1 - dihy stirred overnight, and concentrated to provide the corre sponding chloride 5 , which was used directly in the follow drodibenzo [ c, f ] [ 1,2 ] thiazepine 5,5 -dioxide (40 ) ing reactions without further purification . [ 0638 ] The product 4c was prepared according to the general procedure and obtained as a pale -yellow glass 3 -Bromo -11 - chloro -6 -methyl -6,11 - dihydrodibenzo containing minor impurities (21.1 mg, quantitative ) . ' H [ c , f ] [ 1,2 ] thiazepine 5,5 - dioxide ( 5 ) NMR ( 400 MHz, CDC1z ) 8 8.15 ( d , J =6.5 Hz, 1H ) , 7.63 7.58 ( m , 1H ) , 7.52 (dd , J = 9.1, 0.7 Hz, 1H ) , 7.44-7.32 ( m , [0644 ] The product 5a was prepared according to the 4H ), 6.06 (br s , 1H ), 3.88 (br s, 1H ) , 3.26 ( s, 3H ) ; 13C NMR general procedure and obtained as a white solid ( 1.92 g , (101 MHz, CDC13 ) d 162.8 and 160.3 , 140.8 and 140.7 , 99 % ) . ' H NMR ( 400 MHz, CDC1z ) 08.14 ( d , J = 2.1 Hz , 1H ), 138.1 , 136.5 , 134.4 and 134.3 , 133.81 and 133.79 , 130.1 , 7.66 (dd , J = 8.3 , 2.1 Hz , 1H ), 7.55-7.49 ( m , 2H ), 7.45-7.40 129.6 , 128.2 , 127.1 , 117.1 and 116.8 , 109.3 and 109.1 , 73.6 , ( m , 2H ) , 7.39-7.33 ( m , 1H ) , 6.10 (s , 1H ) , 3.58 ( s, 3H ) ; 13C 38.7 . NMR ( 101 MHz, CDC13 ) d 142.0 , 139.2 , 137.6 , 135.6 , 134.1, 133.0 , 131.7 , 131.0 , 130.2 , 129.5 , 129.0 , 124.3 , 63.7 , 11- Hydroxy - 3 - iodo - 6 -methyl -6,11 - dihydrodibenzo 39.3 ; LR -MS cald. for C14H BrNO S [ M -Cl ] * 335.97 , [cf ] [1,2 ] thiazepine 5,5 -dioxide ( 4 ) found 335.79. [ 0639] The product 4f was prepared according to the general procedure and obtained as a white solid (74.8 mg, 3 - Bromo - 11 -chloro - 2 - fluoro - 6 -methyl - 6 , 11 - dihy 95 % ). ' H NMR (500 MHz, CDC1z ) (observed as a -4 : 1 ratio drodibenzo [ c , f ] [ 1,2 ]thiazepine 5,5 - dioxide ( 50 ) of 2 conformers, resulting in partial integrals ) d 8.27 ( d , J = 1.8 Hz , 1H ), 7.99 (dd , J = 7.7 , 1.1 Hz , 0.2H ), 7.93 (dd , [ 0645 ] The product 5c was prepared according the J = 8.1 , 1.8 Hz, 0.8H ) , 7.68 ( d , J = 7.2 Hz , 0.2H ) , 7.65-7.58 ( m , general and obtained as an off- white solid (21.3 mg, quan 1H ), 7.53 (td , J = 7.6 , 1.3 Hz, 0.2H ) , 7.44-7.37 ( m , 1.8H ), titative) . ' H NMR (500 MHz, CDC13 ) 8 8.21 ( d , J= 6.6 Hz, 7.37-7.29 ( m , 1.8H ), 5.92 ( s , 1H ) , 4.40 ( d , J = 9.6 Hz, 0.2H ) , 1H ), 7.55-7.50 (m , 2H ), 7.44 (d , J= 7.7 Hz , 1H ), 7.40-7.35 4.15 ( d , J = 7.5 Hz, 0.8H ), 3.20 ( s , 2.4H ) , 3.14 (s , 0.6H ) ; 13C ( m , 1H ), 7.32 ( d , J = 8.7 Hz , 1H ), 6.07 ( s , 1H ) , 3.57 ( s , 3H ) ; NMR ( 126 MHz, CDC1z ) (additional peaks due to conform 13C NMR ( 126 MHz, CDC13 ) d 161.7 and 159.6 , 139.0 , ers ) & 142.4 , 138.8 , 138.7 , 137.5 , 136.5 , 135.4 , 133.6 , 132.1 , 137.5 and 137.4 , 137.04 , 136.98 , 133.78 and 133.77 , 131.8 , 131.7 , 131.4 , 130.6 , 130.1, 130.0 , 128.9 , 128.4 , 127.9 , 130.0 , 129.4 , 129.1 , 118.9 and 118.7 , 111.3 and 111.1 , 62.7 , 127.6 , 127.0 , 126.9 , 93.6 , 76.2 , 39.3 ; LR -MS calcd . for 39.1 . C14H1INO S [ M - OH ] * 383.96 , found 383.71. 3,11 - Dichloro - 6 -methyl - 6,11 - dihydrodibenzo [ c , f ] [ 1 , 3 -Ethynyl - 11 -hydroxy - 6 -methyl - 6,11 -dihydrod 2 ] thiazepine 5,5 - dioxide (50 ) ibenzo [ c , f ] [ 1,2 ] thiazepine 5,5 - dioxide (4h ) [ 0646 ] Chloride 5d was purchased from Ark Pharm Inc. [ 0640 ] The product 4h was prepared according to the (Libertyville , 111. ) and used without further purification . general procedure and obtained as an off- white solid (very 11 - Chloro - 3 - iodo -6 -methyl - 6,11 -dihydrodibenzo [ c , f ] [ 1,2 ] slight yellow tint, 253 mg, 98 % ). ' H NMR (500 MHz, thiazepine 5,5 -dioxide (5f ) . The product 5f was prepared CDC1z ) d 8.09 ( d , J = 1.6 Hz , 1H ) , 7.70 ( dd , J = 7.8 , 1.7 Hz , according to the general procedure and obtained as a gray 1H ) , 7.65 ( d , = 7.9 Hz, 1H ) , 7.62 (dd , J= 7.8 , 1.6 Hz, 1H ), solid (73.4 mg, 96 % ) . ' H NMR ( 400 MHz, CDC13 ) d 8.32 7.40 ( td , J= 7.6 , 1.7 Hz , 1H ), 7.34 (td , J= 7.5 , 1.4 Hz , 1H ), ( d , J = 1.8 Hz , 1H ) , 7.87 (dd , J = 8.2 , 1.8 Hz , 1H ) , 7.57-7.48 7.31 ( dd , v = 7.9 , 1.4 Hz, 1H ) , 5.95 ( d , J = 9.8 Hz, 1H ) , 4.27 ( d , ( m , 2H ), 7.43 ( d , J = 7.1 Hz, 1H ), 7.39-7.33 ( m , 1H ) , 7.27 ( d , J = 9.9 Hz, 1H ), 3.22 (s , 1H ) , 3.17 (s , 3H ); 13C NMR (126 J = 7.1 Hz, 1H ), 6.08 (s , 1H ), 3.57 ( s, 3H ); 13C NMR (101 MHz, CDC1z ) d 139.1 , 138.1, 137.4 , 136.7 , 135.1 , 131.74 , MHz , CDC13 ) d 141.8 , 141.5 , 139.3 , 137.6 , 136.7 , 134.7 , 131.68 , 130.4 , 130.1 , 127.8 , 126.9 , 123.3 , 81.5 , 80.2 , 76.6 , 132.9, 131.7 , 130.1 , 129.5 , 129.0 , 95.4 , 63.8 , 39.3 ; LR -MS 39.4 . calcd . for C14H , INOS [M -Cl ] * 383.96 , found 383.70 . US 2020/0079745 A1 Mar. 12 , 2020 52

11- Chloro -3 - ethynyl -6 -methyl - 6,11 - dihydrodibenzo and the resulting colorless solution was stirred at room [c , f] [ 1,2 ]thiazepine 5,5 - dioxide (5h ) temperature for 23 h . The mixture was then boiled for 15 [0647 ] The product 5h was prepared according to the min open to the atmosphere to remove most of the NH3 and general procedure and obtained as an off -white crystalline then fully concentrated in vacuo to give amino acid 6b as a solid (269 mg , quantitative ). ' H NMR (400 MHz, CDC13 ) 8 white solid ( 2.22 g, quantitative ). ' H NMR (500 MHz, 8.13 ( d , J = 1.7 Hz , 1H ) , 7.62 (dd , J = 8.1, 1.7 Hz , 1H ) , MOD ) 8 2.92 ( t , J = 7.5 Hz, 2H ), 2.21 (t , J = 7.5 Hz, 2H ) , 7.56-7.48 (m , 3H ), 7.44 ( d , J= 7.1 Hz , 1H ) , 7.36 (ddd , J = 7.7 , 1.70-1.56 (m , 4H ), 1.43-1.31 (m , 10H ); 13C NMR (126 6.4 , 2.1 Hz, 1H ) , 6.13 (s , 1H ), 3.58 (s , 3H ), 3.22 (s , 1H ); 13C MHz, MeOD ) & 180.5, 40.8 , 37.1, 30.4 , 30.20 , 30.18 , 30.0 , NMR (101 MHz , CDC13 ) 140.7 , 139.3 , 137.5 , 135.6 , 135.2 , 28.5 , 27.3 , 26.8 . 131.74 , 131.67 , 131.5 , 130.2 , 129.4 , 128.9 , 124.8 , 81.3 , 80.8 , 63.9 , 39.2 . 11- Aminoundecanoic acid (60 ) [0652 ] Amino acid 6c was purchased from Thermo Fisher 11- Chloro -6 -methyl - 3- ( methylthio ) -6,11 -dihydrod Scientific Inc. in the neutral zwitterion form and used ibenzo [c ,f ][ 1,2 ] thiazepine 5,5 -dioxide (5i ) without further purification . [0648 ] The product 5i was prepared according to the [0653 ] General Procedure for Preparation of Aminoal general procedure and obtained as an off- white solid (329 kanoic Acid Esters ( 7 ) . mg, 98 % ) H NMR (400 MHz, CDC13 ) 8 7.78 (s , 1H ), [ 0654 ] Thionyl chloride ( 3 equivalents ) was slowly added 7.56-7.47 ( m , 2H ) , 7.45-7.40 ( m , 2H ) , 7.38-7.32 ( m , 2H ) , to anhydrous EtOH ( 0.3 mL per mmol SOC12 ) at room 6.12 ( s , 1H ), 3.58 ( s , 3H ), 2.53 ( s , 3H ). 13C NMR ( 101 MHz , temperature ( some warming ) . This solution was allowed to CDC13 ) 142.9 , 140.9 , 139.4 , 137.9 , 131.9 , 131.5 , 130.9 , return to room temperature and added to the appropriate 130.1, 129.6 , 129.5 , 128.9 , 124.1 , 64.5 , 39.3 , 15.3 ; LR -MS amino acid 6 ( in salt or zwitterion form ), the resulting calcd . for C15H /4NO2S2 [ M -Cl ] + 304.05 , found 304.74 . suspension was sonicated for ~ 1 min as needed to break up large particles , and then the mixture was stirred for 24 h at Preparation of Amine Side Chains (7 ) room temperature. The reaction mixture was concentrated in vacuo and the resulting solid was treated with a small [ 0649 ] quantity of anhydrous EtOH and concentrated again . This procedure was then repeated 2x more to ensure removal of residual HCl. The resulting solid was triturated with boiling Scheme 3. Preparation of aminoalkanoic acid esters . hexanes, allowed to cool and settle , and the supernatant was Br sat. aq . NH3 carefully removed by pipet. This procedure was then CO2H repeated 1x more and the solids dried to provide the corre R.T. sponding amino ester 7 as the hydrochloride salt , which was Br o used directly in the following reactions without further H3N CO2H SOCI2 H3N . CO2Et purification . EtOH , R.T. 6a , n = 8 7a , n = 8 Ethyl 9 - aminononanoate hydrochloride ( 7a ) 6b , n = 9 7b , n = 9 6c , n = 10 , commercially 7c , n = 10 [0655 ] The product 7a was prepared according to the obtained as zwitterion 7d , n = 6 , commercially general procedure and obtained as a pale -yellow solid ( 1.09 obtained g , quantitative) . ' H NMR (500 MHz, MeOD ) d 4.11 (q , CI J = 7.1 Hz , 2H ) , 2.92 (t , J = 7.6 Hz , 2H ) , 2.30 (t , J = 7.4 Hz , 2H ) , H3N CO2Me 1.71-1.57 ( m , 4H ) , 1.44-1.31 ( m , 8H ) , 1.24 (t , J = 7.1 Hz, 3H ); 13C NMR (126 MHz, MeOD 175.5 , 61.4 , 40.8 , 7e , n = 7 , 35.0 , 30.1, 29.98 , 29.97 , 28.5 , 27.4 , 26.0 , 14.5 . commercially obtained Ethyl 10 - aminodecanoate hydrochloride (76 ) [0656 ] The product 7b was prepared according to the 9 - Aminononanoic acid hydrobromide (6 ) general procedure and obtained as an off- white solid (2.38 g , [ 0650 ] Saturated aqueous NH3 (28-30 % NH3, 30 mL ) and quantitative ). ' H NMR ( 400 MHz, MeOD ) d 4.11 (q , J = 7.1 9 -bromononanoic acid (949 mg, 4.00 mmol) were combined Hz, 2H ) , 2.92 (t , J = 7.7 Hz , 2H ) , 2.30 ( t , J = 7.4 Hz, 2H ) , and the resulting colorless solution was stirred at room 1.72-1.56 ( m , 4H ) , 1.44-1.28 ( m , 10H ) , 1.24 (t , J = 7.1 Hz, temperature for 23 h . The mixture was then boiled for ~ 15 3H ) ; 13C NMR ( 101 MHz, MeOD ) 8 175.6 , 61.4 , 40.8 , 35.1 , min open to the atmosphere to remove most of the NH3 and 30.24 , 30.20 , 30.09 , 30.08 , 28.6 , 27.4 , 26.0 , 14.5 . then fully concentrated in vacuo to give amino acid 6a as a white solid ( 1.04 g , quantitative ). ' H NMR ( 500 MHz , Ethyl 11- aminoundecanoate hydrochloride ( 70) MOD ) . 2.91 ( t, J = 7.8 Hz, 2H ) , 2.20 ( t, J = 7.4 Hz, 2H ) , [0657 ] The product 7c was prepared according to the 1.70-1.56 ( m , 4H ), 1.43-1.32 ( m , 8H ); 13C NMR (126 MHz, general procedure but without the hexane wash step and MeOD ) & 180.9 , 40.7 , 37.5 , 30.3 , 30.1 , 29.9 , 28.5 , 27.3 , obtained as an off- white solid (2.07 g , 97 % ). ' H NMR ( 500 26.9 . MHz, MeOD ) d 4.11 ( q , J = 7.1 Hz , 2H ) , 2.92 ( t, J = 7.6 Hz, 2H ) , 2.30 (t , J = 7.4 Hz, 2H ) , 1.71-1.55 ( m , 4H ) , 1.42-1.29 10 -Aminodecanoic acid hydrobromide (6b ) (m , 12H ), 1.24 (t , J= 7.1 Hz, 3H ); 13C NMR ( 126 MHz, [ 0651 ] Saturated aqueous NH3 ( 28-30 % NH3,60 mL ) and MeOD ) 8 175.6 , 61.4 , 40.8 , 35.1 , 30.40 , 30.38 , 30.3 , 30.2 , 10 -bromodecanoic acid ( 2.01 g , 8.00 mmol) were combined 30.1 , 28.6 , 27.4 , 26.0 , 14.5 . US 2020/0079745 A1 Mar. 12 , 2020 53

Ethyl 7 - aminoheptanoate hydrochloride (7d ) Ethyl 7 - ( ( 3 - ethynyl- 6 -methyl - 5,5 -dioxido -6,11 - dihy [ 0658 ] Amino ester 7d was purchased from Ark Pharm drodibenzo [ c, f] [ 1,2 ] thiazepin - 11 -yl )aminoheptano Inc. (Libertyville , Ill. ) as the hydrochloride salt and used ate (Sa ) without further purification . [0663 ] Methyl 8 -aminooctanoate hydrochloride ( 7e ) 8? [0659 ] Amino ester 7e was purchased from AURUM Pharmatech LLC ( Franklin Park , N.J. ) as the hydrochloride salt and used without further purification . Preparation of Diarylthiazepinamine Esters ( 8 ) [0660 ] HN Scheme 4. Preparation of diarylthiazepinamine esters .

C1 Ri H?N COR3 EtzN MeNO2, 60 ° C . CO2Et CI R2 5 [ 0664 ] The product Sa was prepared according to the general procedure and purified by preparative TLC ( 10 : 1 CH , C1 : Et, 0 ) to provide a viscous , yellow oil ( 30.8 mg, 68 % ). ' H NMR (500 MHz, CDC13 ) 88.09 ( d , J= 1.7 Hz, 1H ) , R1 7.59 ( dd , J = 7.9 , 1.7 Hz, 1H ), 7.44 (d , J = 8.0 Hz , 1H ) , 7.41-7.32 (m , 3H ), 7.28 ( td , J= 7.3 , 1.8 Hz , 1H ), 5.03 (s , 1H ), R2 4.11 ( q , J = 7.1 Hz, 2H ) , 3.34 ( s , 3H ) , 3.16 (s , 1H ), 2.46 ( tq , HN J = 7.3 , 4.0 Hz , 2H ) , 2.26 ( t , J = 7.5 Hz, 2H ) , 2.09 (br s , 1H ) , 1.59 ( p , J = 7.3 Hz, 2H ) , 1.53-1.42 ( m , 2H ), 1.34-1.26 ( m , 4H ), 1.24 ( t, J= 7.2 Hz, 3H ); 13C NMR (126 MHz, CDC13 ) R302C 8 173.8 , 139.2 , 139.0 , 138.8 , 138.7 , 135.5 , 132.2 , 130.2 , 8 129.9, 129.4 , 128.1, 127.9 , 122.7 , 81.6 , 79.6 , 66.5 , 60.3 , Rj = Br, I, SM , 48.2 , 38.6 , 34.4 , 30.0 , 29.1, 27.0 , 25.0 , 14.4 . Ethyl 7- ( 3 -bromo - 2 - fluoro - 6 -methyl - 5,5 - dioxido -6 , manCECH 11 - dihydrodibenzo [ c , f ] [ 1,2 ]thiazepin - 11 -yl ) amino ) R2 = H , F. heptanoate (8b ) R3 = Me, Et n = 6-10 [0665 ]

[ 0661 ] General Procedure for Preparation of Diarylthiaz 8b epinamines. [ 0662] To a suspension of the appropriate chloride 5 (1 equivalent) in nitromethane ( 0.5 M based on 5 ) was added the appropriate aminoalkanoic acid ester hydrochloride ( 1.2 equivalents ) and EtzN (2.4 equivalents ) and the mixture was Br warmed to 60 ° C. and left to stir until TLC indicated that the reaction was complete ( typically < 1 h ) . The reaction mixture HN was then concentrated in vacuo and purified directly by column chromatography or preparative TLC . Alternatively , the concentrated reaction residue was partitioned between Et20 (20 mL per mmol 5 ) and water (20 mL per mmol 5 ) . The ethereal layer was separated and the aqueous extracted again with Et20 (20 mL per mmol 5 ). The combined organics were washed with water (20 mL per mmol 5 ) and 10 % NH , OH ( 20 mL per mmol 5 ), dried over Na2SO4, and concentrated to yield the product. If necessary, the product CO2Et was further purified by column chromatography or prepara tive TLC . US 2020/0079745 A1 Mar. 12 , 2020 54

[ 0666 ] The product 8b was prepared according to the Methyl 8- ( 3 -bromo - 6 -methyl - 5,5 - dioxido -6,11 general procedure and purified by column chromatography dihydrodibenzo [cf ] [ 1,2 ] thiazepin - 111 -yl ) amino ) (CH , C1,, 2 column volumes - 20 : 1 CH , C1 , :Et , 0 , 2 column octanoate ( 80 ) volumes - 7 : 3 CH2Cl :Et , 0 , 2 column volumes ) to provide [0669 ] a viscous, pale -yellow oil (20.6 mg, 78 % ). ' H NMR (500 8d MHz, CDC1z ) 8.16 ( d , J = 6.6 Hz , 1H ) , 7.42-7.28 m , 5H ) , lo 5.09 ( s , 1H ) , 4.11 ( q , J = 7.1 Hz, 2H ), 3.39 ( s , 3H ) , 2.57-2.46 ( m , 2H ), 2.27 (t , J = 7.5 Hz , 2H ), 1.99 (br s, 1H ), 1.66-1.57 ( m , 2H ) , 1.52 (p , J = 7.1 Hz, 2H ), 1.39-1.28 ( m , 4H ), 1.24 (t , Br J = 7.1 Hz , 3H ) ; 13C NMR ( 101 MHz, CDC13 ) 8 173.8, 162.2 HN and 159.7 , 141.6 , 139.1 , 138.3 , 135.84 and 135.80 , 134.27 and 134.25 , 129.5 , 128.8 , 128.4 , 127.9 , 116.8 and 116.5 , 108.7 and 108.5 , 64.3 , 60.3 , 48.3 , 38.2 , 34.4 , 30.0 , 29.1 , 27.0 , 25.0 , 14.4 . Ethyl 7- ( 6 -methyl - 3- ( methylthio ) -5,5 -dioxido - 6,11 dihydrodibenzo [ c , f ] [1,2 ] thiazepin - 11 -yl )amino )hep tanoate (80 ) 506671 Me02C [0670 ] The product 8d was prepared according to the general procedure and purified by column chromatography ( CH2Cl2 , 2 column volumes-> 28 : 1 CH2Cl2 :Et20 , 3 column volumes-> 7: 3 CH2Cl2: Et, 0 , 3 column volumes ) to provide 8c a viscous, pale -yellow oil (44.8 mg , 88 % ). ' H NMR (500 MHz , CDC1z ) 8 8.10 ( d , J = 2.1 Hz, 1H ) , 7.62 (dd , J = 8.2 , 2.1 Hz, 1H ) , 7.41-7.33 ( m , 4H ) , 7.29 ( td , J = 7.3 , 1.7 Hz, 1H ) , 4.98 ( s , 1H ) , 3.66 ( s , 3H ) , 3.37 ( s , 3H ) , 2.45 ( t , J = 7.1 Hz, 2H ) , 2.28 ( t, J = 7.5 Hz, 2H ) , 2.04 (br s , 1H ) , 1.59 ( p , J = 7.7 SMe Hz , 2H ), 1.51-1.41 ( m , 2H ) , 1.33-1.23 (m , 6H ); 13C NMR (126 MHz , CDC1z ) 8 174.4 , 140.6 , 138.9, 138.6 , 137.6 , HN 135.3 , 131.4 , 131.3 , 130.1 , 129.5 , 128.3 , 128.1, 122.0 , 66.3 , 51.6 , 48.3 , 38.8 , 34.2 , 30.1, 29.2 , 29.1 , 27.2, 25.0 . Methyl 8- ( 3 - iodo - 6 -methyl - 5,5 - dioxido -6,11 - dihy drodibenzo [ c , f ] [ 1,2 ] thiazepin - 11 -yl ) amino )octano ate ( 80 ) [0671 ]

CO2Et 8e

[ 0668 ] The product 8c was prepared according to the general procedure and obtained as a viscous, pale -yellow oil HN (44.0 mg, 92 % ). ' H NMR (400 MHz, CDC13 ) 8 7.78 (d , J = 1.3 Hz, 1H ) , 7.42-7.31 ( m , 5H ) , 7.31-7.24 ( m , 1H ) , 4.95 ( s , 1H ) , 4.10 ( q , J = 7.1 Hz, 2H ) , 3.34 ( s , 3H ) , 2.50 ( s , 3H ) , 2.45 ( t, J = 7.1 Hz, 2H ), 2.25 ( t, J = 7.5 Hz , 2H ) , 2.13 (br s , 1H ) , 1.64-1.53 ( m , 2H ) , 1.52-1.40 ( m , 2H ) , 1.33-1.24 ( m , 4H ), 1.23 ( t, J= 7.1 Hz, 4H ). 13C NMR ( 101 MHz, CDC13 ) d 173.8 , 140.0 , 139.5 , 139.0 , 138.9 , 134.7 , 130.5 , 130.5 , 129.8 , 129.3 , 128.0 , 125.3 , 66.8 , 60.3 , 48.1, 38.9 , 34.4 , 30.0 , 29.1 , 27.1, 25.0 , 15.6 , 14.4 ; LR -MS calcd . for Me02C C24H33N204S2 [ M + H ] * 477.19 , found 476.70 . US 2020/0079745 A1 Mar. 12 , 2020 55

[ 0672 ] The product 8e was prepared according to the Ethyl 9 -( ( 3 -iodo -6 -methyl - 5,5 -dioxido -6,11 -dihy general procedure and purified by column chromatography drodibenzo [c , f ][ 1,2 ] thiazepin - 11 - yl) amino )decaño ( CH2Cl2 , 4 column volumes-> 20 :1 CH2Cl2 : Et20 , 2 column ate (8g ) 8g volumes-> 7 :3 CH2Cl2: Et20 , 2 column volumes ) to provide [ 0675 ] a viscous, nearly colorless oil (49.0 mg, 88 % ) . 'H NMR ( 400 MHz, CDC1z ) 8 8.26 ( d , J = 1.8 Hz, 1H ), 7.81 ( dd , J = 8.1, 1.8 Hz, 1H ) , 7.40-7.32 ( m , 3H ) , 7.31-7.26 ( m , 1H ) , 7.21 ( d , J = 8.2 Hz , 1H ) , 4.97 ( s , 1H ) , 3.65 ( s , 3H ) , 3.37 ( s , 3H ) , 2.45 ( t, J= 7.1 Hz, 2H ), 2.28 ( t, J= 7.5 Hz , 2H ), 2.01 (br s, 1H ), 1.59 ( p , J = 7.3 Hz , 2H ) , 1.51-1.41 ( m , 2H ) , 1.34-1.24 ( m , HN 6H ); 13C NMR ( 101 MHz, CDC13 ) 174.3 , 141.2 , 140.6 , 139.0 , 138.6 , 138.3 , 136.9 , 131.4 , 130.0 , 129.4 , 128.2 , 128.1, 92.9 , 66.3 , 51.6 , 48.3 , 38.7 , 34.2 , 30.1 , 29.2 , 29.1 , 27.2 , 25.0 . Ethyl 9- ( 3 - iodo - 6 -methyl - 5,5 - dioxido -6,11 -dihy drodibenzo [c , f ][ 1,2 ] thiazepin - 11 -yl ) amino ) nonano ate ( 88 ) [0673 ]

8f EtO2C ino [ 0676 ] The product 8g was prepared according to the general procedure and purified by column chromatography (CH2Cl2 , 2 column volumes- > 20: 1 CH2Cl2: Et , 0 , 3 column volumes-a viscous, > colorless 7: 3 CH Czoíl: Et (42.5 0 ,mg 2 column, 71 % ). volumes'H NMR ) (to400 provide MHz, CDC12 ) / 8.26 (d , J= 1.8 Hz, IH ) , 7.81 (dd , J = 8.1, 1.8 Hz , HN 1H ) , 7.40-7.32 ( m , 3H ), 7.31-7.26 ( m , îH ), 7.22 ( d , J = 8.1 Hz, 1H ) , 4.98 ( s , 1H ) , 4.12 ( 9 , J = 7.1 Hz, 2H ) , 3.37 ( s , 3H ) , 2.46 (t , J = 7.1 Hz, 2H ), 2.27 (t , J= 7.5 Hz, 2H ) , 2.01 (br s, 1H ), 1.60 ( p , J = 7.3 Hz , 2H ) , 1.52-1.40 ( m , 2H ) , 1.33-1.20 ( m , 13H ) ; 13C NMR (101 MHz, CDC13 ) . 174.0 , 141.2 , 140.61, 139.0 , 138.6 , 138.3 , 136.9 , 131.4 , 130.0 , 129.4 , 128.2 , 128.1 , 92.9 , 66.2 , 60.3 , 48.3 , 38.7 , 34.5 , 30.2 , 29.5 , 29.4 , 29.3 , 29.2 , 27.3 , 25.1 , 14.4 . Ethyl 9 -( (3 -iodo -6 -methyl - 5,5 -dioxido -6,11 - dihy drodibenzo [c ,f ] [ 1,2 ] thiazepin - 11- yl) amino )unde canoate ( 8h ) [0677 ] 8h CO2Et

[0674 ] The product 8f was prepared according to the HN general procedure and purified by column chromatography ( CH2Cl2 , 2 column volumes-> 20 :1 CH2Cl2 :Et20,3 column volumes-> 7 :3 CH2Cl2 :Et20 , 2 column volumes ) to provide a viscous, pale -yellow oil ( 36.9 mg, 63 % ). 'H NMR (500 MHz, CDC1 ) 8 8.26 (d , J = 1.8 Hz, 1H ), 7.81 (dd , J = 8.1 , 1.9 Hz , 1H ), 7.40-7.33 (m , 3H ), 7.28 ( td , J = 7.4, 1.6 Hz , 1H ), 7.21 ( d , J = 8.1 Hz, 1H ) , 4.97 ( s , 1H ) , 4.11 ( q , J = 7.1 Hz, 2H ) , 3.37 ( s , 3H ) , 2.45 ( t, J = 7.1 Hz, 2H ) , 2.27 ( t, J = 7.5 Hz , 2H ) , 2.00 (br s , 1H ) , 1.59 (p , J = 7.2 Hz, 2H ) , 1.51-1.41 ( m , 2H ) , 1.32-1.21 ( m , 11H ) ; 13C NMR ( 126 MHz , CDC1, ) 8 173.94 , 141.20 , 140.60 , 139.02 , 138.61, 138.27 , 136.90 , 131.37 , 129.97 , 129.40 , 128.23 , 128.07 , 92.84 , 66.23 , 60.27 , 48.29 , CO2Et 38.69, 34.46 , 30.17 , 29.38 , 29.26 , 29.15 , 27.31, 25.03 , 14.39 . US 2020/0079745 A1 Mar. 12 , 2020 56

[ 0678 ] The product 8h was prepared according to the -continued general procedure and purified by column chromatography B ) ( CH2Cl2 , 2 column volumes-> 20 : 1 CH2Cl2 :Et20 , 3 column volumes-> 7: 3 CH2Cl2 :Et20 , 2 column volumes) to provide a viscous , pale -yellow oil (45.6 mg, 74 % ). ' H NMR (400 MHz, CDC12 ) 8 8.26 ( d , J = 1.9 Hz , 1H ) , 7.81 (dd , J = 8.1 , 1.9

Hz, 1H ) , 7.40-7.32 ( m , 3H ) , 7.31-7.25 ( m , 1H ) , 7.22 ( d , HN J = 8.2 Hz, 1H ) , 4.97 ( s , 1H ) , 4.12 ( 9 , J = 7.1 Hz, 2H ) , 3.37 ( s , LiOH 3H ) , 2.46 ( t, J = 7.1 Hz, 2H ) , 2.27 ( t, J = 7.5 Hz, 2H ) , 2.01 (br THF/ H20 s , 1H ) , 1.66-1.56 ( m , 2H ) , 1.52-1.41 ( m , 2H ) , 1.33-1.20 ( m , 60 ° C. to R.T. 15H ); 13C NMR ( 101 MHz, CDC13 ) 174.0 , 141.2 , 140.6 , 139.1, 138.6 , 138.3 , 136.9 , 131.4 , 129.9 , 129.4 , 128.2 , 128.1, 92.8 , 66.2 , 60.3 , 48.3 , 38.7 , 34.5 , 30.2 , 29.6 , 29.5 , 29.3 , 29.2 , 27.4 , 25.1 , 14.4 . CO2Et 8a Preparation of Diarylthiazepinamine Carboxylic Acids (9 ) [0679 ]

Scheme 5. Preparation of diarylthiazepinamine carboxylic acids. A ) HN

Rj 0.5 Maq . ??? 80-100 ° C. HN R2 Dn CO2H 9a R302C 8

[0680 ] General Procedure for Preparation of Carboxylic Acids (9 ). [0681 ] The appropriate ester 8 ( 0.04 M final concentra R1 tion ) was heated in aqueous HC1 (0.5 M ) at 80 or 100 ° C. until TLC indicated the complete consumption of starting material ( typically < 24 h ) . The reaction mixture was then R2 concentrated and dried thoroughly in vacuo to provide the HN pure HCl salt of the corresponding amino carboxylic acid . In some cases , a powdered or crystalline solid resulted directly , HO2C but in others, it was necessary to triturate the obtained glass with hexanes and then concentrate to provide a powdered Rj = Br, I, SM , solid if desired . R2 = H , F R3 = Me, Et [0682 ] Note : In some cases, yields below 90 % were n = 6-10 obtained due to losses while transferring the poorly soluble product between vessels during the concentration process . US 2020/0079745 A1 Mar. 12 , 2020 57

7 - ( ( 3 -Ethynyl -6 -methyl - 5,5 - dioxido - 6,11 - dihydrod [0686 ] The product 9b was prepared according to the ibenzo [ c , f ] [ 1,2 ] thiazepin - 11 -yl ) amino )heptanoic general procedure and obtained as a glassy , white foam ( 14.1 acid (9a ) mg, 95 % ). ' H NMR ( 400 MHz, MeOD ) 8 8.32 ( d , J =6.6 Hz, 106831 1H ) , 7.84 ( d , J = 8.9 Hz , 1H ) , 7.70 ( dd , J = 7.8 , 1.6 Hz, 1H ) , 9a 7.62 (ddd , J = 8.6 , 7.2 , 1.5 Hz, 1H ) , 7.56 (dd , J = 8.1 , 1.5 Hz, 1H ) , 7.47 ( td , J = 7.5 , 1.5 Hz, 1H ) , 5.87 ( s , 1H ) , 3.25 ( s , 3H ) , 3.00-2.90 ( m , 1H ) , 2.87-2.76 ( m , 1H ) , 2.27 (t , J = 7.3 Hz, 2H ), 1.73-1.52 (m , 4H ), 1.38-1.29 (m , 4H ); 13C NMR (101 MHz, MeOD ) 176.2 , 162.9 and 160.3 , 140.9 , 136.4 and 136.3 , 133.89 and 133.88 , 133.1, 131.9, 127.9 , 127.4 , 121.8 and 121.6 , 111.5 and 111.3 , 65.8 , 47.3 , 38.5 , 33.4 , 28.3 , 26.0 , HN 25.9 , 24.4 . 7-( 6 -Methyl -3- ( methylthio ) -5,5 -dioxido -6,11 - dihy drodibenzo [ c , f ] [ 1,2 ] thiazepin - 11 -yl ) amino )hep tanoic acid ( 90 ) [0687 ] CO2H 9c [ 0684 ] Amino ester 8a (15.7 mg, 0.0345 mmol) , aqueous LiOHTHF (0.48 (0.160 mL mL ) were of 0.216combined M solution and heated , 0.0345 to 60 mmol ° C. )for , and 30 min . and then stirred for an additional 17 h at room tem perature . The THF was then removed in vacuo and the residue was diluted with water (2 mL ) and washed with Et , SMe (2x2 mL ) . The aqueous layer was then acidified to ph 4 with 10 % aqueous HC1, saturated with NaCl, and extracted with CH2Cl2 (3x5 mL ). The combined organics were washed HN with brine ( 1 mL ) and concentrated to give a white foam . This material was purified by preparative TLC (20 : 1 EtoAc : mgMeOH, 46 )% to). provide" H NMR the (500 pure MHz product, CDC1z 9a )as 8 8.10a white (d , foamJ = 1.6 (Hz6.7 , 1H ), 7.61 (dd , J= 7.9 , 1.7 Hz, 1H ), 7.48 ( d, J = 8.0 Hz , 1H ), 7.44 ( d , J = 7.6 Hz, 1H ) , 7.40-7.34 ( m , 2H ) , 7.31-7.26 ( m , 1H ), 5.15 (s , 1H ), 4.98 (br s , 2H ), 3.30 (s , 3H ), 3.18 (s , 1H ) , 2.54-2.46 ( m , 1H ) , 2.44-2.36 ( m , 1H ) , 2.26 (t , J = 1.3 Hz, 2H ) , 1,62-1.54 ( m , 2H ) , 1.53-1.42 ( m , 2H ) , 1.32-1.22 ( m , 4H ) ; 13C NMR ( 126 MHz, CDC12 ) d 178.1, 139.2 , 139.1, 135.8, 132.2 , 131.2 , 131.0 , 129.8 , 128.0 , 127.6 , 123.2 , 81.5 , 80.0 , 66.5 , 47.6 , 38.8 , 34.4 , 29.4 , 29.0 , 27.0 , 24.9 . CO2H 7 - (( 3 -Bromo - 2 -fluoro -6 -methyl -5,5 - dioxido- 6,1 dihydrodibenzo [ c , f ] [ 1,2 ] thiazepin - 11 - yl) amino ) [0688 ] The product 9c was hydrolyzed according to the heptanoic acid hydrochloride salt (9b ) general procedure and purified by acid - base extraction . [0685 ] Specifically , after concentration of the reaction mixture to give the crude hydrochloride salt , this material was parti 9b tioned between saturated aqueous NaHCO3 (with a small amount of NaOH added , 2 mL ) and Et20 (2 mL ) and the LILLO organic layer was removed and discarded . The aqueous layer was washed again with Et20 ( 2 mL ), acidified to ph 6 with Br 10 % aqueous HCl, and extracted with CH , C12 (3x5 mL) . The combined organics were dried over Na2SO4 and con H2N . F centrated to provide the neutral , zwitterion form of the product as an off -white solid ( 10.7 mg, 50 % ). ' H NMR (400 MHz, CDC13 ) 8 7.79 ( d, J= 1.9 Hz, 1H ), 7.45 ( d , J = 7.6 Hz , 1H ) , 7.41 ( d , J = 8.2 Hz, 1H ), 7.38-7.32 ( m , 3H ) , 7.30-7.24 ( m , 1H ), 6.43 (br s , 2H ) , 5.12 (s , 1H ) , 3.28 ( s , 3H ) , 2.52 ( s , 3H ) , 2.53-2.44 ( m , 1H ) , 2.43-2.33 ( m , 1H ) , 2.25 (br s , 2H ) , 1.56 ( br s , 2H ) , 1.50-1.40 ( m , 2H ) , 1.32-1.20 (m , 4H ) ; 13C NMR ( 101 MHz, CDC13 ) d 140.9 , 139.5 , 139.3 , 136.0 , CO2H 132.6 , 131.7 , 131.6 , 129.9 , 129.8, 127.9 , 127.7 , 125.2 , 77.4 , 66.6 , 47.4 , 39.0 , 29.3 , 29.1, 27.0 , 25.2 , 15.5 . US 2020/0079745 A1 Mar. 12 , 2020 58

8 -( (3 -Bromo -6 -methyl - 5,5 - dioxido -6,11 -dihydrod [0692 ] The product 9e was prepared according to the ibenzo [ c , f ] [1,2 ]thiazepin -11 -yl )amino ) octanoic general procedure and obtained as a white solid ( 117 mg, acid hydrochloride salt (90 ) 98 % ) . ÎH NMR ( 400 MHz, MeOD 8 8.36 ( d , J = 1.9 Hz, 1H ) , [0689 ] 8.19 ( dd , J = 8.0 , 1.9 Hz, 1H ), 7.70 ( dd , J = 7.8 , 1.5 Hz, 1H ), Od 7.65-7.58 ( m , 2H ) , 7.55 (dd , J = 8.1 , 1.4 Hz, LH ), 7.47 ( td , ia J = 7.5 , 1.5 Hz , 1H ) , 5.83 ( s , 1H ) , 3.23 ( s , 3H ) , 2.91 (ddd , J = 12.2 , 9.8 , 5.8 Hz, 1H ) , 2.77 (ddd , J = 12.1 , 9.7 , 6.2 Hz , 1H ) , 2.26 ( t , J = 7.4 Hz, 2H ) , 1.71-1.51 ( m , 4H ), 1.36-1.27 ( m , Br 6H ) ; 13C NMR (101 MHz, MeOD ) d 177.6 , 144.3 , 142.3 , 141.4 , 137.9, 136.4 , 134.5 , 133.1, 129.9, 129.1 , 128.6 , H2N 128.3 , 97.5 , 67.8 , 48.4 , 39.7 , 34.8 , 29.8 , 29.7 , 27.3 , 27.2 , 25.8 . 9- ( 3 - Iodo - 6 -methyl - 5,5 -dioxido -6,11 -dihydrod ibenzo [ c , f ] [ 1,2 ] thiazepin - 11 - yl) amino ) nonanoic acid hydrochloride salt ( 9 ) [0693 ]

HO2C 9f [0690 ] The product 9d was prepared according to the general procedure and obtained as a glassy , white foam (37.0 mg, 97 % ) . ' H NMR (500 MHz, MeOD ) 8 8.19 (d , J= 2.1 Hz, 1H ) , 7.99 (dd , J = 8.2 , 2.1 Hz, 1H ) , 7.83 ( d , J = 8.2 Hz , 1H ) , 7.74 (dd , J = 7.7 , 1.5 Hz, 1H ) , 7.62 (ddd , J = 8.7 , 7.2 , 1.5 Hz, 1H ) , 7.56 (dd , J = 8.1 , 1.4 Hz, 1H ) , 7.47 (td , J = 7.5 , 1.4 Hz, 1H ) , 5.90 ( s , 1H ) , 3.25 ( s , 3H ), 2.92 (ddd , J = 12.1 , 10.0 , 5.7 H2N Hz, 1H ) , 2.77 ( ddd , J = 12.1, 9.9 , 6.1 Hz, 1H ) , 2.26 ( t, J = 7.4 Hz, 2H ), 1.72-1.52 ( m , 4H ), 1.36-1.26 ( m , 6H ) ; 13C NMR ( 126 MHz, MeOD ) d 177.5 , 142.2 , 141.8 , 138.1, 136.8 , 134.5 , 133.1 , 132.1 , 129.5 , 129.1, 128.6 , 128.4 , 126.1 , 67.5 , 48.3 , 39.7 , 34.8 , 29.8 , 29.7 , 27.30 , 27.26 , 25.8 . 8 - ( ( 3 - Iodo - 6 -methyl - 5,5 -dioxido -6,11 - dihydrod ibenzo [ c , f ] [ 1,2 ] thiazepin - 11- yl) amino ) octanoic acid hydrochloride salt (9e )

[ 0691 ] CO2H

9e

[0694 ] The product 9f was prepared according to the general procedure run under more dilute conditions (0.02 M , HN because of poor solubility ) and obtained as a glassy, white foam (18.7 mg, 76 % ). 13C NMR (126 MHz, MeOD ) 8.34 (d , CO? J = 1.8 Hz , 1H ) , 8.17 (dd , J = 8.0 , 1.9 Hz , 1H ) , 7.68 ( dd , J = 7.9 , 1.5 Hz , 1H ) , 7.63-7.56 ( m , 2H ) , 7.54 (dd , J = 8.2 , 1.4 Hz , 1H ) , 7.45 ( td , J = 7.5 , 1.5 Hz, 1H ) , 5.75 ( s , 3H ) , 3.24 ( s , 3H ), 2.86 (ddd , J = 12.0 , 9.7 , 5.6 Hz, 1H ) , 2.72 (ddd , J = 12.0 , 9.7 , 6.2 Hz, 1H ) , 2.27 ( t, J = 7.6 Hz , 2H ) , 1.68-1.52 ( m , 4H ) , 1.36 1.22 (m , 8H ) ; 13C NMR (126 MHz ,MeOD ) d 177.7 , 144.1 , 142.1 , 141.5 , 137.9 , 136.2 , 134.2 , 132.8 , 130.9 , 129.5 , HO2C 129.1, 128.6 , 97.0 , 67.8 , 48.4 , 39.7 , 35.0 , 30.0 , 29.9 , 27.6 , 27.5 , 26.0 . US 2020/0079745 A1 Mar. 12 , 2020 59

10- ( 3 - Iodo - 6 -methyl - 5,5 - dioxido - 6,11 - dihydrod [ 0698 ] The product 9h was prepared according to the ibenzo [c ,f ][ 1,2 ]thiazepin - 11 - yl ) amino ) decanoic general procedure run under more dilute conditions (0.01 M , acid hydrochloride salt (98 ) because of poor solubility ) and obtained as a glassy , white [0695 ] 9g foam (14.0 mg, 51 % ) . ' H NMR ( 500 MHz, MeOD ) d 8.34 ( d , J = 1.8 Hz, 1H ) , 8.17 ( dd , J = 8.0 , 1.8 Hz, 1H ) , 7.68 (dd , lo J = 7.9 , 1.5 Hz, 1H ) , 7.63-7.57 ( m , 2H ) , 7.54 (dd , J = 8.1, 1.4 Hz, 1H ) , 7.45 ( td , J = 7.5 , 1.4 Hz, 1H ) , 5.75 ( s , 1H ), 3.23 ( s , 3H ) , 2.87 (ddd , J = 12.0 , 9.7 , 5.7 Hz , 1H ) , 2.72 (ddd , J = 12.1, 9.7,6.2 Hz , 1H ), 2.27 (t , J = 7.4 Hz , 2H ), 1.69-1.52 ( m , 4H ) , 1.36-1.22 (m , 12H ); 13C NMR (126 MHz, MeOD ) & 177.8 , H2N . 144.1 , 142.1 , 141.4 , 137.9 , 136.2 , 134.3 , 132.9 , 129.1 , 128.6 , 97.1, 67.8 , 48.3 , 39.7 , 35.0 , 30.4 , 30.3 , 30.2 , 30.0 , 27.6 , 27.5 , 26.1 . Example 2. In Vitro Activity at Mu and Delta Opioid Receptors [ 0699 ] The diarylthiazepinamine carboxylic acids (9 ) were tested for agonist activity at the human mu opioid receptor (MOR ) and delta opioid receptor (DOR ) using bioluminescence resonance energy transfer (BRET ) assays measuring G protein activation as previously described HO2C ( Table 1 ) ( Rives , M.-L. et al. 2012 ; Negri, A. et al . 2013 ) . [ 0696 ). The product 9g was prepared according to the [0700 ] Transfection . general procedure run under more dilute conditions (0.01 M , because of poor solubility ) and obtained as a glassy , white [0701 ] Human MOR DNA was transfected alongside foam ( 15.6 mg, 70 % ) . ' H NMR ( 500 MHz, MeOD ) : 8.35 Gauß with RLuc8 inserted at position 91 (GAB - RLuc8 ) , ( d , J= 1.7 Hz, 1H ), 8.19 (dd , J = 8.0 , 1.8 Hz, 1H ), 7.71 (dd , GB , (B1 ) , and Gy2 fused to the full - length mVenus at its N J = 7.9 , 1.4 Hz , 1H ), 7.66-7.59 (m , 2H ), 7.55 (dd , v= 8.1 , 1.3 Hz , 1H ) , 7.47 ( td , J = 7.6 , 1.3 Hz, 1H ) , 5.84 ( s , 1H ) , 3.23 ( s , terminus (mVenus - y2 ) into HEK -293T cells ( 5x106 cells / 3H ) , 2.91 (ddd , J = 12.1, 9.9 , 5.6 Hz , 1H ) , 2.75 (ddd , J = 12.1 , plate ) in 10 - cm dishes using PEI (Polysciences Inc.; War 9.8 , 6.1 Hz, 1H ) , 2.27 ( t , J = 7.4 Hz, 2H ), 1.70-1.54 ( m , 4H ) , rington , Pa .) in a 1 : 1 ratio diluted in Opti- MEM ( Life 1.34-1.25 ( m , 10H ) ; 13C NMR ( 126 MÚZ, MOD ) 8 177.1, Technologies Corp .; Grand Island , N.Y.) to assay for G 144.3 , 142.3 , 141.4 , 137.9 , 136.5 , 134.5 , 133.1 , 129.9 , protein activation as described previously (Rives , M.-L. et 129.1 , 128.6 , 128.3 , 97.5 , 67.8 , 48.3 , 39.7 , 34.9 , 30.18 , al. 2012 ; Negri, A. et al . 2013) . Cells were maintained in 30.15 , 30.1, 29.9 , 27.5 , 27.3 , 26.0 . Dulbecco's Modified Eagle Medium (high glucose # 11965 ; 11- ( 3 - Iodo -6 -methyl - 5,5 -dioxido -6,11 -dihydrod Life Technologies ) supplemented with 10 % FBS (Premium ibenzo [ c, f ] [ 1,2 ]thiazepin - 11 -yl ) amino Jundecanoic Select, Atlanta Biologicals ; Atlanta , Ga .) and 100 U /mL acid hydrochloride salt ( 9h ) penicillin and 100 ug /mL streptomycin (# 15140 , Life Tech [ 0697 ] 9h nologies ). After 24 hours the media was changed , and the experiment was performed 24 hours later (48 hours after transfection ) . [0702 ] BRET. [0703 ] Transfected cells were dissociated and re - sus pended in phosphate - buffered saline (PBS ). Approximately H2N 200,000 cells /well were added to a black - framed , white well 96 - well plate (# 60050 ; Perkin Elmer; Waltham , Mass. ) . The CO?I microplate was centrifuged and the cells were re -suspended in PBS. Then 5 uM of the luciferase substrate coelenterazine H was added to each well for 5 minutes . Following coelen terazine H addition , ligands were added and the BRET signal was measured at 5 minutes on a PHERAstar FS plate reader. Quantification of the BRET signal required calcu lating the ratio of the light emitted by the energy acceptor, mVenus (510-540 nm ) , over the light emitted by the energy donor, RLuc8 (485 nm ). This drug - induced BRET signal was normalized using the Emar of [ D - Ala ?, N -MePhe , Gly -ol ] -enkephalin (DAMGO ) as the 100 % maximal response for G protein activation . Dose response curves CO2H were fit using a three -parameter logistics equation in Graph Pad Prism 6 . US 2020/0079745 A1 Mar. 12 , 2020 60

TABLE 1 Functional agonist activity of compounds at human MOR and DOR . Where indicated , error represents = SEM of 2 or more independent trials. The data shows the trend for increasing DOR potency, but not MOR potency, as the length of the carboxylic acid side chain is increased .

Human Human MOR DOR Compound Structure ( EC50 ) (EC50 ) Tianeptine 194 + 70 nM 37.4 + 11.2 UM

Ci

HN

COH

9a 53.3 + 18 nM 5.9 + 0.3 UM

HN

CO2H

9b 83.1 + 5.7 nM 11.5 = 2.2 UM

Br

H?N

CO2H US 2020/0079745 A1 Mar. 12 , 2020 61

TABLE 1 - continued Functional agonist activity of compounds at human MOR and DOR . Where indicated , error represents £ SEM of 2 or more independent trials . The data shows the trend for increasing DOR potency, but not MOR potency , as the length of the carboxylic acid side chain is increased . Human Human MOR DOR Compound Structure ( EC50 ) ( EC50 ) 9c 41.8 nM 2.06 um (Emax = 51 % ) partial agonist

-SMe

HN

CO2H 9d 56 + 24 nM 1.7 + 0.04 uM

Br

H2N

HO2C

9e 24.2 + 11 nM 724 + 99 nM

HN

HO2C US 2020/0079745 A1 Mar. 12 , 2020 62

TABLE 1 - continued

Functional agonist activity of compounds at human MOR and DOR . Where indicated , error represents : SEM of 2 or more independent trials . The data shows the trend for increasing DOR potency , but not MOR potency , as the length of the carboxylic acid side chain is increased .

Human Human MOR DOR Compound Structure ( EC50 ) ( EC50 )

9f 22 + 14 nM 530 + 340 nM

HN

COH

9g 26.6 + 1.8 nM 262 + 25 nM

H?N

HO2C US 2020/0079745 A1 Mar. 12 , 2020 63

TABLE 1 - continued Functional agonist activity of compounds at human MOR and DOR . Where indicated , error represents £ SEM of 2 or more independent trials . The data shows the trend for increasing DOR potency, but not MOR potency , as the length of the carboxylic acid side chain is increased . Human Human MOR DOR Compound Structure ( EC50 ) (EC50 ) 9h 110 + 29 nM 700 + 305 nM

H2N .

CO2H

Example 3. Preparation of Additional Compounds NMR = 77.16 ) , MOD (' H NMR = 3.31 and 13C NMR = 49 . [ 0704 ] General Considerations . 00 ), or DMSO -do ( 'H NMR = 2.50 and 13C NMR = 39.52 ). [0705 ] Reagents and solvents were obtained from com Multiplicity is indicated as follows: s ( singlet ) ; d ( doublet ) ; mercial sources and were used without further purification t (triplet ) ; q ( quartet) ; p (pentet ) ; dd (doublet of doublets ); unless otherwise stated . All compounds were prepared in ddd ( doublet ofdoublet of doublets ) ; dt ( doublet of triplets ) ; racemic form . All reactions were performed in flame- dried td (triplet of doublets ); m (multiplet ); br (broad ) . All carbon glassware under an argon atmosphere unless otherwise peaks are rounded to one decimal place unless such round stated , and monitored by TLC using solvent mixtures appro ing would cause two close peaks to become identical; in priate to each reaction . All column chromatography was these cases, two decimal places are retained . Two carbon performed on silica gel ( 40-63 um ). Nuclear magnetic peaks joined by " and " in the peak list correspond to a single resonance spectra were recorded on Bruker 400 or 500 MHz carbon atom but are split due to F - C coupling . instruments as indicated . Chemical shifts are reported as d Preparation of Additional Diarylthiazepinones ( 3 ) values in ppm referenced to CDC1z ( ' H NMR = 7.26 and 13C [0706 ]

Scheme 6. Preparation of additional diarylthiazepinones.

H?N . 1 ) NaNO2 Cl aq . HC1, 0 ° C. 2 ) SO2, Cuci pyridine , Me02C CI AcOH /H20 Me02C CH2Cl2 0 ° C. to R.T. 0 ° C. to R.T. 54 % lc US 2020/0079745 A1 Mar. 12 , 2020 64

-continued

N 1. LiOH C1 1,4 -doxane / H20 , 80 ° C. 2. SOC12 , R.T. 3. AICIZ , CHCl3 , reflux CI CO2Me 85 % 74 % , 3 steps 2c 3j

H2N . ci 1) NaNO2 aq. HCI, 0 ° C. 2 ) SO2, Cuci pyridine , Me02C F AcOH /H20 Me02C F CH2Cl2 0 ° C. to R.T. 0 ° C. to R.T. 39 % 1d

1. LiOH CI 1,4 -doxane / H20 , 80º C. 2. SOCl2 , R.T. 3. AICI3 , CHCl3 , reflux F F CO2Me 77 % 45 % , 3 steps 2d 3k NH2 ON NH2 1) NaNO2 O2N . I HNO3 aq . HC1, 0 ° C. Bu4NMnO4 H2SO4 2 ) KI, H2O pyridine F -10 ° C. F 0 ° C. to R.T. F 60 ° C. 96 % 80 % 10 11 O2N . O2N . H2SO4 MeOH HO2C reflux MeO2C 52 % 65 % 12 13 SnCl2.2H20 EtOAc/ CH2Cl2 R.T.

10N- s = 0 1. LiOH 1,4 - doxane / 1) NaNO2 H20 , 80 ° C . aq . HCI, 0 ° C. H2N . 2. SOCl2 , R.T. pyridine, Me02C F 2 ) SO2, Cuci 3. AICI3 , CO2Me CH2Cl2 ACOH /H20 Me02c 59 % , 3 steps CHCl3 , 88 % 0 ° C. to R.T. 29 % 0 ° C. to R.T. quantitative 31 reflux 2e le 14

methyl 4,5 -dichloro - 2 - chlorosulfonyl) benzoate (1c ) C., and a solution of NaNO2 (602 mg, 8.73 mmol) in water [0707 ] A suspension ofmethyl 2 -amino -4,5 -dichloroben ( 1.45 mL ) was added dropwise over ~ 5 minutes, maintain zoate (1.92 g, 8.73 mmol) in 20 % aqueous HCl (8.7 mL ) was ing the internal temperature below -5 ° C. The resulting sonicated for several minutes and warmed slightly until all mixture was then stirred for 20 minutes at -5 ° C. Simulta clumps were broken up and the mixture was a uniform neously , a solution of SO2 (4.47 g, 69.84 mmol) in AcOH suspension of fine particles. This mixture was cooled to -5 ° (6.98 mL ) and water (0.73 mL ) was prepared by bubbling US 2020/0079745 A1 Mar. 12 , 2020 65

the gas though the mixed solvents at 0 ° C. until the mass had with water (25 mL ) , dried over Na2SO4, and concentrated to increased by the required amount. To this SO2 solution was give a light- brown solid (1.19 g ) . This material was purified then added CuCl (216 mg, 2.18 mmol) followed by the by column chromatography (hexanes , 1 column volume diazonium salt solution portionwise over 15 minutes at 0 ° C. - > 1 : 1 CH2Cl2 : hexanes , 1 column volumes-> 7 : 3 CH2Cl2: The resulting mixture was then stirred for 30 minutes at 0 ° hexanes, 2 column volumes) to give ketone 3j as an off C. and 30 minutes at room temperature , poured into water white solid ( 960 mg, 74 % over 3 steps) . ' H NMR (400 MHz, (50 mL ), and extracted with CH C12 (3x25 mL ). The com CDC13 ) 8 8.29 (dd , J = 8.1 , 1.7 Hz, 1H ) , 8.07 ( s , 1H ) , 8.04 ( s , bined organics were poured into water (50 mL ) , and solid 1H ) , 7.67 (ddd , J = 8.1 , 7.3 , 1.7 Hz, 1H ) , 7.40 (ddd , J = 8.3 , NaHCO3 was added carefully until effervescence ceased . 7.3 , 1.2 Hz, 1H ) , 7.36 (dd , J = 8.1, 1.1 Hz, 1H ) , 3.36 ( s , 3H ) ; The organic phase was then separated , washed with water 13C NMR ( 101 MHz, CDC13 ) 8 188.3 , 141.3 , 138.3 , 137.1 , ( 25 mL ) and brine ( 25 mL ) , dried over Na2SO4, and con 136.5 , 135.4 , 135.3 , 133.9, 132.4 , 130.8 , 127.5 , 126.6 , centrated to provide the crude sulfonyl chloride lc as a 124.9 , 39.2 . waxy , very pale -yellow solid ( 1.75 g , 82 mass % product by NMR , 54 % yield ). This material was used in the next step methyl 4 -chloro - 2 - chlorosulfonyl) -5 - fluorobenzoate without further purification . (10 ) methyl 4,5 - dichloro -2- ( N -methyl - N - phenylsulfa [ 0710 ] A suspension of methyl 2 -amino - 4 -chloro - 5 - fluo moyl) benzoate (2c ) robenzoate (4.98 g , 24.46 mmol) in 20 % aqueous HCl ( 15.9 mL ) was sonicated for several minutes and warmed slightly [0708 ] To a solution of N -methylaniline (541 uL , 533 mg, until all clumps were broken up and the mixture was a 4.97 mmol) in anhydrous CH2Cl2 ( 4.4 mL ) at 0 ° C. was uniform suspension of fine particles . This mixture was added anhydrous pyridine ( 3.3 mL ) followed by a solution cooled to -5 ° C., and a solution of NaNO2 ( 1.69 g , 24.46 of crude methyl 4,5 -dichloro - 2 - chlorosulfonyl) benzoate lc mmol) in water (4.1 mL ) was added dropwise over -10 ( 1.68 g , 82 % pure , 4.52 mmol) in anhydrous CH C12 (4.4 minutes , maintaining the internal temperature below -5 ° C. mL ) over 3 minutes . The resulting orange solution was then The resulting mixture was then stirred for 20 minutes at -5 ° allowed to warm to room temperature and stirred for 2.5 h . C. Simultaneously , a solution of SO2 (12.56 g , 196 mmol ) in The reaction mixture was then diluted with CH C12 (50 mL ) , ACOH ( 19.6 mL) and water (2.04 mL) was prepared by washed with 3 % aqueous HCl (2x25 mL ), brine ( 25 mL ) , bubbling the gas though the mixed solvents at 0 ° C. until the saturated aqueous NaHCO3 (25 mL ), and brine again (25 mass had increased by the required amount. To this SO2 mL ) , dried over Na2SO4, and concentrated to give a viscous solution was then added CuCl ( 606 mg, 6.12 mmol) fol orange oil ( 1.93 g ) . This material was purified by column lowed by the diazonium salt solution portionwise over 25 chromatography ( 9 : 1 hexanes :EtOAc , 3 column vol minutes at 0 ° C. The resulting mixture was then stirred for umes-> 8 : 2 hexanes: EtOAc, 2 column volumes ) to provide 1 h at 0 ° C. and 1 h at room temperature , poured into ice sulfonamide 2c as a viscous, pale -yellow oil that slowly water ( 75 mL ) , and extracted with CH C12 ( 3x30 mL ) . The crystallized to give a waxy, off -white solid ( 1.44 g, 85 % ). 'H combined organics were poured into water ( 100 mL ) , and NMR (500 MHz , CDC13 ) 8 7.57 ( s , 1H ) , 7.45 ( s , 1H ) , solid NaHCO3 was added carefully until effervescence 7.39-7.30 ( m , 3H ) , 7.22-7.18 ( m , 2H ), 3.83 ( s , 3H ), 3.31 ( s , ceased . The organic phase was then separated , washed with 3H ); 13C NMR (126 MHz, CDC13 ) 8 166.3 , 140.8 , 137.4 , water ( 30 mL ) and brine ( 30 mL ), dried over Na2SO4, and 135.1 , 134.6 , 132.7 , 131.8 , 130.2 , 129.4 , 128.1, 127.4 , 53.6 , concentrated to provide the crude sulfonyl chloride 1d as a 39.1 . waxy brown solid (3.39 g , 81 mass % product by NMR , 39 % yield ) . This material was used in the next step without 2,3 -dichloro - 6 -methyldibenzo [ c , f ] [ 1,2 ]thiazepin - 11 further purification . ( 6H ) -one 5,5 - dioxide ( 3 ) methyl 4 -chloro - 5 - fluoro - 2-( N -methyl - N - phenylsul [0709 ] Sulfonamide 2c ( 1.43 g , 3.82 mmol) was dissolved famoyl) benzoate ( 2 ) in 1,4 - dioxane (31 mL ) , water ( 16 mL ) and LiOH.H2O (480 mg, 11.46 mmol) were added , and the mixture was heated at [0711 ] To a solution of N -methylaniline ( 1.14 mL , 1.12 g, 80 ° C. for 40 minutes . The reaction mixture was diluted with 10.36 mmol) in anhydrous CH2Cl2 ( 9.1 mL ) at 0 ° C. was water ( 125 mL ), washed with Et20 ( 100 mL ) , acidified with added anhydrous pyridine (6.9 mL ) followed by a solution 10 % aqueous HCl, and extracted with CH C12 ( 100 mL , of crude methyl 4 -chloro -2- ( chlorosulfonyl ) -5 - fluorobenzo 2x50 mL ). The combined organics were dried over Na2SO4 ate 1d ( 3.35 g , 81 % pure , 9.42 mmol) in anhydrous CH2Cl2 and concentrated to provide the carboxylic acid intermediate (9.1 mL ) over 3 minutes. The resulting yellow - brown solu as a pale- tan solid ( 1.33 g ) , which was used in the next step tion was then allowed to warm to room temperature and without further purification . To the carboxylic acid ( 1.32 g , stirred for 1.25 h . The reaction mixture was then diluted with 3.66 mmol ) was added thionyl chloride ( 5.9 mL ) , all chunks CH2C12 ( 100 mL ) , washed with 3 % aqueous HCI (2x50 were broken up by sonication , and the mixture was stirred mL ) , brine (50 mL ), saturated aqueous NaHCO3 ( 50 mL ) , for 1.5 h at room temperature ( solids now dissolved ) . The and brine again (50 mL ), dried over Na2SO4, and concen volatiles were then removed in vacuo to provide the crude trated to give a viscous, dark -orange oil ( 3.77 g ) . This acyl chloride as a viscous yellow oil that slowly crystallized material was purified by column chromatography (9 :1 hexa into a waxy yellow solid . This material was dissolved in nes: EtOAc , 3 column volumes- > 8 : 2 hexanes: EtOAc, 2 col anhydrous CHC1z ( 16 mL ) , aluminum chloride ( 1.56 g , umn volumes ) to provide sulfonamide 2d as a viscous , 11.71 mmol) was added , and the mixture was refluxed for 1 pale -yellow oil that slowly crystallized to give a waxy, h . The reaction was then cooled to room temperature , off- white solid (2.60 g , 77 % ). ' H NMR (400 MHz, CDC13 ) quenched with ice water ( 75 mL ) , and extracted with 7.44 ( d , J = 6.8 Hz, 1H ) , 7.39-7.29 ( m , 3H ) , 7.26 ( d , J = 8.3 Hz, CH2C12 ( 3x25 mL ). The combined organics were washed 1H ) , 7.22-7.17 ( m , 2H ), 3.83 ( s , 3H ) , 3.30 ( s , 3H ); 13C NMR US 2020/0079745 A1 Mar. 12 , 2020 66

( 101 MHz, CDC13 ) 8 166.2 , 161.1 and 158.6 , 140.8 , 134.03 ( 126 MHz, CDC13 ) d 154.5 and 152.5 , 145.0 , 133.5 and and 133.96 , 133.0 , 132.5 and 132.4 , 129.4 , 128.1, 127.4 , 133.3 , 125.1 and 125.0 , 119.0 and 118.8 , 113.2 and 113.1 , 123.3 and 123.1 , 116.9 and 116.7 , 53.6 , 39.0 . 20.21. 3 - chloro - 2- fluoro -6 -methyldibenzo [c , f] [ 1,2 ] thiaz 1 - fluoro - 2 - iodo - 5 -methyl - 4 -nitrobenzene ( 11) epin - 11 (6H ) -one 5,5 -dioxide ( 3k ) [0714 ] Aniline 10 ( 10.21 g , 60.00 mmol) was suspended [0712 ] Sulfonamide 2d (2.55 g , 7.13 mmol) was dissolved in 36 % m / m aqueous HCl ( 120 mL ) and the mixture cooled in 1,4 - dioxane (57 mL ) , water (29 mL ) and LiOH.H2O (898 to <0 ° C. To this mixture was added a solution of NaNO2 mg, 21.39 mmol) were added , and the mixture was heated at (4.55 g, 66.00 mmol) in water ( 24 mL ) dropwise over 10 80 ° C. for 1 h . The reaction mixture was diluted with water minutes, maintaining the internal temperature at < 0 ° C., and (250 mL ) , washed with Etz ( 200 mL ) , acidified with 10 % the resulting mixture was stirred for 30 minutes at -10 ° C. aqueous HCl, and extracted with CH C12 (200 mL , 2x100 This diazonium salt solution was then added portionwise mL ). The combined organics were dried over Na2SO4 and over 20 minutes to a solution of KI ( 19.92 g , 120 mmol) in concentrated to provide the impure carboxylic acid interme water ( 36 mL ) at 0 ° C., making sure to maintain the internal diate as a waxy tan solid ( 2.48 g ), which was used in the next temperature of the KI solution below 10 ° C. during the step without further purification . To the crude carboxylic addition . The resulting very dark brown mixture was then acid (2.45 g ) was added thionyl chloride (11.5 mL ) and the allowed to warm to room temperature and stirred for 2 h . To mixture was stirred for 1.5 h at room temperature (solids the reaction mixture was then added water (300 mL ) , now dissolved ) . The volatiles were then removed in vacuo to saturated aqueous Na2S2O3 (50 mL ) , and Et20 ( 200 mL ) , provide the crude acyl chloride as a viscous yellow oil that and the mixture was shaken until the dark color was dissi slowly crystallized into a waxy yellow solid . This material pated . The organic layer was separated and the remaining was dissolved in anhydrous CHC13 (31 mL ), aluminum aqueous extracted with additional Et20 ( 2x200 mL ). The chloride ( 3.04 g , 22.82 mmol) was added , and the mixture combined organics were washed with water ( 100 mL ) and was refluxed for 1 h . The reaction was then cooled to room brine ( 100 mL ) , dried over Na2SO4, and concentrated to temperature , quenched with ice water ( 150 mL ) , and give a dark -orange oil mixed with yellow solids (15.85 g ). extracted with CH2Cl2 (3x50 mL ). The combined organics This material was purified by column chromatography were washed with water (50 mL ) , dried over Na2SO4, and (hexanes , 2 column volumes-> 25 : 1 hexanes: Et 0 , 3 column concentrated to give a brownish - gray solid ( 1.84 g ). This volumes ) to give the pure product 11 as a crystalline , material was purified by column chromatography (7 : 3 pale - yellow solid ( 13.53 g , 80 % ). ' H NMR (400 MHz, hexanes: CH_C12 , 2 column volumes-> 1 : 1 hexanes : CH_C12 , CDC13 ) 8 8.42 ( d , J = 5.8 Hz, 1H ) , 7.03 ( dd , J = 8.0 , 0.8 Hz , 4 column volumes ) to give ketone 3k as a crystalline , 1H ), 2.59 ( s , 3H ) ; 13C NMR ( 101 MHz, CDC13 ) 8 165.3 and off- white solid ( 1.04 g , 45 % over 3 steps ) . ' H NMR ( 500 162.7 , 145.8 , 137.5 and 137.4 , 136.4 and 136.3 , 119.4 and MHz, CDC13 ) 8 8.30 (dd , J = 8.1 , 1.7 Hz, 1H ), 8.04 (d , J = 6.6 119.1, 77.8 and 77.5 , 20.9 . Hz, 1H ), 7.78 ( d , J = 9.0 Hz, 1H ), 7.67 (ddd , J = 8.1 , 7.2 , 1.7 Hz, 1H ) , 7.41 (ddd , J = 8.2 , 7.2 , 1.2 Hz, 1H ), 7.36 (dd , J = 8.1 , 5 - fluoro - 4 - iodo - 2- nitrobenzoic acid (12 ) 1.1 Hz, 1H ) , 3.36 ( s , 3H ) ; 13C NMR ( 126 MHz , CDC13 ) 8 188.2 , 161.8 and 159.8 , 141.4 , 136.8 and 136.7 , 135.4 , [0715 ] Tetrabutylammonium permanganate was prepared 134.11 and 134.08 , 132.5 , 130.6 , 128.6 , 126.6 , 125.9 and fresh according to the literature procedure (Vincent , J. et al. 125.8 , 124.9 , 120.4 and 120.2 , 39.2 . 1987 ) and dried for 21 h under high vacuum before imme diate use . Compound 11 (10.07 g , 35.83 mmol) was dis 2 - fluoro - 4 -methyl - 5 -nitroaniline ( 10 ) solved in anhydrous pyridine ( 170 mL ) and the solution was heated to 60 ° C. To this solution was slowly added a second [0713 ] To H2SO4 (250 mL ) was slowly added 2 - fluoro - 4 solution of tetrabutylammonium permanganate ( 27.19 methylaniline (25.03 g , 200 mmol ) while cooling the mix mmol, 75.24 mmol) in anhydrous pyridine ( 170 mL ) over 19 ture on ice to prevent excessive warming, and the resulting minutes. Details of addition : +3.5 minutes , + 10 ° C. exo mixture was stirred until all precipitated solids dissolved to therm , stopped addition for ~ 1 minute and removed external give a transparent brown solution . This aniline solution was heating ; + 3.5-16.5 minutes, addition continued without then cooled to -10 ° C. A second solution was prepared by external heating , maintaining stable internal temperature at careful addition of 68-70 % m /m HNO3 ( 20.0 g , 14.1 mL , 65-70 ° C .; + 16.5-19 minutes , temperature began dropping, 220 mmol) to H2SO4( 28 mL ) while cooling the mixture on so external heating resumed , final third of addition com ice to maintain the temperature at room temperature or pleted more rapidly over 2.5 minutes. After the addition was below . The HNO3/ H2SO4 solution was then added to the complete , the reaction mixture was stirred for 30 minutes at cooled aniline solution dropwise over 3 h , taking care not to 60° C. and then concentrated in vacuo to give a dark - brown allow the internal temperature to rise above -5 ° C. At the residue . To this material was added EtoAc ( 270 mL ) and end of the addition , the reaction mixture was carefully 10 % aqueous HC1 (270 mL) , followed by solid Na2S2O3 to poured into ice water (1.5 L ) and the resulting mixture was reduce residual oxidant (color dissipated ). The organic layer carefully basified by slow addition of an NaOH solution was separated and the remaining aqueous was extracted with ( ~ 450 g dissolved in 600 mL water) , cooling the mixture in additional EtOAC ( 2x135 mL ) . The combined organics were an ice bath to maintain the internal temperature below 60 ° C. washed with water ( 2x135 mL ) and then extracted with 5 % at all times . The resulting precipitate was collected by aqueous NaOH (270 mL , 2x135 mL ) . The basic aqueous filtration , washed thoroughly with water (4x ), and dried to extracts were washed with EtOAC (2x135 mL ), acidified provide the pure product 10 as a yellow solid (32.65 g , 96 % ). with concentrated aqueous HC1, and extracted with EtOAC ' H NMR (500 MHz, CDC13 ) 8 7.49 ( d , J = 8.2 Hz , 1H ) , 6.92 ( 270 mL , 2x135 mL ) . The combined organics were washed (d , J= 11.2 Hz, 1H ), 3.89 (br s, 2H ), 2.48 (s , 3H ); 13C NMR with brine ( 135 mL ) , dried over Na2SO4, and concentrated US 2020/0079745 A1 Mar. 12 , 2020 67 to give carboxylic acid 12 containing minor impurities as an brine ( 25 mL ) , dried over Na2SO4, and concentrated to orange- brown solid ( 5.80 g , 52 % ) . ' H NMR ( 400 MHz, provide the crude sulfonyl chloride le as a waxy , pale DMSO - d ) 8 8.52 ( d , J = 5.2 Hz, 1H ), 7.72 ( d , J = 7.6 Hz, 1H ) ; yellow solid (2.12 g , 61 mass % product by NMR , 29 % 13C NMR (101 MHz, DMSO -do ) d 164.4 , 164.3 and 161.9 , yield ). This material was used in the next step without 144.74 and 144.70 , 134.81 and 134.77 , 129.8 and 129.7 , further purification. 116.6 and 116.3 , 87.0 and 86.7 . methyl 5 - fluoro - 4 - iodo - 2- ( N -methyl - N -phenylsulfa methyl 5 - fluoro -4 - iodo -2 -nitrobenzoate ( 13 ) moyl) benzoate ( 2e ) [0716 ] To a solution of carboxylic acid 12 (5.76 g , 18.52 [0719 ] To a solution of N -methylaniline (401 ?L , 395 mg, mmol) in MeOH (49 mL ) was added H2SO4 (4.85 mL ) and 3.69 mmol) in anhydrous CH C12 (3.2 mL ) at 0 ° C. was the mixture was refluxed for 21 h . The reaction mixture was added anhydrous pyridine ( 2.5 mL ) followed by a solution then concentrated in vacuo and the resulting oil was diluted of crude methyl 2- ( chlorosulfonyl) -5 - fluoro -4 - iodobenzoate with EtoAc (200 mL ) , washed with saturated aqueous le (2.07 g , 61 % pure, 3.35 mmol) in anhydrous CH2C12 ( 3.2 NaHCO3 ( 200 mL ) and brine ( 100 mL ) , dried over Na2SO4 , mL ) over –3 minutes. The resulting orange solution was and concentrated to give a viscous, dark orange - brown oil then allowed to warm to room temperature and stirred for 30 (5.36 g ). This material was purified by column chromatog minutes . The reaction mixture was then diluted with CH2Cl2 raphy (hexanes , 1 column volume-> 20 : 1 hexanes: Et20 , 2 (30 mL ) , washed with 3 % aqueous HC1 (2x15 mL ) , brine column volumes-> 9 : 1 hexanes : Et 0 , 3 column volumes ) to ( 15 mL ), saturated aqueous NaHCO3 (15 mL) , and brine give ester 13 as a crystalline , pale -yellow solid (3.93 g , again ( 15 mL ), dried over Na2SO4, and concentrated to give 65 % ) . ' H NMR (400 MHz, CDC1 ) 8 8.35 ( d , J = 5.2 Hz , 1H ) , a viscous orange oil (2.07 g ) . This material was purified by 7.37 ( d , J = 7.0 Hz, 1H ) , 3.93 ( s , 3H ) ; 13C NMR ( 101 MHz, column chromatography ( 9 :1 hexanes : EtOAc, 4 column CDC12 ) d 165.3 and 162.8 , 164.3 , 144.4 , 135.70 and 135.66 , volumes-> 8 : 2 hexanes : EtOAc , 2 column volumes) to pro 130.2 and 130.1, 116.8 and 116.5 , 84.5 and 84.2 , 53.8 . vide sulfonamide 2e as a viscous yellow oil (1.33 g , 88 % ) . ' H NMR (500 MHz , CDC13 ) 8 7.72 ( d , J = 5.8 Hz, 1H ) , methyl 2 - amino - 5 - fluoro - 4 - iodobenzoate ( 14 ) 7.39-7.30 ( m , 3H ), 7.21-7.16 ( m , 2H ) , 7.14 ( d , J = 7.3 Hz , [0717 ] To a solution of ester 13 (3.92 g, 12.06 mmol) in 1H ), 3.83 (s , 3H ), 3.29 ( s, 3H ) ; 13C NMR ( 126 MHz, CDC12) EtoAc ( 90 mL ) and CH C12 ( 30 mL ) was added SnCl2 . 8 166.41 and 166.40 , 164.6 and 162.6 , 141.7 and 141.6 , 2H20 (13.61 g , 60.30 mmol ) and the mixture was stirred for 140.9 , 135.9 and 135.8 , 132.48 and 132.45 , 129.4 , 128.1 , 21 h . The reaction mixture was then diluted with water (300 127.4 , 115.5 and 115.3 , 82.9 and 82.7 , 53.6 , 38.9 . mL ), solid NaHCO3 was added with stirring until bubbling stopped , and the mixture was extracted with EtoAc (3x150 2 - fluoro - 3 - iodo -6 -methyldibenzo [c , f] [ 1,2 ]thiazepin mL ). The combined organics were washed with water (150 11 (6H ) -one 5,5 - dioxide (31 ) mL ) and brine ( 150 mL ) , dried over Na2SO4, and concen [0720 ] Sulfonamide 2e ( 1.31 g , 2.91 mmol) was dissolved trated to provide aniline 14 as a crystalline yellow solid in 1,4 - dioxane ( 23 mL ) , water ( 12 mL ) and LiOH.H2O ( 366 (3.55 g , quantitative ). ' H NMR (500 MHz, CDC12 ) 8 7.46 mg, 8.73 mmol ) were added , and the mixture was heated at ( d , J= 8.8 Hz , 1H ), 7.07 ( d , J= 5.1 Hz , 1H ), 5.57 (br s, 2H ), 80 ° C. for 45 minutes . The reaction mixture was diluted with 3.85 ( s, 3H ) ; 13C NMR (126 MHz, CDC13 ) 8 167.4 , 154.0 water ( 125 mL ), washed with Et20 ( 100 mL ), acidified with and 152.2 , 147.4 , 126.7 , 115.9 and 115.7 , 111.04 and 111.00 , 10 % aqueous HCl, and extracted with CH2Cl2 ( 100 mL , 90.0 and 89.8 , 52.0 . 2x50 mL ) . The combined organics were dried over Na2SO4 and concentrated to provide the impure carboxylic acid methyl 2-( chlorosulfonyl) -5 - fluoro - 4 - iodobenzoate intermediate as a viscous orange oil that slowly crystallized (le ) to a pale -orange solid ( 1.10 g ) , which was used in the next [0718 ] A suspension of aniline 14 (3.49 g , 11.83 mmol) in step without further purification . To the crude carboxylic 20 % aqueous HC1 ( 7.7 mL ) was sonicated for several acid ( 1.08 g ) was added thionyl chloride (4.0 mL ) and the minutes and warmed slightly until all clumps were broken mixture was stirred for 5 h at room temperature ( solids now up and the mixture was a uniform suspension of fine dissolved ). The volatiles were then removed in vacuo to particles. This mixture was cooled to < 0 ° C., and a solution provide the crude acyl chloride as a viscous yellow oil . This of NaNO2 (816 mg, 11.83 mmol) in water (2.0 mL ) was material was dissolved in anhydrous CHCl3 ( 11 mL ), alu added dropwise over ~ 10 minutes , maintaining the internal minum chloride ( 1.06 g, 7.94 mmol) was added , and the temperature below 0 ° C. The resulting mixture was then mixture was refluxed for 1 h . The reaction was then cooled stirred for 25 minutes at -5 ° C. Simultaneously , a solution to room temperature, quenched with ice water ( 75 mL ) , and of SO2 (6.06 g, 94.64 mmol) in AcOH (9.5 mL ) and water extracted with CH C12 ( 3x25 mL ) . The combined organics (0.99 mL ) was prepared by bubbling the gas though the were washed with water ( 25 mL ), dried over Na2SO4, and mixed solvents at 0 ° C. until the mass had increased by the concentrated to give a tan solid ( 0.90 g ). This material was required amount. To this SO2 solution was then added Cuci purified by column chromatography (hexanes , 1 column (293 mg, 2.96 mmol) followed by the diazonium salt solu volume-> 7: 3 hexanes: CH2Cl2 , 1 column volume = 1 :1 tion portionwise over 10 minutes at 0 ° C. The resulting hexanes : CH , C1,, 1 column volume-> 3 : 7 hexanes: CH , C1 , 3 mixture was then stirred for 30 minutes at 0 ° C. and 30 column volumes ) to give ketone 31 as an off -white solid minutes at room temperature , poured into water (50 mL ), (717 mg, 59 % over 3 steps) . ' H NMR (500 MHz, CDC13 ) 8 and extracted with CH2Cl2 (3x25 mL ). The combined organ 8.37 (d , J = 5.6 Hz , 1H ) , 8.29 (dd , J = 8.2 , 1.7 Hz, 1H ), ics were poured into water (50 mL ), and solid NaHCO3 was 7.69-7.65 ( m , 1H ) , 7.63 ( d , J = 7.9 Hz, 1H ) , 7.40 ( td , J = 7.8 , added carefully until effervescence ceased . The organic 1.2 Hz, 1H ), 7.35 (dd , J = 8.1, 1.2 Hz, 1H ) , 3.36 (s , 3H ) ; 13C phase was then separated , washed with water (25 mL ) and NMR ( 126 MHz , CDC13 ) 8 188.6 , 165.7 and 163.7 , 141.5 , US 2020/0079745 A1 Mar. 12 , 2020 68

138.74 and 138.68 , 137.11 and 137.08 , 135.4 , 134.3 and 2,3 -dichloro - 11 -hydroxy -6 -methyl - 6,11 -dihydrod 134.2 , 132.4 , 130.6 , 126.5 , 124.9 , 118.8 and 118.6 , 86.4 and ibenzo [ c , f ][ 1,2 ] thiazepine 5,5 - dioxide (41 ) 86.2 , 39.2 . [0722 ] The product 4j was prepared according to the general procedure described in Example 1 and obtained as Preparation of Additional Diarylthiazepinyl an off -white solid (935 mg, 98 % ). 'H NMR (400 MHz, Chlorides ( 5 ) CDC1z ) 8 8.02 ( s , 1H ), 7.84 ( s , 1H ) , 7.63-7.57 ( m , 1H ) , 7.44-7.31 ( m , 3H ) , 6.02 ( d , J = 8.0 Hz, 1H ) , 3.95 ( d , J = 8.4 Hz , [0721 ] 1H ) , 3.25 ( s , 3H ) ; 13C NMR ( 101 MHz, CDC13 ) d 138.2 , 138.0 , 137.7 , 136.8 , 136.2 , 133.2, 131.0 , 130.13 , 130.12 , Scheme 7. Preparation of additional diarylthiazepinyl chlorides . 130.0 , 128.2 , 127.1 , 74.1, 38.9 . 3 - chloro -2 - fluoro - 11 -hydroxy -6 -methyl - 6,11 - dihy drodibenzo [c ,f ][ 1,2 ] thiazepine 5,5 -dioxide (4k ) [0723 ] The product 4k was prepared according to the R1 NaBH4 general procedure described in Example 1 and obtained as MeOH an off -white solid ( 973 mg, 95 % ). ' H NMR ( 500 MHz , 0 ° C. to R.T. CDC13 ) 8 8.01 ( d , J = 6.9 Hz, 1H ), 7.63-7.58 ( m , 1H ), 7.55 ( d , R2 J = 9.5 Hz, 1H ) , 7.41 ( td , J = 7.3 , 1.7 Hz, 1H ) , 7.38-7.32 ( m , 2H ) , 6.07 ( d , J = 6.8 Hz, 1H ) , 3.91 ( d , J = 7.8 Hz, 1H ) , 3.26 ( s , 3j, k , 1 3H ); 13C NMR (126 MHz, CDC13 ) 8 161.5 and 159.4 , 140.0 and 139.9 , 138.0 , 136.6 , 134.1 and 134.0 , 131.0 , 130.1 , 129.7 , 128.2 , 127.1 , 121.6 and 121.5 , 117.3 and 117.1 , 73.6 , 38.7 . Ri SOCI2 CH2Cl2 2 - fluoro - 11- hydroxy - 3 - iodo -6 -methyl -6,11 -dihy 0 ° C. to R.T. R2 drodibenzo [ c , f ] [ 1,2 ] thiazepine 5,5 -dioxide (41 ) OH [0724 ] The product 41 was prepared according to the 4j, k , 1 general procedure described in Example 1 and obtained as an extremely pale -pink solid (669 mg, 94 % ) . ' H NMR (400 MHz, CDC1z ) 8 8.31 ( d , J = 5.9 Hz, 1H ), 7.64-7.57 ( m , 1H ) , 7.45-7.38 ( m , 2H ) , 7.37-7.32 ( m , 2H ), 6.04 ( d , J = 8.4 Hz, R1 1H ) , 3.89 ( d , J = 8.5 Hz, 1H ) , 3.25 ( s , 3H ) ; 13C NMR ( 101 MHz, CDC13 ) 8 165.7 and 163.1 , 141.9 and 141.8 , 139.48 and 139.45 , 138.2 , 136.4 , 134.63 and 134.60 , 130.1, 129.7 , CI R2 128.2 , 127.0 , 116.2 and 115.9 , 80.8 and 80.5 , 73.8 , 38.7 . 5j, k , 1 Modified Procedure for Preparation of Diarylthiazepinyl Chlorides (5 ) [0725 ] Thionyl chloride (12 equivalents ) was added drop wise to a solution of the appropriate alcohol 4 ( 1 equivalent ) in anhydrous CH2Cl2 (0.126 M based on 4 ) at 0 ° C. The CI F reaction mixture was then warmed to room temperature , OH OH 98 % 95 % stirred overnight, and concentrated to provide the corre 4j sponding chloride 5 , which was used directly in the follow 4k ing reactions without further purification . N 2,3,11 -trichloro -6 -methyl - 6,11 -dihydrodibenzo [ c , f ] [ 1,2 ] thiazepine 5,5 -dioxide (5j ) [0726 ] The product 5j was prepared according to the F C1 ?? C1 modified procedure and obtained as an off- white solid (973 94 % quantitative mg, quantitative ). ' H NMR (500 MHz, CDC13 ) d 8.08 (s , 5j 1H ) , 7.67 ( s , 1H ), 7.55-7.49 ( m , 2H ) , 7.43 ( d , J = 7.6 Hz, 1H ) , 7.41-7.34 ( m , 1H ) , 6.06 ( s , 1H ) , 3.57 (s , 3H ) ; 13C NMR ( 126 MHz, CDC13 ) 8 139.9 , 139.0 , 137.1 , 136.7 , 134.9 , 134.79, 132.8 , 131.9 , 130.1, 130.0 , 129.5 , 129.1 , 62.7 , 39.3 . 3,11- dichloro - 2 - fluoro -6 -methyl - 6,11 -dihydrod F ibenzo [ c, f ] [ 1,2 ]thiazepine 5,5 - dioxide (5k ) quantitative quantitative [0727 ] The product 5k was prepared according to the auto5k auto51 modified procedure and obtained as a white solid ( 1.01 g , quantitative ). ' H NMR (500 MHz, CDC13 ) 8 8.07 (d , J= 7.1 Hz , 1H ) , 7.55-7.48 ( m , 2H ) , 7.44 ( d , J = 7.4 Hz, 1H ) , 7.40 US 2020/0079745 A1 Mar. 12 , 2020 69

7.33 (m , 2H ), 6.08 (s , 1H ), 3.57 (s , 3H ); 13C NMR ( 126 138.3 , 136.7 , 132.6 , 130.8 , 130.4 , 129.6 , 129.3 , 128.5 , MHz, CDC1z ) 8 160.6 and 158.5 , 139.0 , 137.28 and 137.25 , 128.1 , 65.0 , 60.3 , 48.3 , 38.5 , 34.4 , 30.0 , 29.1 , 27.0 , 24.9 , 137.1, 136.3 and 136.2 , 131.8 , 131.0 , 130.0 , 129.4 , 129.1 , 14.4 . 123.5 and 123.4 , 119.2 and 119.0 , 62.7 , 39.1 . ethyl 7 - ( ( 3 -chloro - 2 - fluoro - 6 -methyl - 5,5 -dioxido - 6 , 11 - chloro - 2 - fluoro - 3 - iodo -6 -methyl - 6,11 -dihydrod 11 -dihydrodibenzo [c ,f ][ 1,2 ] thiazepin - 11- yl) amino ) ibenzo [ c , f ][ 1,2 ] thiazepine 5,5 -dioxide (51 ) heptanoate (81 ) [ 0728 ] The product 51 was prepared according to the modified procedure and obtained as a white solid (695 mg, [0731 ] The product 8j was prepared according to the quantitative) . ' H NMR (500 MHz, CDC13 ) 8 8.38 (d , J = 6.0 general procedure described in Example 1 and purified by Hz , 1H ) , 7.55-7.48 ( m , 2H ) , 7.44 ( d , J = 7.5 Hz, 1H ) , 7.40 column chromatography ( CH2Cl2, 2 column volumes-> 20 : 1 7.33 ( m , 1H ), 7.24 ( d , J = 8.2 Hz, 1H ) , 6.07 ( s , 1H ) , 3.57 ( s , CH_C12: Et20 , 2 column volumes-> 7 :3 CH2Cl2 :Et , 0 , 2 col 3H ); 13C NMR (126 MHz, CDC13 ) 8 164.5 and 162.5 , umn volumes ) to provide a viscous, pale - yellow oil (433 mg, 139.53 and 139.50 , 139.0 , 138.14 and 138.08 , 137.64 and 90 % ). ' H NMR (500 MHz, CDC12 ) 88.00 (d , J= 7.0 Hz, 1H ), 137.61, 137.1 , 131.8 , 130.0 , 129.4 , 129.1 , 117.8 and 117.6 , 7.41-7.32 (m , 4H ), 7.29 ( td , J= 7.3 , 1.5 Hz , 1H ), 5.09 (s , 1H ), 83.1 and 82.9, 62.8, 39.1 . 4.10 ( 9 , J = 7.1 Hz , 2H ) , 3.38 ( s , 3H ) , 2.51 ( td , J = 7.2 , 1.8 Hz, Preparation of Additional Diarylthiazepinamine 2H ), 2.27 ( t, J = 7.5 Hz, 2H ) , 1.98 (br s , 1H ) , 1.60 ( p , J = 7.4 Esters ( 8 ) Hz, 2H ) , 1.51 (p , J = 7.1 Hz, 2H ) , 1.38-1.26 m , 4H ) , 1.23 ( t , J = 7.1 Hz, 3H ); 13C NMR (126 MHz, CDC13 ) & 173.8 , 160.8 [0729 ] and 158.7 , 140.9 and 140.8, 139.2 , 138.2 , 135.54 and 135.51 , 131.3 , 129.4 , 128.7 , 128.4 , 127.9 , 121.0 and 120.8 , 116.9 and 116.7 , 64.2 , 60.3 , 48.3 , 38.1 , 34.3 , 30.0 , 29.0 , Scheme 8. Preparation of additional diarylthiazepinamine esters . 27.0 , 24.9 , 14.3 . ethyl 7- ( 2 - fluoro - 3 - iodo - 6 -methyl - 5,5 -dioxido -6 , H2N CO2R3 11 - dihydrodibenzo [c ,f ][ 1,2 ]thiazepin -11 - yl) amino ) Ri EtzN heptanoate ( 8k )

.. MeNO2, 60 ° C . R2 [ 0732 ] The product 8k was prepared according to the CI general procedure described in Example 1 and purified by column chromatography (8 : 2 hexanes: EtOAc, 4 column volumes-> 7 : 3 hexanes: EtOAc , 2 column volumes) to pro vide a viscous, pale - yellow oil (240 mg , 84 % ). ' H NMR (500 MHz, CDC13 ) 8 8.30 (d , J= 6.0 Hz, 1H ), 7.41-7.32 (m , R1 3H ) , 7.29 ( td , J = 7.4 , 1.5 Hz, 1H ) , 7.24 ( d , J = 8.6 Hz, 1H ) , 5.08 ( s , 1H ) , 4.11 ( q , J = 7.1 Hz, 2H ), 3.38 ( s , 3H ) , 2.56-2.46 R2 ( m , 2H ) , 2.27 ( t , J = 7.5 Hz, 2H ) , 1.99 ( br s , 1H ) , 1.60 ( p , HN J = 7.4 Hz , 2H ) , 1.51 ( p , J = 7.2 Hz , 2H ) , 1.38-1.26 ( m , 4H ) , In 1.24 ( t, J = 7.1 Hz , 3H ); 13C NMR (126 MHz, CDC13 ) d 173.8 , 164.7 and 162.7 , 142.9 and 142.8 , 139.82 and 139.79 , R302C 139.1, 138.2 , 136.04 and 136.01, 129.4 , 128.7 , 128.3 , 127.8 , 8 115.7 and 115.5 , 80.0 and 79.8 , 64.2 , 60.3 , 48.3 , 38.1, 34.3 , R1 = C1, Br, I R2 = F , CI 30.0 , 29.0 , 27.0 , 24.9 , 14.4 . R3 = Me, Et n = 4 , 6 methyl 5- ( 3 -bromo - 2 - fluoro - 6 -methyl - 5,5 -dioxido 6,11 -dihydrodibenzo [c , f] [ 1,2 ]thiazepin - 11- yl) amino ) pentanoate (81 ) ethyl 7- ( 2,3 -dichloro - 6 -methyl - 5,5 -dioxido -6,11 dihydrodibenzo [ c , f ] [ 1,2 ] thiazepin - 11 - yl) amino ) [0733 ] The product 81 was prepared according to the heptanoate (81 ) general procedure described in Example 1 and purified by [0730 ] The product 8i was prepared according to the column chromatography ( 8 : 2 hexanes: EtOAc , 3 column general procedure described in Example 1 and purified by volumes-> 7 : 3 hexanes : EtOAc, 4 column volumes) to pro column chromatography (CH2C12 , 2 column volumes-> 20 : 1 vide a viscous, pale -yellow oil ( 196 mg, 81 % ). ' H NMR CH2Cl2 :Et20 , 4 column volumes ) to provide a viscous , ( 500 MHz , CDC13 ) d 8.15 ( d , J = 6.6 Hz , 1H ) , 7.40-7.27 ( m , pale -yellow oil (90.2 mg, 90 % ). H NMR (400 MHz, 5H ) , 5.08 (s , 1H ), 3.65 (s , 3H ), 3.37 (s , 3H ), 2.54 ( td , J= 7.0 , CDC1z ) 8 8.02 (s , 1H ), 7.62 ( s, 1H ), 7.42-7.33 (m , 3H ), 2.1 Hz, 2H ) , 2.31 ( t, J = 7.3 Hz , 2H ) , 2.02 (brs , 1H ) , 7.33-7.27 ( m , 1H ) , 5.03 ( s , 1H ) , 4.11 ( q , J = 7.1 Hz, 2H ) , 3.39 1.72-1.63 ( m , 2H ) , 1.59-1.50 ( m , 2H ) ; 13C NMR ( 126 MHz, ( s, 3H ), 2.50 ( t, J = 7.0 Hz, 2H ) , 2.27 (t , J = 7.5 Hz , 2H ), 1.97 CDC13 ) d 173.9 , 161.9 and 159.9 , 141.54 and 141.49 , 138.9 , (br s, 1H ), 1.60 ( p , J= 7.3 Hz, 2H ), 1.51 ( p , J= 6.9 Hz, 2H ), 138.3 , 135.82 and 135.80 , 134.2 , 129.5 , 128.9 , 128.4 , 127.9 , 1.40-1.27 ( m , J = 5.5 , 5.0 Hz, 4H ) , 1.24 (t , J = 7.1 Hz, 3H ) ; 13C 116.8 and 116.6 , 108.7 and 108.5 , 64.3 , 51.6 , 47.8 , 38.2 , NMR ( 101 MHz, CDC13 ) 8 173.8 , 139.0 , 138.8, 138.6 , 33.8 , 29.6 , 22.7 . US 2020/0079745 A1 Mar. 12 , 2020 70

Preparation of Additional Diarylthiazepinamine workup ) . ' H NMR (500 MHz, MeOD ) 8 8.23 ( s, 1H ), 8.19 Carboxylic Acids ( 9 ) ( s , 1H ) , 7.72 (dd , J = 7.9, 1.5 Hz , 1H ), 7.66 (ddd , J = 8.7 , 7.3 , 1.5 Hz, 1H ) , 7.59 (dd , J = 8.2 , 1.3 Hz, 1H ) , 7.50 ( td , J = 7.5 , 1.4 [0734 ] Hz, 1H ), 5.96 ( s , 1H ) , 2.99 (ddd , J = 12.2 , 10.1, 5.7 Hz , 1H ) , 2.88 (ddd , J = 12.2 , 10.1, 6.1 Hz, 1H ) , 2.27 ( t, J = 7.3 Hz, 2H ) , 1.75-1.62 ( m , 2H ), 1.62-1.53 (m , 2H ) , 1.40-1.28 (m , 4H ); Scheme 9. Preparation of additional diarylthiazepinamine carboxylic acids . 13C NMR ( 126 MHz, MeOD ) d 177.4 , 142.4 , 140.1 , 139.1 , 137.0 , 137.0 , 134.8 , 133.6 , 131.3 , 129.4 , 129.2 , 128.6 , 67.0 , www . 39.8 , 34.6 , 29.5 , 27.1 , 26.8 , 25.6 . 7- (3 -chloro - 2 - fluoro -6 -methyl - 5,5 -dioxido -6,11 Ri dihydrodibenzo [cf ] [ , 2 ] thiazepin -11 -yl )amino )hep 0.5 M aq . HCI tanoic acid hydrochloride salt ( 91 ) 50-100 ° C. [0737 ] 9j HN R2 ) n yo R302C 8

H2N F R1

HN R2 In HOC 9 Rj = C1, Br, I CO2H R2 = F , C1 R3 = Me, Et [0738 ]. The product 9j was prepared according to the n = 4,6 angeneral off- white procedure foam described(396 mg , in 92 Example % ) . ' H NMR1 and (obtained400 MHz as, MOD ) 8 8.23 ( d , J = 7.0 Hz, 1H ) , 7.94 ( d , J = 9.2 Hz, 1H ) , 7.74 (dd , J = 7.8, 1.5 Hz, 1H ), 7.65 (ddd , J = 8.5 , 7.3 , 1.5 Hz, 1H ) , 7.58 ( dd , J = 8.2 , 1.3 Hz, 1H ), 7.49 ( td , J = 7.5 , 1.4 Hz , 7 - ( (2,3 -dichloro - 6 -methyl - 5,5 - dioxido -6,11 - dihy 1H ), 5.98 ( s , 1H ) , 3.24 ( s , 3H ) , 3.01 (ddd , J = 12.1 , 9.9 , 5.9 drodibenzo [c , f] [1,2 ] thiazepin - 11- yl ) amino )hep Hz, 1H ), 2.87 (ddd , J = 12.2 , 9.9 , 6.2 Hz, 1H ) , 2.27 (t , J = 7.3 Hz, 2H ) , 1.77-1.63 (m , 2H ), 1.63-1.52 ( m , 2H ) , 1.40-1.27 tanoic acid hydrochloride salt (91 ) ( m , 4H ) ; 13C NMR ( 101 MHz , MeOD ) à 177.4 , 163.0 and [07351 160.4 , 142.5 , 137.50 and 137.46 , 134.8 , 133.6 , 132.4 , 130.9 and123.7 130.8 , 67.1 , , 129.2 48.5 , , 128.639.9 , ,34.6 126.7 , 29.5 , 125.4 , 27.1 and, 26.9125.2 , 25.6 , 124.0 . and 7- ( 2 - fluoro - 3 - iodo -6 -methyl - 5,5 -dioxido -6,11 - dihy 9i drodibenzo [ c , f| [ 1,2 ] thiazepin - 11 -yl ) amino ) hep tanoic acid hydrochloride salt (9k ) [0739 ] Ok

H2N .

HN F

CO2H

[0736 ] The product 9i was prepared according to the CO2H general procedure described in Example 1 and obtained as an off- white foam ( 78.5 mg, 88 % , Note : some spilled during US 2020/0079745 A1 Mar. 12 , 2020 71

[0740 ] The product 9k was prepared according to the Example 4. In Vitro Activity of Additional general procedure described in Example 1 and obtained as a Compounds at Mu Opioid Receptors white solid (210 mg , 91 % ) containing a minor impurity (~ 5 mol % , introduced during preparation of intermediate 41 and [0743 ] The additional diarylthiazepinamine carboxylic carried through following steps) . A portion of this material acids ( 9i , 9j, 9k , and 91) were tested for agonist activity at was further purified by recrystallization . A quantity ( 199 the human mu opioid receptor (MOR ) using biolumines mg) was re- dissolved in CH2Cl2 and concentrated in vacuo cence resonance energy transfer (BRET ) assays measuring to give a white foam . To this was added minimal CH2Cl2 , G protein activation (Table 2) as previously described causing the product to first dissolve and then crystallize . The (Rives , M.-L. et al . 2012; Negri, A. et al. 2013 ; Example 2 product was allowed to settle , the supernatant removed by of the present application ). pipet, and the residue dried in vacuo to give a crystallized sample of product 9k (176 mg ). ' H NMR (400 MHz , TABLE 2 MeOD ) 8 8.47 (d , J= 6.0 Hz, 1H ) , 7.78-7.70 (m , 2H ), 7.65 ( ddd , J = 8.7 , 7.2 , 1.6 Hz, 1H ) , 7.57 (dd , J = 8.1 , 1.4 Hz, 1H ) , Functional agonist activity of compounds at human MOR . All 7.49 ( td , J = 7.5 , 1.5 Hz , 1H ) , 5.95 ( s , 1H ) , 3.23 ( s , 3H ), 3.00 compounds are full agonists relative to the reference agonist DAMGO ( ddd , J = 12.2 , 10.0 , 5.8 Hz, 1H ) , 2.85 (ddd , J = 12.2 , 9.9 , 6.2 with potency equal to or higher than tianeptine . Hz, 1H ) , 2.27 ( t , J = 7.3 Hz, 2H ) , 1.76-1.62 ( m , 2H ) , 1.62 1.53 ( m , 2H ) , 1.39-1.28 ( m , 4H ) ; 13C NMR ( 101 MHz, MOD ) d 177.4 , 167.4 and 164.8 , 142.6 , 141.1 and 141.0 , Human MOR 137.44 and 137.40 , 134.9 , 133.5 , 132.3 and 132.2 , 129.1 , EC 50 128.6 , 126.6 , 122.4 and 122.1, 85.7 and 85.5 , 67.3 , 48.4 , Compound Structure [ 95 % CI] 39.9 , 34.6 , 29.5 , 27.1, 26.8 , 25.6 . 9i 172 nM 5 - ( ( 3 -bromo - 2 - fluoro -6 -methyl - 5,5 - dioxido -6,11 [ 120 , 229 ] dihydrodibenzo [cf ] [ 1,2 ] thiazepin - 11 - yl) amino ) pentanoic acid hydrochloride salt (91 ) [ 0741] H2N CI 91 CI

Br

HN F CO2H

CO2H 9j 129 nM II

CI [0742 ] The product 91 was prepared according to the general procedure described in Example 1 and obtained as a HN . crystalline white solid ( 195 mg, 99 % ) . ' H NMR (500 MHz, CI MOD ) 8 8.35 ( d , J = 6.6 Hz , 1H ) , 7.87 ( d , J = 8.7 Hz , 1H ) , 7.73 (dd , J = 7.9 , 1.5 Hz, 1H ) , 7.66 ( ddd , J = 8.8 , 7.4 , 1.5 Hz, 1H ) , 7.58 (dd , J = 8.2 , 1.4 Hz, 1H ) , 7.49 ( td , J = 7.6 , 1.3 Hz, 1H ) , 5.96 ( s , 1H ) , 3.24 ( s , 3H ) , 3.03 (ddd , J = 12.3, 9.6 , 5.9 Hz, 1H ), 2.90 (ddd , J= 12.3 , 9.6 , 6.2 Hz, 1H ), 2.32 (t , J = 7.0 Hz, 2H ) , 1.81-1.66 ( m , 2H ) , 1.61 (p , J = 7.0 Hz , 2H ) ; 13C NMR ( 126 MHz , MeOD ) d 176.7 , 164.0 and 162.0 , 142.5 , 137.7 and 137.6 , 135.2 , 134.8 , 133.6 , 131.3 , 129.2 , 128.6 , CO2H 126.6 , 123.7 and 123.4 , 113.3 and 113.1, 67.3 , 48.2 , 39.8 , 33.8 , 26.5 , 22.7 . US 2020/0079745 A1 Mar. 12 , 2020 72

TABLE 2 - continued Scheme 10. Additional diarylthiazepinamine esters and carboyxlic acids. Functional agonist activity of compounds at human MOR . All compounds are full agonists relative to the reference agonist DAMGO 8m with potency equal to or higher than tianeptine .

Human MOR EC50 CI Compound Structure [95 % CI] HN CI Ok 4.6 nM [ 3.2 , 6.7 ]

CO2Me H2N 8n CI

Ci

HN CO2H

CO2Me 80 91 45 nM [33 , 60 ] w

Br

H2N HN F F CI

CO2H CO2Me 9m Example 5. Preparation of Additional Compounds

C1 [0744 ] Additional compounds active as agonists of the MOR or DOR are synthesized according to the synthetic HN methods described in Example 1 and Example 3. For CI instance, such additional compounds include 9m , 9n , and 90 (Scheme 10 ), which are active metabolites of compounds 9i, 9j, and 9k , respectively . The ester precursors of these compounds, 8m , 8n , and 80 , are active themselves and also CO2H act as prodrugs for compounds 9m , 9n , and 90 , respectively. US 2020/0079745 A1 Mar. 12 , 2020 73

-continued subject afflicted with an anxiety disorder. The amount of the On compound is effective to treat the subject afflicted with the anxiety disorder. [0748 ] An amount of any one of compounds 8a , 8b , 80 , 8d , 8e, 8f, 8g , Sh , 8i, 83, 8k , 81, 8m , 8n , 80 , 9a , 9b , 9c, 9d , 9e , -C1 9f, 9g , 9h , 9i, 9j, 9k , 91, 9m , 9n , or 90 is administered to a subject afflicted with borderline personality disorder. The H2N . F amount of the compound is effective to treat the subject afflicted with borderline personality disorder. [0749 ] An amount of any one of compounds 8a , 8b , 8c, 8d , 8e , 8f, 8g , 8h , 8i, 83, 8k , 81 , 8m , 8n , 80 , 9a , 9b , 9c, 9d , 9e, 9f, 9g, 9h , 9i, 9j, 9k , 91, 9m , 9n , or 90 is administered to a CO2H subject afflicted with pain . The amount of the compound is effective to treat the subject afflicted with pain . [0750 ] An amount of any one of compounds 8a , 86 , 8c, 8d , 8e, 8f, 8g , 8h , 8i, 83, 8k , 81, 8m , 8n , 80 , 9a , 9b , 9c, 9d , 9e , 9f, 9g , 9h , 9i, 9j, 9k , 91, 9m , 9n , or 90 is administered to a 90 subject afflicted with opioid addiction . The amount of the compound is effective to treat the subject afflicted with the opioid addiction . [0751 ] An amount of any one of compounds 8a , 8b , 8c, 8d , I 8e, 8f, 8g , 8h , 8i, 8j, 8k , 81, 8m , 8n , 80 , 9a , 9b , 9c, 9d , 9e, 9f, 9g , 9h , 9i, 9j , 9k , 91, 9m , 9n , or 90 is administered to a H?N F subject afflicted with opioid withdrawal symptoms. The Oo amount of the compound is effective to treat the subject afflicted with the opioid withdrawal symptoms. Example 7. Solubility Modulation Via CO2H Dihalogenation [0752 ] Dihalo substitution of the tricyclic core provides compounds that are more water soluble than their analogous monohalo counterparts . For example , compound 9b is more soluble than the analogous compound bromotianeptine ( Table 3 ). Likewise , compound 9k is more soluble than the analogous compound iodotianeptine ( Table 4 ). Increased Example 6. Administration of MOR /DOR Agonists solubility is useful for optimizing pharmacokinetic and formulation properties , for example by reducing variability [ 0745 ] An amount of any one of compounds 8a, 8b , 8c, 8d , in pharmacokinetics following oral administration of solid 8e, 8f, 8g , 8h , 8i, 8j, 8k , 81, 8m , 8n , 80 , 9a , 9b , 9c, 9d , 9e, dose forms ( increased solubility decreases the dependence 9f, 9g , 9h , 9i, 9j, 9k , 91, 9m , 9n , or 90 is administered to a of absorption rate on particle size ). subject afflicted with depression . The amount of the com pound is effective to treat the subject afflicted with depres [0753 ] Solubility Determination (Method A ). sion . [0754 ] A quantity of the appropriate compound sufficient to saturate the resulting solution was added to distilled water [ 0746 ] An amount of any one of compounds 8a , 8b , 8c, 8d , (0.50 mL ) and the mixture was stirred vigorously for 24 h at 8e , 8f, 8g , 8h , 8i, 83, 8k , 81, 8m , 8n , 80 , 9a, 9b , 9c , 9d , 9e , room temperature ( 20 ° C.) . The mixture was then centri 9f , 9g , 9h , 9i, 9j , 9k , 91, 9m , 9n , or 9m is administered to a fuged for 3 min . at 21,000xg and the stir bar was carefully subject afflicted with a mood disorder. The amount of the removed . The mixture was then centrifuged again for 5 min . compound is effective to treat the subject afflicted with the at 21,000xg and the supernatant was carefully removed by mood disorder. syringe and passed through a 0.45 uM syringe filter. An [ 0747 ] An amount of any one of compounds 8a, 86 , 8c, 8d , aliquot (300 uL ) of the filtered supernatant was concentrated 8e , 8f, 8g , 8h , 8i, 83, 8k , 81, 8m , 8n , 80 , 9a, 9b , 9c , 9d , 9e , in vacuo and the mass of the residual solids determined in 9f, 9g , 9h , 9i , 9j, 9k , 91 , 9m , 9n , or 90 is administered to a order to calculate the solubility. US 2020/0079745 A1 Mar. 12 , 2020 74

TABLE 3 TABLE 4 Solubility of compounds in neutral water at room Solubility of compounds in neutral water at room temperature ( 20 ° C.) determined using Method A. Data points represent the average of 2 independent trials . temperature ( 20 ° C.) determined using Method B. Aqueous Aqueous Solubility Solubility (mg /mL (mg / mL Compound Structure 20 ° C.) Compound Structure @ 20 ° C.) bromotianeptine 4.5 iodotianeptine 2.3

Br

H2N H?N CI

CO2H CO2H

9b 9.8 9k 5.7

Br

H?N F H2N

CO2H CO2H

[ 0755 ] Solubility Determination (Method B ) . Example 8. Methylthio Substitution Yields Partial [0756 ] A quantity of the appropriate compound sufficient Agonists of DOR to saturate the resulting solution was added to distilled water ( 0.50 mL ) and the mixture agitated on an orbital shaker for [0757 ] In contrast to all other compounds in this class, 2 h at room temperature (20 ° C.) . The mixture was then which are full agonists of DOR , methylthio substitution of centrifuged for 5 min . at 21,000xg and the supernatant was the tricyclic core yields compounds with partial agonist carefully removed by syringe and passed through a 0.45 uM activity at this receptor. For example , compound 9c is a syringe filter . An aliquot ( 300 uL ) of the filtered supernatant partial agonist at DOR (FIG . 1 ). Compound 9c is also more was concentrated in vacuo and the mass of the residual potent at MOR and DOR than both its corresponding ethyl solids determined in order to calculate the solubility . ester analog and tianeptine ( Table 5 ) . US 2020/0079745 A1 Mar. 12 , 2020 75

TABLE 5 Functional agonist activity of compounds at human MOR and DOR . Where indicated , error represents SEM of 2 or more independent trials. The data shows that compound 9c is more potent at MOR and DOR than both its corresponding ethyl ester analog and tianeptine .

Human Human MOR DOR Compound Structure (EC50 ) ( EC50 ) Tianeptine 194 + 70 nM 37.4 + 11.2 uM

CI

HN

CO2H

Ester 222 nM 7.0 UM Analog of ( Emax = 70 % ) 9c partial agonist

SMe

HN

CO2Et

9c 41.8 nM 2.06 UM ( Emax = 51 % ) partial agonist

SMe

HN

CO2H US 2020/0079745 A1 Mar. 12 , 2020 76

Example 9. Ethynyl Substitution Increases Potency [0758 ] Introduction of an ethynyl group at position 3 of the aryl ring system provides compounds of higher MOR and DOR potency than the corresponding analogs with chloro or methyl substituents at this position ( Table 6 ) . TABLE 6

Functional agonist activity of compounds at human MOR and DOR . Where indicated , error represents + SEM of 2 or more independent trials . The data shows that compound 9a is more potent at MOR and DOR than both its corresponding 3 -methyl - substituted analog and tianeptine .

Human Human MOR DOR Compound Structure ( EC50 ) ( EC50 )

Tianeptine 194 + 70 nM 37.4 + 11.2 uM

M

HN

CO2H

3 -Methyl 890 nM >10 ?M substituted Analog

H?N

CO2H US 2020/0079745 A1 Mar. 12 , 2020 77

TABLE 6 - continued Functional agonist activity of compounds at human MOR and DOR . Where indicated , error represents + SEM of 2 or more independent trials . The data shows that compound 9a is more potent at MOR and DOR than both its corresponding 3 -methyl - substituted analog and tianeptine . Human Human MOR DOR Compound Structure (EC50 ) ( EC50 )

9a 53.3 + 18 nM 5.9 + 0.3 UM

HN

CO2H

Example 10. Esters as Prodrugs 11A ). Similarly , compound 9f, with a 9 -carbon side chain , is [0759 ] Carboxylate esters are well known as prodrugs for metabolized sequentially into active metabolite 2 and active the corresponding carboxylic acids obtained by hydrolysis metabolite 3 , with 7- and 5 - carbon side chains respectively (Beaumont , K. et al . 2003 ) . Such ester prodrugs may show improved oral bioavailability , better brain penetration , or (Scheme 11B ). Similarly, compounds 91, 9m , 9n , and 90 are longer duration of action compared to their carboxylic acid active metabolites of compounds 9b , 9i , 9j, and 9k , respec counterparts . Accordingly , compounds of this application tively . Thus, the specific length of the side chain selected is having an ester side chain ( 8 ), although biologically active useful for fine control of the pharmacokinetic and pharma on their own ,may also act as prodrugs for the corresponding codynamic profile in this genus . carboxylic acids ( 9 ) . Further, one skilled in the art will be able to apply themethods and knowledge of this application to prepare additional drugs. For example , the type of ester ( e.g. methyl, ethyl, propyl, isopropyl, tert -butyl , phe Scheme 11. Conversion to active metabolites via beta -oxidation . nyl) or the length of the side chain may be varied to adjust the activity and pharmacokinetic properties of the prodrugs A ) and their corresponding carboxylic acid hydrolysis products . Example 11. Conversion to Active Metabolites Via Beta -Oxidation In Vivo [0760 ] Tianeptine is known to be metabolized primarily via beta - oxidation of the carboxylic acid side chain in a manner similar to fatty acids (Grislain , L. et al. 1990 ). This HN results in metabolites with carboxylic acid side chains beta -oxidation shortened sequentially by 2 -carbon units . Other carboxylic acid analogs , including the compounds described in the present disclosure , are expected to be metabolized in a similar manner. Therefore , the extended chain analogs of this application (8 carbons or longer) , in addition to their higher DOR potency , serve as prodrugs of analogous com pounds with shorter side chains, which are in many cases HO2C also agonists of the MOR and /or DOR . For example , com ge pound 9e, with an 8 -carbon side chain , is metabolized into active metabolite 1 , with a six - carbon side chain (Scheme US 2020/0079745 A1 Mar. 12 , 2020 78

-continued -continued

www.

HN HN

CO2H active metabolite 3 HO2C active metabolite 1 Example 12. Potent Activity of Dihalo -Substituted B ) Compounds is Unexpected

0 [0761 ] Our previous work has found that placement of a chlorine substituent at position 2 of the diarylthiazepine core of compounds of the type described in this invention is detrimental to agonist activity at MOR . For example , in Table 7 , compare compound 15a to compounds 15b and 15c or compound 16a to compounds 16b and 16c . In each case , translocation of the chlorine substituent from position 3 to HN position 2 , or introduction of a chlorine substituent at position 2 of unsubstituted compounds, results in a 6 - fold or greater loss of activity at MOR . Accordingly , it was surpris beta -oxidation ing to find that compounds 9b , 9i, 9j, Ok , and 91 of the present invention , which each bear a fluorine or chlorine substituent at position 2 within their dihalo -substituted core structures , are equipotent or more potent than their analogs lacking such substitution position 2. Accordingly , in this class of compounds, the structure- activity relationship at MOR of disubstituted compounds is different from that of monosubstituted compounds. TABLE 7 CO2H Functional agonist activity of compounds at human MOR . Where indicated , error represents + SEM of 2 or more independent trials . Of The data shows that placement of a chlorine substituent at position 2 of the diarylthiazepine core of compounds of the type described in this invention is generally detrimental to activity at MOR . Human MOR Compound Structure ( EC50 ) 15a 4.15 0.93 UM

HN 2 HN beta - oxidation CI

CO2H CO2Et active metabolite 2 US 2020/0079745 A1 Mar. 12 , 2020 79

TABLE 7 - continued TABLE 7 - continued Functional agonist activity of compounds at human MOR . Where Functional agonist activity of compounds at human MOR . Where indicated , error represents SEM of 2 or more independent trials. indicated , error represents SEM of 2 or more independent trials . The data shows that placement of a chlorine substituent at position 2 The data shows that placement of a chlorine substituent at position 2 of the diarylthiazepine core of compounds of the type described in of the diarylthiazepine core of compounds of the type described in this invention is generally detrimental to activity at MOR . this invention is generally detrimental to activity at MOR . Human MOR Human Compound Structure (EC50 ) MOR 16b 264 + 85.3 nM Compound Structure ( EC50 )

15b 657 + 366 nM

CI

CI HN

HN

Med 16c 2.011 + 0.7 UM

CO2Et HN 15c 156 + 84.7 nM

Meo

HN Example 13. pH Dependence of Solubility [0762 ] Since compounds of type 9 of the present invention are zwitterionic , their aqueous solubility depends on pH . Interestingly , fluoro substitution at position 2 of the tricyclic core provides compounds that are more water soluble than their analogous monohalo counterparts , especially at low pH . As previously described in Example 7 , 2 - fluoro com pounds 9b and 9k are 2-3 - fold more soluble than their CO2Et analogous monohalo counterparts , bromotianeptine and iodotianeptine, respectively , in neutral unbuffered water. However, at PH 1 , the difference in solubility is dramatically 16a enhanced , with compounds 9b and 9k being at least 10 - fold 16.9 + 5.22 uM more soluble than their monohalo counterparts ( Table 8 ) . This trend also holds for compound 9j , which is 8 - fold more soluble than tianeptine at pH 1. In contrast, in Na phosphate buffer at pH 7 , compounds 9b and 9k are of similar or modestly higher solubility than bromotianeptine and iodot ianeptine, respectively ( Table 8 ) . HN [0763 ] The ability to modulate the pH dependence of solubility is useful for optimizing pharmacokinetic and formulation properties , since the pH of the gastrointestinal tract changes from -1.5 in the fasted stomach to 6-8 in the intestines . Accordingly , compounds that change solubility at Meo different pH may also change their rate of dissolution and /or absorption in different compartments of the gastrointestinal tract. For example , 2 - fluoro compounds 9j , 9b , and 9k are US 2020/0079745 A1 Mar. 12 , 2020 80

likely to be more rapidly absorbed from solid dosage forms 30 % acetonitrile /Na - phosphate buffer mixes were prepared than their monohalo counterparts tianeptine, bromotianept to theoretical concentrations of 0 mg/ mL (blank ) , 0.1 ine, and iodotianeptine, respectively, given their much mg/mL , 0.2 mg/ mL , and 0.4 mg/ mL in duplicates to gen higher solubility at low pH , as would be found in the erate calibration curves falling within the optimum UV stomach . absorption range. The filtrates of test compounds were diluted 100 - fold with acetonitrile -buffer mixtures before [0764 ] Solubility Determination . measuring . The filtered supernatant test samples were trans [0765 ] Test compounds (4 mg) were added to 200 uL of ferred to 96 -well plates and measured for absorbance in the one of the tested aqueous solutions (hereinafter - buffer) : 200-550 nm range with 5 nm step increment. The concen 100 mM aqueous HCl (pH 1 ) or 100 mM Na -phosphate trations of compounds in supernatants were calculated using buffer (pH 7 ). The obtained suspensions/ solutions with the the measured absorbance and the previously determined theoretical concentration of 20 mg/mL were further allowed calibration curve . Proper absorbance wavelengths for cal to equilibrate at 25 ° C. on a thermostatic orbital shaker for culations were selected for each compound manually based 24 hours and then centrifuged at 6000 rpm for 4 minutes and on absorbance maxima (absolute absorbance unit values for filtered through HTS filter plates using a vacuum manifold . the minimum and maximum concentration points within In parallel, compound dilutions in 50 % acetonitrile /HCl and 0-2.5 OD range ) . TABLE 8

Solubility of compounds at pH 1 and 7 at room temperature ( 25 ° C.) . Data points represent the average of 2 independent trials .

100 mM Na 100 mM phosphate HCl, pH 1 buffer, pH 7 Compound Structure (mg /mL ) (mg / mL )

tianeptine 0.68 0.26 ( HCl salt )

H2N .

CO2H

9j 5.3 0.07

H2N F

?? , ? US 2020/0079745 A1 Mar. 12 , 2020 81

TABLE 8 - continued Solubility of compounds at pH 1 and 7 at room temperature (25º C.) . Data points represent the average of 2 independent trials .

100 mM Na 100 mM phosphate HCI, PH 1 buffer , pH 7 Compound Structure (mg / mL ) (mg /mL ) bromotianeptine O < 0.1 0.62

Br

H2N CI

CO2H

9b 1.1 0.84

Br

H2N F

CO2H

iodotianeptine < 0.1 0.15

H2N .

CO2H US 2020/0079745 A1 Mar. 12 , 2020 82

TABLE 8 - continued Solubility of compounds at pH 1 and 7 at room temperature ( 25 ° C.) . Data points represent the average of 2 independent trials . 100 mM Na 100 mm phosphate HCl, pH 1 buffer , pH 7 Compound Structure (mg / mL ) (mg / mL ) 9k 2.7 0.39

H2N F

CO2H

Example 14. Analgesic Activity of Compounds TABLE 9 - continued [0766 ] Compounds 9b and Ok are potent analgesics in the mouse hot plate assay, with much higher potency than ED50 for analgesic activity in the hot plate assay in male C57BL /6 mice. tianeptine ( Table 9 and FIG . 2 ) . [0767 ] Analgesic Activity in Hot Plate Assay. [ 0768 ] Male C57BL /6 mice were timed for latency to Analgesic jump on a hot- plate apparatus set to 55 ° C., using a 30 s ED50 cutoff to prevent tissue damage. Following a baseline test , Compound Structure (mg /kg , s.c. ) animals were injected subcutaneously ( s.c. ) with escalating doses of drug and tested at 15 post - injection (time of maximal effect) . Dose - response curves were fit via nonlinear regression using GraphPad Prism (La Jolla , Calif. ) . 9b 5.1 TABLE 9 EDso for analgesic activity in the hot plate assay in male C57BL /6 mice .

Analgesic Br ED50 Compound Structure (mg / kg , s.c. ) HN Tianeptine 15 (Na salt ) CI

C1

HN

CO2H

CO2 Na US 2020/0079745 A1 Mar. 12 , 2020 83

TABLE 9 - continued ( CL - 1848C ) , dexoxadrol, WMS- 2539, NEFA , delucemine (NPS - 1506 ), aptiganel (Cerestat ; CNS - 1102) , midafotel EDs , for analgesic activity in the hot plate assay in male C57BL /6 mice . ( CPPene ; SDZ EAA 494 ) , dexanabinol (HU - 211 or Analgesic ETS2101) , selfotel ( CGS - 19755 ), 7 -chlorokynurenic acid ED50 (7 -CKA ), 5,7 -dichlorokynurenic acid ( 5,7 -DCKA ) , Compound Structure (mg /kg , s.c.) L -683344 , L -689560 , L - 701324 , GV150526A , GV196771A , CERC - 301 ( formerly MK - 0657 ), atomox Ok 1.7 etine , LY - 235959 , CGP 61594 , CGP 37849, CGP 40116 ( active enantiomer of CG 37849 ) , LY - 233536 , PEAQX (NVP -AAM077 ) , ibogaine , noribogaine, Ro 25-6981 , GW468816 , EVT- 101, indantadol, perzinfotel (EAA -090 ) , SSR240600 , 2 -MDP ( U - 23807A ) , AP - 7 H?N F. Example 16. Combinations with NMDA Receptor Partial Agonists [0775 ] Weak partial agonists of NMDAR are also known (Moskal , J. R. et al. 2005 ), and may be expected to produce beneficial or synergistic effects similar to an antagonist when intrinsic glutamate signaling activity is high or over activated ( e.g. during opioid withdrawal) . Therefore , phar maceutical compositions of the compounds of the present CO2H invention , combined with NMDAR partial agonists , may be useful in the treatment of depression , mood disorders , anxi ety disorders , borderline personality disorder , pain , opioid addiction , or opioid withdrawal symptoms, where the Example 15. Combinations with NMDA Receptor NMDAR partial agonist serves as an adjunct to prevent the Antagonists development of tolerance to the compounds of the present [ 0769 ] Antagonists of the N -methyl - D -aspartate receptor invention with chronic use . Similarly , pharmaceutical com (NMDAR ) are known to potentiate the beneficial effects of positions of the compounds of the present invention , com opioid receptor agonists in the treatment of pain and to bined with NMDAR partial agonists , may treat depression prevent development of tolerance to those effects ( Trujillo , or other mood disorders with enhanced efficacy compared to K. A. et al. 1994 ; Mao , J. et al. 1996 ) . Therefore , pharma the compounds of the present invention alone. Alternatively , ceutical compositions of the compounds of the present the opioid modulator and NMDAR partial agonist may be invention , combined with NMDAR antagonists , may be dosed separately , as a novel method for treating the condi useful in the treatment of, depression , mood disorders , tions described above . anxiety disorders , borderline personality disorder, pain , opi [0776 ] Non -Limiting Examples of NMDA Receptor Par oid addiction , or opioid withdrawal symptoms, where the tial Agonists: NMDAR antagonist serves as an adjunct to prevent the development of tolerance to the compounds of the present [0777 ] NRX - 1074 , rapastinel (GLYX - 13 ) invention with chronic use . NMDAR antagonists are also known to be effective in the treatment of depression (Mur Example 17. Combinations with Neurokinin 1 rough , J. W. et al. 2013 ; Zarate , C. A. Jr et al . 2006 ) . Receptor Antagonists Therefore , pharmaceutical compositions of the compounds [0778 ] Antagonists of the neurokinin 1 receptor (NK - 1 ) of the present invention , combined with NMDAR antago are known to modulate the effects of opioid agonists , spe nists , may treat depression or other mood disorders with cifically in reward and self -administration protocols . More enhanced efficacy compared to the compounds of the present specifically , NK - 1 antagonists attenuate opioid reward and invention alone . Alternatively , the opioid modulator and self - administration in animal models (Robinson , J. E. et al . NMDAR antagonist may be dosed separately , as a novel 2012 ; Barbier , E. et al. 2013 ) . Therefore , pharmaceutical method for treating the conditions described above . compositions of the compounds of the present invention , [0770 ] Non -Limiting Examples of NMDA Receptor combined with NK - 1 antagonists , may be useful in the Antagonists : treatment of depression , mood disorders, anxiety disorders, [0771 ] Dextromorphinansdextromethorphan , dextror borderline personality disorder , pain , opioid addiction , or phan , dextrallorphan opioid withdrawal, where the NK - 1 antagonist serves as an [0772 ] Adamantanes memantine , amantadine , rimanta adjunct to reduce the abuse potential of the compounds of dine , nitromemantine (YQW -36 ) the present invention . NK - 1 antagonists are also known to be [0773 ] Arylcyclohexylamines ketamine (and its ana effective in the treatment of depression (Kramer , M. S. et al . logs , e.g. tiletamine ) , phencyclidine ( and its analogs , e.g. 2004 ). Therefore , pharmaceutical compositions of the com tenocyclidine , eticyclidine, rolicyclidine ), methoxetamine pounds of the present invention , combined with NK - 1 ( and its analogs ) , gacyclidine (GK - 11 ) ; antagonists , may treat depression or other mood disorders [0774 ] Miscellaneous — neramexane , lanicemine with enhanced efficacy compared to the compounds of the ( AZD6765 ) , diphenidine, dizocilpine (MK - 801) , 8a - phenyl present invention alone. Alternatively , the opioid modulator decahydroquinoline (8A -PDHQ ) , remacemide, ifenprodil, and NK - 1 antagonist may be dosed separately , as a novel traxoprodil (CP - 101,606 ) , eliprodil (SL -82.0715 ), etoxadrol method for treating the conditions described above . US 2020/0079745 A1 Mar. 12 , 2020 84

[0779 ] Non -Limiting Examples of Neurokinin 1 Receptor [0788 ] Non - Limiting Examples of DOR Agonists : Antagonists : [0789 ] tianeptine, (+ )BW373U86 , SNC -80 , SNC - 121 , [ 0780 ] aprepitant, fosaprepitant, casopitant, maropitant, SNC - 162, DPI- 287 , DPI- 3290 , DPI- 221, TAN -67 , KN - 127 , vestipitant, vofopitant, lanepitant, orvepitant, ezlopitant, AZD2327 , JNJ- 20788560 , NIH11082 , RWJ- 394674 , netupitant, rolapitant, L -733060 , L -703606 , L - 759274 , ADL5747 , ADL5859 , UFP -512 , AR -M100390 , SB -235863 , L - 822429 , L - 760735 , L - 741671 , L - 742694 , L - 732138 , 7 -spiroindanyloxymorphone . CP - 122721, RPR - 100893 , CP - 96345 , CP -99994 , TAK -637 , T -2328 , CJ- 11974 , RP 67580 , NKP608 , VPD - 737 , GR Example 21. Combinations with Naloxone 205171, LY686017 , AV608 , SR140333B , SSR240600C , FK [0790 ] Naloxone is an MOR antagonist that is effective in 888 , GR 82334 blockading all behavioral effects induced by classical MOR agonists and is the standard treatment for opioid overdose . Example 18. Combinations with Neurokinin 2 It is highly bioavailable by parenteral routes of administra Receptor Antagonists tion but not by the oral route (Smith , K. et al. 2012 ) . [0781 ] Antagonists of the neurokinin 2 receptor (NK - 2 ) Accordingly , pharmaceutical compositions containing mix are known to show antidepressant effects and to synergize tures of an MOR agonist and naloxone remain effective with tricyclic antidepressants (Overstreet , D. H. et al . 2010 ) . agonists when given by the oral route but the naloxone Therefore , pharmaceutical compositions of the compounds component inhibits the effects of the MOR agonist compo of the present invention , combined with NK - 2 antagonists , nent when the mixture is administered parenterally . Thus, may be useful in the treatment of depression or other mood addition of naloxone to pharmaceutical compositions con disorders with increased efficacy compared to the com taining MOR agonists is useful for preventing their misuse pounds of the present invention alone. Alternatively , the or abuse by parenteral routes of administration . Therefore , opioid modulator and NK - 2 antagonist may be dosed sepa pharmaceutical compositions of the compounds of the pres rately , as a novel method for treating depression or other ent invention , combined with naloxone, may be useful in mood disorders . providing the therapeutic benefits of the compounds of the [ 0782 ] Non -Limiting Examples of Neurokinin 2 Receptor present invention while having diminished potential for Antagonists : abuse . [0783 ] saredutant, ibodutant, nepadutant, GR - 159897 , MEN - 10376 Example 22. Combinations With SSRI or SNRIs [0791 ] Selective serotonin reuptake inhibitors (SSRIs ) and Example 19. Combinations with Neurokinin 3 serotonin -norepinephrine reuptake inhibitors ( SNRIs ) are Receptor Antagonists the standard of care for a many depressive disorders and [0784 ] Antagonists of the neurokinin 3 receptor (NK - 3 ) mood disorders ( Thase, M. E. 2008 ; Vaswani, M. et al. are known to show antidepressant effects (Salome , et al. 2003 ). They are also useful in the treatment of chronic pain 2006 ) . Further , the actions of NK - 3 modulators show a (Marks , D.M. et al. 2009 ). Therefore , pharmaceutical com dependency on the opioid receptor system (Panocka , I. et al . positions of the compounds of the present invention , com 2001 ) . Therefore, pharmaceutical compositions of the com bined with SSRIs or SNRIs , are useful in the treatment of pounds of the present invention , combined with NK - 3 depressive disorders , mood disorders , borderline personality antagonists , may be useful in the treatment of depression or disorder, or pain with increased efficacy compared to the other mood disorders with increased efficacy compared to compounds of the present invention alone. Alternatively , the the compounds of the present invention alone . Alternatively , opioid modulator and SSRI or SNRI may be dosed sepa the opioid modulator and NK - 3 antagonist may be dosed rately, as a novel method for treating the conditions separately , as a novelmethod for treating depression or other described above. Further, the compound of the present mood disorders . invention may be used as an add -on therapy to enhance the [0785 ] Non -Limiting Examples of Neurokinin 3 Receptor efficacy of preexisting SSRI or SNRI therapy for the con Antagonists : ditions described above . [0786 ] osanetant, talnetant, SB - 222200 , SB - 218795 [0792 ] Non -Limiting Examples of SSRIS : [0793 ] citalopram , escitalopram , fluoxetine , fluvoxamine , Example 20. Combinations with DOR Agonists paroxetine, sertraline , dapoxetine [0787 ] DOR Agonists have been shown to elicit antide [0794 ] Non - Limiting Examples of SNRIS : pressant and anxiolytic effects (Saitoh , A. et al . 2004 ; [0795 ] venlafaxine , desvenlafaxine Torregrossa, et al. 2005 ; Jutkiewicz, E. M. 2006 ) and are analgesic (Vanderah , T. W. 2010 ; Peppin , J. F. and Raffa ,R. Example 23. Combinations with Methylnaltrexone B. 2015 ) . They have also been shown to reverse the respi [0796 ] Constipation is a frequent, unpleasant side effect of ratory depression induced by MOR agonists (Su , Y- F. et al . MOR agonists resulting from inhibition of intestinal smooth 1998 ) . Therefore , pharmaceutical compositions of the com muscle contractions via activation ofMORs located in this pounds of the present invention , combined with DOR ago tissue. Methylnaltrexone (Relistor ) is a clinically approved nists , may be useful in the treatment of depression , mood quaternary ammonium salt of the opioid receptor antagonist disorders , anxiety disorders , borderline personality disorder , naltrexone that does not cross the blood brain barrier. or pain with increased efficacy or reduced side effects Accordingly , this compound is capable of inhibiting MORS compared to the compounds of the present invention alone. in the gastrointestinal tract and preventing opioid - induced Alternatively , the opioid modulator and DOR agonist may constipation while avoiding simultaneous inhibition of cen be dosed separately , as a novel method for treating the trally mediated therapeutic effects . Therefore, pharmaceuti conditions described above . cal compositions of the compounds of the present invention , US 2020/0079745 A1 Mar. 12 , 2020 85 combined with methylnaltrexone, are useful in the treatment [0800 ] Interestingly , similar MOR activation is observed of depressive disorders , mood disorders , borderline person in response to social acceptance events , suggesting that this ality disorder, pain , opioid addiction , or opioid withdrawal signaling system also acts as a positive reinforcer (Hsu , D. symptoms with reduced constipation compared to the com T. et al. 2013 ) . In contrast , patients with major depressive pounds of the present invention alone. Alternatively , the disorder display almost no change in MOR neurotransmis opioid modulator and methylnaltrexonemay be dosed sepa sion following identical rejection and acceptance events , rately, as a novel method for treating the conditions suggesting that their natural MOR signaling pathways are described above with less constipation . dysfunctional (Hsu , D. T. et al. 2013 ; Hsu , D. T. et al. 2015) . [0801 ] Discussion Example 24. Use of Fluoro - Substituted Compounds [ 0802 ] The present invention provides a number of dia as PET Radiotracers rylthiazepinamine carboxylic acids related to the antidepres [0797 ] Positron emission tomography (PET ) is a nonin sant tianeptine that are useful opioid modulators with a vasive in vivo imaging technique that uses radiotracers to number of improved properties compared to other com characterize , visualize , and quantify physiological processes pounds in this structural class. In addition to its primary at the molecular level (Miller , P. W. et al. 2008 ) . Fluorine - 18 activity at the MOR , tianeptine also exhibits low potency is the preferred positron - emitting isotope for use in positron agonist activity at the DOR (Gassaway , M.M. et al. 2014 ). emission tomography (PET ) . However, placement of a fluo Literature reports suggest that simultaneous activation of rine substituent at an inappropriate position may abolish the DOR , in addition to MOR , will provide therapeutic benefits activity of a compound at its target of interest . Accordingly , in treating a number of conditions. For example , DOR drug compounds containing a fluorine substituent and retain agonists alone are known to be efficacious antidepressants ing activity at the target of interest are useful for PET and anxiolytics in animal models (Saitoh , A. et al. 2004 ; imaging of target engagement and /or drug localization in the Torregrossa , et al. 2005 ; Jutkiewicz , E. M. 2006 ) . Accord body . In the case of the present invention , compounds ingly , simultaneous activation of DOR is expected to bearing a fluorine substituent at position 2 of the diarylthi enhance the MOR -dependent antidepressant and anxiolytic azepine core ( e.g. compounds 96, 9j, 9k , 91, 9n , and 90 ) are effects of compounds in the tianeptine class . Similarly , DOR particularly well suited for this purpose since they are agonists possess analgesic properties (Vanderah , T. W. 2010 ; equipotent or more potent as agonists of MOR than their Peppin , J. F. and Raffa , R. B. 2015 ) . Thus, the addition of a non - fluorinated analogs. In any such compound , fluorine- 18 DOR agonist component to the activity profile of tianeptine is substituted in place of fluorine- 19 to provide a PET analogs is also expected to enhance their analgesic activity . radiotracer of MOR . Lastly , DOR agonists have been shown to inhibit the respi [0798 ] A PET radiotracer of MOR is useful to determine ratory depression evoked by MOR agonists (Su , Y - F . et al . the occupancy of MOR achieved following administration 1998 ) . Therefore, dualMOR /DOR agonists are expected to of different doses of compounds binding to MOR , for limit the magnitude of this side effect. The present invention example the compounds of the present invention , to a provides tianeptine analogs with increased DOR agonist subject. Information on the relationship between dosing and potency compared to the parent compound . Specifically , MOR occupancy is useful for setting the appropriate dose increasing the length of the carboxylic acid side chain to 8 for use in clinical trials or in the treatment of disease . It is or more carbons increases the potency of this class as DOR also useful for defining the pharmacodynamic effect of a agonists without analogous shifts in MOR potency, such that compound acting at MOR , since a particular degree of the DOR :MOR potency ratio is shifted in favor of DOR . receptor occupancy may be related to effects on physiology Notably , varying the length of this side chain is also useful (e.g. breath rate ) or behavior ( e.g. analgesia or antidepres for modulating the pharmacokinetic properties within this sant effects ) . class and longer chain analogs are expected to produce a [0799 ] A radiotracer of MOR is also useful for studying number of active metabolites with shorter carboxylic acid release of endogenous opioid peptides , the natural ligands side chains following beta -oxidation in vivo . for MOR in the brain . When an external stimulus induces [0803 ] This invention also provides alternative substitu release of endogenous opioid peptides in a subject, such tion patterns on the aryl ring system ( dihalo , alkynyl, and release can be detected by displacement of an MOR PET methylthio substituents ) that are sufficient to maintain simi radiotracer from MOR binding sites in the brain , demon lar or improved opioid activity compared to the monohalo strating that the endogenous ligand is competing for binding substitution pattern ( and improved potency relative to to these same sites. Accordingly , endogenous opioid peptide tianeptine itself ). These alternative substitution patterns also release and activation of MOR signaling pathways in provide other unique properties . For example , the methyl response to physiological or psychological stimuli may be thio substitution yields compounds with partial agonist studied in vivo . Such study and quantification of endog activity at DOR , a contrast to all other compounds in this enous opioid signaling is useful in the diagnosis of disease class , which are full agonists . Further , dihalo substitution states or as a biomarker of treatment response . For example , provides compounds that are more water soluble than their using such MOR PET imaging techniques, it has been analogous monohalo counterparts , at both neutral pH and in shown that in healthy individuals , there is a robust decrease particular , at low pH . Increased solubility is useful for in availability of MOR binding sites in multiple brain optimizing pharmacokinetic and formulation properties, for regions following social rejection , presumably demonstrat example by reducing variability in pharmacokinetics fol ing a release of endogenous opioid peptides , which displace lowing oral administration of solid dose forms ( increased the radiotracer (Hsu , D. T. et al. 2013) . Accordingly , acti solubility decreases the dependence of absorption rate on vation of MOR signaling pathways appears to serve as a particle size ) . Similarly , compounds that are more soluble at natural coping mechanism that attenuates the negative feel low pH , as found in the stomach , are expected to be ings associated with rejection . absorbed more rapidly from solid dosage forms following US 2020/0079745 A1 Mar. 12 , 2020 86 oral administration due to their increased rate or extent of [0827 ] Overstreet, D. H .; Naimoli, V. M .; Griebel, G. dissolution . Therefore, the alternative substitution patterns Pharmacol. Biochem . Behav. 2010 , 96 , 206-210 . described herein may be combined with any appropriate side [0828 ] Peppin , J. F .; Raffa , R. B. J. Clin . Pharm . Ther . chain modification to generate additional opioid -active com 2015 , 40 , 155-166 . pounds with pharmacological and physical properties tuned [0829 ] Rives, M.- L .; Rossillo , M .; Liu - Chen , L.- Y .; as desired for optimal activity in any particular pharmaceu Javitch , J. A. J. Biol. Chem . 2012 , 287 (32 ), 27050-27054 . tical composition or mode of medical treatment . [0830 ] Robinson , J. E .; Fish , E. W .; Krouse, M. C .; Thor [0804 ] As an adjunct to the novel compositions of matter sell , A .; Heilig , M .; Malanga , C. J. Psychopharmacology described above, the present invention also provides uses of 2012 , 220 , 215-224 . the described compounds, either alone or in combination [0831 ] Panocka , I.; Massi , M .; Lapo , I .; Swiderski, T .; with drugs having synergistic pharmacological properties , Kowalczyk M .; Sadowski, B. Peptides 2001 , 22 , 1037 for treating a number of medical conditions . These indica 1042 . tions include, but are not limited to , depression and related [0832 ] Paul, 1. A .; Skolnick , P. Ann . N. Y. Acad . Sci. 2003 , mood disorders , anxiety disorders , borderline personality 1003 , 250-272 . disorder , pain , and opioid dependence ( as a maintenance [0833 ] Prossin , A. R .; Love, T. M .; Koeppe , R. A .; Zubi therapy ) . eta , J- K .; Silk , K. R. Am . J. Psychiatry 2010 , 167 , [ 0805 ] Lastly , an additional aspect of the invention pro 925-933 . vides synthetic methods and chemical intermediates that [0834 ] Saitoh , A. et al . J. Pharmacol. Sci. 2004 , 95 , may be used to encompass chemical space around the 374-380 . diarythiazepinamine core structure. [ 0835 ] Salomé, N. et al. Pharmacol. Biochem . Behav. REFERENCES 2006 , 83 , 533-539 . [0836 ] Sansone, R. A. et al. Int. J. Psychiatry Med . 2008 , [ 0806 ] Barbier, E. et al. Neuropsychopharmacology 2013, 38 , 217-226 . 38 , 976-984 . [ 0837 ] Smith , K .; Hopp , M .; Mundin , G .; Bond , S .; Bai [0807 ] Bart , G. J. Addict . Dis . 2012 , 31 , 207-25 . ley, P.; Woodward , J.; Bell, D. Int. J. Clin . Pharmacol. [0808 ] Beaumont, K .; Webster , R .; Gardner, I.; Dack , K. Ther. 2012 , 50 , 360-367 . Curr. Drug Metab . 2003 , 4 , 461-485 . [ 0838 ] Su , Y. F .; McNutt , R. W .; Chang , K. J. J. Pharma [0809 ] Berrocoso , E .; Sanchez -Blazquez , P .; Garzón , J .; col. Exp . Ther. 1998 , 287 , 815-823 . Mico , J. A. Curr. Pharm . Des. 2009 , 15 , 1612-1622 . [0839 ] Svoboda, K. R. et al . J. Neurosci. 1999 , 19 , 85-95 . [ 0810 ) Besson , A .; Privat, A. M .; Eschalier , A .; Fialip , J. Psychopharmacology 1996 , 123 , 71-78 . [0840 ] Thase, M. E. Psychopharmacol. Bull. 2008, 41, [ 0811 ] Bodkin , J. A .; Zornberg, G. L .; Lukas, S. E .; Cole , 58-85 . J. O. J. Clin . Psychopharmacol. 1995 , 15, 49-57 . [0841 ] Torregrossa , M. M. et al. Psychopharmacology [0812 ] Corbett , A. D .; Henderson , G .; McKnight, A. T .; (Berl ) . 2005 , 183 , 31-40 . Paterson , S. J.; Brit. J. Pharmacol. 2006 , 147, S153 -S162 . [0842 ] Trujillo , K. A .; Akil, H. Brain Res. 1994 , 633 , [0813 ] Fujimoto , T .; Ritter , T. Org. Lett. , 2015 , 17 , 544 178-188 . 547 . [0843 ] Vanderah , T. W. Clin . J. Pain . 2010 , 26 Suppl, [0814 ] Gassaway, M. M .; Rives , M - L .; Kruegel A. C .; S10-15 . Javitch , J. A .; Sames, D. Transl. Psychiatry 2014 , 4 , e411 . [0844 ] Vaswani, M. et al. Prog . Neuropsychopharmacol. [0815 ] Grislain , L .; Gele , P .; Bertrand , M .; Luijten , W .; Biol . Psychiatry 2003 , 27 , 85-102 . Bromet , N .; Salvadori , C .; Kamoun , A. Drug Metab . [0845 ] Vincent, J. et al . J. Am . Chem . Soc . 1987 , 109 , Dispos. 1990 , 18 , 804-808 . 5703-5711 [ 0816 ] Hsu , D. T. et al. Mol. Psychiatry 2013 , 18 , 1211 [0846 ] Williams, J. T. et al. Pharmacol. Rev. 2013 , 65 , 1217 . 223-254 . [0817 ] Hsu , D. T. et al .Mol . Psychiatry 2015 , 20 , 193-200 . [0847 ] Xie , C. W., Lewis D. V. J. Neurophysiol. 1997 , 78 : [0818 ] Jutkiewicz , E. M.Mol . Interv . 2006 , 6 , 162-169 . 759-766 . [ 0819 ] Kramer, M. S. et al . Neuropsychopharmacology [ 0848 ] Zarate , C. A. Jr et al. Arch . Gen. Psychiatry 2006 , 2004 , 29 , 385-392 . 63 , 856-864 . [0820 ] Mao , J .; Price, D. D .; Caruso , F. S .; Mayer , D. J. What is claimed is : Pain 1996 , 67 , 361-368 . 1. A compound having the structure : [0821 ] Marks, D.M. et al . Curr. Neuropharmacol . 2009, 7 , 331-336 . [0822 ] McNeill, E .; Barder , T. E .; Buchwald , S. L. Org . Rg R1 Lett. 2007 , 99 , 3785-3788 . [0823 ] Miller, P. W. et al. Angew . Chem ., Int. Ed . 2008 , 47 , Ro RA 8998-9033 . [ 0824 ] Moskal, J. R .; et al. Neuropharmacology 2005 , 49 , R5 1077-1087 . R10 [0825 ] Murrough , J. W. et al. Am . J. Psychiatry 2013 , 170 , R11 1134-1142 . R7 Ro [0826 ] Negri , A .; Rives, M.- L .; Caspers , M. J .; Prisinzano , R2 R3 T. E .; Javitch , J. A .; Filizola , M. J. Chem . Inf. Model. 2013 , 53 ( 3 ) , 521-526 . US 2020/0079745 A1 Mar. 12 , 2020 87

wherein O - aryl) , O-( heteroaryl ) , S-( alkyl) , S-( alk Rj is —H or -( alkyl) ; enyl) , S - alkynyl ) , S - Caryl) , S-( heteroaryl) , R2 is (Cz - C20 alkyl) -CO2H or (Cz - C20 alkyl) -CO2 -S (O )- ( alkyl) , -S ( O ) -( aryl ) , -S( O ) -( heteroaryl ) , (alkyl ) ; -SO2-( alkyl ), -SO2- ( aryl) , or —SO2- (heteroaryl ) ; R2 is - H or - (alkyl ) ; R3, R9, R10 and Ru1 are each independently H , C1, R4, R3, R. and R , are each independently —H-H , - Ci, Br, F , GI, CN , CF3 , OCF3, -( alkyl ) , -Br, -F , -1, - CN , OCF3, -( alkyl ) , - (alk -aryl ) , - (heteroaryl ) - (alkenyl ) , -alkynyl) , —NH , enyl) , -( alkynyl ) , -( aryl ) , -NH2CF39 , -NH-( alkyl ) , -NH -NH - alkyl) , -NH - alkenyl) , -NH - alkynyl) ( alkenyl) , NH-( alkynyl ) NH-( aryl ) , NH- Khet -NH - Caryl) , NH-( heteroaryl ) , OH , OA , eroaryl) , OH , OA , O C ( O ) (alkyl ) , 0 0 - C ( O ) (alkyl ) , 0- (alkyl ) , O-(alkenyl ) , O ( alkyl) , O - alkylaryl) , -O-( alkenyl) , O-( alkynyl) , (alkynyl ) , O-( aryl ) , O-( heteroaryl ) , -S-( alkyl ) , O - aryl) , -O-0-( heteroaryl ) , S-( alkyl ) , —S-( alk -S-( alkenyl) , S-( alkynyl) , S - aryl) , S-( het enyl) , S-( alkynyl) , S - aryl) , S-( heteroaryl) , eroaryl) , -SS ( O ) - ( alkyl) ,, -S (O )-aryl ), S ( O )- (het -S ( O ) - ( alkyl) , S (O )-aryl ) , -S (O )- ( heteroaryl ) , eroaryl ), -SO2 - alkyl) , SO2- aryl) , or SO2-( het SO2- ( alkyl) , SO2- ( aryl) , or SO2- (heteroaryl ) ; eroaryl) ; R3, R9, R10 and R11 are each independently H , C1, wherein when R , is (C. alkyl) -CO2H , then one of Rs or -Br, —F, —I, CN , CF3, OCF3, -( alkyl) , Ro is - (alkynyl ) or S-( alkyl) , or R , and Ro are each -aryl) , - (heteroaryl ) -alkenyl) , -alkynyl) , NH ,, independently C1, -Br, —F, or -I, NH - alkyl) , -NH - alkenyl) , -NH - alkynyl) wherein when R , is (Coalkyl )-CO2 - alkyl) , then one of -NH -Caryl ) , -NH-( heteroaryl ) , OH , OA , R , or R. is -( alkynyl ) , or R , and R. are each indepen -0_C ( O ) (alkyl ) , O - alkyl) , O-( alkenyl ) , O dently - Cl, Br, -F, or -I, and (alkynyl ) , O-( aryl ) , O-( heteroaryl ) , S - alkyl ), wherein when R , is CH3, R3, R4, R6, R7, R8, R9, R10 S - alkenyl) , S - alkynyl) , S - aryl) , S - het and R11 are each - H , and R , is Cl, then R2 is other than eroaryl ), -S ( O ) - (alkyl ) , -S( O ) - ( aryl) , -S( O ) - (het (CH2 ) , CO2H , — ( CH2) 1.CO2H , -CH (CH3 ) ( CH2 ) eroaryl) , SO2- ( alkyl) , SO2- ( aryl) , or - S02- het $ CO , H or ( CH2) 2CH (CH ) (CH ) ,CO , H , and eroaryl) ; wherein when Ri is CH3, R3, R4, R6 , R7, R8, R9, R10 wherein when R ; is ( C3-6 alkyl ) -CO , H , then one of Rs and R11 are each — H , and R , is SCH3, then R , is other or Rg is -( alkynyl ) or S-( alkyl) , or R and R , are each than ( CH2) CO H , independently C1, —Br, —F, or —I, or a pharmaceutically acceptable salt or ester thereof. wherein when R2 is - (C3-6 alkyl) -CO2- ( alkyl) , then one 3. ( canceled ) of R , or Ro is - (alkynyl ), or R , and R. are each 4. The compound of claim 2 having the structure : independently C1, -Br, -F , or -I, and wherein when Rj is CH3, R3, R4, R5, R., R7, Rg, R ,, R10 and R11 are each — H , and R , is Cl, then R , is other R8 Ri than ( CH2) -CH, ( CH4) 2COH, CH (CH ) O (CH2 ) ,CO2H or ( CH2) 2CH (CH3 ) ( CH2) 2CO , H , and RO R4 wherein when R , is CH3, R3, R4, R6, R7, Rg, Ry, Rio and R11 are each — H , and Rsis SCH3, then R2 is other -R5 than (CH2 ) &CO H , Rio or a pharmaceutically acceptable salt or ester thereof . Ru1 2. The compound of claim 1 having the structure: R R6 R3 R7

R8 Ri wherein Ro R4 is H or -( alkyl ) ; RYR2 is (C7 - C20 alkyl) -CO2H or (CZ - C20 alkyl) -CO2 (alkyl ) ; R10 -R5 is -H or - ( alkyl) ; R4, Rs, Ro and R , are each independently —H , C1, RU Br, -F, -I, CN , CF3, OCF3, - (alkyl ) , - ( alk R2 R7 RO enyl) , -alkynyl) , -aryl) , -NH2, -NH - alkyl) , -NH (alkenyl ), -NH-( alkynyl) NH-( aryl) , NH-( het eroaryl) , OH , OAc , 0_C ( O ) (alkyl ) , O wherein ( alkyl) , -O-( alkylaryl ) , O - alkenyl) , -O-( alkynyl) , Ris-1 -H or -alkyl) ; O - aryl) , O-( heteroaryl ) , , S-( alkyl) , —S- ( alk R2 is (Co - C20 alkyl) -CO2H or ( Co- C20 alkyl) -CO2 enyl ), S-( alkynyl ) , S -Caryl ) , S-( heteroaryl) , (alkyl ) ; S ( O )-alkyl ) , -S ( O )-aryl ) , -S( O ) - ( heteroaryl) , Rz is —H or -( alkyl ) ; SO2- (alkyl ), -SO2- ( aryl) , or -SO2- (heteroaryl ) ; R4, RS, R , and R , are each independently —H , CI , Rg, R9 , R10 and Rui are each independently —H , CI, -Br, F , —1, CN , OCF3, -alkyl) , - ( alk -Br, -F , I , CN , CF 3 , OCF3, -( alkyl ) , enyl) , -alkynyl) , -aryl) , -NH2CF39 , -NH - alkyl) , -NH -Caryl ) , - (heteroaryl ) - (alkenyl ) , -alkynyl) , NH , (alkenyl ) , -NH-( alkynyl ) NH-( aryl ) , -NH-( het -NH - alkyl) , -NH-( alkenyl) , -NH - alkynyl) eroaryl) , OH , OAc, 0_C (O )( alkyl) , O NH - aryl) , -NH-( heteroaryl ) , OH , OAc, ( alkyl) , O - alkylaryl) , -O-( alkenyl) , O-( alkynyl) , O C ( O ) (alkyl ) , O - alkyl) , _O-( alkenyl) , _O US 2020/0079745 A1 Mar. 12 , 2020 88

(alkynyl ) , -O - aryl) , O-(heteroaryl ) , S - alkyl) , -continued S-( alkenyl ) , S-( alkynyl ), S-( aryl) , S-( het Rg R1 eroaryl) , -S( O ) - (alkyl ) , -S ( O ) - ( aryl) , S ( O )-het eroaryl) , SO2-( alkyl) , SO2-( aryl ), or — SO2- (het RO R4 eroaryl) ; wherein when R , is CH3, R3, R4, R6 , R7, Ry, R9, R10 or and R 1 are each — H , and R , is Cl, then R , is other than R10 (CH2 ) ,CO , H , (CH2 ) 1.CO ,H , CH (CH3 ) (CH2 ) Rii COH or - (CH3 ) 2CH (CH3 ) ( CH ), CO , H , R7 R6 R2 R3 or a pharmaceutically acceptable salt or ester thereof. R8 R1 5. The compound of claim 5 , wherein Ro. O R4 R2 is – ( C8- C20 alkyl) -CO2H or (C8 - C20 alkyl) -CO2 ( alkyl) ; or -SMe, R2 is (Cy - C20 alkyl) -CO2H or (C2 - C20 alkyl) -CO2 Rio (alkyl ) ; or R11 N R6 R2 is (C8 - C20 alkyl ) -CO H or (C8 - C20 alkyl) R2 RT COZCHz; or R3 R2 is (Cy - C20 alkyl) -CO , H or ( Co- C20 alkyl) wherein CO2CH2CH3 Rj is –H or - ( alkyl) ; 6. (canceled ) R2 is ( C7- C20 alkyl) -CO H or (C7 - C20 alkyl) -CO2 (alkyl ) ; 7. The compound of claim 4 , wherein Rz is -H or - (alkyl ) ; R , is - Br, I, -( alkenyl ) , - (alkynyl ) or -S- alkyl ); or R4, R6 and R , are each independently —H , Cl, Br, one of R , or Ro is - (alkynyl ) ; or one of R , or Ro is -F , -1, CN , CF3, OCF3, -alkyl) , - (alkenyl ) , S - alkyl) ; or - ( alkynyl) , - ( aryl) , -NH2, -NH - alkyl) , NH-( alk enyl) , NH - alkynyl) NH - aryl) , -NH-( het R , and R. are each independently - Cl, Br, -F, or — I . eroaryl) , OH , OAc, 0 C (O )( alkyl ) , 0 (alkyl ), O - alkylaryl ), O - alkenyl) , O - alkynyl ), 8.- 9 . (canceled ) O- (aryl ) , O-( heteroaryl) , S-( alkyl) , S-( alk 10. The compound of claim 4 having the structure enyl) , S-( alkynyl) , S - Carylaryl)) , , S-( heteroaryl ) , S ( O )- ( alkyl) , -S (O )- ( aryl ) , S ( O ) - (heteroaryl ) , SO2- (alkyl ) , SO2- ( aryl) , or SO2- (heteroaryl ) ; Rg Ri Rg, Ry, Rio and Ru1 are each independently --H , CI, -Br, -F , -1, CN , OCF3, -( alkyl ) , Ro R4 -Caryl) , -( heteroaryl ) -( alkenyl CF39) , -( alkynyl ) , —NH2, -NH - alkyl) , -NH - alkenyl) , -NH - alkynyl) -Br, -NH - Caryl) , NH-( heteroaryl ) , OH , OAc, Rio 0_C ( O ) (alkyl ) , O-( alkyl ) , O-( alkenyl ) , 0 Ru ( alkynyl) , O - Caryl) , O-( heteroaryl ) , S - alkyl) , R7 R6 S - alkenyl) , S - alkynyl) , S - aryl) , S - het R2 R3 eroaryl) , -S ( O ) - (alkyl ) , -S( O ) -aryl) , -S ( O ) - (het Rg R1 eroaryl) , -S02- ( alkyl) , SO2- ( aryl) , or - SO2- (het eroaryl) ; or R9 www R4

I , Rg Ri R10 Rg R4 Ril RT R6 R2 Br R3 Rio R8 RU N 0 Ru R. R4 R7 R2 R3

Rio wherein Rii Riis -H or -alkyl) ; R7 R6 is (C2 - C20 alkyl ) -CO , H or ( C2- C20 alkyl) -CO2 R2 R3 R2( alkyl ) ; Rz is H or - (alkyl ) ; US 2020/0079745 A1 Mar. 12 , 2020 89

R4 and R , are each independently —H , -Cl, Br, -F, enyl) , —S-( alkynyl ) , S - aryl) , S-( heteroaryl ) , -I, CN , CF3, OCF3 , (alkyl ) , - ( alkenyl) , S ( O )-alkyl ) , S ( O ) - (aryl ) , -S ( O ) - (heteroaryl ) , -( alkynyl) , - ( aryl) , -NH2, -NH-( alkyl ) , -NH-( alk SO2- (alkyl ) , SO2- ( aryl) , or SO2- (heteroaryl ) ; enyl) , -NH - alkynyl) _NH-( aryl ) , NH-( het eroaryl) , ?? , OA , O C ( O ) (alkyl ) , O Rg, R9, R10 and RJ are each independently - H , CI, ( alkyl ), -O-( alkylaryl) , -O-( alkenyl) , - O - alkynyl) , -Br, —F, -1, CN , CF , OCF3 , -alkyl) , O-( aryl ) , O- (heteroaryl ) , S - alkyl) , S-( alk -Caryl ) , - (heteroaryl ) -( alkenyl) , - (alkynyl ), NH , enyl) , S-( alkynyl ) , S - aryl) , S-( heteroaryl ) , NH - alkyl) , -NH-( alkenyl ) , -NH - alkynyl) S ( O )- ( alkyl ) , -S( O )- (aryl ) , S ( O ) - (heteroaryl ) , -NH -Caryl ) , NH-( heteroaryl ) , OH , OA , SO2- (alkyl ) , SO2- ( aryl ), or SO2- (heteroaryl ) ; 0_C ( O ) alkyl) , O - alkyl) , O - alkenyl) , -O Ry, Ry, R10 and Rui are each independently —H , C1, (alkynyl ) , O-( aryl) , O-( heteroaryl ) , -S- alkyl) , -Br, F , -1, CN , CF3, OCF3, - (alkyl ) , S-( alkenyl) , S-( alkynyl ), S - Caryl) , S - het -Caryl ), -( heteroaryl ) -( alkenyl) , -( alkynyl) , -NH2, eroaryl) , -S( O ) - (alkyl ) , -S ( O ) - (aryl ) , -S ( O ) -chet -NH - alkyl) , -NH - alkenyl) , -NH - alkynyl ) eroaryl) , -SO2- ( alkyl) , -SO2- ( aryl) , or —SO2- (het -NH - Caryl ) , NH-( heteroaryl ) , OH , OA , eroaryl) , 0_C ( O ) (alkyl ) , O - alkyl) , O-( alkenyl) . O ( alkynyl) , O - aryl) , O-( heteroaryl) , S-( alkyl) , or a pharmaceutically acceptable salt or ester thereof. S - alkenyl) , S - alkynyl) , S -Caryl ) , S - het 11.- 15 . ( canceled ) eroaryl) , -S (O )-alkyl ) , -S (O )- ( aryl) , S ( O )-het eroaryl) , SO2- ( alkyl) , SO2- ( aryl) , or - S02- het 16. The compound of claim 4 having the structure eroaryl) ; or

Rg 0 R9 R4 Br, CI, R 10 HN R11 R7 CI R2 R3 RO Ri RO R4

Rio Cl or R11 Me02C R7 F R2 R3 Rg Ri Ro R4

Rio

R11 N R7 F R2 R3 HN wherein R , is H or - ( alkyl) ; R2 is (C7 -C20 alkyl) -CO , H or (C7 -C20 alkyl) -CO2 ( alkyl ) ; Rz is –H or - (alkyl ) ; R4 and R , are each independently - H , -Cl, Br, -F, I, CN , CF3, OCF3, - (alkyl ), - (alkenyl ) , -( alkynyl ), -( aryl ), -NH2, -NH-( alkyl ) , -NH-( alk enyl) , NH - alkynyl) -NH -Caryl ) , -NH-( het eroaryl ), OH , OAc, , O C ( O ) alkyl) , O (alkyl ) , O - alkylaryl) , O - alkenyl) , O - alkynyl) , MeO2C O - Caryl) , O-( heteroaryl ) , S - alkyl ), S-( alk US 2020/0079745 A1 Mar. 12 , 2020 90

-continued

Br,

HN HN

HO2C CO2Et

-1,

HN HN

HO2C EtO2C

HN

HN

CO2Et CO2H US 2020/0079745 A1 Mar. 12. 2020 91

-continued -continued 0 // O

-1,

HN H?N

HO2C

HO2C

H2N

HN

CO2H

CO2H ...

or

Br, H?N

HN

HO2C HO , C US 2020/0079745 A1 Mar. 12 , 2020 92

-continued eroaryl) , -S (O ) - (alkyl ) , -S-S ( O )) - - ( ( aryl) , -S( O ) - ( het eroaryl) , -SO2 - alkyl ), SO - (aryl ) , or -SO - het eroaryl) ; wherein one of R , or Ro is - ( alkynyl) or S-( alkyl ) , or RS and Ro are each independently — Cl, Br, -F, or —I, and wherein when R , is CH3, R3 , R4, R , R7, R8, R9, R10 and R11 are each - H , and R , is SCH3, then R , is other than H?N ( CH2) .CO2H , or a pharmaceutically acceptable salt or ester thereof. 19.- 23 . ( canceled ) 24. The compound of claim 18 having the structure

HN CO2H or a pharmaceutically acceptable salt or ester thereof. 17. (canceled ) 18. The compound of claim 2 having the structure: CO2H Rg R. RA

Rio -R5 Br, Ru HN RO F R3 R7

wherein Rz is H or -alkyl) ; R2 is (C. alkyl) -CO H ; Rz is H or -alkyl) ; R4, RS, R. and R , are each independently -H , CI, CO2H Br, -F, -I, CN , CF3, OCF3 , - (alkyl ) , - (alk enyl) ,-alkynyl ) ,-aryl ) , NH - NH - alkyl) , -NH O ( alkenyl ), -NH-( alkynyl ) -NH-( aryl ), _NH-( het eroaryl) , OH , OA , O C ( O ) ( alkyl ) , O (alkyl ) , O - alkylaryl) , O - alkenyl) , O - alkynyl ), CI, -O - aryl) , O-( heteroaryl ) , S-S - ( alkyl ) , S-( alk enyl) , S-( alkynyl ) , -S - Caryl) , S-( heteroaryl) , HN S ( O ) - (alkyl ) , S (O ) - ( aryl) , -S( O ) - (heteroaryl ) , SO2- ( alkyl) , SO2- (aryl ), or — SO2- (heteroaryl ) ; Rg, R9, R10 and R11 are each independently - H , CI, Br, F , I , CN , OCF 3 : -( alkyl ) , -Caryl ), -( heteroaryl ) -( alkenylCF39) , -( alkynyl) , -NH2, -NH - alkyl) , -NH - alkenyl ), NH-( alkynyl ) -NH -Caryl ) , -NH-( heteroaryl ) , OH , OA , O C ( O ) ( alkyl ), O-( alkyl ) , O-( alkenyl ) , O (alkynyl ) , O-( aryl) , O-( heteroaryl ) , S - alkyl) , CO2H S-( alkenyl) , S- (alkynyl ) , S - Caryl) , S - het US 2020/0079745 A1 Mar. 12 , 2020 93

-continued -continued

-CI, Br ,

HN H?N F F

CO2H CO2H

CI,

HN H2N F

CO2H CO2H

Cl or

H2N . H?N F CI

CO2H CO2H US 2020/0079745 A1 Mar. 12 , 2020 94

-continued wherein one of R , or Ro is -alkynyl ), or Rs and Ro are each independently — C1, -Br, —F , or -I, and or a pharmaceutically acceptable salt or ester thereof. 27.- 31 . (canceled ) 32. The compound of claim 26 having the structure

H?N F

HN

CO2H

or a pharmaceutically acceptable salt or ester thereof. 25. ( canceled ) 26. The compound of claim 2 having the structure : CO2Et

Rg Ri RO RA

R 10 -R5 R11 Br, Ra R7 RO R3 HN F wherein R , is H or -( alkyl) ; R is Coalkyl )-C02- ( alkyl) ; Rz is –H or -( alkyl ) ; R4, Rs, R. and R , are each independently -H , CI, Br, -1, CN , CF3, OCF3, -alkyl) , - ( alkenyl) , CO Et -( alkynyl ) , - (aryl ) , NH2, -NH-( alkyl ) , -NH-( alk enyl) , NH-( alkynyl ) -NH-( aryl ) , -NH-( het eroaryl) , OH , OA , 0_C (O ) ( alkyl) , O (alkyl ) , O - alkylaryl) , O - alkenyl) , O - alkynyl) , O - Caryl ), O-( heteroaryl ) , S-( alkyl ) , S- (alk enyl) , S-( alkynyl) , -S - Caryl ), S-( heteroaryl ) , S ( O )- (alkyl ) , S (O )- ( aryl) , S ( O ) - (heteroaryl ) , CI, SO2- ( alkyl) , SO2- (aryl ) , or SO2- (heteroaryl ) ; HN Rg, R9, R10 and Ru are each independently --H , C1, CI -Br, -F , GI, CN , CF3, OCF3, (alkyl ) , -Caryl) , -( heteroaryl ) - (alkenyl ) , -( alkynyl) , NH , -NH - alkyl) , -NH - alkenyl) , -NH - alkynyl) -NH - Caryl) , NH-( heteroaryl ) , OH , OAc, 0_C (O )( alkyl ) , O - alkyl) , _O-( alkenyl ) , 0 (alkynyl ), O-( aryl ) , O-( heteroaryl ) , S - alkyl) , S-( alkenyl) , S - alkynyl) , S - aryl ), S - het eroaryl) , -S (O ) - (alkyl ) , S ( O ) -Caryl-( aryl) , -S( O ) - (het eroaryl) , SO2- ( alkyl) , SO2- ( aryl) , or - S02- het CO2Et eroaryl ) ; US 2020/0079745 A1 Mar. 12 , 2020 95

-continued Ry, Ry, Rio and Ru1 are each independently -H , -Cl, -Br, -F , -1, CN , OCF3, -( alkyl ) , -aryl ) , - (heteroaryl ) - (alkenyl CF) ,39 -alkynyl ) , —NH , -NH - alkyl) , -NH - alkenyl) , -NH - alkynyl) -NH -Caryl ) , -NH-( heteroaryl ) , OH , OA , Cl or 0_C ( O ) (alkyl ) , O - alkyl ) , O - alkenyl) , O (alkynyl ) , O - Caryl) , O-( heteroaryl ) , S-( alkyl) , HN S-( alkenyl ), S-S - (alkynyl ), S - Carylaryl) , S - het F eroaryl) , -S ( O ) - (alkyl ) , -S ( O ) -( aryl ) , -S (O )- (het eroaryl ), -SO2- alkyl) , SOZ- aryl) , or - Soz- het eroaryl) ; wherein Rs and R , are each independently Cl, Br, -F, or —I, or a pharmaceutically acceptable salt or ester thereof . CO2Et 34.- 36 . (canceled ) 37. The compound of claim 33 having the structure

HN F Br,

HN F

CO2Et CO2H or a pharmaceutically acceptable salt thereof. 33. The compound of claim 1 having the structure :

R8 R ] CI, O Rg R4 HN

Rio -R5 Ru R3 R7 R6 R3 CO2H wherein R , is –H or - ( alkyl) ; R2 is – (C3-5 alkyl) -CO2H or ( C3-5 alkyl) -CO2( alkyl) ; Rz is H or - ( alkyl) ; CI, R4, R5, R. and R , are each independently -H , CI, -Br, F , -1, CN , CF39 OCF3, -( alkyl ) , -( alk HN enyl) , - ( alkynyl) , - ( aryl) , -NH2, -NH - alkyl) , -NH F (alkenyl ) , -NH - alkynyl ) -NH-( aryl) , NH-( het eroaryl ), OH , OA , 0 C ( O ) ( alkyl) , 40 ( alkyl ), O - alkylaryl) , O - alkenyl) , O - alkynyl ) , O - Caryl) , O-( heteroaryl ) , S-S - ( alkyl ) , S-( alk enyl) , S-( alkynyl ) , S - aryl) , S- (heteroaryl ) , -S ( O ) -( alkyl ) , S (O )- (aryl ) , -S (O )- ( heteroaryl ) , CO2H SO2- ( alkyl) , SO2-( aryl) , or SO2- (heteroaryl ) ; US 2020/0079745 A1 Mar. 12 , 2020 96

-continued -continued

-I.

HN F HN F

CO2H CO2H

or an ester thereof; or Br ,

HN F

Br,

HN CO2H

CO2Me

-CI,

HN CI CI,

HN

CO2H

CO2Me

//

Cl or -CI, HN F HN F

CO2Me CO2H US 2020/0079745 A1 Mar. 12 , 2020 97

-continued kinin 2 receptor antagonist, a neurokinin 3 receptor antago nist , a DOR agonist, naloxone ,methylnaltrexone , a selective serotonin reuptake inhibitor or a serotonin -norepinephrine reuptake inhibitor , and a pharmaceutically acceptable car rier . -I. 49. A method of activating a mu- opioid receptor or delta - opioid receptor comprising contacting the mu -opioid HN receptor or delta -opioid receptor with the compound of F claim 1 . 50. A method of treating a subject afflicted with a depres sive disorder , a mood disorder , pain , an anxiety disorder , borderline personality disorder, opioid addiction or opioid withdrawal symptoms comprising administering an effective amount of the compound of claim 1 to the subject so as to CO2Me treat the subject. 51. A method of treating a subject afflicted with , a 38. (canceled ) depressive disorder or a mood disorder comprising admin 39. The compound of claim 1 wherein when an F is istering to the subject an effective amount of an NMDA present , the F is 18F, or when an F is present at Ro, the F is receptor antagonist , an NMDA receptor partial agonist , a 18F. neurokinin 1 receptor antagonist, a neurokinin 2 receptor 40. (canceled ) antagonist , a neurokinin 3 receptor antagonist or a DOR 41. A pharmaceutical composition comprising the com agonist and an effective amount of the compound of claim pound of claim 39 and a pharmaceutically acceptable carrier . 1 so as to thereby treat the subject afflicted with the 42. A method of detecting the presence of mu - opioid depressive disorder or the mood disorder ; or receptors in the brain of a subject which comprises deter of treating a subject afflicted with pain , an anxiety disor mining if an amount of the compound of claim 39 is present der , or borderline personality disorder comprising in the brain of the subject at a period of time after admin administering to the subject an effective amount of an istration of the compound or salt thereof to the subject, NMDA receptor antagonist , an NMDA receptor partial thereby detecting the presence of the mu - opioid receptors agonist , a neurokinin 1 receptor antagonist, or a DOR based on the amount of the compound determined to be agonist and an effective amount of the compound so as present in the brain of the subject ; or to thereby treat the subject afflicted with pain , the a method of detecting the location of mu -opioid receptors anxiety disorder, or borderline personality disorder ; or in the brain of a subject which comprises determining of treating a subject afflicted with opioid addiction or where an amount of the compound is present in the opioid withdrawal symptoms comprising administering subject at a period of time after administration of the to the subject an effective amount of an NMDA recep compound or salt thereof to the subject, thereby detect tor antagonist, an NMDA receptor partial agonist or a ing the location of the mu -opioid receptors based on the neurokinin 1 receptor antagonist and an effective location of the compound determined to be present in amount of the compound so as to thereby treat the the subject. subject afflicted with the opioid addiction or opioid a method of quantifying the occupancy of mu- opioid withdrawal symptoms; or receptors by a compound binding to mu- opioid recep of treating a subject afflicted with opioid addiction or tors in the brain of a subject, which comprises deter opioid withdrawal symptoms comprising administering mining the binding competition between said com to the subject an effective amount of naloxone or pound and the compound at a period of time after methylnaltrexone and an effective amount of the com administration of the compounds or salts thereof to the pound so as to thereby treat the subject afflicted with subject , thereby detecting the occupancy of the mu the opioid addiction or opioid withdrawal symptoms; opioid receptors based on the displacement of the or compound binding to mu- opioid receptors in the brain of treating a subject afflicted with pain , a depressive of a subject . disorder , a mood disorder, an anxiety disorder , or a method of quantifying the occupancy of mu -opioid borderline personality disorder , comprising administer receptors by endogenous opioid peptides in the brain of ing to the subject an effective amount of naloxone or a subject, which comprises determining the binding methylnaltrexone and an effective amount of the com competition between said endogenous opioid peptides pound so as to thereby treat the subject afflicted with and the compound at a period of time after adminis pain , the depressive disorder , the mood disorder , the tration of the compound to the subject, thereby detect anxiety disorder , or borderline personality disorder ; or ing the occupancy of the mu- opioid receptors based on of treating a subject afflicted with a depressive disorder, a the displacement of the compound by the endogenous mood disorder, an anxiety disorder, or borderline per opioid peptides . sonality disorder , comprising administering to the sub 43.- 47 . (canceled ) ject an effective amount of a selective serotonin 48. A pharmaceutical composition comprising the com reuptake inhibitor or a serotonin -norepinephrine pound of claim 1 and a pharmaceutically acceptable carrier; reuptake inhibitor and an effective amount of the com or a pharmaceutical composition comprising the compound pound so as to thereby treat the subject afflicted with and , an NMDA receptor antagonist , an NMDA receptor the depressive disorder , mood disorder, anxiety disor partial agonist, a neurokinin 1 receptor antagonist, a neuro der , or borderline personality disorder.