CARBOXYLIC DIARYLTHIAZEPINEAMINES AND USES THEREFOR

All references, including patents and patent applications, cited in this specification are hereby incorporated by reference. No admission is made that any reference constitutes prior art. Nor does discussion of any reference constitute an admission that such reference forms part of the common general knowledge in the art, in any country.

Background of the Invention

The mu opioid receptor (MOR) has been recognized as an important molecular target for several decades. However, the vast majority of MOR agonists used clinically today are structurally related to or derived from morphine (and other poppy alkaloids). These compounds suffer from many serious problems, including development of tolerance (increased dosing is required to achieve the same effects), high addiction liability, and other side effects (e.g., respiratory depression, nausea, and constipation) (Williams, J.T. et al. 2013). Therefore, there is a continuing interest in the development of new MOR agonists with improved therapeutic profile (Corbett, A.D. et al. 2006).

MOR agonists have been widely used for pain treatment. There is also historical and growing interest in the use of MOR agonists as medicaments for depression. Prior to the adoption of tricyclic antidepressants and electroshock therapy as favored treatments for depression, opioids were among the only options available, with the "opium cure" being an accepted treatment modality in the early 20th century (Berrocoso, E. et al. 2009). More recently, studies in both rodents (Besson, A. et al. 1996) and humans (Bodkin, J.A. et al. 1995) have suggested that MOR activation may lead to antidepressant and/or anxiolytic effects.

The antidepressant tianeptine has also been reported to act as a full agonist of the MOR (Gassaway, M.M. et al. 2014). On the molecular level, MORs are extensively expressed in the hippocampus and have been shown to exert a variety of indirect modulatory effects on glutamatergic neurons in this brain region (Xie, C.W. et al. 1997; Svoboda, K.R. et al. 1999). Normalization and modulation of glutamate signaling has been strongly associated with the actions of antidepressants (Paul, I.A. and Skolnick, P. 2003) and indeed, the NMDA receptor antagonist ketamine, shows rapid and efficacious antidepressant activity in human clinical trials (Zarate, C.A. Jr et al. 2006). Further, agonists of the related delta opioid receptor (DOR) have been demonstrated to show robust antidepressant efficacy in animals (JUtkiewicz, E.M. 2006).

Opioid receptor dysfunction may also be associated with borderline personality disorder (BPD). Patients afflicted with BPD exhibit alterations in both basal MOR binding potential and endogenous opioid responses to negative stimuli (Prossin, A.R. et al. 2010). There is also a high prevalence of BPD among patients seeking buprenorphine treatment for opioid addiction (Sansone, R.A. et al. 2008). Accordingly, MOR modulators may be useful medicaments for BPD.

Long-acting prescription opioids may also be used as maintenance (replacement) therapies in the treatment of opioid addiction. In this case, a prescription opioid is provided to the patient chronically and under medical supervision to substitute for the use of illicit opioids (e.g., heroin), thus reducing cravings for, and abuse of, the illicit drug. Opioid maintenance therapy is considered a standard method of care for opioid addiction and is mmoorree successful than behavioral or antagonist interventions (Bart, G. 2012).

In addition to pain, anxiety, behavioral disorders, and mood disorders, there are other serious neurological disorders that afflict patients. Disorders such as Huntington's disease, Rett syndrome, and CDKL5 disorder, amongst others, have significant deleterious effects, with limited or no treatment options available. Therefore, there is an ongoing need for therapeutics to address these neurological disorders and their symptoms. Summary of the Invention

The present disclosure provides a compound having the structure: wherein

R1 is -H or -(alkyl);

R ₂ is -(C3-C20 alkyl)-CO ₂ H or -(C3-C20 alkyl)-CO ₂ -(alkyl);

R3 is -H or -(alkyl);

R4, R5, R6 and R7 are each independently -H, -Cl, -Br, -F, -I, -CN, - CF3, -OCF3, -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -NH ₂ , -NH- (alkyl), -NH-(alkenyl), -NH-(alkynyl) -NH-(aryl), -NH-(heteroaryl), - OH, -OAc, -O-C(0)(alkyl), -0-(alkyl), -O-(alkylaryl), -O-(alkenyl),

-O-(alkynyl), -O-(aryl), -O-(heteroaryl), -S-(alkyl), -S-(alkenyl),

-S-(alkynyl), -S-(aryl), -S-(heteroaryl), -S(O)-(alkyl), -S(O)-

(aryl), -S(O)-(heteroaryl), -SO ₂ -(alkyl), -SO ₂ -(aryl), or -SO ₂ -

(heteroaryl);

R8, R9, R10 and R11 are each independently -H, -Cl, -Br, -F, -I, -CN, - CF3, -OCF3, -(alkyl), -(aryl), -(heteroaryl) -(alkenyl), -(alkynyl), -NH ₂ , -NH-(alkyl), -NH-(alkenyl), -NH-(alkynyl) -NH-(aryl), -NH- (heteroaryl), -OH, -OAc, -O-C(O)(alkyl), -O-(alkyl), -O-(alkenyl), - O-(alkynyl), -O-(aryl), -O-(heteroaryl), -S-(alkyl), -S-(alkenyl), -

S-(alkynyl), -S-(aryl), -S-(heteroaryl), -S(O)-(alkyl), -S(O)-(aryl), -S(O)-(heteroaryl), -SO ₂ -(alkyl), -SO ₂ -(aryl), or -SO ₂ -(heteroaryl); wherein when R ₂ is -(C3-6 alkyl)-CO ₂ H, then one of R5 or R6 is - (alkynyl) or -S-(alkyl), or R5 and R6 are each independently - Cl, -Br, -F, or -I, wherein when R ₂ is -(C3-6 alkyl)-CO ₂ -(alkyl), then one of R5 or R6 is -(alkynyl), or R5 and R6 are each independently -Cl, -Br, -F, or -I,

or a pharmaceutically acceptable salt or ester thereof, wherein the compound is for treating or preventing a neurological disorder in a subject, wherein the neurological disorder is selected from the group consisting of Huntington's disease; Rett syndrome; a

Rett syndrome variant; Angelman syndrome; Prader-Willi syndrome; neonatal onset encephalopathy; X-linked recessive mental retardation; fetal alcohol spectrum disorder; Hirschsprung disease; CDKL5 disorder; West syndrome; FOXG1 syndrome; and Lennox-Gastaut syndrome.

The present disclosure also provides a pharmaceutical coirposition coirprising a compound as described herein, wherein the pharmaceutical coirposition is for treating or preventing a neurological disorder in a subject, wherein the neurological disorder is selected from the group consisting of Huntington's ddiisseeaassee;; RReetttt syndrome; a Rett syndrome variant; Angelman syndrome; Prader-Willi syndrome; neonatal onset encephalopathy; X-linked recessive mental retardation; fetal alcohol spectrum disorder; Hirschsprung disease; CDKL5 disorder; West syndrome; FOXG1 syndrome; and Lennox-Gastaut syndrome.

The present disclosure also provides a method of treating or preventing aa nneeuurroollooggiiccaall ddiissoorrddeerr iinn aa subject, wherein the neurological disorder iiss sseelleecctteedd ffrroomm the group consisting of Huntington's disease; Rett syndrome; a Rett syndrome variant;Angelman syndrome; Prader-Willi syndrome; neonatal onset encephalopathy; X- linked recessive mental retardation; fetal alcohol spectrum disorder; Hirschsprung disease; CDKL5 disorder; West syndrome; FOXG1 syndrome; and Lennox-Gastaut syndrome comprising administering to the subject an effective amount of a compound having the structure:

wherein

R1 is -H or -(alkyl);

R2 is -(C3-C20 alkyl)-CO2H or -(C3-C20 alkyl)-CO2-(alkyl);

R3 is -H or -(alkyl);

R4, R5, R6 and R7 are each independently -H, -Cl, -Br, -F, -I, -CN,

CF ₃ , -OCFs, -(alkyl), -(alkenyl), -(alkynyl), "(aryl), -NH ₂ , -NH-

(alkyl), -NH-(alkenyl), -NH-(alkynyl) -NH-(aryl), -NH-(heteroaryl), - OH, -OAc, -O-C(O)(alkyl), -O-(alkyl), -O-(alkylaryl), -O-(alkenyl),

-O-(alkynyl), -O-(aryl), -O-(heteroaryl), -S-(alkyl), -S-(alkenyl),

-S-(alkynyl), -S-(aryl), -S-(heteroaryl), -S(O)-(alkyl), -S(O)-

(aryl), -S(0)-(heteroaryl), -SO2-(alkyl), -SO2-(aryl), or -SO2-

(heteroaryl);

R8, R9, R10 and R11are each independently -H, -Cl, -Br, -F, -I, -CN,

CF3, -OCF3, -(alkyl), -(aryl), -(heteroaryl) -(alkenyl), -(alkynyl),

-NH ₂ , -NH-(alkyl), -NH-(alkenyl), -NH-(alkynyl) -NH-(aryl), -NH-

(heteroaryl), -OH, -OAc, -O-C(O)(alkyl), -O-(alkyl), -O-(alkenyl), - O-(alkynyl), -O-(aryl), -O-(heteroaryl), -S-(alkyl), -S-(alkenyl), -

S-(alkynyl), -S-(aryl), -S-(heteroaryl), -S(O)-(alkyl), -S(O)-(aryl),

-S(O)-(heteroaryl), -SO2-(alkyl), -SO2-(aryl), or -SO2-(heteroaryl); wherein when R2 is -(C3-6 alkyl)-CO2H, then one of R5 or R6 is

(alkynyl) or -S-(alkyl), or Rs and Re are each independently -

Cl, -Br, -F, or -I, wherein when R2 is -(C3-6 alkyl)-CO2-(alkyl), then one of R5 or R6 is -(alkynyl), or R5 and Re are each independently -Cl, -Br, -F, or -I,

or a pharmaceutically acceptable salt or ester thereof, thereby treating or preventing the neurological disorder.

It should also be appreciated that compound s as defined herein, or coirpositions as defined herein can be used for the manufacture of a medicament for treating aa subject afflicted with aa neurological disorder, wherein the neurological disorder is selected from the group consisting of Huntington's disease; Rett syndrome; a Rett syndrome variant; Angelman syndrome; Prader-Willi syndrome; neonatal onset encephalopathy; X-linked recessive mental retardation; fetal alcohol spectrum disorder; Hirschsprung disease; CDKL5 disorder; West syndrome; FOXG1 syndrome; and Lennox-Gastaut syndrome.

The foregoing brief summary broadly describes certain features and technical advantages. Further features and technical advantages will be described in the detailed description and examples that follow.

Other features and advantages will be better understood from the detailed description read in connection with the accompanying figures and examples. However, the figures and examples provided herein are intended to help illustrate the invention or assist with developing an understanding of the invention, and are not intended to limit the invention’s scope.

Brief Description of the Figures

Fig. 1: Coirpound 9c activates DOR to a lesser E _max than the control agonist DPDPE. Fig. 2: Dose-response curves of analgesic activity of tianeptine, 9b and 9k in the hot plate assay.

Detailed Description of the Invention

The following description sets forth numerous exemplary configurations, parameters, and the like. It should be recognized, however, that such description is not intended as a limitation on the scope of the present disclosure, but is instead provided as a description of exemplary embodiments.

In each instance herein, in descriptions, embodiments, and examples of the present disclosure, the terms "coirprising", "including", etc., are to be read expansively, without limitation. Thus, unless the context clearly requires otherwise, throughout the description and the claims, the words "comprise", "coirprising", and the like are to be construed in an inclusive sense as to opposed to an exclusive sense, that is to say in the sense of "including but not limited to".

The term "consisting essentially of", as used herein, may refer to the presence of a component in a composition. For example, a concentrate may be at least 80% by weight of the composition, or at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.8%, or at least 99.9% by weight of the coirposition (% w/w). For liquids, a concentrate may be at least 80% by volume of the coirposition volume, or at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least

99.8%, or at least 99.9% by volume of the composition volume (% v/v).

In the present description, the articles "a" and "an" are used to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" can be taken to mean one element or more than one element. Throughout this description, tthhee term "approximately" is used to indicate that a value includes the standard deviation of error for the method being employed to determine the value, for example, dosage levels, as described in detail herein. In particular, the term

"approximately" encompasses a 10% to 15% deviation (positive and negative) in the stated value or range, particularly 10% deviation (positive and negative) in the stated value or range.

"Neurological disorder" refers to various conditions of the neurological system including neurodegenerative and neurodevelopmental conditions. Specifically included are Huntington's disease; Rett syndrome; Rett syndrome variants; Angelman syndrome; Prader-Willi syndrome; neonatal onset encephalopathy; X-linked recessive mental retardation; fetal alcohol spectrum disorder; Hirschsprung disease; CDKL5 disorder; West syndrome; FOXG1 syndrome; and Lennox-Gastaut syndrome.

"Symptoms" ooff aa neurological disorder rreeffeerr ttoo various physical effects exhibited in subjects. Physical symptoms can include one or more of: involuntary movements (e.g., chorea); abnormal muscle rigidity or contraction (e.g., dystonia); abnormal hand movements

(e.g., stereotypies); poor muscle tone (e.g., hypotonia), unusual eye movements; unusual facial expressions; tremors; impaired gait, posture, or balance; frequent falls; loss of balance; difficulty with swallowing; teeth grinding (e.g., bruxism); fatigue; and insomnia.

Cognitive symptoms are also noted, and may include oine or more of: difficulties with concentration or organization; communication difficulties; perseveration; lack of impulse control; lack of self- awareness; slowed thought processing; and learning difficulties. Serious symptoms are noted, including breathing problems; irregular heartbeat; and seizures.

"Treating" as used herein refers to reducing, ameliorating, or resolving a disorder, for example a neurological disorder, such as Huntington's disease, Rett syndrome, or CDKL5 disorder. A treatment is expected to result in the reduction, amelioration, or elimination of one or more symptoms of the disorder.

"Preventing" as used herein refers to stopping or delaying the onset of a disorder, for example aa neurological disorder, such as Huntington's disease, Rett syndrome, or CDKL5 disorder.A preventative measure is expected to result in the inhibition or delay in onset of one or more symptoms of the disorder, the lessening of symptoms if such do arise, and/or the inhibition or delay of the progression of the disorder.

It should be understood that the term "treating or preventing" does not exclude the possibility of obtaining both treatment and prevention (e.g., at the same time or at different times) of a disorder in any given subject.

Of particular interest in the present disclosure is the use of a compound of this disclosure in the treatment or prevention of one or more neurological disorders in aa subject. This includes neurodegenerative diseases and neurodevelopmental disorders, for example, Huntington's disease; Rett syndrome which includes Rett syndrome variants, such as tthhee RReetttt syndrome Rolando variant

(congenital variant), the Rett syndrome Zappella variant, the Rett syndrome Hanefeld variant (early epilepsy variant); Angelman syndrome; Prader-Willi syndrome; neonatal onset encephalopathy; X-linked recessive mental retardation (MRX); fetal alcohol spectrum disorder; Hirschsprung disease; CDKL5 disorder; West syndrome (infantile spasms,

ISSX); FOXG1 syndrome; and Lennox-Gastaut syndrome.

Notably, the Huntingtin gene product (Htt), is known to interact with the gene product associated with Rett syndrome (MeCP2). The MeCP2 gene product is also associated with Angelman syndrome, Prader-Willi syndrome, neonatal onset encephalopathy, X-linked recessive mental retardation, ffeettaall alcohol ssppeeccttrruumm disorder, and Hirschsprung disease. CDKL5 and FOXG1 mutations may be associated with Rett syndrome, and CDKL5 and FOXG1 mutations lead to symptoms that overlap with Rett syndrome symptoms. Accordingly, CDKL5 and FOXG1 disorders have been referred to as Rett syndrome related disorders.

The present disclosure provides a compound having the structure: wherein

R1 is -H or -(alkyl);

R2 is -(C3-C20 alkyl)-CO2H or -(C3-C20 alkyl)-CO2-(alkyl);

R3 is -H or -(alkyl);

R4, R5, R6 and R7 are each independently -H, -Cl, -Br, -F, -I,

CN, -CF3, -OCF3, -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -NH2,

-NH-(alkyl), -NH-(alkenyl), -NH-(alkynyl) -NH-(aryl), -NH-

(heteroaryl), -OH, -OAc, -O-C(O)(alkyl), -O-(alkyl), -O-

(alkylaryl), -O-(alkenyl), -O-(alkynyl), -O-(aryl), -O- (heteroaryl), -S-(alkyl), -S-(alkenyl), -S-(alkynyl), -S-

(aryl), -S-(heteroaryl), -S(O)-(alkyl), -S(O)-(aryl), -S(O)-

(heteroaryl), -SO2-(alkyl), -SO2-(aryl), or -SO2-(heteroaryl);

R8, R9, R10 and R11 are each independently -H, -Cl, -Br, -F, -I,

-CN -CF3, -OCF3, -(alkyl), -(aryl), -(heteroaryl) -(alkenyl),

-(alkynyl), -NH2, -NH-(alkyl), -NH-(alkenyl), -NH-(alkynyl) -NH-

(aryl), -NH-(heteroaryl), -OH, -OAc, -O-C(O)(alkyl), -O-(alkyl),

-O-(alkenyl), -O-(alkynyl), -O-(aryl), -O-(heteroaryl), -S-

(alkyl), -S-(alkenyl), -S-(alkynyl), -S-(aryl), -S-

(heteroaryl), -S(O)-(alkyl), -S(O)-(aryl), -S(O)-(heteroaryl),

-SO2-(alkyl), -SO2-(aryl), or -SO2-(heteroaryl); wherein when R2 is -(C3-6 alkyl)-CO2H, then one of R5 or R6is (alkynyl) or -S-(alkyl), or R5 and R6 are each independently - Cl, -Br, -F, or -I,

or a pharmaceutically acceptable salt or ester thereof, wherein the compound is for treating or preventing a neurological disorder in a subject, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein.

In some embodiments, a compound having the structure: wherein

R1 is -H or -(alkyl);

R2 is -(C6-C20 alkyl)-CO2H or -(C6-C20 alkyl)-CO2-(alkyl);

R3 is -H or -(alkyl);

R4, R5, R6 and R7 are each independently -H, -Cl, -Br, -F, -I,

CN, -CF ₃ , -OCF ₃ , -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -NH2, -NH-(alkyl), -NH-(alkenyl), -NH-(alkynyl) -NH-(aryl), -NH- (heteroaryl), -OH, -OAc, -O-C(O)(alkyl), -O-(alkyl), -O-

(alkylaryl), —O—(alkenyl), -O-(alkynyl), -O-(aryl), -O-

(heteroaryl), -S-(alkyl), -S-(alkenyl), -S-(alkynyl), -S-

or a pharmaceutically acceptable salt or ester thereof, wherein the compound is for treating or preventing a neurological disorder in a subject, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein.

In some embodiments, a compound having the structure:

wherein when Rz is -(C6 alkyl)-COzH, then one of R5 or R6is

(alkynyl) or -S-(alkyl), or R5 and R6 are each independently - Cl, -Br, -F, or -I, wherein when R2 is -(C6 alkyl)-COz-(alkyl), then one of R5 or R6 is -(alkynyl), or R5 and Re are each independently -Cl, -Br, -F, or -I, and wherein when R1 is -CH3, R3, R4, R6, R7, R8, R9, R10and R11are each

-H, and Rs is Cl, then Rz is other than -(CH2)7CO2H or -(CH2)10CO2H, or a pharmaceutically acceptable salt or ester thereof, wherein the compound is for treating or preventing a neurological disorder in a subject, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein.

In some embodiments, the compound wherein

R2 is -(C6 alkyl)-CO2H); and one of R5 or R6is -(alkynyl) or -S-(alkyl) and the other is -H, or R5 and Re are each independently -Cl, -Br, -F, or -I.

In some embodiments, the compound wherein

R2 is -(C6 alkyl)-CO2-(alkyl); and one of R5 or R6is -(alkynyl) and the other is -H, or Rs and Re are each independently -Cl, -Br, -F, or -I.

In some embodiments, the compound having the structure: wherein

R1 is -H or -(alkyl);

R2 is -(C7-C20 alkyl)-CO2H or -(C7-C20 alkyl)-CO2-(alkyl);

R3 is -H or -(alkyl);

R4, R5, R6 and R7 areeach independently -H, -Cl, -Br, -F, -I,

CN, -CF3, -OCF3, -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -NH2,

-NH-(alkyl), -NH-(alkenyl), -NH-(alkynyl) -NH-(aryl), -NH-

(heteroaryl), -OH, -OAc, -O-C(O)(alkyl), -O-(alkyl), -O-

(alkylaryl), -O-(alkenyl), -O-(alkynyl), -O-(aryl), -O-

(heteroaryl), -S-(alkyl), -S-(alkenyl), -S-(alkynyl), -S-

(aryl), -S-(heteroaryl), --SS((OO))--((aallkkyyll)),, -S(O)-(aryl), -S(O)- (heteroaryl), -SO2-(alkyl), -SO2-(aryl), or -SO2-(heteroaryl);

R8, R9, R10 and R11 are each independently -H, -Cl, -Br, -F, -I,

-CN, -CF3, -OCF3, -(alkyl), -(aryl), -(heteroaryl) -(alkenyl),

-(alkynyl), -NH2, -NH-(alkyl), -NH-(alkenyl), -NH-(alkynyl) -NH-

(aryl), -NH-(heteroaryl), -OH, -OAc, -O-C(O)(alkyl), -O-(alkyl),

or a pharmaceutically acceptable salt or ester thereof, wherein the compound is for treating or preventing a neurological disorder in a subject, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and

CDKL5 disorder, and the other neurological disorders as described herein.

In some embodiments, the compound wherein

R2 is -(C8-C20 alkyl)-CO2H or -(C8-C20 alkyl)-CO2-(alkyl).

In some embodiments, the compound wherein

R2 is -(C9-C20 alkyl)-CO2H or -(C9-C20 alkyl)-CO2-(alkyl).

In some embodiments, the compound wherein

R2 is -(C ₈ -C ₂ o alkyl)-CO2H or -(C ₈ -C ₂₀ alkyl)-CO2CH3.

In some embodiments, the compound wherein

R2 is -(C9-C20 alkyl)-CO2H or -(C9-C20 alkyl)-CO ₂ CH ₂ CH ₃ .

In some embodiments, the compound wherein

Rs is -Br, -F, -I, -CN, -CF ₃ , -OCF3, -(alkyl), -(alkenyl),

(alkynyl), -(aryl), -NH ₂ , -NH-(alkyl), -NH-(alkenyl), -NH-

(alkynyl) -NH-(aryl), -NH-(heteroaryl), -OH, -OAc, -O-

C(O)(alkyl), -O-(alkyl), -O-(alkylaryl), -O-(alkenyl), -O-

(alkynyl), -O-(aryl), -O-(heteroaryl), -S-(alkyl), -S-

(alkenyl), —S—(alkynyl), -S-(aryl), —S—(heteroaryl), -S(O)- (alkyl), -S(O)-(aryl), -S(O)-(heteroaryl), -S02-(alkyl), -SO2-

(aryl), or -SO2-(heteroaryl).

In some embodiments, the compound wherein

Rs is -Br, -I, -(alkenyl), -(alkynyl) or -S-(alkyl).

In some embodiments, the compound wherein

R5 is -Br, -I, -(C2 alkenyl), -(C2 alkynyl) or -S-CH3.

In some embodiments, the compound wherein one of R5 or R6is -(alkynyl).

In some embodiments, the compound wherein one of R5 or R6is -S-(alkyl).

In some embodiments, the compound wherein R5 and R6 are each independently -Cl, -Br, -F, or -I.

In some embodiments, the compound wherein R5 and R6 are each independently -Br, -F, or -I.

In some embodiments, the compound wherein R5 and R6 are each independently -Br, -Cl, or -I.

In some embodiments, the compound wherein R5 and R6 are each independently -Br or -I.

In some embodiments, the compound having the structure

or a pharmaceutically acceptable salt or ester thereof, wherein the compound is for treating or preventing a neurological disorder in a subject, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein.

In seme embodiments, the compound having the structure

wherein

R1 is -H or -(alkyl);

R2 is -(C7-C20 alkyl)-CO2H or -(C7-C20 alkyl)-CO2-(alkyl);

R3 is -H or -(alkyl);

R4 and R7are each independently -H, -Cl, -Br, -F, -I, -CN, -CF ₃ ,

-OCF ₃ , -(alkyl), -(alkenyl), -(alkynyl), "(aryl), -NH ₂ , -NH-

(alkyl), -NH-(alkenyl), -NH-(alkynyl) -NH-(aryl), -NH-

(heteroaryl), -OH, -OAc, -O-C(O)(alkyl), -O-(alkyl), -O-

(alkylaryl), -O-(alkenyl), -O-(alkynyl), -O-(aryl), -O-

(heteroaryl), -S-(alkyl), -S-(alkenyl), -S-(alkynyl), -S-

(aryl), -S-(heteroaryl), -S(O)-(alkyl), -S(O)-(aryl), -S(O)-

(heteroaryl), -SO2-(alkyl), -SO2-(aryl), or -SO2-(heteroaryl);

R8, R9, R10 and R11 are each independently -H, -Cl, -Br, -F, -I,

-CN, -CF3, -OCF3, -(alkyl), -(aryl), -(heteroaryl) -(alkenyl),

-(alkynyl), -NH2, -NH-(alkyl), -NH-(alkenyl), -NH-(alkynyl) -NH- (aryl), -NH-(heteroaryl), -OH, -OAc, -O-C(O)(alkyl), -O-(alkyl), -0-(alkenyl), -O-(alkynyl), -O-(aryl), -O-(heteroaryl), -S-

(alkyl), —S—(alkenyl), —S—(alkynyl), -S-(aryl), -S-

(heteroaryl), -S(O)-(alkyl), -S(O)-(aryl), -S(O)-(heteroaryl),

-SO2-(alkyl), -SO2-(aryl), or -SO2-(heteroaryl), or a pharmaceutically acceptable salt or ester thereof, wherein the compound is for treating or preventing a neurological disorder in a subject, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein.

In some embodiments, the compound having the structure

wherein

R2 is -(C7-C20 alkyl)-CO2H or -(C7-C20 alkyl)-CO2-(alkyl), or a pharmaceutically acceptable salt or ester thereof, wherein the compound is for treating or preventing a neurological disorder in a subject, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein.

In some embodiments, the compound having the structure or a pharmaceutically acceptable salt or ester thereof, wherein the compound is for treating or preventing a neurological disorder in a subject, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein.

In some embodiments, the compound having the structure wherein

R2 is -(C9-C20 alkyl)-CO2H or -(C9-C20 alkyl)-CO2-(alkyl), or a pharmaceutically acceptable salt or ester thereof, wherein the compound is for treating or preventing a neurological disorder in a subject, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein.

In some embodiments, the compound having the structure wherein

R1 is -H or -(alkyl);

R2 is -(C7-C20 alkyl)-CO2H or -(C7-C20 alkyl)-CO2-(alkyl);

R3 is -H or -(alkyl); R5 is -Br, -I, -(alkenyl) -(alkynyl) or -S-(alkyl), and

R6 is -H, or R5 and R6 are each independently -Cl, -Br, "F, or -I; or a pharmaceutically acceptable salt or ester thereof, wherein the compound is for treating or preventing a neurological disorder in a subject, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders aass described herein.

In some embodiments, the compound having the structure or a pharmaceutically acceptable salt or ester thereof, wherein the compound is for treating or preventing a neurological disorder in a subject, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and,the other neurological disorders as described herein.

In some embodiments, the compound having the structure or an ester thereof, wherein the compound is for treating or preventing a neurological disorder in a subject, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and

CDKL5 disorder, and the other disorders as described herein.

In some embodiments, the compound having the structure: wherein

R1 is -H or -(alkyl);

R2 is -(C7-C20 alkyl)-CO2H or -(C7-C20 alkyl)-CO2-(alkyl);

R3 is -H or -(alkyl);

R4 and R7are each independently -H, -Cl, -Br, -F, -I, -CN, -CF ₃ ,

-OCF3, -(alkyl), --((aallkkeennyyll)),, -(alkynyl), -(aryl), -NH ₂ , -NH-

(alkyl), --NNHH--((aallkkeennyyll)),, -NH-(alkynyl) -NH-(aryl), -NH-

or a pharmaceutically acceptable salt or ester thereof, wherein the compound is for treating or preventing a neurological disorder in a subject, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein.

In some embodiments, the compound having the structure: wherein

R2 is -(C7-C20 alkyl)-CO2H or -(C7-20 alkyl)-CO2-(alkyl), or a pharmaceutically acceptable salt or ester thereof, wherein the compound is for treating or preventing a neurological disorder in a subject, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein.

In some embodiments, wherein R2 is -(C8-C20 alkyl)-CO2H or -(C8-C20 alkyl)-CO2-(alkyl), or a pharmaceutically acceptable salt or ester thereof.

In some embodiments, wherein R2 is -(C9-C20 alkyl)-CO2H or -(C9-C20 alkyl)-CO2-(alkyl), or a pharmaceutically acceptable salt or ester thereof.

In some embodiments, the compound having the structure: wherein

R1 is -H or -(alkyl);

R2 is -(C ₆ alkyl)-CO2H;

R3 is -H or -(alkyl);

R4, R5, R6 and R7 are each independently -H, -Cl, -Br, -F, -1,

CN, -CF3, -OCF3, -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -NH2,

-NH-(alkyl), -NH-(alkenyl), -NH-(alkynyl) -NH-(aryl), -NH-

(heteroaryl), -OH, -OAc, -O-C(O)(alkyl), -O-(alkyl), -O-

(alkylaryl), -O-(alkenyl), -O-(alkynyl), -O-(aryl), -O-

(heteroaryl), -S-(alkyl), —S—(alkenyl), —S—(alkynyl), -S-

(aryl), —S—(heteroaryl), -S(O)-(alkyl), -S(O)-(aryl), -S(O)-

(heteroaryl), -SO2-(alkyl), -SO2-(aryl), or -SO2-(heteroaryl);

R8, R9, R10 and R11 are each independently -H, -Cl, -Br, -F, -I,

-CN, -CF3, -OCF3, -(alkyl), -(aryl), -(heteroaryl) -(alkenyl),

-(alkynyl), -NH2, -NH-(alkyl), -NH-(alkenyl), -NH-(alkynyl) -NH-

(aryl), -NH-(heteroaryl), -OH, -OAc, -O-C(O)(alkyl), -O-(alkyl), wherein one of R5 or R6is -(alkynyl) or -S-(alkyl), or R5 and R6 are each independently -Cl, -Br, -F, or -I, wherein when R1 is -CH3, R3, R4, R6, R7, R8, R9, R10and R11are each

-H, and R5 is SCH3, then R2 is other than -(CH2)6C02H, or a pharmaceutically acceptable salt or ester thereof, wherein the compound is for treating or preventing a neurological disorder in a subject, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein.

In some embodiments, the compound having the structure: wherein

R1 is -H or -(alkyl);

R2 is -(C ₆ alkyl)-CO ₂ H;

R3 is -H or -(alkyl);

R4 and R7are each independently -H, -Cl, -Br, -F, -I, -CN, -CF ₃ ,

-OCF3, -(alkyl), -(alkenyl) -(alkynyl), -(aryl), -NH ₂ , -NH-

(alkyl), -NH-(alkenyl), -NH-(alkynyl) -NH-(aryl), -NH-

(heteroaryl), -OH, -OAc, -O-C(O)(alkyl), -O-(alkyl), -O-

(alkylaryl), -O-(alkenyl), -O-(alkynyl), -O-(aryl), -O-

(heteroaryl), -S-(alkyl), —S—(alkenyl), -S-(alkynyl), -S-

or a pharmaceutically acceptable salt or ester thereof, wherein the compound is for treating or preventing a neurological disorder in a subject, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders aass described herein.

In some embodiments, the compound having the structure: wherein

R1 is -H or -(alkyl);

R2 is -(C ₆ alkyl)-CO2H;

R3 is -H or -(alkyl);

R4, R6 and R7 are each independently -H, -Cl, -Br, -F, -I, -CN,

CF3, -OCF3, -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -NH2, -NH- (alkyl), --NNHH--((aallkkeennyyll)),, -NH-(alkynyl) -NH-(aryl), -NH-

(heteroaryl), -OH, -OAc, -O-C(O)(alkyl), -O-(alkyl), -O-

(alkylaryl), -O-(alkenyl), -O-(alkynyl), -O-(aryl), -O-

(heteroaryl), -S-(alkyl), -S-(alkenyl), -S-(alkynyl), -S- (aryl), -S-(heteroaryl), -S(0)-(alkyl), -S(O)-(aryl), -S(0)-

(heteroaryl), -SO2-(alkyl), -SO2-(aryl), or -SO2-(heteroaryl);

R8, R9, R10 and R11 are each independently -H, -Cl, -Br, -F, -I,

-CN, -CF ₃ , -OCF3, -(alkyl), -(aryl), -(heteroaryl) -(alkenyl), -(alkynyl), -NH2, -NH-(alkyl), -NH-(alkenyl), -NH-(alkynyl) -NH-

(aryl), -NH-(heteroaryl), -OH, -OAc, -O-C(O)(alkyl), -O-(alkyl),

-0-(alkenyl), -O-(alkynyl), -0-(aryl), -O-(heteroaryl), -S-

(alkyl), -S-(alkenyl), -S-(alkynyl), -S-(aryl), -S-

(heteroaryl), -S(O)-(alkyl), -S(O)-(aryl), -S(O)-(heteroaryl),

-SO2-(alkyl), -S02-(aryl), or -SO2-(heteroaryl), or a pharmaceutically acceptable salt or ester thereof, wherein the compound is for treating or preventing a neurological disorder in a subject, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein.

In some embodiments, the compound having the structure: wherein

R1 is -H or -(alkyl);

R2 is -(C ₆ alkyl)-CO ₂ H;

R3 is -H or -(alkyl);

R5 is -(alkynyl) or -S-(alkyl) and R6 is H, or

R5 and Re are each independently -Cl, -Br, -F, or -I, or a pharmaceutically acceptable salt or ester thereof, wherein the compound is for treating or preventing a neurological disorder in a subject, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 ddiissoorrddeerr, and the other neurological disorders aass described herein.

In some embodiments, the compound having the structure: wherein

Rz is -(C ₆ alkyl)-CO ₂ H. or a pharmaceutically acceptable salt or ester thereof, wherein the compound is for treating or preventing a neurological disorder in a subject, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders aass described herein.

In some embodiments, the compound having the structure: or a pharmaceutically acceptable salt or ester thereof, wherein the compound is for treating or preventing a neurological disorder in a subject, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein.

In some embodiments, the compound having the structure: or an ester thereof, wherein the compound is for treating or preventing a neurological disorder in a subject, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, aanndd tthhee ootthheerr nneeuurroollooggiiccaall ddiissoorrddeerrss as described herein.

In some embodiments, the compound having the structure wherein

R1 is -H or -(alkyl);

R2 is -(C ₆ alkyl)-CO2H;

R3 is -H or -(alkyl);

R4 and R5are each independently -H, -Cl, -Br, -F, -I, -CN, -CF ₃ ,

-OCF ₃ , -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -NH ₂ , -NH-

(alkyl), -NH-(alkenyl), -NH-(alkynyl) -NH-(aryl), -NH-

(heteroaryl), -OH, -OAc, -O-C(O)(alkyl), -O-(alkyl), -O-

or a pharmaceutically acceptable salt or ester thereof, wherein the compound is for treating or preventing a neurological disorder in a subject, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein.

In some embodiments, the compound having the structure: or a pharmaceutically acceptable salt or ester thereof, wherein the compound is for treating or preventing a neurological disorder in a subject, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein. In some embodiments, the compound having the structure: or an ester thereof, wherein the compound is for treating or preventing a neurological disorder in a subject, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders aass described herein.

In some embodiments, the compound having the structure: or an ester thereof, wherein the compound is for treating or preventing a neurological disorder in a subject, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein.

In some embodiments, the compound having the structure:

wherein

R1 is -H or -(alkyl);

R2 is -(C6 alkyl)-CO2-(alkyl);

R3 is -H or -(alkyl);

R4, R5, R6 and R7 are each independently -H, -ci, -Br, "F, -I,

CN, -CF3, -OCF3, -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -NHz, -NH-(alkyl), -NH-(alkenyl), -NH-(alkynyl) -NH-(aryl), -NH-

(heteroaryl), -OH, -OAc, -O-C(O)(alkyl), -O-(alkyl), -0-

(alkylaryl), -O-(alkenyl), -O-(alkynyl), -O-(aryl), -O-

(heteroaryl), -S-(alkyl), -S-(alkenyl), -S-(alkynyl), -S-

(aryl), -S-(heteroaryl), -S(O)-(alkyl), -S(O)-(aryl), -S(O)-

(heteroaryl), -SO2-(alkyl), -SO2-(aryl), or -SO2-(heteroaryl);

R8, R9, R10 and R11are each independently -H, -Cl, -Br, -F, -I,

-CN, -CF3, -OCF3, -(alkyl), -(aryl), -(heteroaryl) -(alkenyl),

-(alkynyl), -NH2, -NH-(alkyl), -NH-(alkenyl), -NH-(alkynyl) -NH-

(aryl), -NH-(heteroaryl), -OH, -OAc, -O-C(O)(alkyl), -O-(alkyl),

-0-(alkenyl), -O-(alkynyl), —O—(aryl), -O-(heteroaryl), -S- (alkyl), -S-(alkenyl), -S-(alkynyl), -S-(aryl), -S-

(heteroaryl), -S(O)-(alkyl), -S(O)-(aryl), —S(O)-(heteroaryl),

-SO2-(alkyl), -SO2-(aryl), or -SO2-(heteroaryl); wherein one of R5 or R6is -(alkynyl) or -S-(alkyl), or Rs and Re are each independently -Cl, -Br, -F, or -I, and or a pharmaceutically acceptable salt or ester thereof, wherein the compound is for treating or preventing a neurological disorder in a subject, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein. In some embodiments, the compound having the structure: wherein

R1 is -H or -(alkyl);

R2 is -(C6 alkyl)-CO2-(alkyl);

R3 is -H or -(alkyl);

R4, R5, R6 and R7 are each independently -H, -ci, -Br, -F, -I,

CN, -CF3, -OCF3, -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -NH2,

-NH-(alkyl), -NH-(alkenyl), -NH-(alkynyl) -NH-(aryl), -NH-

(heteroaryl), -OH, -OAc, -O-C(O)(alkyl), -O-(alkyl), -O-

(alkylaryl), -O-(alkenyl), -O-(alkynyl), -O-(aryl), -O-

(heteroaryl), -S-(alkyl), -S-(alkenyl), -S-(alkynyl), -S- (aryl), -S-(heteroaryl), -S(O)-(alkyl), -S(O)-(aryl), -S(O)-

(heteroaryl), -SO2-(alkyl), -SO2-(aryl), or -SO2-(heteroaryl);

R8, R9, R10 and R11 are each independently -H, -Cl, -Br, -F, -I,

-CN, -CF3, -OCF3, -(alkyl), -(aryl), -(heteroaryl) -(alkenyl),

-(alkynyl), -NH2, -NH-(alkyl), -NH-(alkenyl), -NH-(alkynyl) -NH-

(aryl), -NH-(heteroaryl), -OH, -OAc, -O-C(O)(alkyl), -O-(alkyl),

-O-(alkenyl), -O-(alkynyl), -O-(aryl), -O-(heteroaryl), -S- (alkyl), -S-(alkenyl), -S-(alkynyl), -S-(aryl), -S-

(heteroaryl), -S(O)-(alkyl), -S(O)-(aryl), -S(O)-(heteroaryl),

-SO2-(alkyl), -SO2~(aryl), or -SO2-(heteroaryl); wherein one of R5 or R6 is -(alkynyl), or R5 and R6 are each independently -Cl, -Br, -F, or -I, and or a pharmaceutically acceptable salt or ester thereof, wherein the compound is for treating or preventing a neurological disorder in a subject, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein.

In some embodiments, the compound having the structure: wherein

R1 is -H or -(alkyl);

R2 is -(C6 alkyl)-CO2-(alkyl);

R3 is -H or -(alkyl);

R4 and R7are each independently -H, -Cl, -Br, -F, -I, -CN, -CF ₃ ,

-OCF ₃ , -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -NH ₂ , -NH-

(alkyl), -NH-(alkenyl), -NH-(alkynyl) -NH-(aryl), -NH-

(heteroaryl), -OH, -OAc, -O-C(O)(alkyl), -O-(alkyl), -O-

(alkylaryl), -O-(alkenyl), -O-(alkynyl), -O-(aryl), -O-

(heteroaryl), -S-(alkyl), -S-(alkenyl), -S-(alkynyl), -S-

(aryl), -S-(heteroaryl), -S(O)-(alkyl), -S(O)-(aryl), -S(O)-

(heteroaryl), -SO2-(alkyl), -SO2-(aryl), or -SO2-(heteroaryl);

R8, R9, R10 and R11 are each independently -H, -Cl, -Br, -F, -I,

-CN, -CF3, -OCF3, -(alkyl), -(aryl), -(heteroaryl) -(alkenyl),

-(alkynyl), -NH2, -NH-(alkyl), -NH-(alkenyl), -NH-(alkynyl) -NH- (aryl), -NH-(heteroaryl), -OH, -OAc, -O-C(O)(alkyl), -O-(alkyl),

-0-(alkenyl), —O—(alkynyl), -O-(aryl), —O—(heteroaryl), -S-

(alkyl), -S-(alkenyl), -S-(alkynyl), -S-(aryl), -S-

(heteroaryl), -S(O)-(alkyl), -S(O)-(aryl), -S(O)-(heteroaryl),

-SO2-(alkyl), -SO2-(aryl), or -SO2-(heteroaryl), or a pharmaceutically acceptable salt or ester thereof, wherein the compound is for treating or preventing a neurological disorder in a subject, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and

CDKL5 disorder, and the other neurological disorders aass described herein.

In some embodiments, the compound having the structure: wherein

R1 is -H or -(alkyl);

R2 is -(C6 alkyl)-CO2-(alkyl);

R3 is -H or -(alkyl);

R4, R5 and R6are each independently -H, -Cl, -Br, -F, -I, -CN,

CF3, -OCFa, -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -NH2, -NH- (alkyl), --NNHH--((aallkkeennyyll)),, -NH-(alkynyl) -NH-(aryl), -NH-

(heteroaryl), -OH, -OAc, -O-C(O)(alkyl), -O-(alkyl), -O-

(alkylaryl), -O-(alkenyl), -O-(alkynyl), -O-(aryl), -O-

(heteroaryl), -S-(alkyl), -S-(alkenyl), -S-(alkynyl), -S-

(aryl), -S-(heteroaryl), -S(O)-(alkyl), -S(O)-(aryl), -S(O)-

(heteroaryl), -SO2-(alkyl), -SO2-(aryl), or -SO2-(heteroaryl);

R8, R9, R10 and R11 are each independently -H, -ci, -Br, -F, -I,

-CN, -CFa, -OCFa, -(alkyl), -(aryl), -(heteroaryl) -(alkenyl),

-(alkynyl), -NH2, -NH-(alkyl), -NH-(alkenyl), -NH-(alkynyl) -NH- (aryl), -NH-(heteroaryl), -OH, -OAc, -O-C(O)(alkyl), -O-(alkyl),

-0-(alkenyl), -O-(alkynyl), -O-(aryl), -O-(heteroaryl), -S-

(alkyl), -S-(alkenyl), -S-(alkynyl), -S-(aryl), —S—

(heteroaryl), -S(O)-(alkyl), -S(O)-(aryl), -S(O)-(heteroaryl), -SO2-(alkyl), -SO2-(aryl), or -SO2-(heteroaryl), or a pharmaceutically acceptable salt or ester thereof, wherein the compound is for treating or preventing a neurological disorder in a subject, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein.

In some embodiments, the compound having the structure: wherein

R1 is -H or -(alkyl);

R2 is -(C6 alkyl)-CO2-(alkyl);

R3 is -H or -(alkyl);

R5 is -(alkynyl) and R6 is H, or

R5 and R6 are each independently -Cl, -Br, -F, or -I, or a pharmaceutically acceptable salt or ester thereof, wherein the compound is for treating or preventing a neurological disorder in a subject, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein.

In some embodiments, the compound having the structure: wherein

R2 is -(C6 alkyl)-CO2-(alkyl). or a pharmaceutically acceptable salt or ester thereof, wherein the compound is for treating or preventing a neurological disorder in a subject, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders aass described herein.

In some embodiments, the compound having the structure: wherein

R ₂ is -(C ₆ alkyl)-CO ₂ CH ₂ CH ₃ . or a pharmaceutically acceptable salt or ester thereof, wherein the compound is for treating or preventing a neurological disorder in a subject, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders aass described herein.

In some embodiments, the compound having the structure: wherein

R ₂ is -(C ₆ alkyl)-CO ₂ CH ₃ .

In some embodiments, the compound having the structure:

or a pharmaceutically acceptable salt or ester thereof, wherein the compound is for treating or preventing a neurological disorder in a subject, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and

CDKL5 disorder, and the other neurological disorders aass described herein.

In some embodiments, the compound having the structure: wherein

R1 is -H or -(alkyl);

R ₂ is -(C6 alkyl)-CO2-(alkyl);

R3 is -H or -(alkyl); R5 and R6are each independently -H, -Cl, -Br, -F, -I, -CN, -CF ₃ ,

-OCF3, -(alkyl), -(alkenyl), -(alkynyl), "(aryl), -NH ₂ , -NH-

(alkyl), -NH-(alkenyl), -NH-(alkynyl) -NH-(aryl), -NH- (heteroaryl), -OH, -OAc, -O-C(O)(alkyl), -O-(alkyl), -O-

(alkylaryl), —O—(alkenyl), -O-(alkynyl), -O-(aryl), -O-

(heteroaryl), -S-(alkyl), -S-(alkenyl), -S-(alkynyl), -S-

(aryl), -S-(heteroaryl), -S(O)-(alkyl), -S(O)-(aryl), -S(O)-

(heteroaryl), -SO ₂ -(alkyl), -SO ₂ -(aryl), or -SO ₂ -(heteroaryl);

R8, R9, R10 and R11 are each independently -H, -Cl, -Br, -F, -I,

-CN, -CF3, -OCF3, -(alkyl), -(aryl), -(heteroaryl) -(alkenyl), -(alkynyl), -NH ₂ , -NH-(alkyl), -NH-(alkenyl), -NH-(alkynyl) -NH-

(aryl), -NH-(heteroaryl), -OH, -OAc, -O-C(O)(alkyl), -O-(alkyl),

-0-(alkenyl), -O-(alkynyl), -O-(aryl), -O-(heteroaryl), —S—

(alkyl), -S-(alkenyl), -S-(alkynyl), -S-(aryl), -S- (heteroaryl), -S(O)-(alkyl), -S(O)-(aryl), -S(O)-(heteroaryl),

-SO ₂ -(alkyl), -SO ₂ -(aryl), or -SO ₂ -(heteroaryl), or a pharmaceutically acceptable salt or ester thereof, wherein the compound is for treating or preventing a neurological disorder in a subject, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 ddiissoorrddeerr,, and the other neurological disorders as described herein.

In some embodiments, the compound having the structure: wherein

R ₂ is -(C ₆ alkyl)-CO ₂ CH ₃ , or a pharmaceutically acceptable salt or ester thereof, wherein the compound is for treating or preventing a neurological disorder in a subject, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein.

In some embodiments, the compound having the structure:

or a pharmaceutically acceptable salt thereof, wherein the compound is for treating or preventing a neurological disorder in a subject, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein.

In some embodiments, the compound having the structure: wherein

R1 is -H or -(alkyl);

R2 is -(C3-5 alkyl)-CO2H or -(C3-5 alkyl)-CO2(alkyl);

R3 is -H or -(alkyl);

R4, R5, R6 and R7 are each independently -H, -Cl, -Br, -F, -I,

CN, -CF3, -OCF3, -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -NH2,

-NH-(alkyl), -NH-(alkenyl), -NH-(alkynyl) -NH-(aryl), -NH-

(heteroaryl), -OH, -OAc, -O-C(O)(alkyl), -O-(alkyl), -O- (alkylaryl), —O—(alkenyl), —O—(alkynyl), -O-(aryl), -O-

(heteroaryl), -S-(alkyl), —S—(alkenyl), —S—(alkynyl), -S- (aryl), -S-(heteroaryl), -S(O)-(alkyl), -S(O)-(aryl), -S(O)-

(heteroaryl), -SO2-(alkyl), -SO2-(aryl), or -SO2-(heteroaryl); R8, R9, R10 and R11 are each independently -H, -Cl, -Br, -F, -I,

-CN, -CF3, -OCF3, -(alkyl), -(aryl), -(heteroaryl) -(alkenyl), -(alkynyl), -NH2, -NH-(alkyl), -NH-(alkenyl), -NH-(alkynyl) -NH-

(aryl), -NH-(heteroaryl), -OH, -OAc, -O-C(O)(alkyl), -O-(alkyl),

-0-(alkenyl), -O-(alkynyl), -O-(aryl), -O-(heteroaryl), -S-

(alkyl), —S—(alkenyl), -S-(alkynyl), -S-(aryl), -S-

(heteroaryl), -S(O)-(alkyl), -S(O)-(aryl), —S(O)-(heteroaryl),

-SO2-(alkyl), -S02-(aryl), or -SO2-(heteroaryl); wherein R5 and R6 are each independently -Cl, -Br, -F, or -I, or a pharmaceutically acceptable salt or ester thereof, wherein the compound is for treating or preventing a neurological disorder in a subject, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein.

In some embodiments, the compound having the structure: wherein

R1 is -H or -(alkyl);

R2 is -(C3-5 alkyl)-CO2H or -(C3-5 alkyl)-CO2(alkyl);

R3 is -H or -(alkyl); R5 and R7 are each independently -H, -Cl, -Br, -F, -I, -CN, -CF ₃ ,

-OCF3, -(alkyl), -(alkenyl), -(alkynyl), "(aryl), -NH ₂ , -NH-

(alkyl), -NH-(alkenyl), -NH-(alkynyl) -NH-(aryl), -NH-

(heteroaryl), -OH, -OAc, -O-C(O)(alkyl), -O-(alkyl), -O-

(alkylaryl), -O-(alkenyl), -O-(alkynyl), -O-(aryl), -O-

(heteroaryl), -S-(alkyl), -S-(alkenyl), -S-(alkynyl), -S-

(aryl), -S-(heteroaryl), -S(O)-(alkyl), -S(O)-(aryl), -S(O)-

(heteroaryl), -SO2-(alkyl), -SO2-(aryl), or -SO2-(heteroaryl); R8, R9, R10 and R11 are each independently -H, -Cl, -Br, -F, -I,

-CN, -CF3, -OCF3, -(alkyl), -(aryl), -(heteroaryl) -(alkenyl), -(alkynyl), -NH2, -NH-(alkyl), -NH-(alkenyl), -NH-(alkynyl) -NH-

(aryl), -NH-(heteroaryl), -OH, -OAc, -O-C(O)(alkyl), -O-(alkyl),

-0-(alkenyl), -O-(alkynyl), -O-(aryl), -O-(heteroaryl), -S-

(alkyl), -S-(alkenyl), -S-(alkynyl), -S-(aryl), -S-

(heteroaryl), -S(O)-(alkyl), -S(O)-(aryl), -S(O)-(heteroaryl),

-SO2-(alkyl), -SO2~(aryl), or -SO2-(heteroaryl), or a pharmaceutically acceptable salt or ester thereof, wherein the compound is for treating or preventing a neurological disorder in a subject, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein.

In some embodiments, the compound having the structure: wherein

R1 is -H or -(alkyl);

R2 is -(C3-5 alkyl)-CO2H or -(C3-5 alkyl)-CO2(alkyl);

R3 is -H or -(alkyl); and

R5 and R6 are each independently -Cl, -Br, -F, or -I, or a pharmaceutically acceptable salt or ester thereof, wherein the compound is for treating or preventing a neurological disorder in a subject, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein.

In some embodiments, wherein R2 is -(C4 alkyl)-CO2H, or -(C4alkyl)- CO2CH3 or -(C4alkyl)-CO2CH2CH3, or a pharmaceutically acceptable salt or ester thereof.

In some embodiments, the compound having the structure: or an ester thereof, wherein the compound is for treating or preventing a neurological disorder in a subject, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein.

In some embodiments, the compound having the structure: or a pharmaceutically acceptable salt or ester thereof, wherein the compound is for treating or preventing a neurological disorder in a subject, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein.

In some embodiments, the compound having the structure: or a pharmaceutically acceptable salt thereof, wherein the compound is for treating or preventing a neurological disorder in a subject, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 ddiissoorrddeerr,, and the other neurological disorders aass described herein.

The present ddiisscclloossuurree provides a pharmaceutical coirposition comprising oonnee oorr mmoorree compounds of this disclosure and a pharmaceutically acceptable carrier.

In some embodiments, a pharmaceutical composition comprising one or more compounds of the present disclosure, an NMDA receptor antagonist, an NMDA receptor partial agonist, a neurokinin 1 receptor antagonist, a neurokinin 2 receptor antagonist, aa neurokinin 3 receptor antagonist, aa DOR agonist, naloxone oorr methylnaltrexone, and a pharmaceutically acceptable carrier.

In some embodiments, a method of activating a mu-opioid receptor or delta-opioid receptor coirprising contacting the mu-opioid receptor or delta-opioid receptor with a compound of the present disclosure, thereby treating or preventing a neurological disorder in a subject, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein. In some embodiments, a method of treating a neurological disorder in a subject, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein coirprising administering an effective amount of a compound of the present disclosure to the subject so as to treat the disorder.

In some embodiments, a method of treating a neurological disorder, wherein the neurological disorder is Huntington's disease, coirprising administering aann effective aammoouunntt ooff aa compound of the present disclosure to the subject so as to treat the neurological disorder

In some embodiments, a method of treating a neurological disorder, wherein the neurological disorder is Rett syndrome, comprising administering an eeffffeeccttiivvee aammoouunntt of aa compound of the present disclosure to the subject so as to treat the neurological disorder.

In some embodiments, a method of treating a subject afflicted with a neurological disorder, wherein the neurological disorder is CDKL5 disorder, comprising administering an effective amount of a compound of the present disclosure ttoo the subject so aass to ttrreeaatt the neurological disorder.

In some embodiments, a method of treating a neurological disorder in a subject, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein coirprising administering to the subject an effective amount of an NMDA receptor antagonist, an NMDA receptor partial agonist, a neurokinin 1 receptor antagonist, a neurokinin 2 receptor antagonist, a neurokinin 3 receptor antagonist or a DOR agonist and an effective amount of a compound of the present disclosure ssoo aass to thereby treat the neurological disorder. In some embodiments, a method of treating a neurological disorder in a subject, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein comprising administering to the subject an effective amount of an NMDA receptor antagonist, an NMDA receptor partial agonist, a neurokinin 1 receptor antagonist, or a DOR agonist and an effective amount of a compound of the present disclosure so aass ttoo thereby treat the neurological disorder.

In some embodiments, a method of treating a neurological disorder in a subject, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein coirprising administering to the subject an effective amount of an NMDA receptor antagonist, an NMDA receptor partial agonist or a neurokinin 1 receptor antagonist and an effective amount of a compound of the present disclosure so as to thereby treat the neurological disorder.

In some embodiments, a method of treating a neurological disorder in a subject, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein comprising administering to the subject aann effective amount of naloxone or methylnaltrexone and an effective amount of a compound of the present disclosure ssoo aass to thereby treat the neurological disorder.

In some embodiments, a method of treating a neurological disorder in a subject, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein comprising administering to the subject an effective amount of naloxone or methylnaltrexone and an effective amount of a compound of the present disclosure ssoo as to thereby treat the neurological disorder. In some embodiments, a pharmaceutical composition comprising one or more compounds of the present disclosure, aa selective serotonin reuptake inhibitor or a serotonin-norepinephrine reuptake inhibitor, and a pharmaceutically acceptable carrier.

In some embodiments, a method of treating a neurological disorder in a subject, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein comprising administering to the subject an effective amount of a selective serotonin reuptake inhibitor or a serotonin-norepinephrine reuptake inhibitor and an effective amount of a compound of the present disclosure so as to thereby treat the neurological disorder.

In some embodiments, a method of activating a mu-opioid receptor comprising contacting the mu-opioid receptor with a compound of the present disclosure, thereby treating or preventing a neurological disorder in a subject, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein.

In some embodiments, a method of activating a delta-opioid receptor coirprising contacting the delta-opioid receptor with a compound of the present disclosure, thereby treating or preventing a neurological disorder in a subject, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein.

In some embodiments, a method of activating a mu-opioid receptor and delta-opioid receptor comprising contacting the mu-opioid receptor and delta-opioid receptor with a compound of the present disclosure, thereby treating or preventing a neurological disorder in a subject, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein.

In some embodiments, a method of treating a neurological disorder in a subject, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein comprising administering an effective amount of a compound of the present disclosure to the subject so as to treat the neurological disorder.

In some embodiments, a method of treating a neurological disorder in a subject, wherein the neurological disorder is Huntington's disease, Rett syndrome, or CDKL5 disorder comprising administering an effective amount of a compound of the present disorder to the subject so as to treat the neurological disorder.

In some embodiments, a method of treating a neurological disorder in a subject, wherein the neurological disorder is Huntington's disease, comprising administering an effective amount of a compound of the present disclosure to the subject so as to treat the neurological disorder.

In some embodiments, a method of treating a neurological disorder in a subject, wherein the neurological disorder is Rett syndrome coirprising administering an effective amount of a compound of the present disclosure to the subject so as to treat the neurological disorder.

In some embodiments, a method of treating a neurological disorder in a subject, wherein the neurological disorder is CDKL5 disorder coirprising administering an effective amount ooff a compound of the present disclosure to the subject so as to treat the neurological disorder. In some embodiments, a method of treating a neurological disorder in a subject, wherein tthhee neurological disorder is aa Rett syndrome variant coirprising administering an effective amount of a compound of the present disclosure to the subject so as to treat the neurological disorder.

In some embodiments, a method of treating a neurological disorder in a subject, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein coirprising administering to the subject an effective amount of an NMDA receptor antagonist, an NMDA receptor partial agonist, a neurokinin 1 receptor antagonist or a DOR agonist and an effective amount of a compound of the present disclosure so as to thereby treat the neurological disorder.

In some embodiments, a method of treating a neurological disorder in a subject, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein coirprising administering to the subject an effective amount of an NMDA receptor antagonist, an NMDA receptor partial agonist, a neurokinin 1 receptor antagonist, a neurokinin 2 receptor antagonist, a neurokinin 3 receptor antagonist or a DOR agonist and an effective amount of a compound of the present disclosure ssoo aass to thereby treat the neurological disorder.

In some embodiments, a method of treating a neurological disorder in a subject, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders aass described herein comprising administering to the subject an effective amount of an NMDA receptor antagonist, an NMDA receptor partial agonist, a neurokinin 1 receptor antagonist, a neurokinin 2 receptor antagonist, a neurokinin 3 receptor antagonist or a DOR agonist and an effective amount of a compound of the present disclosure so as to thereby treat the neurological disorder. In some embodiments, a method of treating a neurological disorder in a subject, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein comprising administering to the subject an effective amount of an NMDA receptor antagonist, an NMDA receptor partial agonist, a neurokinin 1 receptor antagonist, or a DOR agonist and an effective amount of a compound of the present disclosure or a salt or ester thereof, so as to thereby treat the neurological disorder.

In some embodiments, a method of treating a neurological disorder in a subject, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein comprising administering to the subject an effective amount of an NMDA receptor antagonist, an NMDA receptor partial agonist, a neurokinin 1 receptor antagonist or a DOR agonist and an effective amount of a compound of the present disclosure or a salt or ester thereof, so as to thereby treat the neurological disorder.

In some embodiments, a method of treating a neurological disorder in a subject, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein coirprising administering to the subject an effective amount of an NMDA receptor antagonist, an NMDA receptor partial agonist or a neurokinin 1 receptor antagonist and an effective amount of a compound of the present disclosure or a salt or ester thereof, so as to thereby treat the neurological disorder.

In some embodiments, a method of treating a neurological disorder in a subject, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein comprising administering to the subject an effective amount of an NMDA receptor antagonist, an NMDA receptor partial agonist or a neurokinin 1 receptor antagonist and an effective amount of a compound of the present disclosure or a salt or ester thereof, so as to thereby treat the neurological disorder.

In some embodiments, a method of treating a subject afflicted with a neurological disorder in a subject, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein comprising administering to the subject an effective amount of naloxone or methylnaltrexone and an effective amount of a compound of the present disclosure or a salt or ester thereof, so as to thereby treat the neurological disorder

In some embodiments, a method of treating a neurological disorder in a subject, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders aass described herein comprising administering ttoo the subject an effective amount of naloxone or methylnaltrexone and an effective amount of a compound of the present disclosure or a salt or ester thereof, so as to thereby treat the neurological disorder.

In one embodiment of any of the compounds disclosed herein R2 is -(C7-

20 alkyl)-CO2H or any combination or range within the C7-20 alkyl. The C7-20 alkyl may be linear or branched.

In one embodiment of any of the compounds disclosed herein R2 is -(C7- 20alkyl)-CO2-(alkyl) or any combination or range within the C7-20alkyl. The C7-20 alkyl may be linear or branched.

In one embodiment of any of the compounds disclosed herein R2 is -(C7- 20 alkyl)-CO2H or any combination of any of -(C7 alkyl)-CO2H, -(C ₈ alkyl)-CO2H, -(C ₉ alkyl)-CO2H, -(C10alkyl)-CO ₂ H, -(C11alkyl)-CO ₂ H, -(C12 alkyl)-CO2H, —(C9alkyl)-CO2H, -(C13alkyl)-CO2H, -(C14alkyl)- CO ₂ H,

In one embodiment of any of the compound s disclosed herein, R5 is other than Cl, or other than SCH3.

The present disclosure provides a pharmaceutical coirposition comprising oonnee oorr mmoorree compound this disclosure and a pharmaceutically acceptable carrier.

The present disclosure provides a pharmaceutical coirposition coirprising aa compound ooff tthhiiss ddiisscclloossuurree aanndd aann NMDA receptor antagonist, an NMDA receptor partial agonist, a neurokinin 1 receptor antagonist, aa neurokinin 2 receptor antagonist, aa neurokinin 3 receptor antagonist, a DOR agonist, naloxone or methylnaltrexone and a pharmaceutically acceptable carrier.

The present disclosure provides a method of activating the mu-opioid receptor comprising contacting the mu-opioid receptor with a compound of the present disclosure, thereby treating oorr preventing a neurological disorder in a subject, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein.

The present disclosure provides a method of activating the deltaopioid receptor comprising contacting the delta-opioid receptor with a compound of the present disclosure, thereby treating or preventing a neurological disorder in a subject, wherein the neurological disorder is selected ffrroomm the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein.

The present disclosure provides aa method ooff ttrreeaattiinngg a subject afflicted wwiitthh a neurological disorder, wwhheerreeiinn the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein comprising administering an effective amount of a compound of the present disclosure to the subject so as to treat the neurological disorder in the subject.

The present disclosure provides aa mmeetthhoodd of treating aa subject afflicted with a neurological disorder, wherein the neurological disorder is Huntington's disease comprising administering an effective amount of a compound of the present disclosure to the subject so as to treat the neurological disorder in the subject.

The present disclosure provides a mmeetthhoodd of treating aa subject afflicted a neurological disorder, wherein the neurological disorder is Rett syndrome comprising administering an effective amount of a compound of the present disclosure to the subject so as to treat the neurological disorder in the subject.

The present disclosure provides a mmeetthhoodd of treating aa subject afflicted with a neurological disorder, wherein the neurological disorder is CDKL5 disorder comprising administering an effective amount of a compound of the present disclosure to the subject so as to treat the neurological disorder in the subject.

The present disclosure provides aa mmeetthhoodd of treating aa subject afflicted with a neurological disorder, wherein the neurological disorder is a Rett syndrome variant comprising administering an effective amount of a compound of the present disclosure to the subject so as to treat the neurological disorder in the subject.

In some embodiments, the mu-opioid receptors or delta-opioid receptors are in a human subject.

The present disclosure also provides a compound of this disclosure, or a salt oorr ester thereof, for use as an add-on therapy or in combination with an NMDA receptor antagonist, an NMDA receptor partial agonist, a neurokinin 1 receptor antagonist, a neurokinin 2 receptor antagonist, a neurokinin 3 receptor antagonist, or a DOR agonist in treating a subject afflicted with a neurological disorder, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein.

The present disclosure also provides a compound of this disclosure, or a salt or ester thereof, for use as an add-on therapy or in combination with an NMDA receptor antagonist, an NMDA receptor partial agonist, a neurokinin 1 receptor antagonist or a DOR agonist in treating a subject afflicted with aa neurological disorder, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein.

The present ddiisscclloossuurree also provides a compound of tthhee present disclosure, or a salt or ester thereof, for use as an add-on therapy or in combination with an NMDA receptor antagonist, an NMDA receptor partial agonist, a neurokinin 1 receptor antagonist, a neurokinin 2 receptor antagonist, aa neurokinin 3 receptor antagonist, or a DOR agonist in treating a subject afflicted with a neurological disorder, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein. The present disclosure also provides a compound of this disclosure, or a salt or ester thereof, ffoorr uussee aass an add-on therapy with an NMDA receptor antagonist, an NMDA receptor partial agonist, a neurokinin 1 receptor antagonist, or a DOR agonist in treating a subject afflicted with a neurological disorder, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein.

The present disclosure also provides a compound of this disclosure, or a salt or ester thereof, for use in combination with an NMDA receptor antagonist, an NMDA receptor partial agonist, a neurokinin 1 receptor antagonist or aa DOR agonist in treating aa subject afflicted with a neurological disorder, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein.

The present disclosure also provides a compound of this disclosure, or a salt or ester thereof, for use as an add-on therapy or in combination with an NMDA receptor antagonist, an NMDA receptor partial agonist or a neurokinin 1 receptor antagonist in treating a subject afflicted with a neurological disorder, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein.

The present disclosure further provides a pharmaceutical coirposition coirprising an amount of a compound of this disclosure, or a salt or ester thereof, and an amount of a NMDA receptor antagonist, an NMDA receptor partial agonist, a neurokinin 1 receptor antagonist, a neurokinin 2 receptor antagonist, a neurokinin 3 receptor antagonist, or a DOR agonist for use in treating a subject afflicted with a neurological disorder, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein.

The present disclosure further provides a pharmaceutical composition comprising an amount of a compound of this disclosure, or a salt or ester thereof, and an amount of an NMDA receptor antagonist, an NMDA receptor partial agonist, a neurokinin 1 receptor antagonist or a DOR agonist for use in treating a subject afflicted with a neurological disorder, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein.

The present disclosure further provides a pharmaceutical composition comprising an amount of a compound of this disclosure, or a salt or ester thereof, and an amount of an NMDA receptor antagonist, an NMDA receptor partial agonist, aa neurokinin 1 receptor antagonist, a neurokinin 2 receptor antagonist, a neurokinin 3 receptor antagonist, or a DOR agonist for use in treating a subject afflicted with a neurological disorder, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein.

The present disclosure further provides a pharmaceutical composition comprising an amount of a compound of this disclosure, or a salt or ester thereof, and an amount of an NMDA receptor antagonist, an NMDA receptor partial agonist, a neurokinin 1 receptor antagonist, or a DOR agonist for use in treating a subject afflicted with a neurological disorder, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein.

The present disclosure further provides a pharmaceutical composition comprising an amount of a compound of this disclosure, or a salt or ester thereof, and an amount of an NMDA receptor antagonist, an NMDA receptor partial agonist, a neurokinin 1 receptor antagonist or a DOR agonist in treating a subject afflicted with a neurological disorder, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein.

The present disclosure further provides a pharmaceutical coirposition coirprising an amount of a compound of this disclosure, or a salt or ester thereof, and an amount of an NMDA receptor antagonist, an NMDA receptor partial agonist or a neurokinin 1 receptor antagonist in treating a subject afflicted with a neurological disorder, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein.

The present disclosure also provides a compound of this disclosure, or a salt or ester thereof, for use as an add-on therapy with an SSRI or an SNRI in treating a subject afflicted with a neurological disorder, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein.

The present disclosure also provides a compound of this disclosure, or a salt or ester thereof, for use in combination with an SSRI or an SNRI in treating a subject afflicted with a neurological disorder, wherein the neurological ddiissoorrddeerr iiss sseelleecctteedd ffrroomm tthhee group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein.

The present disclosure also provides a compound of this disclosure, or a salt or ester thereof, and an amount of an SSRI or an SNRI in treating a subject aafffflliicctteedd with aa neurological disorder, wherein the neurological ddiissoorrddeerr iiss selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein. The present disclosure also provides compound of this disclosure, or a salt or ester thereof, and an amount of an SSRI or an SNRI in treating a subject afflicted with a neurological disorder, wherein the neurological disorder is Huntington's disease.

In some embodiments, a package coirprising: a) a first pharmaceutical coirposition coirprising an amount of an

NMDA receptor antagonist, aann NNMMDDAA receptor partial agonist, a neurokinin 1 receptor antagonist oorr aa DDOORR agonist and a pharmaceutically acceptable carrier; b) a second pharmaceutical composition coirprising an amount of any of the compound s of the present disclosure, or a salt or ester thereof; and optionally c) instructions for use of the first and second pharmaceutical coirpositions together to treat a subject afflicted with a neurological disorder, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein.

In some embodiments, a package coirprising: a) a first pharmaceutical composition coirprising an amount of an

NMDA receptor antagonist, an NMDA receptor partial agonist, a neurokinin 1 receptor antagonist, a neurokinin 2 receptor antagonist, a neurokinin 3 receptor antagonist oorr a DDOORR agonist and a pharmaceutically acceptable carrier; b) a second pharmaceutical composition coirprising an amount of any of the compound s of the present disclosure, or a salt or ester thereof; and optionally c) instructions for use of the first and second pharmaceutical coirpositions together to treat a subject afflicted with a neurological disorder, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein. In some embodiments, a package comprising: a) a first pharmaceutical coirposition coirprising an amount of an

NMDA receptor antagonist, an NNMMDDAA receptor partial agonist, a neurokinin 1 receptor antagonist, a neurokinin 2 receptor antagonist, a neurokinin 3 receptor antagonist, or aa DOR agonist and a pharmaceutically acceptable carrier; b) a second pharmaceutical composition coirprising an amount of any of the compound s of the present disclosure, or a salt or ester thereof; and c) instructions for use of the first and second pharmaceutical coirpositions together to treat a subject afflicted with a neurological disorder, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein.

In some embodiments, a package comprising: a) a first pharmaceutical coirposition coirprising an amount of an

NMDA receptor antagonist, aann NMDA receptor partial agonist, a neurokinin 1 receptor antagonist or aa DDOORR agonist and a pharmaceutically acceptable carrier; b) a second pharmaceutical composition coirprising an amount of any of the compound s of the present disclosure, or a salt or ester thereof; and optionally c) instructions for use of the first and second pharmaceutical coirpositions together to treat a subject afflicted with a neurological disorder, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein.

In some embodiments, a package coirprising: a) a first pharmaceutical coirposition coirprising an amount of an

NMDA receptor antagonist, aann NNMMDDAA receptor partial agonist, a neurokinin 1 receptor antagonist or a DOR agonist and a pharmaceutically acceptable carrier; b) a second pharmaceutical composition comprising an amount of any of the compounds of the present disclosure, or a salt or ester thereof; and c) instructions for use of the first and second pharmaceutical coirpositions together to treat a subject afflicted with a neurological disorder, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein.

In some embodiments, a package comprising: a) a first pharmaceutical composition comprising an amount of an NMDA receptor antagonist, aann NMDA receptor partial agonist or a neurokinin 1 receptor antagonist and a pharmaceutically acceptable carrier; b) a second pharmaceutical composition coirprising an amount of any of the compound s of the present disclosure, or a salt or ester thereof; and optionally c) instructions for use of the first and second pharmaceutical coirpositions together to treat a subject afflicted with a neurological disorder, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein.

The therapeutic package of the above embodiment, wherein the respective amounts of said compound(s) and said agonist or antagonist in said unit dose when taken together is mmoorree effective ttoo ttrreeaatt the neurological disorder than when compared to the administration of said compound(s) in the absence of said agonist or antagonist or the administration of said agonist or antagonist in the absence of said compound(s).

In some embodiments, a therapeutic package for dispensing to, or for use in dispensing to, aa subject afflicted with a neurological disorder, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders aass described herein, which coirprises: a) one or more unit doses, each such unit dose comprising:

(i) an amount of any of the compound s of the present disclosure, or a salt or ester thereof; and

(ii) an amount of an NMDA receptor antagonist, an NMDA receptor partial agonist, a neurokinin 1 receptor antagonist or a DOR agonist, wherein the respective amounts of said compound(s) and said agonist or antagonist in said unit dose are effective, upon concomitant administration to said subject, to treat the neurological disorder in the subject, and

(b) a finished pharmaceutical container therefor, said container containing said unit dose or unit doses, said container further containing or coirprising labeling directing the use of said package in the treatment of the neurological disorder.

In some embodiments, a therapeutic package for dispensing to, or for use in dispensing to, aa subject afflicted with a neurological disorder, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders aass described herein, which coirprises: a) one or more unit doses, each such unit dose coirprising:

(i) an amount of any of the compound s of the present disclosure, or a salt or ester thereof; and

(ii) an amount of an NMDA receptor antagonist, an NMDA receptor partial agonist, a neurokinin 1 receptor antagonist, a neurokinin 2 receptor antagonist, a neurokinin 3 receptor antagonist, or a DOR agonist, wherein the respective amounts of said compound(s) and said agonist or antagonist in said unit dose are effective, upon concomitant administration to said subject, to treat the neurological disorder in the subject, and

(b) aa finished pharmaceutical container therefor, said container containing said unit dose or unit doses, said container further containing or coirprising labeling directing the use of said package in the treatment of the neurological disorder.

In some embodiments, a therapeutic package for dispensing to, or for use in dispensing to, aa subject afflicted with aa neurological disorder, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders aass described herein, which comprises: a) one or more unit doses, each such unit dose comprising:

(i) an amount of any of the compound s of the present disclosure, or a salt or ester thereof; and

(ii) aann aammoouunntt ooff an NMDA receptor antagonist, an NMDA receptor partial agonist, aa neurokinin 1 receptor antagonist, a neurokinin 2 receptor antagonist, a neurokinin 3 receptor antagonist, or a DOR agonist, wherein the respective amounts of said compound(s) and said agonist or antagonist in said unit dose are effective, upon concomitant administration to said subject, to treat the neurological disorder in the subject, and

(b) aa finished pharmaceutical container therefor, said container containing said unit dose or unit doses, said container further containing or comprising labeling directing the use of said package in the treatment of the neurological disorder. In some embodiments, a therapeutic package for dispensing to, or for use in dispensing to, a subject afflicted with aa neurological disorder, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders aass described herein, which coirprises: a) one or more unit doses, each such unit dose coirprising:

(i) an amount of any of the compound s of the present disclosure, or a salt or ester thereof; and

(ii) an amount of an NMDA receptor antagonist, an NMDA receptor partial agonist, a neurokinin 1 receptor antagonist, or a DOR agonist, wherein the respective amounts of said compound(s) and said agonist or antagonist in said unit dose are effective, upon concomitant administration to said subject, to treat the neurological disorder in the subject, and

(b) a finished pharmaceutical container therefor, said container containing said unit dose or unit doses, said container further containing or coirprising labeling directing the use of said package in the treatment of the neurological disorder.

In some embodiments, a therapeutic package for dispensing to, or for use in dispensing to, aa subject afflicted with aa neurological disorder, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders aass described herein, which coirprises: a) one or more unit doses, each such unit dose comprising:

(i) an amount of any of the compound s of the present disclosure, or a salt or ester thereof; and (ii) an amount of an NMDA receptor antagonist, an NMDA receptor partial agonist, a neurokinin 1 receptor antagonist or a DOR agonist wherein the respective amounts of said compound(s) and said agonist or antagonist in said unit dose are effective, upon concomitant administration to said subject, to treat the neurological disorder in the subject, and

(b) a finished pharmaceutical container therefor, said container containing said unit dose or unit doses, said container further containing or comprising labeling directing the use of said package in the treatment of the neurological disorder.

In some embodiments, a therapeutic package for dispensing to, or for use in dispensing to, a subject afflicted with aa neurological disorder, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein, which comprises: a) one or more unit doses, each such unit dose comprising:

(i) an amount of any of the compound s of the present disclosure, or a salt or ester thereof; and

(ii) aann aammoouunntt ooff an NMDA receptor antagonist, an NMDA receptor partial agonist or a neurokinin 1 receptor antagonist, wherein the respective amounts of said compound(s) and said agonist or antagonist in said unit dose are effective, upon concomitant administration to said subject, to treat the neurological disorder in the subject, and

(b) aa finished pharmaceutical container therefor, said container containing said unit dose or unit doses, said container further containing or coirprising labeling directing the use of said package in the treatment of the neurological disorder. The therapeutic package of the above embodiment, wherein the respective amounts of said compound (s) and said agonist or antagonist in said unit dose when taken together is mmoorree effective to treat the neurological disorder than when compared to the administration of said compound (s) in the absence of said agonist or antagonist oorr the administration of said agonist or antagonist in the absence of said compound (s).

A pharmaceutical coirposition in unit dosage form, useful in treating a subject aafffflliicctteedd wwiitthh aaa nneeuurroollooggiiccaall ddiissoorrddeerr,, wherein the neurological disorder is sseelleecctteedd ffrroomm tthhee group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein, which comprises:

(i) aann amount of any of the compound s of the present disclosure, or a salt or ester thereof; and

(ii) an amount of an NMDA receptor antagonist, an NMDA receptor partial agonist, a neurokinin 1 receptor antagonist, or a DOR agonist, wherein the respective aammoouunnttss of said corrpound(s) and said agonist or antagonist in said composition are effective, upon concomitant administration to said subject of one or more of said unit dosage forms of said coirposition, to treat the neurological disorder.

A pharmaceutical coirposition in unit dosage form, useful in treating a subject afflicted with a neurological disorder, wherein the neurological disorder iiss sseelleecctteedd ffrroomm tthhee group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein , which coirprises:

(i) aann amount of any of the compound s of the present disclosure, or a salt or ester thereof; and

(ii) an amount of an NMDA receptor antagonist, an NMDA receptor partial agonist, a neurokinin 1 receptor antagonist, a neurokinin 2 receptor antagonist, a neurokinin 3 receptor antagonist, or a DOR agonist, wherein the respective amounts of said compound(s) and said agonist or antagonist in said composition are effective, upon concomitant administration to said subject of one or more of said unit dosage forms of said coirposition, to treat the neurological disorder in the subject.

A pharmaceutical coirposition in unit dosage form, useful in treating a subject afflicted with a neurological disorder, wherein the neurological disorder iiss selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein, which comprises:

(i) an amount of aannyy ooff tthhee ccooiirrppoouunnddss of the present disclosure, or a salt or ester thereof; and

(ii) an amount of an NMDA receptor antagonist, an NMDA receptor partial agonist, a neurokinin 1 receptor antagonist, a neurokinin 2 receptor antagonist, a neurokinin 3 receptor antagonist, or a DOR agonist, wherein the respective amounts of said compound (s) and said agonist or antagonist in said composition are effective, upon concomitant administration to said subject of one or more of said unit dosage forms of said coirposition, to treat the neurological disorder in the subject.

A pharmaceutical coirposition in unit dosage form, useful in treating a subject aafffflliicctteedd wwiitthh aa nneeuurroollooggiiccaall ddiissoorrddeerr,, wherein the neurological disorder iiss sseelleecctteedd ffrroomm the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein, which comprises:

(i) aann amount of any of the compound s of the present disclosure, or a salt or ester thereof; and

(ii) aann aammoouunntt of an NMDA receptor antagonist, an NMDA receptor partial agonist, a neurokinin 1 receptor antagonist, or a DOR agonist, wherein the respective amounts of said corrpound(s) and said agonist or antagonist in said composition are effective, upon concomitant administration to said subject of one or more of said unit dosage ffoorrmmss of said composition, to treat the neurological disorder in the subject.

A pharmaceutical coirposition in unit dosage form, useful in treating a subject afflicted with aa neurological ddiissoorrddeerr,, wherein the neurological disorder is sseelleecctteedd from tthhee group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein, which comprises: (i) an amount of any of the compound s of the present disclosure, or a salt or ester thereof; and

(ii) aann aammoouunntt of an NMDA receptor antagonist, an NMDA receptor partial agonist, a neurokinin 1 receptor antagonist or a DOR agonist, wherein the respective aammoouunnttss of said compound(s) and said agonist or antagonist in said composition are effective, upon concomitant administration to said subject of one or more of said unit dosage ffoorrmmss of said coirposition, to treat the neurological disorder in the subject.

A pharmaceutical coirposition in unit dosage form, useful in treating a subject afflicted with a neurological disorder, wherein the neurological disorder iiss sseelleecctteedd ffrroomm tthhee group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein, which comprises:

(i) aann amount of aannyy of the compound s of the present disclosure, or a salt or ester thereof; and

(ii) an amount of an NMDA receptor antagonist, an NMDA receptor partial agonist or a neurokinin 1 receptor antagonist, wherein the respective amounts of said compound(s) and said agonist or antagonist in said composition are effective, upon concomitant administration to said subject of one or more of said unit dosage ffoorrmmss of said coirposition, to treat the neurological disorder in the subject.

The pharmaceutical coirposition of the above embodiment, wherein the respective amounts of said compound (s) and said agonist or antagonist in said unit dose when taken together is more effective to treat the neurological disorder than when compared to the administration of said compound (s) in the absence of said agonist oorr antagonist or the administration of said agonist or antagonist in the absence of said compound (s).

The present ddiisscclloossuurree aallssoo provides a method ooff treating a neurological disorder, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein comprising administering to the subject an effective amount of an SSRI or an SNRI and an effective amount of any of the compounds of the present disclosure, or a salt or ester thereof, so as to thereby treat the neurological disorder.

The present ddiisscclloossuurree aallssoo provides aa mmeetthhoodd ooff treating a neurological disorder, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein comprising administering to the subject an effective amount of an SSRI or an SNRI and an effective amount of any of the compounds of the present disclosure, or a salt or ester thereof, so as to thereby treat the neurological disorder.

The present disclosure further provides a pharmaceutical coirposition coirprising an amount of any of the compounds of this disclosure, or a salt or ester thereof, and an amount of an SSRI or an SNRI for use in treating a neurological disorder, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein.

The present disclosure further provides a pharmaceutical composition coirprising an amount of any of the compounds of this disclosure, or a salt or ester thereof, and an amount of an SSRI or an SNRI for use in treating a neurological disorder, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein.

The present disclosure also provides a method of treating a subject afflicted with aa neurological disorder, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein comprising administering to the subject an effective amount of an NMDA receptor antagonist and an effective amount of any of the compounds of the present disclosure, or a salt or ester thereof, so as to thereby treat the neurological disorder.

The present disclosure also provides a compound of this disclosure or a salt or ester thereof, for use as an add-on therapy or in combination with an NMDA receptor antagonist, in treating a subject afflicted with a neurological disorder, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein.

The present disclosure further provides a pharmaceutical coirposition coirprising an amount of any of the compounds of this disclosure, or a salt or ester thereof, and an amount of an NMDA receptor antagonist, for use in treating a subject afflicted with a neurological disorder, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein.

The present disclosure also provides a method of treating a subject afflicted with a neurological disorder, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein comprising administering to the subject an effective amount of an NMDA receptor partial agonist, and an effective amount of any of the compound s of the present disclosure, or a salt or ester thereof, so as to thereby treat the neurological disorder.

The present disclosure also provides a compound of this disclosure or a salt or ester thereof, for use as an add-on therapy or in combination with an NMDA receptor partial agonist in treating a subject afflicted with a neurological disorder, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein.

The present disclosure further provides a pharmaceutical coirposition coirprising an amount of any of the compounds of this disclosure, or a salt or ester thereof, and an amount of an NMDA receptor partial agonist, for use in treating a subject afflicted with a neurological disorder, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein.

The present disclosure also provides a method of treating a subject afflicted with a neurological disorder, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein comprising administering to the subject an effective amount of a neurokinin 1 receptor antagonist and an effective amount of any of the compound s of the present disclosure, or a salt or ester thereof, so as to thereby treat the neurological disorder.

The present disclosure also provides a compound of this disclosure or a salt or ester thereof, for use as an add-on therapy or in combination with aa neurokinin 1 receptor antagonist in treating aa subject afflicted with a neurological disorder, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein. The present disclosure further provides a pharmaceutical coirposition coirprising an amount of any of the compounds of this disclosure, or a salt or ester thereof, and an amount of a neurokinin 1 receptor antagonist for use in treating a subject afflicted with a neurological disorder, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein.

The present disclosure also provides a method of treating a subject afflicted with a neurological disorder, wherein the neurological disorder is selected from the ggrroouupp consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein comprising administering to the subject an effective amount ooff a neurokinin 2 receptor antagonist and an effective amount of any of the compounds of the present disclosure, or a salt or ester thereof, so as to thereby treat the neurological disorder.

The present disclosure also provides a compound of this disclosure or a salt or ester thereof, for use as an add-on therapy or in combination with a neurokinin 22 receptor antagonist in treating aa subject afflicted with a neurological disorder, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein.

The present disclosure further provides a pharmaceutical composition comprising an amount of any of the compounds of this disclosure, or a salt or ester thereof, and an amount of a neurokinin 2 receptor antagonist for use in treating a subject afflicted with a neurological disorder, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein. The present disclosure also provides a method of treating a subject afflicted with aa neurological disorder, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein comprising administering to the subject an effective amount of a neurokinin 3 receptor antagonist and an effective amount of any of the compounds of the present disclosure, or a salt or ester thereof, so as to thereby treat the neurological disorder.

The present disclosure also provides a compound of this disorder or a salt or ester thereof, for use as an add-on therapy or in combination with aa neurokinin 3 receptor antagonist in treating aa subject afflicted with a neurological disorder, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein.

The present disclosure further provides a pharmaceutical coirposition coirprising an amount of any of the compound s of this disclosure, or a salt or ester thereof, and an amount of a neurokinin 3 receptor antagonist for use in treating a subject afflicted with a neurological disorder, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein.

The present disclosure also provides a method of treating a subject afflicted with a neurological disorder, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein comprising administering to the subject an effective amount of a DOR agonist and an effective amount of any of the compounds of the present disclosure, or a salt or ester thereof, so as to thereby treat the neurological disorder. The present disclosure also provides a compound of this disclosure or a salt or ester thereof, for use as an add-on therapy or in combination with a DOR agonist in treating a subject afflicted with a neurological disorder, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein.

The present disclosure further provides a pharmaceutical coirposition coirprising an amount of any of the compounds of the present disclosure, or a salt or ester thereof, and an amount of a DOR agonist for use in treating a subject afflicted with aa neurological disorder, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein.

The present disclosure also provides a method of treating a subject afflicted wwiitthh aa neurological disorder, wwhheerreeiinn the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein comprising administering to the subject an effective amount of an NMDA receptor antagonist and an effective amount of any of the compound s of the present disclosure, or a salt or ester thereof, so as to thereby treat the neurological disorder.

The present disclosure also provides a compound of this disclosure or a salt or ester thereof, for use as an add-on therapy or in combination with an NMDA receptor antagonist, in treating a subject afflicted with a neurological disorder, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein.

The present disclosure further provides a pharmaceutical composition coirprising an amount of any of the compounds of the present disclosure, or a salt or ester thereof, and an amount of an NMDA receptor antagonist, for use in treating a afflicted with a neurological disorder, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein.

The present disclosure also provides a method of treating a subject afflicted with aa neurological disorder, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein comprising administering to the subject an effective amount of aann NMDA receptor partial agonist, and an effective amount of any of the compounds of the present disclosure, or a salt or ester thereof, ssoo aass to thereby treat the neurological disorder.

The present disclosure also provides a compound of this disclosure or a salt or ester thereof, for use as an add-on therapy or in combination with an NMDA receptor partial agonist in treating a subject afflicted with a neurological disorder, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein.

The present disclosure further provides a pharmaceutical coirposition coirprising an amount of any of the compounds of the present disclosure, or a salt or ester thereof, and an amount of an NMDA receptor partial agonist, for use in treating a subject afflicted with a neurological disorder, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein.

The present disclosure also provides a method of treating a subject afflicted with a neurological disorder, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein comprising administering to the subject an effective amount of a neurokinin 1 receptor antagonist and an effective amount of any of the compound s of the present disclosure, or a salt or ester thereof, ssoo aass to thereby treat the neurological disorder.

The present disclosure also provides a compound of this disclosure or a salt or ester thereof, for use as an add-on therapy or in combination with aa neurokinin 1 receptor antagonist in treating a subject afflicted with a neurological disorder, wwhheerreeiinn the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein.

The present disclosure further provides a pharmaceutical coirposition coirprising an amount of any of the compounds of the present disclosure, or a salt or ester thereof, and an amount of a neurokinin 1 receptor antagonist for use in treating a subject afflicted with a neurological disorder, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein.

The present disclosure also provides a method of treating a subject afflicted with a neurological disorder, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein comprising administering to the subject an effective amount of a DOR agonist and an effective amount of any of the compounds of the present disclosure, or a salt or ester thereof, so as to thereby treat the neurological disorder.

The present disclosure also provides a compound of this disorder or a salt or ester thereof, for use as an add-on therapy or in combination with a DOR agonist in treating a subject afflicted with a neurological disorder, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein. The present disclosure further provides a pharmaceutical coirposition coirprising an amount of any of the compounds of the present disclosure, or a salt or ester thereof, and an amount of a DOR agonist for use in treating a subject afflicted with a neurological disorder, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein.

In any of the embodiments of the present method, compound, package, use or pharmaceutical composition the subject is afflicted with a neurological disorder, wherein the neurological disorder is selected from the group consisting of Huntington's disease, Rett syndrome, and CDKL5 disorder, and the other neurological disorders as described herein.

In some embodiments of the present method, compound , package, use or pharmaceutical composition, the compound has the structure: In some embodiments of the present method, compound, package, use or pharmaceutical composition, the compound has the structure: or an ester thereof. In some embodiments, a pharmaceutically acceptable salt of any of the above compound s is used according to the present disclosure.

In some embodiments, a salt of a compound of the present disclosure is used in any of the above methods, uses, packages or compositions.

In some embodiments, a pharmaceutically acceptable salt of a compound of the present disclosure is used in any of the above methods, uses, packages or coirpositions.

In some embodiments, an ester of a compound of the present disclosure is used in any of the above methods, uses, packages or compositions.

Any of the above compounds may be used in any of the disclosed methods, uses, packages or pharmaceutical compositions.

Any of the compound s used in the disclosed methods, uses, packages or pharmaceutical compositions may be replaced with any other compound disclosed herein. Any combination of the disclosed compounds may be used.

Any of the above generic compounds may be used in any of the disclosed methods, uses, packages or compositions.

In some embodiments, the methods, uses, packages or pharmaceutical coirpositions of the present disclosure wherein the neurological disorder includes, but is not limited to, Huntington's disease; Rett syndrome; a Rett syndrome variant; Angelman syndrome; Prader-Willi syndrome; neonatal onset encephalopathy; X-linked recessive mental retardation; fetal alcohol spectrum disorder; Hirschsprung disease; CDKL5 disorder; West syndrome; FOXG1 syndrome; and Lennox-Gastaut syndrome.

In some embodiments, the methods, uses, packages or pharmaceutical coirpositions of the present disclosure wherein the neurological disorder is Huntington's disease. In some embodiments, the methods, uses, packages or pharmaceutical coirpositions of tthhee present disclosure wherein the neurological disorder is Rett syndrome.

In some embodiments, the methods, uses, packages or pharmaceutical coirpositions ooff tthhee present disclosure wherein the neurological disorder is CDKL5 disorder.

In some embodiments, the methods, uses, packages or pharmaceutical coirpositions wherein the neurological disorder is a Rett syndrome variant.

In some embodiments, the methods, uses, packages or pharmaceutical coirpositions wherein the symptoms of tthhee neurological disorder include, but are not limited to, involuntary movements; abnormal muscle rigidity or contraction; abnormal hand movements ; poor muscle tone; unusual eye movements; unusual facial expressions; tremors; impaired gait, posture, or balance; frequent falls; loss of balance; difficulty with swallowing; teeth grinding; fatigue; and insomnia.

In some embodiments, the NMDA receptor antagonist is an arylcyclohexylamine, dextromorphinan or adamantane.

In some embodiments, the NMDA receptor antagonist is dextromethorphan, dextrorphan, dextrallorphan, memantine, amantadine, rimantadine, nitromemantine (YQW-36), ketamine (and its analogs, e.g., tiletamine), phencyclidine (and its analogs, e.g., tenocyclidine, eticyclidine, rolicyclidine), methoxetamine (and its analogs), gacyclidine (GK-11), neramexane, lanicemine (AZD6765), diphenidine, dizocilpine (MK-801), 8a-phenyldecahydroquinoline ((88AA--PPDDHHQQ)),, 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), 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, GV150526A, GV196771A, CERC-301 (formerly MK-0657), atomoxetine, 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) or AP-7.

In some embodiments, the NMDA receptor partial agonist is NRX-1074 or rapastinel (GLYX-13).

In some embodiments, the neurokinin 1 receptor antagonist is aprepitant, fosaprepitant, casopitant, maropitant, vestipitant, vofopitant, lanepitant, orvepitant, ezlopitant, netupitant, rolapitant, L-733060, L-703606, L-759274, L-822429, L-760735, L-

741671, L-742694, L-732138, CP-122721, RPR-100893, CP-96345, CP-

99994, TAK-637, T-2328, CJ-11974, RP 67580, NKP608, VPD-737, GR

205171, LY686017, AV608, SR140333B, SSR240600C, FK 888 or GR 82334.

In some embodiments, the neurokinin 2 receptor antagonist is saredutant, ibodutant, nepadutant, GR-159897 or MEN-10376.

In some embodiments, the neurokinin 3 receptor antagonist is osanetant, talnetant, SB-222200 or SB-218795.

In some embodiments, the DOR agonist is tianeptine, (+)BW373U86, SNC-

80, SNC-121, SNC-162, DPI-287, DPI-3290, DPI-221, TAN-67, KN-127,

AZD2327, JNJ-20788560, NIH11082, RWJ-394674, ADL5747, ADL5859, UFP-

512, AR-M100390, SB-235863 or 7-spiroindanyloxymorphone.

The term "MOR agonist" is intended to mean any compound or substance that activates the mu-opioid receptor (MOR). The agonist may be a partial, full or super agonist.

The term "DOR agonist" is intended to mean any compound or substance that activates the delta-opioid receptor (DOR). The agonist may be a partial, full or super agonist. The term "super agonist" is intended to mean a compound or substance that activates a receptor with a greater maximal response (higher Emax) than said receptor's primary endogenous ligand.

In some embodiments, the compound is prepared by the following process:

In some embodiments, the compound is prepared by the following process: wherein R is -(alkyl); R1 is -H or -(alkyl); R3 is -H or -(alkyl); X

In some embodiments, the compound is prepared by the following process: wherein R is -(alkyl); R1 is -H or -(alkyl); R3 is -H or -(alkyl); X

In one embodiment of the above process, the acid is aqueous acid. In some embodiments, the compound is prepared by the following process: wherein R is -(alkyl); R1 is -H or -(alkyl); R ₃ is -H or -(alkyl); Yi

= Cl, Br or I; Y ₂ = F, Cl, Br or I; and n = 7-20.

In one embodiment of the above process, the acid is aqueous acid.

In some embodiments, the compound is prepared by the following process: wherein R is -(alkyl); R1 is -H or -(alkyl); R ₃ is -H or -(alkyl); Yi

= Cl, Br or I; Y ₂ = F, Cl, Br or I; and n = 7-20.

In one embodiment, wherein when F is present in the compound, the F is ¹⁸ F.

In one embodiment, wherein when F is present in the compound at R6, the F is ¹⁸ F.

In some embodiments, the compound having the structure, wherein

Rs is Cl, Br, I, SMe or -C=CH,

R2 is -(C3-5 alkyl)-CO2H or -(C3-5 alkyl)-CO2(alkyl), wherein the F is ¹⁸ F.

In some embodiments, the compound having the structure, wherein

R5 is Cl, Br, I, SMe or -C=CH,

R2 is -(C6 alkyl)-COzH or -(C6 alkyl)-CO2(alkyl), wherein the F is ¹⁸ F.

In some embodiments, the compound having the structure, wherein

R5 is Cl, Br, 1, SMe or -C=CH,

R2 is -(C7-10alkyl)-CO2H or -(C7-10 alkyl)-CO2(alkyl), wherein the F is ¹⁸ F.

In some embodiments, the compound having the structure,

wherein the F is ¹⁸ F.

In some embodiments, a pharmaceutical composition comprising a compound ooff tthhee present disclosure containing an ¹⁸ F and a pharmaceutically acceptable carrier.

In some embodiments, aa pharmaceutical composition comprising a compound of the present disclosure containing an F, the same compound of the present disclosure containing an ¹⁸ F, and a pharmaceutically acceptable carrier. 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 a compound of the present disclosure containing an ¹⁸ F 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. This method is useful to assess a subject suspected of having a neurological disorder, this being a neurological disorder as set out herein.

In some embodiments, a method of detecting the location of mu-opioid receptors in the brain of a subject which comprises determining where an amount of a compound of the present disclosure containing an ¹⁸ F 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 the mu-opioid receptors based on the location of the compound determined to be present in the subject. This method is useful to aasssseessss aa subject suspected of having aa neurological disorder, this being a neurological disorder as set out herein.

In some embodiments, a method of quantifying the occupancy of mu- opioid receptors by a compound of the present disclosure or another compound binding to mu-opioid receptors in the brain of a subject, which comprises determining the binding competition between said compound and a second compound of the present disclosure containing an ¹⁸ F at a period of time after administration of the compound s or salts thereof to the subject, thereby detecting the occupancy of the mu-opioid receptors based oonn the displacement of the compound containing ¹⁸ F by the other compound. This method is useful to assess a subject suspected of having a neurological disorder, this being a neurological disorder as set out herein.

In some embodiments, a method of quantifying the occupancy of mu- opioid receptors by endogenous opioid peptides in the brain of a subject, which coirprises determining the binding coirpetition between said endogenous opioid peptides aanndd aa compound ooff tthhee present disclosure containing an ¹⁸ F at a period of time after administration of the compound to the subject, thereby detecting the occupancy of the mu-opioid receptors based on the displacement of the compound containing ¹⁸ F by the endogenous opioid peptides.This method is useful to assess a subject suspected of having a neurological disorder, this being a neurological disorder as set out herein.

In some embodiments, the method wherein the compound binding to mu- opioid receptors in the brain of a subject is a compound of the present disclosure.

In some embodiments, the method wherein the compound binding to mu- opioid receptors in the brain of a subject is a compound of the present disclosure containing an ¹⁸ F.

In some embodiments, the method further comprising quantifying the amount of the compound containing ¹⁸ F in the subject and coirparing the quantity to a predetermined control.

In some embodiments, the method wherein the determining is performed by a Positron Emission Tomography (PET) device.

In some embodiments, the method further comprising determining whether the subject is afflicted with a neurological disorder, aass set out herein, which is associated with dysregulation, up-regulation or downregulation of mu-opioid receptor based on the amount of the compound containing ¹⁸ F in the subject or its location in the subject.

In some embodiments, the method further comprising determining whether the subject is afflicted with a neurological disorder, as set out herein, which is associated with dysregulation, up-regulation or downregulation of release of endogenous opioid peptides based on displacement of the compound containing ¹⁸ F from mu-opioid receptors in the subject.

In some embodiments, the method further comprising determining whether the subject is afflicted with a neurological disorder, aass set out herein, which is associated with dysregulation, up-regulation or downregulation of release of endogenous opioid peptides based on displacement of the compound containing ¹⁸ F from mu-opioid receptors in the subject.

In some embodiments, the method wherein the neurological disorder is selected from Huntington's disease; Rett syndrome; Rett syndrome variants; Angelman syndrome; Prader-Willi syndrome; neonatal onset encephalopathy; X-linked recessive mental retardation; fetal alcohol spectrum disorder; Hirschsprung disease; CDKL5 disorder; West syndrome; FOXG1 syndrome; and Lennox-Gastaut syndrome.

Additional synthetic methods for preparation of the disclosed compounds are found in PCT International Application No. PCT/US2015/020273 , filed March 12, 2015, the contents of which are hereby incorporated by reference.

Except where otherwise specified, the structure of a compound of this disclosure includes an asymmetric carbon atom, it is understood that the compound occurs as a racemate, racemic mixture, and isolated single enantiomer. All such isomeric forms of these compounds are expressly included in this disclosure. Except where otherwise specified, each stereogenic carbon may be of the R or S configuration. It is to be understood accordingly that the isomers arising from such asymmetry (e.g. , all enantiomers and diastereomers) are included within the scope of this disclosure, unless indicated otherwise. Such isomers can be obtained in substantially pure form by classical separation techniques and by stereochemically controlled synthesis, such as those described in "Enantiomers, Racemates and Resolutions" by J. Jacques, A. Collet and S. Wilen, Pub. John Wiley & Sons, NY, 1981. For example, the resolution may be carried out by preparative chromatography on a chiral column.

The subject disclosure is also intended to include all isotopes of atoms occurring on the compounds disclosed herein. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation , isotopes of hydrogen include tritium and deuterium. I sotopes of carbon include C-13 and CI- 14 .

It will be noted that any notation of a carbon in structures throughout this application, when used without further notation, are intended to represent all isotopes of carbon, such as ¹² C, ¹³ C , or ¹⁴ C . Furthermore , any compounds containing ¹³ C or ¹⁴ C may specifically have the structure of any of the compounds disclosed herein .

It will also be noted that any notation of a hydrogen in structures throughout this application, when used without further notation, are intended to represent all isotopes of hydrogen, such as ⁴ H , ² H , or ³ H . Furthermore , any compounds containing ² H or ³ H may specifically have the structure of any of the compounds dis closed herein .

Isotopically-labeled compounds can generally be prepared by conventional techniques known to those s killed in the art using appropriate isotopically-labeled reagents in place of the non-labeled reagents employed .

In the compounds used in the method of the present disclosure , the substituents may be substituted or unsubstituted, unless specifically defined otherwise .

In the compounds used in the method of the present disclosure , alkyl , heteroalkyl , monocycle , bicycle , aryl , heteroaryl and heterocycle groups can be further substituted by replacing one or more hydrogen atoms with alternative non-hydrogen groups . These include , but are not limited to , halo , hydroxy, mercapto , amino , carboxy, cyano and carbamoyl .

It is understood that substituents and substitution patterns on the compounds used in the method of the present disclosure can be selected by one of ordinary s kill in the art to provide compounds that are chemically stable and that can be readily synthesi zed by techniques known in the art from readily available starting materials , If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons , so long as a stable structure results .

In choosing the coirpounds used in the method of the present disclosure, one of ordinary skill in the art will recognize that the various substituents , i . e . , R1, R2, etc . are to be chosen in conformity with well-known principles of chemical structure connectivity.

As used herein, "alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms . Thus, C1-C _n as in "C1-Cn alkyl" is defined to include groups having 1, 2 > n-1 or n carbons in a linear or branched arrangement, and specifically includes methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, isopropyl, isobutyl, sec- butyl and so on . An embodiment can be C1-C12 alkyl, C2-C12 alkyl, C3-C12 alkyl, C4-C12 alkyl and so on. An embodiment can be C1-Cs alkyl, C2-C8 alkyl, C3-C8 alkyl, C4-C8 alkyl and so on . "Alkoxy" represents an alkyl group as described above attached through an oxygen bridge .

The term "alkenyl" refers to a non-aromatic hydrocarbon radical, straight or branched, containing at least 1 carbon to carbon double bond, and up to the maximum possible number of non-aromatic carboncarbon double bonds may be present . Thus, C2-C _n alkenyl is defined to include groups having 1, 2. . . . , n-1 or n carbons . For example, "C ₂ -C ₆ alkenyl” means an alkenyl radical having 2, 3 , 4 , 5 , oorr 6 carbon atoms, and aatt least 1 carbon-carbon double bond, aanndd up to, for example, 3 carbon-carbon double bonds in the case of a C6 alkenyl, respectively. Alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl . As described above with respect to alkyl, the straight, branched or cyclic portion of the alkenyl group may contain double bonds and may be substituted if aa substituted alkenyl group is indicated. An embodiment can be C2-C12 alkenyl or C2-C8 alkenyl . The term "alkynyl" refers to aa hydrocarbon radical straight or branched, containing at least 1 carbon to carbon triple bond, and up to the maximum possible number of non-aromatic carbon-carbon triple bonds may be present. Thus, C2-C _n alkynyl is defined to include groups having 1, 2...., n-1 or n carbons. For example, "C2-C6 alkynyl" means an alkynyl radical having 2 or 3 carbon atoms, and 1 carbon-carbon triple bond, or having 4 or 5 carbon atoms, and up to 2 carbon-carbon triple bonds, or having 6 carbon atoms, and up to 3 carbon-carbon triple bonds. Alkynyl groups include ethynyl, propynyl and butynyl. As described above with respect to alkyl, the straight or branched portion of the alkynyl group may contain triple bonds and may be substituted if a substituted alkynyl group is indicated.An embodiment can be a C2~C _n alkynyl. An embodiment can be C2-C12 alkynyl or C3-C8 alkynyl.

As used herein, "hydroxyalkyl" includes alkyl groups as described above wherein one or more bonds to hydrogen contained therein are replaced by a bond to an -OH group. In some embodiments, C1-C12 hydroxyalkyl or C1-C6hydroxyalkyl. C1-Cn as in " 1-Cnalkyl" is defined to include groups having 1, 2, ...., n-1 or n carbons in a linear or branched arrangement (e.g., C1-C2hydroxyalkyl, C1-C3hydroxyalkyl, Ci-

C4hydroxyalkyl, C1-C5hydroxyalkyl, or C1-C6hydroxyalkyl) For example,

C1-C ₆ , as in "C1-C6hydroxyalkyl" is defined to include groups having 1, 22,, 3, 4, 5, or 6 carbons in a linear or branched alkyl arrangement wherein a hydrogen contained therein is replaced by a bond to an -OH group.

As used herein, "heteroalkyl" includes both branched and straight- chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms and at least 1 heteroatom within the chain or branch.

As used herein, "monocycle" includes any stable polyatomic carbon ring of up to 10 atoms and may be unsubstituted or substituted. Examples of such non-aromatic monocycle elements include but are not limited to: cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Examples of such aromatic monocycle elements include but are not limited to: phenyl .

As used herein, "bicycle" includes any stable polyatomic carbon ring of up to 10 atoms that is fused to a polyatomic carbon ring of up to 10 atoms with each ring being independently unsubstituted or substituted. Examples of such non-aromatic bicycle elements include but are not limited to: decahydronaphthalene. Examples of such aromatic bicycle elements include but are not limited to: naphthalene.

As used herein, "aryl" is intended to mean any stable monocyclic, bicyclic or polycyclic carbon ring of up to 10 atoms in each ring, wherein at least one ring is aromatic, and may be unsubstituted or substituted. Examples of such aryl elements include but are not limited to: phenyl, p-toluenyl ( 4 -methylphenyl ) , naphthyl, tetrahydro-naphthyl, indanyl, phenanthryl, anthryl or acenaphthyl. In cases where the aryl substituent is bicyclic and one ring is non- aromatic, it is understood that attachment is via the aromatic ring.

The term "heteroaryl", as used herein, represents a stable monocyclic, bicyclic or polycyclic ring of up to 10 atoms in each ring, wherein at least one ring is aromatic and contains from 1 to 4 heteroatoms selected from the group consisting of O, N and S. Bicyclic aromatic heteroaryl groups include phenyl, pyridine, pyrimidine or pyridazine rings that are (a) fused to a 6-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom; (b) fused to a 5- or 6- membered aromatic (unsaturated) heterocyclic ring having two nitrogen atoms; (c) fused to a 5-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom together with either one oxygen or one sulfur atom; or (d) fused to a 5-membered aromatic (unsaturated) heterocyclic ring having one heteroatom selected from O, N or S. Heteroaryl groups within the scope of this definition include but are not limited to: benzoimidazolyl, benzofuranyl, benzof urazanyl , benzopyrazolyl , benzotriazolyl , benzothiophenyl, benzoxazolyl , carbazolyl, carbolinyl, cinnolinyl, furanyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, aziridinyl, 1,4-dioxanyl, hexahydroazepinyl, dihydrobenzoimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyraziny1, dihydropyrazolyl, dihydropyridiny1, dihydropyrimidinyl, dihydropyrroly1, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidiny1, methylenedioxybenzoyl, tetrahydrofuranyl, tetrahydrothienyl, acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrrazolyl, indolyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, isoxazolyl, isothiazolyl, furanyl, thienyl, benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetra-hydroquinoline. IInn cases where the heteroaryl substituent is bicyclic and one ring is non-aromatic or contains no heteroatoms, it is understood that attachment is via the aromatic ring or via the heteroatom containing ring, respectively. If the heteroaryl contains nitrogen atoms, it is understood that the corresponding N-oxides thereof aarree also encompassed by this definition.

The term "heterocycle", "heterocyclyl" or "heterocyclic" refers to a mono- or poly-cyclic ring system which can be saturated or contains one or more degrees of unsaturation and contains one or more heteroatoms. Preferred heteroatoms include N, O, and/or S, including N-oxides, sulfur oxides, and dioxides. Preferably the ring is three to ten-membered and is either saturated or has one or more degrees of unsaturation. The heterocycle may be unsubstituted or substituted, with multiple degrees of substitution being allowed. Such rings may be optionally fused to one or more of another "heterocyclic” ring(s), heteroaryl ring(s), aryl ring(s), or cycloalkyl ring(s). Examples of heterocycles include, but are not limited to, tetrahydrofuran, pyran, 1,4-dioxane, 1,3-dioxane, piperidine, piperazine, pyrrolidine, morpholine, thiomorpholine, tetrahydrothiopyran, tetrahydrothiophene, 1,3-oxathiolane, and the like.

The term "ester" is intended to a mean an organic compound containing the R-O-CO-R' group.

The term "substitution", "substituted" and "substituent" refers to a functional group as described above in which one or more bonds to a hydrogen atom contained therein are replaced by a bond to non-hydrogen or non-carbon atoms, provided that normal valencies are maintained and that the substitution results in a stable compound. Substituted groups also include groups in which one or more bonds to a carbon(s) or hydrogen(s) atom are replaced by one or more bonds, including double or triple bonds, to a heteroatom. Examples of substituent groups include the functional groups described above, and halogens

(i.e., F, Cl, Br, and I); alkyl groups, such as methyl, ethyl, n- propyl, isopropryl, nn--bbuuttyyll,, tert-butyl, and trifluoromethyl; hydroxyl; alkoxy groups, suc_ha as methoxy, ethoxy, n-propoxy, and isopropoxy; aryloxy groups, such as phenoxy; arylalkyloxy, such as benzyloxy (phenylmethoxy) and p-trifluoromethylbenzyloxy (4- trifluoromethylphenylmethoxy); heteroaryloxy groups; sulfonyl groups, such as trifluoromethanesulfonyl, methanesulfonyl, and P" toluenesulfonyl; nitro, nitrosyl; mercapto; sulfanyl groups, such as methylsulfanyl, ethylsulfanyl and propylsulfanyl; cyano; amino groups, such as amino, methylamino, dimethylamino, ethylamino, and diethylamino; and carboxyl. Where multiple substituent moieties are disclosed or claimed, the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or plurally. By independently substituted, it is meant that the (two or more) substituents can be the same or different.

The compounds used in the method of the present disclosure may be prepared by techniques well known in organic synthesis and familiar to a practitioner ordinarily skilled in the art. However, these may not be the only means by which to synthesize or obtain the desired compounds .

The compounds used in the method of the present disclosure may be prepared by techniques described in Vogel' s Textbook of Practical Organic Chemistry, A. I. Vogel, A.R. Tatchell, B.S. Furnis, A. J. Hannaford, P.W.G. Smith, (Prentice Hall) 5 ^th Edition (1996) , March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Michael B. Smith, Jerry March, ( Wiley-Interscience ) 5 ^th Edition (2007) , and references therein, which are incorporated by reference herein. However, these may not be the only means by which to synthesize or obtain the desired compounds.

The various R groups attached to the aromatic rings of the compounds disclosed herein may be added to the rings by standard procedures, for example those set forth in Advanced Organic Chemistry: Part B: Reactions and Synthesis, Francis Carey and Richard Sundberg, (Springer) 5th ed. Edition. (2007) , the content of which is hereby incorporated by reference.

Another aspect of the disclosure comprises a compound used in the method of the present disclosure as a pharmaceutical composition.

As used herein, the term "pharmaceutically active agent" means any substance or compound suitable for administration to a subject and furnishes biological activity or other direct effect in the treatment, cure, mitigation, diagnosis, or prevention of disease, or affects the structure or any function of the subject. Pharmaceutically active agents include, but are not limited to, substances and compounds described in the Physicians' Desk Reference (PDR Network, LLC; 64th edition; November 15, 2009) and "Approved Drug Products with Therapeutic Equivalence Evaluations" (U.S. Department Of Health And Human Services, 30 ^th edition, 2010) , which are hereby incorporated by reference. Pharmaceutically active agents which have pendant carboxylic acid groups may be modified in accordance with the present disclosure using standard esterification reactions and methods readily available and known to those having ordinary skill in the art of chemical synthesis. Where a pharmaceutically active agent does not possess a carboxylic acid group, the ordinarily skilled artisan will be able to design and incorporate a carboxylic acid group into the pharmaceutically active agent where esterification may subsequently be carried out so long as the modification does not interfere with the pharmaceutically active agent' s biological activity or effect.

The compounds used in the method of the present disclosure may be in a salt form. As used herein, a "salt" is a salt of the instant compounds which has been modified by making acid or base salts of the compounds. In the case of compounds used to treat an infection or disease caused by a pathogen, the salt is pharmaceutically acceptable. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as phenols; alkali or organic salts of acidic residues such as carboxylic acids. The salts can be made using an organic or inorganic acid. Such acid salts are chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formates, tartrates, maleates, malates, citrates, benzoates, salicylates, ascorbates, and the like. Phenolate salts are the alkali metal salts, sodium, potassium or lithium. The salts can be made using an organic or inorganic base. Such basic salts are alkali metal salts, such as sodium, potassium or lithium and alkaline earth metal salts, such as magnesium and calcium.

The term "pharmaceutically acceptable salt" in this respect, refers to the relatively non-toxic, inorganic and organic acid or base addition salts of compounds of the present disclosure. These salts can be prepared in situ during the final isolation and purification of the compounds of the disclosure, or by separately reacting a purified compound of the disclosure in its free base or free acid form with a suitable organic or inorganic acid or base, and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate , and laurylsulphonate salts and the like. Representative salts also include the sodium, potassium, lithium, magnesium and calcium salts and the like. (See, e. g. , Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci . 66: 1-19) .

Administration of one or more compounds and/or one or more compositions (e.g. , pharmaceutical compositions) disclosed herein may be used for preventing, slowing, halting, or reversing the progression of a neurological disorder, as set out herein. Administration may also be used for improving one or more symptoms of the neurological disorder .

The compounds used in the method of the present disclosure may be administered in various forms, including those detailed herein. Treatment with the compounds may be a component of a combination therapy or an adjunct therapy, i.e. , the subject or patient in need of the drug is treated or given another drug for the disorder in conjunction with one or more of the instant compounds. This combination therapy can be sequential therapy where the patient is treated first with one drug and then the other or the two drugs are given simultaneously. These can be administered independently by the same route or by two or more different routes of administration depending on the dosage forms employed.

As used herein, a "pharmaceutically acceptable carrier" is a pharmaceutically acceptable solvent, suspending agent or vehicle, for delivering the instant compounds to the animal or human. The carrier may be liquid or solid and is selected with the planned manner of administration in mind. Liposomes are also a pharmaceutically acceptable carrier.

The dosage of the compounds administered in treatment will vary depending upon factors such as the pharmacodynamic characteristics of a specific therapeutic agent and its mode and route of administration; the age, sex, metabolic rate, absorptive efficiency, health and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment being administered; the frequency of treatment with; and the desired therapeutic effect.

A dosage unit of the compounds used in the method of the present disclosure may comprise a single compound or mixtures thereof with additional antibacterial agents. The compound s can be administered in oral dosage forms as tablets, capsules, pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. The compounds may also be administered in intravenous (bolus oorr infusion), intraperitoneal, subcutaneous, or intramuscular form, or introduced directly, e.g., by injection, topical application, or other methods, into or onto a site of infection, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts.

The compounds used in the method of the present disclosure can be administered in admixture with suitable pharmaceutical diluents, extenders, excipients, or carriers (collectively referred to herein as a pharmaceutically acceptable carrier) suitably selected with respect to the intended form of administration and as consistent with conventional pharmaceutical practices. The unit will be in a form suitable for oral, rectal, topical, intravenous or direct injection or parenteral administration. The compounds can be administered alone or mixed with a pharmaceutically acceptable carrier. This carrier can be a solid or liquid, and the type of carrier is generally chosen based on the type of administration being used.

The active agent can be co-administered in the form of a tablet or capsule, liposome, as an agglomerated powder or in a liquid form. Examples of suitable solid carriers include lactose, sucrose, gelatin and agar. Capsule or tablets can be easily formulated and can be made easy to swallow or chew; other solid forms include granules, and bulk powders. Tablets may contain suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow- inducing agents, and melting agents. Examples of suitable liquid dosage forms include solutions or suspensions in water, pharmaceutically acceptable fats and oils, alcohols or other organic solvents, including esters, emulsions, syrups or elixirs, suspensions, solutions and/or suspensions reconstituted from non-ef fervescent granules and effervescent preparations reconstituted from effervescent granules. Such liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, thickeners, and melting agents . Oral dosage forms optionally contain flavorants and coloring agents . Parenteral and intravenous forms may also include minerals and other materials to make them compatible with the type of injection or delivery system chosen.

Techniques and compositions for making dosage forms useful in the present disclosure are described in the following references: 7 Modern Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes, Editors, 1979) ; Pharmaceutical Dosage Forms: Tablets (Lieberman et al. , 1981) ; Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976) ; Remington's Pharmaceutical Sciences, 17th ed. (Mack Publishing Company, Easton, Pa. , 1985) ; Advances in Pharmaceutical Sciences (David Ganderton, Trevor Jones, Eds. , 1992) ; Advances in Pharmaceutical Sciences Vol. 7. (David Ganderton, Trevor Jones, James McGinity, Eds. , 1995) ; Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms (Drugs and the Pharmaceutical Sciences, Series 36 (James McGinity, Ed. , 1989) ; Pharmaceutical Particulate Carriers: Therapeutic Applications: Drugs and the Pharmaceutical Sciences, Vol 61 (Alain Rolland, Ed. , 1993) ; Drug Delivery to the Gastrointestinal Tract (Ellis Horwood Books in the Biological Sciences. Series in Pharmaceutical Technology; J. G. Hardy, S. S. Davis, Clive G. Wilson, Eds. ) ; Modem Pharmaceutics Drugs and the Pharmaceutical Sciences, Vol 40 (Gilbert S. Banker, Christopher T. Rhodes, Eds. ) . All of the aforementioned publications are incorporated by reference herein.

Tablets may contain suitable binders, lubricants, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents. For instance, for oral administration in the dosage unit form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such aass lactose, gelatin, agar, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrators include, without limitation, starch,methyl cellulose, agar, bentonite, xanthan gum, and the like.

The compounds used in the method of the present disclosure may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, llaarrggee unilamallar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cchhoolleesstteerrooll,, stearylamine, or phosphatidylcholines. The compound s may be administered as components of tissue-targeted emulsions.

The compounds used in the method of the present disclosure may also be coupled to soluble polymers as targetable drug carriers or as a prodrug. Such polymers include polyvinylpyrrolidone, pyran copolymer, polyhydroxylpropylmethacrylamide-phenol, polyhydroxyethylasparta- midephenol, oorr polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, the compounds may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked or amphipathic block copolymers of hydrogels. Gelatin capsules may contain the active ingredient compounds and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as immediate release products or as sustained release products to provide for continuous release of medication over a period of hours . Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract .

For oral administration in liquid dosage form, the oral drug components are combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Examples of suitable liquid dosage forms include solutions or suspensions in water, pharmaceutically acceptable fats and oils, alcohols or other organic solvents, including esters, emulsions, syrups or elixirs, suspensions, solutions and/or suspensions reconstituted from non-ef fervescent granules and effervescent preparations reconstituted from effervescent granules. Such liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, thickeners, and melting agents.

Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance. In general, water, a suitable oil, saline, aqueous dextrose (glucose) , and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water-soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents. Also used are citric acid and its salts and sodium EDTA. In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl- paraben, and chlorobutanol. Suitable pharmaceutical carriers are described in Remington’s Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field.

The compounds used in the method of the present disclosure may also be administered in intranasal form via use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will generally be continuous rather than intermittent throughout the dosage regimen. Parenteral and intravenous forms may also include minerals and other materials to make them compatible with the type of injection or delivery system chosen.

In specific aspects, a disclosed compound may be administered at a dosage unit of about 0.1 mg to about 1000 mg, or about 1 mg to about

400 mg, or about 5 mg to about 300 mg, about 10 mg to about 200 mg, about 100 mg to about 200 mg, or at least 400 mg, at least 300 mg, at least 200 mg, at least 150 mg, at least 120 mg, at least 100 mg, at least 50 mg, at least 40 mg, at least 30 mg, at least 20 mg, at least

10 mg, at least 9 mg, at least 8.5 mg, at least 8 mg, at least 7.5 mg, at least 7 mg, at least 6.5 mg, at least 6 mg, at least 5.5 mg, at least 5 mg, at least 4.5 mg, at least 4 mg, at least 3.5 mg, at least 3 mg, at least 2.5 mg, at least 2 mg, or at least 1 mg.

In specific exemplifications, for a compound of the structure: or its pharmaceutically acceptable salts or esters thereof, administration may be carried out at a dosage unit of about 0.5 mg to about 20 mg, or about 1 mg to about 10 mg, or about 2 mg to about 6 mg, or at least 10 mg, at least 9.5 mg, at least 9 mg, at least 8.5 mg, at least 8 mg, at least 7.5 mg, at least 7 mg, at least 6.5 mg, at least 6 mg, at least 5.5 mg, at least 5 mg, at least 4.5 mg, at least 4 mg, at least 3.5 mg, at least 3 mg, at least 2.5 mg, at least 2 mg, or at least 1 mg.

In further exemplifications, for a compound of the structure: or its pharmaceutically acceptable salts or esters thereof, administration may be carried out at a dosage unit of about 1 mg to about 60 mg, or about 3 mg to about 40 mg, or about 7.5 mg to about

20 mg, or at least 40 mg, at least 30 mg, at least 20 mg, at least 15 mg, at least 10 mg, at least 9.5 mg, at least 9 mg, at least 8.5 mg, at least 8 mg, at least 7.5 mg, at least 7 mg, at least 6.5 mg, at least 6 mg, at least 5.5 mg, at least 5 mg, at least 4.5 mg, at least

4 mg, at least 3.5 mg, or at least 3 mg.

In specific exemplifications, for a compound of the structure: or its pharmaceutically acceptable salts or esters thereof, administration may be carried out at a dosage unit of about 1 mg to about 40 mg, or about 2 mg to about 20 mg, or about 4 mg to about 12 mg, or at least 20 mg, at least 18 mg, at least 16 mg, at least 14 mg, at least 12 mg, at least 10 mg, at least 9.5 mg, at least 9 mg, at least 8.5 mg, at least 8 mg, at least 7.5 mg, at least 7 mg, at least 6.5 mg, at least 6 mg, at least 5.5 mg, at least 5 mg, at least

4.5 mg, at least 4 mg, at least 3.5 mg, at least 3 mg, at least 2.5 mg, at least 2 mg, or at least 1 mg.

The dosage units as noted herein may be administered once per day, twice per day, three times per day, four times per day, or more as needed. Administration of a dosage unit twice or three times per day is specifically noted. The dosage and administration regime may be adjusted for pediatric, geriatric, overweight, underweight, or other patients, where required. The dosage and administration regime may also be adapted for extended release formulations. All such modifications can be made in accordance with known methods.

Each embodiment disclosed herein is contemplated as being applicable to each of the other disclosed embodiments. Thus, all combinations of the various elements described herein are within the scope of this disclosure.

This invention will be better understood by reference to the

Experimental Details which follow, but those skilled in the art will readily appreciate that the specific experiments detailed are only illustrative and that the invention is described in the claims which follow thereafter.

Experimental Details

Example 1. Preparation of Compounds

General Considerations. Reagents and solvents were obtained from commercial sources and were used without further purification unless otherwise stated. All compounds were prepared in racemic form. All reactions were performed in flame-dried glassware under an argon atmosphere unless otherwise stated, and monitored by TLC using solvent mixtures appropriate to each reaction. All column chromatography was performed on silica gel (40-63 pm). Preparative TLC was conducted on

20x20 cm plates coated with a 1 mm silica layer. Nuclear magnetic resonance spectra were recorded on Bruker 400 or 500 MHz instruments as indicated. Chemical shifts are reported aass 55 values in ppm referenced to CDC1 ₃ NMR = 7.26 and ¹³ C NMR = 77.16), MeOD ( ³ H NMR = 3.31 and ¹³ C NMR = 49.00), or DMSO-d ₆ (1H NMR = 2.50 and ¹³ C NMR =

39.52). Multiplicity is indicated as follows: s (singlet); d

(doublet); t (triplet); q (quartet); P (pentet); dd (doublet of doublets); ddd (doublet of doublet of doublets); dt (doublet of triplets); td (triplet of doublets); m (multiplet); br (broad). All carbon peaks are rounded to oonnee decimal place unless such rounding would cause two close peaks to become identical; in these cases, two decimal places are retained. Two carbon peaks joined by "and" in the peak list correspond to a single carbon atom but are split due to F- C coupling. Low-resolution mass spectra were recorded on a JEOL LCmate (ionization mode: APCI+). For compounds 4 and 5 mass spectra are reported for carbocations corresponding to loss of OH or Cl respectively.

Preparation of Diarylthiazepinones (3)

Scheme 1. Preparation of diaryIthiazepinones.

Methyl 4-bromo-2-(chlorosulfonyl)benzoate (la). A suspension of methyl 2-amino-4-bromobenzoate (10.35 g, 45.0 mmol) in 20% aqueous

HC1 (29 mL) was sonicated for several minutes and warmed slightly until all clumps were broken up and the mixture was a uniform suspension of fine particles. This mixture was cooled to 0 C, and a solution of NaNO2 (3.11 g, 45.0 mmol) in water (7.5 mL) was added dropwise, maintaining the internal temperature below 5 C. The resulting mixture was then stirred for 2 h at 0 °C. Simultaneously, a solution of SO2 (23.1 g, 360 mmol) in AcOH (36.0 mL) and water (3.75 mL) was prepared by bubbling the gas though the mixed solvents at 0 °C until the mass had increased by the required amount. To this SO2 solution was then added CuCl (1.11 g, 11.25 mmol) followed by the diazonium salt solution portionwise over 30 minutes at 0 °C. The resulting mixture was then stirred for 1 h at 0 °C and 1 h at room temperature, poured into ice water (150 mL) , and extracted with CH2CI2 (3 x 50 mL) . The combined organics were poured into saturated aqueous NaHCO3 (75 mL) , and solid NaHCO3 was added carefully until effervescence ceased. The organic phase was then separated, washed with brine (50 mL) , dried over Na2SO4, and concentrated to provide the crude sulfonyl chloride la as a waxy brown solid (6.11 g, 74 mass% product by NMR, 32% yield) . This material was used in the next step without further purification.

Methyl 4 -bromo-2- (N-methyl-N-phenylsulfamoyl) benzoate (2a) . To a solution of crude methyl 4-bromo-2- ( chlorosulfonyl ) benzoate la (6.04 g, 74% pure, 14.25 mmol) in anhydrous pyridine (10.7 mL) was added N-methylaniline (1.71 mL, 1.68 g, 15.68 mmol) at room temperature, and the resulting mixture was stirred for 1 h. The reaction mixture was then diluted with CH2CI2 (100 mL) and washed with 7% aqueous HC1 (2 x 100 mL) , brine (100 mL) , saturated aqueous NaHCO3 (100 mL) , and brine again (100 mL) , dried over Na2SO4, and concentrated to give a yellow-brown oil. This material was purified by column chromatography (9:1 hexanes : EtOAc, 4 column volumes 8:2 hexanes : EtOAc, 4 column volumes) to provide pure sulfonamide 2a as a yellow oil (3.71 g, 68%) . ¹ H NMR (500 MHz, CDC1 ₃ ) 5 7.69 (dd, J = 8.2, 1.9 Hz, 1H) , 7.52 (d, J = 1.9 Hz, 1H) , 7.38 - 7.29 (m, 4H) , 7.21 - 7.17 (m, 2H) , 3.82 (s, 3H) , 3.30 (s, 3H) ; ¹³ C NMR (126 MHz, CDC1 ₃ ) 5 167.7, 141.0, 137.1, 135.5, 132.8, 132.3, 129.8, 129.3, 128.0, 127.4, 123.9, 53.4, 39.0.

3-Bromo-6-methyldibenzo [c,f] [1,2] thiazepin-11 (6H) -one 5,5- dioxide (3a) . To a solution of sulfonamide 2a (3.69 g, 9.60 mmol) in MeOH (24 mL) was added water (12 mL) and NaOH (1.15 g, 28.80 mmol) and the mixture was refluxed for 1 h. Most of the MeOH was then removed in vacuo and the resulting clumpy white mixture was diluted with water (30 mL) , acidified with 10% aqueous HC1 (20 mL) , and extracted with CH2CI2 (50 mL, 2 x 20 mL) . The combined organics were dried over Na2SO4 and concentrated to provide the carboxylic acid as a pale-pink glass (3.46 g) , which was used in the next step without further purification. The carboxylic acid (3.43 g, 9.26 mmol) was dissolved in thionyl chloride (15 mL) and the solution was stirred for 13 h at room temperature. The volatiles were then removed to provide the crude acyl chloride as a yellow-orange oil. This material was dissolved in CHCI3 (40 mL) , aluminum chloride (3.95 g, 29.63 mmol) was added, and the mixture was refluxed for 1 h. The reaction was then cooled to room temperature, quenched with ice water (150 mL) , and extracted with CH2CI2 (3 x 50 mL) . The combined organics were filtered through a silica plug, washing with additional CH2CI2 until all of the product had passed through, and the filtrate was concentrated to provide an off-white solid. This material was recrystallized from MeOH (-250 mL) to provide the pure ketone 3a as cream-colored needles (2.08 g, 62% over 3 steps) . ¹ H NMR (500 MHz, CDC1 ₃ ) 5 8.30 (dd, J = 8.1, 1.5 Hz, 1H) , 8.11 (t, J = 1.0 Hz, 1H) , 7.84 (d, J = 1.1 Hz, 2H) , 7.68 - 7.62 (m, 1H) , 7.41 - 7.37 (m, 1H) , 7.35 (dd, J = 8.1, 0.7 Hz, 1H) , 3.36 (s, 3H) ; ¹³ C NMR (126 MHz, CDC1 ₃ ) 5 189.8, 141.5, 138.5, 136.4, 135.1, 135.0, 133.4, 132.3, 131.0, 128.4, 126.9, 126.4, 124.8, 39.2; LR-MS calcd. for Ci^HnBrNOsS [M+H] ⁺ 351.96, found 351.85.

Methyl 2-amino-4-bromo-5-fluorobenzoate . To a solution of methyl 4-bromo-5-fluoro-2-nitrobenzoate (2.50 g, 9.00 mmol) in EtOAc (67.5 mL) and CH2CI2 (22.5 mL) was added SnC12 • 2H2O (10.15 g, 45.00 mmol) and the white suspension was stirred for 15 h. The reaction mixture was then poured into saturated aqueous NaHCO ₃ (200 mL) , solid NaHCO ₃ was added with stirring until bubbling stopped, and the mixture was extracted with EtOAc (3 x 200 mL) . The combined organics were washed with water (200 mL) and brine (200 mL) , dried over Na2SO4, and concentrated to provide methyl 2-amino-4-bromo-5-fluorobenzoate as a pale-tan crystalline solid (2.14 g, 96%) . ¹ H NMR (500 MHz, CDC1 ₃ ) 5 7.58 (d, J = 9.4 Hz, 1H) , 6.88 (d, J = 5.7 Hz, 1H) , 5.62 (br s, 2H) , 3.87 (s, 3H) ; ¹³ C NMR (126 MHz, CDC1 ₃ ) 5 167.39 and 167.36, 151.4 and 149.5, 147.41 and 147.39, 120.7, 117.4 and 117.2, 116.5 and 116.3, 110.2 and 110.1, 52.1. Methyl 4 -bromo-2- (chlorosulfonyl) -5-fluorobenzoate (lb) . A suspension of methyl 2-amino-4-bromo-5-f luorobenzoate (4.18 g, 16.85 mmol) in 20% aqueous HC1 (10.9 mL) was sonicated for several minutes and warmed slightly until all clumps were broken up and the mixture was a uniform suspension of fine particles. This mixture was cooled to -5 °C, and a solution of NaNO2 (1.16 g, 16.85 mmol) in water (2.8 mL) was added dropwise over 10 minutes, maintaining the internal temperature below 0 °C. The resulting mixture was then stirred for 30 minutes at -5 °C, during which time, most solids dissolved to leave a cloudy yellow solution. Simultaneously, a solution of SO2 (8.65 g, 135 mmol) in AcOH (13.5 mL) and water (1.4 mL) was prepared by bubbling the gas though the mixed solvents at 0 °C until the mass had increased by the required amount. To this SO2 solution was then added CuCl (417 mg, 4.21 mmol) followed by the diazonium salt solution portionwise over 25 minutes at 0 °C. The resulting mixture was then stirred for 1 h at 0 °C and 1 h at room temperature, poured into ice water (75 mL) , and extracted with CH2CI2 (3 x 30 mL) . The combined organics were poured into saturated aqueous NaHCOs (100 mL) containing excess solid NaHCOs and the mixture was stirred until effervescence ceased. The organic phase was then separated, washed with brine (30 mL) , dried over Na2SO4, and concentrated to provide the crude sulfonyl chloride lb as a waxy tan solid (3.57 g, 82 mass? product by NMR, 52% yield) . This material was used in the next step without further purification.

Methyl 4-bromo-5-fluoro-2- (N-methyl-N-phenylsulf amoyl) benzoate (2b) . To a solution of N-methylaniline (1.05 mL, 1.04 g, 9.66 mmol) in anhydrous CH2CI2 (8.5 mL) at 0 °C was added anhydrous pyridine (6.4 mL) followed by a solution of crude methyl 4-bromo-2- ( chlorosulf onyl ) - 5-fluorobenzoate lb (3.54 g, 82% pure, 8.78 mmol) in anhydrous CH2CI2 (8.5 mL) over ~3 minutes. The resulting bright orange solution was then allowed to warm to room temperature and stirred for 1 h. The reaction mixture was then diluted with CH2CI2 (100 mL) and washed with 3% aqueous HC1 (2 x 50 mL) , brine (50 mL) , saturated aqueous NaHCOs (50 mL) , and brine again (50 mL) , dried over Na2SO4, and concentrated to give a viscous orange oil. This material was purified by column chromatography (9:1 hexanes : EtOAc, 4 column volumes 8:2 hexanes : EtOAc, 2 column volumes) to provide sulfonamide 2b as a viscous, pale-yellow ooiill tthhaatt slowly crystallized to off-white crystals (3.00 g, 85%). NMR (500 MHz, CDCI3) 57.58 (d, J = 6.3 Hz,

1H), 7.39 - 7.29 (m, 3H), 7.25 - 7.16 (m, 3H), 3.83 (s, 3H), 3.30 (s,

3H); ¹³ C NMR (126 MHz, CDC1 ₃ ) 5 166.28 and 166.26, 161.9 and 159.9,

140.9, 135.84 and 135.83, 134.81 and 134.76, 132.59 and 132.55, 129.4,

128.1, 127.4, 116.6 and 116.41, 111.1 and 110.9, 53.6, 39.0.

3-Bromo-2-hydroxy-6-rnethyldibenzo[c,f][1,2]thiazepin-11( 6H)- one 5,5-dloxlde (3b). To a solution of sulfonamide 2b (2.98 g, 7.41 mmol) in MeOH (19 mL) was added water (9.5 mL) and NaOH (889 mg, 22.23 mmol) and the mixture was refluxed for 50 minutes. The volatiles were removed in vacuo and the resulting white mass was triturated with water (50 mL) and 10% aqueous HC1 (20 mL) and extracted with CH2CI2

(250 mL, 150 mL, 50 mL; poor solubility). The combined organics were dried over Na2SO< and concentrated to provide the carboxylic acid as a white solid (2.99 in which the fluoro substituent had been replaced with a methoxy group via nucleophilic aromatic substitution occurring concurrent with hydrolysis. This material was used in the next step without further purification. To the methoxy carboxylic acid

(2.95 g, 7.37 mmol) was added thionyl chloride (11.9 mL) and the mixture was stirred for 2.5 h at room temperature (solids now dissolved). The volatiles were then removed to provide the crude acyl chloride as a white solid. This material was dissolved in anhydrous CHCI3 (32 mL), aluminum chloride (3.14 g, 23.58 mmol) was added, and the mixture was refluxed for 1.25 h. The reaction was then cooled to room temperature, quenched with ice water (150 mL), diluted with CH2CI2 (50 mL), and stirred until all black sludge had broken up. The mixture was then extracted with CH2CI2 (3 x 50 mL) and the combined organics washed with water (100 mL), dried over Na2SO«, and concentrated to provide an olive solid. This material was purified by column chromatography (20:1 CH2CI2:Et2<D, 2 column volumes -» 10:1 CH2C12:Et2O,

2 column volumes) to give a pale-yellow solid still containing impurities (0.78 g). The crude product was washed 2 times with small portions of CH2CI2, removing the supernatant by pipet each time. It was then dissolved in CH2CI2, boiled down until most of the solvent was removed and the product had partially crystallized, cooled to 0

°C, and the supernatant was again removed by pipet to provide the phenolic ketone 3b (O-demethylation occurs concomitant to cyclization) as a crystalline, pale-yellow solid (595 mg, 22% over 3 steps). ¹ H NMR

(500 MHz, EMSO-dg) 511.92 (s, 1H), 8.12 (dd, J = 8.1, 1.7 Hz, 1H),

7.96 (s, 1H), 7.79 7.73 (m, 1H), 7.58 (dd, J = 8.2, 1.2 Hz, 1H),

7.44 (ddd, J = 8.3, 7.2, 1.2 Hz, 1H), 7.38 (s, 1H), 3.28 (s, 3H); ^1S C

NMR (126 MHz, DMSO-d,) 5 190.2, 158.9, 141.7, 136.8, 135.3, 131.1,

129.9, 129.7, 126.9, 125.9, 125.4, 117.6, 113.0, 39.0.

3-Bromo-2-fluoro-6-mathyldibenzo[c,f][1,2]thiazepin-11(6H )-one

5,5-dioxide (3c). PhenoFluorMix (230 mg; aa mixture of N,N'-1,3- bis(2,6-diisopropylphenyl)chloroimidazolium chloride and CsF;

Fujimoto, T. and Ritter, TT.. 2015) was dried under high vacuum at 140 °C in a vial for 1.5 h. After cooling to room temperature, phenolic ketone 3b (38.7 mg, 0.105 mmol)was added followed by anhydrous toluene

(1.0 mL) and the mixture was stirred for 30 minutes at room temperature, 10 minutes at 80 C, and 45 minutes at 100 °C. The supernatant was then removed from residual solids by pipet, the solids were washed 3 times with CH2CI2, aanndd the combined organics were concentrated to give a pale-yellow solid. This material was purified by repeated preparative TLC (Plate 1: 7:3 hexanes:EtOAc; Plate 2:

CH ₂ C1 ₂ ) to provide ketone 3c as a white, crystalline solid (21 mg, 54%) ¹ .H NMR (400 MHz, CDCI3) 68.29 (dd, J = 8.1, 1.7 Hz, 1H), 8.19

(d, J = 6.2 Hz, 1H), 7.73 (d, J = 8.5 Hz, 1H), 7.67 (ddd, J = 8.1,

7.2, 1.7 Hz, 1H), 7.40 (ddd, JJ == 88..33,, 77..22,, 1.2 Hz, 1H), 7.35 (dd, J =

8.1, 1.2 Hz, 1H), 3.36 (s, 3H); ¹³ C NMR (101 MHz, CDC1 ₃ ) 5188.4, 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 and 119.8, 114.0 and 113.8, 39.2.

3-Chloro-6-methyldibenzo[a,f][1,2]thiazepin-11(6H)-one 5,5- dioxide (3d). Ketone 3d was purchased from Ark Pharm Inc. (Libertyville, IL) and used without further purification.

6-Methyl-3-(trimethylsilyl)dibenzo[c,^][1,2]thiazepin-11( 6H)- one 5,5-dioxide (3e). Ketone 3e was prepared from the aryl chloride utilizing the trimethylsilylation procedure of Buchwald (McNeill, E. et al. 2007). Ketone 3d (462 mg, 1.50 mmol), Pd2dbaa (20.6 mg, 0.0225 mmol), t-BuDavePhos (2'-(Di-tert-butylphosphino)-N,N- dimethylbiphenyl-2-amine, 46.1 mg, 00..113355 mmmmooll)),, and LiOAc (495 mg, 7.50 mmol) were combined under argon. Anhydrous DMF (4.5 mL), water (54 pL, 3.00 mmol) , and hexamethyldisilane (369 pL, 1.80 mmol) were then added, and the resulting orange-brown mixture was heated to 100 °C for 33 h. After cooling to room temperature, the reaction mixture was diluted with water (20 mL) and extracted with Et2O (3 x 10 mL) . The combined organics were washed with water (10 mL) , dried over Na ₃ SO4, and concentrated to yield a yellow crystalline solid. This crude material was recrystallized from MeOH to obtain pure ketone 3e as fine yellow needles (301 mg, 58%) . ¹ H NMR (500 MHz, CDC1 ₃ ) 5 8.30 (dd, J = 8.1, 1.6 Hz, 1H) , 8.04 (d, J = 0.8 Hz, 1H) , 7.91 (d, J = 7.5 Hz, 1H) , 7.85 (dd, J = 7.6, 1.1 Hz, 1H) , 7.63 (ddd, J = 8.1, 7.3, 1.7 Hz, 1H) , 7.41 - 7.29 (m, 2H) , 3.35 (s, 3H) , 0.36 (s, 9H) ; ¹³ C NMR (126 MHz, CDCls) 5 191.2, 147.4, 141.9, 138.3, 136.6, 136.0, 134.8, 132.1, 131.2, 130.5, 129.7, 126.0, 124.6, 39.1, -1.2; LR-MS calcd. for Ci ₇ H ₂ oN0 ₃ SSi [M+H] ⁺ 346.09, found 345.86.

3-Iodo-6-methyldibenzo [a,f] [1 , 2 ] thiazepin-11 ( 6H) -one 5,5- dioxide (3f) . To a solution of trimethylsilylketone 3e (108 mg, 0.313 mmol) in anhydrous CH2CI2 (0.94 mL) at 0 °C was added a solution of iodine monochloride (173 mg, 1.06 mmol) in anhydrous CH2CI2 (0.63 mL) dropwise over 3 min. The resulting dark-brown solution was allowed to warm to room temperature, stirred for 35 min (extended reaction times produce polyiodinated byproducts) , and quenched with saturated aqueous Na ₃ S2O ₃ (3 mL) . The resulting mixture was diluted with water (15 mL) and extracted with CH2CI2 (2 x 15 mL) . The combined organics were washed with water (15 mL) , dried over Na ₃ SO4, and concentrated to yield a yellow solid. This material was purified by column chromatography (1:1 CH2CI2 : hexanes ) to yield impure product. This crude product was recrystallized from MeOH and the resulting fine-white needles were dissolved in CH2CI2 and concentrated, causing a second crystallization to occur once most of the solvent had been removed. The powdery white crystals thus obtained were washed with ice-cold MeOH and dried to yield the pure ketone 3f (68.4 mg, 55%) . ¹ H NMR (400 MHz, CDC1 ₃ ) 5 8.32 - 8.27 (m, 2H) , 8.06 (dd, J = 8.1, 1.7 Hz, 1H) , 7.69 - 7.62 (m, 2H) , 7.38 (ddd, J = 8.2, 7.3, 1.1 Hz, 1H) , 7.34 (dd, J = 8.1, 0.9 Hz, 1H) , 3.35 (s, 3H) ; ¹³ C NMR (101 MHz, CDC1 ₃ ) 5 190.1, 142.4, 141.5, 138.1, 135.6, 135.1, 133.9, 133.1, 132.2, 131.0, 126.3, 124.7, 98.7, 39.2; LR-MS calcd. for CI ₄ HIIINO ₃ S [M+H] ⁺ 399.95, found 399.78. 6-Methyl-3-( (trimethyl silyl) ethynyl) dibenzo [c,f] [1,2] thiazepin-11 (6H) -one 5,5-dioxide (3g) . Pc^dbas (20.6 mg, 0.0225 mmol) , XPhos (21.5 mg, 0.0450 mmol) , and K2CO3 were combined in anhydrous DMF (3.0 ml) and the dark-brown mixture was stirred at room temperature for 5 min. Ketone 3d (462 mg, 1.50 mmol) and (trimethylsilyl ) acetylene (505 pL, 2.25 mmol) were then added and the mixture was heated to 110 °C for 3 h. The mixture was then cooled to room temperature, diluted with water (20 mL) , and extracted with Et2O (3 x 30 mL) . The combined organics were washed with water (2 x 20 mL) and brine (20 mL) , dried over Na2SO4, and concentrated to give an orange-brown solid. This material was purified by column chromatography (6:4 hexanes : CH2CI2 , 3 column volumes -^ 1:1 hexanes : CH2CI2 , 5 column volumes) to provide pure ketone 3g as pale-yellow foam, which, on addition of a little Et2O, formed powdery, pale-yellow crystals (553 mg, 81%) . ¹ H NMR (400 MHz, CDCI3) 5 8.31 (dd, J = 8.1, 1.7 Hz, 1H) , 8.01 (d, J = 1.6 Hz, 1H) ,

7.91 (d, J = 8.0 Hz, 1H) , 7.75 (dd, J = 8.0, 1.6 Hz, 1H) , 7.68 - 7.61 (m, 1H) , 7.38 (ddd, J = 8.2, 7.3, 1.2 Hz, 1H) , 7.34 (dd, J = 8.1, 1.1 Hz, 1H) , 3.36 (s, 3H) , 1.21 - 1.10 (m, 21H) ; ¹³ C NMR (101 MHz, CDC1 ₃ ) 5 190.1, 141.6, 137.3, 136.4, 135.3, 135.0, 132.2, 131.8, 131.2, 128.6, 128.1, 126.3, 124.8, 104.3, 97.5, 39.2, 18.8, 11.4.

3-Ethynyl-6-methyldibenzo [c,f] [1 , 2 ] thiazepin-11 ( 6H) -one 5,5- dioxide (3h) . To a solution of ketone 3g ( 531 mg, 1.17 mmol) in anhydrous THF (5.0 mL) was added a solution of tetrabutylammonium fluoride (1.0 M in THF, 2.34 mL, 2.34 mmol) at room temperature and the resulting black solution was stirred for 2 h. The reaction mixture was then diluted with CH2CI2 (50 mL) , washed with water (2 x 20 mL) and brine (20 mL) , dried over Na2SO4, and concentrated to give a brown solid. This material was purified by column chromatography (1: 1 hexanes : CH2CI2 , 3 column volumes CH2CI2, 3 column volumes) to provide the product contaminated with residual silane. This material was washed 2x with small portions of hexanes and dried to give pure ketone 3h as powdery, off-white crystals (265 mg, 76%) . ¹ H NMR (400 MHz, CDCI3) 5 8.30 (dd, J = 8.1, 1.7 Hz, 1H) , 8.05 (d, J = 1.6 Hz, 1H) ,

7.92 (d, J = 8.0 Hz, 1H) , 7.78 (dd, J = 8.0, 1.6 Hz, 1H) , 7.68 - 7.62 (m, 1H) , 7.38 (ddd, J = 8.2, 7.3, 1.1 Hz, 1H) , 7.34 (dd, J = 8.1, 1.1 Hz, 1H) , 3.36 (s, 1H) , 3.35 (s, 3H) ; ¹³ C NMR (101 MHz, CDC1 ₃ ) 5 190.2, 141.7, 137.3, 136.5, 136.0, 135.0, 132.2, 131.9, 130.9, 128.8, 126.7,

126.2, 124.7, 82.2, 81.3, 39.1.

6-Methyl-3-(methylthio)dibenzo[c,f][1,2]thiazepin-11(6H)- one

5,5-dioxide (3i). To a solution of sodium thiomethoxide (116 mg, 1.65 mmol) in anhydrous DMF (2.0 mL) was added ketone 3d (462 mg, 1.50 mmol) and the resulting yellow suspension was stirred at room temperature for 1 h. Additional sodium 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 CH2CI2

(10 mL, 2 x 5 mL). The combined organics were washed with water (20 mL), dried over Na ₂ SO ₄ , and concentrated to yield aa yellow oil containing residual DMF. This crude was diluted with Et2<D and chilled on ice causing the product to crystallize as pale-yellow needles.

These crystals were washed with several small portions of ice-cold EtaO and dried to give the pure ketone 3i (331 mg, 69%). ¹ H NMR (500

MHz, CDCl,) 58.31 (dd, J = 8.1, 1.6 Hz, 1H), 7.92 (d, J = 8.3 Hz,

1H), 7.73 (d, J = 2.0 Hz, 1H), 7.62 (ddd, J = 8.0, 7.4, 1.7 Hz, 1H),

7.48 (dd, J = 8.3, 2.0 Hz, 1H), 7.40 7.33 (m, 2H), 3.33 (s, 3H),

2.59 (s, 3H); ¹³ C NMR (126 MHz, CDCl _a ) 5189.5, 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. for C15H14NO3S2 [M+H] ⁺ 320.04, found 320.75.

Preparation of Diarylthiazepinyl Chlorides (5)

Scheme 2. Preparation of diarylthiazepinyl chlorides.

General Procedure for Preparation of Diarylthiazepinyl Alcohols

(4). Sodium borohydride (2 equivalents) was added to an ice-cooled solution (or suspension) of the appropriate ketone 3 (1 equivalent) in MeOH (0.05 M based on 3) and the mixture was allowed to warm to room temperature and stirred until TLC indicated the complete consumption of starting material. The reaction was then quenched with saturated aqueous ammonium chloride (5 mL per mmol 3) and saturated aqueous NaHCO3 (5 mL per mmol 3). The MeOH was evaporated and the precipitate was filtered, washed with water, and dried (alternatively, the residue was extracted with EtOAc and the combined organic layers were washed with water, dried over Na2SO<, filtered, and concentrated).

The resulting product 4 was used in the next step without further purification. 127.9, 127.0, 122.7, 76.2, 39.4; LR-MS calcd. for Ci ₄ HnBrNO ₂ S [M-OH] ⁺ 335.97, found 335.89.

3-Bromo-2 -fluoro- 11 -hydroxy- 6-methyl- 6 , 11 -dihydrodibenzo [c,f] [1 , 2 ] thiazepine 5,5-dioxide (4c) . The product 4c was prepared according to the general procedure and obtained as a pale-yellow glass containing minor impurities (21.1 mg, quantitative) . ¹ H NMR (400 MHz, CDC1 ₃ ) 5 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, 4H) , 6.06 (br s, 1H) , 3.88 (br s, 1H) , 3.26 (s, 3H) ; ¹³ C NMR (101 MHz, CDC1 ₃ ) 5 162.8 and 160.3, 140.8 and 140.7, 138.1, 136.5, 134.4 and 134.3, 133.81 and 133.79, 130.1, 129.6, 128.2, 127.1, 117.1 and 116.8, 109.3 and 109.1, 73.6, 38.7. ll-Hydroxy-3-iodo-6-methyl-6 , 11 -dihydrodibenzo [c,f] [1,2] thiazepine 5,5-dioxide (4f) . The product 4f was prepared according to the general procedure and obtained as a white solid (74.8 mg, 95%) . ¹ H NMR (500 MHz, CDC1 ₃ ) (observed as a ~4 : 1 ratio of 2 conformers, resulting in partial integrals) 5 8.27 (d, J = 1.8 Hz, 1H) , 7.99 (dd, J = 7.7, 1.1 Hz, 0.2H) , 7.93 (dd, J = 8.1, 1.8 Hz, 0.8H) , 7.68 (d, J = 7.2 Hz, 0.2H) , 7.65 - 7.58 (m, 1H) , 7.53 (td, J = 7.6, 1.3 Hz, 0.2H) , 7.44 - 7.37 (m, 1.8H) , 7.37 - 7.29 (m, 1.8H) , 5.92 (s, 1H) , 4.40 (d, J = 9.6 Hz, 0.2H) , 4.15 (d, J = 7.5 Hz, 0.8H) , 3.20 (s, 2.4H) , 3.14 (s, 0.6H) ; ¹³ C NMR (126 MHz, CDC1 ₃ ) (additional peaks due to conformers) 5 142.4, 138.8, 138.7, 137.5, 136.5, 135.4, 133.6,

132.1, 131.7, 131.4, 130.6, 130.1, 130.0, 128.9, 128.4, 127.9, 127.6, 127.0, 126.9, 93.6, 76.2, 39.3; LR-MS calcd. for CI ₄ HHINO ₂ S [M-OH] ⁺ 383.96, found 383.71.

3-Ethynyl-ll-hydroxy-6-methyl-6 , 11-dihydrodibenzo [c,f] [1 ,2 ] thiazepine 5,5-dioxide (4h) . The product 4h was prepared according to the general procedure and obtained as an off-white solid (very slight yellow tint, 253 mg, 98%) . ¹ H NMR (500 MHz, CDC1 ₃ ) 5 8.09 (d, J = 1.6 Hz, 1H) , 7.70 (dd, J = 7.8, 1.7 Hz, 1H) , 7.65 (d, J = 1.9 Hz, 1H) , 7.62 (dd, J = 7.8, 1.6 Hz, 1H) , 7.40 (td, J = 1.6, 1.7 Hz, 1H) , 7.34 (td, J = 7.5, 1.4 Hz, 1H) , 7.31 (dd, J = 7.9, 1.4 Hz, 1H) , 5.95 (d, J = 9.8 Hz, 1H) , 4.27 (d, J = 9.9 Hz, 1H) , 3.22 (s, 1H) , 3.17 (s, 3H) ; ¹³ C NMR (126 MHz, CDC1 ₃ ) 5 139.1, 138.1, 137.4, 136.7, 135.1, 131.74, 131.68, 130.4, 130.1, 127.8, 126.9, 123.3, 81.5, 80.2, 76.6, 39.4. ll-Hydroxy-6-methyl-3- (methyl thio) -6, 11 -dihydrodibenzo [c,f]

[1 ,2 ] thiazepine 5,5-dioxide (4i) . The product 4i was prepared according to the general procedure and obtained as a pale-yellow crystalline solid (323 mg, quantitative) . ¹ H NMR (500 MHz, CDCI3) 5 7.75 (d, J = 2.0 Hz, 1H) , 7.57 (dd, J = 7.6, 1.3 Hz, 1H) , 7.54 (d, 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 (s, 3H) , 2.51 (s, 3H) ; ¹³ C NMR (126 MHz, CDC1 ₃ ) 5 140.8, 138.8, 137.4, 136.0, 134.0, 131.2, 130.4, 130.3, 129.7, 127.7, 127.0, 124.8, 75.9, 39.2, 15.4; LR-MS calcd. for C15H14NO2S2 [M-OH] ⁺ 304.05, found 304.71.

General Procedure for Preparation of Diaryl thiazepinyl Chlorides (5) . Thionyl chloride (6 equivalents) was added dropwise to a solution of the appropriate alcohol 4 (1 equivalent) in anhydrous CH2CI2 (0.065 M based on 4) at 0 °C. The reaction mixture was then warmed to room temperature, stirred overnight, and concentrated to provide the corresponding chloride 5, which was used directly in the following reactions without further purification.

3 - Bromo - 11 - chi or o - 6 -methyl -6,11 -dihydrodibenzo [ c , f]

[1 ,2 ] thiazepine 5,5-dioxide (5a) . The product 5a was prepared according to the general procedure and obtained as a white solid (1.92 g, 99%) . ¹ H NMR (400 MHz, CDC1 ₃ ) 5 8.14 (d, J = 2.1 Hz, 1H) , 7.66 (dd, J = 8.3, 2.1 Hz, 1H) , 7.55 - 7.49 (m, 2H) , 7.45 - 7.40 (m, 2H) , 7.39 - 7.33 (m, 1H) , 6.10 (s, 1H) , 3.58 (s, 3H) ; ¹³ C NMR (101 MHz, CDC1 ₃ ) 5 142.0, 139.2, 137.6, 135.6, 134.1, 133.0, 131.7, 131.0, 130.2, 129.5, 129.0, 124.3, 63.7, 39.3; LR-MS cald. for Ci ₄ HnBrNO ₂ S [M-C1] ⁺ 335.97, found 335.79.

3-Bromo-ll-chloro-2-fluoro-6-methyl-6 , 11-dihydrodibenzo [c,f]

[1 ,2 ] thiazepine 5,5-dioxide (5c) . The product 5c was prepared according to the general and obtained as an off-white solid (21.3 mg, quantitative) . ¹ H NMR (500 MHz, CDC1 ₃ ) 5 8.21 (d, J = 6.6 Hz, 1H) , 7.55 - 7.50 (m, 2H) , 7.44 (d, J = 7.7 Hz, 1H) , 7.40 - 7.35 (m, 1H) , 7.32 (d, J = 8.7 Hz, 1H) , 6.07 (s, 1H) , 3.57 (s, 3H) ; ¹³ C NMR (126 MHz, CDCI3) 5 161.7 and 159.6, 139.0, 137.5 and 137.4, 137.04, 136.98, 133.78 and 133.77, 131.8, 130.0, 129.4, 129.1, 118.9 and 118.7, 111.3 and 111.1, 62.7, 39.1. 3 , 11 -Dichloro- 6-methyl -6 , 11 -dihydrodibenzo [c,f] [1,2] thiazepine 5,5-dioxide (5d) . Chloride 5d was purchased from Ark Pharm Inc. (Libertyville, IL) and used without further purification.

11 -Chloro- 3-iodo- 6-methyl- 6 , 11 -dihydrodibenzo [c, f ]

[1 ,2 ] thiazepine 5,5-dioxide (5f) . The product 5f was prepared according to the general procedure and obtained as a gray solid (73.4 mg, 96%) . ¹ H NMR (400 MHz, CDC1 ₃ ) 5 8.32 (d, J = 1.8 Hz, 1H) , 7.87 (dd, J = 8.2, 1.8 Hz, 1H) , 7.57 - 7.48 (m, 2H) , 7.43 (d, J = 7.1 Hz, 1H) , 7.39 - 7.33 (m, 1H) , 7.27 (d, J = 7.1 Hz, 1H) , 6.08 (s, 1H) , 3.57 (s, 3H) ; ¹³ C NMR (101 MHz, CDC1 ₃ ) 5 141.8, 141.5, 139.3, 137.6, 136.7, 134.7, 132.9, 131.7, 130.1, 129.5, 129.0, 95.4, 63.8, 39.3; LR-MS calcd. for C14H11INO2S [M-C1] ⁺ 383.96, found 383.70. ll-Chloro-3-ethynyl-6-methyl-6 , 11 -dihydrodibenzo [c,f]

[1 ,2 ] thiazepine 5,5-dioxide (5h) . The product 5h was prepared according to the general procedure and obtained as an off-white crystalline solid (269 mg, quantitative) . ¹ H NMR (400 MHz, CDC1 ₃ ) 5 8.13 (d, J = 1.7 Hz, 1H) , 7.62 (dd, J = 8.1, 1.7 Hz, 1H) , 7.56 - 7.48 (m, 3H) , 7.44 (d, J = 7.1 Hz, 1H) , 7.36 (ddd, J = 7.7, 6.4, 2.1 Hz, 1H) , 6.13 (s, 1H) , 3.58 (s, 3H) , 3.22 (s, 1H) ; ¹³ C NMR (101 MHz, CDC1 ₃ ) 5 140.7, 139.3, 137.5, 135.6, 135.2, 131.74, 131.67, 131.5, 130.2, 129.4, 128.9, 124.8, 81.3, 80.8, 63.9, 39.2.

11 -Chloro- 6-methyl -3- (methylthio) -6 , 11 -dihydrodibenzo [ c, f ]

[1 ,2 ] thiazepine 5,5-dioxide (5i) . The product 5i was prepared according to the general procedure and obtained as an off-white solid (329 mg, 98%) ^T H NMR (400 MHz, CDC1 ₃ ) 5 7.78 (s, 1H) , 7.56 - 7.47 (m, 2H) , 7.45 - 7.40 (m, 2H) , 7.38 - 7.32 (m, 2H) , 6.12 (s, 1H) , 3.58 (s, 3H) , 2.53 (s, 3H) . ¹³ C NMR (101 MHz, CDC1 ₃ ) 5 142.9, 140.9, 139.4, 137.9, 131.9, 131.5, 130.9, 130.1, 129.6, 129.5, 128.9, 124.1, 64.5, 39.3, 15.3; LR-MS calcd. for C15H14NO2S2 [M-C1] ⁺ 304.05, found 304.74.

Preparation of Amine Side Chains (7)

Scheme 3. Preparation of aminoalkanoic acid esters.

9-Aminononanoic acid hydrobromide (6a) . Saturated aqueous NH3

(28-30% NH3, 30 mL) and 9-bromononanoic acid (949 mg, 4.00 mmol) were combined and the resulting colorless solution was stirred at room temperature for 23 h. The mixture was then boiled for ~15 min open to the atmosphere to remove most of the NH3 and then fully concentrated in vacuo to give amino acid 6a as a white solid (1.04 g, quantitative) .

¹ H NMR (500 MHz, MeOD) 5 2.91 (t, J = 7.8 Hz, 2H) , 2.20 (t, J = 7.4 Hz, 2H) , 1.70 - 1.56 (m, 4H) , 1.43 - 1.32 (m, 8H) ; ¹³ C NMR (126 MHz, MeOD) 5 180.9, 40.7, 37.5, 30.3, 30.1, 29.9, 28.5, 27.3, 26.9.

10 -Aminodecanoic acid hydrobromide (6b) . Saturated aqueous NH3 (28-30% NH3, 60 mL) and 10-bromodecanoic acid (2.01 g, 8.00 mmol) were combined and the resulting colorless solution was stirred at room temperature for 23 h. The mixture was then boiled for ~15 min open to the atmosphere to remove most of the NH ₃ and then fully concentrated in vacuo to give amino acid 6b as a white solid (2.22 g, quantitative) . 1H NMR (500 MHz, MeOD) 8 2.92 (t, J = 7.5 Hz, 2H) , 2.21 (t, J = 7.5 Hz, 2H) , 1.70 - 1.56 (m, 4H) , 1.43 - 1.31 (m, 10H) ; ¹³ C NMR (126 MHz, MeOD) 5 180.5, 40.8, 37.1, 30.4, 30.20, 30.18, 30.0, 28.5, 27.3, 26.8.

11-Aminoundecanoic acid (6c) . Amino acid 6c was purchased from Thermo Fisher Scientific Inc. in the neutral zwitterion form and used without further purification.

General Procedure for Preparation of Aminoalkanoic Acid Esters (7) . Thionyl chloride (3 equivalents) was slowly added to anhydrous EtOH (0.3 mL per mmol SOCI2) at room temperature (some warming) . This solution was allowed to return to room temperature and added to the appropriate amino acid 6 (in salt or zwitterion form) , the resulting suspension was sonicated for ~1 min as needed to break up large particles, and then the mixture was stirred for 24 h at room temperature. The reaction mixture was concentrated in vacuo and the resulting solid was treated with a small quantity of anhydrous EtOH and concentrated again. This procedure was then repeated 2x more to ensure removal of residual HC1. The resulting solid was triturated with boiling hexanes, allowed to cool and settle, and the supernatant was carefully removed by pipet. This procedure was then repeated lx more and the solids dried to provide the corresponding amino ester 7 as the hydrochloride salt, which was used directly in the following reactions without further purification.

Ethyl 9 -aminononanoate hydrochloride (7a) . The product 7a was prepared according to the general procedure and obtained as a paleyellow solid (1.09 g, quantitative) . ¹ H NMR (500 MHz, MeOD) 5 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 - 1.57 (m, 4H) , 1.44 - 1.31 (m, 8H) , 1.24 (t, J = 7.1 Hz, 3H) ; ¹³ C NMR (126 MHz, MeOD) 5 175.5, 61.4, 40.8, 35.0, 30.1, 29.98, 29.97,

28.5, 27.4, 26.0, 14.5.

Ethyl 10 -aminodecanoate hydrochloride (7b) . The product 7b was prepared according to the general procedure and obtained as an off- white solid (2.38 g, quantitative) . ¹ H NMR (400 MHz, MeOD) 5 4.11 (q, J = 7.1 Hz, 2H) , 2.92 (t, J = 7.7 Hz, 2H) , 2.30 (t, J = 7.4 Hz, 2H) , 1.72 - 1.56 (m, 4H) , 1.44 - 1.28 (m, 10H) , 1.24 (t, J = Hz, 3H) ; ¹³ C NMR (101 MHz, MeOD) 5 175.6, 61.4, 40.8, 35.1, 30.24, 30.20, 30.09, 30.08, 28.6, 27.4, 26.0, 14.5.

Ethyl 11 -aminoundecanoate hydrochloride (7c) . The product 7c was prepared according to the general procedure but without the hexane wash step and obtained as an off-white solid (2.07 g, 97%) . ^-H NMR (500 MHz, MeOD) 5 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 (m, 12H) , 1.24 (t, J = 7.1 Hz, 3H) ; ¹³ C NMR (126 MHz, MeOD) 5 175.6, 61.4, 40.8, 35.1, 30.40, 30.38, 30.3, 30.2, 30.1, 28.6, 27.4, 26.0, 14.5.

Ethyl 7-aminoheptanoate hydrochloride (7d) . Amino ester 7d was purchased from Ark Pharm Inc. (Libertyville, IL) as the hydrochloride salt and used without further purification. Methyl 8-aminooctanoate hydrochloride (7e). Amino ester 7e was purchased from AURUM PPhhaarrmmaatteecchh LLLLCC (Franklin Park, NJ) as the hydrochloride salt and used without further purification.

Preparation of Diarylthiazep "e Esters (8)

Scheme 4. Preparation of diarylthiazepinamine esters.

General Procedure for Preparation of Diarylthiazepinamines. To a suspension ooff the appropriate chloride 55 (1 equivalent) in nitromethane (0.5 M based oonn 5) was aaddddeedd the appropriate aminoalkanoic acid ester hydrochloride (1.2 equivalents) and EtaN (2.4 equivalents) and the mixture was warmed to 6600 °C and left to stir until TLC indicated that the reaction was complete (typically <1 h). The reaction mixture was then concentrated in vvaaccuuoo and purified directly by column chromatography or preparative TLC. Alternatively, the concentrated reaction residue was partitioned between EtaO (20 mL per mmol 5) and water (20 mL per mmol 5). The ethereal layer was separated and the aqueous extracted again with Et2O (20 mL per mmol 5). The combined organics were washed with water (20 mL per mmol 5) and 10% NH4OH (20 mL per mmol 5), dried over Na2SO«, and concentrated to yield the product. If necessary, the product was further purified by column chromatography or preparative TLC.

Ethyl 7-((3-ethynyl-6-methyl-5,5-dioxido-6,11-dihydrodibenzo

[o,f][1,2]thiazepin-11-yl)amino)heptanoate (8a).

The product 8a was prepared according to the general procedure and purified by preparative TLC (10:1 CH2C12:Et2O) to provide a viscous, yellow oil (30.8 mg, 68%). ¹ H NMR (500 MHz, CDC1 ₃ ) 58.09 (d, J = 1.7

Hz, 1H), 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),

4.11 (q, J = 7.1 Hz, 2H), 3.34 (s, 3H), 3.16 (s, 1H), 2.46 (tq, 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); ¹³ C NMR (126 MHz, GDC1 ₃ ) 5173.8, 139.2, 139.0, 138.8,

138.7, 135.5, 132.2, 130.2, 129.9, 129.4, 128.1, 127.9, 122.7, 81.6,

79.6, 66.5, 60.3, 48.2, 38.6, 34.4, 30.0, 29.1, 27.0, 25.0, 14.4.

Ethyl 7-((3-brotno-2-fluoro-6-methyl-5,5-dioxido-6,ll- dihydrodibenzo[a,f][1,2]thiazepin-ll-yl)amino)heptanoate (8b).

The product 8b was prepared according to the general procedure and purified by column chromatography (CH2CI2, 2 column volumes -» 20:1

CH ₂ Cl ₂ :Et ₂ O, 2 column volumes → 7:3 CH2C12:Et2O, 2 column volumes) to provide a viscous, pale-yellow oil (20.6 mg, 78%). ¹ H NMR (500 MHz,

CDClg) 58.16 (d, J= 6.6 Hz, 1H), 7.42 - 7.28 (m, 5H), 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, J = 7.1 Hz, 3H); ¹³ C NMR

(101 MHz, CDCla) 5173.8, 162.2 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-ll-yl)amino)heptanoate (8c).

The product 8c was prepared according to the general procedure and obtained as a viscous, pale-yellow oil (44.0 mg, 92%). ^l H NMR (400

MHz, CDCls) 57.78 (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). ¹³ C NMR (101 MHz, CDC1 ₃ ) 5173.8, 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 C24H33N2O4S2 [M+H] ⁺ 477.19, found 476.70.

Methyl 8-((3-bromo-6-methyl-5,5-dioxido-6,11-dihydrodibenzo

[a,f][1,2]thiazepin-ll-yl)amino)octanoate (8d).

The product 8d was prepared according to the general procedure and purified by column chromatography (CH2CI2, 2 column volumes 20: 1 CH2Cl ₂ :Et ₂ O, 3 column volumes 7:3 CH2C12:Et2O, 3 column volumes) to provide a viscous, pale-yellow oil (44.8 mg, 88%) . ¹ H NMR (500 MHz, CDCI3) 5 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 = 1.1 Hz, 2H) , 1.51 - 1.41 (m, 2H) , 1.33 - 1.23 (m, 6H) ; ¹³ C NMR (126 MHz, CDC1 ₃ ) 5 174.4, 140.6, 138.9, 138.6, 137.6, 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-dihydrodibenzo [c,f] [1 , 2 ] thiazepin- 11 -yl) amino) octanoate (8e) .

The product 8e was prepared according to the general procedure and purified by column chromatography (CH2CI2, 4 column volumes 20: 1 CH2Cl ₂ :Et ₂ O, 2 column volumes 7:3 CH2C12:Et2O, 2 column volumes) to provide a viscous, nearly colorless oil (49.0 mg, 88%). ¹ H NMR (400

MHz, CDCI3) 58.26 (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, <7= 7.5 Hz, 2H), 2.01 (br s, 1H), 1.59 (p, <7 = 7.3 Hz,

2H), 1.51- 1.41 (m, 2H), 1.34- 1.24 (m, 6H); “C NMR (101 MHz, CDC1 ₃ )

5 174.3, 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-dihydrodibenzo

[c,f][1,2]thiazepin-11-yl)amino)nonanoate (8f).

The product 8f was prepared according to the general procedure and purified by column chromatography (CH ₂ C1 ₂ , 2 column volumes -» 20:1

CH ₂ Cl ₂ :Et ₂ O, 3 column volumes -» 7:3 CH ₂ Cl ₂ :Et ₂ O, 2 column volumes) to provide a viscous, pale-yellow oil (36.9 mg, 63%). ¹ H NMR (500 MHz,

CDCI3) 58.26 (d, J = 1.8 Hz, 1H), 7.81 (dd, <7 = 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, <7= 8.1

Hz, 1H), 4.97 (s, 1H), 4.11 (q, <7= 7.1 Hz, 2H), 3.37 (s, 3H), 2.45

(t, <7= 7.1 Hz, 2H), 2.27 (t, J= 7.5 Hz, 2H), 2.00 (br s, 1H), 1.59

(p, <7= 7.2 Hz, 2H), 1.51 1.41 (m, 2H), 1.32 1.21 (m, 11H); ¹³ C

NMR (126MHz, CDC1 ₃ ) 5173.94, 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, 38.69, 34.46, 30.17, 29.38, 29.26, 29.15, 27.31, 25.03, 14.39.

Ethyl 9-((3-iodo-6-methyl-5,5-dioxido-6,11-dihydrodibenzo

[c,fl[1,2]thiazepin-11-yl)amino)decanoate (8g).

The product 8g was prepared according to the general procedure and purified by column chromatography (CH2CI2, 2 column volumes 20: 1 CH2C12:Et2O, 3 column volumes 7:3 CH2C12:Et2O, 2 column volumes) to provide a viscous, colorless oil (42.5 mg, 71%) . ¹ H NMR (400 MHz, CDC1 ₃ ) 5 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) , 7.22 (d, J = 8.1 Hz, 1H) , 4.98 (s, 1H) , 4.12 (q, 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) ; ¹³ C NMR (101

MHz, CDCI3) 5 174.0, 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 -dihydrodibenzo

[c,f] [1 , 2 ] thiazepin- 11 -yl) amino) undecanoate (8h) .

General Procedure for Preparation of Carboxylic Acids (9). The appropriate ester 8 (0.04 M final concentration) 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 concentrated and dried thoroughly in vacuo to provide the pure HC1 salt of the corresponding amino carboxylic acid, In some cases, a powdered or crystalline solid resulted directly, but in others, it was necessary to triturate the obtained glass with hexanes and then concentrate to provide a powdered solid if desired.

Note: In some cases, yields below 90% were obtained due to losses while transferring the poorly soluble product between vessels during the concentration process.

7-((3-Ethynyl-6-methyl-5,5-dioxido-6,11-dihydrodibenzo

[a,fl[1,2]thlazepin-ll-yl)amino)heptanoic acid (9a).

9a

Amino ester 8a (15.7 mg, 0.0345 mmol), aqueous LiOH (0.160 mL of 0.216 M solution, 0.0345 mmol), and THF (0.48 mL) were combined and heated to 60 C for 30 min. and then stirred for an additional 17 h at room temperature. The THF was then removed in vacuo and the residue was diluted with water (2 mL) and washed with Et2O (2x 2 mL). The aqueous layer was then acidified to ~ph 4 with 10% aqueous HC1, saturated with NaCl, and extracted with CH2CI2 (3 x 5 mL). The combined organics were washed with brine (1 mL) and concentrated to give a white foam. This material was purified by preparative TLC (20:1 EtOAc:MeOH) to provide the pure product 9a as a white foam (6.7 mg, 46%). ¹ H NMR (500 MHz,

CDCI3) 58.10 (d, J = 1.6 Hz, 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 =

7.3 Hz, 2H), 1.62 - 1.54 (m, 2H), 1.53 1.42 (m, 2H), 1.32 1.22

(m, 4H); ¹³ C NMR (126 MHz, GDCl ₃ ) 5178.1, 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.

7-((3-Bromo-2-fluoro-6-methyl-5,5-dioxido-6,11-dihydrodib enzo

[a,f][1,2]thiazepin-ll-yl)amino)heptanoic acid hydrochloride salt

(9b).

The product 9b was prepared according to the general procedure and obtained as a glassy, white foam (14.1 mg, 95%). ¹ H NMR (400 MHz,

MeOD) 58.32 (d, J = 6.6 Hz, 1H), 7.84 (d, J = 8.9 Hz, 1H), 7.70 (dd,

J = 7.8, 1.6 Hz, 1H), 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); ¹³ C NMR (101

MHz, MeOD) 5176.2, 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, 25.9, 24.4. The product 9c was hydrolyzed according to the general procedure and purified by acid-base extraction. Specifically, after concentration of the reaction mixture to give the crude hydrochloride salt, this material wwaass partitioned between saturated aqueous NaHCOs (with a small amount of NaOH added, 2 mL) and Et ₂ O (2 mL) and the organic layer was removed and discarded, The aqueous layer was washed again with Et2O ((22 mmLL)),, acidified to ~ph 6 with 10% aqueous HC1, and extracted with CH2CI2 (3 x 5 mL). The combined organics were dried over Na ₂ SO4 and concentrated to provide the neutral, zwitterion form of the product as an off-white solid (10.7 mg, 50%). ¹ H NMR (400 MHz,

CDClg) 57.79 (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); ¹³ C NMR (101 MHz, CDC1 ₃ ) 5140.9, 139.5,

139.3, 136.0, 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.

8-((3-Bromo-6-methyl-5,5-dioxido-6,11-dihydrodibenzo

[c,f][1,2]thiazepin-ll-yl)amino)octanoic acid hydrochloride salt

(9d).

The product 9d was prepared according to the general procedure and obtained as a glassy, white foam (37.0 mg, 9977%%)).. ¹ H NM(5R00 MHz,

MeOD) 58.19 (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 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); ¹³ C NMR (126

MHz, MeOD) 5177.5, 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-d±oxido-6,11-dihydrodibenzo

[c,f][1,2]thiazepin-ll-yl)amino)octanoic acid hydrochloride salt

(9e).

The product 9e was prepared according to the general procedure and obtained as a white solid (117 mg, 98%). ¹ H NMR (400 MHz, MeOD 68.36

(d, J = 1.9 Hz, 1H), 8.19 (dd, J = 8.0, 1.9 Hz, 1H), 7.70 (dd, J =

7.8, 1.5 Hz, 1H), 7.65 - 7.58 (m, 2H), 7.55 (dd, J= 8.1, 1.4 Hz, 1H),

7.47 (td, 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, 6H);

¹³ C NMR (101 MHz, MeOD) 5 177.6, 144.3, 142.3, 141.4, 137.9, 136.4,

134.5, 133.1, 129.9, 129.1, 128.6, 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-dihydrodibenzo

[a,f][1,2]thiazepin-ll-yl)amino)nonanoic acid hydrochloride salt

(9f)-

The product 9f was prepared according to the general procedure run under more dilute conditions (0.02 M, because of poor solubility) and obtained as a glassy, white foam (18.7 mg, 76%). ¹³ C NMR (126 MHz,

MeOD) 8.34 (d, 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); ¹³ C NMR (126 MHz, MeOD) 5 177.7, 144.1, 142.1, 141.5,

137.9, 136.2, 134.2, 132.8, 130.9, 129.5, 129.1, 128.6, 97.0, 67.8,

48.4, 39.7, 35.0, 30.0, 29.9, 27.6, 27.5, 26.0.

10-((3-Iodo-6-methyl-5,5-dioxido-6,11-dihydrodibenzo

[a,f][1,2]thiazepin-ll-yl)amino)decanoic acid hydrochloride salt

(9g)-

The product 9g was prepared according to the general procedure run under more dilute conditions (0.01 M, because of poor solubility) and obtained as a glassy, white foam (15.6 mg, 70%). ¹ H NMR (500 MHz,

MeOD) 58.35 (d, J = 1.7 Hz, 1H), 8.19 (dd, J = 8.0, 1.8 Hz, 1H), 7.71

(dd, J = 7.9, 1.4 Hz, 1H), 7.66 7.59 (m, 2H), 7.55 (dd, J = 8.1,

1.3 Hz, 1H), 7.47 (td, J = 7.6, 1.3 Hz, 1H), 5.84 (s, 1H), 3.23 (s,

3H), 2.91 (ddd, J = 12.1, 9.9, 5.6 Hz, 1H), 2.75 (ddd, J = 12.1, 9.8,

6.1 Hz, 1H), 2.27 (t, J = 7.4 Hz, 2H), 1.70 1.54 (m, 4H), 1.34

1.25 (m, 10H); ^XS C NMR (126 MHz, MeOD) 5177.7, 144.3, 142.3, 141.4,

137.9, 136.5, 134.5, 133.1, 129.9, 129.1, 128.6, 128.3, 97.5, 67.8,

48.3, 39.7, 34.9, 30.18, 30.15, 30.1, 29.9, 27.5, 27.3, 26.0.

11-((3-Iodo-6-methyl-5,5-dioxido-6,11-dihydrodibenzo

[c,f][1,2]thiazepin-ll-yl)amino)undecanoic acid hydrochloride salt

(9h).

The product 9h was prepared according to the general procedure run under more dilute conditions (0.01 M, because of poor solubility) and obtained as a glassy, white foam (14.0 mg, 51%). ¹ H NMR (500 MHz,

MeOD) 58.34 (d, J = 1.8 Hz, 1H), 8.17 (dd, J = 8.0, 1.8 Hz, 1H), 7.68

(dd, 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); ¹³ C NMR (126 MHz, MeOD) 5177.8, 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 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 (Table 1) (Rives, M.-L. et al. 2012; Negri, A. et al. 2013).

Transfection. Human MOR cDNA was transfected alongside with RLuc8 inserted at position 91 fused to the full-length mVenus at its N terminus into HEK-293T cells (5 x 10 ⁶ cells/plate) in 10-cm dishes using PEI (Polysciences

Inc.; Warrington, PA) in aa 1:1 ratio diluted in Opti-MEM (Life Technologies Corp.; GGrraanndd Island, NY) ttoo assay for G protein activation as described previously (Rives, M.-L. et al. 2012; Negri,

A. et al. 2013). Cells were maintained in Dulbecco's Modified Eagle Medium (high glucose #11965; Life Technologies) supplemented with 10% FBS (Premium Select, Atlanta Biologicals; Atlanta, GA) and 100 U/mL penicillin and 100 pg/mL streptomycin (#15140, Life Technologies). After 24 hours the media was changed, and the experiment was performed 24 hours later (48 hours after transfection).

BRET. Transfected cells were dissociated and re-suspended in phosphate-buffered saline (PBS). Approximately 200,000 cells/well were added to a black-framed, white well 96-well plate (#60050; Perkin Elmer; Waltham, MA). The microplate was centrifuged and the cells were re-suspended in PBS. Then 5 ppMM of the luciferase substrate coelenterazine H was added to each well for 5 minutes. Following coelenterazine 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 calculating 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 E _M IX _: of [D-Ala ² , N-MePhe ⁴ , Gly-ol]-enkephalin (DAMGO) aass the 100% maximal response for G protein activation, Dose response curves were fit using a three-parameter logistics equation in GraphPad Prism 6. 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.

Example 3. Preparation of Additional Compounds

General Considerations. Reagents and solvents were obtained from commercial sources and were used without further purification unless otherwise stated. All compounds were prepared in racemic form. All reactions were performed in flame-dried glassware under an argon atmosphere unless otherwise stated, and monitored by TLC using solvent mixtures appropriate to each reaction. All column chromatography was performed on silica gel (40-63 pm).Nuclear magnetic resonance spectra were recorded on Bruker 400 or 500 MHz instruments as indicated.

Chemical shifts are reported aass 5 values in ppm referenced to CDCI3 ( ¹ H NMR = 7.26 and ¹³ C NMR = 77.16), MeOD ( ¹ H NMR = 3.31 and ¹³ C NMR =

49.00), or DMSO-d6 ( ¹ H NMR = 2.50 and ¹³ C NMR = 39.52). Multiplicity is indicated as follows: s (singlet); d (doublet); t (triplet); q

(quartet); P (pentet); dd (doublet of doublets); ddd (doublet of doublet of doublets); dt (doublet of triplets); td (triplet of doublets); m (multiplet); br (broad). All carbon peaks are rounded to one decimal place unless such rounding would cause two close peaks to become identical; in these cases, two decimal places are retained.

Two carbon peaks joined by "and" in the peak list correspond to a single carbon atom but are split due to F-C coupling.

Preparation of Additional Diazylthiazepinones (3)

Scheme 6. Preparation of additional diarylthiazepinones.

methyl 4,5-dichloro-2-(chlorosulfonyl)benzoate (1c).A suspension

Of methyl 2-amino-4,5-dichlorobenzoate (1.92 g, 8.73 mmol) in 20% aqueous HC1 (8.7 mL) was sonicated for several minutes and warmed slightly until all clumps were broken up and the mixture was a uniform suspension of fine particles. This mixture was cooled to -5 °C, and a solution of NaNO2 (602 mg, 8.73 mmol) in water (1.45 mL) was added dropwise over ~5 minutes, maintaining the internal temperature below

-5 C. The resulting mixture was then stirred for 20 minutes at -5

°C. Simultaneously, a solution of SO2 (4.47 g, 69.84 mmol) in AcOH

(6.98 mL) and water (0.73 mL) was prepared by bubbling the gas though the mixed solvents at 0 C until the mass had increased by the required amount. To this SO2 solution was then added CuCl (216 mg, 2.18 mmol) followed by the diazonium salt solution portionwise over 15 minutes at 0 °C. The resulting mixture was then stirred for 30 minutes at 0 °C and 30 minutes at room temperature, poured into water (50 mL), and extracted with CH2CI2 (3 x 25 mL). The combined organics were poured into water (50 mL), and solid NaHCO ₃ was added carefully until effervescence ceased. The organic phase was then separated, washed with water (25 mL) and brine (25 mL), dried over Na ₂ SO ₄ , and concentrated to provide the crude sulfonyl chloride 1c as a waxy, very pale-yellow solid (1.75 g, 82 mass% product by NMR, 54% yield). This material was used in the next step without further purification. methyl 4,5-dlchloro-2-(N-methyl-N-phenylsulfamoyl)benzoate (2c).

To a solution of N-methylaniline (541 pL, 553333 mg, 4.97 mmol) in anhydrous CH2CI2 (4.4 mL) at 0 o C was added anhydrous pyridine (3.3 mL) followed by aa solution of crude methyl 4,5-dichloro-2- (chlorosulfonyl)benzoate 1c (1.68 g, 82% pure, 4.52 mmol) in anhydrous

CH2CI2 (4.4 mL) over ~3 minutes. The resulting orange solution was then allowed to warm to room temperature and stirred for 2.5 h. The reaction mixture was then diluted with CH2CI2 (50 mL), washed with 3% aqueous HC1 (2 x 25 mL), brine (25 mL), saturated aqueous NaHCOa (25 mL), and brine again (25 mL), dried over Na2SO«, and concentrated to give a viscous orange oil (1.93 g). This material was purified by column chromatography (9:1 hexanes:EtOAc, 3 column volumes 8:2 hexanes:EtOAc, 2 column volumes) to provide sulfonamide 2c as a viscous, pale-yellow oil that slowly crystallized to give a waxy, off- white solid (1.44 g, 85%). ¹ H NMR (500 MHz, CDC1 ₃ ) 5 7.57 (s, 1H),

7.45 (s, 1H), 7.39 - 7.30 (m, 3H), 7.22 - 7.18 (m, 2H), 3.83 (s, 3H),

3.31 (s, 3H); ¹³ C NMR (126 MHz, CDC1 ₃ ) 5166.3, 140.8, 137.4, 135.1,

134.6, 132.7, 131.8, 130.2, 129.4, 128.1, 127.4, 53.6, 39.1.

2,S-dichloro-S-methyldibenzo[a,f][1,2]thiazepin-11(6H)-on e 5,5- dioxide (3j). Sulfonamide 2c (1.43 g, 3.82 mmol) was dissolved 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 80 °C for 40 minutes.The reaction mixture was diluted with water (125 mL), washed with EtaO (100 mL), acidified with 10% aqueous HC1, and extracted with CH2CI2 (100 mL, 2 x 50 mL). The combined organics were dried over Na2SO<and concentrated to provide the carboxylic acid intermediate as a pale-tan solid (1.33 g), which was used in the next step without further purification. To the carboxylic acid (1.32 g, 3.66 mmol) was added thionyl chloride (5.9 mL), all chunks were broken up by sonication, and the mixture was stirred for 1.5 h at room temperature (solids now dissolved). The volatiles were then removed in vacuo to provide the crude acyl chloride as a viscous yellow oil that slowly crystallized into a waxy yellow solid.This material was dissolved in anhydrous CHCls (16 mL), aluminum chloride (1.56 g, 11.71 mmol) was added, and the mixture was refluxed for 1 h. The reaction was then cooled to room temperature, quenched with ice water (75 mL), and extracted with CH2CI2 (3 x 25 mL). The combined organics were washed with water (25 mL), dried over Na2SO«, and concentrated to give a light-brown solid (1.19 g). This material was purified by column chromatography (hexanes, 1 column volume -»1:1 CH2CI2:hexanes, 1 column volumes -»7:3 CH2CI2:hexanes, 2 column volumes) to give ketone 3j aass an off-white solid (960 mg, 74% over 3 steps).

¹ H NMR (400 MHz, CDC1 ₃ ) 5 8.29 (dd, J = 8.1, 1.7 Hz, 1H), 8.07 (s,

1H), 8.04 (s, 1H), 7.67 (ddd, J = 8.1, 7.3, 1.7 Hz, 1H), 7.40 (ddd, J

= 8.3, 7.3, 1.2 Hz, 1H), 7.36 (dd, J= 8.1, 1.1 Hz, 1H), 3.36 (s, 3H);

^1S C NMR (101 MHz, CDC1 ₃ ) 5188.3, 141.3, 138.3, 137.1, 136.5, 135.4,

135.3, 133.9, 132.4, 130.8, 127.5, 126.6, 124.9, 39.2. methyl 4-chloro-2-(chlorosulfonyl)-5-fluorobenzoate (Id). A suspension of methyl 2-amino-4-chloro-5-fluorobenzoate (4.98 g, 24.46 mmol) in 20% aqueous HC1 (15.9 mL) was sonicated for several minutes and warmed slightly until all clumps were broken up and the mixture was a uniform suspension of fine particles. This mixture was cooled to -5 °C, and a solution of NaNOa (1.69 g, 24.46 mmol) in water (4.1 mL) was added dropwise over ~10 minutes, maintaining the internal temperature below -5 °C. The resulting mixture was then stirred for

20 minutes at -5 C. Simultaneously, a solution of SO2 (12.56 g, 196 mmol) in AcOH (19.6 mL) and water (2.04 mL) was prepared by bubbling the gas though the mixed solvents at 0 °C until the mass had increased by the required amount. To this SO2 solution was then added CuCl (606 mg, 6.12 mmol) followed by the diazonium salt solution portionwise over 25 minutes at 0 °C. The resulting mixture was then stirred for 1 h at 0 o C and 1 h at room temperature, poured into ice water (75 mL), and extracted with CH2CI2 (3 x 30 mL). The combined organics were poured into water (100 mL), and solid NaHCOawas added carefully until effervescence ceased. The organic phase was then separated, washed with water (30 mL) and brine (30 mL), dried over Na ₂ SO ₄ , and concentrated to provide the crude sulfonyl chloride Id as a waxy brown solid (3.39 g, 81 mass% product by NMR, 39% yield). This material was used in the next step without further purification. methyl 4-chloro-5-fluoro-2-(N-methy1-N-phenylsulfamoyl)benzoate

(2d). To a solution of N-methylaniline (1.14 mL, 1.12 g, 10.36 nunol) in anhydrous CH2CI2 (9.1 mL) at 0 C was added anhydrous pyridine (6.9 mL) followed by a solution of crude methyl 4-chloro-2-

(chlorosulfonyl)-5-fluorobenzoate Id (3.35 g, 81% pure, 9.42 mmol) in anhydrous CH2CI2 (9.1 mL) over ~3 minutes. The resulting yellow-brown solution was then allowed to warm to room temperature and stirred for

1.25 h. The reaction mixture was then diluted with CH2CI2 (100 mL), washed with 3% aqueous HC1 (2 x 50 mL), brine (50 mL), saturated aqueous NaHCCh (50 mL), and brine again (50 mL), dried over Na2SO ₄ , and concentrated to give a viscous, dark-orange oil (3.77 g). This material was purified by column chromatography (9:1 hexanes:EtOAc, 3 column volumes 8:2 hexanes:EtOAc, 2 column volumes) to provide sulfonamide 2d as a viscous, pale-yellow oil that slowly crystallized to give a waxy, off-white solid (2.60 g, 77%). ¹ H NMR (400 MHz, CDC1 ₃ )

5 7.44 (d, J = 6.8 Hz, 1H), 7.39 - 7.29 (m, 3H), 7.26 (d, J = 8.3 Hz,

1H), 7.22 7.17 (m, 2H), 3.83 (s, 3H), 3.30 (s, 3H); ¹³ C NMR (101

MHz, CDClg) 5166.2, 161.1 and 158.6, 140.8, 134.03 and 133.96, 133.0,

132.5 and 132.4, 129.4, 128.1, 127.4, 123.3 and 123.1, 116.9 and

116.7, 53.6, 39.0.

3-chloro-2-fluoro-6-methyldibenzo[c,f][1,2]thiazepin-11(6 H)- one 5,5-dioxide (3k). Sulfonamide 2d (2.55 g, 7.13 mmol) was dissolved in 1,4-dioxane (57 mL), water (29 mL) and LiOH • H ₂ O (898 mg, 21.39 mmol) were added, and the mixture was heated at 80 °C for 1 h. The reaction mixture was diluted with water (250 mL), washed with Et ₂ O

(200 mL), acidified with 10% aqueous HC1, and extracted with CH2CI2

(200 mL, 2 x 100 mL). The combined organics were dried over Na2SO ₄ and concentrated to provide the impure carboxylic acid intermediate as a waxy tan solid (2.48 g), wwhhiicchh wwaass used in the next step without further purification. To the crude carboxylic acid (2.45 g) was added thionyl chloride (11.5 mL) and the mixture was stirred for 1.5 h at room temperature (solids now dissolved). The volatiles were then removed in vacuo to provide the crude acyl chloride as a viscous yellow oil that slowly crystallized into a waxy yellow solid. This material was dissolved in anhydrous CHCI3 (31 mL), aluminum chloride (3.04 g, 22.82 mmol) was added, and the mixture was refluxed for 1 h. The reaction was then cooled to room temperature, quenched with ice water (150 mL), and extracted with CH2CI2 (3 x 50 mL). The combined organics were washed with water (50 mL), dried over Na ₂ SO ₄ , and concentrated to give a brownish-gray solid (1.84 g). This material was purified by column chromatography (7:3 hexanes:CH2C12, 2 column volumes -» 1:1 hexanes:CH2C12, 4 column volumes) to give ketone 3k as a crystalline, off-white solid (1.04 g, 45% over 3 steps). ¹ H NMR (500

MHz, CDClg) 58.30 (dd, J = 8.1, 1.7 Hz, 1H), 8.04 (d, J = 6.6 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, 77..22,, 1.2 Hz, 1H), 7.36 (dd, J = 8.1, 1.1 Hz, 1H),

3.36 (s, 3H); ¹³ C NMR (126 MHz, CDC1 ₃ ) 5188.2, 161.8 and 159.8, 141.4,

136.8 and 136.7, 135.4, 134.11 and 134.08, 132.5, 130.6, 128.6, 126.6,

125.9 and 125.8, 124.9, 120.4 and 120.2, 39.2.

2-fluoro-4-methyl-5-nitroaniline (10). To H ₂ SO ₄ (250 mL) was slowly added 2-fluoro-4-methylaniline (25.03 g, 200 mmol) while cooling the mixture oonn ice to prevent excessive warming, and the resulting mixture was stirred until all precipitated solids dissolved to give a transparent brown solution. This aniline solution was then cooled to -10 °C. A second solution was prepared by careful addition of 68-70% m/m HNO3 (20.0 g, 14.1 mL, ~220 mmol) to H2SO4 (28 mL) while cooling the mixture on ice to maintain the temperature at room temperature or below, The HNO3/H2SO4 solution was then added to the cooled aniline solution dropwise over 3 h, taking care not to allow the internal temperature to rise above -5 C. At the end of the addition, the reaction mixture was carefully poured into ice water

(1.5 L) and the resulting mixture was carefully basified by slow addition of an NaOH solution (~450 g dissolved in 600 mL water), cooling the mixture in an ice bath to maintain the internal temperature below 60 °C at all times. The resulting precipitate was collected by filtration, washed thoroughly with water (4x), and dried to provide the pure product 10 as a yellow solid (32.65 g, 96%). ¹ H NMR (500 MHz,

CDCI3) 57.49 (d, J = 8.2 Hz, 1H), 6.92 (d, J = 11.2 Hz, 1H), 3.89 (br s, 2H), 2.48 (s, 3H); ¹³ C NMR (126 MHz, CDC1 ₃ ) 5 154.5 and 152.5,

145.0, 133.5 and 133.3, 125.1 and 125.0, 119.0 and 118.8, 113.2 and

113.1, 20.21. l-fluoro-2-iodo-5-xnethyl-4-nitrobenzene (11). Aniline 10 (10.21 g, 60.00 mmol) was suspended in 36% m/m aqueous HC1 (120 mL) and the mixture cooled to <0 C. To this mixture was added a solution of NaNOz

(4.55 g, 66.00 mmol) iinn wwaatteerr (24 mL) dropwise over 10 minutes, maintaining the internal temperature aatt <0 °C, and the resulting mixture was stirred for 30 minutes at -10 ° CC.. This diazonium salt solution was then added portionwise over 20 minutes to a solution of

KI (19.92 9, 120 mmol) in water ((3366 mmLL)) at 0 °C, making sure to maintain the internal temperature of the KI solution below 10 °C during the addition. The resulting very dark-brown mixture was then allowed to warm to room temperature and stirred for 2 h. To the reaction mixture was then added water (300 mL), saturated aqueous

NazSzOa (50 mL), and EtzO (200 mL), and the mixture was shaken until the dark color was dissipated. The organic layer was separated and the remaining aqueous extracted with additional EtzO (2 x 200 mL). The combined organics were washed with water (100 mL) and brine (100 mL), dried over NazSO4, and concentrated to give a dark-orange oil mixed with yellow solids (15.85 g). This material was purified by column chromatography (hexanes, 2 column volumes 25:1 hexanes:EtzO, 3 column volumes) to give the pure product 11 as a crystalline, paleyellow solid (13.53 g, 80%). ¹ H NMR (400 MHz, CDCI3) 5 8.42 (d, J =

5.8 Hz, 1H), 7.03 (dd, J = 8.0, 0.8 Hz, 1H), 2.59 (s, 3H); ¹³ C NMR

(101 MHz, CDClg) 6165.3 and 162.7, 145.8, 137.5 and 137.4, 136.4 and

136.3, 119.4 and 119.1, 77.8 and 77.5, 20.9.

5-fluoro-4-iodo-2-nitr6benzo±c acid (12). Tetrabutylammonium permanganate was prepared fresh according to the literature procedure (Vincent, J. et al. 1987) and dried for 21 h under high vacuum before immediate use. CCoommppoouunndd 1111 ((1100..0077 gg,, 3355..8833 mmmmooll)) was dissolved in anhydrous pyridine (170 mL) and the solution was heated to 60 °C. To this solution was slowly added a second solution of tetrabutylammonium permanganate (27.19 mmol, 75.24 mmol) in anhydrous pyridine (170 mL) over 19 minutes. Details of addition: +3.5 minutes, +10 °C exotherm, stopped addition for ~1 minute and removed external heating; +3.5- 16.5 minutes, addition continued without external heating,maintaining stable internal temperature at 65-70 o C; +16.5-19 minutes, temperature began dropping, so external heating resumed, final third of addition completed more rapidly over 2.5 minutes. After the addition was complete, the reaction mixture was stirred for 30 minutes at 60 C and then concentrated in vacuo to give a dark-brown residue. To this material was added EtOAc (270 mL) and 10% aqueous HC1 (270 mL), followed by solid Na2S2O5 to reduce residual oxidant (color dissipated). The organic layer was separated and the remaining aqueous was extracted with additional EtOAc (2 x 135 mL).The combined organics were washed with water (2 x 135 mL) and then extracted with 5% aqueous NaOH (270 mL, 2 x 135 mL). The basic aqueous extracts were washed with

EtOAc (2 x 135 mL), acidified with concentrated aqueous HC1, and extracted with EtOAc (270 mL, 2 x 135 mL). The combined organics were washed with brine (135 mL), dried over Na2SO«, and concentrated to give carboxylic acid 12 containing minor impurities as an orange-brown solid (5.80 g, 52%). ¹ H NMR (400 MHz, DMSO-c^) 58.52 (d, <7= 5.2 Hz,

1H), 7.72 (d, J = 7.6 Hz, 1H); ^la C NMR (101 MHz, DMSO-ds) 5 164.4,

164.3 and 161.9, 144.74 and 144.70, 134.81 and 134.77, 129.8 and

129.7, 116.6 and 116.3, 87.0 and 86.7. methyl 5-fluoro-4-iodo-2-nitrabenzoate (13). To a solution of carboxylic acid 12 (5.76 g, 18.52 mmol) in MeOH (49 mL) was added

H2SO4 (4.85 mL) and the mixture was refluxed for 21 h. The reaction mixture was then concentrated in vacuo and the resulting oil was diluted with EtOAc (200 mL), washed with saturated aqueous NaHCOs (200 mL) and brine (100 mL), dried over Na2SO«, and concentrated to give a viscous, dark orange-brown oil (5.36 g). This material was purified by column chromatography (hexanes, 1 column volume 20:1 hexanes:EtaO, 2 column volumes -> 9:1 hexanes:Et2O, 3 column volumes) to give ester 13 as a crystalline, pale-yellow solid (3.93 g, 65%). ¹ H NMR (400 MHz, CDC1 ₃ ) 58.35 (d, J = 5.2 Hz, 1H), 7.37 (d, J- = 7.0

Hz, 1H), 3.93 (s, 3H); ¹³ C NMR (101 MHz, CDCla) 5 165.3 and 162.8,

164.3, 144.4, 135.70 and 135.66, 130.2 and 130.1, 116.8 and 116.5,

84.5 and 84.2, 53.8. methyl 2-amino-5-fluoro-4-ioddbenzoate (14). To a solution of ester 13 (3.92 g, 12.06 mmol) in EtOAc (90 mL) and CH ₂ C1 ₂ (30 mL) was added SnCl ₂ • 2H ₂ O (13.61 g, 60.30 mmol) and the mixture was stirred for 21 h. The reaction mixture was then diluted with water (300 mL), solid NaHCOs was added with stirring until bubbling stopped, and the mixture was extracted with EtOAc (3 x 150 mL). The combined organics were washed with water (150 mL) and brine (150 mL), dried over Na ₂ SO ₄ , and concentrated to provide aniline 14 as a crystalline yellow solid (3.55 g, quantitative). ¹ H NMR (500 MHz, CDClg) 57.46 (d, J = 8.8

Hz, 1H), 7.07 (d, J = 5.1 Hz, 1H), 5.57 (br s, 2H), 3.85 (s, 3H); ¹³ C

NMR (126MHz, CDC1 ₃ ) 5167.4, 154.0 and 152.2, 147.4, 126.7, 115.9 and

115.7, 111.04 and 111.00, 90.0 and 89.8, 52.0. methyl 2-(chlorosulfonyl)-5-fluoro-4-iodobenzoate (le). A suspension of aniline 14 (3.49 g, 11.83 mmol) in 20% aqueous HC1 (7.7 mL) was sonicated for several minutes and warmed slightly until all clumps were broken up and the mixture was a uniform suspension of fine particles. This mixture was cooled to <0 ° CC,, and a solution of NaN0 ₂

(816 mg, 11.83 mmol) in water (2.0 mL) was added dropwise over ~10 minutes, maintaining the internal temperature below 0 c. The resulting mixture was then stirred for 2255 minutes at -5 °C. Simultaneously, aa solution of SO ₂ (6.06 g, 94.64 mmol) in AcOH (9.5 mL) and water (0.99 mL) was prepared by bubbling the gas though the mixed solvents at 0 °C until the mass had increased by the required amount. To this SO ₂ solution was then added CuCl (293 mg, 2.96 mmol) followed by the diazonium salt solution portionwise over 10 minutes at 0 C. The resulting mixture was then stirred for 30 minutes at 0 °C and 30 minutes at room temperature, poured into water (50 mL), and extracted with CH ₂ C1 ₂ (3 x 25 mL). The combined organics were poured into wwaatteerr (50 mL), aanndd solid NaHCOa wwaass added carefully until effervescence ceased. The organic phase was then separated, washed with water (25 mL) and brine ((2255 mL), dried over Na ₂ SO ₄ , and concentrated to provide the crude sulfonyl chloride le aass a waxy, pale-yellow solid (2.12 g, 61 mass% product by NMR, 29% yield). This material was used in the next step without further purification. methyl 5-fluoro-4-iodo-2-(N’-methyl-N’-phenylsulfamoyl)benzoate (2e). To a solution of //-methylaniline (401 pL, 395 mg, 3.69 mmol) in anhydrous CH2CI2 (3.2 mL) at 0 °C was added anhydrous pyridine (2.5 mL) followed by a solution of crude methyl 2-(chlorosulfonyl)-5- fluoro-4-iodobenzoate le (2.07 g, 61% pure, 3.35 mmol) in anhydrous

CH2CI2 (3.2 mL) over ~3 minutes. The resulting orange solution was then allowed to warm to room temperature and stirred for 30 minutes. The reaction mixture was then diluted with CH2CI2 (30 mL), washed with

3% aqueous HC1 (2 x 15 mL), brine (15 mL), saturated aqueous NaHCOa (15 mL), and brine again (15 mL), dried over Na2SO4, and concentrated to give a viscous orange oil (2.07 g). This material was purified by column chromatography (9:1 hexanes:EtOAc, 4 column volumes -» 8:2 hexanes:EtOAc, 2 column volumes) ttoo provide sulfonamide 2e as a viscous yellow oil (1.33 g, 88%). NMR (500 MHz, CDC1 ₃ ) 57.72 (d,

J = 5.8 Hz, 1H), 7.39 - 7.30 (m, 3H), 7.21 - 7.16 (m, 2H), 7.14 (d, J

= 7.3 Hz, 1H), 3.83 (s, 3H), 3.29 (s, 3H); ¹³ C NMR (126 MHz, CDC1 ₃ ) 5

166.41 and 166.40, 164.6 and 162.6, 141.7 and 141.6, 140.9, 135.9 and

135.8, 132.48 and 132.45, 129.4, 128.1, 127.4, 115.5 and 115.3, 82.9 and 82.7, 53.6, 38.9.

2-fluoro-3-iodo-6-mathyldibenzo[c,f][1,2]thiazepin-11(6H) -one

5,5-dioxide (31). Sulfonamide 2e (1.31 g, 2.91 mmol) was dissolved in

1,4-dioxane (23 mL), water (12 mL) and LiOH •H2O (366 mg, 8.73 mmol) were added, and the mixture was heated at 80 C for 45 minutes. The reaction mixture was diluted with water (125 mL), washed with EtaO

(100 mL), acidified with 10% aqueous HC1, and extracted with CH2CI2 (100 mL, 2 x 50 mL). The combined organics were dried over Na2SO< and concentrated to provide the impure carboxylic acid intermediate as a viscous orange oil that slowly crystallized to a pale-orange solid (1.10 g), which was used in the next step without further purification. To the crude carboxylic acid (1.08 g) was added thionyl chloride (4.0 mL) and the mixture was stirred for 5 h at room temperature (solids now dissolved). The volatiles were then removed in vacuo to provide the crude acyl chloride as a viscous yellow oil. This material was dissolved in anhydrous CHCI3 (11 mL), aluminum chloride (1.06 g, 7.94 mmol) was added, and the mixture was refluxed for 1 h. The reaction was then cooled to room temperature, quenched with ice water (75 mL), and extracted with CH2CI2 (3 x 25 mL). The combined organics were washed with water (25 mL), dried over Na2SO«, and concentrated to give a tan solid ((00..9900 g). This material was purified by column chromatography (hexanes, 1 column volume -»7:3 hexanes:CH2CI2, 1 column volume -» 1:1 hexanes:CH2CI2, 1 column volume -» 3:7 hexanes:CH2C12, 3 column volumes) to give ketone 31 as an off-white solid (717 mg, 59% over 3 steps). ¹ H NMR (500 MHz, CDC1 _S ) 58.37 (d, <7 = 5.6 Hz, 1H),

8.29 (dd, J = 8.2, 1.7 Hz, 1H), 7.69 - 7.65 (m, 1H), 7.63 (d, <7= 7.9

Hz, 1H), 7.40 (td, <7 = 7.8, 1.2 Hz, 1H), 7.35 (dd, <7 = 8.1, 1.2 Hz,

1H), 3.36 (s, 3H); 13, NMR (126 MHz, CDC1 ₃ ) 5188.6, 165.7 and 163.7,

141.5, 138.74 and 138.68, 137.11 and 137.08, 135.4, 134.3 and 134.2,

132.4, 130.6, 126.5, 124.9, 118.8 and 118.6, 86.4 and 86.2, 39.2.

Preparation of Additional Diarylthiazepinyl Chlorides (5)

Schema 7. Preparation of additional diarylthiazepinyl chlorides. quantitative quantitative quantitative 5J 5k 51

2,3-dichloro-ll-hydroxy-6-methyl-6,11-dihydrodibenzo

[a,fl[1,2]thiazepine 5,5-dioxide (4j). The product 4j was prepared according to the general procedure described in Example 1 and obtained as an off-white solid (935 mg, 98%). ¹ H NMR (400 MHz, CDC1 ₃ ) 58.02 (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, 1H), 3.25 (s, 3H); ¹³ C NMR

(101 MHz, CDCI3) 5 138.2, 138.0, 137.7, 136.8, 136.2, 133.2, 131.0,

130.13, 130.12, 130.0, 128.2, 127.1, 74.1, 38.9.

3-cshloro-2-fluoro-ll-hydroxy-6-methyl-6,11-dihydrodibenz o

[c,f][1,2]thiazepine 5,5-dioxide (4k). The product 4k was prepared according to the general procedure described in Example 1 and obtained as an off-white solid (973 mg, 95%). ¹ H NMR (500 MHz, CDC1 ₃ ) 58.01

(d, J = 6.9 Hz, 1H), 7.63 - 7.58 (m, 1H), 7.55 (d, 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, 3H); ¹³ C NMR (126 MHz,

CDCI3) 5 161.5 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.

2-fluoro-ll-hydroxy-3-iodo-6-methyl-6,11-dihydrodibenzo

[c,f][1,2]thiazepine 5,5-dioxide (41). The product 41 was prepared according to the general procedure described in Example 1 and obtained as an extremely pale-pink solid (669 mg, 94%). ¹ H NMR (400 MHz, CDCl _a )

5 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, 1H), 3.89 (d, J = 8.5 Hz,

1H), 3.25 (s, 3H); ¹³ C NMR (101 MHz, CDClg) 5165.7 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, 128.2, 127.0, 116.2 and 115.9, 80.8 and 80.5, 73.8, 38.7.

Modified Procedure for Preparation of Diarylthiazepinyl

Chlorides (5). Thionyl chloride (12 equivalents) was added dropwise to a solution of the appropriate alcohol 4 (1 equivalent) in anhydrous

CH2CI2 (0.126 M based on 4) at 0 °C. The reaction mixture was then warmed to room temperature, stirred overnight, and concentrated to provide the corresponding chloride 5, which was used directly in the following reactions without further purification.

2,3,ll-trichloro-6-methyl-6,11-dihydrodibenzo

[c,f][1,2]thiazepine 5,5-dioxide (5j). The product 5j was prepared according to the modified procedure and obtained as an off-white solid

(973 mg, quantitative). ¹ H NMR (500 MHz, CDC1 ₃ ) 58.08 (s, 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); ¹³ C NMR (126 MHz, CDC1 ₃ ) 5139.9,

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,ll-dichloro-2-fluoro-6-methyl-6,11-dihydrodibenzo

[o,f][1,2]thiazepine 5,5-dioxide (5k). The product 5k was prepared according to the modified procedure and obtained as a white solid

(1.01 g, quantitative). ¹ H NMR (500 MHz, CDC1 ₃ ) 5 8.07 (d, J = 7.1

Hz, 1H), 7.55 7.48 (m, 2H), 7.44 (d, J = 7.4 Hz, 1H), 7.40 7.33

(m, 2H), 6.08 (s, 1H), 3.57 (s, 3H); 13. NMR (126 MHz, CDC1 ₃ ) 5160.6 and 158.5, 139.0, 137.28 and 137.25, 137.1, 136.3 and 136.2, 131.8,

131.0, 130.0, 129.4, 129.1, 123.5 and 123.4, 119.2 and 119.0, 62.7,

39.1. ll-chloro-2-fluoro-3-iodo-6-methyl-6,11-dihydrodibenzo

[c,f][1,2]thiazepine 5,5-dioxide (51). The product 51 was prepared according to the modified procedure and obtained as a white solid (695 mg, quantitative). ¹ H NMR (500 MHz, CDC1 ₃ ) 58.38 (d, J = 6.0 Hz, 1H),

7.55 - 7.48 (m, 2H), 7.44 (d, J = 7.5 Hz, 1H), 7.40 - 7.33 (m, 1H),

7.24 (d, 8.2 Hz, 1H), 6.07 (s, 1H), 3.57 (s, 3H); ¹³ C NMR (126

MHz, CDC1 ₃ ) 5164.5 and 162.5, 139.53 and 139.50, 139.0, 138.14 and

138.08, 137.64 and 137.61, 137.1, 131.8, 130.0, 129.4, 129.1, 117.8 and 117.6, 83.1 and 82.9, 62.8, 39.1.

Preparation of Additional Diarylthiazepinamine Esters (8)

Scheme 8. Preparation of additional diarylthiazepinamine esters. ethyl 7-((2,3-dichloro-6-methyl-5,5-dioxido-6,11-dihydrodibenzo

[c,f][1,2]thiazepin-ll-yl)amino)heptanoate (81). The product 81 was prepared according to the general procedure described in Example 1 and purified by column chromatography (CH2CI2, 2 column volumes -*20:1 CH ₂ Cl ₂ :Et ₂ O, 4 column volumes) to provide a viscous, pale-yellow oil

(90.2 mg, 90%). ¹ H NMR (400 MHz, CDCla) 58.02 (s, 1H), 7.62 (s, 1H),

7.42 - 7.33 (m, 3H), 7.33 - 7.27 (m, 1H), 5.03 (s, 1H), 4.11 (q, J =

7.1 Hz, 2H), 3.39 (s, 3H), 2.50 (t, J = 7.0 Hz, 2H), 2.27 (t, J = 7.5

Hz, 2H), 1.97 (br s, 1H), 1.60 (p, J = 7.3 Hz, 2H), 1.51 (p, <7= 6.9

Hz, 2H), 1.40 1.27 (m, J = 5.5, 5.0 Hz, 4H), 1.24 (t, J = 7.1 Hz,

3H); ¹³ C NMR (101 MHz, CDC1 ₃ ) 5 173.8, 139.0, 138.8, 138.6, 138.3,

136.7, 132.6, 130.8, 130.4, 129.6, 129.3, 128.5, 128.1, 65.0, 60.3,

48.3, 38.5, 34.4, 30.0, 29.1, 27.0, 24.9, 14.4. ethyl 7-((3-chloro-2-fluoro-6-methyl-5,5-dloxldo-6,Ildihydrodibenz o[c,f][1,2]thiazepin-ll-yl)amino)heptanoate (8j). The product 8j was prepared according to the general procedure described in Example 1 and purified by column chromatography (CH ₂ C1 ₂ , 2 column volumes -»20:1 CH ₂ Cl ₂ :Et ₂ O, 2 column volumes -»7:3 CH ₂ Cl ₂ :Et ₂ O, 2 column volumes) to provide a viscous, pale-yellow oil (433 mg, 90%). ¹ H NMR

(500 MHz, CDCla) 58.00 (d, <7= 7.0 Hz, 1H), 7.41 - 7.32 (m, 4H), 7.29

(td, J = 7.3, 1.5 Hz, 1H), 5.09 (s, 1H), 4.10 (q, J = 7.1 Hz, 2H),

3.38 (s, 3H), 2.51 (td, <7 = 7.2, 1.8 Hz, 2H), 2.27 (t, J = 7.5 Hz,

2H), 1.98 (br s, 1H), 1.60 (p, <7= 7.4 Hz, 2H), 1-51 (p, J = 7.1 Hz,

2H), 1.38 - 1.26 (m, 4H), 1.23 (t, J = 7.1 Hz, 3H); ¹³ C NMR (126 MHz,

CDCla) 5173.8, 160.8 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, 27.0, 24.9, 14.3. ethyl 7-((2-fluoro-3-iodo-6-methyl-5,5-dioxido-6,11- dihydrodibenzo[c,f][1,2]thiazepin-ll-yl)amino)heptanoate (8k). The product 8k was prepared according to the 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 provide a viscous, pale-yellow oil (240 mg, 84%). ¹ H NMR (500 MHz, CDCl _a ) 58.30

(d, J = 6.0 Hz, 1H), 7.41- 7.32 (m, 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 (m, 2H), 2.27 (t, J = 7.5 Hz, 2H), 1.99 (br s, 1H), 1.60 (p, J = 7.4 Hz, 2H), 1.51 (p, J = 7.2 Hz, 2H), 1.38

1.26 (m, 4H), 1.24 (t, J = 7.1 Hz, 3H); ¹³ C NMR (126 MHz, CDCla) 5

173.8, 164.7 and 162.7, 142.9 and 142.8, 139.82 and 139.79, 139.1,

138.2, 136.04 and 136.01, 129.4, 128.7, 128.3, 127.8, 115.7 and 115.5, 80.0 and 79.8, 64.2, 60.3, 48.3, 38.1, 34.3, 30.0, 29.0, 27.0, 24.9,

14.4. methyl 5-((3-bromo-2-fluoro-6-methyl-5,5-dioxido-6,11- dihydrodibenzo[c,f][1,2]thiazepin-ll-yl)amino)pentanoate (81). The product 81 was prepared according to the general procedure described in Example 1 and purified by column chromatography (8:2 hexanes:EtOAc,

3 column volumes -*7:3 hexanes:EtOAc, 4 column volumes) to provide a viscous, pale-yellow oil (196 mg, 81%). ¹ H NMR (500 MHz, CDCl _a ) 58.15

(d, J= 6.6 Hz, 1H), 7.40 - 7.27 (m, 5H), 5.08 (s, 1H), 3.65 (s, 3H),

3.37 (s, 3H), 2.54 (td, J = 7.0, 2.1 Hz, 2H), 2.31 (t, J = 7.3 Hz,

2H), 2.02 (br s, 1H), 1.72 1.63 (m, 2H), 1.59 1.50 (m, 2H); 13 _C

NMR (126 MHz, GDC1 ₃ ) 5 173.9, 161.9 and 159.9, 141.54 and 141.49,

138.9, 138.3, 135.82 and 135.80, 134.2, 129.5, 128.9, 128.4, 127.9,

116.8 and 116.6, 108.7 and 108.5, 64.3, 51.6, 47.8, 38.2, 33.8, 29.6,

22.7.

Preparation of Additional Carboxylic Acids (9)

Scheme 9. Preparation of additional diarylthiazepinamine carboxylic acids.

7-((2,3-dichloro-6-methyl-5,5-dioxido-6,11-dihydrodibenzo

[a,f][1,2]thiazepin-ll-yl)amino)heptanoic acid hydrochloride salt

(9i)- 9i

The product 9i wwaass prepared according to the general procedure described in Example 1 and obtained as an off-white foam (78.5 mg, 88%, Note: some spilled during workup). ¹ H NMR (500 MHz, MeOD) 58.23

(s, 1H), 8.19 (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 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); ¹³ C NMR

(126 MHz, MeOD) 5 177.4, 142.4, 140.1, 139.1, 137.0, 137.0, 134.8,

133.6, 131.3, 129.4, 129.2, 128.6, 67.0, 39.8, 34.6, 29.5, 27.1, 26.8,

25.6.

7-((3-chloro-2-fluoro-6-methyl-5,5-dioxido-6,ll-dihydrodi benzo

[c,f][1,2]thiazepin-ll-yl)amino)heptanoic acid hydrochloride salt

(9j).

9j

The product 9j wwaass prepared according to tthhee general procedure described in Example 1 and obtained aass an off-white foam (396 mg, 92%). ¹ H NMR (400 MHz, MeOD) 58.23 (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, 1H), 5.98 (s, 1H), 3.24 (s, 3H), 3.01 (ddd, J = 12.1, 9.9, 5.9

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 (m, 4H);

¹³ C NMR (101 MHz, MeOD) 5 177.4, 163.0 and 160.4, 142.5, 137.50 and

137.46, 134.8, 133.6, 132.4, 130.9 and 130.8, 129.2, 128.6, 126.7,

125.4 and 125.2, 124.0 and 123.7, 67.1, 48.5, 39.9, 34.6, 29.5, 27.1,

26.9, 25.6. 7-((2-fluoro-3-iodo-6-methyl-5,5-dioxido-6,11-dihydrodibenzo

[c,fl[1,2]thiazepin-ll-yl)amino)heptanoic acid hydrochloride salt

(9k).

The product 9k was prepared according to the general procedure described in Example 1 and obtained as a white solid (210 mg, 91%) containing a minor inpurity (~5 mol%, introduced during preparation of intermediate 41 and carried through following steps). A portion of this material was further purified by recrystallization. A quantity

(199 mg) was re-dissolved in CH2CI2 and concentrated in vacuo to give a white foam. To this was added minimal CH2CI2, causing the product to first dissolve and then crystallize. The product was allowed to settle, the supernatant removed by pipet, and the residue dried in vacuo to give a crystallized sample of product 9k (176 mg). ¹ H NMR

(400 MHz, MaOD) 68.47 (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), 7.49

(td, J = 7.5, 1.5 Hz, 1H), 5.95 (s, 1H), 3.23 (s, 3H), 3.00 (ddd, J =

12.2, 10.0, 5.8 Hz, 1H), 2.85 (ddd, J = 12.2, 9.9, 6.2 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); 13, NMR (101 MHz, MeOD) 5177.4, 167.4 and 164.8, 142.6,

141.1 and 141.0, 137.44 and 137.40, 134.9, 133.5, 132.3 and 132.2,

129.1, 128.6, 126.6, 122.4 and 122.1, 85.7 and 85.5, 67.3, 48.4, 39.9,

34.6, 29.5, 27.1, 26.8, 25.6.

5-((3-bromo-2-fluoro-6-methyl-5,5-dioxido-6,11-dihydrodib enzo

[o,f][1,2]thiazepin-ll-yl)amino)pentanoic acid hydrochloride salt

(91).

The product 91 was prepared according to the general procedure described in Example 1 and obtained as a crystalline white solid (195 mg, 99%). ^L H NMR (500 MHz, MeOD) 58.35 (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); ¹³ C NMR (126

MHz, MeOD) 5176.7, 164.0 and 162.0, 142.5, 137.7 and 137.6, 135.2,

134.8, 133.6, 131.3, 129.2, 128.6, 126.6, 123.7 and 123.4, 113.3 and

113.1, 67.3, 48.2, 39.8, 33.8, 26.5, 22.7.

Example 4. In Vitro Activity of Additional Compounds at Mu Opioid

Receptors

The additional diarylthiazepinamine carboxylic acids (9i, 9j, 9k, and

91) were tested for agonist activity at the human mu opioid receptor

(MOR) using bioluminescence resonance energy transfer (BRET) assays measuring G protein activation (Table 2) as previously described

(Rives, M.-L. et al. 2012; Negri, A. et al. 2013; Example 2 of the present application).

Table 2. Functional agonist activity of compounds at human MOR. All compound s are full agonists relative to the reference agonist DAMGO with potency equal to or higher than tianeptine.

Example 5. Preparation of Additional Compounds

Additional compounds active as agonists of the MOR or DOR are synthesized according to the synthetic methods described in Example 1 and Example 3. FFoorr iinnssttaannccee,, such additional compounds include 9m, 9n, and 9o (Scheme 10), which are active metabolites of compounds 9i,

9j, and 9k, respectively. The ester precursors of these compounds,

8m, Bn, and 8o, are active themselves and also act as prodrugs for compound s 9m, 9n, and 9o, respectively. Scheme 10. Additional diarylthiazepinamine esters and carboxylic acids.

Example 6. Administration of MOR/DOR agonists

An amount of any one of compounds 8a, 8b, 8c, 8d, 8e, 8f, 8g, 8h, 8i, 8j, 8k, 81, 8m, 8n, 8o, 9a, 9b, 9c, 9d, 9e, 9f, 9g, 9h, 9i, 9j, 9k,

91, 9m, 9n, or 9o is administered to a subject afflicted with

Huntington's disease. The amount of the compound is effective to treat the Huntington's disease.

An amount of any one of compounds 8a, 8b, 8c, 8d, 8e, 8f, 8g, 8h, 8i,

8j, 8k, 81, 8m, 8n, 8o, 9a, 9b, 9c, 9d, 9e, 9f, 9g, 9h, 9i, 9j, 9k,

91, 9m, 9n, or 99oo iiss aaddmmiinniisstteerreedd ttoo aa subject afflicted with Rett syndrome. The amount of the compound is effective to treat the Rett syndrome.

An amount of any one of compounds 8a, 8b, 8o, 8d, Be, 8f, 8g, 8h, 81,

8j, 8k, 81, 8m, 8n, 8o, 9a, 9b, 9c, 9d, 9e, 9f, 9g, 9h, 91, 9j, 9k,

91, 9m, 9n, or 9o is administered to a subject afflicted with CDKL5 disorder. The amount of the compound is effective to treat the CDKL5 disorder.

An amount of any one of compounds 8a, 8b, 8o, 8d, 8e, 8f, 8g, 8h, 81,

8j, 8k, 81, 8m, 8n, 8o, 9a, 9b, 9c, 9d, 9e, 9f, 9g, 9h, 91, 9j, 9k,

91, 9m, 9n, or 9o is administered to a subject afflicted with a Rett syndrome variant. The amount of the compound is effective to treat the Rett syndrome variant.

An amount of any one of compounds 8a, 8b, 8c, 8d, 8e, 8f, 8g, 8h, 81,

8j, 8k, 81, 8m, 8n, 8o, 9a, 9b, 9c, 9d, 9e, 9f, 9g, 9h, 91, 9j, 9k, 91, 9m, 9n, or 9o is administered to a subject afflicted with Angelman syndrome . The amount of the compound is effective to treat the

Angelman syndrome.

An amount of any one of compounds 8a, 8b, 8o, 8d, 8e, 8f, 8g, 8h, 81,

8j, 8k, 81, 8m, 8n, 8o, 9a, 9b, 9c, 9d, 9e, 9f, 9g, 9h, 91, 9j, 9k,

91, 9m, 9n, or 9o is administered to a subject afflicted with Prader- Willi syndrome. The amount of the compound is effective to treat the Prader-Willi syndrome.

An amount of any one of compounds 8a, 8b, 8c, 8d, 8e, 8f, 8g, 8h, 81,

8j, 8k, 8811,, 88mm,, 8n, 8o, 9a, 9b, 9c, 9d, 9e, 9f, 9g, 9h, 91, 9j, 9k, 91, 9m, 9n, or 9o is administered to aa subject afflicted with a neurological disorder, wherein the neurological disorder is neonatal onset encephalopathy; X-linked recessive mental retardation; fetal alcohol spectrum disorder; Hirschsprung disease; West syndrome; FOXG1 syndrome; or Lennox-Gastaut syndrome. The amount of the compound is effective to treat the neurological disorder.

Example 7. Solubility Modulation via Dihalogenation

Dihalo substitution of the tricyclic core provides compounds that are more water soluble than their analogous monohalo counterparts, For example, compound 9b iiss mmoorree ssoolluubbllee tthhaann the analogous compound bromotianeptine (Table 3). Likewise, compound 9k is more soluble than the analogous compound iodotianeptine (Table 4). Increased solubility is useful for optimizing pharmacokinetic and formulation properties, for example by reducing variability in pharmacokinetics following oral administration of solid dose forms (increased solubility decreases the dependence of absorption rate on particle size).

Solubility Determination (Method A). A quantity of the appropriate compound sufficient to saturate the resulting solution was added to distilled water (0.50 mL) and the mixture was stirred vigorously for 24 h at room temperature (20 °C). The mixture was then centrifuged for 3 min. at 21,000 x g and the stir bar was carefully removed. The mixture was then centrifuged again for 5 min. at 21,000 x g and the supernatant was carefully removed by syringe and passed through a 0.45 pM syringe filter.An aliquot (300 pL) of the filtered supernatant was concentrated in vacuo and the mass of the residual solids determined in order to calculate the solubility.

Table 3. Solubility of compounds in neutral water at room temperature (20 °C) determined using Method A. Data points represent the average of 2 independent trials. Solubility Determination (Method B).A quantity of the appropriate compound sufficient to saturate the resulting solution wwaass added to distilled water (0.50 mL) and the mixture agitated on an orbital shaker for 2 h at room temperature (20 °C). The mixture was then centrifuged for 5 min. at 21,000 x g and the supernatant was carefully removed by syringe and passed through a 0.45 pM syringe filter. An aliquot (300 pL) of the filtered supernatant was concentrated in vacuo and the mass of the residual solids determined in order to calculate the solubility.

Table 4. Solubility of compounds in neutral water at room temperature (20 °C) determined using Method B.

Example 8. Methylthio Substitution Yields Partial Agonists of DOR

In contrast to all other compounds in this class, which are full agonists of DOR, methylthio substitution of the tricyclic core yields compounds with partial agonist activity at this receptor. For example, compound 9c is a partial agonist at DOR (Fig. 1). Coirpound 9c is also more potent at MOR and DOR than both its corresponding ethyl ester analog and tianeptine (Table 5). 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.

Example 9. Ethynyl Substitution Increases Potency

Introduction of an ethynyl group at position 3 of the aryl ring system provides compound s of higher MOR and DOR ppootteennccyy 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.

Example 10. Esters as Prodrugs

Carboxylate esters are well known as prodrugs for the corresponding carboxylic acids obtained by hydrolysis (Beaumont, K. et al. 2003). Such ester prodrugs may show improved oral bioavailability, better brain penetration, oorr longer duration of action compared to their carboxylic acid counterparts. Accordingly, compounds of this application having an ester side chain (8), although biologically active on their own, may also act as prodrugs for the corresponding carboxylic acids (9). Further, one skilled in the art will be able to apply the methods and knowledge of this application to prepare additional prodrugs. For example, the type of ester (e.g., methyl, ethyl, propyl, isopropyl, tert-butyl, phenyl) or the length of the side chain may be varied to adjust the activity and pharmacokinetic properties of the prodrugs and their corresponding carboxylic acid hydrolysis products.

Example 11. Conversion to Active Metabolites via Beta-Oxidation In

Vivo

Tianeptine is known to be metabolized primarily via beta-oxidation of the carboxylic acid side chain in aa manner similar to fatty acids (Grislain, LL.. et aall.. 1990). This rreessuullttss in metabolites with carboxylic acid side chains shortened sequentially by 2-carbon units. Other carboxylic acid analogs, including the compounds described in the present disclosure, can be metabolized in aa 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 compounds with shorter side chains, which are in many cases also agonists of the MOR and/or DOR. For example, compound 9e, with an 8-carbon side chain, is metabolized into active metabolite 1, with a six-carbon side chain (Scheme 11A). Similarly, compound 9f, with a 9-carbon side chain, is metabolized sequentially into active metabolite 2 and active metabolite 3, with 7- and 5-carbon side chains respectively (Scheme 11B). Similarly, compound s 91, 9m, 9n, and 9o are active metabolites of compounds 9b, 9i, 9j, and 9k, respectively.

Thus, the specific length of the side chain selected is useful for fine control of the pharmacokinetic and pharmacodynamic profile in this genus.

Scheme 11. Conversion to active metabolites via beta-oxidation.

Example 12. Potent Activity of Dihalo-Substituted Compounds

Unexpected

Our previous work has found that placement of a chlorine substituent at position 2 of the diaryIthiazepine core of compounds of the type described in this disclosure 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 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 surprising to find that compounds

9b, 9i, 9j, 9k, and 91 of the present disclosure, 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 at position 2. Accordingly, in this class of compounds, the structure-activity relationship at MOR of disubstituted compounds is different from that of monosubstituted compound s. Table 7. Functional agonist activity of compounds at human MOR. Where indicated, eerrrroorr represents ± SEM of 2 or more independent trials. The data shows that placement of a chlorine substituent at position 2 of the diarylthiazepine core of compounds of the type described in this disclosure is generally detrimental to activity at MOR.

Example 13. pH Dependence of Solubility

Since compounds of type 9 of the present disclosure are zwitterionic, their aqueous solubility depends oonn 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 compounds 9b and 9k are 2-3-fold more soluble than their analogous monohalo counterparts, bromotianeptine and iodotianeptine, respectively, in nneeuuttrraall unbuffered wwaatteerr.. However, at pH 1, the difference in solubility is dramatically enhanced, with compounds 9b and 9k being aatt least 1100--ffoolldd more soluble tthhaann 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 iodotianeptine, respectively (Table

8).

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 different pH may also change their rraattee of dissolution and/or absorption in different compartments of the gastrointestinal tract. For example, 2-fluoro compounds 9j, 9b, and 9k are likely to be more rapidly absorbed from solid dosage forms than their monohalo counterparts tianeptine, bromotianeptine, and iodotianeptine, respectively, given their much higher solubility at low pH, aass would be found in the stomach.

Solubility Determination. Test compounds (4 mg) were added to 200 pL of one of the tested aqueous solutions (hereinafter - buffer): 100 mM aqueous HHCC11 (pH 1) oorr 110000 mM Na-phosphate buffer (pH 7). The obtained suspensions/solutions with the theoretical concentration of 20 mg/mL were further allowed to equilibrate at 25°C on a thermostatic orbital shaker for 24 hours and then centrifuged at 6000 rpm for 4 minutes and filtered through HHTTSS filter plates using a vacuum manifold. In parallel, compound dilutions in 50% acetonitrile/HCl and 30% acetonitrile/Na-phosphate bbuuffffeerr mixes wweerree prepared to theoretical concentrations of 0 mg/mL (blank), 0.1 mg/mL, 0.2 mg/mL, and 0.4 mg/mL in duplicates to generate calibration curves falling within the optimum UV absorption range. TThhee filtrates of test compound s were diluted 100-fold with acetonitrile-buffer mixtures before measuring. The filtered supernatant test samples were transferred to 96-well plates and measured for absorbance in the 200- 550 nm range with 5 nm step increment. The concentrations of compounds in supernatants were calculated using the measured absorbance and the previously determined calibration ccuurrvvee.. Proper absorbance wavelengths for calculations were selected for each compound manually based on absorbance maxima (absolute absorbance unit values for the minimum and maximum concentration points within 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.

Example 14. Analgesic Activity of Compounds

Coirpounds 9b and 9k are potent analgesics in the mouse hot plate assay, with much higher potency than tianeptine (Table 9 and Fig. 2).

Analgesic Activity in Hot Plate Assay. Male C57BL/6 mice were timed for latency to jump on a hot-plate apparatus set to 55 °C, using a 30 s cutoff to prevent tissue damage. Following a baseline test, animals were injected subcutaneously (s.c.) with escalating doses of drug and tested at 15 post-injection (time of maximal effect). Doseresponse curves were fit via nonlinear regression using GraphPad Prism (La Jolla, CA).

Table 9. EDso for analgesic activity in the hot plate assay in male C57BL/6 mice.

Example 15. Combinations with NM)A Receptor Antagonists

Antagonists of the W-methyl-D-aspartate receptor (NMDAR) are known to potentiate the beneficial effects of opioid receptor agonists (Trujillo, K.A. eett aall.. 1994; MMaaoo,, J. et al. 1996). Therefore, pharmaceutical compositions ooff the compound s of the present disclosure, combined with NMDAR antagonists, can be used in the treatment of neurological disorders, as set out herein, The NMDAR antagonist can serve as an adjunct to prevent the development of tolerance to the compounds of the present disclosure with chronic use. Several NMDAR antagonists are also known to be effective therapeutics (Murrough, J.W. et al. 2013; Zarate, C.A. Jr et al. 2006). Therefore, pharmaceutical compositions of the compound s of the present disclosure, combined with NMDAR antagonists, can be used to treat neurological disorders, as set out herein, with enhanced efficacy compared to the compound s ooff the present disclosure alone. Alternatively, the opioid modulator and NMDAR antagonist may be dosed separately, as a novel method for treating neurological disorders, as set out herein.

Non-Limiting Examples of NMDA Receptor Antagonists:

Dextromorphinans - dextromethorphan, dextrorphan, dextrailorphan

Adamantanes memantine, amantadine, rimantadine, nitromemantine

(YQW-36)

Arylcyclohexylamines - ketamine (and its analogs, e.g., tiletamine), phencyclidine (and its analogs, e.g., tenocyclidine, eticyclidine, rolicyclidine), methoxetamine (and its analogs), gacyclidine (GK-11); Miscellaneous neramexane, lanicemine (AZD6765), diphenidine, dizocilpine (MK-801), 8a-phenyldecahydroquinoline (8A-PDHQ), remacemide, ifenprodil, traxoprodil (CP-101,606), eliprodil (Si¬

82.0715), etoxadrol (CL-1848C), dexoxadrol, WMS-2539, NEFA, delucemine (NPS-1506), aptiganel (Cerestat; CNS-1102), midafotel

(CPPene; SDZ EAA 494), 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, GV150526A, GV196771A, CERC-

301 (formerly MK-0657), atomoxetine, 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

Example 16. Combinations with NMDA Receptor Partial Agonists

Weak partial agonists of NMDAR are also known (Moskal, J.R. et al. 2005), and can be used 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, pharmaceutical compositions of tthhee compound s of tthhee present disclosure, combined with NMDAR partial agonists, can be used in the treatment of neurological disorders, aass set out herein. The NMDAR partial agonist can serve as an adjunct to prevent the development of tolerance to the compounds of the present disclosure with chronic use. Similarly, pharmaceutical coirpositions of the compounds of the present disclosure, combined with NMDAR partial agonists, can be used to treat neurological disorders, aass sseett out herein, with enhanced efficacy compared to the compounds of tthhee present disclosure alone. Alternatively, the opioid modulator and NMDAR partial agonist may be dosed separately, as a novel method for treating neurological disorders, as set out herein.

Non-Limiting Examples of NMDA Receptor Partial Agonists:

NRX-1074, rapastinel (GLYX-13)

Example 17. Combinations with Neurokinin 1 Receptor Antagonists Antagonists of the neurokinin 1 receptor (NK-1) are known to modulate the effects of opioid agonists. More specifically, NK-1 antagonists attenuate opioid agents in animal models (Robinson, J.E. et al. 2012; Barbier, EE.. et al. 2013). Therefore, pharmaceutical compositions of the compound s of the present disclosure, combined with NK-1 antagonists, can be used in the treatment of neurological disorders, as set out herein. The NK-1 antagonist can serve as an adjunct to reduce the abuse potential of the compounds of the present disclosure. Specific NK-1 antagonists aarree known to be effective therapeutics (Kramer, M.S. et al. 2004). Therefore, pharmaceutical coirpositions of the compound s of the present disclosure, ccoommbbiinneedd with NK-1 antagonists, can be used to treat neurological disorders, as set out herein, with enhanced efficacy compared to the compounds of the present disclosure alone. Alternatively, the opioid modulator and NK- 1 antagonist may be dosed separately, aass a novel method for treating neurological disorders, as set out herein.

Non-Limiting Examples of Neurokinin 1 Receptor Antagonists: aprepitant, fosaprepitant, casopitant, maropitant, vestipitant, vofopitant, lanepitant, orvepitant, ezlopitant, netupitant, rolapitant, L-733060, L-703606, L-759274, L-822429, L-760735, L-

741671, L-742694, L-732138, CP-122721, RPR-100893, CP-96345, CP-

99994, TAK-637, T-2328, CJ-11974, RP 67580, NKP608, VPD-737, GR

205171, LY686017, AV608, SR140333B, SSR240600C, FK 888, GR 82334

Example 18. Combinations with Neurokinin 2 Receptor Antagonists

Antagonists of the neurokinin 2 receptor (NK-2) are known to show efficacy in treating certain disorders (Overstreet, D.H. et al. 2010). Therefore, pharmaceutical compositions of the compounds of the present disclosure, combined with NK-2 antagonists, ccaann be used in the treatment of neurological disorders, as set out herein, with increased efficacy compared to the compounds of the present disclosure alone. Alternatively, the opioid modulator and NK-2 antagonist may be dosed separately, as a novel method for treating neurological disorders, as set out herein. Non-Limiting Examples of Neurokinin 2 Receptor Antagonists: saredutant, ibodutant, nepadutant, GR-159897, MEN-10376

Example 19. Combinations with Neurokinin 3 Receptor Antagonists

Antagonists of the neurokinin 3 receptor (NK-3) are known to show therapeutic effects (SalomS, et al. 2006). Further, the actions of

NK-3 modulators show a dependency on the opioid receptor system

(Panocka, I. et al. 2001). Therefore, pharmaceutical compositions of the compound s ooff the present disclosure, ccoommbbiinneedd with NK-3 antagonists, can be used in the treatment of neurological disorders, as set out herein, with increased efficacy compared to the compounds of the present disclosure alone. Alternatively, the opioid modulator and NK-3 antagonist may be dosed separately, as a novel method for treating neurological disorders, as set out herein.

Non-Limiting Examples of Neurokinin 3 Receptor Antagonists: osanetant, talnetant, SB-222200, SB-218795

Example 20. Combinations with DOR Agonists

DOR Agonists have been shown to elicit therapeutic effects (Saitoh,

A. et al. 2004; Torregrossa, et al. 2005; Jutkiewicz, E.M. 2006;

Vanderah, T.W. 2010; Peppin, JJ..FF.. and Raffa, R.B. 2015). They have also been shown to reverse the respiratory depression induced by MOR agonists (Su, Y-F. eett al. 1998). Therefore, pharmaceutical coirpositions of the compounds of the present disclosure, combined with DOR agonists, can be used in the treatment of neurological disorders, as set out herein, with increased efficacy, increased safety, or reduced side effects compared ttoo the compounds ooff the present disclosure alone. Alternatively, the opioid modulator and DOR agonist may be dosed separately, as a novel method for treating neurological disorders, as set out herein.

Non-Limiting Examples of DOR Agonists: tianeptine, (+)BW373U86, SNC-80, SNC-121, SNC-162, DPI-287, DPI-3290,

DPI-221, TAN-67, KN-127, AZD2327, JNJ-20788560, NIH11082, RWJ-394674, ADL5747, ADL5859, UFP-512, AR-M100390, SB-235863, 7- spiroindanyloxymorphone.

Example 21. Combinations with Naloxone

Naloxone is an MOR antagonist that is effective in blockading effects induced by classical MOR agonists and is the standard treatment for opioid overdose. It is highly bioavailable by parenteral routes of administration but not by the oral route (Smith, K. et al. 2012). Accordingly, pharmaceutical compositions containing mixtures of an MOR agonist and naloxone remain effective agonists when given by the oral route but the naloxone component inhibits the effects of the MOR agonist component when the mixture is administered parenterally. Thus, addition of naloxone to pharmaceutical compositions containing MOR agonists is useful for preventing their misuse or abuse by parenteral routes of administration. Therefore, pharmaceutical compositions of the compound s of the present disclosure, combined with naloxone, can be used in providing the therapeutic benefits of the compounds of the present disclosure while having diminished potential for abuse.

Example 22. Combinations With SSRI or SNRIs

Selective serotonin reuptake iinnhhiibbiittoorrss (SSRIs) and serotonin- norepinephrine reuptake inhibitors (SNRIs) are effective therapeutic agents (Thase, M.E. 2008; Vaswani, M. et al. 2003; Marks, D.M. et al. 2009). Therefore, pharmaceutical coirpositions of the compound s of the present disclosure, combined with SSRIs or SNRIs, are useful in the treatment of neurological disorders, as set out herein, with increased efficacy compared to the compound s of the present disclosure alone. Alternatively, the opioid modulator and SSRI oorr SNRI may be dosed separately, as a novel method for treating neurological disorders, as set out herein. Further, the compounds of the present disclosure may be used as an add-on therapy to enhance the efficacy of preexisting SSRI or SNRI therapy for neurological disorders, as set out herein.

Non-Limiting Examples of SSRIs: citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, dapoxetine Non-Limiting Examples of SNRIs: venlafaxine, desvenlafaxine

Example 23. Combinations with Methylnaltrexone

Constipation is a frequent, unpleasant side effect of MOR agonists resulting from inhibition of intestinal smooth muscle contractions via activation of MORs located in this tissue. Methylnaltrexone (Relistor) is a clinically approved quaternary ammonium salt of the opioid receptor antagonist naltrexone that does not cross the blood brain barrier. Accordingly, this compound is capable of inhibiting MORs in the gastrointestinal tract and preventing opioid-induced constipation while avoiding simultaneous inhibition of centrally mediated therapeutic effects. Therefore, pharmaceutical coirpositions of the compounds of the present disclosure, combined with methylnaltrexone, are useful in the treatment of neurological disorders, aass set out herein, with reduced constipation compared to the compounds of the present disclosure aalloonnee.. Alternatively, the opioid modulator and methylnaltrexone may be dosed separately, as a novel method for treating the conditions described above with less constipation.

Example 24. Use of Fluoro-Substituted Compounds as PET Radiotracers

Positron emission tomography (PET) is a noninvasive in vivo imaging technique that uses radiotracers to characterize, visualize, and quantify physiological processes at the molecular level (Miller, P.W. et al. 2008). Fluorine-18 is the preferred positron-emitting isotope for use in positron emission tomography (PET). However, placement of a fluorine substituent at an inappropriate position may abolish the activity of a compound at its target of interest. Accordingly, drug compounds containing a fluorine substituent and retaining activity at the target of interest are useful for PET imaging of target engagement and/or drug localization in the body.

In the case of the present disclosure compound s bearing a fluorine substituent at position 2 of the diarylthiazepine ccoorree (e.g., compounds 9b, 9j, 9k, 91, 9n, and 9o) are particularly well suited for this purpose since they are equipotent or more potent as agonists of MOR than their non-fluorinated analogs. In any such compound, fluorine-18 is substituted in place of fluorine-19 to provide a PET radiotracer of MOR.

A PET radiotracer of MOR is useful to determine the occupancy of MOR achieved following administration of different doses of compounds binding to MOR, for example the compounds of the present disclosure, to a subject. Information on the relationship between dosing and MOR occupancy is useful for setting the appropriate dose for use in clinical trials or in the treatment of neurological disorders, as set out herein. It is also useful for defining the pharmacodynamic effect of a compound acting at MOR, since a particular degree of receptor occupancy may be related to effects on physiology (e.g., breath rate) or behavior (e.g., neurological effects).

A radiotracer of MOR is also useful for studying release of endogenous opioid peptides, the natural ligands for MOR in the brain. When an external stimulus induces release of endogenous opioid peptides in a subject, such release can be detected by displacement of an MOR PET radiotracer from MOR binding sites in the brain, demonstrating that the endogenous ligand is competing for binding to these same sites. Accordingly, endogenous opioid peptide release and activation of MOR signaling pathways in response to physiological oorr psychological stimuli may be studied in vivo. Such study and quantification of endogenous opioid signaling is useful in the diagnosis of neurological disorders, as set out herein, or as a biomarker of treatment response.

For example, using such MOR PET imaging techniques, it has been shown that in hheeaalltthhyy individuals, tthheerree is aa rroobbuusstt ddeeccrreeaassee in availability of MOR binding sites in multiple brain regions following social rejection, presumably demonstrating a release of endogenous opioid peptides, which displace the radiotracer (Hsu, DD..TT.. et al.

2013). Accordingly, activation of MOR signaling pathways appears to serve as a natural coping mechanism that attenuates the negative feelings associated with rejection. Interestingly, similar MOR activation is observed in response ttoo social acceptance events, suggesting that tthhiiss signaling system also acts aass aa positive reinforcer (Hsu, D.T. et al. 2013). In contrast, patients with major depressive disorder display almost no change in MOR neurotransmission following identical rejection and acceptance events, suggesting that their natural MOR signaling pathways are dysfunctional (Hsu, D.T. et al. 2013; Hsu, D.T. et al. 2015).

Example 25. Efficacy of Compounds In Treating Huntington's Disease

(HD)

Overview The compounds of the present disclosure are tested for their potential ability to reverse a Huntington's disease-like behavioral pphheennoottyyppee in mice using the SmartCube® system and associated data analysis methods. The tested compounds are expected to demonstrate activity likely to rreevveerrssee the disease phenotype and therefore, potential efficacy in treating Huntington's disease.

Animals All mouse husbandry and experimental procedures are conducted with the approval of the appropriate Animal Care and Use

Committee. Q175 HD model heterozygous mice (PsychoGenics) are bred and aged. These mice are subjected to testing at 6 months of age in the Smartcube® system to establish aa Huntington's Disease-like behavioral phenotype ffoorr comparison drug-induced behavioral phenotypes, as described further below. For screening of the test compound s, wild-type male C57BL/6 mice are used. All animals are examined, handled, and weighed prior to initiation of testing to assure adequate health and suitability and to minimize non-specific stress associated with manipulation. During the course of the study, mice are group-housed in OPTI mouse ventilated cages with 4 mice/cage. 12/12 light/dark cycles aarree maintained. The rroooomm temperature is maintained between 20 and 23°C with a relative humidity maintained between 30 and 70%. Chow and water are provided ad libitum for the duration of the study. Animals are acclimated to the vivarium for at least one week prior to commencing testing and tested at 8-9 weeks of age. Body weight is measured prior to testing. Treatment groups - 12 mice are used in each of the following groups:

1. Vehicle

2. compound 9k 1.0 mg/kg

3. compound 9k 2.0 mg/kg

4. compound 9k 4.0 mg/kg

5. compound 9k 8.0 mg/kg

6. compound 9b 2.5 mg/kg

7. compound 9b 5.0 mg/kg

8. compound 9b 10 mg/kg

9. compound 9b 20 mg/kg

10. compound 9o 1.5 mg/kg

11. compound 9o 3.0 mg/kg

12. compound 9o 6.0 mg/kg

13. compound 9o 12 mg/kg

Other compounds as disclosed herein may also be utilized.

Administration of test compound s is by subcutaneous injection at an injection volume of 10 mL/kg. Saline is used as the vehicle for all test compounds. All testing and data analysis is carried out blinded to treatment.

Behavior testing - The Smartcube® system (PsychoGenics) is utilized to measure numerous spontaneous behaviors and response to challenges in the same testing environment. The hardware includes force sensors and a number of aversive stimuli to elicit behavior. Three high- resolution video cameras provide a constant 3D view of the mouse in the Smartcube® apparatus (SC) throughout the entire testing period. The mice are exposed to a sequence of challenges during the 45-minute test period. Mice aarree injected with vehicle or test compound and placed in the SC 15 minutes after administration.The cubes are cleaned between each run. Computational modelling is performed for behavioral signatures, including tail flick, grooming/sniffing, eeaarr twitch (orientation response), and orientation (walking, running, rearing, freezing). Data analysis - SSeevveerraall analytical methods including Bayesian probabilistic density models are utilized alongside data mining algorithms (Alexandrov, V. et al. 2015). The algorithms consider more than 2,000 measures including frequency and duration of behavioral states such as grooming, rearing, mobility, behavioral transitions and many other features obtained during the test session, Two major types of analyses are routinely conducted: class and subclass.

For class and subclass analysis, a reference data set is built from hundreds of drug doses in multiple drug classes plus a control group. Each reference drug is tested at multiple doses appropriate for that drug in mice. The best performing classifiers aarree chosen from evaluation tests and two separate types of classifiers are built that make independent predictions at drug class and subclass levels.

The class consists of drugs that are currently on the market or have been clinically validated for that specific indication. The sub-class consists of both marketed drugs and other compound s that have been mechanistically validated and is aa larger set than the class. The reference databases are expanded and nneeww databases are kept in development. Once validated, these new databases are incorporated into the analysis to provide additional information about each compound tested.

Data from the screening is processed using proprietary computer vision and data mining algorithms developed by PsychoGenics and the results are compared to signatures of the reference compound s in the database. Multiple analyses of the data are performed to quantitatively produce independent predictions ooff drug class, and drug subclass. The behavioral signatures of the test drugs aarree evaluated using these classifiers to confirm therapeutic utility. The results for the class and subclass analyses are presented as standardized bar charts with percentages that ssuumm to 100 for each dose. The results of the classification at the drug level are presented as individual similarities. Similarity analysis - The outcome from Smartcube® is a large set of features (behavioral parameters) that is used for various analyses. Many of these features are correlated. Therefore, it is useful to form statistically independent combinations ooff the original features (further referred to as de-correlated features). Each de-correlated feature extracts information from the whole cluster of original features, so the new feature space has lower dimensionality. Next, a feature ranking algorithm is applied to score each feature for its discrimination power (ability to separate the two groups, e.g., reference and test).

Ranking is used in the analyses because it weighs each feature change by its relevance. If there is a significant change in some irrelevant features measured for a particular phenotype, the low rank of these features will automatically reduce the effect of such change in the analyses. This means that a conventional "feature selection" approach does not need to be used and information is not lost among the less informative features. Ranking is applied to either the original or the de-correlated features.

It is also useful to examine the de-correlated ranked features as

"clouds". This refers to Gaussian distributions approximating the groups of mice (e.g., between test compound and vehicle or between test compound and a reference compound like tianeptine) in the ranked de-correlated features space. This is used to calculate a quantitative measure of separability (distinguishability) between the two groups. The two highest ranked de-correlated features are chosen to form the 2D coordinate plane for visualization purposes. For visualization purposes, it is possible to plot each cloud with its semi-axes equal to one standard deviation along the corresponding dimensions.

In "proximity-to-the-drug" experiments, the data are typically presented as three classes: reference, target, aanndd test drug,

Therefore, it is instructive to consider and plot the third group, test drug, in the same coordinate system that best discriminates the other groups (reference and target). The drug treatment effect can then be represented as a combination of two components: one along the direction of the "proximity line" (the line connecting the centers of the target and reference clouds) and the component orthogonal to ("pointing away" from) that direction. The relative length of the "proximity" line with respect to the target-reference distance can then be interpreted as the "proximity to target", whereas the relative length of the "other effect" line represents feature changes that move the target + treatment group away from the reference group.The summary of this analysis can be effectively represented as a bar graph, which is referred to as the proximity signature.

Drug-induced behavior similarity analysis - Computational methods for in vivo drug discovery using large-scale datasets have substantially reduced the high cost of drug screening by providing comprehensive and systematic means to discover new biological targets for existing drugs. One of the most successful computational methods for drug screening is the correlative analysis, which uses a wide collection of genome-wide transcriptional expression data from cultured human cells or in vivo behavioral data following treatment with bioactive small molecules together with pattern-matching algorithms to discover functional connections between drugs and diseases.

The underlying hypothesis for correlative analysis is that a drug effective in the treatment of a disease (or reduction of side-effects of another compound) should induce an opposite behavioral profile to that seen in the un-treated disease state (or the other compound), whereas drugs with similar therapeutic indications should induce similar behavioral profiles. Based on this principle, an algorithm called Drug Behavioral Signature Analysis (DBSA; PsychoGenics) is employed. This utilizes drug-induced behavioral data to predict functional connections among drugs or between drugs and diseases.

DBSA compares the behavioral profile induced by a test drug in the SC to the behavioral profile of the disease model of interest in the SC and computes a similarity score to identify the potential therapeutic benefit of the test drug. This analysis identifies compound s with three different sets of profiles: aa)) 'similar' indicating a profile similar to that of the test compound or disease; b) 'reverse' indicating a profile opposite to that of the test compound or disease, thus suggesting a potential therapeutic effect on the disease; and c) 'random' indicating no similarity. The profile of any desired compound or disease can be queried against an existing database of compounds and disease states in order to identify compounds with similar or reverse profiles, depending on the underlying requirements.

For DBSA analysis in the present experiment, the SC behavioral profile induced by each test compound in wild-type mice is compared to the SC behavioral profile of Q175 heterozygous mice (a mmoouussee model of Huntington's disease) at 6 and 10 months of age. Results of DBSA are presented as normalized enrichment ssccoorreess (the sign +/- of which indicates similar/reverse signature), associated p-value (signifying random or non-random), and odds-ratio (level of enrichment).

Additional information on data analysis with the SC can be found in Alexandrov, V. et al. 2015, the contents of which aarree herein incorporated by reference.

In follow-up experiments, Q175 heterozygous mice (6 months of age) are treated with the test compounds or saline vehicle, either acutely or twice-daily for 4 weeks, and the behavioral phenotype of each group as determined in the SC is compared to the SC behavioral phenotype of wild-type littermates using aa proximity signature analysis, as described above.The test compound s are expected to at least partially reverse the behavioral deficits in the Q175 heterozygous mice, with the drug-treated group having a greater proximity than the vehicle- treated group to the wild-type group.

Results - Administration of the disclosed compounds is expected to improve behavioral deficits exhibited by Q175 mice. The compounds are thereby expected to be beneficial in the treatment of Huntington's disease. Discussion

The present disclosure provides aa nnuummbbeerr of diarylthiazepinamine carboxylic acids related to the antidepressant tianeptine that are useful opioid modulators with a number of inproved properties compared to other compounds in this structural class. In addition to its primary activity at the MOR, tianeptine also exhibits low potency agonist activity at the DOR (Gassaway, M.M. et al. 2014). Literature reports suggest that simultaneous activation of DOR, in addition to MOR, will provide therapeutic benefits in treating a number of conditions, For example, DOR agonists alone are known to be efficacious antidepressants and anxiolytics in animal models (Saitoh, A. et al. 2004; Torregrossa, et al. 2005; Jutkiewicz, E.M. 2006). Accordingly, simultaneous activation of DOR can be used to enhance the MOR-dependent antidepressant and anxiolytic effects of compounds in the tianeptine class. Similarly, DOR agonists possess analgesic properties (Vanderah, T.W. 2010; Peppin, J.F. and Raffa, R.B. 2015). Thus, the addition of aa DOR agonist component to the activity profile of tianeptine analogs can be used to enhance their activity. Lastly, DOR agonists have been shown to inhibit the respiratory depression evoked by MOR agonists (Su, YY--FF.. et al. 1998). Therefore, dual MOR/DOR agonists can be used to limit the magnitude ooff this side effect. The present ddiisscclloossuurree provides tianeptine analogs with increased DOR agonist potency compared to the parent compound. Specifically, increasing the length of the carboxylic acid side chain to 8 or more carbons increases the potency of this class as DOR agonists without analogous shifts in MOR potency, such that the DOR:MOR potency ratio is shifted in favor of DOR. Notably, varying the length of this side chain is also useful for modulating the pharmacokinetic properties within this class and longer chain analogs can be used to produce a number of active metabolites with shorter carboxylic acid side chains following beta-oxidation in vivo.

This disclosure also provides alternative substitution patterns on the aryl ring system (dihalo, alkynyl, and methylthio substituents) that are sufficient to maintain similar or improved opioid activity compared to the monohalo substitution pattern (and improved potency relative to tianeptine itself).These alternative substitution patterns also provide other unique properties. For example, the methylthio substitution yields compounds with partial agonist activity at DOR, a contrast to all other compounds in this class, which aarree full agonists. Further, dihalo substitution provides compounds that are more water soluble than their analogous monohalo counterparts, at both neutral pH and in particular, at low pH. Increased solubility is useful for optimizing pharmacokinetic and formulation properties, for example by reducing variability in pharmacokinetics following oral administration of solid dose forms (increased solubility decreases the dependence of absorption rate on particle size). Similarly, compounds that are more soluble at low pH, as found in the stomach, can be absorbed more rapidly from solid dosage forms following oral administration due to their increased rate or extent of dissolution. Therefore, the alternative substitution patterns described herein may be combined with any appropriate side chain modification to generate additional opioid-active compounds with pharmacological and physical properties tuned as desired for optimal activity in any particular pharmaceutical coirposition or mode of medical treatment.

As an adjunct to the novel coirpositions of matter described above, the present disclosure also provides uses of the described compounds, either alone or in combination with drugs having synergistic pharmacological properties, for treating a number of neurological disorders, as set out herein. These indications include, but are not limited to, Huntington's disease, Rett syndrome, and CDKL5 disorder. Maintenance therapy is specifically encompassed.

Lastly, an additional aspect of the disclosure provides synthetic methods and chemical intermediates that may be used to encompass chemical space around the diarythiazepinamine core structure.

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Zarate, C.A. Jr et al. Arch. Gen. Psychiatry 2006, 63, 856-864. Persons of ordinary skill can utilize the disclosures and teachings herein to produce other embodiments and variations without undue experimentation. All such embodiments and variations are considered to be part of this invention.

Accordingly, one of ordinary skill in the art will readily appreciate from the disclosure that later modifications, substitutions, and/or variations performing substantially the same function or achieving substantially the same result as embodiments described herein may be utilized according to such related embodiments of the present invention. Thus, the invention is intended to encompass, within its scope, the modifications, substitutions, and variations to processes, manufactures, coirpositions of matter, compounds, means, methods, and/or steps disclosed herein.

The description herein may contain subject matter that falls outside of the scope of the claimed invention. This subject matter is included to aid understanding of the invention.

In this specification, where reference has been made to external sources of information, including patent specifications and other documents, this is generally for the purpose of providing a context for discussing the features of the present invention.