ZA200705028B

ZA200705028B - Amino substituted diaryl [a,d] cycloheptene analogs as muscarinic agonists and methods of treatment of neuropsychiatric disorders

Info

Publication number: ZA200705028B
Application number: ZA200705028A
Authority: ZA
Inventors: Ek Fredrik; Ohlsson Joergen; Olsson Roger
Original assignee: Acadia Pharm Inc
Priority date: 2003-12-22
Filing date: 2007-06-04
Publication date: 2009-02-25
Also published as: CN1913900A; CN1913900B

Description

® ° : [III bE

AMINO SUBSTITUTED DIARYL [a,d|[CYCLOHEPTENE ANALOGS AS

MUSCARINIC AGONISTS AND METHODS OF TREATMENT OF

NEUROPSYCHIATRIC DISORDERS

This is a fresh application (i.e. a so-called divisional application) filed in terms of

Section 37 of the South African Patents Act 57/1978, in respect of part of the matter disclosed in South African patent application 2006/05124 filed as a national phase PCT application on 21 June 2006 (i.e. the "parent application") based on PCT intemational application

PCT/US2004/043224 filed 21 December 2004.

The term "invention" is used herein to describe the subject matter of both parent and _ fresh (divisional) applications.

Background of the Invention

Field of the Invention Co

[0001] Certain aspects of the present disclosure relate to methods for treatment of neuropsychitaric disorders, pain and other disorders by compounds that modulate the activity of muscarinic receptors, in particular the subtypes M1, thereby modulating neuronal activities associated with the development of neuropsychiatric disorders. Aspects of the invention also relate to compounds that selectively interact with this receptor subtype and methods of identifying said compounds.

Description of the Related Art © [0002] Muscarinic cholinergic receptors mediate the actions of the neurotransmitter acetylcholine in the central and peripheral nervous systems, gastrointestinal system, heart, endocrine glands, lungs, and other tissues. Muscarinic receptors play a central role in the central nervous system for higher cognitive functions, as well as in the peripheral parasympathetic nervous system. Five distinct muscarinic receptor subtypes have been identified, m1-m5. The ml subtype is the predominant subtype found in the cerebral cortex and is believed to be involved in the control of cognitive functions; m2 is the predominant subtype found in heart and is believed to be involved in the control of heart rate; m3 is believed to be involved in gastrointestinal and urinary tract stimulation as well as sweating and salivation; m4 is present in brain and may be involved in locomotion; and m5, present in brain, may be involved in certain functions of the central nervous system associated with the dopaminergic system. y

® ® 1B

[0003] Conditions associated with cognitive impairment, such as Alzheimer's disease, are accompanied by loss of acetylcholine in the brain. this is believed to be the result of degeneration of cholinergic neurons in the basal forebrain, which innervate areas of the association cortex, and hippocampus, which is involved in higher processes.

[0004] Efforts to increase acetylcholine levels have focused on increasing levels of choline, the precursor for acetylcholine synthesis, and on blocking acetylcholine esterase (AChE), the enzyme that metabolizes acetylcholine. Administration of choline or phosphatidylcholine has not been very successful. AChE inhibitors have shown some therapeutic efficacy, but may cause cholinergic side effects due to peripheral acetylcholine stimulation, including abdominal cramps, nausea, vomiting, diarrhea, anorexia, weight loss, myopathy and depression. Gastrointestinal side effects have been observed in about a third of the patients treated. In addition, some AChE inhibitors, such as tacrine, have also been , found to cause significant hepatotoxicity, with elevated liver transaminases observed in about 30% of patients. The adverse effects of AChE inhibitors have limited their clinical utility.

[0005] Known m1 muscarinic agonists such as arecoline have also been found to be weak agonists of m2 as well as m3 subtype and are not very effective in treating cognitive impairment, most likely because of dose-limiting side effects.

[0006] There is a need for compounds that increase acetylcholine signaling or effect in the brain. Specifically there is a need for muscarinic agonists that are active at various muscarinic receptor subtypes in the central and peripheral nervous system.

Furthermore, there is a need for more highly selective muscarinic agonists, such as m1- or mé4-selective agents, both as pharmacological tools and as therapeutic agents.

Summary of the Invention

[0007] Disclosed herein is a compound of Formula I, II, or XV: oo a ~

A Qn —R

L Y 1

Rg I4 R, Rg / Ry \ X=X / : \ X=X! !

Rpg?” ZAR Ry?" Ny Re \ \ ' / \ v 1 / ’

Ry \ / R4 Re / Ra

Re Rs Ro Rs

M (In

A

I

R +

Y X=X R od 12

A

\ \ ' gs Zz R

RS h 13 i

Rg *

XV)

_ ® or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein A is selected from the group consisting of ’ (gn h INT Aye ¢ A n EN ( ) n J z “ , ( , and , ;

X is nitrogen, CH, or CH,; X’ is C or CH, wherein when X’ is C, there is a double bond between X and X’ and wherein when X’ is CH, there is a single bond between X and X’; each Y is separately selected from the group consisting of nitrogen, oxygen, or CH; each W is separately selected from the group consisting of nitrogen, CH, oxygen, or sulfur; each n 1s separately selected from the group consisting of 0, 1, 2, 3, and 4; m is selected from the group consisting of 1, 2, and 3; each R; is separately absent or is separately selected from the group consisting of hydrogen, halogen, amine, optionally substituted Cj.» alkyl, optionally substituted Cs.g cycloalkyl, optionally substituted C,., alkenyl, optionally substituted Cy.30 alkynyl, optionally substituted C;.0 —alkoxyalkyl, and optionally substituted aryl and arylalkyl; L is absent or is selected from the group consisting of — . NH(CH),— and —(CH3),—; a, b, c, and d are each independently selected from the group consisting of carbon, nitrogen, oxygen, and sulfur, or each is independently absent, provided that at least three of a, b, ¢, or d are present, provided that at least one of a, b, c, or d is carbon, and provided that no two adjacent a, b, c, or d are both oxygen or both sulfur; e, f, g, and h are each independently selected from the group consisting of carbon, nitrogen, oxygen, and sulfur, or each is independently absent, provided that at least three of’ e, f, g, or h are present, provided that at least one of e, {, g, or h is carbon, and provided that no two adjacent e, f, g, or h are both oxygen or both sulfur; Ry, Ri, Rs, and Rs, are each independently selected from the group consisting of hydrogen, halogen, optionally substituted C;.¢ alkyl, optionally substituted C;.¢ alkyloxy, optionally substituted C,¢ alkenyl, optionally substituted Cj. alkynyl, optionally substituted C;s-alkoxyalkyl, . optionally substituted C,. alkylthio, perhaloalkyl, CN, COR, CONHR 9, NHCONHRj,

SO;NHR 4, SOR 19, OSO,R yg, heteroalkyl, NO,, NHCOR,q, or R; and Rs, or R; and Ry, or ) R,4 and Rs taken together, along with the ring carbons to which they are attached, form a five-membered or six-membered cycloalkyl, heterocyclyl or heteroaryl ring, or a six- membered aryl ring moiety; Rs, Ry, Rg, and Rs, are each independently selected from the

® group consisting of hydrogen, halogen, optionally substituted Ci.6 alkyl, optionally substituted Cy. alkyloxy, optionally substituted Cj.¢ alkenyl, optionally substituted Ca.¢ © alkynyl, optionally substituted Ci.-alkoxyalkyl, optionally substituted Cis alkylthio, perhaloalkyl, CN, COR;p, CONHR,y, NHCONHRo, SONHRjp, SO2R;10, OSO2Rj, . heteroalkyl, NO,, NHCOR jo, or Rg and Rs, or R; and Rj, or Rg-and Ro taken together, along with the ring carbons to which they are attached, form a five-membered or six-membered °, cycloalkyl, heterocyclyl or heteroaryl ring, or a six-membered aryl ring moiety; Z is selected from the group consisting of NR, oxygen, sulfur, and CH; Ryo is selected from the group consisting of hydrogen, optionally substituted Cis alkyl, optionally substituted Cs. cycloalkyl, optionally substituted Ca. alkenyl, optionally substituted C,.¢ alkynyl optionally substituted aryl, optionally substituted arylalkyl, and perhaloalkyl; and Ry, is selected from the group consisting of hydrogen, optionally substituted Cy.¢ alkyl, optionally substituted

Cas cycloalkyl, optionally substituted Cz.6 alkenyl, optionally substituted Cz alkynyl, and optionally substituted arylalkyl; Riz and Ry; are separately selected from the group consiting of hydrogen, halogen, optionally substituted C;.¢ alkyl, optionally substituted Ci. alkyloxy, optionally substituted Caz. alkenyl, optionally substituted Cz-6 alkynyl, optionally substituted C,.¢-alkoxyalkyl, optionally substituted C,.¢ alkylthio, perhaloalkyl, CN, CORjo,

CONHR,, NHCONHR 0, SO;NHR 0, SOzRi0, 0SO,R, heteroalkyl, NOz, NHCORq, or

R;, and Ris, taken together, along with the ring carbons to which they are attached, form a five-membered or six-membered cycloalkyl, heterocyclyl or heteroaryl ring, or a Six- membered aryl ring moiety; and any bond represented by a dashed and solid line represents a bond selected from the group consisting of a carbon-carbon single bond and a carbon- carbon double bond; provided that the compound of Formulae I or XV are not clozapine or

N-desmethylclozapine.

[0008] In some embodiments, the compound has a structure set forth in

Formulas II or IV.

w A

W-

R

(In) (()n !

Ry

R FR R FOR

: Fo X=X 2 Eo X=X 2

Ra Rj Rs Rs , z Zz

R{ Ry R{: Ry

Rs Rs Rs Rs (Im) av)

[0009] In some embodiments, the compound is selected from. the group consisting of: " cy

BD) J \

Re "Ry Re © / Ry Re R;

A ry z z z

R R R R Rg R4 8 Rg Rs 4 s 8 Rg Rs 4 > Re Rs >

R .

R R 1 4 " x a “R, : { “R, ( SR,

N<R ~R; ~R4

Re of Fo Re (Fe Re (Rs z R R z R R z R

Re Ry Rs ® Re Rg © ,and T° Rg Rg

[0010] In some embodiments, the compound is selected from the group consisting of: :

® ® " C" ( v ) J

N= — s®sl

Fo Hi So an? an an: y-Ri y-R y-Ri

N= —

AT s , and .

[0010] In some embodiments, none of a, b, ¢, or d is absent. In some embodiments, none of e, f, g, or h is absent. In some embodiments a, b, ¢, and d are carbon.

In some embodiments ¢, f, g, and h are carbon. In some embodiments, Ro is selected from the group consisting of hydrogen, halogen, optionally substituted Cy alkyl, and optionally substituted Ci. alkyloxy. In some embodiments, the alkyl is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl. In some embodiments, the alkyloxy is selected from the group consisting of methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, and tert-butoxy. In some embodiments, the halogen is selected from the group consisting of fluoro, chloro, and bromo. In some embodiments, R; is selected from the group consisting of hydrogen, methyl, methoxy, and chloro. In some embodiments, Rs is selected from the group consisting of hydrogen, halogen, optionally substituted C;.¢ alkyl, optionally substituted C;.¢ alkyloxy, and NO. In some embodiments, the alkyl is selected from the group consisting of methyl, ethyl, propyl, i isopropyl, butyl, sec-butyl, and tert-butyl. In some embodiments, the alkyloxy is selected from the group consisting of methoxy, ethoxy, PrOpOXY, isopropoxy, butoxy, sec-butoxy, and tert-butoxy. In some embodiments, the halogen is selected from the group consisting of 7 chloro, bromo, and iodo. In some embodiments, Rj is selected from the group consisting of ] hydrogen, methyl, methoxy, chloro, bromo, iodo, and NO,. In some embodiments, Ry is ’ selected from the group consisting of hydrogen, halogen, optionally substituted Ci.¢ alkyl, pethaloalkyl, SO2R 0, and NO,. In some embodiments, the alkyl is selected from the group

® . . ( consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl.

In some embodiments, the perhaloalkyl is perfluoroalkyl.

In some embodiments, the perfluoroalkyl is trifluoromethyl.

In some embodiments, the halogen is selected from the group consisting of fluoro, chloro, and bromo.

In some embodiments, Rj is hydrogen or optionally substituted Cy. alkyl, wherein in some embodiments, the alkyl is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl.

In some embodiments, Ry is selected from the group consisting of hydro gen, methyl, fluoro, chloro, bromo, trifluoromethyl, SO,CHs, and NO,. In some embodiments, Rs is selected from the group consisting of hydrogen, halogen, and optionally substituted C,.¢ alkyl, wherein in some embodiments, the alkyl is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl and wherein in some embodiments, the halogen is selected from the group consisting of fluoro, chloro, and bromo.

In some embodiments, Rs is hydrogen or chloro.

In some embodiments, Rs is hydrogen or optionally substituted Cg alkyl.

In some embodiments, Rg is hydrogen.

In some embodiments, Ry is selected from the group consisting of hydrogen, halogen, optionally substituted Cj. allyl, perhaloalkyl, ~ CN, SO3R}p, and NO, wherein in some embodiments, the alkyl is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl; wherein in some embodiments, the halogen is selected from the group consisting of fluoro, chloro, and bromo; wherein in some embodiments, perhaloalkyl is perfluoroalkyl; wherein in some embodiments, perfluoroalkyl is trifluoromethyl.

In some embodiments, Rg is hydrogen or optionally substituted C,.¢ alkyl, wherein in some embodiments, the alkyl is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl.

In some embodiments, Ry is selected from the group consisting of hydrogen, methyl, chloro, trifluoromethyl, SO,CHj, CN, and NO,. In some embodiments, Rg is selected from the group consisting of hydrogen, halogen, optionally substituted Ci. alkyl, wherein in some embodiments, the alkyl is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl and wherein in some embodiments, the halogen is h selected from the group consisting of fluoro, chloro, and bromo.

Insome embodiments, Rg ; is selected from the group consisting of hydrogen, chloro, and bromo.

In some ) embodiments, Ry is selected from the group consisting of hydrogen, halogen, optionally substituted Cy.¢ alkyl, and perhaloalkyl; wherein in some embodiments, the alkyl is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl; wherein in some embodiments, the halogen is selected from the group consisting _ . :

® ® of fluoro, chloro, and bromo; wherein in some embodiments, perhaloalkyl is perfluoroalkyl; wherein in some embodiments, perfluoroalkyl is trifluoromethyl. In some embodiments, Ry is selected from the group consisting of hydrogen, chloro, methyl, and trifluoromethyl. In some embodiments, R; is selected from the group consisting of . hydrogen, optionally substituted Cy.¢ alkyl, and optionally substituted aryl, wherein in some embodiments, the alkyl is selected from the group consisting of methyl, ethyl, propyl, LL isopropyl, butyl, sec-butyl, and tert-butyl. In some embodiments, R; is hydrogen. In some embodiments, X is nitrogen. In some embodiments, Y is NH. In some embodiments, L is absent or is selected from the group consisting of -NHCH,—, -NH-, and ~CH,-. In some embodiments, A is selected from the group consisting of:

J va od u oe Oo Op ") " y= Y J “ | Cand and n is selected from the group consiting of 0, 1, and 2. : [0011] Also disclosed herein is a method of synthesizing a compound of

Formula V or VI, . a " 4 2) q no

Re wl Ra Re Nel Ry ™ r yafey VD) ~

Rg N R4 Rg N Rs

Re Rs | Ro Rs comprising reacting a compound of Formula VII

Ry, O (VI) Ra OH

RJ “NH,

Rs . with a compound of Formula VIII

Rg ; (VID) ON Ry

Rg

® @® to form a fused ring compound of Formula IX,

Re P Ra 0 ~S

Rg N R,

Rg Rs and reacting the compound of Formula IX with a compound of Formula X

Ry

X) W &) to obtain a compound of Formula V, wherein X is a halogen; R; is selected from the group : consisting of hydrogen, optionally substituted C,¢ alkyl, optionally substituted Cig cycloalkyl, optionally substituted C,.¢ alkenyl, optionally substituted C,.¢ alkynyl, optionally substituted C;.¢ —alkoxyalkyl, and optionally substituted aryl and arylalkyl; Ry, Rs, Rs, and

Rs, are each independently selected from the group consisting of hydrogen, halogen, optionally substituted Ci.¢ alkyl, optionally substituted C;.¢ alkyloxy, optionally substituted

Cy alkenyl, optionally substituted C,.¢ alkynyl, optionally substituted C,.¢-alkoxyalkyl, optionally substituted C,. alkylthio, perhaloalkyl, CN, COR;o, CONHR;9, NHCONHR;o,

S0,NHRq, SO;R 19, OSO,R 0, heteroalkyl, NO, NHCOR;o, or R, and Rj, or R3 and Ry, or

Rs and Rs taken together, along with the ring carbons to which they are attached, form a five-membered or six-membered cycloalkyl, heterocyclyl or heteroaryl ring, or a six- membered aryl ring moiety; Rg, R,, Rg, and Ry, are each independently selected from the group consisting of hydrogen, halogen, optionally substituted C,¢ alkyl, optionally substituted C,. alkyloxy, optionally substituted C,.¢ alkenyl, optionally substituted C,.6 alkynyl, optionally substituted C;¢-alkoxyalkyl, optionally substituted Ci.s alkylthio, perhaloalkyl, CN, COR,;, CONHR,;q, NHCONHR,q, SO,NHR;y, SOzR;p, OSO.R0, heteroalkyl, NO,, NHCOR,q, or R¢ and R7, or R; and Rg, or Rg and Ry taken together, along with the ring carbons to which they are attached, form a five-membered or six-membered : cycloalkyl, heterocyclyl or heteroaryl ring, or a six-membered aryl ring moiety. - [0012] Also disclosed herein is a combinatorial library of at least 220 dibenzo[b,e][1,4]diazepine[a,d]cycloheptene compounds that can be formed by reacting a compound of Formula VII, :

® _

R, O (VI) Rs OH

R4 NH,

R Rs with a compound of Formula VIII and ’

Re - (VI) O2N R;

Be

Ro a compound of Formula X,

R4 ® » wherein X is a halogen; R; is selected from the group consisting of hydrogen, optionally substituted C.¢ alkyl, optionally substituted Cig cycloalkyl, optionally substituted Cas alkenyl, optionally substituted Cy. alkynyl, optionally substituted Cj.c —alkoxyalkyl, and optionally substituted aryl and arylalkyl; Ry, R3, Rs, and Rs, are each independently selected from the group consisting of hydrogen, halogen, optionally substituted C,.¢ alkyl, optionally substituted C;.¢ alkyloxy, optionally substituted Cy alkenyl, optionally substituted C,.¢ alkynyl, optionally substituted C¢-alkoxyalkyl, optionally substituted Cis alkylthio, perhaloalkyl, CN, COR;;, CONHRjo, NHCONHR,o, SO,NHR;y, SO2R10, OSO2R10, heteroalkyl, NO,, NHCORy, or R; and Rj, or R3 and Ry, or R4 and Rs taken together, along with the ring carbons to which they are attached, form a five-membered or six-membered cycloalkyl, heterocyclyl or heteroaryl ring, or a six-membered aryl ring moiety; Rs, Ry, Rs, and Ro, are each independently selected from the group consisting of hydrogen, halogen, optionally substituted Cys alkyl, optionally substituted Cg alkyloxy, optionally substituted

C,.¢ alkenyl, optionally substituted Ci. alkynyl, optionally substituted C,.¢-alkoxyalkyl, optionally substituted Cy. alkylthio, perhaloalkyl, CN, COR10, CONHR1o, NHCONHR;o, .

SO,NHR 0, SO2R 0, OSO2R, heteroalkyl, NO, NHCOR;, or Rg and Ry, or R7 and Rs, or

Rs and Ro taken together, along with the ring: carbons to which they are attached, form a ; five-membered or six-membered cycloalkyl, heterocyclyl or heteroaryl ring, or a six- membered aryl ring moiety.

® : ®

[0013] Also disclosed herein is a combinatorial library of at least 220 dibenzo[b,e][1,4]diazepine[q,d]cycloheptene compounds that can be formed by reacting a compound of Formula VII, : - R, O (VID Rs OH n Rg NH,

Rs with a compound of Formula VIII and

Re (VI) OoN Ry;

Rel

Rg a compound of Formula XII,

T om bo

N . wherein X is a halogen; R; is selected from the group consisting of hydrogen, optionally substituted C; alkyl, optionally substituted Cs.3 cycloalkyl, optionally substituted Cs; : alkenyl, optionally substituted C,¢ alkynyl, optionally substituted C.¢ —alkoxyalkyl, and optionally substituted aryl and arylalkyl; Ry, Rs, Rs, and Rs, are each independently selected from the group consisting of hydrogen, halogen, optionally substituted C,.¢ alkyl, optionally substituted C,.s alkyloxy, optionally substituted C,.¢ alkenyl, optionally substituted C, alkynyl, optionally substituted Cj.g-alkoxyalkyl, optionally substituted Cg alkylthio, perhaloalkyl, CN, COR;, CONHR;p, NHCONHR;, SO,NHR;g3, SO2R19, OSO2R,0, heteroalkyl, NO, NHCOR, or R; and Rj, or R; and Ry, or R4 and Rs taken together, along with the ring carbons to which they are attached, form a five-membered or six-membered cycloalkyl, heterocyclyl or heteroaryl ring, or a six-membered aryl ring moiety; Rg, R7, Rs, ~ and Ry, are each independently selected from the group consisting of hydrogen, halogen, . optionally substituted C, alkyl, optionally substituted Cs alkyloxy, optionally substituted ) Cs alkenyl, optionally substituted C,¢ alkynyl, optionally substituted C;.g-alkoxyalkyl, optionally substituted C, alkylthio, perhaloalkyl, CN, COR, CONHR;p, NHCONHR,,

SO,NHR 5, SO2R 9, OSO5R yy, heteroalkyl, NO,, NHCOR, or Rg and Ry, or R; and Rg, or

® @

Rg and Ro taken together, along with the ring carbons to which they are attached, form a five-membered or six-membered cycloalkyl, heterocyclyl or heteroaryl ring, or a six- membered aryl ring moiety.

[0014] Also disclosed herein is a pharmaceutical composition comprising a ) physiologically acceptable carrier, diluent, or excipient, or a combination thereof; and a compound of Formula J, II, or XV. ~

[0015] Also disclosed herein is a method of treating a neuropsychiatric disorder comprising administering to the patient a therapeutically effective amount of a compound of Formula I, II, or XV.

[0016] Also disclosed herein is a method of treating a neuropsychiatric disorder comprising contacting a therapeutically effective amount of a compound of Formula, I, or

XV with the patient. {0017) Also disclosed herein is a pharmaceutical composition comprising a compound of Formula I, II, or XV and an neuropsychiatric agent. In some embodiments, _ the neuropsychiatric agent is selected from the group consisting of a selective serotonin reuptake inhibitor, norepinephrine reuptake inhibitor, dopamine agonist, muscarinic receptor antagonist, antipsychotic agent, serotonin 2A antagonist, and inverse serotonin 2A agonist. In some embodiments, the antipsychotic agent is selected from the group consisting of a phenothiazine, phenylbutylpiperadine, debenzapine, benzisoxidil, and salt of lithium. In some embodiments, the phenothiazine is selected from the group consisting of chlorpromazine (Thorazine®), mesoridazine (Serentil®), prochlorperazine (Compazine®), and thioridazine (Mellaril®). In some embodiments, the phenylbutylpiperadines is selected from the group consisting of haloperidol (Haldol®), and pimozide (Orap®). In some embodiments, the debenzapine is selected from the group consisting of clozapine (Clozaril®), loxapine (Loxitane®), olanzapine (Zyprexa®) and quetiapine (Seroquel®). In some embodiments, the benzisoxidil is selected from the group consisting of resperidone (Resperidal®) and ziprasidone (Geodon®). In some embodiments, the salt of lithium is lithium carbonate. In some embodiments, the antipsychotic agent is selected fromthe } “group consisting of Clozaril, Compazine, Etrafon, Geodon, Haldol, Inapsine, Loxitane,

Mellaril, Moban, Navane, Orap, Permitil, Prolixin, Phenergan, Reglan, Risperdal, Serentil, :

Seroquel, Stelazine, Taractan, Thorazine, Triavil, Trilafon, and Zyprexa. In some embodiments, the selective serotonin reuptake inhibitor is selected from the group consisting of fluoxetine, fluvoxamine, sertraline, paroxetine, citalopram, escitalopram,

® ® sibutramine, duloxetine, and venlafaxine, and pharmaceutically acceptable salts or prodrugs thereof. In some embodiments, the norepinephrine reuptake inhibitor is selected from the group consisting of thionisoxetine and reboxetine. In some embodiments, the dopamine , agonist 1s selected from the group consisting of sumatriptan, almotriptan, naratriptan, frovatriptan, rizatriptan, zomitriptan, cabergoline, amantadine, lisuride, pergolide, : ropinirole, pramipexole, and bromocriptine. In some embodiments, the inverse serotonin 2A agonist is the compound of Formula XII, or a related analog thereof. or

N al, orth

S Eve]

Oo (X10)

In some embodiments, the serotonin 2A antagonist is the compound of Formula XIV, or a related analog thereof: oH po i (XIV)

[0018] Also disclosed herein is a method of treating neuropsychiatric disorder in a patient comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula I, II, or XV and an

J neuropsychiatric agent.

[0019] Also disclosed herein is a method of treating neuropsychiatric disorder in - a patient comprising administering to the patient a therapeutically effective amount of a compound of Formula I, II, or XV and a therapeutically effective amount of a neuropsychiatric agent. In some embodiments, the administering step comprises administering the compound of Formula I, II, or XV and the neuropsychiatric agent nearly simultaneously. In other embodiments, the administering step comprises administering one of the compound of Formula I, IT, or XV and the neuropsychiatric agent first and then administering the other one of the compound of Formula I, ., or XV and the neuropsychiatric agent. In some embodiments, the neuropsychiatric disorder is selected . from the group consisting of schizophrenia and related idiopathic psychoses, anxiety, sleep disorders, appetite disorders, affective disorders such as major depression, bipolar disorder, y and depression with psychotic features, and Tourette’s Syndrome, drug-induced psychoses, psychoses secondary to neurodegenerative disorders such Alzheimer’s or Huntington’s

Disease. :

Detailed Description of the Preferred Embodiment

[0020] In the first aspect, the present disclosure is related to a compound of

Formula I, II, or XV: i ~ 4 (Qn —R

R ; R : R ; R v X=X / 2 X=X J 2 ~y x NR Rr—¢7" AA \ \ { / \ \ ! /

Re \ . / R4 Ry \ ) Rs

Rg Rs Rg Rs ey | an

A

.

R ~ vo X=X "

Rye?" " i 12 \ \ ! g==y yA R

RS \ 13

CL Ro

XV) or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein: )

A is selected from the group consisting of

_ ®

R, o ; of n o .

CE TIN Lr a TE ce wy ( )n J ’ , ( , and a, ;

A X is nitrogen, CH, or CHy;

X’ is C or CH, wherein when X’ is C, there is a double bond between X and X’ and wherein when X’ is CH, there is a single bond between X and X’; each Y is separately selected from the group consisting of nitrogen, oxygen, or CH; each W is separately selected from the group consisting of nitrogen, CH, oxygen, or sulfur; each n is separately selected from the group consisting of 0, 1,2, 3, and 4;

[0021] m is selected from the group consisting of 1, 2, and 3; each R, is separately absent or is separately selected from the group consisting of hydrogen, halogen, amine, optionally substituted Ci.zo alkyl, optionally substituted Ci.g - cycloalkyl, optionally substituted Cppo alkenyl, optionally substituted Co alkynyl, optionally substituted C,.50—alkoxyalkyl, and optionally substituted aryl and arylalkyl;

L is absent or is selected from the group consisting of -NH(CH;),— and —(CHz)s—; a, b, c, and d are each independently selected from the group consisting of carbon, nitrogen, oxygen, and sulfur, or each is independently absent, provided that at least three of a, b, ¢, or d are present, provided that at least one of a, b, ¢, or d is carbon, and provided that no two adjacent a, b, c, or d are both oxygen or both sulfur; e, f, g, and h are each independently selected from the group consisting of carbon, nitrogen, oxygen, and sulfur, or each is independently absent, provided that at least three of e, f, g, or h are present, provided that at least one of e, f, g, or h is carbon, and provided that no two adjacent e, f, g, or h are both oxygen or both sulfur;

E Ry, Ri, Ry, and Rs, are each independently selected from the group consisting of ] hydrogen, halogen, optionally substituted Ci.¢ alkyl, optionally substituted Cys alkyloxy, optionally substituted C,.¢ alkenyl, optionally substituted C,.¢ alkynyl, optionally substituted 'Cy.6-alkoxyalkyl, optionally substituted Cy.¢ alkylthio, perhaloalkyl, CN, COR yp, CONHR;0,

NHCONHR 0, SO:NHR 10, SO;R 10, OSO;R 0, heteroalkyl, NO», NHCOR jo,

( . or R; and Rs, or R; and Ry, or R4 and Rs taken together, along with the ring carbons to which they are attached, form a five-membered or six-membered cycloalkyl, heterocyclyl or heteroaryl ring, or a six-membered aryl ring moiety;

Rg, Ry, Rg, and Ry, are each independently selected from the group consisting of . hydrogen, halogen, optionally substituted Ci. alkyl, optionally substituted C,.s alkyloxy, optionally substituted Cy.¢ alkenyl, optionally substituted C,.¢ alkynyl, optionally substituted ~~.

C,.¢-alkoxyalkyl, optionally substituted Cy.¢ alkylthio, perhaloalkyl, CN, COR, CONHRo,

NHCONHR 5, SO,NHR 0, SO2R10, OSO2R jg, heteroalkyl, NOz2, NHCOR jo, or Rg and Ry, or R7 and Rg, or Rg and Rg taken together, along with the ring carbons to which they are attached, form a five-membered or six-membered cycloalkyl, heterocyclyl or heteroaryl ring, or a six-membered aryl ring moiety; 7 is selected from the group consisting of NR, oxygen, sulfur, and CHp;

Ryo is selected from the group consisting of hydrogen, optionally substituted Ci-¢ alkyl, optionally substituted Cs. cycloalkyl, optionally substituted Ci. alkenyl, optionally substituted Cp. alkynyl optionally substituted aryl, optionally substituted arylalkyl, and perhaloalkyl;

Ry is selected from the group consisting of hydrogen, optionally substituted Ci.¢ alkyl, optionally substituted Cs. cycloalkyl, optionally substituted Ca-6 alkenyl, optionally substituted C,_¢ alkynyl, and optionally substituted arylalkyl;

R,, and R,3 are separately selected from the group consiting of hydrogen, halogen, optionally substituted Ci.¢ alkyl, optionally substituted Cy.¢ alkyloxy, optionally substituted

C, alkenyl, optionally substituted Cp.¢ alkynyl, optionally substituted Ci.¢-alkoxyalkyl, optionally substituted C,.¢ alkylthio, perhaloalkyl, CN, COR;;, CONHR;9, NHCONHR, 0,

SO,NHR 10, SO;R 10, OSO2R 10, heteroalkyl, NO, NHCOR 0, or Rj; and Rys, taken together, along with the ring carbons to which they are attached, form a five-membered or six-membered cycloalkyl, heterocyclyl or heteroaryl ring, or a six-membered aryl ring moiety. oo [0022] Bonds represented by a dashed and solid line represents a bond selected from the group consisting of a carbon-carbon single bond and a carbon-carbon double bond.

The dashed bond between X and X’ in Formulae I, II, and XV indicates that X and X’ may A be joined by either a single or a double bond. : [0023] In certain embodiments, the compound of Formulae I and XV does not include clozapine or N-desmethylclozapine, the structures of which are shown below:

® - ) :

J CN

() w

N= N=— 0

Clozapine N-desmethylclozapine

[0024] In certain embodiments, in compounds of Formulae I and XV, Y is nitrogen or CH. In other embodiments, in compounds of Formula II, Y is nitrogen, oxygen or CH.

[0025] The term “pharmaceutically acceptable salt” refers to a formulation of a compound that does not cause significant irritation to an orgamism to which it is administered and does not abrogate the biological activity and properties of the compound.

Pharmaceutical salts can be obtained by reacting a compound of the invention with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. Pharmaceutical salts can also be obtained by reacting a compound of the invention with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-

D-glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like. :

[0026] The term “ester” refers to a chemical moiety with formula -(R),-COOR’, where R and R’ are independently selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon), and wherenis Oor 1.

[0027] An “amide” is a chemical moiety with formula -(R),-C(O)NHR”’ or - (R),-NHC(O)R’, where R and R’ are independently selected from the group consisting of i alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic . (bonded through a ring carbon), and where nis 0 or 1. An amide may be an amino acid or a peptide molecule attached to a molecule of the present invention, thereby forming a prodrug.

® ®

[0028] Any amine, hydroxy, or carboxyl side chain on the compounds of the present invention can be esterified or amidified. The procedures and specific groups to be used to achieve this end are known to those of skill in the art and can readily be found in reference sources such as Greene and Wats, Protective Groups in Organic Synthesis, 31 .

Ed., John Wiley & Sons, New York, NY, 1999, which is incorporated herein in its entirety. )

[0029] A “prodrug” refers to an agent that is converted into the parent drug in " vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. An example, without limitation, of a prodrug would be a compound of the present invention which is administered as an ester (the “prodrug”) to facilitate transmittal across a cell membrane where water solubility is detrimental to mobility but which then is metabolically hydrolyzed to the carboxylic acid, the active entity, once inside the cell where water-solubility is beneficial. A further example of a prodrug might be a short peptide (polyaminoacid) bonded to an acid group where the peptide is metabolized to reveal the active moiety.

[0030] The term “aromatic” refers to an aromatic group which has at least one ring having a conjugated pi electron system and includes both carbocyclic aryl (e.g., phenyl) and heterocyclic aryl groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups. The term “carbocyclic” refers to a compound which contains one or more covalently closed ring structures, and that the atoms forming the backbone of the ring are all carbon atorus. The term thus distinguishes carbocyclic from heterocyclic rings in which the ring backbone contains at least one atom which is different from carbon. The term “heteroaromatic” refers to an aromatic group which contains at least one heterocyclic ring.

[0031] As used herein, the term “alkyl” refers to an aliphatic hydrocarbon group. The alkyl moiety may be a “saturated alkyl” group, which means that it does not oo "contain any alkene or alkyne moieties. The alkyl moiety may also be an “unsaturated alkyl” moiety, which means that it contains at least one alkene or alkyne moiety. An “alkene” “moiety refers to a group consisting of at least two carbon atoms and at least one carbon- - carbon double bond, and an “alkyne” moiety refers to a group consisting of at least two : carbon atoms and at least one carbon-carbon triple bond. The alkyl moiety, whether saturated or unsaturated, may be branched, straight chain, or cyclic.

® ®

[0032] The alkyl group may have 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as “1 to 20” refers to each integer in the given range; e.g, “1 to 20 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon

E atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is 3 designated). The alkyl group may also be a medium size alkyl having 1 to 10 carbon atoms.

The alkyl group could also be a lower alkyl having 1 to 5 carbon atoms. The alkyl group of the compounds of the invention may be designated as “C;-Cq alkyl” or similar designations. - By way of example only, “C;-C4 alkyl” indicates that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl.

[0033] The alkyl group may be substituted or unsubstituted. When substituted, the substituent group(s) is(are) ome or more group(s) individually and independently selected from cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl,

O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C- carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, and amino, including mono- and di-substituted amino groups, and ; the protected derivatives thereof. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, ethenyl, propenyl, butenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. Wherever : a substituent is described as being “optionally substituted” that substitutent may be : substituted with one of the above substituents.

[0034] The substituent “R” appearing by itself and without a number designation refers to a substituent selected from the group consisting of of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon). . [0035] An “O-carboxy” group refers to a RC(=0)O- group, where R is as defined herein.

E [0036] A “C-carboxy” group refers to a -C(=0)OR groups where R is as defined herein.

[0037] An “acetyl” group refers to a -C(=0)CHs, group.

® ®

[0038] A “trihalomethanesulfony!” group refers to a X3CS(=0),- group where X is a halogen.

[0039] A “cyano” group refers to a -CN group.

[0040] An “isocyanato” group refers to a-NCO group. 5

[0041] A “thiocyanato” group refers to a -CNS group.

[0042] An “isothiocyanato” group refers to a -NCS group. K

[0043] A “sulfinyl" group refers to a -S(=0)-R group, with R as defined herein. 10044] A “S-sulfonamido” group refers to a -S(=0),NR, group, with R as defined herein.

[0045] A “N-sulfonamido” group refers to a RS(=0),NH- group with R as defined herein.

[0046] A “trihalomethanesulfonarnido” group refers to a X3CS(=0),NR- group with X and R as defined herein.

[0047] An “O-carbamyl” group refers to a -OC(=O)-NR, group-with R as defined herein.

[0048] An “N-carbamyl” group refers to a ROC(=O)NH- group, with R as defined herein.

[0049] An “O-thiocarbamyl” group refers to a -OC(=S)-NR, group with R as defined herein.

[0050] An “N-thiocarbamyl” group refers to an ROC(=S)NH- group, with R as defined herein.

[0051] A “C-arnido” group refers to a -C(=0)-NR; group with R as defined herein.

[0052] An “N-amido” group refers to a RC(=0)NH- group, with R as defined herein.

[0053] The term “perhaloalkyl” refers to an alkyl group where all of the hydrogen atoms are replaced by halogen atoms.

[0054] The term “acylalkyl” refers to a RC(=O)R’- group, with R as defined E herein, and R’ being a diradical alkylene group. Examples of acylalkyl, without limitation, may include CH3C(=O)CHp-, CH;C(=0)CH:CH.-, CH3;CH,C(=O)CH,CH,-, J

CH;C(=0)CH,CH,CH;-, and the like.

® ®

[0055] Unless otherwise indicated, when a substituent is deemed to be “optionally subsituted,” it is meant that the subsitutent is a group that may be substituted with one or more group(s) individually and independently selected from cycloalkyl, aryl,

N heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamy}, C- amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, and amino, including mono- and di-substituted amino groups, and the protected derivatives thereof. The protecting groups that may form the protective derivatives of the above substituents are known to those of skill in the art and may be found in references such as Greene and Wuts, above.

[0056] In the present context, the term “cycloalkyl” is intended to cover three-, four-, five-, six-, seven-, and eight- or more membered rings comprising carbon atoms only.

A cycloalkyl can optionally contain one or more unsaturated bonds situated in such a way, however, that an aromatic pi-electron system does mot arise. Some examples of “cycloalkyl” are the carbocycles cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclopentadiene, cyclohexane, cyclohexene, 1,3-cyclohexadiene, 1,4-cyclohexadiene, cycloheptane, or cycloheptene.

[0057] The term “heterocyclyl” is intended to mean three-, four-, five-, six-, seven-, and eight- or more membered rings wherein carbon atoms together with from 1 to 3 : heteroatoms constitute said ring. A heterocyclyl can optionally contain one or more unsaturated bonds situated in such a way, however, that an aromatic pi-electron system does not arise. The heteroatoms are independently selected from oxygen, sulfur, and nitrogen.

[0058] A heterocyclyl can further contain one or more carbonyl or thiocarbonyl functionalities, so as to make the definition include oxo-systems and thio-systems such as lactams, lactones, cyclic imides, cyclic thioimides, cyclic carbamates, and the like. . [0059] Heterocycly! rings can optionally also be fused to aryl rings, such that the definition includes bicyclic structures. Typically such fused heterocyclyl groups share - one bond with an optionally substituted benzene ring. Examples of benzo-fused heterocyclyl groups include, but are not limited to, benzimidazolidinone, tetrahydroquinoline, and methylenedioxybenzene ring structures.

@®

[0060] Some examples of “heterocyclyls” include, but are not limited to, tetrahydrothiopyran, 4H-pyran, tetrahydropyran, piperidine, 1,3-dioxin, 1,3-dioxane, 1,4- dioxin, 1,4-dioxane, piperazine, 1,3-oxathiane, 1,4-oxathiin, 1,4-oxathiane, tetrahydro-1,4- thiazine, 2H-1,2-oxazine , maleimide, succinimide, barbituric acid, thiobarbituric acid, k dioxopiperazine, hydantoin, dihydrouracil, morpholine, trioxane, hexahydro-1,3,5-triazine, tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine, pyrrolidone, pyrrolidione, ~ pyrazoline, pyrazolidine, imidazoline, imidazolidine, 1,3-dioxole, 1,3-dioxolane, .1,3- dithiole, 1,3-dithiolane, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine, and 1,3-oxathiolane. Binding to the heterocycle can be at the position of a heteroatom or via a carbon atom of the heterocycle, or, for benzo-fused derivatives, via a carbon of the benzenoid ring.

[0061] In the present context the term “aryl” is intended to mean a carbocyclic aromatic ring or ring system. Moreover, the term “aryl” includes fused ring systems wherein at least two aryl rings, or at least one aryl and at least one Ca.g-cycloalky! share at least one chemical bond. Some examples of “aryl” rings include optionally substituted phenyl, naphthalenyl, phenanthrenyl, anthracenyl, tetralinyl, fluorenyl, indenyl, and indanyl. : The term “aryl” relates to aromatic, including, for example, benzenoid groups, connected via one of the ring-forming carbon atoms, and optionally carrying one or more substituents selected from heterocyclyl, heteroaryl, halo, hydroxy, amino, cyano, nitro, alkylamido, acyl, .

C. alkoxy, Ci. alkyl, Ci. hydroxyalkyl, Cis aminoalkyl, Cys alkylamino, alkylsulfenyl, alkylsulfinyl, alkylsulfonyl, sulfamoyl, or trifluoromethyl. The aryl group can be substituted at the para and/or meta positions. In other embodiments, the aryl group can be substituted at the ortho position. Representative examples of aryl groups include, but are not limited to, phenyl, 3-halopheny}, 4-halophenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3- aminophenyl, 4-aminophenyl, 3-methylphenyl, 4-methylphenyl, 3-methoxyphenyl, 4- methoxyphenyl, 4-trifluoromethoxyphenyl 3-cyanophenyl, 4-cyanophenyl, dimethylphenyl, naphthyl, hydroxynaphthyl, hydroxymethylphenyl, trifluoromethylphenyl, alkoxyphenyl, 4- morpholin-4-ylphenyl, 4-pyrrolidin-1-ylphenyl, 4-pyrazolylphenyl, 4-triazolylphenyl, and 4- (2-oxopyrrolidin-1-yl)phenyl.

[0062] In the present context, the term “heteroaryl” is intended to mean a h heterocyclic aromatic group where one or more carbon atoms in an aromatic ring have been replaced with one or more heteroatoms selected from the group comprising nitrogen, sulfur, phosphorous, and oxygen.

® )

[0063] Furthermore, in the present context, the term “heteroaryl” comprises fused ring systems wherein at least one aryl ring and at least one heteroaryl ring, at least two heteroaryl rings, at least one heteroaryl ring and at least one heterocyclyl ring, or at - least one heteroaryl ring and at least one cycloalkyl ring share at least one chemical bond.

[0064] The term “heteroaryl” is understood to relate to aromatic, Cs.g cyclic 3 groups further containing one oxygen or sulfur atom or up to four nitrogen atoms, or a combination of one oxygen or sulfur atom with up to two nitrogen atoms, and their substituted as well as benzo- and pyrido-fused derivatives, for example, connected via one of the ring-forming carbon atoms. Heteroaryl groups can carry one or more substituents, selected from halo, hydroxy, amino, cyano, nitro, alkylamido, acyl, C,.¢-alkoxy, C;¢-alkyl,

Cis-hydroxyalkyl, Cj¢-aminoalkyl, Cjs-alkylamino, alkylsulfenyl, alkylsulfinyl, alkylsulfonyl, sulfamoyl, or trifluoromethyl. In some embodiments, heteroaryl groups can be five- and six-membered aromatic heterocyclic systems carrying 0, 1, or 2 substituents, which can be the same as or different from one another, selected from the list above.

Representative examples of heteroaryl groups include, but are not limited to, unsubstituted and mono- or di-substituted derivatives of furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, indole, oxazole, benzoxazole, isoxazole, benzisoxazole, thiazole, benzothiazole, isothiazole, imidazole, benzimidazole, pyrazole, indazole, - tetrazole, quionoline, isoquinoline, pyridazine, pyrimidine, purine and pyrazine, furazan, 1,2,3- oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, triazole, benzotriazole, pteridine, phenoxazole, oxadiazole, benzopyrazole, quinolizine, cinnoline, phthalazine, quinazoline, : and quinoxaline. In some embodiments, the substituents are halo, hydroxy, cyano, O-C,- alkyl, C.¢-alkyl, hydroxy-C,.¢-alkyl, and amino-C;¢-alkyl. :

[0065] In certain embodiments, disclosed herein is a compound selected from the following structures: a : WwW W,

J (2) »,

Re Nl Rj Re J Re Rg YR,

Zz Zz . | Re Ry Rs 4 RR i Re Re Rs

R R .

Ww. Ww. | / ~ ~ Wo

R, R, 4 R, -R -R -R

Y 1 Y h] 1

Re nf Re Re _( Ro Re YR,

Ry Rs; Ry Cy [1 Rs Ry; Cy [) Ra .

R z R R z R R ‘ R ® Rg Rg ® Rg Rs ® Rg Ry " where R;-Ro, W, Y, and Z are as described herein.

[0066] In certain other embodiments, disclosed herein is a compound selected from the following structures:

C Cc

N= — 0 x. Ds, x 0 : R R R / w ! Wl 1

W. “ : to, - Cn v—Ri1 y- Ri y Ri

N= — where Rj, W, Y, and Z are as described herein.

[0067] In certain embodiments, disclosed herein is a compound having a structure set forth in Formula Il or Formula IV.

R R4 / of

WwW —-

R4 (in) (dn

Y yo

R / R R / R 2 Xe Rr 2 2 Xe Xo 2

Rs Ra Rs Ra

Zz Z

R{ Ry R{ Rq i

Rs Rs Rs Rs (1419) Iv) where R;-Rs, W, X, X’, Y, and Z are as described herein. :

® . _

[0068] In certain embodiments, none of a, b, c, or d is absent, and the ring formed thereby is a six-membered ring. In further embodiments, none of e, f, g, or h is absent, and consequently, the ring formed thereby is a six-membered ring. In some ; embodiments, a, b, c, and d are carbon, and the ring formed thereby is an optionally substituted phenyl ring. In further embodiments, e, f, g, and h are carbon, which similarly 3 form an optionally substituted phenyl ring.

[0069] In certain embodiments, R; may be selected from the group consisting of hydrogen, halogen, optionally substituted Cj. alkyl, and optionally substituted Cie alkyloxy. In some embodiments, the alkyl may be selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl. In other embodiments, the alkyloxy may be selected from the group consisting of methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, and tert-butoxy. In further embodiments, the halogen may be selected from the group consisting of fluoro, chloro, and bromo. In certain embodiments, R, may be selected from the group consisting of hydrogen, methyl, methoxy, and chloro.

[0070] In some embodiments, R; may be selected from the group consisting of hydrogen, halogen, optionally substituted Cis alkyl, optionally substituted Ci. alkyloxy, ‘and NO,. The alkyl group may be selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl, while the alkoxy ay be selected from the group consisting of methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, and tert- butoxy. In further embodiments, the halogen may be selected from the group consisting of chloro, bromo, and iodo. In other embodiments, R; may be selected from the group consisting of hydrogen, methyl, methoxy, chloro, bromo, iodo, and NO.

[0071] In certain embodiments, R4 may be selected from the group consisting of hydrogen, halogen, optionally substituted Ci.¢ alkyl, perhaloatkyl, SOR, and NO,. In some embodiments, the alkyl may be selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl. In further embodimetns, the perhaloalkyl _ may be perfluoroalkyl, which in some embodiments, may be trifluoromethyl. In other embodiments, the halogen may be selected from the group consisting of fluoro, chloro, and bromo. When Ry is SO;Ry, the Ryo may be hydrogen or optionally substituted Ci.¢ alkyl, which alkyl may be selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl. In certain embodiments, R4 may be selected from the group consisting of hydrogen, methyl, fluoro, chloro, bromo, trifluoromethyl, SO.CHs, and NO,.

® ®

[0072] In some embodiments, Rs may be selected from the group consisting of hydrogen, halogen, and optionally substituted Ci.¢ alkyl. The alkyl may be selected from - the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl, while the halogen may be selected from the group consisting of fluoro, chloro, and bromo. }

In certain embodiments, Rs may be hydrogen or chloro.

[0073] In certain embodiments, Rg may be hydrogen or optionally substituted

Ci alkyl. The alkyl may be selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl. In some embodiments, Rs may be hydrogen.

[0074] In certain embodiments, R; may be selected from the group consisting of hydrogen, halogen, optionally substituted Ci. alkyl, perhaloalkyl, CN, SO;Rjp, and NO.

The alkyl may be selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl, while the halogen may be selected from the group consisting of fluoro, chloro, and bromo. In some embodiments, the perhaloalkyl is perfluoroalkyl, which in some embodiments, may be trifluoromethyl. In the embodiments in which Ry may be SOR 10, Rio may be hydrogen or optionally substituted Cy.6 alkyl, which alkyl may be selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl. In certain embodiments, R; may be selected from the group consisting of hydrogen, methyl, chloro, trifluoromethyl, SO,CHj, CN, and NOs.

[0075] In some embodiments, Rg may be selected from the group consisting of hydrogen, halogen, optionally substituted Cj.¢ alkyl, which alkyl may be selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl. The halogen may be selected from the group consisting of fluoro, chloro, and bromo. In certain embodiments, Rg may be selected from the group consisting of hydrogen, chloro, and bromo.

[0076] Embodiments of the present disclosure include those in which Rg may be selected from the group consisting of hydrogen, halogen, optionally substituted Ci.¢ alkyl, and perhaloalkyl. The alkyl may be selected from the group consisting of methyl, ethyl, ~ propyl, isopropyl, butyl, sec-butyl, and tert-butyl. The halogen may be selected fromthe group consisting of fluoro, chloro, and bromo. The perhaloalkyl may be perfluoroalkyl, which in some embodiments may be trifluoromethyl. In some embodiments, Ro may be a selected from the group consisting of hydrogen, chloro, methyl, and trifluoromethyl.

[0077]: In some embodiments, R; may be selected from the group consisting of hydrogen, optionally substituted Cj. alkyl, and optionally substituted aryl. The alkyl may

_ . ® be selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl, while the aryl may be phenyl or naphthyl. In other embodiments, R; may be a heteroaryl. In certain embodiments, R; may be hydrogen. In certain embodiments, R; is - absent. ~ [0078] In some embodiments, X may be nitrogen. In other embodiments, Y 3 may be NH and W may be nitrogen or CH.

[0079] In some embodiments of the compounds of Formula I or Formula XV, L is absent or is selected from the group consisting of -NHCH,—, -NH-, and -CH,~. In some embodiments of the compounds of Formula I or Formula XV, A is selected from the group consisting of: a va | a I on (OO 0 Oy r y= Y - “d,, |, md Cand where n is selected from the group consiting of 0, 1, and 2.

[0080] Some embodiments of the compounds of Formula I, Formula IH, or

Formula XV, include:. 2,7-Dichloro-11-(piperazin-1-yl)-5H-dibenzo[b, e](1,4]diazepine, 2-Chloro-11-(piperazin-1-yl)-5H-dibenzo[b,e]{1,4]diazepine, 2,8-Dichloro-11-(piperazin-1-yl)-5H-dibenzo[b, e]( 1,4]diazepine, 8-Bromo-2-chloro-11-(piperazin-1-y1)-5H-dibenzo[ b,e][ 1,4 ]diazepine, 2-Chloro-11-(piperazin-1-yl)-8-trifluoromethyl-5H-dibenzo[b,e}{1,4] diazepine, 6-Chloro-11-(piperazin-1-yl)-8-trifluoromethyl-5H-dibenzofb, e][1,4]diazepine, 7-Chloro-11-(piperazin-1-yl)-5H-dibenzo[b,e][ 1,4]diazepine, 8-Bromo-1-chloro-11-(piperazin-1-yl)-5H-dibenzo[ b,e][ 1,4]diazepine, 8-Bromo-2-methyl-11-(piperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine, 4,8-Dichloro-11-(piperazin-1-yl)-5H-dibenzo[b,e][ 1,4]diazepine, -. 8-Chloro-2-methyl-11-(piperazin-1-yl)-5 H-dibenzo[b,e][ 1 ,4]diazepine, 8-Chloro-2-fluoro-11-(piperazin-1-yl)-5H-dibenzo[b,e][ 1,4]diazepine,

E 3,8-Dichloro-11-(piperazin-1-yl)-5H-dibenzo[b, e][ 1,4]diazepine, 2-Bromo-8-chloro-11-(piperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine, 3,7-Dichloro-1 1-(piperazin-1-yl)-5H-dibenzo[d, e][1 ,4]diazepine,

® ® 8-Bromo-3-chloro-11-(piperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine, 3-Chloro-11-(piperazin-1-yl)-5H-dibenzo[b,e][1 ,4]diazepine, 3-Chloro-11-(piperazin-1-yl)-8-trifluoromethyl-5H-dibenzo{ b,e][ 1,4] diazepine, 7-Chloro-2-methyl-11-(piperazin-1-yl)-5SH-dibenzo[b, €][1,4] diazepine, . 2-Methyl-11-(piperazin-1-yl)-5H-dibenzo[b,e][ 1 4]diazepine, 2-Methyl-11-(piperazin-1-yl)-8-trifluoromethyl- 5H-dibenzo[b,e][1,4]diazepine, 8-Chloro-4-methyl-11-(piperazin-1-yl)-5H-dibenzo[b, e][1,4]diazepine, 1,8-Dichloro-11-(piperazin-1-yl)-5H-dibenzo[b,e][1 ,4]diazepine, 8-Bromo-5-methyl-11-(piperazin-1-yl)-5H-dibenzo[b, e][1,4]diazepine, 7 8-Dichloro-11-(piperazin-1-yl)-5H-dibenzo[b,e](1,4] diazepine, 11-(Piperazin-1 -yl)-8-trifluoromethyl-5 H-dibenzo[b, e][1,4]diazepine, 11-(Piperazin-1-yl)-5H-dibenzo[b,e][1 ,4]diazepine, 8-Fluoro-11-(piperazin-1-yl)-5H-dibenzo[b,e][1 ,4]diazepine, 11-(Piperazin-1-yl)-5H-dibenzo[b,e](1 ,4]diazepine-8-carbonitrile, 8-Bromo-11-(piperazin-1-y1)-5H-dibenzo[b, e][1,4]diazepine, 8-Methyl-11-(piperazin-1-yl)-5H-dibenzo [b,e][1,4]diazepine, 3-Fluoro-6-piperazin-1-yl-1 1H-dibenzo[b,elazepine, - 2-(Trifluoromethanesulfonyloxy)-11 -(piperazin-1 1)-SH - dibenzo[b,e][1,4]diazepine, 2-(Trifluoromethanesulfonyloxy)-11 -(piperazin-1-yl)-5H- dibenzo[b,e][1,4]oxazepine, 8-Chloro-2-(trifluoromethanesulfonyloxy)- 11-(piperazin-1-yl)-SH- dibenzo[b,e][1,4]diazepine, 8-(Trifluoromethanesulfonyloxy)-11 -(piperazin-1-yl)-SH- dibenzo[b,e][1,4]diazepine, 11-(Piperazin-1-yl)-dibenzo[b,f][1 ,4]thiazepin, 11-(Piperazin-1-yl)-2,3-dihydro-1 ,A-benzodioxino[6,7-b]{ 1 4]benzothiazepin, 8-Chloro-11-[1,4]diazepam-1-yl-5H -dibenzo[b,¢] [1,4]diazepine,

N°-(8-Chloro-5H-dibenzo[b,e][ 1 ,4]diazepine-1 1-y1)-N,N-dimethyl-ethane-1,2- diamine, h

N°~(8-Chloro-5H-dibenzo[b,e][1,4] diazepine-11-y1)-N,N-diethyl-ethane-1 ,2- diamine, 8-Chloro-11-(4-methyl-[1,4]diazepam-1 -yl)-5H-dibenzo[b,e][1,4] diazepine,

® ® 8-Chloro-2-methoxy-11-(piperazin-1-yl)-5H-dibenzo[b,e][ 1,4]diazepine,

N’-(SH-Dibenzo[b,e](1,4]diazepine-11-yl)-N,N-dimethyl-ethane-1,2-diamine, 11-[1,4]Diazepam-1-yl-5H-dibenzo[b,e][1,4]diazepine, - N’-(8-Fluoro-SH-dibenzo[b,e][1,4]diazepine-11-yl)-N.N-dimethyl-ethane-1,2- diamine, ; ~ 8-Fluoro-1 1-[1,4]diazepam-1-yl-5H-dibenzo[b,e][1,4]diazepine,

N’-(8-Chloro-5H-dibenzo[b,e][ 1,4]diazepine-11-yl)-N-methyl-ethane-1,2-diamine, 8-Chloro-11-(trans-2,5-dimethyl-piperazin-1-yl)-5H-dibenzo[b,e][ 1,4 ]diazepine, 8-Chloro-11-(3,5-dimethyl-piperazin-1-yl)-5H-dibenzo[b,e][ 1,4]diazepine, 8-Chloro-11-(3-methyl-piperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine, 8-Chloro-11-(3-phenyl-piperazin-1-yl)-5 H-dibenzo[b,e](1,4]diazepine, 8-Chloro-5-methyl-11-(piperazin-1-yl)-5H-dibenzo(b,e][1,4]diazepine, 8-Chloro-5-benzyl-11-(piperazin-1-yl)-5 H-dibenzo[b,e][1,4]diazepine, 8-Iodo-11-(piperazin-1-yl)-5H-dibenzo[b,e][ 1,4]diazepine, 2-Todo-8-chloro-11-(piperazin-1-yl)-SH-dibenzo[b,e][ 1,4]diazepine, 8-Phenyl-11-(piperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine, : 8-Chloro-11-(piperidin-1-yl)-5H-dibenzo[b,e][1,4]diazepine, 8-Chloro-11-(morpholin-4-yl)-5H-dibenzo[b,e][ 1,4]diazepine, 5-Allyl-8-chloro-11-(piperazin-1-yl)-SH-dibenzo[b,e][1,4]diazepine, : 6-Chloro-11-(piperazin-1-yl)-5H-dibenzo[ b,e]{1,4]diazepine, 8-Chloro-5-piperazin-1-yl-11H-benzo[b]pyrido[2,3-¢][1,4]diazepine, : 2-Chloro-10-piperazin- 1-yl-5H-dibenzo[b,f]azepin, 8-Chloro-11-(piperazin-1-yl)-dibenzo[5,f][ 1,4]thiazepine, 8-Chloro-11-(piperazin-1-yl)-dibenzo[b,f][ 1,4 Joxazepine, 8-Chloro-11-(4-methyl-piperazin-1-yl)-dibenzo[b,f][1,4]oxazepine, 3-Chloro-6-piperazin-1-yl-11H-dibenzo[b, e]azepine, 8-Bromo-11-(piperazin-1-yl)-dibenzo[d,f][ 1,4]oxazepine, . 11-(Piperazin-1-yl)-dibenzo[d,f]{ 1,4]oxazepine, 7-Chloro-11-(piperazin-1-yl)-dibenzo[b f][1,4]oxazepine, . 8-Chloro-3-methoxy-11-(piperazin-1-yl)-dibenzo[b,f][1,4]oxazepine, 8-Bromo-3-methoxy-11-(piperazin-1-yl)-dibenzo[b,f][ 1,4 ]oxazepine, 3-Methoxy-11 -(piperazin-1-yl)-dibenzo[,f][1,4]oxazepine, 7-Chloro-3-methoxy-11-(piperazin-1 -yl)-dibenzo [6.f]1[1,4]oxazepine,

® ® :

* 8-Chloro-4-methyl-11-(piperazin-1-yl)-dibenzo[b,f][ 1,4]oxazepine, 8-Bromo-4-methyl-11-(piperazin-1-yl)-dibenzo[b,f][1,4]Joxazepine, 4-Methyl-11-(piperazin-1-yl)-dibenzo[b f][1,4]oxazepine, 2-Bromo-8-chloro-11-(piperazin-1-yl)-dibenzo{b,f][1,4]oxazepine, . 2,8-Dibromo-1 1-(piperazin-1-yl)-dibenzo[b,f] [1,4)oxazepine, : 2-Bromo-11-(piperazin-1-yl)-dibenzo[b,f][1,4]oxazepine, 2-Bromo-7-chloro-11-(piperazin-1-yl)-dibenzo[b,f][1,4]oxazepine, 11-(Piperazin-1-yl)-8-trifluoromethyl-dibenzo[b,f][ 1,4]oxazepine, 4-Methyl-11-(piperazin-1-yl)-8-trifluoromethyl-dibenzo[b,f][ 1,4] oxazepine, 8-Fluoro-11-(piperazin-1-yl)-dibenzo[b,f][1,4]oxazepine,

8-Fluoro-3-methoxy-11-(piperazin-1-yl)-dibenzo[b f][ 1,4]oxazepine, 8-Fluoro-4-methyl-1 1-(piperazin- 1-yl)-dibenzo[b,f}[1,4Joxazepine, 2-Bromo-8-fluoro-11-(piperazin-1-yl)-dibenzo[b,f][1,4]oxazepine, 8-Methyl-11-(piperazin-1-yl)-dibenzo[5,/][ 1,4] oxazepine, 3-Methoxy-8-methyl-1 1-(piperazin-1 -yl)-dibenzo{b,f][1,4] oxazepine, 4,8-Dimethyl-11-(piperazin-1-yl)-dibenzo[b,f][1,4]oxazepine, 3-Methoxy-11-(piperazin-1-yl)-8-trifluoromethyl-dibenzo[ 6,f][1,4] oxazepine, 2-Bromo-1 1-(piperazin-1-yl)-8-trifluoromethyl-dibenzo[b,/][1,4] oxazepine, 6-Chloro-11-(piperazin-1-yl)-dibenzo[b,f][1 ,4loxazepine, 2-Bromo-8-methyl-11-(piperazin-1-yl)-dibenzo[,f][ 1,4]oxazepine, 7-Chloro-4-methyl-11-(piperazin-1-yl)-dibenzo[b,f][ 1 ,4]oxazepine, 8-Phenyl-11-(piperazin-1-yl)-dibenzo[b,f][1,4]oxazepine, 8-Chloro-11-(piperidin-4-yl)-5H-dibenzo([b,e][1,4]diazepine

- 5-Benzyl-8-chloro-11-(piperidin-4-y1)-5H-dibenzo[b,e][1 ,4]diazepine,

8-Bromo-5,10-dihydro-dibenzo[b,e][1,4]diazepine-11-one, 5,10-Dihydro-dibenzo[,e][1,4]diazepine-11-one, 8-Fluoro-5,10-dihydro-dibenzo[b,e][1,4]diazepine-11-one, 8,5-Dichloro-5H-dibenzo[b,e][ 1,4]diazepine, 8-Chloro-11-methylsulfanyl-5H-dibenzo[b,e][1,4]diazepine (8-Chloro-5H-dibenzo[b,e][1,4]diazepin-11-y})-(5)-1 -pyrrolidin-2-yl-methyl-amine, ; 1-(8-Chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)-piperidine-4-yl-amine, 1-(8-Chloro-5H-dibenzo[b,e][ 1,4]diazepin-11-yl)-pyrrolidin-3-yl-amine, (8-Chloro-5H-dibenzo[b,e][ 1,4]diazepin-11-yl)-(R)-1 _pyrrolidin-2-yl-methyl-amine,

®

PY . (8-Chloro-5H-dibenzo[b,e][ 1 4]diazepin-1 1-yl)-pyrrolidin-3-yl-amine, 8-Chloro-11-(2,5-diaza-bicyclo[2.2.1]hept-2-y1)-5H-dibenzo[b,e][ 1,4]diazepine,

Acetidin-3-yl—(8-chloro-5H-dibenzo[b,e}[1,4]diazepme-11-yl)amine, - 7-Bromo-4-(piperazin-1-yl)-2,3-dihydro-1H-benzo[b][ 1,4] diazepine, 7-Bromo-2-methyl-(piperazin-1-yl)-2,3-dihydro-1H-benzo[b][1,4]diazepine : 7-Bromo-2-phenyl-4-(piperazine-1-yl)-2,3-dihydro-1H-benzo[b][1,4]diazepine, 7-Bromo- 10-(piperazin- 1-y1)-1,2,3,3a,4,10a-hexahydro- benzo[b]cyclopentafe][1,4]diazepine, 8-Chloro-11-(4-fluorobenzyl)-5H-dibenzo[b,e}[ 1,4]diazepine, 8-Chloro-11-(4-fluorophenyl)-5H-dibenzo [b,€][1,4]diazepine, 8-Chloro-11-(4-nonylphenyl)-5H-dibenzo{ b; e][ 1,4]diazepine, 8-Chloro-11-(pyridin-4-yl)-5H-dibenzo[b,e][ 1,4]diazepine, and 8-Chloro-11-(1H-pyrazol-4-yl)-5 H-dibenzo[b,e][ 1,4]diazepine.

[0081] In another aspect, the present disclosure is directed to a method of synthesizing a compound of Formula V or Formula VI, oo i x

Gr n) { a n oR

Rg Nl Ra Rs Nl Ro oo v) paPeg VD) paPig

N N

Rg L, " 1 Ry Rg he o Rq comprising - reacting a compound of Formula VII

R, O : (VI) Ra OH

Rs . with a compound of Formula VIII . (VID) ON Ry

Bel

Rg to form a fused ring compound of Formula IX,

_ ®

Rs PR, (IX) TY Rs

Rg N Ry

Rg Rs : and reacting the compound of Formula IX with a compound of Formula X : R R4 . & 5 A Weg be) GG to obtain a compound of Formula V or VI; wherein X is a halogen; and R;-Rg are as defined herein. In some embodiments, the compound of Formula V synthesized according to the disclosed method is clozapine while in other embodiments, the compound is N-desmethylclozapine. In certain other embodiments, the compound of Formula V synthesized according to the disclosed method does not include clozapine or N-desmethylclozapine.

[0082] Consistent with this aspect, Schemes 1 and 2 depict the synthesis of some of the compounds disclosed herein. The first series of steps generating the intermediate lactam have been described by, inter alia, Liao et al. J. Med. Chem. 1997, 40, 4146-4153. The last step has been described by e.g. Liao et al. J. Med. Chem. 1999, 42, 2235-2244. Both of these references are hereby incorporated herein by reference in their entirety, including any drawings.

Scheme 1 oo ] R, O ) Ry Re in 9 R,

TL OC =e] Tye + —— . N . Rj NH, X Ry Rq N Re : Rs Rs Rs Rs h A B Ri

W.

A ) TiCl, or POCy

N

H Ri : Ww

Io

R2 N= R,

Rs Rs

R N R

* Rs Rs ‘

Scheme 2

SO == + ———

N

Rg NH, X Ry Ry N R,

Rs Rs Rs Rs

A B Ra

WC ir Ry | TiCly or POCI, ( NH

H R;

W

( gn “Ry

NT

R2 N= Ry

Rs Rs

R N R

* Rg Rs - [0083] In certain embodiments of the invention the building blocks A and B are selected from but not limited to a

®

A

Si AO ave CO,H

NH, NH, NH, ON” _ - corr Or jou jo

F NH, NH, cl NH, FaC NH,

Br CO5H Me ~0 CO5H .

TC | Ean [en | CX

Br NH, : Me NHo

NH, NH,

Br CO,H CO,H cl CO,H ~

NH, Ss NH, NH, 02 NH,

CO,H Or Or or _ - NH, NH, NH,

Cl

B

O,N CF, O,N O,N cl 0, [Cn [et

F F Br F Cl Tr

Cl F

Or SON ON NO, Or

F F Ct Ci

CF, ] Cl Ci

Me

[0084] In another aspect, the present disclosure relates to a combinatorial library of at least 10, or at least 30, or at least 50, or at least 100, or at least 200, or at least 220 dibenzo[b,e][1,4]diazepine compounds that can be formed by reacting a compound of

Formula VII,

R, O (VI) Ra OH } Ry NH, B

Re with a compound of Formula VIII and

Rg - (vi) ON Ry

X Rg a compound of Formula XI,

N | R4

CD he) ( N

H wherein X is a halogen; W is nitrogen, CH, oxygen, or sulfur; nis 1, 2, 3, or 4 and

R;-Ry are as defined herein. In some embodiments, the combinatorial library includes clozapine and/or N-desmethylclozapine. In certain other embodiments, the combinatorial library does not include clozapine or N-desmethylclozapine.

[0085] In another aspect, the present disclosure relates to a combinatorial library of at least 10, or at least 30, or at least 50, or at least 100, or at least 200, or at least 220 dibenzo[b,e][1,4]diazepine compounds that can be formed by reacting a compound of

Formula VII,

R, O (Vv) Rs OH

Rj NH,

Rs with a compound of Formula VIII and

Re (VII) O2N Ry

X Rg

Re a compound of Formula XII,

Tr ) oD

Gn 5 ~ H wherein X is a halogen; W is nitrogen, CH, oxygen, or sulfur; nis 1, 2, 3, or 4; and

R;-Ry are as defined herein.

Claims

CLAIMS: — . 1. A compound of Formula I: I in rT | cL Ro rR TT \ X=X_ I - \ LJ EE a GY Rg Rs ® : or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein: A has the structure G { | : (4; Te, , wherein each bond represented by a dashed and solid-line in A represents a carbon-carbon single bond; a, b, ¢, and d are each carbon; ; e, f, g, and h are each carbon; X is nitrogen; X 1s C; L is absent; : eachnis 1; Y is nitrogen; W is nitrogen; R; is selected from the group consisting of hydrogen, halogen, amine, optionally substituted Ci.20-alkyl, optionally substituted C;.g cycloalkyl, optionally substituted Cs.50 alkenyl, optionally substituted C,., alkynyl, optionally substituted Cy.2 —alkoxyalkyl, and optionally substituted aryl and arylalkyl; Ry, Rs, Ry, and Rs, are each independently selected from the group consisting of hydrogen, halogen, optionally substituted C,.¢ alkyl, optionally substituted C;.¢ alkyloxy, optionally substituted C,¢ alkenyl, optionally substituted Cy alkynyl, optionally :

¢ fo men TT TE substituted C;¢-alkoxyalkyl, optionally substituted Ci. alkylthio, perhaloalkyl, CN, CORj9, CONHR;y, NHCONHR;o, SO;NHR}g, SO2R19, OSO2Ryg, heteroalkyl, NO, NHCOR, or R; and Rj, or R; and Ry, or Ry and Rs taken together, along with the ring carbons to which they are attached, form a five-membered or six-membered cycloalkyl, heterocyclyl or heteroaryl ring, or a six-membered aryl ring moiety; Rg, Ry, Rg, and Ry, are each independently selected from the group consisting of ) hydrogen, halogen, optionally substituted Cj alkyl, optionally substituted C,.¢ alkyloxy, optionally substituted C,¢ alkenyl, optionally substituted C,¢ alkynyl, optionally substituted Cj.¢-alkoxyalkyl, optionally substituted Ci.¢ alkylthio, perhaloalkyl, CN, COR), CONHR;3, NHCONHR}o, SO;NHRp, SOsR;9, OSO2R 0, heteroalkyl, NO, . NHCOR,, or R¢ and R5, or Ry and Rg, or Rg and Ro taken together, along with the ring carbons to which they are attached, form a five-membered or six-membered cycloalkyl, heterocyclyl or heteroaryl ring, or a six-membered aryl ring moiety; .Z is selected from the group consisting of NR;;, oxygen, sulfur, and CH; Rio is selected from the group consisting of hydrogen, optionally substituted Cj.6 alkyl, optionally substituted C;.g cycloalkyl, optionally substituted C,.¢ alkenyl, optionally substituted C,.¢ alkynyl optionally substituted aryl, optionally substituted arylalkyl, and

. perhaloalkyl; and each bond represented by a dashed and solid line in Formula I represents a carbon-carbon double bond; : provided that the compound of Formulae I is not clozapine or N- - desmethylclozapine.
2. The compound of claim 1, wherein R; is selected from the group consisting of hydrogen, halogen, optionally substituted Cs alkyl, and optionally substituted C;_¢ alkyloxy.
3. The compound of claim 2, wherein said alkyl is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl.
4. The compound of claim 2, wherein said alkyloxy is selected from the group consisting of methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, and tert-butoxy. -112- oo

@ tr i me LP
5. The compound of claim 2, wherein said halogen is selected from the group consisting of fluoro, chloro, and bromo.
6. The compound of claim 1, wherein R; is selected from the group consisting of hydrogen, methyl, methoxy, and chloro.
7. The compound of claim 1, wherein Rj is selected from the group consisting of : hydrogen, halogen, optionally substituted C,.¢ alkyl, optionally substituted C,.¢ alkyloxy, and NO:
8. The compound of claim 7, wherein said alkyl is selected from the group : consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl.
9. The compound of claim 7, wherein said alkyloxy is selected from the group : consisting of methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, and tert-butoxy.
10. The compound of claim 7, wherein said halogen is selected from the group consisting of chloro, bromo, and iodo.
11. . The compound of claim 1, wherein Rj is selected from the group consisting of hydrogen, methyl, methoxy, chloro, bromo, iodo, and NO..
12. The compound of claim 1, wherein Ry is selected from the group consisting of hydrogen, halogen, optionally substituted C,.¢ alkyl, perhaloalkyl, SO;R 0, and NO.
13. The compound of claim 12, wherein said alkyl is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl.
14. The compound of claim 12, wherein said perhaloalkyl is perfluoroalkyl.
15. The compound of claim 14, wherein said perfluoroalkyl is trifluoromethyl. :
16. The compound of claim 12, wherein said halogen is selected from the group consisting of fluoro, chloro, and bromo. oo :
17. The compound of claim 12, wherein R,¢ is hydrogen or optionally substituted Cy.¢ : alkyl.
18. The compound of claim 17, wherein said alkyl is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl.
19. The compound of claim 1, wherein Ry is selected from the group consisting of hydrogen, methyl, fluoro, chloro, bromo, trifluoromethyl, SO,CH3, and NO,.
20. The compound of claim 1, wherein Rs is selected from the group consisting of hydrogen, halogen, and optionally substituted C,.¢ alkyl.

» SUPERS E
21. The compound of claim 20, wherein said alkyl is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl.
22. The compound of claim 20, wherein said halogen is selected from the group consisting of fluoro, chloro, and bromo. -
23. The compound of claim 1, wherein Rs is hydrogen or chloro.
24, The compound of claim 1, wherein Rg is hydrogen or optionally substituted C6 alkyl.

25. The compound of claim 1, wherein Rg is hydrogen. ,

26. The compound of claim 1, wherein R; is selected from the group consisting of . hydrogen, halogen, optionally substituted C,.¢ alkyl, perhaloalkyl, CN, SOR 9, and NOx. Co

27. The compound of claim 26, wherein said alkyl is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl.

28. The compound of claim 26, wherein said halogen is selected from the group consisting of fluoro, chloro, and bromo.

29. The compound of claim 26, wherein said perhaloalkyl is perfluoroalkyl.

30. The compound of claim 29, wherein said perfluoroalkyl is trifluoromethyl.

31. The compound of claim 26, wherein Ryo is hydrogen or optionally substituted C,.¢ alkyl. | :

32. The compound of claim 31, wherein said alkyl is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl.

33. The compound of claim 1, wherein Ry is selected from the group consisting of : hydrogen, methyl, chloro, trifluoromethyl, -SO,CHj3, CN, and NO.

34. © The compound of claim 1, wherein Rg is selected from the group consisting of hydrogen, halogen, optionally substituted C,.¢ alkyl.

35. The compound of claim 34, wherein said alkyl is selected fom the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl. ~~ - :

36. The compound of claim 34, wherein said halogen is selected from the group consisting of fluoro, chloro, and bromo. | -

37. The compound of claim 1, wherein Rg is selected from the group consisting of hydrogen, chloro, and bromo. S114 -

38. The compound of claim 1, wherein Ry is selected from the group consisting of hydrogen, halogen, optionally substituted C,.¢ alkyl, and perhaloalky!.

39. The compound of claim 38, wherein said alkyl is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl.

40. The compound of claim 38, wherein said halogen is selected from the group consisting of fluoro, chloro, and bromo.

41. The compound of claim 38, wherein said perhaloalkyl is perfluoroalkyl.

42. The compound of claim 41, wherein said perfluoroalkyl is trifluoromethyl.

43. The compound of claim 1, wherein Ry is selected from the group consisting of hydrogen, chloro, methyl, and trifluoromethyl.

44. The compound of claim 1, wherein R; is selected from the group consisting of hydrogen, optionally substituted C;.¢ alkyl, and optionally substituted aryl.

45. The compound of claim 44, wherein said alkyl is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl. ’

46. The compound of claim 1, wherein R; is hydrogen.

47. The compound of claim 1, wherein X is nitrogen.

48. The compound of claim 1, selected from the group consisting of: 4,8-Dichloro-11-(piperazin-1-yl)-SH-dibenzo[b,e][ 1,4]diazepine, 8-Chloro-4-methyl- 11-(piperazin-1-yl)-5H-dibenzo[b,e][ 1,4]diazepine, 8-Chloro-4-methyl-11-(piperazin-1-yl)-dibenzo[b,/][ 1,4Joxazepine, 8-Bromo-4-methyl-11-(piperazin-1-yl)-dibenzo[b,f][ 1 ,4Joxazepine, 4-Methyl-11-(piperazin-1-yl)-8-trifluoromethyl-dibenzo[3,/][ 1,4 Joxazepine, 8-Fluoro-4-methyl-11-(piperazin- 1-yl)-dibenzo[b,f][ 1,4 Joxazepine, and 4,8-Dimethyl-11-(piperazin-1-yl)-dibenzo[b,/][1,4]oxazepine.

49. The compound of claim 1, selected from the group consisting of: 2,7-Dichloro-11-(piperazin-1-yl)-5H-dibenzo[b,e][ 1,4]diazepine, 2-Chloro-11-(piperazin-1-yl)-5 H-dibenzo[b,e][ 1 ,4]diazepine, 2,8-Dichloro-11-(piperazin-1-yl)-5H-dibenzo[b,e][ 1 4]diazepine, 8-Bromo-2-chloro-11-(piperazin- 1-yl)-5H-dibenzo[b,e][ 1,4]diazepine, 2-Chloro-11-(piperazin-1-yl)-8-trifluoromethyl-5 H-dibenzo[b,e][ 1 ,4]diazepine, 6-Chloro-11-(piperazin-1-yl)-8-trifluoromethyl-5 H-dibenzo[b,e][ 1,4 ]diazepine,

CNEVS Ga 7-Chloro-11-(piperazin-1-yl)-5H-dibenzo[b,e][ 1,4]diazepine, 8-Bromo- 1-chloro-11-(piperazin-1-yl)-5H-dibenzo[b,e][ 1 ,4]diazepine, 8-Bromo-2-methyl-11-(piperazin-1-yl)-5H-dibenzo[b,e][ 1,4]diazepine, 8-Chloro-2-methyl-1 1-(piperazin-1-yl)-5H-dibenzo[b,e][ 1,4]diazepine, 8-Chloro-2-fluoro-11-(piperazin-1-yl)-5H-dibenzo[b,e][ 1,4]diazepine, 3,8-Dichloro-11-(piperazin-1-yl)-5H-dibenzo[b,e][ 1,4]diazepine, 2-Bromo-8-chloro-1 1-(piperazin- 1-yl)-5H-dibenzo[b, ell 1,4]diazepine, 3,7-Dichloro-11-(piperazin-1-yl)-5H-dibenzo[b,e][ 1,4]diazepine, : 8-Bromo-3-chloro-1 1-(piperazin-1-yl)-5H-dibenzo[b,e][ 1,4]diazepine, 3-Chloro-11-(piperazin-1-yl)-5H-dibenzo[b,e][ 1,4]diazepine, 3-Chloro-11-(piperazin-1-yl)-8-trifluoromethyl-5H-dibenzo[b, e][ 1 ,4]diazepine, 7-Chloro-2-methyl-11-(piperazin-1-yl)-5H-dibenzo[,e][ 1,4]diazepine, : 2-Methyl-11-(piperazin- 1-yl)-5H-dibenzo[b,e][1,4]diazepine, 2-Methyl-11 (piperazin- 1-y1)-8-trifluoromethyl-5 H-dibenzo[b, e][ 1,4]diazepine, 1,8-Dichloro-11 -(piperazin-1 -yl)-5H-dibenzo[b,e][1 A]diazepine, 8-Bromo-5-methyl-11-(piperazin-1-yl)-5H-dibenzo[b,e][ 1,4]diazepine, 7,8-Dichloro-11-(piperazin-1-yl)-5H-dibenzo[b,e][ 1,4]diazepine, 11-(Piperazin-1-yl)-8-trifluoromethyl-5H-dibenzo[ b,e][1,4]diazepine, 11-(Piperazin-1-yl)-5H-dibenzo[,e][ 1,4]diazepine, . 8-Fluoro-11-(piperazin-1-yl)-5H-dibenzo[b,e][ 1,4]diazepine, 11-(Piperazin-1-yl)-5H-dibenzo[b,e][ 1,4]diazepine-8-carbonitrile, 8-Bromo-11-(piperazin-1-yl)-5H-dibenzo[b,e][ 1,4]diazepine, oo 8-Methyl-11-(piperazin- 1-y})-5H-dibenzolb, e][1,4]diazepine, 3-Fluoro-6-piperazin- I-yl- 11H-dibenzo[b,e]azepine, 2-(Trifluoromethanesulfonyloxy)-11-(piperazin-1-yl)-5H- dibenzo[b,¢][1,4]diazepine, 2-(Trifluoromethanesulfonyloxy)-11-(piperazin-1-yl)-5H- dibenzo[b,e][1,4]oxazepine, 8-Chloro-2-(trifluoromethanesulfonyloxy)-11-(piperazin-1-yl)-5SH- dibenzo[b,e][1,4]diazepine,

8-(Trifluoromethanesulfonyloxy)-11-(piperazin-1-yl)-SH-

dibenzo[b,e][1,4]diazepine,

11-(Piperazin-1-yl)-dibenzo[b,f][1,4]thiazepin,

11-(Piperazin- 1-y1)-2,3-dihydro-1,4-benzodioxino[6,7-b][ 1,4]benzothiazepin,

8-Chloro-2-methoxy-11-(piperazin-1-yl)-5SH-dibenzo[b,e][ 1,4]diazepine,

8-Chloro-5-benzyl-11-(piperazin-1-yl)-5H-dibenzo[b,e][ 1 ,4]diazepine,

8-lodo-11-(piperazin-1-yl)-5SH-dibenzo[b,e][ 1 ,4]diazepine,

2-Iodo-8-chloro-11-(piperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine,

8-Phenyl-11-(piperazin-1-yl)-5SH-dibenzo[b,e][ 1,4]diazepine,

8-Chloro-11 -(piperidin-1-yl)-5H-dibenzo[b, e][ 1,4]diazepine,

5-Allyl-8-chloro-11-(piperazin-1-yl)-5H-dibenzo[ b,e][ 1,4]diazepine, 6-Chloro-11-(piperazin-1-yl)-5H-dibenzo[b,e][ 1,4]diazepine,

8-Chloro-5-piperazin-1-yl-11H-benzo[b]pyrido[2,3-¢][1,4]diazepine,

2-Chloro-1 0-piperazin- 1-yl-5H-dibenzo[b,f]azepin,

’ 8-Chloro-11-(piperazin-1-yl)-dibenzo[b,f][1,4]thiazepine, 8-Chloro-11-(piperazin-1-yl)-dibenzo[b,f][1,4]oxazepine, : 8-Chloro-11-(4-methyl-piperazin-1-yl)-dibenzo[b,f][ 1,4]oxazepine, : 11-(Piperazin-1-yl)-dibenzo[b,f][1,4]oxazepine, 7-Chloro-11-(piperazin-1-yl)-dibenzo[b,f][1,4]oxazepine, 8-Chloro-3-methoxy-11-(piperazin-1-yl)-dib enzo[bf][ 1,4]oxazepine, 8-Bromo-3-methoxy-11-(piperazin- 1-yl)-dibenzo[b,f][ 1 ,4]oxazepine, 3-Methoxy- 1 1-(piperazin- 1-yl)-dibenzo[b,f][ 1,4]oxazepine,

7-Chloro-3-methoxy-11-(piperazin-1-yl)-dibenzo[b,f][1,4]oxazepine, 4-Methyl-11-(piperazin-1 -yl)-dibenzo[b,/][ 1,4]oxazepine, © 2-Bromo-8-chloro-11-(piperazin-1-yl)-dibenzo[b,f][ 1,4 ]oxazepine, 2,8-Dibromo-11-(piperazin-1-yl)-dibenzo[b,f][ 1,4]oxazepine, : 2-Bromo-11 -(piperazin-1-yl)-dibenzo[b,f][ 1,4]Joxazepine, 2-Bromo-7-chloro-11-(piperazin-1-yl)-dibenzo[b,f][ 1,4 Joxazepine, 11-(Piperazin- 1-yl)-8-trifluoromethyl-dibenzo[b,f][ 1 ,4]oxazepine, 8-Fluoro-3-methoxy-11-(piperazin- 1-yl)-dibenzo[b,f][ 1,4]oxazepine, 2-Bromo-8-fluoro-11-(piperazin-1-yl)-dibenzo[b,f][ 1 ,4]oxazepine, S117-

® | PE SL 8-Methyl-11-(piperazin- 1-yl)-dibenzo[b A] 1,4Joxazepine, 3-Methoxy-8-methyl-11-(piperazin-1-yl)-dibenzo[,f][ 1,4]oxazepine, 3-Methoxy-11-(piperazin-1-yl)-8-trifluoromethyl-dibenzo[,/][1,4]oxazepine, : | 2-Bromo- 11-(piperazin-1 _yl)-8-trifluoromethyl-dibenzo[b,f][1,4]Joxazepine, : 6-Chloro-11-(piperazin-1-yl)-dibenzo[b,f][ 1,4]oxazepine, 2-Bromo-8-methyl-11-(piperazin- 1 -yl)-dibenzo{b,f][ 1,4]oxazepine, 7-Chloro-4-methyl-11-(piperazin-1-yl)-dibenzo[b,f][ 1 ,4]oxazepine, 8-Phenyl-11-(piperazin-1-yl)-dibenzo[b,f][ 1,4]oxazepine, and 8-Chloro-11-(piperidin-4-yl)-5 H-dibenzo[b,e][ 1,4]1diazepine.

50. The compound of claim 1, selected from the group consisting of’. : 8-Chloro-4-methyl-11-(piperazin-1-yl)-dibenzo[b,f][1,4]oxazepine, 8-Fluoro-4-methyl-11-(piperazin- 1-yl)-dibenzo[b,f][ 1,4]oxazepine, : 3-Chloro-6-piperazin-1-yl-11H-dibenzo[b,e]azepine, 8-Chloro-5-methyl- 11-(piperazin-1-yl)-5SH-dibenzo[b,e][1,4]diazepine, 4-Methyl-11-(piperazin-1-yl)-8-trifluoromethyl-dibenzo[b,f][ 1,4]oxazepine, 8-Bromo-11-(piperazin-1-yl)-dibenzo[b,f][ 1,4]Joxazepine, and 8-Fluoro-11-(piperazin-1-yl)-dibenzo[b,f][ 1,4 ]oxazepine.

51. The compound of claim 1, selected from the group consisting of: 8-Chloro-5-methyl-11-(piperazin-1 _yl)-5H-dibenzo[b,e][ 1,4]diazepine, 3-Chloro-6-piperazin-1-yl-11H-dibenzo[b,e}azepine, 8-Fluoro-4-methyl-11-(piperazin-1-yl)-dibenzo[b,f][1,4Joxazepine, and 8-Chloro-4-methyl-11-(piperazin-1-yl)-dibenzo[b,f][ 1,4]oxazepine. ]

+52. A compound having the structure set forth in Formula I: . A : i No ox=x JP CY J \ CU! RS ’ hk ‘ F - “ry : Re Rs ® or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein:

SE SP A has the structure G J (gn HI a, , wherein each bond represented by a dashed and solid line in A represents a carbon-carbon single bond, Y is CH, and each n is 1, or A has the structure n Sy —R = , wherein each n is separately selected from the group consisting of 0, 1, 2, 3, and 4; a, b, c, and d are each carbon; e, f, g, and h are each carbon; X is nitrogen; N X is C; L is absent; m is selected from the group consisting of 1, 2, and 3; W is nitrogen; R; is selected from the group consisting of hydrogen, halogen, amine, optionally substituted C,.xp-alkyl, optionally substituted Cj;.g cycloalkyl, optionally substituted C,.2 alkenyl, optionally substituted C;.5g alkynyl, optionally substituted C;.50—alkoxyalkyl, and optionally substituted aryl and arylalkyl; ‘Ra, Rs, Ry, and Rs, are each independently selected from the group consisting of hydrogen, halogen, optionally substituted C,. alkyl, optionally substituted C,.¢ alkyloxy, optionally substituted C,.¢ alkenyl, optionally substituted Cys alkynyl, optionally substituted C.¢-alkoxyalkyl, optionally substituted C,.s alkylthio, perhaloalkyl, CN, COR}y, CONHRy, NHCONHR , SO,NHR yy, SO2R;10, OSO;Rg, heteroalkyl, NO,, NHCORyj, or R; and Rj, or R3 and Ry, or Ry and Rs taken together, along with the ring carbons to which they are attached, form a five-membered or six-membered cycloalkyl, heterocyclyl or heteroaryl ring, or a six-membered aryl ring moiety; : oo | S119-

® ba Rs, Rg, and Ro, are each independently selected from the group consisting of hydrogen, halogen, optionally substituted C;.¢ alkyl, optionally substituted C.¢ alkyloxy, optionally substituted C, alkenyl, optionally substituted C,¢ alkynyl, optionally substituted Cjg-alkoxyalkyl, optionally substituted C,.¢ alkylthio, perhaloalkyl, CN, COR}9, CONHRp, NHCONHR;o, SO,NHR;j9, SO;R}9, OSO2R}0, heteroalkyl, NO,, NHCORy, or Rg and Ry taken together, along with the ring carbons to which they are attached, form a five-membered or six-membered cycloalkyl, heterocyclyl or heteroaryl ring, or a six-membered aryl ring moiety; Rj; is selected from the group consisting of -CF3, phenyl, -OSO,CF3, methyl, -CN, and halogen, or Rg and R7, or R; and Rg taken together, along with the ring carbons to which they are attached, form a 1,4-dioxane; Z is oxygen; Ryo is selected from the group consisting of hydrogen, optionally substituted C.¢ alkyl, optionally substituted C;._g cycloalkyl, optionally substituted C,.¢ alkenyl, optionally substituted C,.¢ alkynyl optionally substituted aryl, optionally substituted arylalkyl, and perhaloalkyl; and each bond represented by a dashed and solid line in Formula I represents a carbon-carbon double bond.

53. The compound of claim 52, selected from the group consisting of: 8-Chloro-11-(piperidin-4-yl)-5H-dibenzo[b,e][ 1,4]diazepine 5-Benzyl-8-chloro-11-(piperidin-4-yl)-5 H-dibenzo[b,e][ 1,4]diazepine, : 8-Chloro-11-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)-5SH-dibenzo[b,e][ 1 ,4]diazepine, CL and 8-Chloro-11-(pyridin-4-y1)-5H-dibenzo[b,e][1,4]diazepine.

54. A method of synthesizing a compound of Formula V,

; ® Bl "i Ton TY UH EE TER FE San FF pb lem eid SUES sme R4 ’ / a ww Re N— Ra Mv) R7 Rs ¥ R Re Re Re 4 comprising: reacting a compound of Formula VII Ry, O (VII) Rs OH R; NH, Rs with a compound of Formula VIII - . Rg . . (VIII) ON Ry X Rg Rg to form a fused ring compound of Formula IX, . 0) IX) ( Ry; Rs R N Ry ® Rg Rs and reacting the compound of Formula IX with a compound of Formula X R, SH (1n ) ( N H to obtain a compound of Formula V, wherein X is a halogen; W is nitrogen; :

® +§ ) Cr nis 1; R; is selected from the group consisting of hydrogen, optionally substituted C,. alkyl, optionally substituted Cj.g cycloalkyl, optionally substituted C,.¢ alkenyl, optionally substituted C,¢ alkynyl, optionally substituted C;¢ —alkoxyalkyl, and optionally substituted aryl and arylalkyl; Ra, Ri, Rs, and Rs, are each independently selected from the group consisting of hydrogen, halogen, optionally substituted Cis alkyl, optionally substituted Ci.¢ alkyloxy, optionally substituted C,.¢ alkenyl, optionally substituted C,.¢ alkynyl, optionally substituted C;_¢- alkoxyalkyl, optionally substituted C;¢ alkylthio, perhaloalkyl, CN, COR, CONHR, NHCONHR 4, SO;NHR 19, SO2R yo, OSO:R0, heteroalkyl, NO,, NHCORq, or R, and Rj, or Rj; and Ry, or R; and Rs taken together, along with the ring carbons to which they are attached, form a five-membered or six-membered cycloalkyl, heterocyclyl or heteroaryl ring, or a six-membered aryl ring moiety; ] Rs, Rs, Rg, and Ro, are each independently selected from the group consisting of hydrogen, halogen, optionally substituted C;¢ alkyl, optionally substituted Ci. alkyloxy, optionally substituted Cs ¢ alkenyl, optionally substituted C,.¢ alkynyl, optionally substituted Ci.¢- Co alkoxyalkyl, optionally substituted Cg alkylthio, perhaloalkyl, CN, COR, CONHR|o, NHCONHR 9, SO;NHR 0, SO2R 19, OSO:2R 10, heteroalkyl, NO2, NHCOR yo, or Rg and R5, or Ry and Rg, or Rg and Ry taken together, along with the ring carbons to which they are attached, form a five-membered or six-membered cycloalkyl, heterocyclyl or heteroaryl ring, or a six-membered aryl ring moiety.

55. A combinatorial library of at least 220 dibenzo[b,e][1,4]diazepine[a,d]cycloheptene compounds that can be formed by reacting a compound of Formula VII, : R, OO. (VII) Rs OH oo

OL . ’ Rs with a compound of Formula VIII and -

® 5 EE oo . Re (VIII) O2N Rs Reo Rg a compound of Formula X, R, © ol ‘wherein : X is a halogen; W is nitrogen; R, is selected from the group consisting of hydrogen, optionally substituted C,. alkyl, optionally substituted Cs. cycloalkyl, optionally substituted Cs. alkenyl, optionally substituted

C,.¢ alkynyl, optionally substituted Cc —alkoxyalkyl, and optionally substituted aryl and arylalkyl; Ry, Rs, Ry, and Rs, are each independently selected from the group consisting of hydrogen, halogen, optionally substituted C; alkyl, optionally substituted C;¢ alkyloxy, optionally substituted C, ¢ alkenyl, optionally substituted C,.¢ alkynyl, optionally substituted Cy.¢- alkoxyalkyl, optionally substituted Ci.¢ alkylthio, perhaloalkyl, CN, COR;o, CONHRq, : NHCONHR jy, SO,NHR 9, SO2R 19, OSO2R 1, heteroalkyl, NO,, NHCOR jo, or R; and Rj, or R3 and Ry, or Ry and Rs taken together, along with the ring carbons to which they are attached, form a five-membered or six-membered cycloalkyl, heterocyclyl or heteroaryl ring, or a six-membered aryl ring moiety;Rs, Ry, Rg, and Rg, are each independently selected from the group consisting of hydrogen, halogen, optionally substituted C,.s alkyl, optionally substituted Cg alkyloxy, optionally substituted C.¢ alkenyl, optionally substituted C,.¢ alkynyl, optionally substituted C;- alkoxyalkyl, optionally substituted C,.¢ alkylthio, perhaloalkyl, CN, COR;y, CONHR,o, : NHCONHR jo, SO,NHR 9, SO2R 19, OSO2R jg, heteroalkyl, NO, NHCOR, or Rg and R5, or R;7 and Rg, or Rg and Ry taken together, along with the ring carbons to which they are attached, form a five-membered or six-membered cycloalkyl, heterocyclyl or heteroaryl ring, or a six-membered aryl ring moiety. :

®

56. A compound according to any one of claims 1-53 for use in treating a neuropsychiatric disorder. .

57. A compound according to any one of claims 1-53 for use in treating cognitive impairment. :

58. A compound according to any one of claims 1-53 in combination with a neuropsychiatric agent for use in treating a neuropsychiatric disorder.

59. The compound of claim 58, wherein said neuropsychiatric disorder is selected from the group consisting of schizophrenia and related idiopathic psychoses, anxiety, sleep disorders, appetite disorders, affective disorders such as major depression, bipolar disorder, and depression with. psychotic features, and Tourette’s Syndrome, drug-induced psychoses, . psychoses secondary to neurodegenerative disorders such Alzheimer’s or Huntington’s Disease.

60. A compound according to any one of claims 1-53 in combination with a neuropsychiatric agent for use in treating cognitive impairment. :

61. A pharmaceutical composition comprising a physiologically acceptable carrier, diluent, or excipient, or a combination thereof; and a compound according to any one of claims 1-53.

62. A pharmaceutical composition comprising a compound according to any one of claims 1-53 and a neuropsychiatric agent.

63. The composition of claim 62, wherein said neuropsychiatric agent is selected from the group consisting of a selective serotonin reuptake inhibitor, norepinephrine reuptake inhibitor, dopamine agonist, muscarinic receptor antagonist, antipsychotic agent, serotonin 2A . antagonist, and inverse serotonin 2A agonist.

64. The composition of claim 63, wherein said antipsychotic agent is selected from the group consisting of a phenothiazine, phenylbutylpiperadine, debenzapine, benzisoxidil, and salt of lithium.

65. The composition of claim 64, wherein said phenothiazine is selected from the group consisting of chlorpromazine (Thorazine®), mesoridazine (Serentil®), prochlorperazine (Compazine®), and thioridazine (Mellaril®).

66. The composition of claim 64, wherein said phenylbutylpiperadines is selected from the group consisting of haloperidol (Haldol®), and pimozide (Orap®). S124-

®

67. The composition of claim 64, wherein said debenzapine is selected from the group consisting of clozapine (Clozaril®), loxapine (Loxitane®), olanzapine (Zyprexa®) and quetiapine (Seroquel®).

68. The composition of claim 64, wherein said benzisoxidil is selected from the group consisting of resperidone (Resperidal®) and ziprasidone (Geodon®).

69. The composition of claim 64, wherein said salt of lithium is lithium carbonate.

70. The composition of claim 63, wherein said antipsychotic agent is selected from the group consisting of Clozaril, Compazine, Etrafon, Geodon, Haldol, Inapsine, Loxitane, Mellaril, Moban, Navane, Orap, Permitil, Prolixin, Phenergan, Reglan, Risperdal, Serentil, Seroquel, Stelazine, Taractan, Thorazine, Triavil, Trilafon, and Zyprexa.

71. The composition of claim 63, wherein said selective serotonin reuptake inhibitor is selected from the group consisting of fluoxetine, . fluvoxamine, sertraline, paroxetine, citalopram, escitalopram, sibutramine, duloxetine, and venlafaxine, and pharmaceutically acceptable salts or prodrugs thereof.

72. The composition of claim 63, wherein said norepinephrine reuptake inhibitor is selected from the group consisting of thionisoxetine and reboxetine.

73. The composition of claim 63, wherein said dopamine agonist is selected from the group consisting of sumatriptan, almotriptan, naratriptan, frovatriptan, rizatriptan, zomitriptan, cabergoline, amantadine, lisuride, pergolide, ropinirole, pramipexole, and bromocriptine.

74. The composition of claim 63, wherein said inverse serotonin 2A agonist is the compound of Formula XIII, or a related analog thereof. Te N F 9 oJ Wa LT l (XIII)

75. The composition of claim 63, where in said serotonin 2A antagonist is the compound of Formula XIV, or a related analog thereof:

ol ) Co J . oH : N oo Ey oo / F . X1V) :

76. A composition according to any one of claims 61-75 for use in treating a neuropsychiatric disorder.

77. A composition according to any one of claims 61-75 for use in treating cognitive impairment.

78. A compound as claimed in claim 1 or claim 52, substantially as herein described with reference to and as illustrated in any of the examples.

79. A method as claimed in claim 54, substantially as herein described with reference to and as illustrated in any of the examples.

80. A combinatorial library as claimed in claim 55, substantially as herein described with reference to and as illustrated in any of the examples. A

81. A pharmaceutical composition as claimed in claim 61 or claim 62, substantially as herein described with reference to and as illustrated in any of the examples. Dated this 4" day of June 2007 : ~ JGALVAD ) Adams & Adams Applicants Patent Attorneys Clean copies as filed. : Dated 30% day of August 2007 + Adams & Adams : : "Applicants Patent Attorne