Title of Invention	"A LOXAPINE ANALOGUE OF FORMULA (1) AND PHARMACEUTICAL COMPOSITION THEREOF"
Abstract	The invention relates to novel compounds and methods of using them for modulating sleep.

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LOXAPINE ANALOGS AND METHODS OF USE THEREOF FIELD OF THE INVENTION The invention relates to methods for treating sleep disorders and compositions useful in such methods. BACKGROUND OF THE INVENTION Difficulty falling asleep or remaining asleep is a significant medical issue that arises for a variety of reasons. Sometimes, these problems arise from endogenous conditions such as sleep apnea or insomnia. Other times, these problems arise from exogenous stresses such as the disruptive effect of shift work schedules and "jet lag." Whether caused by an endogenous or exogenous source, difficulty falling asleep or remaining asleep can result in problem sleepiness, which impairs the health, quality of life, and safety of those affected. Existing pharmaceutical treatments for inducing sleep include sedatives or hypnotics such as benzodiazepine and barbiturate derivatives. These treatments have numerous drawbacks, including rebound insomnia, delayed onset of desired sedative effects, persistence of sedative effects after the desired sleep period, and side effects due to nonspecific activity such as psychomotor and memory deficits, myorelaxation, and disturbed sleep architecture, including REM sleep inhibition. Additionally, sedatives and hypnotics can be habit forming, can lose their effectiveness after extended use, and may be metabolized more slowly by some people. Consequently, physicians often recommend or prescribe antihistamines as a milder treatment for sleep disorders when hypnotics are less appropriate. However, many antihistamines suffer from a number of side effects. These side effects include prolongation of the QT interval hi a subject's electrocardiogram, as well as central nervous system (CNS) side effects such as decreased muscle tone and drooping eyelids. Finally, such compounds can bind to muscarinic receptors, which leads to anti-cholinergic side effects such as blurted vision, dry mouth, constipation, urinary problems, dizziness and anxiety. As a result, there is a need for sleep-promoting treatments with reduced side effects. Additionally, while known sleep-inducing compounds are effective for treating sleep-onset insomnia, i.e., a subject's difficulty hi falling asleep, there are no drugs currently indicated for treating sleep maintenance insomnia, i.e., maintaining a subject's sleep throughout a normal sleep period after falling asleep. Therefore, there is also a need for improved pharmaceutical treatments for maintaining sleep in subjects in need of such treatment. SUMMARY OF THE INVENTION The present invention relates to loxapine analogs and their use to modulate sleep. Loxapine (LOXAPAC™, LOXTTANE™) is a tricyclic dibenzoxazepine antipsychotic agent used in the management of the manifestations of schizophrenia. Loxapine (2-chloro-l l-(4-methyl-l-piperazinyl)dibenz[bl[l,4] oxazepine) has the following structure: (Figure Removed)one aspect, the invention relates to a method of modulating sleep in a subject by administering to the subject a therapeutically effective amount of a compound of Formula I: (Figure Removed)or a pharmaceutically effective salt thereof, wherein: m, n, o, p, and q ar§, independently, an integer 0,1,2,3,4,5, or 6; X and Y are, independently, absent, O, S, C(O), SO, or SO2; and RS are, independently, H, F, Cl, Br, dJH, CF3, CH3, C2-C6 straight chain alkyl, C3-C6 branched alkyl, C3-C7 cycloalkyl, C3-C7 hetenyclyl, OCH3 OCF3, CH2OCH3> CH2CH2OCH3, CH2OCH2CH3, C1-C6 hydroxyalkyl, or Ci-c| alkoxy; any hydrogen hi the CH2 groups ia the linker is optionally substituted with H, F, Cl, OH, Br, CF3, CH3, C2-Ce straight chain alkyl, C3-Ce branched alkyl, C3-C7 cycloalkyl, C3-C7 heterocyclyl, OCH3, OCF3, CH2OCH3, CH2CH2OCH3, CH2OCH2CH3, Ci-C6 hydroxyalkyl, or Ci-C6 alkoxy; Rp, RIO, RH, and Rt2 are, independently, H, Ci-Ce straight chain alkyl, C2-C6 branched alkyl, or R9 and RIO together with the carbon to which they are attached are absent or are connected to form a spiro ring of size 3,4, 5, 6, or 7 atoms, or RH and Ri2 together with the carbon to which they are attached are connected to form a spiro ring of size 3,4> 5,6, or 7 atoms, or substituents on two different carbon atoms are connected to form a ring of size 3,4, 5,6, or7; Z is selected from CO2H, CC^Ris (where Ri3 is Ci-C6 alkyl) CONR^is (where R14 and RIS are, independently, hydrogen or lower alkyl) CONHS(O)2-alkyl, CONIjS(O)2-cycloalkyl, CONHS(O)2-heteroalkyl, CONHS(O)2-aryl, CONHS(O)2-heteroaryl, SP^NHCO alkyl, S(O)2NHCO-cycloalkyi, S(O)2NHCO-heteroalkyl, S(O)2NHCO-aryl, S(Cj)2NHCO-heteroaryl, CONHS(O)2NH-alkyl, CONHS(O)2NH-cycloalkyl, CONHS(O)2NHJ-heteroalkyl, CONHS(0)2NH-aryl, CONHS(O)2NH-heteroaryl, SO3H, SO^, S(O)NHCO-alkyl, (Figure Removed)provided that when Z is COOH or COORj3, and RS is H or halogen, Rj-Rs and R7-Ri2 are not each hydrogen, further provided that when m is zero, X is absent. In one embodiment, Z is a sulfonamide. Examples of sulfonamides include acyl (Figure Removed)sulfonamides. For example, Z can have the formula W is a substituent chosen as needed to modulate the effects of the polar surface area of the Z moiety such that the desired level of oral absorption, CNS penetration, and rate of excretion into urine or bile is obtained. Examples of useful W substituents for this purpose include an alkyl group (optionally containing a double or triple bond or heteroatom substituted e.g,, CH2OCH3 or CH2OCH2CH3), a cycloalkyl group (optionally containing a doubje bond), a heterocyclyl group, an aryl group or a heteroaryl group, both optionally substituted, such as(Figure Removed)properties of the compound. Examples of V side chains include halogens such as F, Cl, or Br, Ci-Ce alkoxy groups such as OCH3 or OCH2CHa; (Figure Removed) In one embodiment, Z is a sulfamide. Examples of sulfamides include acyl sulfamides. (Figure Removed)Rb are, independently, for example an alkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group or a heteroaryl group, optionally substituted. Examples include the following: (Figure Removed)where V is a halogen such as F, Cl, or Br; Ci-Ce alkoxy such as OCH3 or OCH2CH3; CCe alkyl or cycloalkyl, such as CHs, CFs, or cyclopropyl; heteroatom substituted Ci-Ce alkyl or Cs-Cg cycloalkyl, such as CHaOCHs, or CHzOCHjCHa; an electron wifedrawing group such as CN, a (Figure Removed)In one embodiment, the compounds of Formula I for use in the methods of the invention have one or more of the following characteristics: an inhibition constant (Kj) with regard to HI receptor binding of less than 500 nM; a Kj with regard to off target binding to an off target selected from Ml, M2, M3, Dl, D2, ccl and o2 that is greater than 500 nM and/or more than 5 times greater than the K, with regard to the HI receptor; a nonREM peak time value that is greater than 55% nonREM sleep per hour by the third hour after the compound is administered to a subject; a cumulative total increase in nonREM sleep of not less than 20 minutes for compound doses that produce maximum sleep consolidation; a longest sleep bout that is greater than 13 minutes in duration; net longest sleep bout post treatment is greater than or equal to 3 minutes when adjusted using a baseline value obtained at least 24 hours prior to administration of the compound to a subject; an average sleep bout that is greater than 5 minutes at absolute peak; administration of the compound to a subject does not produce appreciable amounts of rebound insomnia; administration of the compound to a subject does not appreciably inhibit REM sleep; and administration of the compound to a subject does not disproportionately inhibit locomotor activity relative to the normal effects of sle^p. In another embodiment, the compound of Formula I for use in the methods of the invention has one or more of the following characteristics: an inhibition constant (K,-) with regard to HI receptor binding of less than 300 nM; a K; with regard to off target binding to an off target selected from Ml, M2, M3, Dl, D2, al and o2 that is greater than 1 |Jjn; a nonREM peak time value that is greater than 55% nonREM sleep per hour by the third hour after the compound is administered to a subject; a cumulative total increase in nonREM sleep of not less than 20 minutes for compound doses that produce maximum sleep consolidation; a longest sleep bout that is greater than 13 minutes in duration; net longest sleep bout post treatment is greater man or equal to 3 minutes when adjusted using a baseline value obtained at least 24 hours prior to administration of the compound to a subject; an average sleep bout that is greater than 5 minutes at absolute peak; administration of the compound to a subject does not produce appreciable amounts of rebound insomnia; administration of the compound to a subject does not appreciably inhibit REM sleep; and administration of the compound to a subject does not disproportionately inhibit locomotor activity relative to the normal effects of sleep. hi another embodiment, the compound of Formula I for use in the methods of the invention has one or more of the following characteristics: an inhibition constant (Kj) with regard to HI receptor binding of less man 150 nM; a Kj with regard to off target binding to an off target selected from Ml, M2, and M3, that is greater than 10 pM; a nonREM peak time value that is greater than 55% nonREM sleep per hour by the third hour after the compound is administered to a subject; a cumulative total increase in nonREM sleep not less than 20 minutes for compound doses that produce maximum sleep consolidation; a longest sleep bout that is greater than 17 minutes in duration; net longest sleep bout post treatment is greater than or equal to 5 minutes when adjusted using a baseline value obtained at least 24 hours prior to administration of the compound to a subject; an average sleep bout that is greater man 6 minutes at absolute peak; administration of the compound to a subject does not prbduce appreciable amounts of rebound insomnia; administration of the compound to a subject does not appreciably inhibit REM sleep; and administration of the compound to a subject does not disproportionately inhibit locomotor activity or motor tone relative to the normal effects of sleep. hi one embodiment, in the compound of Formula I used in the method of the invention, RS is not hydrogen or halogen. In another embodiment, in the compound used in the method of the invention, Re is methyl, methoxy, methoxymethylene (CHaOCHa), or hydroxy. hi another embodiment, in the compound used in the method of the invention, RG is methylj methoxy, methoxymethylene, fluoro, chloro, bromo or hydroxy. In another embodiment, in the compound of Formula I used in the method of the invention, RI - R5 and R? - Rg are each hydrogen. In another embodiment, in the compound of Formula I used in the method of the invention, at least one of RI - Rg is a non-hydrogen substituent and the remaining Rj - Rg are hydrogen. In another embodiment, in the compound used in the method of the invention, at least one non-hydrogen RI - Rg is independently methyl, methoxy, methoxymet%lene, fluoro, chloro, bromo, or hydroxy. In another embodiment, in the compound of Formula I used in the metho^ of the invention, at least two of Rj — Rg are non-hydrogen substituents, and the remaining RI — Rg are hydrogen. In another embodiment, hi the compound used in the method of the invention, at least 2 non-hydrogen RI - Rg are independently methyl, methoxy, methoxymethylene, fluoro, chloro, bromo, or hydroxy. In another embodiment, in the compound of Formula I used in the method of the invention, at least three of RI - Rg are non-hydrogen substituents, and the remairiing R! - Rg are hydrogen. In another embodiment, in the compound used in the method of the invention, at least 3 non-hydrogen RI - Rg are independently methyl, methoxy, methoxymethylene, fluoro, chloro, bromo, or hydroxy. In another embodiment, in the compound of Formula I used in the method of the invention, R2 is a non-hydrogen substituent For example, Rz is, e,g., methyl, mjethoxy, methoxymethylene, fluoro, chloro, bromo, or hydroxy. In another embodiment, in the compound of Formula I used in the method of the invention, R3 is a non-hydrogen substituent For example, Ra is, e,g., methoxy, methyl, methoxymethylene, fluoro, chloro, bromo, or hydroxy. In another embodiment, in the compound of Formula I used in the method of the i invention, R? is a non-hydrogen substituent. For example, R/ is, e.g., methyl, methoxy, methoxymethylene, fluoro, chloro, bromo, or hydroxy. In another embodiment, in the compound of Formula I used in the method of the invention, RZ and RS are non-hydrogen substituents. For example, RZ and Rj are^ e.g., independently, methyl, methoxy, methoxymethylene, fluoro, chloro, bromo, or hydroxy. In another embodiment, in the compound of Formula I used in the method of the invention, Ra and Re are non-hydrogen substituents. For example, Rz and Re are, e.g., independently, methyl, methoxy, methoxymethylene, fluoro, chloro, bromo or rrydroxy. In another embodiment, in the compound of Formula I used in the method of the invention, R2 and R7 are non-hydrogen substituents. For example, R2 and R7 are, e.g., independently, methyl, methoxy, methoxymethylene, fluoro, chloro, bromo or hydroxy. In another embodiment, in the compound of Formula I used in the method of the invention, Rj and Re are non-hydrogen substituents. For example, RS and Re are, e.g., independently, methyl, methoxy, methoxymethylene, fluoro, chloro, bromo or hydroxy. In another embodiment, in the compound of Formula I used in the method of the invention, Ra and R7 are non-hydrogen substituents. For example, Ra and R7 are, e.g., independently, methyl, methoxy, methoxymethylene, fluoro, chloro, bromo or hydroxy. In another embodiment, in the compound of Formula I used in the method of the invention, Re and R7 are non-hydrogen substituents. For example, Re and R7 are, e.g., independently, methyl, methoxy, methoxymethylene, fluoro, chloro, bromo or hydroxy. In another embodiment, in the compound of Formula I used in the method of the invention, Re is methoxy, and Ri-Rs and RrRg are hydrogen. In another embodiment* hi the compound of Formula I used in the method of the invention, Rz is methyl or methoxy, and Rj and Ra-Rg are hydrogen. In another embodiment, in the compound of Formula I used in the method of the invention, Ra is methyl and Ri-Ra and R4-R« are hydrogen. In another embodiment, in the compound of Formula I used in the method of the invention, R? is methoxy and Ri-Re and Rg are hydrogen. In one embodiment, in the compound of Formula I used in the method of the invention, at least one of Ra, Re, and R7 is not hydrogen. In another embodiment, in the compound of Formula I used in the method of the invention, at least one of Ra, Re, and R7 is fluoro, methyl, or methoxy. In one embodiment Rg and RIO together with the carbon to which they are attached are absent. In another embodiment, in the compound of Formula I used in the method of the invention, RI i and R^ are each methyl. In another embodiment, in the compound used in the method of the invention, RI i and Rn are each ethyl. In another embodiment, in the compound used in the method of the invention, RI i and Rn, together with the carbon to which they are attached, are connected to form a spiro ring of size 3 to 7. The spiro ring is, e.g.t a cyclopropyl ring. In one embodiment, in the compound of Formula I used in the method of the invention, q is zero. In another embodiment, q is zero, and R and RJO together with the carbon to which they are attached are absent. Li another embodiment, q is zero, Rg and RIO together with the carbon to which they are attached are absent, X and Y are absent. In another embodiment, q is zero, Rg and RIO together with the carbon to which they are attached are absent, X and Y are absent, and the sum of m, n, o, and p is 1 or 2. In another embodiment, the compound of Formula I used in the method of the invention, is selected from Compounds 1-88. For example, the compound used in the methods of the invention is Compound 1,2, 3,4, 5,6,7, 8, 9,10,11,12,13,14,15,16,17,18,19,20, 21, 22, 23, 24, 25,26,27,28,29, 30, 31, 32,33, 34, 35, 36,37, 38, 39,40,41,42,43,44,45, 46,47,48,49, 50,51,52,53,54,55,56, 57,58, 59,60,61,62,63,64,65,66,67,68, 69,70, 71,72,73,74, 75,76,77,78,79,80, 81, 82,83, 84, 85, 86,87, or 88. In another embodiment, the compound used in the method of the invention, is Compound 1,12,13,40,61,62,63,70,71,74, 75,76,77,78,79, 80, 81,82, 83j or 84. In one embodiment, the method of the invention is used to modulate sleep by administering a compound of Formula I, for example the method is used to decrease the time to sleep onset, increase the average sleep bout length, and/or increase the maximum sleep bout length. In another embodiment, the method of the invention is used to treat a sleep disorder by administering a compound of Formula I. The sleep disorder is, for example, circadian rhythm abnormality, insomnia, parasomnia (such as, e.g., somnambulism, pavor noctumus, REM sleep behavior disorder, sleep bruxism and sleep enuresis), a sleep apnea disorder, such as, .for example, central sleep apnea, obstructive sleep apnea and mixed sleep apnea, sleep apnea syndrome, narcolepsy or hypersomnia. In one embodiment, the method of the invention is used to treat circadianj rhythm abnormality. In another embodiment, the method of the invention is used to treat insomnia including, for example, extrinsic insomnia, psychophysiologic insomnia, altitude insomnia, restless leg syndrome, periodic limb movement disorder, medication-dependent insomnia, drug-dependent insomnia, alcohol^dependent insomnia, and insomnia associated with mental disorders. In another embodiment, the method of the invention is used to treat slfeep apnea. In another embodiment, the method of the invention is used to treat narcolepsy. In another embodiment, the method of the invention is used to treat hypersomnia. In one embodiment, in the method of the invention, the compound of Formula I, or pharmaceutically acceptable salt thereof, is administered as a pharmaceutical composition mat includes a pharmaceutically acceptable excipient. In another embodiment, in the method of the invention, the compound of Formula I or pharmaceutically acceptable salt thereof, is co-administered with one or more additional therapies. In another embodiment, the subject treated by the method of the invention is selected from humans, companion animals, farm animals, laboratory animals, and wild animals. In one embodiment, the subject is a human. In another aspect, the invention relates to a method of modulating sleep in a subject by administering to the subject a therapeutically effective amount of a compound of Formula II: (Figure Removed) or a pharmaceutically effective salt thereof, wherein: m, n, and o are, independently, 0, 1,2,3,4,5, or 6, X is absent, O, S, C(O), SO, or SO2; R2, R3, Re, and R7 are, independently, selected from H, F, Cl, Br, OH, CF3, CH3, CH2CH3, CH(CH3)2, cyclopropyl, OCH3, OCF3, CH20CH3, and CH2OCH2CH3; R9 and RJO are, independently, H, Ci-Ce straight chain alkyl, C2-C6 branched alkyl, or Rg and RIO together with the carbon to which they are attached, are connected to form a spiro ring of size 3,4,5,6, or 7 atoms; Z is COOH, COORis (where Rj3 is Ci-C6 alkyl), CONHS(O)2-alkyl, CONHS^-heteroalkyl, CONHS-aryl, C0NHS(O)2-heteroaryl, S(O)2NHCO-alkyl, SCO^NHCO-heteroalkyl, S(O)2NHCO-aryl, SCO^NHCO-heteroaryl, CONHSCO^NH-alkyl; CONHSCO^NH-heteroalkyl; CONHSCO^NH-aryl; COMHSCO^NH-heteroaryl; or tetrazole, provided that when Z is COOH or COORn, and R$ is H or halogen, Ri-Rs, and R7-Ri2 are not each hydrogen, further provided that whbn m is zero, X is absent. Li one embodiment, the compounds of Formula n for use in the methods of the invention have one or more of the following characteristics: an inhibition constant (Kj) with regard to HI receptor binding of less man 500 nM; a Kj with regard to off target jjinding to an off target selected from Ml, M2, M3, Dl, D2, al and o2 that is greater than SOOJnM and/or more than 5 times greater than the K, with regard to the HI receptor; a nonREM|peak time value that is greater than 55% nonREM sleep per hour by the third hour after the compound is administered to a subject; a cumulative total increase in nonREM sleep of not leSs than 20 minutes for compound doses that produce maximum sleep consolidation; a longest sleep bout that is greater than 13 minutes in duration; net longest sleep bout post treatment is greater than or equal to 3 minutes when adjusted using a baseline value obtained at least 24 ijours prior to administration of the compound to a subject, an average sleep bout that is greater than 5 minutes at absolute peak; administration of the compound to a subject does not produce appreciable amounts of rebound insomnia; administration of the compound to a Subject does not appreciably inhibit REM sleep; and administration of the compound to a subject does not disproportionately inhibit locomotor activity relative to the normal effects of sleep. In another embodiment, the compound of Formula n for use in the methods of the invention has one or more of the following characteristics: an inhibition constant (K,-) with regard to HI receptor binding of less than 300 nM; a K, with regard to off target binding to an off target selected from Ml, M2, M3, Dl, D2, ccl and a.2 that is greater than 1 jlm; a nonREM peak time value that is greater man 55% nonREM sleep per hour by the third hour after the compound is administered to a subject; a cumulative total increase in nonREM sleep of not less than 20 minutes for compound doses that produce maximum sleep consolidation; a longest sleep bout that is greater than 13 minutes in duration; net longest sleep bout post treatment is greater than or equal to 3 minutes when adjusted using a baseline value obtained at least 24 hours prior to administration of the compound to a subject; an average sleep bout that is greater than 5 minutes at absolute peak; administration of the compound to a subject does not produce appreciable amounts of rebound insomnia; administration of the compound to a subject does not appreciably inhibit REM sleep; and administration of the compound to a subject does not disproportionately inhibit locomotor activity relative to the normal effects of sleep. In another embodiment, the compound of Formula n for use in the methods of the invention has one or more of the following characteristics: an inhibition constant (Kj) with regard to HI receptor binding of less than 150 nM; a K\ with regard to off target binding to an off target selected from Ml, M2, and M3, that is greater than 10 joM; a nonREM peak time value that is greater than 55% nonREM sleep per hour by the third hour after the compound is administered to a subject; a cumulative total increase in nonREM sleep not less man 20 minutes for compound doses that produce maximum sleep consolidation; a longest sleep bout that is greater than 17 minutes in duration; net longest sleep bout post treatment is greater than or equal to 5 minutes when adjusted using a baseline value obtained at least 24 kours prior to administration of the compound to a subject; an average sleep bout that is greater than 6 minutes at absolute peak; administration of the compound to a subject does not produce appreciable amounts of rebound insomnia; administration of the compound to ai subject does not appreciably inhibit REM sleep; and administration of the compound to a suljjject does not disproportionately inhibit locomotor activity or motor tone relative to the normal effects of sleep. In one embodiment, in the compound of Formula n used in the method of the invention, Re is not H, F, Cl, or Br. In another embodiment, in the compound of Formula n used in the method of the invention, R« is methyl, methoxy methoxymethylene, or hydroxy. In another embodiment, in the compound of Formula II used in the method of the invention, R? — Ra and R? are each hydrogen. In another embodiment, in the compound of Formula II used in the method of the invention, Rj - RS and R« - R? are independently hydrogen, methyl, methoxy, methoxymethylene, fluoro, chloro, bromo or hydroxy. In another embodiment, in the compound of Formula n used in the method of the invention, Ra is a non-hydrogen substituent In another embodiment, in the compound of Formula n used in the method of the invention, Rs is a non-hydrogen substituent In another embodiment, in the compound of Formula n used in the method of the invention, Re is a non-hydrogen substituent. In another embodiment, in the compound of Formula II used in the method of the invention, R7 is a non-hydrogen substituent In another embodiment, in the compound of Formula n used I in the method of the invention, Rz and Ra are non-hydrogen substituents. In another embodiment, in the compound of Formula n used in the method of the inventioi, Ra and Re are non-hydrogen substituents. In another embodiment, in the compound of Formula n used in the method of the invention, RI and R? are non-hydrogen substituents. In another embodiment, in the compound of Formula n used in the method of the invention, RS and Re are fton-hydrogen substituents. In another embodiment, in the compound of Formula II used in th^ method of the invention, RS and R7 are non-hydrogen substituents. In another embodiment, in the compound of Formula II used in the method of the invention, Re and R/ are non-hydrogen s^ibstituents. In another embodiment, in the compound of Formula n used in the method of the invention, Re is methoxy, and Ra, Rj, and R? are hydrogen. In another embodiment, in the compound of Formula n used in the method of the invention, R2 is methyl or methoxy, and RS, Re, and Ry are hydrogen. In another embodiment, in the compound of Formula JQ used in the method of the invention, RS is methyl and Ra, Re, and Ry are hydrogen. In another embodiment, in the compound of Formula II used in the method of the invention, wherein R7 is methoxy and R2, Ra, and Re are hydrogen. In another embodiment, in the compound of Formula n used in the method of the invention, Rg and RIQ are each methyl. In another embodiment, in the compound of Formula II used in the method of the invention, Rg and RIO are each ethyl. In another embodiment, in the compound of Formula n used in the method of the invention, Rg and RIO, together with the carbon to which they are attached, are connected to form a spiro ring of size 3 to J7. For example, the spiro ring is, e.g., a cyclopropyl ring. In one embodiment, in the compound of Formula n used in the method of the invention, o is zero. In another embodiment, o is zero, and X is absent. In another embodiment, o is zero, X is absent, and the sum of m and n is 1 or 2. In one embodiment, the method of the invention is used to modulate sleep! by administering a compound of Formula Hi, for example the method is used to decrease the time to sleep onset, increase the average sleep bout length, and/or increase the maximum sleep bout length. In another embodiment, the method of the invention is used to treat a sleep disorder by administering a compound of Fonnula n. The sleep disorder is, for example, cii^adian rhythm abnormality, insomnia, parasomnia, sleep apnea syndrome, narcolepsy or hyperstramia. In another aspect, the invention relates to a method of modulating sleep in a subject by administering to the subject a therapeurically effective amount of a compound of Formula HI: (Figure Removed) or a pharmaceutically effective salt thereof, wherein: m and n are, independently, 0,1, 2,3, or 4, X is absent, O, S, C(O), SO, or SO2; R2, Ra, Re, and R7 are, independently, selected from H, F, Cl, Br, OH, CF3, CH3, CH2CH3, CH(CH3)2, OCH3, CH2OCH3, and CJH2OCH2CH3; Rg and RIO, are, independently, H, Ci-Ce straight chain alkyl; C2-Ce branched aljcyl, or R9 and RIO, together with the carbon to which they are attached, are connected to form ^ spiro ring of size 3,4, 5,6, or 7 atoms; Z is selected from CO2H, CONHS(O)2-alkyl, CONHS(O)2-cycloalkyl, CONHS(0)2-heteroalkyl, CONHS(O)2-aryl, CONHS(O)2-heteroaryi, and tetrazole; provided that when Z is COOH and Re is H, F, Cl, or Br, R2, Rs, R?, and R9-Rio are not each hydrogen, further provided that when m is zero, X is absent. In one embodiment, the compounds of Formula HI for use in the metho4s of the invention have one or more of the following characteristics: an inhibition constant (Kj) with -regard to HI receptor binding of less than 500 nM; a K, with regard to off target binding to an off target selected from Ml, M2, M3, Dl, D2, ctl and o2 that is greater than 50^) nM and/or more than 5 times greater than the Ki with regard to the HI receptor; a nonREM! peak time value that is greater than 55% nonREM sleep per hour by the third hour after th$ compound is administered to a subject; a cumulative total increase in nonREM sleep of not lejjs than 20 minutes for compound doses that produce maximum sleep consolidation; a longest sleep bout that is greater than 13 minutes in duration; net longest sleep bout post treatment is greater than or equal to 3 minutes when adjusted using a baseline value obtained at least 24 hours prior to administration of the compound to a subject; an average sleep bout that is greater than 5 minutes at absolute peak; administration of the compound to a subject does not produce appreciable amounts of rebound insomnia; administration of the compound to a Subject does not appreciably inhibit REM sleep; and administration of the compound to a subject does not disproportionately inhibit locomotor activity relative to the normal effects of sleep. In another embodiment, the compound of Formula HI for use in the methods of the invention has one or more of the following characteristics: an inhibition constant (Ki) with regard to HI receptor binding of less than 300 nM; a K, with regard to off target binding to an off target selected from Ml, M2, M3, Dl, D2, ccl and cc2 that is greater than 1 ukn; a nonREM peak time value that is greater than 55% nonREM sleep per hour by the third hoiir after the compound is administered to a subject; a cumulative total increase in nonREM sleep of not less than 20 minutes for compound doses that produce maximum sleep consolidation; a longest sleep bout that is greater than 13 minutes in duration; net longest sleep bout post treatment is greater than or equal to 3 minutes when adjusted using a baseline value obtained at least 24 hours prior to administration of the compound to a subject; an average sleep bout that is greater than 5 minufc s at absolute peak; administration of the compound to a subject not produce appreciable amounts of rebound insomnia; administration of the compound to a does not appreciably inhibit REM sleep; and administration of the compound to a subject does not disproportionately inhibit locomotor activity relative to the normal, effects of sleep. In another embodiment, the compound of Formula HI for use in the methods of the invention has one or more of the following characteristics: an inhibition constant! (Kj) with j regard to HI receptor binding of less than 150 nM; a K, with regard to off target binding to an off target selected from Ml, M2, and M3, that is greater than 10 pM; a nonREM peak time value that is greater than 55% nonREM sleep per hour by the third hour after the compound is | administered to a subject; a cumulative total increase in nonREM sleep not less than 20 minutes for compound doses that produce maximum sleep consolidation; a longest sleep bout that is greater than 17 minutes in duration; net longest sleep bout post treatment is greater than or equal to 5 minutes when adjusted using a baseline value obtained at least 24 hours prior to administration of the compound to a subject; an average sleep bout that is greater than 6 minutes at absolute peak; administration of the compound to a subject does not produce appreciable amounts of rebound insomnia; administration of the compound to a subject does not appreciably inhibit REM sleep; and administration of the compound to a subject does not. disproportionately inhibit locomotor activity or motor tone relative to the normal effects of sleep. In one embodiment, in the compound of Formula in used in the method of the invention, Re is not H, F, Cl, or Br. In another embodiment, in the compound of Formula HI, used hi the method of the invention, , Ra, and are hydrogen. In another embodiment, in the compound of Formula ffi used in the method of the invention, Ra, and are independently H, F, Cl, Br, methyl, methoxy, methoxymethylene or hydroxy. Iij. anotherembodiment, in the compound of Formula in used in the method of the inventio, Re is methoxy. In another embodiment, in the compound of Formula HI used in the method of the invention, R« is methoxy, and Ra, Ra> and R? are hydrogen. In another embodiment, in the compound of Formula used in the method of the invention, Ra is methyl or methoxy, and Ra, Re, and R? are hydrogen. i In another embodiment, in the compound of Formula in used in the method of the invention, Ra is methyl and Rj, Re, and Ry are hydrogen. In another embodiment, in the compound of Formula ffl used in the method of the invention, wherein R? is methoxy and Rj, Ra, and Re are hydrogen. In another embodiment, in the compound of Formula III used in the meti lod of the invention, R9 and RIO are each methyl. In another embodiment, in the compoun 1 of Formula HI used in the method of the invention, Rg and RIO, together with the carbon t In one embodiment, in the compound of Formula ffl used in the method^ of the invention, X is absent. In another embodiment, X is absent, and the sum of m and n is 1 or 2. In one embodiment, the method of the invention is used to modulate slesp by administering a compound" of Formula HI, for example the method is used to decrease the time to sleep onset, increase the average sleep bout length, and/or increase the maximum sleep bout length. In another embodiment, the method of the invention is used to treat a sbep disorder by administering a compound of Formula HI. The sleep disorder is, for example, circadian rhythm abnormality, insomnia, parasomnia, sleep apnea syndrome, narcolepsy or hypersomnia. In another aspect, the invention relates to a method of modulating sleep hi a subject by administering to the subject a therapeutically effective amount of a compound of Formula IV: (Figure Removed)or a phannaceutically effective salt thereof, wherein: t is 1,2,3, or 4; RZ, R3, Re, and R7 are, independently, H, F, Cl, Br, CF3, CH3, OH, OCH3, CH2OCH3, or CH2OCHiCH3; R9-Ri0 are H, CH3, CH2CH3, or Rg and RJQ, together with the carbon to which they are attached are connected to form a spiro ring of size 3,4,5,6, or 7 atoms; and Z is selected frofti CC^H, CONHS(O)2-alkyl, CONHS(O)2-cycloalkyl, CONHS(O)2-heteroalkyl, CONHS^-aryl, CONHS(O)2-heteroaryl, or tetrazole; provided that when Z is COOH and is H, F, Cl, or Br, R2, R3, R?, and Rg-Rjo are not each hydrogen. In one embodiment, the compounds of Formula IV for use in the methods of the invention have one or more of the following characteristics: an inhibition constant (K,) with i regard to HI receptor binding of less man 500 nM; a Kj with regard to off target binding to an off target selected from Ml, M2, M3, Dl, D2, cd and cc2 that is greater than 50d nM and/or time more man 5 times greater than the Kj with regard to the HI receptor; a nonREM value that is greater than 55% nonREM sleep per hour by the third hour after the compound is administered to a subject; a cumulative total increase in nonREM sleep of not lens than 20 minutes for compound doses that produce maximum sleep consolidation; a long j disproportionately inhibit locomotor activity relative to the normal effects of sle^p. In another embodiment, the compound of Formula IV for use in the methods of the invention has one or more of the following characteristics: an inhibition constant (Kj) with regard to HI receptor binding of less than 300 nM; a K,- with regard to off target binding to an off target selected from Ml, M2, M3, Dl, D2, al and o2 that is greater than 1 p;m; a nonREM peak time value that is greater than 55% nonREM sleep per hour by the third hour after the compound is administered to a subject; a cumulative total increase in nonREM sleep of not less than 20 minutes for compound doses that produce maximum sleep consolidation; a longest sleep bout that is greater than 13 minutes in duration; net longest sleep bout post treatment is greater than or equal to 3 minutes when adjusted using a baseline value obtained at least 24 hours prior to administration of the compound to a subject; an average sleep bout that is greater than 5 minutes at absolute peak; administration of the compound to a subject do«ss not produce appreciable amounts of rebound insomnia; administration of the compound to a subject does not appreciably inhibit REM sleep; and administration of the compound to a subject does not disproportionately inhibit locomotor activity relative to the normal effects of sle^p. In another embodiment, the compound of Formula IV for use in the methods of the invention has one or more of the following characteristics: an inhibition constan| (Kj) with regard to HI receptor binding of less than 150 nM; a Kj with regard to off target binding to an off target selected from Ml, M2, and M3, that is greater than 10 pM; a nonKEMJ peak time value that is greater than 55% nonREM sleep per hour by the third hour after the^ compound is administered to a subject; a cumulative total increase in nonREM sleep not less $ian 20 minutes for compound doses that produce maximum sleep consolidation; a longest sleep bout that is greater than 17 minutes in duration; net longest sleep bout post treatment {is greater than or equal to 5 minutes when adjusted using a baseline value obtained at least 24 Hours prior to administration of the compound to a subject; an average sleep bout that is greater than 6 minutes at absolute peak; administration of the compound to a subject does not produce I appreciable amounts of rebound insomnia; administration of the compound to a pubject does not appreciably inhibit REM sleep; and administration of the compound to a subject does not disproportionately inhibit locomotor activity or motor tone relative to the normal effects of sleep. In one embodiment, in the compound of Formula IV used in the method bf the invention, t is 1 or 2. In one embodiment, the compound of Formula IV used in the method of the invention is selected from a compound of Formula IVa, IVb, IVc, IVd, and IVe. • In one embodiment, the method of the invention is used to modulate sleep by administering a compound of Formula IV, for example the method is used to decrease the time I to sleep onset, increase the average sleep bout length, and/or increase the maximum sleep bout length. In another embodiment, the method of the invention is used to treat a sleep disorder by administering a compound of Formula IV. The sleep disorder is, for example, circadian rhythm abnormality, insomnia, parasomnia, sleep apnea syndrome, narcolepsy or hypersomnia. In another aspect, the invention relates to a method of modulating sleep in a subject by administering to the subject a therapeutically effective amount of a compound of selected from Compound 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,2?, 23,24,25, 26,27,28,29, 30, 31, 32, 33,34, 35,36, 37,38, 39,40,41,42,43,44,45,46,4J, 48,49, 50, 51,52,53,54,55,56,57,58,59, 60,61,62,63,64,65,66,67,68, 69,70,71,72^ 73,74,75, 76,77,78,79,80, 81, 82,83,84, 85,86,87, or 88. In another aspect, the invention relates to a compound of Formula I: (Figure Removed) or a pharmaceutically effective salt thereof, wherein m, n, o, p, and q are, independently, an integer 0, 1, 2, 3, 4, 5, or 6; X and Y are, independently, absent, O, S, C(O), SO, or SO2; RI, R2, R3, R4, R5, Re, R?, and Rg are independently selected from HJ F, Cl, Br, OH, CF3, CH3j C2-C6 straight chain alkyl, C3-C6 branched alkyl, C3-C7 cycloalkyl, C3-C7 heterocyclyl, OCH3, OCF3, CH2OCH3, CH2CH2OCH3, CH2OCH2CH3, C,-C6 hyjlroxyalkyl, and Ci-Cg alkoxy; any hydrogen in the CH2 groups hi the linker is optionally substituted with H, F, Q, Br, OH, CF3, CH3, C2-C6 straight chain alkyl, C3-C6 branched alkyl, C3+C7 cycloalkyl, C3-C7 heterocyclyl, OCH3, OCF3, CH2OCH3, CH2CH2OCH3, CH2OCH2CH3, C,ic6 hydroxyalkyl, or Ci-Ce alkoxy; Rg, RIO, RII, and Rj2 are, independently, H, Ci-Cfe straight chain alkyl, C2-Ce branched alkyl, or Rg and RIO together with the carbon to whic|h they are attached are absent or are connected to form a spiro ring of size 3, 4, 5, 6, or 7 atoms, or RH I and Ri2 together with the carbon to which they are attached, are connected to form a spiro ring of size 3, 4, 5, 6, or 7 atoms, or substituents on two different carbon atoms are connected to form a ring of size 3, 4, 5, 6, or 7; Z is selected from CO2H, CC^Rn (where Rj3 is Ci-C6 alkyl), CONRnRis (where RH and RIS are, independently, hydrogen or lower alkyl), CONHS^V alkyl, CONHS(0)rcycloalkyl, CONHS(O)2-heteroalkyl, CONHS(O)2-aryl, COl(lHS(O)2-heteroaryl, S(0)2NHCO-alkyl, S(O)2NHCO-cycloalkyl, S(O)2NHCO-heteroalky^, S(Q)2NHCO-aryl, S(O)2NHCO-heteroaryl, CONHS(0)2NH-alkyl, CONHS(O)2^H-cycloalkyl, CONHS(O)2NH-heteroa]kyl, CONHS^N-aryl, CONHS(O)aNH-heteroaryl, s6sH, S02H, (Figure Removed)W is a substituent chosen as needed to modulate the effects of the polar surface area of the Z moiety such that the desired level of oral absorption, CNS penetration, and rate of excretion into urine or bile is obtained. Examples of useful W substituents for this purpose include an alkyl group (optionally containing a double or triple bond or heteroatom substituted e.g., CHzCHa or CEfeOCHaCHa), a cycloalkyl group (optionally containing a double tjond), a heterocyclyl group, an aryl group, or a heteroaryl group, optionally substituted, such as those (Figure Removed)where V is one or more side chains selected to modulate the pKa of the acylsulfonamide moiety, or to affect the physical or metabolic properties of the compound. Examples of V side chains include halogens such as F, Cl, or Br; Cj-Cg alkoxy groups such as OCHs or OCHzCHs; pi-Q alkyl or Cs-Cg cycloalkyl groups such as CHa, CFs, or cyclopropyl; heteroatom substitute! Cj-Cg alkyl or Cs-Cs cycloalkyl, such as CHkOCHs, or CEbOCEbCHs; electron withdrawing jjroups such (Figure Removed)where V is a halogen such as F, Cl, or Br; Ci-C6 alkoxy such as OCH3 or OCH2CH3; C]-C6 alkyl or C3-C8 cycloalkyl such as CH3, CF3, cyclopropyl; heteroatom substituted C]-Ce alkyl or C3-Cg cyclcjalkyl, such as i (Figure Removed)3, or CKfeOCHaCHs; an electron withdrawing group such as CN, a ketonb, an amide, In one embodiment, in the compound of Formula I, Re is not hydrogen or halogen. In another embodiment, in the compound of Formula I, Rg is methyl, methoxy, methoxymethylene or hydroxy. In another embodiment, in the compound of Formula I, RI - RS and R? - R8 are each hydrogen. In another embodiment, in the compound of Formula I, at least one of R i - Rg is a non-hydrogen substituent and the remaining RI - Rg are hydrogen. In another embodiment, at least one non-hydrogen RI - Rg is independently methyl, methoxy, methoxymethyleie, fluoro, chloro, bromo, or hydroxy. In another embodiment, in the compound of Formula I, at least two of RI - Rg are non-hydrogen substituents, and the remaining RI - Rg are hydrogen. In another embodiment, at least two non-hydrogen RI - Rg are independently methyl, methoxy, methoxyniithylene, fluoro, chloro, bromo, or hydroxy. In another embodiment, in the compound of Formula I, at least three of R] - Rg are non- hydrogen substituents, and the remaining RI - Rg are hydrogen. In another embodiment, at least three non-hydrogen RI - Rg are independently methyl, methoxy, methoxymethylene, fluoro, chloro, bromo, or hydroxy. In another embodiment, in the compound of Formula I, R2 is a non-hydrogen substituent For example, Ra is, e.g., methyl, methoxy, methoxymethylene, fluono, chloro, bromo, or hydroxy. In another embodiment, in the compound of Formula I, Ra is a non-hydrogen substituent. For example, Rs is, e.g., methyl, methoxy, methoxymethylene, fluoro, chloro, bromo, or hydroxy. In another embodiment, in the compound of Formula I, R7 is a non-hydrogen substituent. For example, R? is, e.g., methyl, methoxy, methoxymethylene, fluoro, chloro, bromo, or hydroxy. la another embodiment, in the compound of formula I, R2 and RS are non-hydrogen substituents. For example, R2 and RS are, e.g., independently, methyl, methoxy, methoxymethylene, fluoro, chloro, bromo, or hydroxy. In anolher embodiment, in the compound of Formula I, R2 and R$ are non-hydrogen substituents. For example, R2 and Re are, e.g., independently, methyl, methoxy, methoxymethylene, fluoro, chloro, bromo, or hydroxy. In another embodiment, in the compound of Formula! I, R2 and Ry are non-hydrogen substituents. For example, R2 and Ry are, e.g., independently, jnethyl, methoxy, methoxymethylene, fluoro, chloro, bromo, or hydroxy. In another embodiment, in the compound of Formula I, RS and R$ are non-hydrogen substituents. For example, R3 and R$ are, e.g., independently, methyl, methoxy, methoxymethylene, fluoro, chloro, brqmo or hydroxy. In another embodiment, in the compound of Formula I, Ra and R; are nbn-hydrogen substituents. For example, Rj and Ry are, e.g., independently, methyl, methoxy, methoxymethylene, fluoro, chloro, bromo or hydroxy. In another embodiment, ii. the compound of Formula I, R« and R? are non-hydrogen substituents. For example and R/ are, e.g., independently, methyl, methoxy, methoxymethylene, fluoro, chloro, bromd, or hydroxy. In another embodiment, in the compound of Formula I, Re is methoxy, and Rj-Ifc and R7-Rg are hydrogen. In another embodiment, in the compound of Formula I, Ra is methyl or methoxy, and R] and Rs-Rg are hydrogen. In another embodiment, in the compound of Formula I, Rj is methyl and Rj-R2 and R^Rg are hydrogen. In another embodiment, in the compound of Formula I, RT is methoxy and RI -Re and Rg are hydrogen. In one embodiment, at least one of RZ, Re, and R? is not hydrogen. In anbther embodiment, at least one of Rz, Rg, and Ry is fluoro, methyl, or methoxy. In one embodiment, Rg and RIO together with the carbon to which they are attached are absent. In another embodiment, in the compound of Formula I, RH and RU are each methyl. In another embodiment, RI i and RU are each ethyl. In another embodiment, Rj i and RH, together with the carbon to which they are attached, are connected to form a spirjo ring of size 3 to 7. The spiro ring is, e.g., a cyclopropyl ring. In one embodiment, q is zero. In another embodiment, q is zero, and Rg iind RIO together with the carbon to.which they are attached are absent In another embcxliment, q is zero, R9 and RIO together with the carbon to which they are attached are absent, X and Y are absent In another embodiment, q is zero, Rg and RIO together with the carbon td which they are attached are absent, X and Y are absent, and the sum of m, n, o, and p is 1 or 2. In another embodiment, the compound of Formula I is selected from Compounds 1-88. In another embodiment, the compound of Formula I is selected from Compounds 1,12, 13,40,61,62,63,70,71,74,75,76,77,78,79,80, 81, 82,83, and 84. In another aspect, the invention relates to a compound of Formula II: (Figure Removed)or a pharmaceutically effective salt thereof, wherein: m, n, and o are, independently, 0, 1,2,3,4,5, or 6, X is absent, O, S, C(O), SO, or SO2; R2, RS, R& and R7 are, kuiependently H, F, Cl, Br, OH, CF3, CH3, CH2CH3, CH(CH3)2, cyclopropyl, OCH3, OCF3, CH2QCH3, or CH2OCH2CH3; Rp, and RIO, are, independently, H, Ci-Ce straight chain alkyl; QrCe branched alkyl, or Rg and RIO together with the carbon to which they are attached, are connected to form a spiro ring of size 3,4, 5,6, or 7 atoms; Z is COOH, COOR^ (where RJ3 is Ci-Cg alkyl) CONHS(O)a-a]kyl, CONHS(O)rheteroalkyl, CONHS(O)2-aryl, CONHS(O)2-heteroaryl, S(O)2NHCO-alkyl, S(O)2NHCO-heteroalkyl, S(0)2NHCO-aryl, SCO^NHCO-heteroaryl, CONHS(O)2NH-alkyl; CONHS(O)2NH-heteroalkyl; CONHSCO^NH-aryl; CO^HS(O)2NH-heteroaryl; or tetrazole, provided that when Z is COOH or COORi3, and Rg is H or halogen, Ri-R5 and R7-Rn are not each hydrogen, further provided that when m is zero, X is absent. In one embodiment, in the compound of Formula n, Rg is not hydrogen are In another embodiment, in the compound of Formula n, R2—R3 and Ry i each hydrogen. In another embodiment, in the compound of Formula II, R2 - R3 and Rg- 3 independently hydrogen, methyl, methoxy, methoxymethylene, fiuoro, chloro, bijomo, or hydroxy. In another embodiment, in the compound of Formula n, R2 is a non-hydrogen substituent. For example, R2 is, e.g., methyl, methoxy, methoxymethylene, fluor), chloro, is a non- bromo, or hydroxy. In another embodiment, in the compound of Formula n, RS hydrogen substituent. For example, RS is, e.g., methyl, methoxy, methoxymethylene, fluoro, chloro, bromo, or hydroxy. In another embodiment, in the compound of Formui a n, R? is a non-hydrogen substituent. For example, R7 is, e.g., methyl, methoxy, methoxymethylene, fluoro, chloro, bromo, or hydroxy. In another embodiment, in the compound of Formula n, Ra j and RS are non-hydrogen substituents. For example, Ra and RS are, e.g., independently, methyl, methoxy, methoxymethylene, fluoro, chloro, bromo, or hydroxy. In another embodiment, in the compound of Formula n, Ra and Rg are non-hydrogen substituents. For example, Ra and Rg are, e.g., independently, methyl, methoxy, methoxymethyleue, fluoro, chloro, bromo, or hydroxy. In another embodiment, in the compound of Formulja n, Ra and Ry are non-hydrogen substituents. For example, Ra and R? are, e.g., independently, methyl, methoxy, methoxymethylene, fluoro, chloro, bromo, or hydroxy. In another eml x>diment, in the compound of Formula n, R$ and Rj are non-hydrogen substituents. For exai iple, RS and are, e.g., independently, methyl, methoxy, methoxymethylene, fluoro, chloro, bromo, or hydroxy. In another embodiment, in the compound of Formula n, RS and R? are non-hydrogen substituents. For example, Ra and Ry are, e.g., independently, methyl, methoxy, methoxymethylene, fluoro, chloro, bromo, or hydroxy. In another embodiment, hi the compound of Formula n, Rg and R? are non-hydrogen substituents. For example, Rg and R? are, e.g., independently, methyl, methoxy, methoxymethylene, fluoro, chloro, bromo, or hydroxy. In another embodiment, in the compound of Formula n, Rg is methoxy, and R2, RS, and R? are hydrogen. In another embodiment, in the compound of Formula E, RJa is methyl or methoxy, and RS, Re, and Ry are hydrogen. In another embodiment, in the compound of Formula n, RS is methyl and Ra, Re, and Ry are hydrogen. In another embodiment, in the compound of Formula II, Ry is methoxy and Ra, RS, and Rg are hydrogen. In another embodiment, hi the compound of Formula II, Ry and RIO are epch methyl. In another embodiment, R? and RIO are each ethyl, hi another embodiment, R9 and RIO, together with the carbon to which they are attached, are connected to form a spiro ring of size 3 to 7. The spiro ring is, e.g., a cyclopropyl ring. In one embodiment, in the compound of Formula n, o is zero. In another^ embodiment, o is zero, and X is absent. In another embodiment, o is zero, X is absent, and the^ sum of m and n is 1 or 2. In another aspect, the invention relates to a compound of Formula ffl: (Figure Removed)or a. pharmaceutically effective salt thereof, wherein: m and n are, independently, 0,1, 2,3, or 4, X is absent, O, S, C(O), SO, or SO2; R2, Rj, R& and R7 are, independently, selected from H, F, CI, Br, OH, CF3, CH3, CH2CH3, CH(CH2)2, OCH3, CH2OCH3, and CH2OCH2CH3; Rg and RIO, are, independently, H, Ci-Ce straight chain alkyl; C2-Cg branched alkyl, or Rg and RIO, together with the carbon to which they are attached, are connected to form a spko ring of size 3,4,5,6, or 7 atoms; Z is selected from CCbH, CONHS(O)r-aIkyI, CONHS(O)2-cycloalkyl, CONHS(O>2-heteroalkyl, CONHS(O)2-aryl, CONHS(O)2-heteroaryl, and tetrazole; provided that when Z is COOH and Re is H, F, CI, or Br, then R2, R3, R/, and Rg- R.JO are not each hydrogen, further provided that when m is zero, X is absent) In one embodiment, in the compound of Formula HI, Rg is not hydrogen or F, CI, or Br. In one embodiment, in the compound of Formula HI, Rg is not hydrogen or F, CI, or Br and R2, R3, and R? are hydrogen. In one embodiment, in the compound of Formula ffi, R2) R3, Rg, and R? ar^, independently, hydrogen, halogen, methyl, methoxymethylene, methoxy, or hydnixy. In one embodiment, in the compound of Formula HI, Re is methoxy. In another embodiment, in the compound of Fonnula ffl, Re is methoxy, and R2, R3, and R? a^e hydrogen. In another embodiment, in the compound of Formula HI, R2 is methyl or methoxy] and R3, Rg and R; are hydrogen. In another embodiment, in the compound of Formula HI, R3 is methyl and R2, RS and R? are hydrogen. In another embodiment, in the compound of Fonnula HI, R? is methoxy and RZ, R3 and Rg are hydrogen. In another embodiment, in the compound of Formula El, R9 and RIO are each methyl. I In another embodiment, Rg and RIO, together with the carbon to which they are Attached, are connected to form a spiro ring of size 3, e.g., a cyclopropyl ring. In one embodiment, in the compound of Formula HI, X is absent. In another embodiment, X is absent, and the sum of m and n is 1 or 2. In another aspect, the invention relates to a compound of Formula IV: (Figure Removed)or a pharmaceutically effective salt thereof, wherein: t is 1,2,3, or 4; R^ R3,Re, and R/ are, independently, H, F, Cl, Br, CF3, CH3, OH, OCH3, CH2OCH3, or CH2OCH^CH3; Rg-Rio are H, CH3, CH2CH3, or R? and RIO, together with the carbon to which they are ^ttached, are connected to form a spiro ring of size 3,4, 5,6, or 7 atoms; and Z is selected frojm CO2H, CONHS(O)ralkyl, CONHSCO-cycloalkyl, CONHS(O)rheteroalkyl, and tetrazole; provided that when Z is COOH and R$ is H, F, Cl, or Br, then R2, RB, R?, and R^-Rio are not each hydrogen, further provided that when m is zero, X is absent. In one embodiment, in the compound of Formula IV, t is 1 or 2. In one embodiment, the compound of Formula IV is selected from a compound of formula Wa, F/b, IVc, IVd, or F/e. In another aspect the invention relates to a compound selected from Conipound 1,2, 3, 4,5,6,7, 8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,2J7,28,29,30, 31,32,33,34, 35, 36,37,38,39,40,41,42,43,44,45,46,47,48,49, 50, 51,5^, 53,54,55, 56, 57,58,59, 60, 61,62,63,64, 65,66,67,68,69,70,71,72,73,74,75,76,7J7,78, 79, 80, 81, 82, 83,84, 85, 86, 87, or 88. In another aspect the invention relates to a compound selected from Compounds 1,12, 13,40, 61,62,63,70,71,74,75,76,77,78,79,80,81, 82,83, and 84. In one embodiment, the invention relates to a compound having the fornula of (Figure Removed)Compound 1: HOOC t or a salt, solvate, hydrate, or prodrug thereof. For example, the invention relates to a solvate of Compound 1. In one embodiment, the invention relates to a hydrate of Compound 1. In another embodiment, the invention relates to a prodrug of Compound 1. In another embodiment, the invention relates to a pharmaceutically acceptable salt of I Compound 1. For example, the salt can be an acid addition salt, such as a hydrochloride salt. In one aspect, Hie invention relates to the compound: In another aspect, the invention relates to the compound: In another aspect, the invention relates to a composition compound of the (Figure Removed)formula: HOOC (Compound 1) or a salt, solvate, hydrate, or prodrtfg thereof, and at least one pharmaceutically acceptable excipient. In one embodiment, the composition includes a solvate of Compound 1. In another embodiment, the composition includes a hydrate of Compound 1. In one embodiment, the composition includes a prodrug of Compound 1. In another embodiment, the composition includes a pharmaceutically acceptable salt of Compound 1. For example, the salt can be an acid addition salt. One of an acid addition salt is a hydrochloride salt. In one embodiment, the invention relates to a composition of least one pharmaceutically acceptable excipient. In another embodiment, the invention relates to a composition of at least one pharmaceutically acceptable excipient. In another aspect, the invention relates to a method of modulating sleep in a subject, by administering to a subject in need thereof a therapeutically effective amount of Compound !•: (Figure Removed)HOOC or a pharmaceutically acceptable salt, solvate, hydrate, or prodrugj thereof. For example, the subject is a human. In one embodiment, the sleep modulation is selected from, for example, decreasing the time to sleep onset, increasing the average sleep bo^it length, and increasing the maximum sleep bout length. In one embodiment, the sleep modulation treats a sleep disorder. Examples of sleep disorders include circadian rhythm abnormality, insomnia, parasomnia, sleep apnea syndrome, narcolepsy and hypersomnia. In another aspect, the invention relates to a method of modulating sleep p a subject, by administering to a subject in need thereof a therapeutically effective amount of Compound 1: thereof as a (Figure Removed)or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug pharmaceutical composition which includes at least one pharmaceutically acceptable excipient. For example, the subject is a human. In one embodiment, Compound 1, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is co-administered with one or more additional therapies for modulating sleep in a subject. For example, the subject is a human. The above description sets forth rather broadly the more important features of the present invention in order mat the detailed description thereof that follows may be understood, and in order that the present contributions to the art may be better appreciated. Other objects and features of the present invention will become apparent from the following detailed j description considered in conjunction with the examples. i DETAILED DESCRIPTION The details of one or more embodiments of the invention are set forth in t(he accompanying description below. Although any methods and materials similar qr equivalent to those described herein can be used in the practice or testing of the present invention, the methods and materials are now described. Other features, objects, and advantages of the invention will be apparent from the description. In the specification, the singular^ forms also i include the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In the case of conflict, the present specification will control. Definitions For convenience, certain terms used in the specification, examples and appended claims are collected here. "Treating", includes any effect, e.g., lessening, reducing, modulating, or eliminating, that results in the improvement of the condition, disease, disorder, etc. "Treating", includes any effect, e.g., lessening, reducing, modulating, or eliminating, that results in the improvement of the condition, disease, disorder, etc. "Treating" or "treatment" of a disease state includes: (1) preventing the disease state, i.e., causing the clinical symptoms of the disease state not to develop in a subject that may be exposed to or predisposed to the disease state, but does not yet experience or display symptoms of the disease state; (2) inhibiting the disease state, i.e., arresting the development of the disease state or its clinical syraptoms; or (3) relieving the disease state, i.e., causing temporary or permanent regression of the disease state or its clinical symptoms. "Disease state" means any disease, condition, symptom, or i i indication. i "Alkyl" includes saturated aliphatic groups, including straight-chain alky^ groups (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl), branchedjchain alkyl groups (e.g., isopropyl, tert-butyl, isobutyl), cycloalkyl (e.g., alicyclic) groups (e\g., cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl), alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups. "Alkyl" further includes alkyl groups that have oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more hydrocarbon backbone carbon atoms e.g., heteroatom substituted CHfeOCHa or CHzOCHzCHa. In certain embodiments, a straight chain or branched chain alkyl has six or fewer carbon atoms in its backbone (e.g., Ci-Ce for straight chain, Ca-Ce for branched chain), and in other embodiments four or fewer carbon atoms. Likewise, cycloalkyls have from three to eight carbon atoms in ' their ring structure, and in other embodiments have five or six carbons in the rinj; structure. "Ci-Cfi" includes alkyl groups containing 1,2,3,4,5, or 6 carbon atoms. "Ca-Cg' includes alkyl groups containing 2,3,4,5, or 6 carbon atoms. The term "alkyl" also includes both "unsubstituted alkyls" and "substituted alkyls", the latter of which refers to alkyl moieties having substituents replacing a hydrogen utom on one or more carbon atoms of the hydrocarbon backbone. Such substituents can include! for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, , . i alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including -NH2, alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acYlamino i (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amiqino, imino, sulfhydryl, alkylthio, arylthio, tbiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Cycloalkyls can be further substituted, e.g., with the substituents described above. An "alkylaryr or an "aralkyl" moiety is an alkyl substituted with an aryl (e.g., phenylmethyl (ben2yl)). "Alkyl" also includes the side chains of natural and unnatural amino acids. h "Aryl" includes groups with aromaticity, including 5- and 6-membered^ "unconjugated", or single-ring, aromatic groups that may include 0,1,2,3, or |i heteroatoms, as well as "conjugated" or multicyclic systems with at least one aromatic ring. Examples of aryl groups include benzene, phenyl, pyrrole, furan, thiophene, thiazole, isothijjzole, imidazole, triazole, tetrazole, pyrazole, oxazole, isooxazole, pyridine, pyrazine, pyridazine> and pyrimidine, and the like. Furthermore, the term "aryl" includes multicyolic aryE groups, e.g., tricyclic, bicyclic, e.g., naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzoimidazole, benzothiophene, methylenedloxyphenyl, quinoline, isoquinoliue, napthridine, indole, benzofuran, purine, benzofuran, deazapurine, or indolizine. Those aryl groups having heteroatoms in the ring structure may also be referred to as "aryl heterocycles", "heterocycles," "heteroaryls" or "heteroaromati.es". The aromatic ring can be substituted at one or more ring positions with such substituents as described above, as for example, alkyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamiib), acylamino (including alkylcaibonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, ! sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Aryl groups can also be fused or bridged with alicyclic ^r heterocyclic rings, which are not aromatic so as to form a multicyclic system (e.g.s tetralin, methylenedioxyphenyl). "Alkenyl" includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double bond. For example, the term "alkenyl" includes straight-chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, and decenyl), branched-chain alkenyl groups, cycloalkenyl (e.g., alicyclic) groups (e.g., cyclopropenyl, cyclopentenyl, iyclohexenyl, cycloheptenyl, cyclooctenyl), alkyl or alkenyl substituted cycloalkenyl groups, arjd cycloalkyl j or cycloalkenyl substituted alkenyl groups. The term "alkenyl" further includes alkenyl groups, which include oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more hydrocarbon backbone carbons. In certain embodiments, a straight chain or branc jhed chain alkenyl group has 1,2,3,4,5, or 6 carbon atoms in its backbone (e.g., Cz-Ce foi straight chain, Cs-Ce for branched chain.) Likewise, cycloalkenyl groups may have 3,4, 5,6,7l, or 8 carbon atoms in their ring structure, and in another embodiment, have five or six carbor s in the ring structure. The term "Ca-Ce" includes alkenyl groups containing 2,3,4,5, or 6 cirbon atoms. The term "alkenyl" also includes both "unsubstituted alkenyls" and "substituted j alkenyls", the latter of which refers to alkenyl moieties having substiruents replacing a hydrogen on one or more hydrocarbon backbone carbon atoms. Such substituente can include, for example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcaibonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminjjcarbonyl, alkyltbiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including - NHa, alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino I (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidtino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluorpmethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or , heteroaromatic moiety. "Alkynyl" includes unsaturated aliphatic groups analogous hi length and possible substitution to the alkyls described above, but which contain at least one triple bond. For example, "alkynyl" includes straight-chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl), branched-chain alkyny groups, and cycloalkyl or cycloalkenyl substituted alkynyl groups. The term "alkynyl" forth ir includes alkynyl groups having oxygen, nitrogen, sulfur, or phosphorous atoms replacing One or more hydrocarbon backbone carbons. In certain embodiments, a straight chain or branched chain " alkynyl group has 2,3,4,5, or 6 carbon atoms in its backbone (e.g., Ca-Ce for straight chain, • Ca-Cs for branched chain). The term "C2-C6" includes alkynyl groups containing 2,3,4,5, or 6 carbon atoms. The term "alkynyl" also includes both "unsubstituted alkynyls" and "substituted alkynyls", the latter of which refers to alkynyl moieties having substiruents replacing a hydrogen on one or more hydrocarbon backbone carbon atoms. Such substituente can include, for example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including - alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amfaiino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an i aromatic or heteroaromatic moiety. Unless the number of carbons is otherwise specified, "lower alkyl" includes an alkyl group, as defined above, but having 1,2,3,4,5,6, 7, 8,9, or 10 carbon atoms, ik another embodiment, an alkyl group has 1,2,3,4,5, or 6 carbon atoms in its backbone structure. "Lower alkenyl" and "lower alkynyl" have chain lengths of, for example, 2,3,4L 5, or 6 carbon atoms. "Acyl" includes compounds and moieties that contain the acyl radical (CJHaCO-) or a I carbonyl group. "Substituted acyl" includes acyl groups where one or more of t^e hydrogen - atoms are replaced by for example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, capoxylate, j alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbon^l, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phos|>hinato, cyano, amino (including -NH2, alkylamino, dialkylamino, arylamino, diarylamic(o, and alkylarylamrno), acylamino (including alkylcarbonylamino, arylcarbonylamino, ^arbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates|alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. "Acylamino" includes moieties wherein an acyl moiety is bonded to an ajnino group (-C(0)N- or -NC(O)-). For example, the term includes alkylcarbonylamino, arylc^rbonylamrno, carbamoyl and ureido groups. "Aroyl" includes compounds and moieties with an aryl or heteroaromatic) moiety bound to a carbonyl group. Examples of aroyl groups include phenylcarboxy, naphthyl carboxy, etc. "Alkoxyalkyl", "alkylaminoalkyl" and "thioalkoxyalkyl" include alkyl gifoups, as described above, which further include oxygen, nitrogen or sulfur atoms replacirig one or more hydrocarbon backbone carbon atoms e.g., CH3OCH2-, CHsNHCHi-, or CH3SCH2-. The term "alkoxy" or "alkoxyl" includes substituted and unsubstituted aljcyl, alkenyl, and alkynyl groups covalenfly linked to an oxygen atom. Examples of alkoxy groups (or alkoxyl radicals) include methoxy, ethoxy, isopropyloxy, propoxy, butoxy, and pentoxy groups. Examples of substituted alkoxy groups include halogenated alkoxy groups. Hie alkoxy groups can be substituted with groups such as alkenyl, alkynyl, halogen, ijrydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, caboxylate, alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, karbamoyl, i and ureido), amidino, imino, sulfhydryl, alkyltbio, arylthio, tbiocarboxylate, sulfjites, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, a£ido, i heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moieties. Examples of halogen substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, and trichloromethoxy. The terms "heterocyclyl" or "heterocyclic" group include closed ring structures, e.g., 3, 4, 5, 6, 7, 8, 9, or 10-, or 4, 5, 6, or 7-membered rings, which include one or mor^s heteroatoms. In one embodiment, the ring structure is a 5 or 6-membered ring. "Heteroatom" includes atoms of any element other than carbon or hydrogen. Examples of heteroatoms include nitrogen, oxygen, sulfur and phosphorus. Heterocyclyl groups can be saturated or unsaturated and include for exan pie, pyrrolidine, oxolane, thiolane, piperidine, piperazine, morpholine, lactones, lactams such as azetidinones and pyrrolidinones, sultams, and sultones. Heterocyclic groups e.g., pyrrole and • furan can have aromatic character. Heterocyclic groups include fused ring structures such as , quinoline and isoquinoline. Other examples of heterocyclic groups include pyridine and purine. i i The heterocyclic ring can be substituted at one or more positions with such substituents as i described above, as for example, halogen, hydroxyl, alkylcarbonyloxy, arylcarbojnyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbbnyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato> cyano, amino (including -NHa, alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, ^arbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, tbiocarboxylate, sutfates, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, or an ^iromatic or heteroaromatic moiety. Heterocyclic groups can also be substituted at one or moire constituent | atoms with, for example, a lower alkyl, a lower alkenyl, a lower alkoxy, a lower fclkylthio, a lower alkylamino, a lower alkylcarboxyl, a nitro, a hydroxyl, -CF3, or -CN, or the like. The term "thiocarbonyl" or "thiocarboxy" includes compounds and moieties which contain a carbon atom connected with a double bond to a sulfur atom (Figure Removed)The term "ether" includes compounds or moieties which contain an oxy jen bonded to two different carbon atoms or heteroatoms. For example, the term includes "allpxyalkyl" which refers to an alkyl, alkenyl, or alkynyl group covalently bonded to an oxyjpn atom which is covalently bonded to another alkyl group. The term "ester" includes compounds and moieties which contain a carbon or a heteroatom bound to an oxygen atom which is bonded to the carbon of a carbom/1 group. The j term "ester" includes alkoxycarboxy groups such as methoxycarbonyl, ethoxycafrbonyl, propoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, etc. The alkyl, alkenyl, or klkynyl groups are as defined above. The term "thioether" includes compounds and moieties which contain a sulfur atom bonded to two different carbon or heteroatoms. Examples of thioethers include, but are not limited to alkthioalkyls, alkthioalkenyls, and alkthioalkynyls. The term "alkthio^lkyls" include compounds with an alkyl, alkenyl, or alkynyl group bonded to a sulfur atom which is bonded to an alkyl group. Similarly, the term "alkthioalkenyls" and alkthioalkynyls" refer to compounds or moieties wherein an alkyl, alkenyl, or alkynyl group is bonded to a sulfur atom which is covalently bonded to an alkynyl group. The term "hydroxy" or "hydroxyl" includes groups with an -OH or -O". The term "halogen" includes fluorine, bromine, chlorine, iodine, etc. Th term "perhalogenated" generally refers to a moiety wherein all hydrogens are replaced by halogen atoms. • • | The term "non-hydrogen substituenf ' refers to substituents other than hydrogen. Non-limiting examples include alkyl groups, alkoxy groups, halogen groups, hydroxyt groups, aryl I groups, etc. "Polycyclyl" or "polycyclic radical" refers to two or more cyclic rings (e.$., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls) in which rvVo or more carbons are common to adjoining rings. Rings that are joined through non-adjacent atoms are termed "bridged" rings. Each of the rings of the polycycle can be substituted wiljh such substituents as described above, as for example, halogen, hydroxyl, alkyl, alkylc^rbonyloxy, I ' arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarljjonyl, alkoxycarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, aminocarbonyl, alkylthiocatbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including -a, alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acVlamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amid bo, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonatq, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkyl, alkylaryl, or an aromatic or heteroaromatic moiety. An "anionic group," as used herein, refers to a group that is negatively charged at physiological pH. Anionic groups include carboxylate, sulfate, sulfonate, sulfnuite, sulfamate, tetrazolyl, phosphate, phosphonate, phosphinate, or phosphorothioate or functional equivalents thereof. "Functional equivalents" of anionic groups are intended to include bioiiosteres, e.g., bioisosteres of a carboxylate group. Bioisosteres encompass both classical bioisosteric equivalents and non-classical bioisosteric equivalents. Classical and non-classic il bioisosteres are known in the art (see, e.g., Silverman, R. B. The Organic Chemistry of Drug besign and Drug Action, Academic Press, Inc.: San Diego, Calif., 1992, pp.19-23). One example of an anionic group is a carboxylate. "Protecting group" refers to a grouping of atoms that when attached to a reactive group i, in a molecule masks, reduces or prevents that reactivity. Examples of protecting groups can be found in Green and Wuts, Protective Groups in Organic Chemistry, (Wiley, 2nd Harrison and Harrison et al., Compendium of Synthetic Organic Methods, Vols. -8 (John Wiley and Sons, 1971 -1996); and Kocienski, Protecting Groups, (Verlag, 3rd ed. 2003). The term "amine protecting group" is intended to mean a functional group that converts an amine, amide, or other nitrogen-containing moiety into a different chemical group that is substantially inert to the conditions of a particular chemical reaction. Amine protecting groups I are preferably removed easily and selectively in good yield under conditions that do not affect other functional groups of the molecule. Examples of amine protecting groups include, but are not limited to, formyl, acetyl, benzyl, f-butyldimethylsilyl, f-butdyldiphenylsilyl, p-butyloxycarbonyl (Boc), j7-methoxybenzyl, methoxymethyl, tosyl, trifluoroaceryl, trimethylsilyl (TMS), fluorenyl-methyloxycarbonyl, 2-trimethylsilyl-ethyoxycarb^nyl, 1- I" methyl-l-(4-biphenylyl) ethoxycarbonyl, allyloxycarbonyl, benzyloxycarbonyl ((pBZ), 2- trimethylsilyl-ethanesulfbnyl (SES), trityl and substituted trityl groups, 9- i fluorenylmethyloxycarbonyl (FMOC), nitro-veratryloxycarbonyl (NVOC), and the like. Other suitable amine protecting groups are straightforwardly identified by those of skill in the art. Representative hydroxy protecting groups include those where the hydroxjr group is either acylated or alkylated such as benzyl, and trityl ethers as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers and allyl ethers. "Stable compound" and "stable structure" are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. In the present specification, the structural formula of the compound represents a certain isomer for convenience in some cases, but the present invention includes all isomers such as geometrical isomer, optical isomer based on an asymmetrical carbon, stereoisorfler, tautomer and the like which occur structurally and an isomer mixture and is not limited tc the description of the formula for convenience, and may be any one of isomer or a mixture. Therefore, an asymmetrical carbon atom may be present in the molecule and an optically active compound and a racemic compound may be present in the present compound, but the present invention is not limited to them and includes any one. In addition, a crystal polymorphism may be present but is not limiting, but any crystal form may be single or a crystal form mixture, or an anhydride or hydrate. Further, so-called metabolite which is produced by degradation of the present compound in vivo is included in the scope of the present invention. It will be noted that the structure of some of the compounds of the invention include asymmetric (chiral) carbon atoms. It is to be understood accordingly that the isomers arising from such asymmetry are included within the scope of the invention, unless indicated otherwise. Such isomers can be obtained in substantially pure form by classical separation techniques and by stereochemically controlled synthesis. The compounds of this; invention may exist in stereoisomeric form, therefore can be produced as individual stereoisomers or as mixtures. "Isomerism" means compounds that have identical molecular formulae but that differ in the nature or the sequence of bonding of their atoms or in the arrangement of thejr atoms in _ space. Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers". Stereoisomers that are not mirror images of one another are termed "diastereoisomers", and stereoisomers that are non-superimposable mirror image^ are termed "enantiomers", or sometimes optical isomers. A carbon atom bonded to four nonidentical j substituents is termed a "chiral center". "Chiral isomer" means a compound with at least one chiral center. It has two enantiomeric forms of opposite chirality and may exist either as an individual entaitiomer or as a mixture of enantiomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is termed a "racemic mixture". A compound that has jmore than one chiral center has 2n"!enantiomeric pairs, where n is the number of chiral centers, pompounds with more than one chiral center may exist as either an individual diastereomer Q> as a mixture of diastereomers, termed a "diastereomeric mixture". When one chiral center is present, a j stereoisomer may be characterized by the absolute configuration (R or S) of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. The substituents attached to the chiral center under consideration itre ranked in i accordance with the Sequence Rule of Cahn, Ingold and Prelog. (Cahn et al, An^ew. Chem. Inter. Edit. 1966, 5,385; errata 511; Cahn et al., Angew. Chem. 1966, 78,413; CJahnand Ingold, J. Chem. Soc. 1951 (London), 612; Cahn et al., Experientia 1956,12, 81f Cahn, J., Chem. Educ. 1964,41,116). i "Geometric Isomers" means the diastereomers that owe their existence to hindered rotation about double bonds. These configurations are differentiated in their names by the prefixes cis and trans, or Z and E, which indicate that the groups are on the same: or opposite side of the double bond in the molecule according to the Cahn-Ingold-Prelog rules. Further, the structures and other compounds discussed in this application include all atropic isomers thereof. " Atropic isomers" are a type of stereoisomer in which tjie atoms of j two isomers are arranged differently in space. Atropic isomers owe then: existence to a restricted rotation caused by hindrance of rotation of large groups about a central bond. Such, atropic isomers typically exist as a mixture, however as a result of recent advances in chromatography techniques, it has been possible to separate mixtures of two atropic isomers in select cases. The terms "crystal polymorphs" or "polymorphs" or "crystal forms" me4ns crystal structures in which a compound (or salt or solvate thereof) can crystallize in different crystal I packing arrangements, all of which have the same elemental composition. Different crystal forms usually have different X-ray diffraction patterns, infrared spectral, melting points, density hardness, crystal shape, optical and electrical properties, stability and solubility. Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause one crystal form to dominate. Crystal polymorphs of the compounds can |be prepared by crystallization under different conditions. For example, using different solvents or different solvent mixtures for recrystallization; crystallization at different temperatures; vjarious modes of cooling, ranging from very fast to very slow cooling during crystallization, and the like. Polymorphs are also obtained by heating or melting the disclosed compounds followed by gradual or fast cooling. The presence of polymorphs is determined by solid prope nuclear magnetic resonance spectroscopy, infrared spectroscopy, differential scanning cbilorrmetry, i powder X-ray diffraction, and other techniques known to one skilled in the art. Additionally, the compounds of the present invention, for example, the salts of the compounds, can exist in either hydrated or unhydrated (the anhydrous) form or ks solvates with other solvent molecules. Nonlimiting examples of hydrates include monohydra^es, dfliydrates, etc. Nonlimiting examples of solvates include ethanol solvates, acetone solvatek, etc. "Tautomers" refers to compounds whose structures differ markedly in arrangement of atoms, but which exist in easy and rapid equilibrium. It is to be understood that) compounds of Formulae I-IVe may be depicted as different tautomers. It should also be understood that when compounds have tautomeric forms, all tautomeric forms are intended to be within the scope of the invention, and the naming of the compounds does not exclude any tautomer form. Some compounds of the present invention can exist in a tautomeric form which are also intended to be encompassed within the scope of the present invention. The compounds, salts and prodrugs of the present invention can exist in jeveral tautomeric forms, including the enol and imine form, and the keto and enamine form and geometric isomers and mixtures thereof. All such tautomeric forms are includec. within the scope of the present invention. Tautomers exist as mixtures of a tautomeric set in solution. In solid form, usually one tautomer predominates. Even though one tautomer may [be described, the present invention includes all tautomers of the present compounds A tautomer is one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another. This reaction results in the formal migration of a hydrogen atom accompanied by a switch of adjacent conjugated double bonds. In solutions where tautomerization is possible, a chemical equilibrium of the tautomers will be reached. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. The concept of tautomers that are interconvertable by tautomerizations is called tautomerism. Of the various types of tautomerism that are possible, two are commonly observed. In keto-enol tautomerism a simultaneous shift of electrons and a hydrogen atom occurs. Ring-chain tautomerism, is exhibited by glucose. It arises as a result of the aldehyde group (-CHO) in a sugar chain molecule reacting with one of the hydroxy groups (-OH) in the same molecule to give it a cyclic (ring-shaped) form. Tautomerizations are catalyzed by: Base: 1. deprotonation; 2. formation Of a delocalized anion (e.g., an enolate); 3. protonation at a different position of the anion; Acid: 1. protonation; 2. formation of a delocalized cation; 3. deprotonation at a different position adjacent to the cation. Common tautomeric pairs are: ketone - enol, amide - nitrile, lactam - laotim, amide -imidic acid tautomerism in heterocyclic rings (e.g., in the nucleobases guanine, thymine, and cytosine), amine - enamine and enamine - enamine. Examples include: (Figure Removed)Solvates" means solvent addition forms that contain either stoichiometr c or non stoichiometric amounts of solvent. Some compounds have a tendency to trap a] ixed molar I. ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate, when the solvent is alcohol, the solvate formed is an i • alcoholate. Hydrates are formed by the combination of one or more molecules of water with one of the substances in which the water retains its molecular state as HzO, such combination being able to form one or more hydrate. As used herein, the term "analog" refers to a chemical compound that is structurally similar to another but differs slightly in composition (as in the replacement of one atom by an i j atom of a different element or in the presence of a particular functional group, or the replacement of one functional group by another functional group). Thus, an analog is a compound that is similar or comparable in function and appearance, but not in stmcture or origin to the reference compound. As defined herein, the term "derivative", refers to compounds that have a common core structure, and are substituted with various groups as described herein. For example, all of the compounds represented by Formula I are loxapine derivatives, and have Formula I as a common core. The term "bioisostere" refers to a compound resulting from the exchange of an atom or pf a group of atoms with another, broadly similar, atom or group of atoms. The objective of a bioisosteric replacement is to create a new compound with similar biological properties to the parent compound. The bioisosteric replacement may be physicochemically or pologicalry based. Examples of carboxylic acid bioisosteres include acyl sulfonimides, tetr izoles, sulfonates, and phosphonates. See, e.g., Patani and LaVoie, Chem. Rev. 96, 3147-3176 (1996). In some embodiments, Z is a carboxylic acid or a carboxylic acid bioisostere. The language "loxapine-like compounds" or "loxapine-analog compounds" "loxapine-like compounds" or "loxapine derivative compounds" is intended to include analogs of loxapine or antihistamines that include two aryl groups linked to the same atom that are linked i through a tricyclic ring system, e.g., a seven membered oxygen- and nitrogen-containing ring (i.e., similar to that of loxapine) bonded to position a piperazine ring. The term "antihistamine" refers to a compound that binds to an HI recepjtor and blocks the activity of histamine, and/or reduces the constitutive activity of the receptor. I As used herein, the term "sleep disorder" includes conditions recognized by one skilled in the art as sleep disorders, for example, conditions known in the art or conditions that are proposed to be sleep disorders or discovered to be sleep disorders. A sleep disorder also arises in a subject that has other medical disorders, diseases, or injuries, or in a subject being treated with other medications or medical treatments, where the subject, as a result, has difficulty falling asleep and/or remaining asleep, or experiences unrefreshing sleep or non-restorative sleep, e.g., the subject experiences sleep deprivation. The term "treating a sleep disorder" also includes treating a sleep disorder component of other disorders, such as CNS disorders (e.g., mental or neurological disorders iSuch as anxiety). Additionally, the term "treating a sleep disorder" includes the beneficial effect of j ameliorating other symptoms associated with the disorder. The term "nonREM peak sleep time" is defined as an absolute peak amount of nonREM sleep per hour post treatment, with drug administration occurring at Orcadian Time j • (CT) 18, which is 6 hours after lights off in a nocturnal laboratory rat when housed in a LD 12:12 (12-hours light and 12 hours dark) light-dark cycle. The nominal criteria o|?55% nonREM sleep per hour is equivalent to 33 minutes of nonREM sleep per hour, j As used herein, the term "cumulative nonREM sleep" is defined as the ne| total aggregate increase in the number of minutes of nonREM sleep, measured throughput the entire duration of a drug's soporific effect, which typically, but not always occurs in the first 6 hours post-treatment, adjusted for the net total aggregate number of minutes of nonREM sleep that occurred during the corresponding non-treatment baseline times of day recorded 24 hours earlier, relative to like vehicle control treatment. As defined herein, the term "sleep bout" refers to a discrete episode of continuous or near continuous sleep, comprised of nonREM sleep, REM sleep, or both nonREM and REM sleep stages, delimited prior and after the episode by greater than two contiguous 10 second epochs of wakefuhiess. As used herein, the term "longest sleep bout length" is defined as the total number of minutes an animal remains asleep (nonREM and/or REM sleep stages) during the single longest sleep episode or "bout" that occurred beginning in a given hour post-treatment. The "sleep bout length" measurement criteria assumes sleep is measured continuously in 10 second epochs, and is scored based upon the predominant state, computed or otherwise determined as • a discrete sleep stage (where sleep stages are defined as nonREM sleep, REM sleep, or wakefuhiess) during the 10 second interval that defines the epoch. The term "average sleep bout length" is defined as the average duration (in minutes) of I every sleep bout that began in a given hour, independent of the individual duration of each episode or bout. "Rebound insomnia" is defined as period of rebound, paradoxical, or compensatory wakefuhiess that occurs after the sleep promoting effects of a hypnotic or soporilic agent "REM sleep inhibition" is defined as the reduction of REM sleep time post-treatment at CT-18 (6 hours after lights-off; ID 12:12) or at CT-5 (5 hours after lights-on; Lib 12:12). Compounds that reduce REM sleep time by greater than 15 minutes (relative to baseline and adjusted for vehicle treatment) when administered at either CT-18 or CT-5 are considered unacceptable. Compared with NREM sleep or wakefuhiess, REM sleep causes ventilat As defined herein, "disproportionate locomotor activity inhibition" is a reduction of locomotor activity that exceeds the normal and expected reduction in behavioral activity attributable to sleep. j "Combination therapy" (or "co-therapy") includes the administration of a compound of the invention and at least a second agent as part of a specific treatment regimen jntended to provide the beneficial effect from the co-action of these therapeutic agents. The beneficial effect of the combination includes, but is not limited to, pharmacoldnetic or phapnacodynamic co-action resulting from the combination of therapeutic agents. Combinations of the compounds of the present invention and the other active agents may be administered together in a single combination or separately. Where separate administration is employed, the administration of one element may be prior to, concurrent with, or subsequent t0 the administration of other agents. Administration of these therapeutic agents in combination typically is carried out over a defined time period (usually minutes, hours, days q>r weeks depending upon the combination selected). In one embodiment, "combination tierapy" I encompasses the administration of two or more of these therapeutic agents as pap of separate monotherapy regimens that incidentally and arbitrarily result in the combinations of the present invention. In another embodiment, "combination therapy" is intended to embrace administration of these therapeutic agents in a sequential manner, that is, wherein each i therapeutic agent is administered at a different time, as well as administration of these therapeutic agents, or at least two of the therapeutic agents, in a substantially simultaneous manner. Substantially simultaneous administration can be accomplished, for exumple, by administering to the subject a single capsule having a fixed ratio of each therapeutic agent or in multiple, single capsules for each of the therapeutic agents. Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular route 3, and direct • absorption through mucous membrane tissues. The therapeutic agents can be administered by the same route or by different routes. For example, a first therapeutic agent of the combination selected may be administered by i intravenous injection while the other therapeutic agents of the combination may be administered orally. Alternatively, for example, all therapeutic agents may be administered orally or all therapeutic agents may be administered by intravenous injection. The sequence in which the therapeutic agents are administered is not narrowly critical. "Combination therapy" also embraces the administration of the therapeutic agents as described above in [further combination with other biologically active ingredients and non-drug therapies (e\g., surgery, radiation treatment, or a medical device). Where the combination therapy furtheir comprises a non-drug treatment, the non-drug treatment may be conducted at any suitable tiri^e so long as a beneficial effect from the co-action of the combination of the therapeutic agents and non-drug treatment is achieved. For example, in appropriate cases, the beneficial effect is still achieved when the non-drug treatment is temporally removed from the administration of tne therapeutic agents, perhaps by days or even weeks. The terms "parenteral administration" and "administered parenterally" as used herein refer to modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intra-arterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, tanstracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrastemal injection and infusion. The term "pulmonary" as used herein refers to any part, tissue or organ whose primary function is gas exchange with the external environment, e.g., (VCCh exchange, 'vitbin a the phrase patient. "Pulmonary" typically refers to the tissues of the respiratory tract. Thus, "pulmonary administration" refers to administering the formulations described herein to any part, tissue or organ whose primary function is gas exchange with the external environment (e.g., mouth, nose, pharynx, oropharynx, laryngopharynx, larynx, trachea, caring bronchi, j bronchioles, alveoli). For purposes of the present invention, "pulmonary" also includes a tissue or cavity that is contingent to the respiratory tract, in particular, the sinuse^. viaA "pharmaceutical composition" is a formulation containing the disclosed compounds in a form suitable for administration to a subject In one embodiment, the j pharmaceutical composition is in bulk or in unit dosage form. The unit dosage form is any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump on an aerosol inhaler, or a vial. The quantity of active ingredient (e.g., a formulation of the disclosed compound or salts thereof) in a unit dose of composition is an effective amount jind is varied according to the particular treatment involved. One skilled in the art will appreciate that it is sometimes necessary to make routine variations to the dosage depending on the age and condition of the patient The dosage will also depend on the route of administration. A variety of routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, I . subcutaneous, intravenous, intramuscular, intraperitoneal, intranasal, and the like. Dosage forms for the topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. In one embodiment, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propfellants that are required. The term "flash dose" refers to compound formulations that are rapidly dispersing dosage forms. I The term "immediate release" is defined as a release of compound from a dosage form in a relatively brief period of time, generally up to about 60 minutes. The term 'tmodified release" is defined to include delayed release, extended release, and pulsed release. The term "pulsed release" is defined as a series of releases of drug from a dosage form. The term "sustained release" or "extended release" is defined as continuous release of a compound from a dosage form over a prolonged period. A "subject" includes mammals, e.g., humans, companion animals (e.g., dogs, cats, birds, and the like), farm animals (e.g., cows, sheep, pigs, horses, fowl, and the iike) and laboratory animals (e.g., rats, mice, guinea pigs, birds, and the like). Most preferably, the subject is human. As used herein, the phrase "pharmaceutically acceptable" refers to those compounds, materials, compositions, carriers, and/or dosage forms which are, within the scqae of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. "Pharmaceutically acceptable excipient" means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipient that is acceptable for veterinary use as well as i human pharmaceutical use. A "pharmaceutically acceptable excipient" as used ^n the specification and claims includes both one and more than one such excipient. The compounds of the invention are capable of further forming salts. All of these forms are also contemplated within the scope of the claimed invention. "Pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. As used herein, "pharmaceutically acceptable salts" refer to derivatives df the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. The pharmaceutically acceptable salts inc hide the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, sjich conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 2-acetoxybenzoic, 2-hydroxyethane sulfonic, acetic, ascorbic, 111 i benzene sulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, 1,2-ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, grycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodic, hydroxymkleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methane sulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicyclic, stearic, subacetic, succinic, sulfamic, sulfanilic, ds, e.g., sulfuric, tannic, tartaric, toluene sulfonic, and the commonly occurring amine ac glycine, alanine, phenylalanine, arginine, etc. Other examples include hexanoic acid, cyclopentane propionic acid, pyruVic acid, malonic acid, 3-(4~hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenssulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo-[2.2.2]-oct-2-ene-l-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid^ tertiary butylacetic acid, muconic acid, and the like. The invention also encompasses salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with aft organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methy]glucamine, and the like. It should be understood mat all references to phannaceutically acceptable solvent addition forms (solvates) or crystal forms (polymorphs) as defined herein, of the same salt. i _ The phannaceutically acceptable salts of the present invention can be formed from a,, (Figure Removed)parent compound mat contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are used. For example, the scheme shows the formation of a phannaceutically acceptable hydrochloric salt of the parent compound, Compound 1, upon treatment with hydrochloric acid. The number of atoms protonated and counterions associated with the salt can be controlled and depends on the number of acidic/basic atoms in the parent compojund and amount of acid which is used to treat the parent compound. In one embodiment of the invention, the monohydrochloride salt of the parent compound is formed upon treatment with hydrochloric acid. In another embodiment, the dihydrochloride salt of the paretit compound is formed upon treatment with hydrochloric acid. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 18th ed. (Mack Publishing Company, 1990). For example, salts can include, but are not limited to, the hydrochloride and acetate salts of the aliphatic amine-containing, hydroxyl amiie-containing, and imine-containing compounds of the present invention. The compounds of the present invention can also be prepared as esters, for example pharmaceutically acceptable esters. For example a carboxylic acid function group in a compound can be converted to its corresponding ester, e.g., a methyl, ethyl, or other ester. Also, an alcohol group in a compound can be converted to its corresponding est ir, e.g., an acetate, propionate, or other ester. The compounds of the present invention can also be prepared as prodrugs, for example pharmaceutically acceptable prodrugs. The terms "pro-drug" and "prodrug" are used interchangeably herein and refer to any compound which releases an active parent drug in vivo. Since prodrugs are known to enhance numerous desirable qualities of Pharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc.) the compounds of the present invention can be delivered in prodrug form. Thus, the present invention is intended to cover prodrugs of the • presently claimed compounds, methods of delivering the same and compositions containing the 'same. "Prodrugs" are intended to include any covalently bonded carriers that release an active parent drug of the present invention in vivo when such prodrug is administered to a subject Prodrugs the present invention are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of the present invention wherein a hydroxy, amino, sulfhydryl, carboxy, or carbonyl group is bonded to any group that, may be cleaved in vivo to form a free hydroxyl, free amino, free sulfhydryl, free carboxy or free carbonyl group, respectively. Examples of prodrugs include, but are not limited to, esters (e.g., acetate^ dialkylaminoacetates, formates, phosphates, sulfates, and benzoate derivatives) and carbamates (e.g., N,N-dimethylaminocarbonyl) of hydroxy functional groups, esters groups (e.g., ethyl esters, morpholinoethanol esters) of carboxyl functional groups, N-acyl derivatives (e.g., N-acetyl) N-Mannich bases, Schiff bases and enaminones of amino functional groups, oximes, acetals, ketals and enol esters of ketone and aldehyde functional groups in compounds of Formulae I-IVe, and the like, See Bundegaard, H. "Design of Prodrugs" pl-92, Ijlesevier, New York-Oxford (1985). In the specification, the singular forms also include the plural, unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms jised herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In the case of conflict, the present specification will cor trol. All percentages and ratios used herein, unless otherwise indicated, are by weight. An "effective amount*' of a compound of the disclosed invention is the c uantity which, when administered to a subject having a disease or disorder, results in regression of the disease or disorder in the subject The amount of the disclosed compound to be administered to a . subject will depend on the particular disorder, the mode of administration, co-administered compounds, if any, and the characteristics of the subject, such as general health, other diseases, i age, sex, genotype, body weight and tolerance to drugs. The skilled artisan will be able to determine appropriate dosages depending on these and other factors. As used herein, the term "effective amounf' refers to an amount of a compound, or a combination of compounds, of the present invention effective when administered alone or in combination as a sleep promoting agent. For example, an effective amount refers to an amount of the compound present in a formulation or on a medical device given to a recipient patient or subject sufficient to elicit biological activity. The combination of compounds optionally is a synergistic combination. Synergy, as described, for example, by Chou and Talalay, Adv. ' Enzyme Regul. vol. 22, pp. 27-55 (1984), occurs when the effect of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent In general, a synergistic effect is most clearly demonstrated at sub-optimal concentrations of the compounds. Synergy can be Jn terms of lower cytotoxicity, or increased sleem-promoting effect, lesser hangover effect, Or some other beneficial effect of the combination compared with the individual components "A therapeutically effective amount" means the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated. i "Pharmacological effect" as used herein encompasses effects produced ir^ the subject that achieve the intended purpose of a therapy. In one embodiment, a pharmacological effect means that primary indications of the subject being treated are prevented, alleviated, or reduced. For example, a pharmacological effect would be one that results in the prevention, alleviation or reduction of primary indications in a treated subject. In another embodiment, a pharmacological effect means that disorders or symptoms of the primary indications of the subject being treated are prevented, alleviated, or reduced. For example, a pharmacological effect would be one that results in the prevention or reduction of primary indications in a treated subject. The invention provides a method of modulating sleep by administering ah effective amount of a loxapine analog of the invention, which is a moiety that antagonizes a histamine receptor or a collection of histamine receptors. The invention also relates to nov^l loxapine analogs. Effective sleep modulators have certain characteristics that correspond with increased efficacy and decreased side effects. These characteristics include a desired half-life in a subject, controlled onset of desired sedative effects, and minimal to no detectabl^ effect on psychomotor or other central nervous system (CNS) side effects (e.g., memory deficits, decreased muscle tone, drooping eyelids or drowsiness). For example, effective sleep modulators have a half life in humans of less man 7 hours, less than 6 hours, less than 5 hours, less man 4 hours, approximately 3 hours, or hi the range of 3 to 7 hours. One approach to developing an effective sleep modulator is strategically derivitizing a ! known compound or family of compounds with sleep modulating activity. Derhfitization of a known compound may enhance one or more biological properties to allow the resulting compound to perform in an improved manner. Examples of favorable biological properties include, but are not limited, to induction of a discrete sleep or hypnotic state, activity of the therapeutic compound for a discrete period of time, penetration through the blood brain barrier into the CNS, e.g., resulting from lipophilicity of substituents or conformational }ipophilicity (i.e., lipophilicity as a result of a particular conformation, such as internal salt formation between a carboxylate anion and a protonated amine), modulation of the half-life^ of the therapeutic compound, an alteration of charge, an alteration of pharmacokinetics, an alteration of log P by a value of one or more, increased receptor selectivity, reduced peripheral half-life, the ability to increase dosage, increased peripheral elimination, decreased anti-miiscarinic activity, decreased anti-cholinergic, and any combination thereof. i Derivitization of a compound results in a variety of effects and can alter t^e mechanism of action. For example, in some circumstances, a compound containing a particular functional group, such as, e.g., an ester, carboxylic acid, or alcohol group, possesses an improved selectivity for a desired receptor versus undesired receptors when compared with a compound without this group. In other circumstances, the compound containing the particular functional | group is more active as a therapeutic agent for treating sleep disorders than the corresponding I compound without this group. The effect of the derivitized compound depends dn the identity of the addition. By derivitizing a compound in order to enhance favorable biological pro] ierties and decrease undesirable side effects, it is possible to implement a strategy based on potential mechanistic effects or interactions. For example, in some compounds, the presence of a carboxylic acid results in the ability to form an intramolecular ionic bond that includes the ! corresponding carboxylate ion, e.g., zwitterion species formation with a nitrogerj atom within the compound or salt bridge formation. These interactions result in favorable biological effects such as conformational lipophilicity, i.e., increased lipophilicity as a result of a particular conformation, such as internal salt formation between a carboxylate anion and a protonated amine. Such conformational lipophilicity allows penetration through the blood brain barrier into the CNS, despite that the presence of two polar ions is generally thought to pihibit crossing of the non-polar blood-brain barrier. Another benefit of the presence of the carboxylic acid is an improved ability of the compound to bind selectively to tihd desired receptor. Compounds of the invention can also be derivitized to produce prodrugs. "Prodrug" includes a precursor form of the drug which is metabolically converted in vivo to produce the active drag. The invention further contemplates the use of prodrugs which are converted in vivo to the sleep modulating compounds used in the methods of the invention (see, e.g., R. B. Silverman, 1992, "The Organic Chemistry of Drug Design and Drug Action", Acfademic Press, Chp. 8). Such prodrugs can be used to alter the biodistribution (e.g., to allow compounds which would not typically cross the blood-brain barrier to cross the blood-brain 1 mrrier) or the pharmacokinetics of the sleep modulating compound. For example, an anionic group, e.g., a carboxylate, sulfate or sulfonate, can be esterified, e.g., with an alkyl group (e.g.^ a methyl group) or a phenyl group to yield an ester. When the ester is administered to a subject, the ester is cleaved, enzymatically or non-enzymatically, reductively or hydrolytically, to reveal j the anionic group. Such an ester can be cyclic, e.g., a cyclic sulfate or sulfone, o|r two or more anionic moieties may be esterified through a linking group. An anionic group ca^n be esterified i' with moieties (e.g.t acyloxymethyl esters) which are cleaved to reveal an intermediate sleep modulating compound which subsequently decomposes to yield the active sleep modulating compound. In one embodiment, the prodrug is a reduced form of a carboxylate, sulfate or sulfonate, e.g., an alcohol or thiol, which is oxidized in vivo to the sleep modulating compound. Furthermore, an anionic moiety can be esterified to a group which is actively transported in vivo, or which is selectively taken up by target organs. I This strategy is applied to sleep modulating compounds to improve their effectiveness and safety in clinical use. One group of compounds useful in modulating sleep is related to loxapine, which is a psychotherapeutic agent belonging to the family of compounds commonly known as tricyclic anti-depressants ("TCAs"). Loxapine is a dibenzoxazepine imtipsychotic agent, which produces pharmacological responses in various animal species wlich are characteristic of those seen with the majority of antipsychotic drugs. Although ^he precise mechanism of action is not known, loxapine succinate administration results in strong inhibition of spontaneous motor activity. Loxapine is recommended for treating schizophrenia. 1 In one aspect, the invention provides a method of modulating sleep in a Subject by administering a therapeutically effective amount of a compound having the Formula I: (Figure Removed) (D Z is selected from C02H, CO2Ri3, where R13 is Ci-C6 alkyl, CONRuRis, jvhere R|4 and are, independently, hydrogen or lower alkyl, CONHS(O)2-alkyl, CONHS(O)2[-cycloalkyl, CONHS(O)2-heteroalkyl, CONHS(O)2-aryI, CONHS(O)2-heteroaryl, S(O)2NHC(j>-alkyl, S(O)2NHCO-cycloalkyl, S(0)2NHCO-heteroalkyI, S(O)2NHCO-aryl, SCD^NH CONHS(O)2NH-alkyl, CONHS(O)2NH-cycloalkyl, CONHS(O)2NH-heteroalkyl, CONHS(O)2NH-aryl, CONHS(O)2NH-heteroaryl, SO3H, SO2H, S^NHCO- (Figure Removed) provided mat when Z is COOH or OOORis, and RS is H or halogen, Ri-Rs and Ry-Ru are not each hydrogen, further provided th.it when m is zero, X is absent In one embodiment, the compounds of Formula I for use in the methods j>f the invention have one or more of the following characteristics: an inhibition constant (KO with regard to HI receptor binding of less than 500 nM; a Kj with regard to off target binding to an off target selected from Ml, M2, M3, Dl, D2, cd and cc2 that is greater than 50(j nM and/or more than 5 times greater than the Kj with regard to the HI receptor, a nonREM peak time I value that is greater than 55% nonREM sleep per hour by the third hour after the compound is administered to a subject; a cumulative total increase in nonREM sleep of not less than 20 minutes for compound doses that produce maximum sleep consolidation; a longest sleep bout that is greater than 13 minutes in duration; net longest sleep bout post treatment s greater than or equal to 3 minutes when adjusted using a baseline value obtained at least 24 hours prior to administration of the compound to a subject; an average sleep bout mat is greater than 5 i minutes at absolute peak; administration of the compound to a subject does not produce i appreciable amounts of rebound insomnia; administration of the compound to a subject does i not appreciably inhibit REM sleep; and administration of the compound to a subject does not disproportionately inhibit locomotor activity relative to the normal effects of slei ip. In another embodiment, the compound of Formula I for use in the methods of the j invention has one or more of the following characteristics: an inhibition constant (K,) with regard to HI receptor binding of less than 300 nM; a Kj with regard to off target binding to an i • off target selected from Ml, M2, M3, Dl, D2, al and cc2 that is greater than 1 njm; a nonREM peak time value that is greater than 55% nonREM sleep per hour by the third hour after the compound is administered to a subject; a cumulative total increase in nonREM sleep of not less than 20 minutes for compound doses that produce maximum sleep consolidation^ a longest sleep bout that is greater than 13 minutes in duration; net longest sleep bout posli treatment is greater man or equal to 3 minutes when adjusted using a baseline value obtained at least 24 hours prior to administration of the compound to a subject; an average sleep bout that is greater than 5 minutes at absolute peak; administration of the compound to a subject does not produce i ! • appreciable amounts of rebound insomnia; administration of the compound to a subject does not appreciably inhibit REM sleep; and administration of the compound to a subject does not disproportionately inhibit locomotor activity relative to the normal effects of sleep. In another embodiment, the compound of Formula I for use in the methods of the r invention has one or more of the following characteristics: an inhibition constan|t (Kj) with I regard to H1 receptor binding of less than 150 nM; a Kj with regard to off target] binding to an . off target selected from Ml, M2, and M3, that is greater than 10 ^M; a nonRElv! peak time value that is greater than 55% nonREM sleep per hour by the third hour after tb.4 compound is administered to a subject; a cumulative total increase in nonREM sleep not less than 20 minutes for compound doses that produce maximum sleep consolidation; a longest sleep bout that is greater than 17 minutes in duration; net longest sleep bout post treatment is greater than or equal to 5 minutes when adjusted using a baseline value obtained at least 24 hours prior to administration of the compound to a subject; an average sleep bout that is greater than 6 | minutes at absolute peak; administration of the compound to a subject does not produce appreciable amounts of rebound insomnia; administration of the compound to a subject does not appreciably inhibit REM sleep; and administration of the compound to a sub ect does not disproportionately inhibit locomotor activity or motor tone relative to the norma effects of sleep. As used herein, the "linker" is the chain of atoms connecting the piperazijae nitrogen to the Z group. The methods of the invention are used to treat a variety of subjects, including, for example, humans, companion animals, farm animals, laboratory animals and wild animals. In one embodiment, the compound used in the method of modulating slee^p is Compound 1,2,3,4,5,6,7, 8,9,10,11,12,13,14,15,16,17,18,19,20,21,2|, 23,24,25, 26,27,28,29, 30,31,32, 33,34, 35,36, 37,38,39,40,41,42,43,44,45,46,47J, 48,49,50, 51,52,53, 54,55,56,57, 58, 59,60,61,62,63,64,65,66,67, 68, 69, 70, 71,1% 73, 74,75, 76,77,78, 79,80, 81,82, 83, 84, 85,86, 87, or 88. • In one embodiment, Rg and RIO and the carbon they are attached to are absent. In one embodiment, Rg and RIO, together with the carbon to which they are attached, are^ connected to i form a spiro ring of size 3 to 7. In one embodiment, RU and Rj2, together with ttye carbon to which they are attached, are connected to form a spiro ring of size 3 to 7. For example, R9 and RIO, together with the carbon to which they are attached, or RI i and R^, together with the carbon to which they are attached, are connected to form a spiro 3-membered cyqlopropyl ring. In one embodiment, Z is CO2H, tetrazole, or sulfonamide. Examples of sulfonamides include acyl sulfonamides. For example, Z can have the formula (Figure Removed) where W is a substituent chosen as needed to modulate the effects of the polar surface area of the Z moiety such that the desired level of oral absorption, CNS penetration, and rate of excretion into urine or bile is obtained. Examples of useful W substipuents for this purpose include an alkyl group (optionally containing a double or triple bond or heteroatom substituted e.g., CH2OCH3 or CH2OCH2CH3), a cycloalkyl group (optionally containing a double bond), a heterocyclyl group, an aryl group, or a heteroaryl group, optionally substituted, side chains selected to modulate the pKa of the acylsulfonamide moiety, or to affect the physical or me tabolic properties of the compound. Examples of V side chains include halogens such as F, Cl, or Br; Cj-Cg alkoxy groups such as OCH3 or OCH2CH3; Q-Ce alkyl or Ca-Cg cycloalkyl groups such as CHj, CF3, or cyclopropyl; heteroatom substituted Ci-Ce alkyl or C3-Cg cycloallkyl, such as CH2OCH3, or CH2OCH2CH3; electron withdrawing groups such as CN, a ketone, an amide, or (Figure Removed)In another embodiment, when Z is COOH, at least one of Rj - Rg and at Ibast one of Rg are not hydrogen. i In one embodiment, Re is not H or halogen, hi another embodiment, Ri-ks and Ry-Rg are each hydrogen, and Rg is not H or halogen. In one embodiment, at least one of Ri-Rg is not hydrogen, and the remaining Ri-Rg are hydrogen. In another embodiment, at least two of Ri-Rg are not hydrogen, and tjie remaining Ri-Rg are hydrogen. In another embodiment, at least three of Ri-Rg are not hydrbgen and the remaining Rj-Rg are hydrogen. In another embodiment, at least four of Rj-Rg ar0 not hydrogen and the remaining Rj-Rg are hydrogen. In one embodiment, R2 is not hydrogen. In one embodiment, RS is not hydrogen. In one embodiment, Re is not hydrogen. Inon|e embodiment, RV is not hydrogen. In one embodiment, Rj and Re are not hydrog In one embodiment, at least one of Ri-Rg is methyl, chloro, fluoro, bromu, hydroxy, methoxymethylene or methoxy. In another embodiment, RZ is methyl, chloro, fluoro, bromo, hydroxy, methoxymethylene, or methoxy. In another embodiment, RS is methyli chloro, fluoro, bromo, hydroxy, methoxymethylene, or methoxy. In another embodiment, Rg is j methyl, chloro, fluoro, bromo, hydroxy, methoxymethylene, or methoxy. In another embodiment, R? is methyl, chloro, fluoro, bromo, hydroxy, methoxymethylene, ]»r methoxy. ' 1 •• In another embodiment, at least two of Ri-Rg are methyl, chloro, fluoro, fcromo, hydroxy, methoxymethylene, or methoxy. In another embodiment, at least two of Ri-Rg are methyl, methoxymethylene, chloro, fluoro, bromo, hydroxy, or methoxy; and Z :is COOH. In another embodiment, at least two of Ri-Rg are methyl, methoxymethylene, chloio, fluoro, bromo, hydroxy, or methoxy; Rg and RIO are hydrogen; and Z is COOH. In one embodiment, RS and Re are both methyl, methoxy, hydroxy, methpxymethylene, chloro, fluoro, or bromo, and the remaining Ri-Rz, Rt-Rs, and R;-Rg are hydrogen. In another embodiment, RZ and RS are both methyl, methoxy, hydroxy, methoxymethylenei chloro, fluoro, or bromo, and the remaining RI, Rs-Rs, and R?-Rg are hydrogen. In one embodiment, RS and I R7 are both methyl, methoxy, hydroxy, methoxymethylene, chloro, fluoro, or bromo, and the remaining Ri-Rz, RrRs, and Rg are hydrogen. In one embodiment, Rz and R? aife both methyl, methoxy, hydroxy, methoxymethylene, chloro, fluoro, or bromo, and the remaining Rb and Rg are hydrogen. In one embodiment, Rz and RS are both methyl, methoxy, hydroxy, i • methoxymethylene, chloro, fluoro, or bromo, and the remaining RI and R^Rs aije hydrogen. In one embodiment, RS is methyl. In one embodiment, Rg is methyl and R2 or RS is methyl, methoxy, methoxymethylene, chloro, fluoro, or bromo. In another emb idiment, RS is fluoro, and R2 or RS is methyl, methoxymethylene, or methoxy. In one embodir lent, RS is methoxy. In one embodiment, R$ is methoxy and R2 or R3 is methyl, methoxy, Jrydroxy, methoxymethylene, chloro, fluoro, or bromo. In another embodiment, Rs is fhicjro and R2 or RS is methoxy. In one embodiment, Rg and RIO are hydrogen. In one embodiment, Rg and RIO are methyl. In another embodiment, Rg £.nd R]0 are methyl, RS is hydrogen or halogen, and RI - Rs and R? - Rg are hydrogen. In another embodiment, Rg and RIO are methyl, RS is hydrogen or halogen, RI - RS and R? -f- RS are hydrogen, and Z is COOH. In one embodiment, Rg and RIO are ethyl. In another embodiment, Rg and RIO are ethyl, RS is hydrogen or halogen, and RI - RS and Ry - Rg are hydrogen. In another en.bodiment, Rg and RIO are ethyl, RS is hydrogen or halogen, RI - RS and R; - Rg are hydrogen,; tad Z is COOH. I In one embodiment, Rg and RIO and the carbon to which they are attached are connected i to form a three-membered spiro (cyclopropyl) ring. In another embodiment, Rg and RIO and the carbon to which they are attached are connected to form a three-membered spiro (cyclopropyl) ring, RS is hydrogen or halogen, and RI - R5, R7 - Rg are hydroger, In another embodiment, Rg and RIO and the carbon to which they are attached are connectec to form a three-membered spiro (cyclopropyl) ring, Rs is hydrogen or halogen, and RI - R and R7 - Rg are hydrogen, and Z is COOH. In another embodiment, Rg and RIO are methyl, RS is methoxy, and RI - Rs and R? - Rg are hydrogen. In another embodiment, Rg and RIO are methyl, RS is methoxy, RI - RS and R? - i Rg are hydrogen, and Z is COOH. j In another embodiment, Rg and RIO are ethyl, RS is methoxy, and RI - RS and R? - Rg |. are hydrogen. In another embodiment, Rg and RIO are ethyl, Rs is methoxy, RI - Rs and R7 -Rg are hydrogen, and Z is COOH. In another embodiment, Rg and RIO and the carbon to which they are attached are connected to form a three-membered spiro (cyclopropyl) ring, RS is methoxy, and RI - R5 and R? - RS are hydrogen. In another embodiment, Rg and RIO and the carbon to whijjh they are attached are connected to form a three-membered spiro (cyclopropyl) ring, RS is ^nethoxy, and R] - RS and R? - Rg are hydrogen and Z is COOH. In one embodiment, RU and Rn are methyl. In another embodiment, R^ and Rn are methyl, Re is hydrogen or halogen, and RI - RS and R7 - RIO are hydrogen. In another embodiment, Ru and Rn are methyl, Re is hydrogen or halogen, RI - R5 and R7 [- RIO are hydrogen, and Z is COOH. In one embodiment, RI i and Rn are ethyl. In another embodiment, RI i ajnd Rn are ethyl, Re is hydrogen or halogen, and RI - RS and R7 - RIO are hydrogen. In another embodiment, RI i and RU are ethyl, Re is hydrogen or halogen, RI - R5 and R7 - fe.i0 are hydrogen, and Z is COOH. In one embodiment, Rn and RU and the carbon to which they are attached are connected to form a three-membered spiro (cyclopropyl) ring. In another embodiment, Rn and Ri2 and the carbon to which they are attached are connected to form a three-membered spiro (cyclopropyl) ring, Re is hydrogen or halogen, and RI - RS and R7 - RIO are hydiogen. In another embodiment, RU and Rn and the carbon to which they are attached are connected to form a three-membered spiro (cyclopropyl) ring, Re is hydrogen or halogen, and R] - R5 and Ry - RIO are hydrogen, and Z is COOH. In one embodiment, RU and Rn are methyl, and Re is methoxy. In another embodiment, RI i and Rn are methyl, Re is methoxy, and RI - RS and R7 - RIO a^e hydrogen. i In another embodiment, RU and Rn are methyl, Re is methoxy, Rj - RS and R7 -Rio are I hydrogen, and Z is COOH. In one embodiment, RU and Rn are ethyl and Re is methoxy. In another embodiment, RU and Rn are ethyl, Re is methoxy, and RI - RS and R7 - RIO are hydrogen. In another embodiment, RI i and Rn are ethyl, Re is methoxy, RI - RS and R7 - RIO are hydrogen, and Z is COOH. In one embodrment, RU and Rn and the carbon to which they are attached are connected to form a three-membered spiro (cyclopropyl) ring, and Re is methoxy. In another embodiment, RU and Rn and the carbon to which they are attached are connect* sd to form a three-membered spiro (cyclopropyl) ring, Re is methoxy, and RI - RS and R7 - RIO are hydrogen. In another embodiment, RI i and Rn and the carbon to which they ar^ attached are connected to form a three-membered spiro (cyclopropyl) ring, Re is methoxy, ar|d RI - RS and R7 - RIO are hydrogen, and Z is COOH. In one embodiment, in the compound of Formula I used in the method of the invention, q is zero. In another embodiment, q is zero, and Rp and RIO together with the carbon to which they are attached are absent In another embodrment, q is zero, Rp and Rio together with the carbon to which they are attached are absent, and X and Y are absent In another embodiment, q is zero, R$ and RIO together with the carbon to which they are attached are absent, X and Y are absent, and the sum of m, n, o, and p is 1 or 2. In one aspect, the compounds of the invention are used to modulate sleep, e.g., by decreasing the time to sleep onset, increasing the average sleep bout length, ancl/or increasing the maximum sleep bout length. In another aspect, the loxapine analogs of the invention are used to treat a sleep disorder. For example, the loxapine analogs of the inventic n are used to treat circadian rhythm abnormality, insomnia, parasomnia, sleep apnea syndronje, narcolepsy and/or hypersomnia. In one embodiment, the loxapine analogs of the invention are used in the treatment of a circadian rhythm abnormality, such as, for example, jet lag, shift-work disorders, delayed sleep phase syndrome, advanced sleep phase syndrome, and non-24 hour sleep-wake disorder. In another embodiment, the loxapine analogs are used in the treatment o; 'insomnia, including, for example, extrinsic insomnia, psychophysiologic insomnia, altitude insomnia, restless leg syndrome, periodic limb movement disorder, medication-dependent insomnia, drug-dependent insomnia, alcohol-dependent insomnia and insomnia associated with mental disorders. In one embodiment, the loxapine analogs of the invention are used to treat a parasomnia disorder, such as, e.g., somnambulism, pavor nocturmts, REM sleep behavior disorder, sleep bruxism and sleep enuresis. In another embodiment, the loxapine analogs are used to treat a sleep apnea disorder, such as, for example, central sleep apnea, obstructive sleep apnea and mixed sleep apnea. Pharmaceutical compositions that include a compound of Formula I or a i pharmaceutically acceptable salt thereof are used in the methods of modulating sleep. In one i embodiment, the compound of Formula I or a pharmaceutically acceptable salt thereof is co-administered with one or more additional therapies. In another aspect, the present invention provides a method of modulating 0eep in a subject by administering a therapeutically effective amount of a compound having the formula af Formula II: (Figure Removed)or a pharmaceutically effective salt thereof, wherein m, n, and o are, independently, 0,1,2,3, 4,5, or 6; X is absent, O, S, C(O), SO, or SO?, RZ» RS, Rs. and Ry are, independently, selected from H, F, Cl, Br, CF3, CH3, CH2CH3, CH(CH3)2, cyclopropyl, OH, OCH3, OC^3, CH2OCH3, and CH2OCH2CH3; R$, and RIO, are, independently, H, Ci-Ce straight chain alky^; C2-C6 branched alkyl, or Rg and RIO together with the carbon to which they are attached, are connected to form a spiro ring of size 3,4,5,6, or 7 atoms; and Z is COOH, CC ORi3 (where R13 is CrC6 alkyl) CONHSCO^-alkyl, CONHS(O)2-heteroalkyl, CONHS(O)2-aEyl, CONHSCO^-heteroaryl, SCO^NHCO-alkyl, S(O)2NHCO-heteroalkyl, S(O)2NECO-aryl, SCO^NHCO-heteroaryl, CONHS(O)2NH-alkyl; CONHS(O)2NH-heteroalkyl; CONHSCO^NH-aryl; CONHS(O)2NH-heteroaryl; or tetrazole, provided that when Z is COOH o; COORis, and Rg is H or halogen, then Rj-Rs and R7-Ri2 are not each hydrogen, further provided that when m j is zero, X is absent In one embodiment, the compounds of Formula II for use in the method! •> of the invention have one or more of the following characteristics: an inhibition constant (Kj) with regard to HI receptor binding of less than 500 nM; a Kj with regard to off target binding to an off target selected from Ml, M2, M3, Dl, D2, ccl and that is greater than 13 minutes in duration; net longest sleep bout post treatment is greater than or equal to 3 minutes when adjusted using a baseline value obtained at least 24 hours prior to administration of the compound to a subject; an average sleep bout that is greater than 5 minutes at absolute peak; administration of the compound to a subject does not produce appreciable amounts of rebound insomnia; administration of the compound to a subject does not appreciably inhibit REM sleep; and administration of the compound to a sul ject does not disproportionately inhibit locomotor activity relative to the normal effects of slefep. In another embodiment, the compound of Formula II for use in the methpds of the invention has one or more of the following characteristics: an inhibition constant (Kj) with regard to HI receptor binding of less than 300 nM; a K, with regard to off target binding to an off target selected from Ml, M2, M3, Dl, D2, al and a2 that is greater than 1 pm; a nonREM peak time value that is greater than 55% nonREM sleep per hour by the third hour after the compound is administered to a subject; a cumulative total increase in nonREM sleep of not less than 20 minutes for compound doses that produce maximum sleep consolidation; a longest sleep bout that is greater than 13 minutes in duration; net longest sleep bout post treatment is greater than or equal to 3 minutes when adjusted using a baseline value obtained at least 24 hours prior to administration of the compound to a subject; an average sleep bout that is greater than 5 minutes at absolute peak; administration of the compound to a subject do i . not appreciably inhibit REM sleep; and administration of the compound to a subject does not disproportionately inhibit locomotor activity relative to the normal effects of sleep. In another embodiment, the compound of Formula n for use in the methods of the invention has one or more of the following characteristics: an inhibition constant(K,) with regard to HI receptor binding of less than 150 nM; a Kj with regard to off target binding to an off target selected from Ml, M2, and M3, that is greater than 10 uM; a nonREM] peak time value that is greater than 55% nonREM sleep per hour by the third hour after the compound is administered to a subject; a cumulative total increase hi nonREM sleep not less than 20 minutes for compound doses that produce maximum sleep consolidation; a longest sleep bout that is greater than 17 minutes in duration; net longest sleep bout post treatment: s greater than or equal to 5 minutes when adjusted using a baseline value obtained at least 24 hours prior to administration of the compound to a subject; an average sleep bout that is greater than 6 minutes at absolute peak; administration of the compound to a subject does not produce appreciable amounts of rebound insomnia; administration of the compound to a subject does not appreciably inhibit REM sleep; and administration of the compound to a subject does not disproportionately inhibit locomotor activity or motor tone relative to the normal effects of sleep. In one embodiment, Z is COaH or tetrazole. In another embodiment, when Z is COOH, at least one of Ra, Ra, Re, and R?, and at least one of Rg-Rio are not hydrogen. In one embodiment, o is zero. In one embodiment, at least one of Ra, Ra, Re, R?> and at least one of Rg-Rio are not hydrogen when Z is COOH. In one embodiment, R2, Ra, and R7 are each hydrogen and Re is not hydrogen or halogen. In one embodiment, Ra, Ra, and R7, are each hydrogen, and Re is methyl, methoxy, methoxymethylene, or hydroxy. In one embodiment, at least two of Ra,Ra, Re, and R7 are not hydrogen, and the remaining Ra, Ra, Re, and R? are hydrogen. In another embodiment, at least three of Ra, Ra, Re and R? are not hydrogen and the remaining Ra, Ra, Re, and R? are hydrogen. In one embodiment, Ra is not hydrogen. In one embodiment, Ra is not hydrogen. In one embodiment, Re is not hydrogen. In one embodiment, R? is not hydrogen. In one embodiment, Ra and Re are not hydrogen. In another embodiment, Ra and Re are not hydrogen. In another embodiment, Ra and R? are not hydrogen. In one embodiment, Rg and RIO are each methyl. In another embodiment, Rg and RIO are each ethyl. In another embodiment, Rg and RIO are each hydrogen. In one embodiment, Rg and RIO and the carbon to which they are attached are connected to form a spiro ring of size from three to seven. For example, in one embodiment, Rg and RIO and the carbon to which they are attached are connected to form a three-membered spiro (cyclopropyl) ring. . In one embodiment, Rg and RIO are methyl, Re is hydrogen or halogen, and the remaining Ra, Ra, and R/ are hydrogen. Rg and RIO are methyl, Re is hydrogen or halogen, and the remaining Ra, Ra, and R? are hydrogen, and Z is COOH. In one embodiment, Rg and RIO are ethyl, Re is hydrogen or halogen, and the remaining Ra, Ra, and R7 are hydrogen. In another embodiment, Rg and RIO are ethyl, R$ is hydrogen or halogen, and the remaining Ra, Ra, and R? are hydrogen, and Z is COOH. In one embodiment, Rg and RIO and the carbon to which they are attached are connected to form a three-membered spiro (cyclopropyl) ring. In another embodiment, Rg and RIO and the carbon to which they are attached are connected to form a three-membered spiro (cyclopropyl) ring, Re is hydrogen or halogen, and the remaining Ra, Ra, and R7 are hydrogen. In another embodiment, Rg and RIO and the carbon to which they are attached are connected to form a three-membered spiro (cyclopropyl) ring, Rg is hydrogen or halogen, and the remaining R2, R3, and R7 are hydrogen, and Z is COOH. In one embodiment, in the compound of Formula n used in the method of the invention, o is zero. In another embodiment, o is zero, and X is absent. In another embodiment, o is zero, X is absent, and the sum of m and n is 1 or 2. In one embodiment, the sleep modulation is, e.g., decreasing the time to sleep onset, increasing the average sleep bout length, and/or increasing the maximum sleep bout length. In one embodiment, the sleep modulation treats a sleep disorder. Pharmaceutical compositions that include a compound of Formula II or a pharmaceutically acceptable salt thereof are also used in the compounds of modulating sleep in a subject. In one embodiment, the compound of Formula II or a pharmaceutically acceptable salt thereof is co-administered with one or more additional therapies. In another aspect, the invention provides a compound of modulating sleep in a subject by administering a therapeutically effective amount of a compound having the formula of Formula ffl: (Figure Removed)or a pharmaceutically effective salt thereof, wherein m and n are, independently, 0,1, 2,3, or 4, X is absent, O or S; R2, R3, R& and RV are, independently, selected from H, F, Cl, Br, CF3, CH3, OH, CH2CH3, CH(CH3)2, OCH3, CH2OCH3, and CH2OCH2CH3; Rg, and R,0, are, independently, H, Cj-Ce straight chain alkyl; C2-Ce branched alkyl, or Rg, and RIO, together with the carbon to which they are attached, are connected to form a spiro ring of size 3,4,5,6, or 7 atoms; and Z is selected from CO2H, COMHSCOValkyl, CONHS(O)2-cycloaikyl, CONHS(O)2-heteroalkyl, CONHS(O)2-aryl, CONHS(O)2-heteroaryl, and tetrazole; provided that when Z is COOH and Re is H, F, Cl, or Br, then R2> RS, R?, and R9-Ri0 are not each hydrogen, further provided that when m is zero, X is absent In one embodiment, the compounds of Formula HI for use in the methods! of the invention have one or more of the following characteristics: an inhibition constant (Kj) with regard to HI receptor binding of less than 500 nM; a Kj with regard to off target binding to an off target selected from Ml, M2, M3, Dl, D2, al and o2 that is greater than 500 nM and/or more than 5 times greater than the Kj with regard to the HI receptor; a nonREM peak time value that is greater than 55% nonREM sleep per hour by the third hour after the compound is administered to a subject; a cumulative total increase in nonREM sleep of not less than 20 minutes for compound doses mat produce maximum sleep consolidation; a longest sleep bout that is greater than 13 minutes in duration; net longest sleep bout post treatment is greater than or equal to 3 minutes when adjusted using a baseline value obtained at least 24 hours prior to administration of the compound to a subject; an average sleep bout mat is greater than 5 minutes at absolute peak; administration of the compound to a subject does not produce appreciable amounts of rebound insomnia; administration of the compound to a subject does not appreciably inhibit REM sleep; and administration of the compound to a subject does not disproportionately inhibit locomotor activity relative to the normal effects of sleep. In another embodiment, the compound of Formula III for use in the methods of the invention has one or more of the following characteristics: an inhibition constant (Kj) with regard to HI receptor binding of less than 300 nM; a Kj with regard to off target binding to an off target selected from Ml, M2, M3, Dl, D2, al and o2 mat is greater than 1 (Jin; a nonREM peak time value that is greater than 55% nonREM sleep per hour by the third hour after the compound is administered to a subject; a cumulative total increase in nonREM sleep of not less than 20 minutes for compound doses mat produce maximum sleep consolidation; a longest sleep bout that is greater than 13 minutes in duration; net longest sleep bout post treatment is greater than or equal to 3 minutes when adjusted using a baseline value obtained at least 24 hours prior to administration of the compound to a subject; an average sleep bout mat is greater than 5 minutes at absolute peak; administration of the compound to a subject does not produce appreciable amounts of rebound insomnia; administration of the compound to a subject does not appreciably inhibit REM sleep; and administration of the compound to a subject does not disproportionately inhibit locomotor activity relative to the normal effects of sleep. In another embodiment, the compound of Formula HI for use in the methods of the invention has one or more of the following characteristics: an inhibition constant (Kj) with regard to HI receptor binding of less than 150 nM; a Kj with regard to off target binding to an off target selected from Ml, M2, and M3, that is greater than 10 pM; a nonREM peak time value that is greater than 55% nonREM sleep per hour by the third hour after the compound is administered to a subject; a cumulative total increase in nonREM sleep not less than 20 minutes for compound doses that produce maximum sleep consolidation; a longest sleep bout that is greater than 17 minutes in duration; net longest sleep bout post treatment is greater than or equal to 5 minutes when adjusted using a baseline value obtained at least 24 hours prior to administration of the compound to a subject; an average sleep bout that is greater than 6 minutes at absolute peak; administration of the compound to a subject does not produce appreciable amounts of rebound insomnia; administration of the compound to a subject does not appreciably inhibit REM sleep; and administration of the compound to a subject does not disproportionately inhibit locomotor activity or motor tone relative to the normal effects of sleep. In one embodiment, Z is COzH or tetrazole. In one embodiment, m is zero. In one embodiment, at least one of Rz, Ra, Re, and Ry, and at least one of Rp-Rio, are not hydrogen when Z is COOH. In one embodiment, RZ, Ra, and Ry are each hydrogen and Rg is not hydrogen or halogen. In one embodiment, Rz, Ra, and R?, are each hydrogen, and Re is methyl, methoxymethylene, methoxy, or hydroxy. In one embodiment, R2, R3, and R7 are each hydrogen, and Re is not hydrogen or halogen. In one embodiment, Rz, Ra, and R7, are each hydrogen, and Re is methyl, methoxymethylene, methoxy, or hydroxy. In one embodiment, at least two of RZ, Ra, Re, and Ry are not hydrogen, and the remaining RZ, Ra, Re, and R? are hydrogen. In another embodiment, at least three of RZ, Ra, Re, and R? are not hydrogen and the remaining RZ, Ra, Re, and R/ are hydrogen. In one embodiment, RZ is not hydrogen. In one embodiment, Ra is not hydrogen. In one embodiment, Re is not hydrogen. In one embodiment, Ry is not hydrogen. In one embodiment, Ra and Re are not hydrogen. In another embodiment, RZ and Re are not hydrogen. In another embodiment, Ra and Ry are not hydrogen. In one embodiment, Rg and RIO are each methyl. In another embodiment, Rg and RIO are each ethyl. In another embodiment, Rp and RIO are each hydrogen. In one embodiment, Rg and RIO and the carbon to which they are attached are connected to form a spiro ring of size from three to seven. For example, in one embodiment, R9 and RIO and the carbon to which they are attached are connected to form a three-membered spiro (cyclopropyl) ring. In one embodiment, Rg and RIO are methyl, Re is hydrogen or halogen, and the remaining R2, RS, and R7 are hydrogen. In another embodiment, R9 and RIO are methyl, Re is hydrogen or halogen, and the remaining R2, Rs. and Ry are hydrogen, and Z is COOH. hi one embodiment, R9 and RIO are ethyl, Re is hydrogen or halogen, and the remaining Rz, Ra, and R? are hydrogen. In another embodiment, Rg and Rj0 are ethyl, Re is hydrogen or halogen, and the remaining R2, RS, and R? are hydrogen, and Z is COOH. In one embodiment, Rg and RIO and the carbon to which they are attached are connected to form a three-membered spiro (cyclopropyl) ring, hi another embodiment, Rp and RIO and the carbon to which they are attached are connected to form a three-membered spiro (cyclopropyl) ring, Re is hydrogen or halogen, and the remaining R2, Ra, and R? are hydrogen. In another embodiment, R? and RIO and the carbon to which they are attached are connected to form a three-membered spiro (cyclopropyl) ring, Re is hydrogen or halogen, and the remaining R2, Ra, and R? are hydrogen, and Z is COOH. hi one embodiment, in the compound of Formula HI used in the method of the invention, X is absent In another embodiment, X is absent, and the sum of m and n is 1 or 2. hi one embodiment, the sleep modulation is, e.g., decreasing the time to sleep onset, increasing the average sleep bout length, and/or increasing the maximum sleep bout length. In one embodiment, the sleep modulation treats a sleep disorder. Pharmaceutical compositions that include a compound of Formula in or a pharmaceutically acceptable salt thereof are also used in the compounds of modulating sleep according to the invention. In another aspect, the invention provides a compound of modulating sleep in a subject by administering a therapeutically effective amount of a compound having the formula of Formula IV: (Figure Removed)or a pharmaceutically effective salt thereof wherein t is 1,2, 3, or 4; R2, R3 Rg aind R7 are, independently, H, F, Cl, Br, CF3, CH3, OH, OCH3, CH2OCH3) or CH2OCH2CH3; R9-Rio are H, CH3i CH2CH3, or R9 and RIO, together with the carbon to which they are attached, are connected to form a spiro ring of size 3,4, 5,6, or 7 atoms; and Z is selected from COaH, CONHS(O)2-alkyl, CONHS(O)2-cycloalkyl, CONHS(O)2-heteroalkyl, CONHS(O)2-aryl, CONHS(O)i-heteroaryl, or tetrazole; provided that when Z is COOH and R$ is H, F, Cl, or Br, then R2, R3, R?, and Rg-Rio are not each hydrogen. In one embodiment, t = 1 or 2. In one embodiment, the compounds of Formula IV for use in the methods of the invention have one or more of the following characteristics: an inhibition constant (Kj) with regard to HI receptor binding of less than 500 nM; a K,- with regard to off target binding to an off target selected from Ml, M2, M3, Dl, D2, al and a2 that is greater than 500 nM and/or more than 5 times greater man the Kj with regard to the HI receptor, a nonREM peak time value that is greater than 55% nonREM sleep per hour by the third hour after the compound is administered to a subject; a cumulative total increase in nonREM sleep of not less than 20 minutes for compound doses that produce maximum sleep consolidation; a longest sleep bout that is greater man 13 minutes in duration; net longest sleep bout post treatment is greater than or equal to 3 minutes when adjusted using a baseline value obtained at least 24 hours prior to administration of the compound to a subject; an average sleep bout that is greater than 5 minutes at absolute peak; administration of the compound to a subject does not produce appreciable amounts of rebound insomnia; administration of the compound to a subject does not appreciably inhibit REM sleep; and administration of the compound to a subject does not disproportionately inhibit locomotor activity relative to the normal effects of sleep. In another embodiment, the compound of Formula IV for use in the methods of the invention has one or more of the following characteristics: an inhibition constant (Kj) with regard to HI receptor binding of less than 300 nM; a Kj with regard to off target binding to an off target selected from Ml, M2, M3, Dl, D2, al and a2 that is greater than 1 fan; a nonREM peak time value that is greater than 55% nonREM sleep per hour by the third hour after the compound is administered to a subject; a cumulative total increase in nonREM sleep of not less than 20 minutes for compound doses that produce maximum sleep consolidation; a longest sleep bout that is greater than 13 minutes in duration; net longest sleep bout post treatment is greater than or equal to 3 minutes when adjusted using a baseline value obtained at least 24 hours prior to administration of the compound to a subject; an average sleep bout that is greater than 5 minutes at absolute peak; administration of the compound to a subject does not produce appreciable amounts of rebound insomnia; administration of the compound to a subject does not appreciably inhibit REM sleep; and administration of the compound to a subject does not disproportionately inhibit locomotor activity relative to the normal effects of sleep. In another embodiment, the compound of Formula IV for use in the methods of the invention has one or more of the following characteristics: an inhibition constant (Kj) with regard to HI receptor binding of less than 150 nM; a K; with regard to off target binding to an off target selected from Ml, M2, and M3, that is greater than 10 uM; a nonREM peak time value that is greater than 55% nonREM sleep per hour by the third hour after the compound is administered to a subject; a cumulative total increase in nonREM sleep not less than 20 minutes for compound doses mat produce maximum sleep consolidation; a longest sleep bout that is greater than 17 minutes in duration; net longest sleep bout post treatment is greater than or equal to 5 minutes when adjusted using a baseline value obtained at least 24 hours prior to administration of the compound to a subject; an average sleep bout that is greater than 6 minutes at absolute peak; administration of the compound to a subject does not produce appreciable amounts of rebound insomnia; administration of the compound to a subject does not appreciably inhibit REM sleep; and administration of the compound to a subject does not disproportionately inhibit locomotor activity or motor tone relative to the normal effects of sleep. In one embodiment, Z is COaH or tetrazole. In another embodiment, when Z is COOH, at least one of RZ, Rs, and Ry, and at least one of Rs-Rio, are not hydrogen. In one embodiment, R9 and RIO are each methyl. In another embodiment, Rg and RIO are each ethyl. In one embodiment, Rp and RIO and the carbon to which they are attached are connected to form a spiro ring of size from three to seven. For example, in one embodiment, R9 and RIO and the carbon to which they are attached are connected to form a three-membered spiro (cyclopropyl) ring. In one embodiment, Rg and RIO are methyl; Re is hydrogen or halogen; and Rz RS and R? are hydrogen. In another embodiment, Rg and RIO are methyl; R$ is hydrogen or halogen; and Rj RS and R? are hydrogen; and Z is COOH. In one embodiment, R$ and RIO are ethyl; Rg is hydrogen or halogen; and Rj RS and R? are hydrogen, hi another embodiment, Rg and RIO are methyl; R$ is hydrogen or halogen; and and R? are hydrogen; and Z is COOH. In one embodiment, Rg and RIO and the carbon to which they are attached are connected to form a three-membered spiro (cyclopropyl) ring. In another embodiment, Rg $nd RIO and the carbon to which they are attached are connected to form a three-membered spiro (cyclopropyl) ring, Rg is hydrogen or halogen; and Ra Rs and R? are hydrogen. In another embodiment, Rg and RIO and the carbon to which they are attached are connected to form a three-membered spiro (cyclopropyl) ring, R$ is hydrogen or halogen; and Rz Rj and RV are hydrogen; and Z is COOH. In one embodiment, the sleep modulation is selected from decreasing the time to sleep onset, increasing the average sleep bout length, and increasing the maximum sleep bout length. In one embodiment, the sleep modulation treats a sleep disorder. Pharmaceutical compositions that include a compound of Formula IV or a pharmaceutically acceptable salt thereof are also used in the compounds of modulating sleep according to the invention. In one embodiment, the compound of Formula IV used in the methods of the invention is IVa, IVb, IVc, IVd, or IVe. For example, when Rg and RIO are methyl, compounds have the general formula IVa: (Figure Removed)when Rg and RIO are connected to form a 3 membered spiro ring (cyclopropyl), compounds have the general formula IVb: when Rg and RIO are ethyl, compounds have the general formula IVc: (Figure Removed)when R9 and RIO are ethyl, and the C-1 carbons are connected to form a 3 mernbered spiro ring (cyclopropyl), compounds have the general formula IVd: (Figure Removed) independently, 0, 1,2,3,4,5, or 6; X and Y are, independently, absent, O, S, C(O), SO, or SO2; RI, R2, R3, R*, Rs, Rg, R?, and Rg are, independently selected from H, F, Cl, Br, CF3, CH3, Cz-Ce straight chain alkyl, C3-C6 branched alkyl, C3-C7 cycloalkyl, C3-C7 heterocyclyl, OH, OCH3, OCF3, CH2OCH3, CH2CH2OCH3, CH2OCH2CH3, and d-C6 hydroxyalkyl; any hydrogen in the CH2 groups in the linker is optionally substituted with H, F., Cl, Br, CF3, CH3, C2-Ce Straight chain alkyl, C3-C6 branched alkyl, C3-C7 cycloalkyl, C3-C7 heterocyclyl, OCH3, OCF3, CH2OCH3, CH2CH2OCH3, CH2OCH2CH3, or Ci-C6 hydroxyalkyl; R9, RIO, RH, and Rtt are, independently, H, Ci-Ce straight chain alkyl, C2-Ce branched alkyl, or Rg and RIO together with the carbon to which they are attached are absent or are connected to form a spiro ring of size 3, 4, 5,6, or 7 atoms, or Rn and Rj2 together with the carbon to which they are attached, are connected to form a spiro ring of size 3,4,5,6, or 7 atoms; or substituents on two different atoms are connected to form a ring of size 3,4,5,6, or 7 atoms; and Z is selected from CO2H, CO2Ri3, where Rn is Ci-Ce alkyl, CONR^is, where Rw and RIS are, independently, hydrogen or lower alkyl, CONHSCO^-alkyl, CONHS(0)2-cycloalkyl, CONHS(O)2-heteroalkyl, CONHSCO^-aryl, CONHS(O)2-heteroaryl, S(O)2NHCO-alkyl, cycloalkyl, S(O)2NHCO-heteroalkyl, S(O)2NHCO-aryl, S(O)2NHCO-heteroaryl, CONHS(O)2NH-alkyl, CONHS(O)2NH-cycloalkyl, CONHS(O)2NH-heteroaIkyl, CONHS(O)2N-aryl, CONHS(0)2N-heteroaryl, SO3H, SO2H, S(O)NHCO-alkyl, S(O)NHCO- aiyl,S(0)NHCO-heteroaryl,P(0)(OH)2,P(0)OH5 '- (tetrazole), or (Figure Removed)halogen, then Ri-Rs and Rr-Ri2 are not each hydrogen, further provided that when m is zero, X is absent. In one embodiment, the compound is Compound 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 1 3, 14, 15, 16,. 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, or 88. In one embodiment, Z is CO2H, tetrazole, a sulfonamide, or a sulfamide. In another embodiment, when Z is COOH, at least one of RI - Rg and at least one of Rg - Ri2 are not hydrogen. In one embodiment, Re is not H or halogen. In another embodiment, Rj-Rs and Ry-Rg are each hydrogen and Re is not H or halogen. In one embodiment, at least one of Ri-Rg is not hydrogen, and the remaining Ri-Rg are hydrogen. In another embodiment, at least two of Rj-Rg are not hydrogen, and the remaining Ri-Rs are hydrogen. In another embodiment, at least three of Ri-Rg are not hydrogen and the remaining Ri-Rg are hydrogen. In another embodiment, at least four of Ri-Rg are not hydrogen and the remaining RpRg are hydrogen. In one embodiment, R2 is not hydrogen. In one embodiment, Ra is not hydrogen. In one embodiment, Re is not hydrogen. In one embodiment, Ry is not hydrogen. In one embodiment, RS and Rg are not hydrogen. In another embodiment, Rj and Re are not hydrogen. In another embodiment, Ra and R? are not hydrogen. In another embodiment, R2 and Ry are not hydrogen. In another embodiment, R2 and RS are not hydrogen. In another embodiment, Rg and R? are not hydrogen. In one embodiment, at least one of Ri-Rg is methyl, methoxymethylene, chloro, fluoro, bromo, hydroxy, or methoxy. In another embodiment, R2 is methyl, methoxymethylene, chloro, fluoro, bromo, hydroxy, or methoxy. In another embodiment, Ra is methyl, methoxymethylene, chloro, fluoro, bromo, hydroxy, or methoxy. In another embodiment, Rg is methyl, methoxymethylene, chloro, fluoro, bromo, hydroxy, or methoxy. In another embodiment, R? is methyl, methoxymethylene, chloro, fluoro, bromo, hydroxy, or methoxy. In another embodiment, at least two of Rj-Rg are methyl, methoxymethylene, chloro, fluoro, bromo, hydroxy, or methoxy. In another embodiment, at least two of Rj-Rg are methyl, methoxymethylene, chloro, fluoro, bromo, hydroxy, or methoxy; and Z is COOH, In another embodiment, at least two of Ri-Rg are methyl, methoxymethylene, chloro, fluoro, bromo, hydroxy, or methoxy; Rg and RIO are hydrogen; and Z is COOH. In one embodiment, Ra and Re are both methyl, methoxy, methoxymethylene, methoxymethylene, hydroxy, chloro, fluoro, or bromo, and the remaining Ri-Ra, R^-Rs, and R/-Rg are hydrogen. In another embodiment, Rz and Rg are both methyl, methoxy, methoxymethylene, hydroxy, chloro, fluoro, or bromo, and the remaining RI, Ra-Rs, and Rr-Rg are hydrogen. In one embodiment, Ra and R? are both methyl, methoxy, methoxyniethylene, hydroxy, chloro, fluoro, or bromo, and the remaining Rj-Rz. R4-Re» and Rg are hydrogen. In one embodiment, Rz and Rv are both methyl, methoxy, hydroxy, methoxymethylene, chloro, fluoro, or bromo, and the remaining RI, Rj-Rg, and Rg are hydrogen. In one embodiment, RZ and R3 are both methyl, methoxy, hydroxy, methoxymethylene, chloro, fluoro, or bromo, and the remaining RI and R4-Rg are hydrogen. In one embodiment, Rg is methyl. In one embodiment, Rg is methyl and Ra or Ra is methyl, methoxy, methoxymethylene, chloro, fluoro, or bromo. In another embodiment, Rg is fluoro and RZ or Ra is methyl methoxymethylene, or methoxy. In one embodiment, Rg is methoxy. In one embodiment, Rg is methoxy and Rz or Ra is methyl, methoxy, methoxymethylene, hydroxy, chloro, fluoro, or bromo. In another embodiment, Rg is fluoro and Ra or Ra is methoxy. In one embodiment, Rg and RIO, together with the carbon to which they are attached, are connected to form a spiro ring of size 3 to 7. hi one embodiment, R9 and R^ together with the carbon to which they are attached are absent, and RU and R^, together with the carbon to which they are attached, are connected to form a spiro ring of size 3 to 7. For example, Rg and RIO together with the carbon to which they are attached or Rj i and Rn together with the carbon to which they are attached, are connected to form a spiro 3-membered cyclopropyl ring. In one embodiment, Rg and RIO are hydrogen. In one embodiment, Rg and RIO are methyl. In another embodiment, Rg and RIO are methyl, Rg is hydrogen or halogen, and Rj - RS, R/ - Rg are hydrogen. In another embodiment, Rg and RIO are methyl, Re is hydrogen or halogen, RI - R5, R7 - Rg are hydrogen, andZisCOOH. In one embodiment, Rg and Rj0 are ethyl. In another embodiment, R9 and RIO are ethyl, Re is hydrogen or halogen, and RI - RS, R? - Rg are hydrogen. In another embodiment, Rg and Rio are ethyl, R In one embodiment, Rg and RIO and the carbon to which they are attached are connected to form a three-membered spiro (cyclopropyl) ring. In another embodiment, Rg and RIO and the carbon to which they are attached are connected to form a three-membered spiro (cyclopropyl) ring, Re is hydrogen or halogen, and RI - R5, Ry - Rg are hydrogen. In another embodiment, Rg and RJO and the carbon to which they are attached are connected to form a three-membered spiro (cyclopropyl) ring, Re is hydrogen or halogen, and RI - RS, R7 - Rg are hydrogen and Z is COOH. In another embodiment, Rg and RIO are methyl, Re is methoxy, and RI - RS, Ry - Rg are hydrogen. In another embodiment, Rg and RJO are methyl, Re is methoxy, RI - R$, R/ - Rg are hydrogen, and Z is COOH. In another embodiment, Rg and RIO are methyl, Re is methoxymethylene, and RI - RS, R? - Rg are hydrogen. Li another embodiment, Rg and RIO are methyl, Re is methoxymethylene, RI — RS, Ry — R?are hydrogen, and Z is COOH. In another embodiment, Rg and RIO are ethyl, Re is methoxy, and RI - RS, RV - Rg are hydrogen. In another embodiment, Rg and RIO are ethyl, Re is methoxy, RI - RS, R? - Rg are hydrogen, and Z is COOH. In another embodiment, Rg and RIO and the carbon to which they are attached are connected to form a three-membered spiro (cyclopropyl) ring, Re is methoxy, and RI - R5, R7 -Rg are hydrogen. In another embodiment, Rg and RIO and the carbon to which they are attached are connected to form a three-membered spiro (cyclopropyl) ring, Re is methoxy, and RI - RS, R7 - Rg are hydrogen and Z is COOH. In one embodiment Rg and RIO together with the carbon to which they are attached are absent In one embodiment, RH and Rj2 are methyl. In another embodiment, RH and R^ are methyl, Re is hydrogen or halogen, and Rj - RS, R? - RJO are hydrogen. In another embodiment, RI i and Rn are methyl, Re is hydrogen or halogen, RI — RS, Ry—RIQ are hydrogen, and Z is COOH. In one embodiment, Rn and RIJ are ethyl. In another embodiment, Rn and Rn are ethyl, Re is hydrogen or halogen, and Rj - RS, R? - RIO are hydrogen. In another embodiment, RI i and Rn are ethyl, RS is hydrogen or halogen, RI - RS, R? - RIO are hydrogen, and Z is COOH. hi one embodiment, RI \ and RU and the carbon to which they are attached are connected to form a three-membered spiro (cyclopropyl) ring. In another embodiment, Rn and Ri2 and the carbon to which they are attached are connected to form a three-membered spiro (cyclopropyl) ring, Re is hydrogen or halogen, and Rj - RS, R/ - RIO are hydrogen. In another embodiment, RU and R^ and the carbon to which they are attached are connected to form a three-membered spiro (cyclopropyl) ring, RS is hydrogen or halogen, and RI - RS, Ry - RIO are hydrogen and Z is COOH. hi one embodiment, Rn and RU are methyl and RS is methoxy. In another embodiment, Rn and Rn are methyl, Re is methoxy, and RI - RS, R; - RJO are hydrogen. In another embodiment, RI i and Rj2 are methyl, RS is methoxy, Rj - RS, R/ — RIO are hydrogen, and Z is COOH. hi one embodiment, Rn and RU are ethyl and Re is methoxy. In another embodiment, Rn and RU are ethyl, Re is methoxy, and RI - RS, Ry - RIO are hydrogen. In another embodiment, Rn and Ri2 are ethyl, RS is methoxy, RI - RS, R? - RIO are hydrogen, and Z is COOH. In one embodiment, RI i and RU and the carbon to which they are attached are connected to form a three-membered spiro (cyclopropyl) ring and RS is methoxy. In another embodiment, Rn and RU and the carbon to which they are attached are connected to form a three-membered spiro (cyclopropyl) ring, RS is methoxy, and Rj - RS, R? — RIO are hydrogen. In another embodiment, Rn and RU and the carbon to which they are attached are connected to form a three-membered spiro (cyclopropyl) ring, RS is methoxy, and RI - RS, Ry - RIO are hydrogen and Z is COOH. In one embodiment, q is zero. In another embodiment, q is zero, and Rg and RIO together with the carbon to which they are attached are absent. In another embodiment, q is zero, Rg and RIO together with the carbon to which they are attached are absent, X and Y are absent In another embodiment, q is zero, Rg and RIO together with the carbon to which they are attached are absent, X and Y are absent, and the sum of m, n, o, and p is 1 or 2. Pharmaceutical compositions mat include a compound of Formula I or a pharmaceutically acceptable salt thereof are also used in the methods of modulating sleep according to the invention. In another aspect, the present invention provides a compound having the formula of Formula II: (Figure Removed)or a pharmaceutically effective salt thereof, wherein m, n, and o are, independently, 0,1,2,3, 4, 5, or 6; X is absent, O, S, C(O), SO, or SO2; R2, R3, RS, and R7 are, independently selected from H, F, Cl, Br, CF3, CH3, CH2CH3, CH(Otl^)z, cyclopropyl, OH, OCH3, OCFj, CH2OCH3 and CH2OCH2CH3; Rp, and RIO, are, independently, H, Cj-Ce straight chain alkyl; C2-Ce branched alkyl, or R$ and RIO together with the carbon to which they are attached, are connected to form a spiro ring of size 3,4,5,6, or 7 atoms; and Z is COOH, COORi3 (where Rn is CrQ alkyl) CONHS(O>2-alkyl, CONHS(O)r-heteroalkyl, CONHSCO^-aryl, CONHSp^-heteroaryl, SCO^NHCO-alkyl, SCO^NHCO-heteroalkyl, S(O)iNHCO-aryl, SCO^NHCO-heteroary^CONHSCO^NH-alkyl; CONHS(O)2NH-heteroalkyl; CONHS(O>2NH-aryl; CONHS(O)2NH-heteroaryl; or tetrazole, provided that when Z is COOH or COORn, and R« is H or halogen, RrRs and Ry-Ru are not each hydrogen, further provided that when m is zero, X is absent. In one embodiment, Z is CO2H or tetrazole. In another embodiment, when Z is COOH, at least one of R2, R3, Re, and R?, and at least one of Rg-Rio, are not hydrogen. In one embodiment, o is zero. In one embodiment, at least one of R2, R3, R$, R?, and at least one of Rp-Rjo, are not hydrogen when Z is COOH. In one embodiment, Ra, R3, and R? are each hydrogen and RS is not hydrogen or halogen. In one embodiment, R2, R3> and R?, are each hydrogen, and R$ is methyl, methoxy, or hydroxy. In one embodiment, at least two of Ra, R3, R& R? are not hydrogen, and the remaining R2, R3, Re, R? are hydrogen. In another embodiment, at least three of R2, R3, Rg, R7 are not hydrogen and the remaining R2, RS, Re, R? are hydrogen. In one embodiment, Rj is not hydrogen. In one embodiment, RS is not hydrogen. In one embodiment, Re is not hydrogen. In one embodiment, R; is not hydrogen. In one embodiment, RS and Re are not hydrogen. In another embodiment, R2 and Re are not hydrogen. In another embodiment, R* and R/ are not hydrogen. In one embodiment, R9 and RIO are each methyl. In another embodiment, Rg and RIO are each ethyl, hi another embodiment, Rg and RIO are each hydrogen. In one embodiment, Rg and RIO and the carbon to which they are attached are connected to form a spiro ring of size from three to seven. For example, in one embodiment, Rg and RIO and the carbon to which they are attached are connected to form a three-membered spiro (cyclopropyl) ring. In one embodiment, Rg and RIO are methyl, Re is hydrogen or halogen, and the remaining R2, RS, and R? are hydrogen. Rg and RIO are methyl, Re is hydrogen or'halogen, and the remaining Ra, RS, and R7 are hydrogen, and Z is COOH. hi one embodiment, Rg and RIO are ethyl, Re is hydrogen or halogen, and the remaining R2, RS, and R? are hydrogen. In another embodiment, Rg and RIO are ethyl, Re is hydrogen or halogen, and the remaining R2, RS, and R? are hydrogen, and Z is COOH. In one embodiment, Rg and RIO and the carbon to which they are attached are connected to form a three-membered spiro (cyclopropyl) ring. In another embodiment, Rg and RIO and the carbon to which they are attached are connected to form a three-membered spiro (cyclopropyl) ring, R$ is hydrogen or halogen, and the remaining R2, Ra, and R? are hydrogen. In another embodiment, Rg and RIO and the carbon to which they are attached are connected to form a three-membered spiro (cyclopropyl) ring, Re is hydrogen or halogen, and the remaining R2, RS, and R? are hydrogen, and Z is COOH. In one embodiment, in the compound of Formula n, o is zero. In another embodiment, o is zero, and X is absent. In another embodiment, o is zero, X is absent, and the sum of m and n is 1 or 2. Pharmaceutical compositions that include a compound of Formula JH or a pharmaceutically acceptable salt thereof are also used in the methods of modulating sleep according to the invention. hi another aspect, the invention provides a compound having the formula of Formula III: (Figure Removed)or a pharmaceutically effective salt thereof, wherein m and n are, independently^ 0,1,2,3, or 4, X is absent, O, or S; R2, R3, Re, and R7 are, independently, selected from H, Fl, Cl, Br, CF3, CH3, OH, CH2CH3, CH(CH3)2, OCH3, CH2OCH3, and CH2OCH2CH3; Rg, and RIO, are, independently, H, d-Ce straight chain alkyl; C2-Ce branched alkyl, or Rp and R^o, together with the carbon to which they are attached, are connected to form a spiro ring ofi size 3,4,5,6, or 7; and Z is selected from CCfeH, CONHS(0)2-alkyl, CONHSCO^-cycloalkyl, CONHSCOV heteroalkyl, CONHSCO^-aryl, CONHS(O)rheteroaryl, and tetrazole; provided that when Z is COOH and Re is H, F, Cl, or Br, then Ra, R3, R7, and R9-Rio are not each hydrogen, further provided that when m is zero, X is absent. hi one embodiment, Z is CO2H or tetrazole. In one embodiment, m is zero. In one embodiment, at least one of R2, R3, RS, R7, and at least one of Rj-Rio are not hydrogen when Z is COOH. hi one embodiment, R2, R3, and R7 are each hydrogen and Re is not hydrogen or halogen, hi one embodiment, Ra, R3, and R7, are each hydrogen, and Re is methyl, methoxy, or hydroxy. In one embodiment, R2, R3, and R7 are each hydrogen and Re is not hydrogen or halogen. In one embodiment, R2, R3, and R7, are each hydrogen, and Re is methyl, methoxymethylene, methoxy, or hydroxy. hi one embodiment, at least two of R2, R3, Re, and R7 are not hydrogen, and the remaining R2, R3, Re, and R7 are hydrogen. In another embodiment, at least three of R2,'. and R7 are not hydrogen and the remaining R2, R3, Re, and R7 are hydrogen. In one embodiment, R2 is not hydrogen. In one embodiment, R3 is not hydrogen, hi one embodiment, Re is not hydrogen, hi one embodiment, R7 is not hydrogen, hi one embodiment, RS and R$ are not hydrogen. In another embodiment, Rj and Re are hot hydrogen. In another embodiment, Ra and R? are not hydrogen. In one embodiment, Rg and RIO are each methyl. In another embodiment, Rg and RIO are each ethyl, hi another embodiment, Rg and RIO are each hydrogen. In one embodiment, Rg and RIO and the carbon to which they are attached are connected to form a spiro ring of size from three to seven. For example, in one embodiment, Rg and RIO and the carbon to which they are attached are connected to form a three-membered spiro (cyclopropyl) ring. In one embodiment, Rg and RIO are methyl, Rg is hydrogen or halogen, and the remaining Rj, Ra, and R/ are hydrogen. In another embodiment, Rg and RIO are methyl, Re is hydrogen or halogen, and the remaining R2, RS, and R? are hydrogen, and Z is COOH. hi one embodiment, Rg and RIO are ethyl, R& is hydrogen or halogen, and the remaining Ra, Ra, and Ry are hydrogen. In another embodiment, Rg and RIO are ethyl, Rg is hydrogen or halogen, and the remaining Ra, Ra, and R? are hydrogen, and Z is COOH. In one embodiment, Rg and RIO and the carbon to which they are attached are connected to form a three-membered spiro (cyclopropyl) ring. In another embodiment, Rg and RIO and the carbon to which they are attached are connected to form a three-membered spiro (cyclopropyl) ring, Re is hydrogen or halogen, and the remaining Ra, Ra, and R? are hydrogen. In another embodiment, Rg and RIO and the carbon to which they are attached are connected to form a three-membered spiro (cyclopropyl) ring, Re is hydrogen or halogen, and the remaining R2, Ra, and R? are hydrogen, and Z is COOH. In one embodiment, hi the compound of Formula HI, X is absent. In another * embodiment, X is absent, and the sum of m and n is 1 or 2. Pharmaceutical compositions that include a compound of Formula III or a pharmaceutically acceptable salt thereof are also used in the methods of modulating sleep according to the invention. In another aspect, the invention provides a compound having the formula of Formula IV: (Figure Removed)or a phannaceutically effective salt thereof wherein t is 1,2,3, or 4; R2, R3 and Rg are, independently, H, F, Cl, Br, CF3, CH3, OH, OCH3, CH2OCH3, or CH2OCH2CH3; Rg-Rio are H, CH3, CH2CH3, or Rg and RIO, together with the carbon to which they are attached, are connected to form a spiro ring of size 3,4,5,6, or 7 atoms; and Z is selected from CC^H, CONHS(O)2-alkyl, CONHS(O>2-cycloalkyl, CONHS(O)2-heteroalkyl, and tetrazole; provided that when Z is COOH and Re is H, F, Cl, or Br, then RZ, RS, R?, and Rg-Rio are not each hydrogen, further provided that when m is zero, X is absent In one embodiment, the compounds have t = 1 or 2. Pharmaceutical compositions mat include a compound of Formula IV or a phannaceutically acceptable salt thereof are also used in the methods of modulating sleep according to the invention. In one embodiment, Z is CO2H, sulfonamide, sulfamide, or tetrazole. In another embodiment, when Z is COOH, at least one of R2, R3, and Ry, and at least one of Rp-Rio, are not hydrogen. In one embodiment, Rg and RIO are each methyl. In another embodiment, Rg and RIO are each ethyl. In one embodiment, R9 and RIO and the carbon to which they are attached are connected to form a spiro ring of size from three to seven. For example, in one embodiment, Rg and RIO and the carbon to which they are attached are connected to form a three-membered spiro (cyclopropyl) ring. In one embodiment, Rg and RIO are methyl; Re is hydrogen or halogen; and R2 R3 and R? are hydrogen. In another embodiment, Rg and RIO are methyl; Re is hydrogen or halogen; and R2 R3 and R; are hydrogen; and Z is COOH. In one embodiment, Rg and RIO are ethyl; Rg is hydrogen or halogen; and Ra, Ra, and R; are hydrogen. In another embodiment, Rg and RIO are methyl; Re is hydrogen or halogen; and R2, Rs, and R7 are hydrogen; and Z is COOH. In one embodiment, Rg and RIO and the carbon to which they are attached |are connected to form a three-membered spiro (cyclopropyl) ring. In another embodiment, Rg and RIO and the carbon to which they are attached are connected to form a three-membered spiro (cyclopropyl) ring, Rg is hydrogen or halogen; and RZ, RS, and Ry are hydrogen. In another embodiment, Rg and RIO and the carbon to which they are attached are connected to form a three-membered spiro (cyclopropyl) ring, Re is hydrogen or halogen; and R2, Ra, and R? are hydrogen; and Z is COOH. Pharmaceutical compositions that include a compound of Formula IV or a pharmaceutically acceptable salt thereof are also used in the methods of modulating sleep according to the invention. In one embodiment, the compound of Formula IV is IVa, IVb, IVc, IVd or IVe. For example, when Rg and RIO are methyl, compounds have the general formula IVa: (Figure Removed)when Rg and RIO are connected to form a 3 membered spiro ring (cyclopropyl), compounds have the general formula IVb: (Table removed)general, in another aspect, the present invention relates to the use of loxaptae-analogs of Formulae I-IVe to modulate sleep. Preferably, compounds of Formulae I-IVe modulate sleep with decreased side effects: e.g., the compounds do not inhibit REM sleep (consequently, sleep induced by these compounds may more closely resemble a person's natural sleep cycles), use of the compounds does not result in rebound insomnia, and/or the compounds d The in vitro selection criteria for loxapine analogs of the invention are shown in Table (Table Removed)In one embodiment, the off target binding Ki is 50 times the measured H)l receptor Ki. In some embodiments, the off target binding Ki is 100 times the measured HI receptor Ki. In vitro binding assays are used to determine HI binding (i.e., primary tai'get binding) and Ml, M2 and M3 binding (i.e., off target binding). These binding assays measure the ability of loxapine analogs to displace known standards from the HI, Ml, M2, anijl M3 receptors, wherein HI is a histamine receptor, and Ml, M2, and M3 are choliner^ic (muscarinic) receptors. Similar assays are performed with HI and dopamine receptors (Dl, and D2), and with HI and adrenergic receptors (ccl and cc2). The binding studies against the histamine receptor, HI, indicate binding affinity, and | j therefore, the results of the binding assays are an indication of the activity of the Jjoxapine analog compound. The binding studies against the muscarinic receptors indicate the extent to which the compounds bind the muscarinic receptors responsible for anti-choliner jic activity of the compound. Binding to muscarinic receptors results in several undesired side ^ffects of many known antihistamines, e.g., dry-mouth. A decrease in the binding of the compounds to the M1-M3 receptors, relative to the binding of the compound to the HI receptor, is an indication of the greater specificity of the compound for the histamine receptor o>jer the muscarinic receptor. Moreover, a drug with increased specificity for the histamiri^ receptor possesses less anti-cholinergic side effects. The HI binding of loxapine analogs of the invention (also referred to herein as "test compounds" or "compounds of the invention") is determined by measuring the specific binding of a given test compound, or series of test compounds, to the HI receptor, and comparing it with the specific binding of known standard (i.e., reference compound). j; Reference compounds used in this HI binding assay include, for example, triprolijine (K, 3.3 nM), chlorpheniramine (Kj 103.0 nM), pyrilamine (Kj 1.9 nM), cyproheptadine (I 8.5 nM), cimetidine (Kj >10,000) and dimaprit (Ki >10,000). (See e.g., Chang et al, J. Nejirochem., 32:1653-63 (1979) (with modifications); Martinez-Mir, et al., Brain Res., 526:32^-27 (1990); i and Haaksme, et al, Phaimac. Ther., 47:73-104 (1990). | determinant, mMNA- For example, in one embodiment of the HI binding assay, the HI receptct is from bovine cellular membranes, and a radioligand, [3H]Pyrilamine (15-25 Ci/mmol) ^t a final ligand concentration of 2.0 nM is used to detect specific binding for the HI receptor. The assay characteristics include a KD (binding affinity) of 1.3 nM and a Bmax (recepl^r number) of 6.2 finol/mg tissue (wet weight). Tripolidine (10 jjM) is used as the non-specific reference compound and positive control. Binding reactions are carried out in 5( KPO4 (pH 7.5) at 25 °C for 60 minutes. The reaction is terminated by rapid vacuum filtration i i .onto glass fiber filters. The level of radioactivity trapped on the filters is measured and compared to control values to ascertain any interaction between a given test compound and the HI binding site. j : The Ml binding assay determines the Ml binding of a test compound by Measuring the specific binding of a given test compound to Ml and comparing it with the specific binding of a reference compound. (See e.g., Buckley, et a/., Mol. Pharmacol. 35:469-76 (IS '89) (with modifications)). Reference compounds used in the Ml binding assay include, fo^t example, scopolamine, MethylBr (Kj 0.09 nM); 4-DAMP methiodide (Ki 0.27 nM); pirenzfepine (Ki 2.60 nM); HHSID (Ki 5.00 nM); and methoctramme (Kj 29.70 nM). For example, in one embodiment of the Ml binding assay, the Ml muscajrinic receptor is a human recombinant Ml expressed in CHO cells, and a radioligand, [3H]-scopolamine, N-methyl chloride (80-100 Ci/mmol) at a final ligand concentration of 0.5 nM is uspd to detect specific binding for Ml. The assay characteristics include a KD (binding affinity)) of 0.05 nM and a Bmax (receptor number) of 4.2 pmol/mg protein. (-)-scopolamine, methyl-, bromide (methylscopolamine bromide) (1.0 pM) is used as the non-specific determinant, inference compound and positive control. Binding reactions are carried out in PBS for 60 minutes at 25 °C. The reaction is terminated by rapid vacuum filtration onto glass fiber filters. The level j of radioactivity trapped on the filters is measured and compared to control value^ to ascertain any interaction between a given test compound and the cloned muscarinic Ml bidding site. The M2 binding assay determines the M2 binding of a test compound by measuring the specific binding of a given test compound to M2 and comparing it with the specific binding of a reference compound. (See e.g., Buckley, et al, Mol. Pharmacol. 35:469-76 (19/89) (with modifications)). Reference compounds used in the M2 binding assay include, fojr example, i scopolamine, MethylBr (Ki 0.3 nM); 4-DAMP methiodide (Kj 20.7 nM); metho^tramine (Kj 20.460 nM); HHSID (Kj 212.7 nM); and pirenzepine (K; 832.9 nM). arini' For example, in one embodiment of the M2 binding assay, the M2 muse c receptor is a human recombinant M2 expressed in CHO cells, and a radioligand, [3H]-sc j methyl chloride (80-100 Ci/mmol) at a final ligand concentration of 0.5 nM is uied to detect specific binding for Ml. The assay characteristics include a KD (binding affinitjf) of 0.29 nM and a Bmax (receptor number) of 2.1 pmol/mg protein. (-)-scopolamine, methyl-] bromide (methylscopolamine bromide) (1.0 |jM) is used as the non-specific determinant, reference compound and positive control. Binding reactions are carried out in PBS for 60 minutes at 25 °C. The reaction is terminated by rapid vacuum filtration onto glass fiber filters. The level of radioactivity trapped on the filters is measured and compared to control value s to ascertain any interaction between a given test compound and the cloned muscarinic M2 bijnding site. The M3 binding assay determines the M3 binding of a test compound b> measuring the specific binding of a given test compound to M3 and comparing it with the spectec binding of a reference compound. (See e.g., Buckley, et al, Mol. Pharmacol. 35:469-76 (1^89) (with modifications)). Reference compounds used in the M3 binding assay include, ftp example, j ; scopolamine, MethylBr (Ki 0.3 nM); 4-DAMP methiodide (Ki 0.8 nM); HHSID (Ki 14-5 nM); j; pirenzepine (Ki 153.3 nM); and methoctramine (Kj 700.0 nM). For example, in one embodiment of the M3 binding assay, the M3 muscarinic receptor is a human recombinant M3 expressed in CHO cells, and a radioligand, [3H]-sc4jpolamine, N-methyl chloride (80-100 Ci/mmol) at a final ligand concentration of 0.2 nM is used to detect specific binding for Ml. The assay characteristics include a KD (binding affinity!) of 0.14 nM 11 and a Bmax (receptor number) of 4.0 pmol/mg protein. (-)-scopolamine, methyl-i bromide (methylscopolamine bromide) (1.0 yM) is used as the non-specific determinant, reference compound and positive control. Binding reactions are carried out in 50 mM TR|S-HC1 (pH 7.4) containing 10 mM MgCla, 1 mM EDTA for 60 minutes at 25 °C. The reaction is terminated by rapid vacuum filtration onto glass fiber filters. The level of radioactivity trapped • ' •! i . on the filters is measured and compared to control values to ascertain any intera In vitro selection criteria for loxapine analogs of the invention are shown in Table 3. (Table Removed)HI binding (primary target binding) and Ml, M2 and M3 binding (off tarjget binding) are determined using the HI, Ml, M2 and M3 binding assays described above. )Res. Cardiol. 174-81 Other in vitro selection criteria for loxapine analogs of the invention incl ides hERG binding. Primary target binding and off target binding are determined as described above. If the test compound exhibits the desired primary target (HI) binding and primary jarget/off target binding ration, hERG binding (off target binding) is determined using a hi !RG block comparative study to evaluate the effect of a given test compound on cloned hEl :G channels expressed in mammalian cells. (See e.g., Brown and Rampe, Pharmaceutical NeVs 7:15-20 (2000); Rampe et al, FEBS Lett., 417:28-32 (1997); Weirich and Antoni, Basic 93 Suppl. 1:125-32 (1998); and Yap and Camm, Clin. Exp. Allergy, 29 Suppl 3, (1999)). Off target binding of hERG, the cardiac potassium channel responsible f k the rapid |l delayed rectifier current (!KT) in human ventricles, is evaluated because inhibitiojrji of IRT is the most common cause of cardiac action potential prolongation by non-cardiac drugs. (See Brown and Rampe (2000), Weirich and Antoni (1998); and Yap and Camm (19^9)). Increased action potential duration causes prolongation of the QT interval that has been associated with a dangerous ventricular arrhythmia, torsade depointes. (Brown and Rampe (200Q)). In the hERG assay, hERG channels are expressed in a human embryonic kidney cell line (HEK293) that lacks endogenous IKT- Expression in a mammalian cell line i.|s preferable to transient expression in Xenopus oocytes, as the latter demonstrates a consistent ;.0-100 fold • lower sensitivity to hERG channel blockers. (See, Rampe 1997). j In one embodiment of the hERG assay, the positive control (i.e., referencfe compound) is terfenadine (Sigma, St. Louis MO), which has been shown, at a concentration of 60 nM, to block hERG current by approximately 75%. Test compounds are delivered in HEPES-buffered physiological saline (HB-PS) -f 0.1% dimethyl sulfoxide (DMSO). Eaih test compound is applied at a concentration of 10 pM to the HEK293 cells expressing hERG (n > 3, where n = the number of cells). Cells are exposed to the test compound for th^ time necessary to reach steady-state block, but not longer than 10 minutes. The posit Ve control (60 mM terfenadine) is applied to two cells (n > 2). The hERG-exposed cells are then transferred to the recording chamber ai^d superfused with HB-PS solution. The pipette solution for whole cell recordings includes potassium aspartate (130 mM), MgCl2 (5 mM), EGTA (5 mM), ATP (4 mM), and HEPES J10 mM) at a pH adjusted to 7.2 with KOH. Onset and steady state block of hERG current du$ to the test compound are measured using a pulse pattern with fixed amplitudes (depolarization: +20 mV for 2 seconds; repolarization: -50 mV for 2 seconds), repeated at 10 second internals, from a holding potential of-80 mV. Peak tail current is measured during the 2 second ^tep to -50 mV. A steady state is maintained for at least 30 seconds before applying the test compound or positive control compound. Peak tail currents are measured until a new steady sr^ite is achieved. i In addition to the in vitro selection criteria described above, loxapine analogs of the invention are selected using the following in vivo sleep-wake and physiological Assessments: NonREM Sleep: Loxapine analogs are selected if, in adult, male Wistar ^ats, (i) peak nonREM amount exceeds 55% nonREM per hour by no later than the third hour post-treatment; and (ii) the nature of this increase in nonREM sleep is such that the n« t cumulative total increase in nonREM sleep in the initial 6 hours post-treatment (adjusted for baseline at the corresponding circadian time 24 hours earlier, and relative to Vehicle control tre itment) is not less man 20 minutes in total for compound doses mat produces maximum sleep Consolidation as measured by sleep bout length, when drug is delivered orally. The term "nonREM peak sleep time" is defined as an absolute peak amount of nonREM sleep per hour post treatment, with drug administration occurring at Cifcadian Time (CT) 18, which is 6 hours after lights off in a nocturnal laboratory rat when housid in a LD ] I I 12:12 (12-hours light and 12 hours dark) light-dark cycle. The nominal criteria i ; nonREM sleep per hour is equivalent to 33 minutes of nonREM sleep per hour. As used herein, the term "cumulative nonREM sleep" is defined as the net total aggregate increase in the number of minutes of nonREM sleep, measured througi out the entire duration of a drag's soporific effect, which typically, but not always occur j in the first 6 hours post-treatment, adjusted for the net total aggregate number of minutes of ntonREM sleep that occurred during the corresponding non-treatment baseline times of day recorded 24 hours earlier, relative to like vehicle control treatment. As defined herein, the term "sleep bout" refers to a discrete episode of continuous or near continuous sleep, comprised of nonREM sleep, REM sleep, or both nonRE^I and REM sleep stages, delimited prior and after the episode by greater than two contiguous^ 10 second epochs of wakefulness. The following non-limiting description illustrates this concept WWWWSSSSWSSSSSSSWWSSSSSSSWWWW. wherein each letter represent the predominant state of arousal (S=sleep, W=wake) observed each 10 seconds. The ineasured sleep "bouf' is 21 ten-second epochs or 3.5 minutes in duration. Sleep Consolidation: Loxapine analogs are selected if, in adult male Wistar rats, (i) the absolute duration of longest continuous sleep episodes (i.e., "sleep bout") post-treatment is greater than 13 minutes in duration; (ii) the net longest sleep bout post treatment is greater than or equal to 3 minutes when adjusted for baseline 24 hours earlier and calculated relative to vehicle treatment; and (iii) the mean absolute duration of every sleep bout when ^veraged per hour, on an hour by hour basis, is greater than or equal to 5 minutes. The aforementioned selection criteria assume that stages of sleep and wakefulness are determined continuously Ii every 10 seconds (e.g., 10 second sleep scoring "epochs"), that sleep and wakefulness are measured polygraphically using EEG and EMG criteria, and sleep episodes (comprised of I • nonREM and/or REM sleep) are defined as continuous "bouts" until the episode {is interrupted by greater than two contiguous 10 second epochs of wakefulness. As used herein, the term "longest sleep bout length" is defined as the total number of minutes an animal remains asleep (nonREM and/or REM sleep stages) during th^ single {| longest sleep bout that occurred beginning in a given hour post-treatment. The "^leep bout length" measurement criteria assumes sleep is measured continuously in 10 second epochs, and is scored based upon the predominant state, computed or otherwise determined as a discrete sleep stage (where sleep stages are defined as nonREM sleep, REM sleep, or wakefulness) during the 10 second interval that defines the epoch. The term "average sleep bout length" is defined as the average duration (Jin minutes) of every and all sleep episodes or bouts that began in a given hour, independent of the individual duration of each episode or bout. Concurrently Measured Side Effects: Loxapine analogs are selected if, in adult, male Wistarrats, these compounds (i) do not produce appreciable amounts of reboumj insomnia; (ii) do not appreciably inhibit REM sleep; and (iii) do not disproportionately inhibit locomotor motor activity and/or motor tone relative to the normal effects of sleep itself. T^e threshold j! definitions for these three side-effect variables are as follows: i "Rebound insomnia" is defined as period of rebound, paradoxical, or compensatory wakefulness that occurs after the sleep promoting effects of a hypnotic or soporific agent. Rebound insomnia is typically observed during the usual circadian rest phase 6-|8 hours post- i j treatment at CT-18 (6 hours after lights-off, given LD 12:12), but can occur at afty time during the initial 30 hours post-treatment Rebound is considered unacceptable when, in the adult, male Wistar rat, excess cumulative wakefulness associated with rebound insomiUa is greater man 10 % reduction in average of hourly NonREM sleep times during post-treal Jnent circadian rest phase (lights-on). In adult, male Wistar rats, rebound insomnia manifests as an increase in wakefulness relative to corresponding times at baseline (24 hours earlier) subsequent to a drug-induced sleep effect, and rebound insomnia is measured cumulatively. "REM sleep inhibition" is defined as the reduction of REM sleep time p 12:12). Compounds that reduce REM sleep time by greater than 15 minutes (relative to paseline and adjusted for vehicle treatment) when administered at either CT-18 or CT-5 are considered unacceptable. As defined herein, "disproportionate locomotor activity inhibition" is a reduction of locomotor activity that exceeds the normal and expected reduction in behavioral) activity attributable to sleep. Logic dictates that if an animal is asleep, there will normally be a corresponding reduction in locomotor activity. If a hypnotic or soporific compound reduces locomotor activity levels in excess of 20% greater than that explained by sleep a^lone, the compound is deemed unacceptable. Locomotor activity (LMA) or motor tone nifty be quantified objectively using any form of behavioral locomotor activity monitor (non-specific movements, telemetry-based activity monitoring, 3-dimensional movement detection devices, wheel running activity, exploratory measures, electromyographic recording, etc.|j so long as it is measured concurrently with objective sleep-wakefulness measures in the samt\ animal. In one embodiment, locomotor activity within the.animal's cage is measured using a I biotelemetry device surgically implanted in the animal's peritoneal cavity; the irhplantable device and associated telemetry receiver detects if and how much animal moves ^vithin the I cage. Sleep and wakefulness is measured in 10 second epochs simultaneously, founts of locomotor activity per unit time are divided by the concurrent amount of wakeft Jness per the same unit, yielding a "locomotor activity intensity" (LMAI) measure for that unit time. Hypnotic or soporific compounds administered at CT-18 (6 hours after lights-offj LD 12:12) that decrease locomotor activity per unit time awake by greater than 20% relatrv4 to vehicle would be judged unacceptable. i: In another embodiment, the loxapine analogs of the invention are selected using the in vivo sleep-wake and physiological assessment criteria shown in Table 5: (Table Removed)Methods for evaluating these sleep-wake and physiological assessment criteria are described above. The "absolute value" shown in second column of Table 5 refer^ to the value as determined for each test compound, while the "change" value shown in the third column of Table 5 reflects an adjusted value in which the absolute value is the difference from vehicle, when the vehicle values are adjusted for baseline. In some embodiments, the longest sleep bout is greater than 13 minutes in duration. In others, it is greater than 17 minutes in duration. In some embodiments, the net 1 ingest sleep bout post treatment is greater than or equal to 3 minutes in duration. In others, i j is greater than or equal to 6 minutes in duration. Other in vivo sleep-wake and physiological assessment criteria used to select loxapine analogs of the invention include measurement of acute body temperature and latent body temperature as a change in baseline relative to vehicle. The acute body temperate change should not exceed - 0.50 °C, and the latent body temperature change should not ^xceed + 0.50 °C at Time 1-6 hours. The acute body temperature (Ti^) is adjusted for the corresponding baseline measured 24 hours earlier, relative to vehicle (the decrease from vehicl^). The latent body temperature, measured 7-18 hours post drug treatment (Ty.ig), is adjusted for the corresponding baseline measured 24 hours earlier, relative to vehicle (the decrease from vehicle). The invention provides a method of modulating sleep by administering to a subject a j therapeutically effective amount of a compound of Formula I - IVe or a pharmaceutically effective salt thereof. The compounds modulate sleep in several ways, including decreasing the time to sleep onset, increasing the average sleep bout length, and increasing the maximum sleep bout length. sd orally, The compounds, or pharmaceutically acceptable salts thereof, is adminis nasally, transdermally, pulmonary, inhalationally, buccally, sublingually, intrapej^ntoneally, intravenously, rectally, intrapleurally, intrathecally and parenterally. In one embodiment, the compound is administered orally. One skilled in the art will recognize the advanlages of certain routes of administration. The method of modulating sleep by administering to a subject a therapeui Really effective amount of a compound of Formula I - IVe or a pharmaceutically effective salt thereof is used to treat a variety of sleep disorders including circadian rhythm abnormality, insomnia, parasomma, sleep apnea syndrome, narcolepsy and/or hypersomnia. In one embodiment, the method treats circadian rhythm abnormalities such as jet lag, shift-work disorderfj, delayed sleep phase syndrome, advanced sleep phase syndrome and non-24 hour sleep-wj^ke disorder. In another embodiment, the method treats insomnia including extrinsic insomnia^ psychophysiologic insomnia, altitude insomnia, restless leg syndrome, periodic Ijjnb i i movement disorder, medication-dependent insomnia, drug-dependent insomnia, dependent insomnia and insomnia associated with mental disorders. In another embodiment, the method treats parasomnias including somnarr ibulism, pavor nocturnus, REM sleep behavior disorder, sleep bruxism and sleep enuresis. In y«s|t another embodiment, the method treats sleep apnea disorder including central sleep apneiij, obstructive sleep apnea and mixed sleep apnea. Additionally, the method treats other sleep disorders such 11 as narcolepsy or hypersomnia. In some embodiments, a compound of Formula I - IVe is administered as ^ pharmaceutically acceptable salt. One skilled in the art will recognize the variouk methods for creating pharmaceutically acceptable salts and identifying the appropriate salt. Lfi a one li embodiment, the compound or a pharmaceutically acceptable salt thereof is included in a pharmaceutical composition. As used herein, the term "sleep disorder" includes conditions recognized j(jy one skilled i! in the art as sleep disorders, for example, conditions known in the art or conditions that are proposed to be sleep disorders or discovered to be sleep disorders. See, for example, Thorpy, MJ International Classification of Sleep Disorders, Revised: Diagnostic and Coiling Manual. American Sleep Disorders Association; Rochester, Minnesota 1997; and ICD-9-( *\M, International Classification of Diseases, Ninth Revision, Clinical Modification, Rational Center for Health Statistics, Hyattsville, MD. For example, sleep disorders can be generally classed into dyssomnias, e.g., intrinsic, extrinsic, and ckcadian rhythm disorders; parasomnias, e.g., arousal, sleep-wake transition, and rapid eye movement (REM) associated disorders, and other parasomnias; disorders associated with mental, neurological, and other medical disorders; and other sleep disorders^ Intrinsic sleep disorders include, for example, psychophysiological insomnia, sleep i j state misperception, idiopathic insomnia, narcolepsy, recurrent hypersomnia, iditypathic i i hypersomnia, post-traumatic hypersomnia, obstructive sleep apnea syndrome, central sleep apnea syndrome, central alveolar hypoventilation syndrome, periodic limb movement disorder, and restless legs syndrome. Extrinsic sleep disorders include, for example, inadequate sleep hygiene, bnvironmental sleep disorder, altitude insomnia, adjustment sleep disorder, insufficient sleep syndrome, limit-setting sleep disorder, sleep-onset association disorder, food allergy insomnia, npcturnal eating (drinking) syndrome, hypnotic-dependent sleep disorder, stimulant-dependent sljeep disorder, alcohol-dependent sleep disorder, and toxin-induced sleep disorder. Orcadian rhythm sleep disorders include, for example, time-zone changfi (jet lag) syndrome, shift work sleep disorder, irregular sleep-wake pattern, delayed sleep phase i syndrome, advanced sleep phase syndrome, and non-24-hour sleep-wake disorder. Arousal sleep disorders include, for example, confusional arousals, sleepwalking and sleep terrors. I i Sleep-wake transition disorders include, for example, rhythmic movenu^it disorder, i sleep starts, sleeptalking, and nocturnal leg cramps. j !! REM-associated sleep disorders include, for example, nightmares, sleerj paralysis, impaired sleep-related penile erections, sleep-related painful erections, REM s%p-related sinus arrest, and REM sleep behavior disorder. 11 Other parasomnias include, for example, sleep bruxism, sleep enuresis, sleep-related abnormal swallowing syndrome, nocturnal paroxysmal dystonia, sudden unexplained nocturnal death syndrome, primary snoring, infant sleep apnea, congenital central hypovepilation i j syndrome, sudden infant death syndrome, and benign neonatal sleep myoclonus. A "sleep disorder" also arises in a subject that has other medical disorders, diseases, or injuries, or in a subject being treated with other medications or medical treatments, where the subject as a result has difficulty falling asleep and/or remaining asleep, or experiences unrefreshing sleep or non-restorative sleep, e.g., the subject experiences sleep deprivation. For example, some subjects have difficulty sleeping after undergoing medical treatment for other conditions, e.g., chemotherapy or surgery, or as a result of pain or other effects It is well known in the art that certain medical disorders, for example, central nervous system (CNS) disorders, e.g., mental or neurological disorders, e.g., anxiety, cai^ have a sleep disorder component, e.g., sleep deprivation. Thus, "treating a sleep disorder" al;k> includes treating a sleep disorder component of other disorders, e.g., CNS disorders. Furnher, treating the sleep disorder component of CNS disorders can also have the beneficial effect of ameliorating other symptoms associated with the disorder. For example, in som^ subjects experiencing anxiety coupled with sleep deprivation, treating the sleep deprivation component also treats the anxiety component. Thus, the present invention also includes a method of treating such medical disorders. For example, sleep disorders associated with mental disorders include psychoses, mood disorders, anxiety disorders, panic disorder, addictions, and the like. Specific mental disorders include, for example, depression, obsessive compulsive disorder, affective neurosis/disorder, depressive neurosis/disorder, anxiety neurosis; dysthymic disorder, behavior disorder, mood I disorder, schizophrenia, manic depression, delirium, and alcoholism. Sleep disorders associated with neurological disorders include, for example, cerebral degenerative disorders, dementia, parkinsonism, Huntington's disease, Alzheimej-'s, fatal familial insomnia, sleep related epilepsy, electrical status epilepticus of sleep, atifi sleep-related headaches. Sleep disorders associated with other medical disorders include, for Example, sleeping sickness, nocturnal cardiac ischemia, chronic obstructive pulmonary dijease, sleep-related asthma, sleep-related gastroesophageal reflux, peptic ulcer disease, and f tbrositis i! syndrome. In some circumstances, sleep disorders are also associated with pain, e.gjj, neuropathic pain associated with restless leg syndrome; migraine; hyperalgesia, fibromyalgify pain; enhanced or exaggerated sensitivity to pain, such as hyperalgesia, causalgia and allodynia; acute pain; burn pain; atypical facial pain; neuropathic pain; back pain; complex^ regional pain syndromes I and II; arthritic pain; sports injury pain; pain related to infection, e.g., HIV, post-polio syndrome, and post-herpetic neuralgia; phantom limb pain; labor pain; caricer pain; post-chemotherapy pain; post-stroke pain; post-operative pain; neuralgia; conditions Associated with visceral pain including irritable bowel syndrome, migraine and angina. Other sleep disorders include, for example, short sleeper, long sleeper, s^bwakefulness i ! syndrome, fragmentary myoclonus, sleep hyperhidrosis, menstrual-associated sleep disorder, pregnancy-associated sleep disorder, terrifying hypnagogic hallucinations, sleep^related neurogenic tachypnea, sleep-related laryngospasm, and sleep choking syndrome] i i Insomnia is typically ckssed into sleep onset insomnia, where a subject takes more than 30 minutes to fall asleep; and sleep maintenance insomnia, where the subject spends more than 30 minutes awake during an expected sleep period, or, for example, waking before the desired wake-up time with difficulty or an inability to get back to sleep. The disclosed ^ompounds i ; may be effective in treating sleep onset and sleep maintenance insomnias, insomlnia resulting from circadian rhythm adjustment disorders, or insomnia resulting from CNS disorders. A one embodiment is treating a subject for a circadian rhythm adjustment disorder. Another embodiment is treating a subject for insomnia resulting from a mood disorder. In other embodiments, a subject is treated for sleep apnea, somnambulism, night terrors, Restless leg syndrome, sleep onset insomnia, and/or sleep maintenance insomnia; or more preferably, sleep onset insomnia or sleep maintenance insomnia. The disclosed compounds may fee effective for treating sleep onset insomnia. The disclosed compounds may also be effective |or treating sleep maintenance insomnia. The dosage regimen utilizing the compounds is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and Jiepatic function of the patient; and the particular compound or salt thereof employed, '^jn ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition. Oral dosages of the present invention, when used for the indicated effectsL will range 11 between about 0.05 to 5000 mg/day orally. Effective amounts of the disclosed ccpipounds typically range between about 0.01 mg/kg per day and about 100 mg/kg per day, ^nd preferably between 0.1 mg/kg per day and about 10 mg/kg/day. Techniques for a[iministration of the disclosed compounds of the invention can be found in Remington: the Science and * I Practice of Pharmacy, 19 edition, Mack Publishing Co., Easton, PA (1995). i; For example, in some embodiments, an acid salt of a compound containing an amine or other basic group is obtained by reacting the compound with a suitable organic or inorganic acid, such as hydrogen chloride, hydrogen bromide, acetic acid, perchloric acid ajjd the like. Compounds with a quaternary ammonium group also contain a counter anion such as chloride, bromide, iodide, acetate, perchlorate and the like. Other examples of such salts i hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, maleates, a 11 ;lude ietates, citrates, fumarates, tartrates (e.g., (+)-tartrates, (-)-tartrates or mixtures thereof including racemic mixtures), succinates, benzoates and salts with amino acids such as glutamic acid. Salts of compounds containing a carboxylic acid or other acidic functiona. group are prepared by reacting with a suitable base. Such a pharmaceutically acceptable sa t is made with a base which affords a pharmaceutically acceptable cation, which includes a kali metal salts (especially sodium and potassium), alkaline earth metal salts (especially calc him and magnesium), aluminum salts and ammonium salts, as well as salts made from physiologically acceptable organic bases such as trimethylamine, triethylamine, morpholine, pyri In some embodiments, certain compounds and their salts also exist in the form of solvates, for example hydrates, and the present invention includes each solvate anil mixtures thereof. In an embodiment, the compounds described herein, and the pharmaceutically acceptable salts thereof are used in pharmaceutical preparations in combination with a pharmaceutically acceptable carrier or diluent Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions. The|^ompounds I will be present in such pharmaceutical compositions in amounts sufficient to pro jdde the desired dosage amount in the range described herein. Techniques for formulation and administration of the disclosed compounds of the invention can be found in. Remington: the Science and Practice of Pharmacy, above. disclosed Typically, the compound is prepared for oral administration, wherein the compounds or salts thereof are combined with a suitable solid or liquid carrier 01 diluent to form capsules, tablets, pills, powders, syrups, solutions, suspensions and the likej The tablets, pills, capsules, and the like contain from about 1 to about 99 weight percent of the active ingredient and a binder such as gum tragacanth, acacias, com starcl or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as com starch, potato starch or algjnic acid; a lubricant such as magnesium stearate; and/or a sweetening agent such as sucrose, lactose, saccharin, xylitol, and the like. When a dosage unit form is a capsule, it often contains, in addition to materials of the above type, a liquid carrier such as |a fatty oil. In some embodiments, various other materials are present as coatings or i:b modify the physical form of the dosage unit For instance, in some embodiments, tablets ard coated with shellac, sugar or both. In some embodiments, a syrup or elixir contains, in addit on to the j I active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor, and the like. For some embodiments relating to parental administration, the disclosed compounds, or j 'salts, solvates, or polymorphs thereof, can be combined with sterile aqueous or organic media to form injectable solutions or suspensions. Injectable compositions are preferably aqueous isotonic solutions or suspensions. The compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solutio^ promoters, | i salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances. The compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1 to 75%, preferably about 1 to 50%, of the active ingredient. For example, injectable solutions are produced using solvents such as sesame or peanut oil or aqueous propylene glycol, as well as aqueous solutions of water-soluble pharmaceutically-acceptable salts of the compounds. In some embodiments, dispersions are prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. U^der ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. The terms "parenteral administration" and "administered pai:enterally" as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular^ intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, tifanstracheal, • ^ subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspihal ^nd intrastemal injection and infusion. For rectal administration, suitable pharmaceutical compositions are, for 11 fatty emulsions or suspensions. The compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoter^ salts for regulating the osmotic pressure and/or buffers. In addition, they may also contaiji other therapeutically valuable substances. The compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1 to It |' In some embodiments, the compounds are formulated to deliver the activ^ agent by pulmonary administration, e.g., administration of an aerosol formulation contain^ the active agent from, for example, a manual pump spray, nebulizer or pressurized meteredfjdose inhaler. In some embodiments, suitable formulations of this type also include other agents, such as antistatic agents, to maintain the disclosed compounds as effective aerosols. A drug delivery device for delivering aerosols comprises a suitable aeros canister with a metering valve containing a pharmaceutical aerosol formulation as described and an actuator housing adapted to hold the canister and allow for drug delivery. The canister in the drug delivery device has a headspace representing greater than about 15% of the pjtal volume of the canister. Often, the polymer intended for pulmonary administration is dissolved, suspended or emulsified in a mixture of a solvent, surfactant and propellant. The^ jnixture is maintained under pressure in a canister that has been sealed with a metering valve. For nasal administration, either a solid or a liquid carrier can be used. Th^ solid carrier i i includes a coarse powder having particle size in the range of, for example, from aWut 20 to about 500 microns and such formulation is administered by rapid inhalation through the nasal passages. In some embodiments where the liquid carrier is used, the formulation Js administered as a nasal spray or drops and includes oil or aqueous solutions of the active ingredients. Also contemplated are formulations that are rapidly dispersing dosage forms, also known as "flash dose" forms. In particular, some embodiments of the present invention are formulated as compositions that release their active ingredients within a short period of time, e-S-> typically less than about five minutes, preferably less than about ninety seconds, more preferably in less than about thirty seconds and most preferably in less than abojit ten or fifteen ij seconds. Such formulations are suitable for administration to a subject via a variety of routes, for example by insertion into a body cavity or application to a moist body surface or open wound. Typically, a "flash dosage" is a solid dosage form that is administered oijally, which j rapidly disperses in the mouth, and hence does not require great effort in swallojying and allows the compound to be rapidly ingested or absorbed through the oral mucosal membranes. In some embodiments, suitable rapidly dispersing dosage forms are also used in other applications, including the treatment of wounds and other bodily insults and diseased states in which release of the medicament by externally supplied moisture is not possible. "Flash dose" forms are known in the art; see for example, effervescent dosage forms 11 and quick release coatings of insoluble microparticles in U.S. Pat. Nos. 5,578,3^2 and i 5,607,697; freeze dried foams and liquids in U.S. Pat. Nos. 4,642,903 and 5,631^23; melt spinning of dosage forms in U.S. Pat. Nos. 4,855,326,5,380/173 and 5,518,730; solid, free-fbrm fabrication in U.S. Pat. No. 6,471,992; saccharide-based carrier matrix and a liquid binder in U.S. Pat. Nos. 5,587,172, 5,616,344,6,277,406, and 5,622,719; and other forins known to theart The loxapine analogs of the invention are also formulated as "pulsed release" formulations, in which the analog is released from the pharmaceutical compositions in a series of releases (i.e., pulses). The loxapine analogs are also formulated as "sustained release" formulations in which the analog is continuously released from the pharmaceutical composition over a prolonged period. j Also contemplated are formulations, e.g., liquid formulations, including jtyclic or acyclic encapsulating or solvating agents, e.g., cyclodextrins, polyethers, or potyfcaccharides (e.g., methylcellulose), or more preferably, polyanionic p-cyclodextrin derivatives with a sodium sulfonate salt group separate from the lipophilic cavity by an alkyl ether Spacer group or polysaccharides. In one embodiment, the agent is methylcellulose. In anothej^ embodiment, the agent is a polyanionic P-cyclodextrin derivative with a sodium sulfonate salt Separated from the lipophilic cavity by a butyl ether spacer group, e.g., CAPTISOL® (Cyljjex, Overland, KS). One skilled in the art can evaluate suitable agent/disclosed compound forntolation ratios by preparing a solution of the agent in water, e.g., a 40% by weight solution; preparing serial dilutions, e.g., to make solutions of 20%, 10,5%, 2.5%, 0% (control), and the lik>; adding an excess (compared to the amount that can be solubilized by the agent) of the diseased compound; mixing under appropriate conditions, e.g., heating, agitation, sonication, and the like; centrifuging or filtering the resulting mixtures to obtain clear solutions; and analyzing the solutions for concentration of the disclosed compound. • In addition to the therapeutic formulations described above, a therapy including the compounds of the present invention optionally includes, co-administration with pne or more i I additional therapies, e.g., drugs or physical or behavioral treatments (e.g., light therapy, electrical stimulation, behavior modification, cognitive therapy, circadian rhythiiji modification, and the like). Such a practice is referred to as "combination therapy." The othe:i therapy or 11 therapies in the combination therapy include therapies recognized by one skilled] in the art as I desirable in combination with the compound of the invention, for example, therapies known to j i the art or therapies which are proposed or discovered in the art for treating sleep disorders or treating diseases associated with sleep disorders, for example, therapies for any Typically, the compound is administered as a monotherapy. One skilled in the art will appreciate that a therapy administered in combination with the compounds of the present invention is directed to the same or a different disorder target as that being targeted by the compounds of the present invention. Administration of the compound of the invention is first, followed by the other therapy; or alternatively!, administration of the other therapy may be first. The other therapy is any knowd in the art to treat, prevent, or reduce the symptoms of the targeted disorder, e.g., a sleep disorder, or other disorders, e.g., other CNS disorders. In addition, some embodiments of the preset invention have compounds administered in combination with other known therapies for th4 target disorder. Furthermore, the other therapy includes any agent of benefit to the patient when administered in combination with the disclosed compound. For example, in some embodiments where the other therapy is a drug, it i$ administered as a separate formulation or in the same formulation as the compound of the invention. A compound of the invention is administered in combination therapy with any one I antiarrhythmic agents, coronary dilation agents, glycosides, spasmolytics, antihyflertensive agents, antidepressants, antianxiety agents, other psychotherapeutic agents, stero ds, corticosteroids, analgesics, cold medications, vitamins, sedatives, hypnotics, contraceptives, nonsteroidal anti-inflammatory drugs, blood glucose lowering agents, cholesterol lowering agents, anticonvulsant agents, other antiepileptic agents, immunomodulators, anticholinergics, sympatholytics, sympathomimetics, vasodilatory agents, anticoagulants, antiarrh^thmics, prostaglandins having various pharmacologic -activities, diuretics, sleep aids, antihistaminic agents, antineoplastic agents, oncolytic agents, antiandrogens, antimalarial agents, antileprosy agents, and various other types of drugs. See Goodman and Oilman's The Basis pf Therapeutics (Eighth Edition, Pergamon Press, Inc., USA, 1990) and The Merely Index (Eleventh Edition, Merck & Co., Inc., USA, 1989). Examples of drugs used in combination with the compounds of the invention include, but are not limited to, AMBIEN® STILNOX® (zolpidem tartrate), indiplon, ESTfc>RRA™ | ' (eszopiclone), NEURONTDSf® (gabapentin), LYRICA® (pregabalin), eplivanserik SONATA® i TM (zaleplon), ESTORRA™ (eszopiclone), ZOPICLONE™ (imovane), DESYREL (trazodone ® ZYPREXA hydrochloride), SEROQUEL (quetiapine fumarate), CLOZARIL® (clozapine), (olanzapine), RISPERDAL® (risperidone), Ml 00907 and LUNESTA™. In one embodiment, the compounds of the invention are useful in combination with a mechanical therapy, such as CPAP. "CPAP" or "continuous positive airway pressure" is a mechanical device for the treatment for sleep apnea and other sleep-related breaking disorders (including snoring). Treatment with a CPAP device is typically administered via the nose or mouth of the patient. Under CPAP treatment, a subject wears a tight-fitting plastic mask over ^he nose when sleeping. The mask is attached to a compressor, which forces air into the nose cjfeating a positive pressure within the subject's airways. The principle of the method is th# pressurizing i i the airways provides a mechanical "splinting" action, which prevents or lessens iirway collapse and therefore, obstructive sleep apnea. Although an effective therapeutic response is observed in most subjects who undergo CPAP treatment, many subjects cannot apparatus or pressure and refuse treatment. Moreover, recent covert monitoringistudies demonstrated that long-term compliance with CPAP treatment is very poor. It i$ known that subjects remove their mask while sleeping. I In one aspect, the compound of the invention is administered in conjunction with a I CPAP device to promote sleep. In another aspect, the compound of the invention is administered in conjunction with a CPAP device to improve sleep. In another aspect, the compound of the invention is administered in conjunction with a CPAP device 10 improve compliance regarding with CPAP treatment. Without wishing to be bound by tiijeory, it is thought that by administering an effective amount of a sleep promoting compouijid of the invention to a subject in conjunction with CPAP treatment, the subject will slee] j better and more soundly and therefore, not be as likely to remove the mask. In one embodiment, the compound of the present invention is administered prior to the CPAP treatment. In another embodiment, the compound of the present invention is administered at substantially the same time as the CPAP treatment. In one embodiment, parallel administration of an effective amount of the compound is accomplished by adding an additional aerosol channel to the air pressure treatment portion of the CPAP device, thus administering the compound of the present invention in a nebulized form via the nasal or oral I! mask of the CPAP device. Alternatively, an effective amount of the compound |}an be added to the water or into the liquid reservoir that is typically part of the CPAP treatment device. ! Using the CPAP mask treatment, the compound of the invention is administered in a low concentration throughout the night, or at higher concentrations, as a bolus, at different time points in the beginning and during the course of the night. All publications and patent documents cited herein are incorporated herein by reference ! as if each such publication or document was specifically and individually indicated to be incorporated herein by reference. Citation of publications and patent documents |is not intended as an admission that any is pertinent prior art, nor does it constitute any admission as to the contents or date of the same. The invention having now been described by way of written description, those of skill in the art will recognize that the invention can ^|e practiced in a variety of embodiments and that the foregoing description and examples beloWJare for purposes of illustration and not limitation of the claims that follow. EXAMPLE 1: Synthesis of Loxapine Analogs The compounds of the invention, and related derivatives, can be synthesized by methods known to one skilled in the art. EXAMPLE 2: Sleep-Inducing Properties of Compounds of the Invention Sleep in mammals can be divided into sleep occurring during periods of r&pid eye movement (REM), accompanied by substantial brain activity, and periods of nor^REM (NREM) sleep, accompanied by decreased brain activity. Typically, a normal nighttime sleep period is occupied primarily by NREM sleep, and thus NREM cumulation can scjrve as a measure of total sleep cumulation, e.g., significantly decreased NREM can be associated with insomnia and an accumulation of "sleep debt", e.g., an accumulated physiological need for i j sleep that tends to persist until a sufficient amount of additional sleep is accumulated. Thus, an | ': increase in NREM associated with a treatment can indicate the treatment's effectiveness in treating insomnia. j, Sleep quality can be associated with sleep continuity or sleep maintenance. For j; example, a subject with sleep apnea wakes up numerous times during a sleep period, e.g., the j i subject has difficulty maintaining continuous sleep. Although such a subject can accumulate a typical nights length of sleep, e.g., 8 hours, the sleep is unrefreshing or non-restc^ative due to the waking caused by the sleep apnea. Thus, an increase in the longest uninterrupted sleep bout (LUSB, also known as longest sleep bout) associated with a treatment can indicate the treatment's effectiveness in enhancing sleep continuity, and therefore in treating sleep maintenance insomnia. Sleep-wakefulness, locomotor activity and body temperature are monitored in male Wistar rats treated with a test compound (i.e., loxapine analog) initially at a concentration of 10 mg/kg. Higher and lower doses are assayed for select compounds (e.g., as higty as 45 mg/kg, and as low as necessary to establish a no-effect dose). Treatments are administered at CT-18, the peak of the activity dominated period (6 hours after lights-off), and produce fcoporific (sleep-inducing) effects characterized by increased non-REM sleep time, increased sleep continuity, but without evidence of REM sleep inhibition or rebound insomnia. j:Sleep-wakefulness, locomotor activity and body temperature were monitored in vivo with certain of the disclosed sleep-inducing agents (e.g., compounds 1,2,3, 5, 6p 7, 8,9,10, 12,14,17,19,20,21,23,30,31, 32, 39,40,42,46,50, 51,52, 54, 56, and 58) zjftd other compounds listed in Table 1. Adult, male Wistar rats (250 g at time of surgery, I^harles River Laboratories, Wilmington MA) were anesthetized (2 % isoflourane in medical g jade oxygen) and surgically prepared with a cranial implant to permit chronic electro-encephalogram (EEG) and electromyogram (EMG) recording. Body temperature and locomotor activity were i, monitored via a miniature transmitter (Mini-Mitter, Bend, OR) surgically placed ;in the abdomen. The cranial implant consisted of stainless steel screws (two frontal (+3.2 AP from bregma, ±2.0 ML) and two occipital (-6.9 AP, ±5.5 ML)) for EEG recording. T^o Teflon®-coated stainless steel wires were positioned under the nuchal trapezoid muscles jji>r EMG recording. All leads were soldered to a miniature connector prior to surgery, and gas sterilized in ethylene oxide. The implant assembly was affixed to the skull with dental acrylic. A minimum of three weeks was allowed for surgical recovery. Each rat was permanently housed in its own individual recording cage located within separate, ventilated compartments of custom-designed stainless steel cabinets. Each cage was enhanced with a filter-top riser and low-torque swivel-commutator. Food and waiter were available ad libitum. A 24-hr light-dark cycle (12 hours light, 12 hours dark) wa^ maintained throughout the study. Animals were undisturbed for at least 48 hours before and after treatments. Sleep and wakefulness were determined using "SCQ/Ui-2000TMI'(Hypnion, \Vbrcester, MA) - an internet-based sleep-wake and physiological monitoring system. The System monitored amplified EEG (bandpass 1-30 Hz), integrated EMG (bandpass 10-10) Hz), body temperature and non-specific locomotor activity (LMA) via telemetry, and drinkihg activity, continuously and simultaneously. Arousal states were classified on-line as non-^EM (NREM) sleep, REM sleep, wake, or theta-dommated wake every 10 seconds. Total drinkiiig and locomotor activity counts, and body temperature were quantitiated and recorded each minute, using EEG feature extraction and pattern-matching algorithms. From this data, tile longest uninterrupted sleep bout (LUSB) was obtained. The classification algorithm usefl individually-taught EEG-arousal-state templates, plus EMG criteria to differentiate REM sleep from theta-dominated wakefulness, plus behavior-dependent contextual rules (e.g., if the anijmal was drinking, it is awake). Drinking and locomotor activity intensity (LMA) were recorded every 10 seconds, while body temperature was recorded each minute. Locomotor activity was detected by a telemetry receiver (Mini-Mitter) beneath the cage. Telemetry measures (LMA and body temperature) were not part of the scoring algorithm; thus, sleep-scoring and telemetry data were independent measures. Compounds were administered at CT-18, the peak of the activity-dominated period, j I sufficient time was allowed to view the time course of the treatment effect befor^ lights-on (6 hours post-treatment). Compounds were suspended in sterile 0.25% or 0.5% m^hylcellulose (1-2 ml/kg). Treatments were administered orally as a bolus. A parallel group study design was employed. Vehicle controls were drawn from a large | ; pool (N> 200): a subset of the pooled vehicle controls was selected, based on computerized matching with the 24-hour pre-treatment baseline of the active treatment group. The results of NREM and LUSB parameters were measured for the loxapine^ derivatives such as Compounds 1,2,3,5, 6,7,8, 9,10,12,14,17,19,20,21,23, 30,31, 32JJ 39,40,42, 46,50,51,52, 54,56, and 58 and other compounds listed in Table 1. Representative results are shown in Table 6. (Table Removed)The Irwin screen can provide useful information on potential side effects of i: ompounds on general physiological and behavioural functions. The screen is conducted by administering the test compounds orally in 0.25% aqueous methylcellulose using male Wistar rats a frequently used species in such studies and for which background data are readily available^ The Irwin screen tests for numerous parameters in animals that have been administered the test compound. For example, the screen can include: in-cage effects, e.g., dispersion, respiratory rate, locomotor activity, restlessness, fighting, alertness, apathy, and iixophthalmus; in-arena effects, e.g., transfer arousal, spatial locomotion, ptosis, startle, tail elevation, piloerection, touch escape, positional passivity, catalepsy, tighting reflex, visual placing, grip strength, pinna, comeal, pain response, and wire manoeuvre; parameters observe i in handling, e.g., cyanosis, cutaneous blood flow, hypothermia, body tone, pupil size, light-pi:ipil response, lacrimation, grooming, red staining, salivation, and provoked biting; general scoies e.g., fearfulness, irritability, abnormal gait, abnormal body carriage, tremors, twitches (, convulsions, bizarre behaviour, writhing, vocalisation, diarrhoea, number of defaecations, nui iber of 3 found in e procedure urinations, moribund, lethality, and abnormalities detected. Further details can t Irwin, S; Comprehensive observational assessment: I a. A systematic, quantitati for assessing the behavioural and physiological state of the mouse. Psychophan tacologia (Berl.) 13:222-257,1968, the entire teachings of which are incorporated herein >y reference. Irwin screening of the disclosed sleep-inducing agents are performed by Cov^ce (Princeton, NJ) according to Irwin, above; Covance Standard Operating Procedure (current revision of SOP PHARM 8.10); relevant regulatory authority guidelines ICH (International Committee for Harmonization) Guideline (Topic S7A; CPMP/ICH/539/00) on Safety Pharmacology Studies for human pharmaceuticals (November 2000); and all procedures | carried out on live animals are subject to the provisions of United Kingdom Lawj in particular ] the Animals (Scientific Procedures) Act, 1986. which obliges all UK laboratories to maintain a local ethical review process to ensure that all animal use in the establishment is Carefully considered and justified; that proper account is taken of all possibilities for reduction, refinement or replacement and that high standards of accommodation and care ajje achieved. All chemicals used are purchased from Colorcon, Ltd, Dartford Kent, UK unless otherwise noted and are of ACS reagent grade purity or higher. All test compound formulations are prepared on the day of dosing by Covance Harrogate Dispensary. The test comiounds are formulated in 0.25% aqueous methylcellulose at the highest concentration required. Lower doses are obtained by serial dilution of the highest concentration using 0.25% aqueous methylcellulose. Dose levels are expressed in terms of the amount of test compound administered without regard to purity or active content All formulations are stcjred at room temperature (nominally 10 to 30 °C) in sealed containers and protected from ligljt An adequate number of male Wistar (Crl:WI(Glx/BRl/Han) BR:WH) rats aije obtained from Charles River Ltd. (Margate, Kent, United Kingdom). The rats are approximately 5 weeks of age and weigh between 150 and 170 g on arrival. The animals are housed in groups of no more than six in polypropylene cages (33 x 15 x 13 cm) or (45 x 28 x 20 cc^i) with solid floors and Grade 10 woodflakes (Datesand Ltd., Cheshire, United Kingdom) as lidding. The cages are cleaned and dried before use. Aspen chew blocks are placed within th^ cages as a form of environmental enrichment. Routinely, holding rooms are maintained wiihin acceptable limits for temperature and relative humidity (nominally 19 to 25 °C sind 40% to 70%, respectively). These rooms are illuminated by fluorescent light for 12 houi js out of each i 24 hour cycle and designed to receive at least 15 fresh air changes per hour. Die^ j i (RM1 .(E).SQC. (Special Diets Services Ltd. Witham, United Kingdom) and walier from the j j mains tap supply are provided ad libitum (except during handling). These are roiitinely analysed for specific constituents and are not found to contain any biological or chemical entity which might interfere with the test system. On arrival, all animals are examined for ill-health. Animals are acclimatised for a period of at least 5 days. During this time, animals are identified by their cage labels. A veterinary examination is performed before the start of any experimental procedures to ensure their suitability for the study. Prior to the start of the study, I i animals are allocated randomly to treatment groups and individually tail-marked as they come to hand. At the end of the study, the animals are euthanized. Each animal receives a single oral administration of vehicle or test article, ustyig a constant dose of 1 mg/kg. Individual doses are based on individual body weights, obtainep on the day of dosing. The Irwin screen parameters above are systematically assessed in accordance with the relevant controls. In general, drug-induced changes, absent in normal animals, ate scored using increasing integers with '0' being normal (+/-, present/absent may also be tjsed). Parameters present in normal animals are scored using an integer that allows for increases and decreases to be recorded. Detailed observations are performed at 30,60,90,180 minutes post-dose. The animals are kept for a 7-day post-dose period during whfch time they are observed daily for gross signs of toxicity and mortality. EXAMPLE 4: hERG Side Effects of Disclosed Agents The cardiac potassium channel, hERG, is responsible for the rapid delayed rectifier current (ocr) in human ventricles. This channel has been selected for evaluation because: iihibition of Kris the most common cause of undesirable cardiac action potential prolongation by non-cardiac drugs. Increased action potential duration causes prolongation of the Ql interval that I has been associated with a dangerous ventricular arrhythmia, torsade depointes (Brown, AM; Ij Rampe, D. (2000). Drug-induced long QT syndrome: is,hERG the root of all evil?; and Pharmaceutical News 7,15-20; Rampe, D; Roy, ML; Dennis, A; Brown, AM. (lj>97), the entire teachings of which are incorporated herein by reference). hERG channels Were expressed in a human embryonic kidney (HEK293) cell line that lacks endogenous KT. Expression in a mammalian cell line is preferable to transient expression inXencpus oocytes because the latter shows a consistent 10-100 fold lower sensitivity to hERG channel blockers. I See also, for example: A mechanism for the pro-arrhythmic effects of cisapride ^propulsid): high affinity blockade of the human cardiac potassium channel hERG. FEBS Le^t- 417,28-32; Weirich, J; Antoni, H. (1998); Rate-dependence of anti-arrhythmic and pro-arrhythmic properties of class I and class IH anti-arrhythmic drugs. Basic Res Cardiol 93 Sujpl 1, 125-132; and Yap, YG; Camm, AJ. (1999); and Arrhythmogenic mechanisms of nonjsedating antihistamines. Clin. Exp. Allergy 29 Suppl 3,174-181. The entire teachings of l|he preceding articles are incorporated herein by reference. The in vitro effects of the disclosed sleep-inducing agents on the hERG (hunijan ether-a-go-go-related gene) channel current (KT, the rapidly activating, delayed rectifier cardiac potassium current) were determined by ChanTest (Cleveland, OH), according to Standard Operating Procedures of ChanTest. All chemicals used were purchased from Sigma (St. Louis, MO) unless otherwise noted and were of ACS reagent grade purity or higher. Stock solutions of test articles and terfenadine (positive control) were prepared using dimethyl sulfoxide (DMSO) and stored frJQzen. Test article and positive control concentrations were prepared by diluting stock solutions into a HEPES (N-[2-hydroxyethyl]piperazine-N'-[2-ethanesulfonic acid])-buffered physiological saline (HB-PS) solution (composition in mM): NaCl, 137; KC1,4.0; CaCl2,1.8; | i HEPES, 10; Glucose, 10; pH adjusted to 7.4 with NaOH (prepared weekly and jbfrigerated until use). Since previous results have shown that 0.3% DMSO does not affect channel current, all test and control solutions will contain 0.1% DMSO. If the final DMSO concentration must be greater than 0.3%, to reach a specified test article concentration, a separate vcihicle control test with an n > 2 was performed at the highest final DMSO concentration. Test &nd control solutions were prepared from stock solutions on a daily basis. Cells used were human embryonic epithelial kidney cells (HEK293; source strain, American Type Culture Collection, Manassas, VA; sub-strain, ChanTest, Cleveltod, OH), transformed with adenovirus 5 DNA and transfected with hERG cDNA. Stable I ransfectants were selected by coexpression with the G418-resistance gene incorporated into tl IB expression plasmid. Selection pressure was maintained by including G418 in the culture mi: dium. Cells were cultured in Dulbecco's Modified Eagle Medium / Nutrient Mixture F-12 (l^j-MEM/F-12) supplemented with 10% fetal bovine serum, 100 U/mL penicillin G sodium, 100 Mg/mL streptomycin sulfate and 500 [ig/mL G418. Data acquisition and analyses were performed using the suite of pCLAMP programs (Axon Instruments, CA). Steady state was a limiting constant rate of change with time linear time dependence) before and after test article application. The decrease in current amplitude upon reaching steady state was used to calculate the percent block relative to control. All experiments were performed at room temperature (18 °C -24 °C). Each c^ll acted as its own control. One concentration (10 \JM) of each test article was applied to cells expressing ' hERG (n £ 3, where n = the number cells). Duration of exposure to each concentration was limited to the time necessary to reach steady-state block, but no longer than 10 reputes. One concentration of the positive control article (60 nM terfenadine) was applied to tfyo cells (n £ 2). Cells were transferred to the recording chamber and superfused with HB-PS solution. Pipette solution for whole cell recordings were (composition in mM): potassium ^ispartate, 130; i ! Mg C12, 5; EGTA (ethylene glycol tetraacetate), 5; ATP(adenosine triphosphate) 1| 4; HEPES, 10; pH adjusted to 7.2 with KOH. Pipette solution was prepared in batches, aliqupted, stored frozen, and a fresh aliquot thawed each day. Patch pipettes were made from glass capillary tubing using a P-97 micropipette puller (Sutler Instruments, CA). A commercial patch clamp amplifier was used for whole cell recordings. Before digitization, current record^ were low-pass filtered at one-fifth of the sampling frequency. I Onset and steady state block of hERG current due to test article were measured using a pulse pattern with fixed amplitudes (depolarization: +20 mV for 2 s; repolarizatibn: -50 mV for 2 s) repeated at 10 s intervals, from a holding potential of-80 mV. Peak tail current was I measured during the 2 s step to -50 mV. A steady state was maintained for at leajst 30 seconds before applying test article or positive control. Peak tail currents were measured ^ntil a new steady state was achieved. Table 7 shows the % blocking of the hERG channel at the indicated concentrations for various disclosed sleep inducing agents. Typically, values of about 10% or less are regarded as desirable, values from about 12% to about 30% can be acceptable if the compound has strong sleep-inducing performance and no other significant side effects; and values greater than about 30% are regarded as undesirable. (Table Removed) Binding assays were performed using the disclosed sleep-inducing agents and derivatives selected from those listed in Table 1 in competitive binding assays with known standards for the HI histamine receptor, and the Ml, M2, and M3 muscarinic receptors, alpha 1 and alpha 2 receptors, and Dl and D2 receptors. The histamine HI assays are described in Chang, et al., Heterogeneity of Histamine Hi-Receptors: Species Variation in [3H]Mepyramine Binding of Brain Membranes. \Journal of Neurochemistry. 32: 1653-1663 (1979); Martinez-Mir, M.I., Pollard, H., Moreau, J., et al Three Histamine Receptors (Hi, H^ and HS) Visualized in the Brain of Human and Non-Human Primates. Brain Res. 526: 322-327 (1990); Haaksma, E.E.J., Leurs, R. and Tirnmerrnan, H. Histamine Receptors: Subclasses and Specific Ligands. Pharmac. Tlier. 47: 73^104 (1990). The muscarinic assays are described in Buckley, N.J., Bonner, T.I., Buckley, CM., and Brann, M.R. Antagonist Binding Properties of Five Cloned Muscarinic Receptors Expressed in CHO-Kl Cells. Mol. Pharmacol. 35: 469-476 (1989). The assays were performed according to the preceding articles, with the following modifications. Chemical reagents in the fallowing were obtained from Sigma, St Louis, MO. For the histamine HI assays, the receptors were obtained from bovine cerebejilar membrane tissue, with a B^ax (receptor number) of 6.2 femtomol/mg tissue (wet weight) an in 50 rnM Na-KPO4 (pH 7.5) at 25 °C for 60 minutes. The reaction was terminated by rapid . vacuum filtration onto glass fiber filters. Radioactivity from the displaced radioabtive ligand trapped onto the filters was determined and compared to control values in order tj> measure any interactions of the test compound with the histamine HI binding site. For the muscarinic assays, the receptors were obtained from human recombin^nt receptors expressed in CHO cells (PerkinElmer, Inc., Wellesley, MA). The radioactive ligand employed was [3H]-scopolamine, N-methyl chloride (80-100 Ci/mmol). (-)-Methylscopolaiiine bromide, 1.0 uM, was employed as the non-specific determinant, reference compound, and^ positive • control. After incubation, reactions were terminated by rapid vacuum filtration ^nto glass fiber filters. Radioactivity from the displaced radioactive ligand trapped onto the filters was determined and compared to control values in order to measure any interactions of the test compound with the respective receptor. For the Ml receptor assay, the Bmax (receptor number) was 4.2 picombl/mg protein, and the KD (binding affinity) of the receptor was 0.05 nM. The radioactive ligand was einployed at a final concentration 0.5 nM, while the (-)-methylscopolamine bromide had a Kj of 0.09 nM. The receptor and the radioactive ligand were combined with the test compound it a range of test compound concentrations from about 10"12 to about 10"5 M, incubated in Du^becco's Phosphate Buffered Saline (PBS) for 60 minutes at 25 °C, and worked up as described above. For the M2 receptor assay, the Bmax (receptor number) was 2.1 picomol/mg pjrotein, and the KD (binding affinity) of the receptor was 0.29 nM. The radioactive ligand was einployed at a final concentration 0.5 nM, while the (-)-methylscopolamine bromide had a K, of 0.3 nM. The I receptor and the radioactive ligand were combined with the test compound at a range of test compound concentrations from about 10"12 to about 10"5 M, incubated in DulbeccVs Phosphate Buffered Saline (PBS) for 60 minutes at 25 °C, and worked up as described above. For the M3 receptor assay, the Bmax (receptor number) was 4.0 picomol/mg protein, and the KD (binding affinity) of the receptor was 0.14 nM. The radioactive ligand was employed at a i final concentration 0.2 nM, while the (-)-methylscopolamine bromide had a Kj oJ^0.3 nM. The receptor and the radioactive ligand were combined with the test compound at a range of test compound concentrations from about 10"12 to about 10"5 M, incubated in 50 mM ITRIS-HC1 (pH 7.4) containing 10 mM MgCl2,1 mM EDTA for 60 minutes at 25 °C, and worked up as described above. Adenosine, purinergic AI binding assay was performed according to published procedures. See, e.g., Bruns, et al., Naunyn Schmiedebergs Arch. Pharmacol, 335(1): 59-63 (1987), with minor modifications; and Ferlany, et al. DrugDev. Res. 9: 85-93 (086). Adenosine, purinergic Aa binding assay was performed according to published procedures. See, e.g., Jarvis,ef al., J. Pharmacol. Exper. Tlier. 251(3): 888-93 (1989) with modifications; and Bruns, et al, Mol. Pharmacol. 29(4): 331-46 (1986) with modifications Dopamine, DI (human recombinant) binding assay was performed according to published procedures. See, e.g., Jarvie, etal.J. ReceptRes., 13(1-4): 573-90 (19$3); and Billard, etal Life Sciences, 35(18): 1885-93 (1984), with modifications Dopamine, DI (human recombinant) binding assay was performed according to published procedures. See, e.g., Jarvie, et al. J. ReceptRes., 13(1-4): 573-90 (1$>93); and Gundlach, et al. Life Sciences, 35(19): 1981-8 (1984) with modifications Binding to HI can be an indication of the desired sleep-inducing activity of the compound. Binding to muscarinic receptors shows non-specific binding, and caji indicate anti- _ cholinergic activity which can result in undesired side effects, e.g., the side effects of many known antihistamines, e.g., blurred vision, dry mouth, constipation, urinary problems, dizziness, anxiety, and the like. A decrease in the binding of the compounds to Table 8 shows the inhibition constant K, in nM for HI and the muscarinic receptors. It can be seen that the disclosed compounds are highly specific for HI over the muscarinic receptors. Thus, the disclosed compounds can be expected to exhibit good sleepj-inducing performance with limited side effects associated with muscarinic receptor inhibition. (Table Removed) The following pharmacokinetic parameters are computed from the individual plasma concentrations of the modified antihistamine compound using a noncompartmenial approach and appropriate validated pharmacokinetic software (e.g., WinNonlin Professional). Concentration values reported as BLQ are set to zero. If concentration data are available, interim calculations are done (non-QC.d data) between periods if possible. Dosq escalation does not depend on pharmacokinetic calculations. Descriptive statistics, including mean, standard deviation, coefficient of Variation, geometric mean, median, minimum and maximum are computed for each pharmacokinetic parameter by dose group. Descriptive statistics for natural-log transformed AUC(0-t), AUC(0-inf), and Cmax are provided for each dose level. In addition, mean and median concentration versus time graphs are provided. Dose proportionality following study medication is explored by analyzing; natural log-transformed pharmacokinetic variables AUC(O-t), AUC(O-inf), and Cmax with a linear model including the natural log-transformed dose as covariates. Dose proportionality is concluded if j the 95% confidence interval for the slope of the covariate includes the value of 1 . Dose linearity for AUC(O-t), AUC(0-inf), and Cmax is also explored by a linear modety See, e.g., Gibaldi and Perrier, Pharmacokinetics, Second Ed., Marcel Dekker: New York, New York (1982). Nominal sample collection times were used in calculations, except wher^ actual sampling times fell outside the protocol-specified acceptable time ranges. The following parameters were estimated: Maximum plasma concentration. Time to maximum concentration. were reported directly from the concentration-time data. Area under the plasma concentration-time curve from time 9 to the last . time point with measurable concentrations, estimated by linear Area under the plasma concentration-time curve extrapolated to infinity, calculated using the formula: Where Q is the last measurable concentration in plasma and "h is the terminal phase elimination rate constant estimated using lo^-linear I regression during the terminal elimination phase. The number of points used hi Xz calculation was determined by visual inspection of the data describing the terminal phase. At lest the last three time points with measurable values were used in Xz calculation. The mimber of points used n Xz calculation is based on the best correlation fo adjusted) obtained for the time points describing the terminjal elimination phase. A ii adjusted value for the regression Irjie is considered to accurately define the terminal elimination ph^se if the value is X).7. Elimination half-life, determined by In(2) Xz. Systemic clearance; for intravenous bolus or infusion, calculated using the formula: CL=Dose/AUCo-oo Report CL/F, where F= Absolute I bioavailability, for all other routes of administration. Volume of distribution for all routes of administration, calc ;ulated using the formula: Vz = CL X* CL/F is used to calculate V2/F fpr extravascular routes of administration. Pharmacokinetic analysis is performed using WinNonlin Professional Edition (Pharsight Corporation, Version 3.3 or 4.1). Descriptive statistics such as mean and standard deviation are calculated in Microsoft Excel (Version 8.0e). Metabolism of test articles in monkey and human cryopreserved hepatocj tes was assayed as follows: (Table Removed) Pre-Incubation Preparation: Sample is diluted with DMSO, to prepare 100 uM and 10 uM stocks. 0.1% formic acid (store RT for in acetonitrile is prepared by the addition of 1 mL formic acid per 1L acetonitril 3 months). 10 minute, 60 and 120 minute 96 well quenching plates are prepared with 150 uL acetonitrile + 0.1% formic acid in each well. Store on ice or refrigerated. Next, hepatocytes are thawed and lOOuL of cell suspension is placed int^ a microfuge I tube with 100 uL 0.4% Trypan Blue solution and gently mix by inversion. A snkall amount of the stained cell suspension (approximately 15 uL) is placed into a clean hemacytometer with a coverslip. The hemacytometer is placed onto the stage of the microscope and the focus and power are adjusted until a single counting square fills the field. The number of (iells in the four i outside comer subdivided squares of the hemacytometer are counted. Viable ce] Is are opalescent, round, and pale with a darker outline. Non-viable cells are dark, ops que blue. The % viability is calculated as the number of viable cells divided by thd total of cells X 100. The v/able cell density and total number of viable cells are calculated: Ffable cell Density (D) = Mean 3 of v/able cells counted (C) x104x c; Total number of viable cells (E) = D x 26 (resuspension volume). The additional media required to achieve a concentration of 1 x 106 cells/mL is calculated: Volume of additional medium = total viable cells (E) -26 mL 1 x 106 Cells are diluted accordingly and stored at room temperature. Incubations 198 uL of hepatocytes are transferred to relevant wells on dosing plate. ^The remaining hepatocyte suspension is combined and placed in a suitable container of near boiling water and left for 5 minutes to inactivate the cells (for inactive controls and standard curve preparation). 198 uL of inactive hepatocytes are transferred to control wells and 198 uJL of blank media are transferred to buffer control wells. Plates are preincubated for at least 15 min. Reactions are started 2 uL of appropriate test compound dilution from dosing plate. Plates are incubated in an incubator set at 37 °C for approximately 10 minutes, then 50 uL pf incubate is removed to 10 a minute quenching plate containing 150 uL acetonitrile + 0.1% formic acid and stored refrigerated or on ice. Following 60 minutes, 50 uL of incubate is removed to 60 minute quenching plate containing 150 uL acetonitrile + 0.1% formic acid and sjored refrigerated or on ice. Following 120 minutes, 50 uL of incubate is removed to 1^0 minute quenching plate containing 150 uL acetonitrile + 0.1% formic acid and stored refrigerated or on ice. The remaining 50 uL is frozen in incubation plates. Tubes are then centrifuged at ~4°C at -1400 x g for -10 minutes. 100 uL of supernatant is diluted with 100 uL watej- in analysis plates, plates are stored frozen at -20°C prior to analysis. i Preparation of Standard Curves 0.1 uM standard is prepared by the addition of 2 uL of 10 uM dosing solutions to 198 uL of inactive hepatocytes in standard prep plate. 150 uL acetonitrile + 0.1% forflric acid is added to the standard quenching plate. 150 uL of 0.1 uM standard is transferred into one column of a standard plate. 75 pL inactive hepatocytes is added to remaining we Is. 75 uL from 0.1 uM standard is transferred into adjacent well in column in the plate, and mixed well by titration. Serial dilution is continued. 75 uL is removed from final standard (ill wells contain 75 uL). Plates are incubated at approximately 37 °C for 10 minutes. 50 ^L is transferred into standard quench plate containing 150 uL acetonitrile + 0.1% fornkic acid. Plates are centrifuged along with samples and dilute supernatant 1:1 with water ajs above. Samples are stored frozen at ~-20 °C. . For compound 5, the hepatocytes remaining 120 minutes after treatment it 1 jam, was 75.105 for primate and 90.405 for human. EXAMPLE 7: Clinical Evaluation of Loxapine Analogs i The goal of a human clinical trial is to collect data on the effects of loxapjbtie _ derivatives. Such data includes, for example, clinical signs and symptoms from physical exam, adverse events, laboratory safety (e.g., hematology, serum clinical chemisjry, urinalysis), vital signs (e.g., blood pressure, heart rate, temperature, respiratory r$te), and electrocardiogram (ECG) data. The clinical trials are conducted as follows: I. Subject Selection A minimum of 18 subjects are used (2 enrollment groups of 9 subjects eajch). Subject candidates fulfilling the following inclusion criteria are eligible for participation in the study: • Healthy adult male subjects, 18-45 years of age. • Weighing at least 60 kg and within 15% of their ideal weights (see Table of Desirable Weights of Adults, Metropolitan Life Insurance Company, 1983). • Medically healthy subjects with clinically insignificant screening results (e.g., laboratory profiles, medical histories, EGGS, physical exam). Subject candidates fulfilling one of the following exclusion criteria are ineligible for participation in the study: • History or presence of significant cardiovascular, pulmonary, hepatic, renal, hematologic, gastrointestinal, endocrine, immunologic, dermatolgic, neurologic, or psychiatric disease. • History or presence of sleep disorders. • History of chronic or seasonal allergies requiring treatment with Hi receptor antagonists (i.e., terfenadine, astemizole) within the 90 days prior to the study. • History or presence of alcoholism or drug abuse within the past 2 years. • Tobacco or nicotine use within the 90 days prior to the study. j • Known hypersensitivity or idiosyncratic reaction to the study drug, possible excipients of the study formulation (Captisol®; sodium saccharin^ F.C.C.; glycerin, U.S.P.; orange flavor; methylcellulose 400 centipoise, TJ.S.P.; opurified water), or related compounds. • Donation (standard donation amount or more) of blood or blood products within 90 days prior to the study. • Participation in another clinical trial within 90 days prior to the fi^st dose. • History or presence of any disease, medical condition, or surgery, which may have an effect on drug absorption, metabolism, distribution, or excretion. • Weight loss or gain (±10%) within 3 0 days prior to the study. j • Regular consumption of (e.g., more days than not) excessive quantities of caffeine-containing beverages (e.g., more than 5 cups of coffee or equivalent per day) within 30 days prior to the study. • Any condition that, in the opinion of the Investigator or Sponsor makes the subject unsuitable for the study. [ • • Use of any prohibited prior or concomitant medications. Each subject who completes the study screening assessments, meets all eligibility criteria, and is accepted for the study is assigned a unique identification number and receives designated doses of the modified antihistamine and placebo according to a randomization scheme. The randomization scheme is available only to the clinic phannacy staff preparing the drug (who are not involved in the administration of the drug) and is not made available to the subjects, analysts, or members of the staff responsible for the monitoring and evaluation of the adverse experiences. Subjects may be withdrawn from the study by the Principal Investigator fpr the following reasons: • Secondary occurrence of a major exclusion criteria. • To protect their health. • Adverse events. • Difficulties in blood collection. • To protect the integrity of the study. • Protocol violation. • Failure to comply with study directions. The clinical report includes reasons for subject withdrawals as well as details relevant to withdrawal. Subjects withdrawn from the trial prior to study completion undergo all procedures scheduled for study completion. Subjects withdrawn due to any adverse event (whether serious or non-serious) or clinically significant abnormal laboratory testj values are evaluated by the Investigator, or a monitoring physician, and are treated and/or followed up until the symptoms or values return to normal or acceptable levels, as judged by the Investigator. K Study Restrictions Subjects do not take prescription or over-the-counter medication (including herbal products) during the 7 days preceding the study until the final sample of the final pharmacokinetic sampling period has been collected. Additionally, consumption of foods and beverages containing the following substances is prohibited as indicated: • Methylxantbine: 72 hours before each dosing and throughout the period of sample collection, i.e., caffeine beverages and equivalents (e.g., chocolate bars) are prohibited. i • Alcohol: 72 hours before each dosing and throughout the period 0f sample collection. All medications taken during the 30 days prior to study start are recorded] Any medications taken for chronic or seasonal allergies in the 90 days prior to the study is recorded. Pre-Study Subject Screening: The Informed Consent Form is administered at screening. Within 14 days prior to dosing, medical history and demographic data, including name, sex, age, race, body weight (kg), height (cm), alcohol use, and tobacco usd are recorded. Each subject receives a physical examination including complete vital signs, 12-lead EGG, and laboratory tests as specified. The laboratory tests include the following: a) Hematology including hemoglobin, MCV, red blood cell count, ijematocrit, I MCHC, white blood cell count with differential platelet count and MCH; ;reatinine, b) Serum Chemistry including bun, albumin, ALT (SGOT), alkaline phosphatase, glucose, total bilirubin, creatine phosphokinase (CPK), sodium, uric acid, AST (SGOT) and triglycerides; c) Urinalysis including appearance and color, glucose, nitrite, pH, k^tones, urobilinogen, specific gravity, bilirubin, leukocytes, protein and blood; d) Additional Tests including HIV, urine drug screen, HbsAg, cann^binoids, HCV, benzodiasepines, HCV, amphetamines, hepatitis A (IgM), opiates^ alcohol, cocaine, and contmine. Subject Management: Subjects are housed from at least 36 hours before dosing until completion of the 24-hour postdose events. They will return for a follow-up visit one week following the final dose or upon early withdrawal. Subjects remain semi-recumbent in bed for the first 4 hours following administration. However, should adverse events occur at any time, subjects are placed in an appropriate position or are permitted to lie down on their right side. Subjects do not engage in strenuous activity at any time during the confinement period. Standard meals are provided on Day 1 and Day 2. On Day 1, subjects ar£ required to fast for a minimum of 10 hours overnight before dosing and for at least 4 hours thereafter. However, if the option for a previous dose in the fed state is used in Period 3 of Group 2, a j standard high-fat meal is given 30 minutes prior to dose. In this case, the high-fat breakfast (i.e., approximately 50% of calories from fat) consists of two eggs fried in butteij, two strips of bacon, two slices of buttered toast, four ounces of hash brown potatoes, and eight ounces of whole milk. Foods and beverages containing caffeine or equivalent (e.g., chocolate bars) are j prohibited during confinement. Water is not permitted from 2 hours before until 2 hours after dosing. W&ter is allowed at all other times. Standard meals are provided at approximately 4 and 9 hours aifter dosing, and at appropriate times thereafter. IH. Drug Administration Subjects receive the dose for each period as assigned according to the randomization schedule for dosing sequence for each dose (enrollment) group. Subjects receivft the assigned dose in a glass dosing cup, and within each dose group, all doses, active and placebo, are administered at the same volume to maintain the double-blind. Subjects are instructed to swallow the dose. A total of 240 mL of water is given with dosing. A designated portion of the water (assigned by pharmacist based on dosing volume) is added to the emptied dosing cup, swirled to rinse, and swallowed by the subject. This process is repeated twice and then ttye remainder of the water is consumed by the subject. The starting dose for the first human dose level is based on the toxicity afld safety profiles in the precluded studies. The equivalent body jsurface area conversion from human to rat is 1/6 (Toxicological Handbook, Michael J. Dereleko, CRC .press, Boca [Raton, FL). Based on NOAEL of 30 mg/kg/day for rat and body surface equivalent criteria, the equivalent dose in an individual of 60 kg is 300 mg/day (1/6 x 30 mg/kg/day [rat NOAEL] jj. 60 kg). Based on NOAEL dose in rat (30 mg/kg/day), the dose of 3 mg is approximately 1/10 of the NOAEL dose in rats. The highest dose proposed of 160 mg is also below the N0AEL in rats. If a dose limiting toxicity (Grade 3 or 4 according to the grade scale modified from the WHO Common Toxicity Criteria - Appendix I) deemed to be related to the study medication is observed in any 2 of the 6 subjects at any dose level, dose escalations are stopped, and the prior dose is considered the maximum tolerated dose (MTD). If one subject at any dose level experiences a dose limiting toxicity, the Principal Investigator (in consultation with the Sponsor) decides, using good clinical judgment, whether to proceed to the next dose level as planned, or to adjust the next dose level downward from the dose planned. This consultation is done for all groups following the previous^ dose group to decide whether to proceed with planned doses or to adjust doses downward. Additionally, the planned doses may be substituted with intermediate doses if emerging safety or tjolerability issues become apparent (i.e., there does not have to be a Grade 3 or 4 event) from the preceding dose that suggests the need to escalate more slowly. Dose increments is only permitted if, in the opinion of the Principal Investigator, adequate safety and tolerability have been demonstrated at the previous lower d0se. In all cases, the Principal Investigator uses good clinical judgment to decide whether to adjust the dose or to stop the study based on an assessment of all factors relevant to the safety of the subjects. The Principal Investigator reviews check-in data (eg., physical examination results, vital signs, questionnaire, and clinical laboratory results (e.g., serum chemistry, hematology, urinalysis, and urine drug screen)) for clinically significant changes since screening or the previous period. The Principal Investigator determines if the subject will be dosjed or withdrawn for the study based on this review. IV. Clinical Observation A hematology panel, a serum chemistry panel and a urinalysis is performed at screening, at each check-in, 24 hours following each dose, and one week following the final dose, or upon early withdrawal. Blood samples (approximately 7 mL) are collected from an indwelling intravenous catheter into evacuated glass tubes containing sodium heparin predose and at 0.25,0.5, 0.75,1.0,1.5,2,3,4, 6,8,10,12,18, and 24 hours postdose. Urine samples are collected predose and during the 0-8 hour interval each period. Samples collected during the interval are not pooled. Each void is considered a sample. The voiding timejs are at will, not scheduled (with the exception of the predose void and the void at the end of tjhe 8 hour interval). Vital signs are measured during the screenings. When the time of vital signs coincides with an EGG only, the vital signs are taken 10 minutes prior to the ECG. When i)he time of vital signs coincides with a blood draw or a blood draw and ECG, the vital signs ^ire taken 10 minutes prior to the blood draw. Respirations and temperature is monitored at ch^eck-in, 24 hours following each dose, and one week following the final dose, or upon early Withdrawal. Single measurements of blood pressure and heart rate are taken after a minimum of 5 minutes in a semi-recumbent position. Measurements taken during study confinement are monitored with an AVS machine at check-in; 0 (predose); 0.25,0.5,0.75,1,1.5,2,3,4,6, 8,10,12,18, and 24 hours postdose; and one week following the final dose, or upon early withjdrawal. For any heart rate measurement greater than 100 beats per minute, the heart rate will te rechecked two minutes later. On Day 1, at approximately 24 hours prior to dosing, 3 measurements of blood pressure and heart rate, taken 2 minutes apart, are taken as described as described above. A standard 12-lead ECG is performed for each subject at screening, on D^y 1 at times I coinciding with Day 1 times of 1 hours prior to dose and 1,1.5,2,3,4, and 6 houjrs postdose; on Day 1 at 1 hour predose and 1,1.5,2,3,4,6, and 24 hours postdose; and one AJveek following the final dose or upon early withdrawal. Additional ECGs may be performed at other times if deemed necessary. All standard 12-lead ECGs are recorded for 10 Seconds. Timing and registration technique for ECGs is standardized for all subjects. Subjects should be lying down for at least 1 minute prior to each 12-lead ECG evaluation. The Principal Investigator evaluates PR, QRS, QT, and QTc intervals. When the time of ECGs Coincides with a blood draw, the ECG will be taken following the draw. A physician examines each subject at screening, each check-in, 24 hours following each dose, and one week following the final dose, or upon early withdrawal. Additional examinations are performed at other times if deemed necessary. Immediately before vital signs measurements 1 hour predose and at 1,2, $, and 24 hours postdose (the vital signs are taken 10 minutes prior to the blood draw designated at these i times), subjects are presented a visual analogue scale and asked to draw a vertical mark across a 100 mm line at the point ranging between Very Sleepy and Alert/Wide Awake, which best describes their level of alertness at that time. The subjects are instructed to inform the study physician or staff of any adverse events or intercurrent illnesses experienced during the trial. Additionally, a specific inquiry regarding adverse events is conducted prior to dosing, at 2,4, 8, and 24 hours postdose, an4 one week j following the final dose, or upon early withdrawal. Questions are posed in a nonfspecific manner so as not to bias the response. Any subject who has any adverse event (whether serious or non-serious) 4>r clinically significant abnormal laboratory test values is evaluated by the Investigator, or a monitoring physician, and is treated and/or followed up until the symptoms or values return to normal or acceptable levels, as judged by the Investigator. A physician, either on-site or at a nearby hospital emergency room, administers treatment of any serious adverse events. Where appropriate, medical tests and examinations are performed to document resolution of event(s). Outcome is classified asre.g., resolved, improved, unchanged, worse, fatal, or urjknown (lost to follow-up). V. Reporting All adverse events occurring during the clinical trial are recorded. Adveijse events are coded using MedDRA (version 4.1). An adverse event/experience (AE) is any unwarranted medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product that does not necessarily have a causal relationship with this treatment (iCH/WHO). An adverse event (AE) is, therefore, any unfavorable and unintended sign, (including, for example, an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medical product, whether or not considered related to the medical product (ICH/WHO). The Investigator reviews each event and assesses its relationship to drug treatment (i.e., unrelated, unlikely, possibly, probably, almost certainly). Each sign or symptom reported is graded on a 3-point severity scale (mild, moderate, or severe) and the date and time of onset, time relationship to drug dosing, duration, and outcome of each event is noted. "[The following definitions for rating severity are used: (1) Mild: The adverse event is easily tolerated and does not interfere with daily activity; (2) Moderate: The adverse event interferes with daily activity, but the subject is still able to function; (3) Severe: The adverse event is] incapacitating i and requires medical intervention. If any of the above adverse events are serious, special procedures are followed. All serious adverse events are reported to the Sponsor within 24 hours and followed by written reports within 48 hours, whether or not the serious events are deemed drug-related. A Serious Adverse Event (SAE) is any untoward medical occurrence tha{, at any dose, i results in death, is life-threatening, results in permanently disability or incapacitation, requires inpatient hospitalization, prolongs inpatient hospitalization, is a congenital anomaly, may jeopardize the subject or may require intervention to prevent one or more of the other outcomes listed above. VI. Pharmacokinetics I The following pharmacokinetic parameters are computed from the individual plasma concentrations of the modified antihistamine compound using a noncompartmental approach and appropriate validated pharmacokinetic software (e.g., WinNonlin Professional). Concentration values reported as BLQ are set to zero. If concentration data are available, interim calculations are done (non-QC.d data) between periods if possible. Dose escalation does not depend on pharmacokinetic calculations. Descriptive statistics, including mean, standard deviation, coefficient of variation, geometric mean, median, minimum and maximum are computed for each pharmacokinetic parameter by dose group. Descriptive statistics for natural-log transformed AUC(0-t), AUC(0-inf), and Cmax are provided for each dose level. In addition, mean and median concentration versus time graphs are provided. Dose proportionality following study medication is explored by analyzing natural log-transformed pharmacokinetic variables AUC(O-t), AUC(O-ini), and Cmax with a jinear model including the natural log-transformed dose as covariates. Dose proportionality is Concluded if the 95% confidence interval for the slope of the covariate includes the value of 1. Dose linearity for AUC(O-t), AUC(0-inf), and Cmax is also explored by a linear model. VII. Assessment of Safety A by-subject treatment-emergent adverse event data listing including verbatim term, preferred term, treatment, severity, and relationship to treatment is provided. The number of subjects experiencing adverse events and number of adverse events is summarized by dose level using frequency counts. Safety data including laboratory evaluations and vital signs assessments is summarized by dose level and time point of collection. Descriptive statistics are calculated for quantitative safety data and frequency counts are compiled for classification of qualitative saf itydata. In addition, a mean change from baseline table is provided for vital signs and a shift table describing out of normal range shifts is provided for clinical laboratory results. . i ECG results are classified as normal and abnormal and summarized using^ frequency counts by dose group and time point of collection. Descriptive statistics are calculated for PR, QRS, QT, and QTc intervals. Changes in physical exams are described in the text of the final report. Heart rate data are summarized by treatment group and time point using descriptive statistics, as will individual change from baseline values. Mean change from baseline results are used to compare active dose groups to placebo at each time point. Data from six completed subjects per dose level should provide 80% certainty to detect a difference of 20 peats per minute. An interim analysis is completed following each period. VTEL. Assessment of Efficacy VAS sedation scores are summarized by time point of collection for each dose level using descriptive statistics. EXAMPLE 8: Preclinical Evaluation of Loxapine Analogs i i Prior to human clinical testing of compounds, pre-clinical testing is perfobned. Preclinical evaluation includes the following tests: i. Preclinical Absorption, Distribution, Metabolism and Excretion The compound is administered to rats, dogs, and cynomolgus monkeys at a dose of approximately 3 mg/kg orally and intravenously. Plasma samples were collected from all species for pharmacokhietic analysis. The Tmax and half life (in hours) is measured in the rat, dog, and monkey. Percent protein bound in rat and human plasma is also measured. The brains are collected from rats after oral administration to determine biain levels of the parent drug. Cytochrome P450 inhibition is studied in vitro. In addition, the in vitro rate of metabolism in rat, dog, monkey, and human hepatocyte cultures is determined for each compound. z'z. Cardiac Effects Focus The primary lexicological issue studied during the clinical candidate selection phase of the project is QT interval prolongation. Historically, HI antagonists have been associated with this effect. QT prolongation in rare instances can evolve into life-threatening cardiac arrhythmias. The best in vitro test to predict the likelihood of a compound causing QT prolongation, the hERG binding assay, was the test system chosen to study the potential of a compound to produce this effect. The human hERG channel, transfected to a stable cell line, is studied electrophysiologically and the percent inhibition of the channel current is reported. To determine if a compound can produce any changes in QT interval, the compound is studied in telemetered Beagle dogs. Dogs are implanted with devices to continuously monitor EGG and arterial blood pressure. Dogs (groups of 4) are studied in a Latin square cross-over design, with each dog receiving 3 different doses and a placebo. Two studies are conducted with doses of 0.3,1,3,10, and 30 mg/kg. in. Acute Rat Study The purpose of this study is to evaluate the toxicity and maximum tolerated dose (MTD) of the test articles when given via oral gavage to rats. Male Crl: CD®(SIJ>)IGS BR rats (3/grbup) are assigned to 5 groups. At initiation of dosing, animals are approximately 7 weeks old with body weights ranging from 172 to 206 g. Each group receives either 50,j 100,150, 200, or 250 mg/kg of the compound once daily for 5 days. All surviving animals are sacrificed on Day 6. Assessment of toxicity is based on mortality, clinical observations, an(jl body weight data. iv. Acute Dog Study The purpose of this study is to evaluate the toxicity and the maximum-tolerated dose (MTD) of the compound when given at escalating doses via oral gavage to dogs. Two male purebred Beagles are assigned to the study. At initiation of dosing, animals are at least 6 months old with body weights ranging from 8.0 to 10.9 kg. Dogs receive dose preparations containing the compound once daily for 5 days in escalating doses of 25, 50, or 7$ mg/kg. The dogs are observed at 0.25, 0.5,0.75,1.0,1.5, and 2.0 hours ± 5 minutes and 4, 6, 8, and 24 hours ±15 minutes postdose. They are weighed on Days 1 and 6. Electrocardiograms are performed and blood pressures are taken prior to dosing and at 1,4, and 24 hours after the 40 mg/kg dose on Day 5. Based on the range and severity of the clinical signs observed, the MTD is calculated for the compound. v. 14-Day Rat Study with Recovery Study The purpose of this study is to evaluate the toxicity of the compound when administered via oral gavage to rats for at least 14 days and to assess the reversibility, persistence, or delayed occurrence of any effects after a recovery period of up to 14 days. Male and female Crl:CD®(SD)IGS BR rats are assigned to seven groups[ four main study groups and three groups for toxicokinetics. Each group receives dose preparations containing 0.25% methylcellulose, 400 cps in 200 mM acetate buffer, or 10,30, o^r 150 mg of test article/kg of body weight (mg/kg/day) at a dose volume of 5 mL/kg. Assessment of toxicity is based on mortality, clinical and ophthalmic observations, body weights, food consumption, clinical pathology, organ weights, and macroscopic and microscopic findings. Blood samples are collected for toxicokinetic evaluation. 14-Day Dog Study with Recovery Phase The toxicity and the toxicokinetics of a compound of the invention when administered daily via oral gavage (Phase 1) or capsules (Phase 2) to dogs for at least 14 days ijs determined. The reversibility, persistence, or delayed occurrence of observable effects following a 7-day (Phase 1) or 14-day (Phase 2) recovery period is also assessed. Doses of 3,10,3Q; and 70 mg/kg/day are studied. All Phase 1 and 2 dogs survived until scheduled sacrifice. The above compounds and protocols are useful in the pre-clinical evaluation of loxapine compounds of the invention. | EXAMPLE 9: Evaluation of Analgesic Activity The analgesic activity of a loxapine analog following oral administratiori is analyzed. Analgesic activity is assessed by abdominal spasm tests in the rat and mouse. Analgesic activity is also assessed using the tail clip test in the mouse, tail flick test in thi rat, Randall-Selitto test in the rat and comparisons are made with a vehicle control £roup. Reference compounds ASA (acetylsalicylic acid) and morphine are also included for comparison. The tail clip and tail flick test provide useful information about the central analgesic activity of the test article. The Randall-Selitto test provides information on the Compound's ability to modify a hyperalgesic state and the abdominal spasm test provides information on the peripheral analgesic activity of the test article. The test article is administered by oral gavage, this being the intended clinical route of administration. The dose levels employed are expected to encompass the efficacy dose and provide an adequate safety margin. Test article, reference compound and irritant formulation All formulations are prepared on each day of dosing. The test article is formulated in 0.25% (w/v) MC at the highest concentration required. Lower doses are obtainbd by serial dilution of the highest concentration using 0.25% (w/v) MC. The reference compound, acetylsalicylic acid, is formulated in 0.25% (w/v) MC at the required concentrations. Brewer's yeast is formulated in water for injection at the required concentration. Acetic acid is diluted with water for injection to provide the required concentration for administration. Dose levels will be expressed in terms of the amount of test article I reference compound/irritant administered without regard to purity or active content. i Animals An adequate number of male Crl:CD-I(ICR)BR mice and Wistar rats are obtained from Charles River (UK) Ltd., Margate, Kent. The mice are approximately 4 wfeeks of age and weigh between 18 and 22 g on arrival. The rats are approximately 5 weeks jof age and weigh between 150 and 170 g on arrival. The age and weight of the animals at tjhe start of the study is documented in the raw data and final report. The animals are housed in groups appropriate to the size of caging used, in cages that conform to the Code of Practice for the housing and care of animals used in the Scientific Procedures Act (Home Office Animals Scientific Procedures Act 1986). Bedding is provided on a weekly basis to each cage by use of clean Aspen wood chips (Dates and Ltd, Manchester, UK). The bedding is analyzed for specific contaminants and the results retained on file at Covance. The cages are cleaned and dried before use. Aspen chew blocks are placed within the cages as a form of environmental enrichment. Routinely, holding rooms are maintained within acceptable limits for temperature and relative humidity (i^ominally 19 to 25 °C and 40 to 70%, respectively). These rooms are illuminated by fluorescent light for 1.2 hours out of each 24 hour cycle and designed to receive at least 15 fresh air changes per hour. RM1.(E).SQC., (Special Diets Services Ltd., Witham, UK) and water frj>m the mains tap supply will be provided ad libitum, except where specified below. These are routinely analyzed for specific constituents and are not known to contain any biological pr chemical entity which might interfere with the test system. The treatment groups employed for the study are as shown in Table 9: (Table Removed) (Table Removed) Measurements of pressure is taken from the left and right hind paws of each animal immediately prior to administration of vehicle, test article or reference compound and at 30, 60,120 and 240 minutes post-oral administration. The order of the pressure measurements is left paw followed by right paw. Abdominal Spasm Test in the Rat Each animal receives a single administration of vehicle, test article or reference compound by oral gavage, using a constant dose volume lOmg/kg. Individual pose volumes are based on individual body weights obtained on the day of dosing. The treatment groups are shown in Table 10. Table 10 Treatment Groups. (Table Removed) Forty-five minutes following oral administration each animal receives a1 ImL intraperitoneal injection of 1% acetic acid. Animals are immediately placed into individual observation chambers and the number of abdominal spasms elicited over the subsequent 25-minute period is recorded. Abdominal Spasm Test in the Mouse I Each animal receives a single administration of vehicle, test article or reference compound by oral gavage, using a constant dose volume lOmL/kg. Individual (Table Removed) Forty-five minutes following oral administration each animal receives a p.25mL intraperitoneal injection of 0.5% acetic acid. Animals are immediately placed i^ito individual observation chambers and the number of abdominal spasms elicited over the subsequent 25-minute period is recorded. Terminal Procedures At the end of each test, the animals are humanely killed by a Schedule 1 (e.g.e.g., exposure to carbon dioxide gas in a rising concentration followed by dislocation of the neck) and discarded without necropsy. If an animal showed any sign of serious j discomfort during the study it is sacrificed immediately and humanely. Any anitnal found dead or killed prematurely during the study is subjected to a necropsy. A macroscopic examination is performed, after opening the thoracic and abdominal cavities, by observing the appearance of the tissues in situ. Any abnormalities are recorded. EXAMPLE 10: Synthesis of Acylsulfonamides The synthesis of acylsulfonamide Compound 40 is summarized in Scheme I. This procedure is applicable as a general synthesis of acylsulfonamides from the corresponding ac»ds described herein. (Table Removed) The treatment of tricyclic 10H-Dibenzo[b,f][l,4]oxazepin-l 1-one (3) with phosphorous oxychloride in the presence of NJN-dimethylaniline in toluene provided imidoyl chloride(4), which was converted to 1 l-Piperazm-l-yl-dibenzo[b,f] [l,4]oxazepine (5) upon •reaction with excess piperazine. Reductive amination of the tricyclic amidine (5f) with 2- carbomethoxy 2-methyl propionaldehyde gave alkylated piperazine (6), which as purified over silica gel. Basic hydrolysis of the methyl ester of 5 in aqueous ethanol followed by acidification gave the carboxylic acid (7). The carboxylic acid (7) was converted to the acyl methyl sulfonamide by coupling with methane sulfonamide using the water-solufble carbodiimide, EDCI in dichloromethane with dimethylamino pyridine as a catalyst. Acidification of the coupling product gave the desired acylsulfonamide Compound 40 (HY-10427) as the bis-HCl salt. Other Embodiments While the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects advantages, and modifications are within the scope of the following claims. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims WE CLAIM: 1. A compound having the formula: (Formula Removed) or a pharmaceutically acceptable salt thereof. 2. The compound as claimed in claim 1, wherein the compound is a pharmaceutically acceptable salt. 3. The compound as claimed in claim 2, wherein the salt is an acid addition salt. 4. The compound as claimed in claim 3, wherein the salt is a hydrochloride salt. 5. The compound as claimed in claim 4, wherein the compound is: (Formula Removed) 6. A compound comprising a compound of the formula: (Formula Removed) or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. 7. The composition as claimed in claim 6, wherein the compound is a pharmaceutically acceptable salt. 8. The composition as claimed in claim 7, wherein the slat is an acid addition salt. 9. The composition as claimed in claim 8, wherein the salt is a hydrochloride salt. 10. The pharmaceutical composition as claimed in claim 9, wherein the composition is: (Formula Removed) 11. A compound of the formula: (Formula Removed) or a pharmaceutically acceptable salt thereof. 12. The compound as claimed in claim 11, wherein the salt is an acid addition salt. 13. The compound as claimed in claim 12, wherein the salt is a hydrochloride salt. 14. The salt as claimed in claim 13, wherein the salt is: (Formula Removed)

Documents:

2976-delnp-2007-Abstract-(21-11-2013).pdf

2976-delnp-2007-Abstract-(31-05-2013).pdf

2976-delnp-2007-abstract.pdf

2976-DELNP-2007-Claims-(19-09-2008).pdf

2976-delnp-2007-Claims-(21-11-2013).pdf

2976-delnp-2007-Claims-(28-10-2010).pdf

2976-delnp-2007-Claims-(31-05-2013).pdf

2976-delnp-2007-claims.pdf

2976-DELNP-2007-Correspondence Others-(10-05-2011).pdf

2976-delnp-2007-Correspondence Others-(17-10-2013).pdf

2976-delnp-2007-Correspondence Others-(23-10-2013).pdf

2976-delnp-2007-Correspondence Others-(28-10-2013).pdf

2976-DELNP-2007-Correspondence Others-(29-06-2012).pdf

2976-delnp-2007-Correspondence-Others-(03-03-2014).pdf

2976-DELNP-2007-Correspondence-Others-(08-05-2009).pdf

2976-DELNP-2007-Correspondence-Others-(19-04-2011).pdf

2976-DELNP-2007-Correspondence-Others-(19-09-2008).pdf

2976-delnp-2007-Correspondence-Others-(21-11-2013).pdf

2976-delnp-2007-Correspondence-Others-(28-10-2010).pdf

2976-delnp-2007-Correspondence-Others-(31-05-2013).pdf

2976-delnp-2007-correspondence-others.pdf

2976-delnp-2007-description (complete).pdf

2976-DELNP-2007-Form-1-(29-06-2012).pdf

2976-delnp-2007-form-1.pdf

2976-delnp-2007-form-13-(08-05-2009).pdf

2976-delnp-2007-form-13-(19-09-2008).pdf

2976-delnp-2007-Form-13-(28-10-2010).pdf

2976-delnp-2007-Form-2-(17-10-2013).pdf

2976-delnp-2007-Form-2-(21-11-2013).pdf

2976-delnp-2007-Form-2-(31-05-2013).pdf

2976-delnp-2007-form-2.pdf

2976-delnp-2007-Form-3-(31-05-2013).pdf

2976-delnp-2007-form-3.pdf

2976-delnp-2007-form-5.pdf

2976-DELNP-2007-GPA-(10-05-2011).pdf

2976-delnp-2007-GPA-(23-10-2013).pdf

2976-DELNP-2007-GPA-(29-06-2012).pdf

2976-delnp-2007-pct-210.pdf

2976-delnp-2007-pct-220.pdf

2976-delnp-2007-pct-237.pdf

2976-delnp-2007-pct-301.pdf

2976-delnp-2007-pct-304.pdf

2976-delnp-2007-pct-308.pdf

2976-delnp-2007-Petition-137-(17-10-2013).pdf

2976-delnp-2007-Petition-137-(21-11-2013).pdf