FUSED TRICYCLIC HETEROCYCLES FOR THE TREATMENT OF SCHIZOPHRENIA

BACKGROUND OF THE INVENTION

FIELD OF THE INVENTION

This invention relates to ortho- and peri-fused tricyclic heterocycles, including 4,5-dihydro-1 H- pyrrolo[3,2,1-/7/]indol-2-ones, 1 ,2,5,6-tetrahydro-pyrrolo[3,2,1-//]quinoiin-4-ones, and 1 ,2,6,7-tetrahydro- 5/-/-pyrido[3,2,1-//]quinolin-3-ones, and to their pharmaceutically acceptable complexes, salts, solvates and hydrates. This invention also relates to pharmaceutical compositions containing the fused tricyclic heterocycles and to the use of these compounds for treating central nervous system (CNS) disorders such as schizophrenia.

DISCUSSION

Schizophrenia is a complex psychiatric disorder. Patients suffering from schizophrenia may exhibit multiple symptoms falling within three general categories — positive, negative, and cognitive symptoms. Positive symptoms may include delusions, hallucinations, and paranoia (psychotic symptoms), as well as distorted language and thought processes, and grossly disorganized or catatonic behavior (disorientation symptoms). Negative symptoms may include affective flattening and social withdrawal, poverty of speech, anhedonia, and poor hygiene. Cognitive symptoms may include memory deficits, impaired attention, and the inability to plan actions. The number, type, and severity of these symptoms often vary from patient to patient and may evolve during the course of the disease.

Most of the drugs currently marketed for treating schizophrenia are D ₂ dopamine receptor antagonists which primarily treat the positive symptoms of schizophrenia. They include first generation antipsychotics, such as haloperidol, pimozide and various phenothiazines, and include second generation or atypical antipsychotics, such as clozapine, olanzapine, risperidone, quetiapine, sertindole, and ziprasidone. In contrast to the earliest antipsychotic medications, atypical antipsychotics appear to selectively block specific dopamine-mediated neurotransmission pathways in the brain and may block or partially block one or more serotonin receptors, including 5-HT _2A , 5-HT _2C , and 5-HT _1A receptors. The combination of serotonin receptor activity and selective D ₂ dopamine receptor activity may be responsible for the lower incidence of extrapyramidal side effects (EPS) with atypical antipsychotics and for their ability to moderate, to some extent, the negative symptoms associated with schizophrenia.

Despite the advantages of atypical antipsychotics, problems remain. For example, a significant fraction of patients undergoing treatment with atypical antipsychotics suffer residual positive symptoms, which may lead to poor treatment compliance and subsequent relapse. Compared to their treatment of positive symptoms, atypical antipsychotics have been less successful at treating negative and cognitive symptoms, which may ultimately prevent schizophrenia patients from functioning normally in society. Although atypical antipsychotics may exhibit lower EPS liability than first generation antipsychotic medications, the use of atypical antipsychotics may nevertheless result in other side effects, such as weight gain, insulin resistance, dyslipidemia, hyperlipidemia, and sexual dysfunction.

Furthermore, a high percentage of patients diagnosed with schizophrenia also suffer from other serious CNS disorders, including clinical depression, anxiety disorders, or substance abuse. These concomitant disease states may be treated by administering an antipsychotic with a second pharmaceutically active agent to treat the comorbid condition. However, such combination therapies may have drawbacks, including potential toxicity arising from undesirable pharmacodynamic interactions of the active agents; difficulties in establishing proper dosing regimen because of pharmacokinetic interactions; and non- compliance and medication errors associated with any multiple drug therapy.

The present invention is directed to overcoming or reducing the effects of one or more of the problems described above.

SUMMARY OF THE INVENTION

This invention provides ortho- and peri-fused tricyclic heterocycles, including various 4,5-dihydro-1 H- pyrrolo[3,2,1-/7/]indol-2-ones, 5,6-dihydro-1H,4W-pyrrolo[3,2,1-//]quinoline-2-ones, 1 ,2,5,6-tetrahydro- pyrrolo[3,2,1-//|quinolin-4-ones, 1 ,2,6,7-tetrahydro-5H-pyrido[3,2,1-/)]quinolin-3-ones, 1 ,2,6,7-tetrahydro- 5/-/-azepino[3,2,1-/7/jindol-4-ones, 2,3,7,8-tetrahydro-1/-/,6/-/-azepino[3,2,1-/7]quinoline-5-on es, and pharmaceutically acceptable complexes, salts, solvates, and hydrates thereof. This invention also provides pharmaceutical compositions containing the fused tricyclic heterocycles, which may be used to treat CNS disorders, including schizophrenia.

One aspect of the invention provides a compound of Formula 1 ,

or a pharmaceutically acceptable salt thereof, wherein

L is selected from a bond and Ci _-6 alkanediyl; Z ¹ is selected from a bond and Ci _-2 alkanediyl; Z ² is selected from Ci _-2 alkanediyl;

R ¹ , R ² , R ³ , R ⁴ R ⁵ , R ⁶ , R ⁷ R ⁸ , and R ⁹ are each independently selected from H, halogeno, cyano, C _1-6 alkyl, halo-Ci. ₆ alkyl, and carbamoyl; and

R ¹⁰ is selected from H, C _1-6 alkyl, halo-Ci _-6 alkyl, Ci _-7 alkanoyl, carbamoyl, C _1-6 alkylaminocarbonyl, Ci _-6 alkylsulfonyl, Ci _-6 alkylsulfonyl-Ci _-2 alkyl, C _1-6 alkylaminosulfonyl, and C _1-6 alkylaminosulfonyl-C _1-2 alkyl.

Another aspect of the invention provides a compound of Formula 1A,

or a pharmaceutically acceptable salt thereof, or a compound of Formula 1 B,

or a pharmaceutically acceptable salt thereof, wherein L, Z\ Z ² , R ¹ , R ² , R ³ , R ⁴ R ⁵ , R ⁶ , R ⁷ R ⁸ , R ⁹ , and R ¹⁰ in Formula 1A and 1B are as defined above for Formula 1.

A further aspect of the invention provides a compound selected from the following group of compounds and pharmaceutically salts thereof:

9-{3-[4-(5-fluoro-1H-indol-3-yl)-3,6-dihydro-2W-pyridin-1 -yl]-propyl}-1,2,6,7-tetrahydro-5H- pyrido[3,2, 1 -/y]quinolin-3-one;

9-{3-[4-(5-fluoro-1 H-indol-3-yl)-piperidin-1 -yl]-propyl}-1 ,2,6,7-tetrahydro-5H-pyrido[3,2, 1 - /y]quinolin-3-one;

9-{2-[4-(5-fluoro-1 H-indol-3-yl)-3,6-dihydro-2H-pyridin-1 -yl]-ethyl}-1 ,2,6,7-tetrahydro-5H- pyrido[3,2,1-/)]quinolin-3-one; g^-μ-Cδ-fluoro-IH-indol-S-yO-piperidin-i-yO-ethylJ-i ^.e.T-tetrahydro-δH-pyridotS^.I-

//lquinolin-3-one;

9-{2-[4-(1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-yl]-ethy l}-1 ,2,6,7-tetrahydro-5H-pyrido[3,2,1- /;]quinolin-3-one;

9-{2-[4-(1H-lndol-3-yl)-piperidin-1-yl]-ethyl}-1 ,2,6,7-tetrahydro-5H-pyrido[3 _I 2,1-/y]quinolin-3- one;

9-{2-[4-(4 _J 6-difluoro-1/-/-indol-3-yl)-piperidin-1-yl]-ethyl}-1 ,2 _l 6,7-tetrahydro-5H-pyrido[3,2 ₎ 1-

/y]quinolin-3-one;

9-{2-[4-(6-chloro-5-fiuoro-1 AY-indol-3-yl)-piperidin-1 -yi]-ethyl}-1 ,2,6,7-tetrahydro-5H- pyrido[3,2,1-/y]quinolin-3-one; 9-{2-[4-(2,6-dimethyl-1 W-indol-3-yl)-3,6-dihydro-2H-pyridin-1 -yl]-ethyl}-1 ,2,6,7-tetrahydro-5H- pyrido[3,2,1-/)]quinolin-3-one;

9-{2-[4-(2,6-dimethyl-1H-indol-3-yl)-piperidin-1-yi]-ethyl}- 1 ,2,6 _I 7-tetrahydro-5H-pyrido[3,2,1- /)]quinolin-3-one;

9-{2-[4-(2,4-dimethyl-1Ay-indol-3-yl)-3,6-dihydro-2H-pyri din-1-yl]-ethyl}-1 ,2,6,7-tetrahydro-5/V- pyrido[3,2,1-/y]quinolin-3-one;

3-{1 -[2-(3-oxo-2,3,6,7-tetrahydro-1 H,5H-pyrido[3,2, 1 -/y]quinolin-9-yl)-ethyl]-piperidin-4-yl}-1 H- indole-5-carboxylic acid amide;

8-{3-[4-(5-fluoro-1 AV-indol-3-yl)-3,6-dihydro-2H-pyridin-1 -yl]-propyl}-1 ,2,5,6-tetrahydro- pyrrolo[3,2,1-/y]quinolin-4-one; 8-{3-[4-(5-fluoro-1Ay-indol-3-yl)-piperidin-1-yl]-propyl}-1 ,2,5,6-tetrahydro-pyrrolo[3,2,1-

/y]quinolin-4-one;

8-{2-[4-(5-fluoro-1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1 -yl]-ethyl}-1,2,5,6-tetrahydro- pyrrolo[3,2,1-/y]quinolin-4-one;

8-{2-[4-(5-fluoro-1 H-indol-3-yl)-piperidin-1 -yl]-ethyl}-1 ,2,5,6-tetrahydro-pyrrolo[3,2, 1 -/y]quinolin- 4-one;

8-{2-[4-(5-fluoro-1H-indol-3-yl)-3,3-dimethyl-3,6-dihydro -2/V-pyridin-1-yl]-ethyl}-1 ,2,5,6- tetrahydro-pyrrolo[3,2,1-/y]quinolin-4-one;

8-{2-[4-(5-fluoro-1 H-indol-3-yl)-3,3-dimethyl-piperidin-1 -yl]-ethyl}-1 ,2,5,6-tetrahydro- pyrrolo[3,2,1-/y]quinolin-4-one; 8-{3-[4-(5-fluoro-1H-indol-3-yl)-3,6-dihydro-2H-pyridiπ-1-y l]-propyl}-6,6-dimethyl-1, 2,5,6- tetrahydro-pyrrolo[3,2,1-/y]quinolin-4-one;

8-{3-[4-(5-fluoro-1 H-indol-3-yl)-piperidin-1 -yl]-propyl}-6,6-dimethyl-1 ,2,5,6-tetrahydro- pyrrolo[3,2,1-/y]quinolin-4-one;

8-{2-[4-(5-fluoro-1H-indol-3-yl)-3,6-dihydro-2λ/-pyridin -1-yl]-ethyl}-6,6-dimethyl-1 ,2,5,6- tetrahydro-pyrrolo[3,2,1-/y]quinolin-4-one; δ-ia-μ-Cδ-fluoro-IH-indol-S-ylJ-piperidin-i-yπ-ethylJ-e. e-dimethyl-I^.S.e-tetrahydro- pyrrolo[3,2,1-/y]quinolin-4-one;

8-{2-[4-(1H-indol-3-yl)-3,6-dihydro-2λ/-pyridin-1-yl]-et hyl}-6,6-dimethyl-1 ,2,5,6-tetrahydro- pyrrolo[3,2, 1 -/y]quinolin-4-one; 8-{2-[4-(1 H-indol-3-yl)-piperidin-1 -yl]-ethyl}-6,6-dimethyl-1 ,2,5,6-tetrahydro-pyrrolo[3,2, 1 -

/y]quinolin-4-one;

8-{2-[4-(7-chloro-1H-indol-3-yl)-3,6-dihydro-2f/-pyridin- 1-yl]-ethyl}-6,6-dimethyl-1 ,2,5,6- tetrahydro-pyrrolo[3,2,1-/y]quiπolin-4-one;

8-{2-[4-(7-chloro-1 W-indol-3-yi)-piperidin-1 -yl]-ethyl}-6,6-dimethyl-1 ,2,5,6-tetrahydro- pyrrolo[3,2,1-/y]quinolin-4-oπe;

8-{2-[4-(6-chloro-1 W-indol-3-yl)-piperidin-1 -yl]-ethyl}-6,6-dimethyl-1 ,2,5,6-tetrahydro- pyrrolo[3,2,1-//]quinolin-4-one;

8-{2-[4-(4,6-difluoro-1H-indol-3-yl)-3,6-dihydro-2λ/-pyr idin-1-yl]-ethyl}-6,6-dimethyl-1 ,2,5,6-. tetrahydro-pyrrolo[3,2,1-/y]quinolin-4-one; 8-{2-[4-(4,6-difluoro-1 tt-indol-3-yl)-piperidin-1 -yl]-ethyl}-6,6-dimethyl-1 ,2,5,6-tetrahydro- pyrrolo[3,2,1-/;]quinolin-4-one;

8-{2-[4-(2,4-dimethyl-1H-indol-3-yl)-3,6-dihydro-2Ay-pyri din-1-yl]-ethyl}-6,6-dimethyl-1 ,2,5,6- tetrahydro-pyrrolo[3,2, 1 -/y]quinolin-4-one;

8-{2-[4-(2,6-dimethyl-1W-indol-3-yl)-piperidin-1-yl]-ethy l}-6,6-dimethyl-1,2,5,6-tetrahydro- pyrrolo[3,2,1-//lquinolin-4-one;

9-fluoro-8-{2-[4-(1W-indol-3-yl)-piperidin-1-yl]-ethyl}-1 ,2,5,6-tetrahydro-pyrrolo[3,2,1-//lquinolin- 4-one; θ-fluoro-δ^-^-Ce-fluoro-I H-indol-S-yO-piperidin-i-ylJ-ethylJ-i ^.δ.e-tetrahydro-pyrrolotS^.I- /y]quinolin-4-one; θ-fluoro-δ^-^-CS-fluoro-I H-indol-S-yO-piperidin-i-yπ-ethylJ-I^.S.e-tetrahydro-pyrrol oP^.I-

/y]quinolin-4-one;

7,9-difluoro-8-{2-[4-(1H-indol-3-yl)-piperidin-1-yl]-ethy l}-1,2,5,6-tetrahydro-pyrrolo[3,2,1- //lquinoiin-4-one;

7-fluoro-8-{2-[4-(1H-indol-3-yl)-piperidin-1-yl]-ethyl}-1 ,2,5,6-tetrahydro-pyrrolo[3,2,1-/y]quinolin- 4-one;

7-{2-[4-(5-fluoro-3a,7a-dihydro-1 /-/-indol-3-yl)-piperidin-1 -yl]-ethyl}-4,5-dihydro-1 H- pyrrolo[3,2,1-/7/]indol-2-one; and

7-{2-[4-(6-fluoro-3a,7a-dihydro-1 H-indol-3-yl)-piperidin-1 -yl]-ethyl}-4,5-dihydro-1 H- pyrrolo[3,2,1-/j/]indol-2-one.

An additional aspect of the invention provides a pharmaceutical composition comprising: a compound of Formula 1, Formula 1A, or Formula 1B, as defined above, or a pharmaceutically acceptable salt thereof, or a compound selected from the group of compounds defined in the preceding paragraph, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

Another aspect of the invention provides a method of treating a condition or disorder in a subject, the method comprising administering to the subject in need of treatment a therapeutically effective amount of a compound of Formula 1, Formula 1A, or Formula 1B, as defined above, or a pharmaceutically acceptable salt thereof, or a compound selected from the group of compounds defined above, or a pharmaceutically acceptable salt thereof, wherein the disorder or condition is selected from schizophrenia and other psychotic disorders, mood disorders, anxiety disorders, sleep disorders, cognitive disorders, or a combination thereof.

A further aspect of the invention provides a use of a compound of Formula 1, Formula 1A, or Formula 1B, as defined above, or a pharmaceutically acceptable salt thereof, or a compound selected from the group of compounds defined above, or a pharmaceutically acceptable salt thereof, for the preparation of a

medicament for the treatment of a disorder or condition selected from schizophrenia and other psychotic disorders, mood disorders, anxiety disorders, sleep disorders, cognitive disorders, or a combination thereof.

An additional aspect of the invention provides a combination of one or more compounds of Formula 1, Formula 1A, or Formula 1B, as defined above, or pharmaceutically acceptable salts thereof, or one or more compounds selected from the group of compounds defined above, or pharmaceutically acceptable salts thereof, and one or more pharmacologically active compounds which are different than the one or more compounds of Formula 1, Formula 1A, Formula 1B, or group of compounds defined above, or pharmaceutically acceptable salts thereof.

Compounds of this invention include all pharmaceutically acceptable complexes, salts, solvates, and hydrates thereof. Compounds of this invention also include all stereoisomers, tautomers, and polymorphic forms thereof, including all crystalline and amorphous forms, whether they are pure, substantially pure, or mixtures.

DETAILED DESCRIPTION

DEFINITIONS AND ABBREVIATIONS

Unless otherwise indicated, this disclosure uses definitions provided below. Some of the definitions and formulae may include a dash ("-") to indicate a bond between atoms or a point of attachment to a named or unnamed atom or group of atoms. Other definitions and formulae may include an equal sign ("=") or an identity symbol ("≡") to indicate a double bond or a triple bond, respectively. Certain formulae may also include one or more asterisks (" ^* ") to indicate stereogenic (asymmetric or chiral) centers, although the absence of an asterisk does not indicate that the compound lacks a stereocenter. Such formulae may refer to the racemate or to individual enantiomers or to individual diastereomers, which may or may not be pure or substantially pure. Other formulae may include one or more wavy bonds ("λ™λ,"). When attached to a stereogenic center, the wavy bonds refer to both stereoisomers, either individually or as mixtures. Likewise, when attached to a double bond, the wavy bonds indicate a Z-isomer, an E-isomer, or a mixture of Z and E isomers. Some formulae may include a dashed bond " " to indicate a single or a double bond.

"Substituted" groups are those in which one or more hydrogen atoms have been replaced with one or more non-hydrogen atoms or groups, provided that valence requirements are met and that a chemically stable compound results from the substitution.

"About" or "approximately," when used in connection with a measurable numerical variable, refers to the indicated value of the variable and to all values of the variable that are within the experimental error of the indicated value (e.g., within the 95% confidence interval for the mean) or within ±10 percent of the indicated value, whichever is greater.

"Alkyl" refers to straight chain and branched saturated hydrocarbon groups, generally having a specified number of carbon atoms (i.e., C _1-6 alkyl refers to an alkyl group having 1 , 2, 3, 4, 5, or 6 carbon atoms and C _1-I2 alkyl refers to an alkyl group having 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , or 12 carbon atoms). Examples of alkyl groups include methyl, ethyl, π-propyl, /-propyl, n-butyl, s-butyl, /-butyl, f-butyl, pent-1-yl, pent-2-yl, pent-3-yl, 3-methylbut-1-yl, 3-methylbut-2-yl, 2-methylbut-2-yl, 2,2,2-trimethyleth-1-yl, and n-hexyl.

"Alkenyl" refers to straight chain and branched hydrocarbon groups having one or more double carbon- carbon bonds, and generally having a specified number of carbon atoms. Examples of alkenyl groups include ethenyl, 1-propen-1-yl, 1-propen-2-yi, 2-propen-1-yl, 1-buten-1-yl, 1-buten-2-yl, 3-buten-1-yl, 3- buten-2-yl, 2-buten-1-yl, 2-buten-2-yl, 2-methyl-1-propen-1-yl, 2-methyl-2-propen-1-yl, 1 ,3-butadien-1-yl, and 1 ,3-butadien-2-yl.

"Alkynyl" refers to straight chain or branched hydrocarbon groups having one or more triple carbon-carbon bonds, and generally having a specified number of carbon atoms. Examples of alkynyl groups include ethynyl, 1-propyn-1-yl, 2-propyn-1-yl, 1-butyn-1-yl, 3-butyn-1-yl, 3-butyn-2-yl, and 2-butyn-1-yl.

"Alkanediyl" refers to divalent straight chain and branched saturated hydrocarbon groups, generally having a specified number of carbon atoms. Examples include methylene, ethan-1 ,2-diyl, propan-1 ,3-diyl, butan-1 ,4-diyl, pentan-1,5-diyl, and hexan-1 ,6-diyl.

"Alkanoyl" refers to alkyl-C(O)-, where alkyl is defined above, and generally includes a specified number of carbon atoms, including the carbonyl carbon. Examples of alkanoyl groups include formyl, acetyl, propionyl, butyryl, pentanoyl, and hexanoyl.

"Alkenoyl" and "alkynoyl" refer, respectively, to alkenyl-C(O)- and alkynyl-C(O)-, where alkenyl and alkynyl are defined above. References to alkenoyl and alkynoyl generally include a specified number of carbon atoms, excluding the carbonyl carbon. Examples of alkenoyl groups include propenoyl, 2- methylpropenoyl, 2-butenoyl, 3-butenoyl, 2-methyl-2-butenoyl, 2-methyl-3-butenoyl, 3-methyl-3-butenoyl, 2-pentenoyl, 3-pentenoyl, and 4-pentenoyl. Examples of alkynoyl groups include propynoyl, 2-butynoyl, 3-butynoyl, 2-pentynoyl, 3-pentynoyl, and 4-pentynoyl.

"Alkoxy" and "alkoxycarbonyl" refer, respectively, to alkyl-O-, alkenyl-O-, and alkynyl-O-, and to alkyl-O- C(O)-, alkenyl-O-C(O)-, alkynyl-O-C(O)-, where alkyl, alkenyl, and alkynyl are defined above. Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, /-propoxy, n-butoxy, s-butoxy, f-butoxy, n-pentoxy, and s-pentoxy. Examples of alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, n- propoxycarbonyl, /-propoxycarbonyl, /7-butoxycarbonyl, s-butoxycarbonyl, f-butoxycarbonyl, n- pentoxycarbonyl, and s-pentoxycarbonyl.

"Alkylaminocarbonyl," "alkylsulfonyl," "alkylsulfonylalkyl," "alkylamino-sulfonyl," and "alkylaminosulfonyl- alkyl," refer, respectively, to alkyl-NH-C(O)-, alkyl-S(O ₂ )-, alkyl-S(O ₂ )-alkyl-, alkyl-NH-S(O ₂ )-, and alkyl-NH- S(O ₂ )-alkyl-.

"Halo," "halogen" and "halogeno" may be used interchangeably, and refer to fluoro, chloro, bromo, and iodo.

"Haloalkyl," "haloalkenyl," "haloalkynyl," "haloalkanoyl," "haloalkenoyl," "haloalkynoyl," "haloalkoxy," and "haloalkoxycarbonyl" refer, respectively, to alkyl, alkenyl, alkynyl, alkanoyl, alkenoyl, alkynoyl, alkoxy, and alkoxycarbonyl groups substituted with one or more halogen atoms, where alkyl, alkenyl, alkynyl, alkanoyl, alkenoyl, alkynoyl, alkoxy, and alkoxycarbonyl are defined above. Examples of haloalkyl groups include trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.

"Cycloalkyl" refers to saturated monocyclic and bicyclic hydrocarbon rings, generally having a specified number of carbon atoms that comprise the ring (i.e., C _3-7 cycloalkyl refers to a cycloalkyl group having 3, 4, 5, 6 or 7 carbon atoms as ring members). The cycloalkyl may be attached to a parent group or to a substrate at any ring atom, unless such attachment would violate valence requirements. Likewise, the cycloalkyl groups may include one or more non-hydrogen substituents unless such substitution would violate valence requirements. Useful substituents include alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, alkoxycarbonyl, alkanoyl, and halo, as defined above, and hydroxy, mercapto, nitro, and amino.

Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of bicyclic cycloalkyl groups include bicyclo[1.1.0]butyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.0]pentyl, bicyclo[2.1.1]hexyl, bicyclo[3.1.0]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.0]heptyl, bicyclo[3.1.1]heptyl, bicyclo[4.1.0]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[4.1.1]octyl, bicyclo[3.3.0]octyl, bicyclo[4.2.0]octyl, bicyclo[3.3.1]nonyl, bicyclo[4.2.1]nonyl, bicyclo[4.3.0]nonyl, bicyclo[3.3.2]decyl, bicyclo[4.2.2]decyl, bicyclo[4.3.1]decyl, bicyclo[4.4.0]decyl, bicyclo[3.3.3]undecyl, bicyclo[4.3.2]undecyl, and bicyclo[4.3.3]dodecyl.

"Cycloalkenyl" refers monocyclic and bicyclic hydrocarbon rings having one or more unsaturated carbon- carbon bonds and generally having a specified number of carbon atoms that comprise the ring (i.e., C _3-7 cycioalkenyl refers to a cycloalkenyl group having 3, 4, 5, 6 or 7 carbon atoms as ring members). The cycloalkenyl may be attached to a parent group or to a substrate at any ring atom, unless such attachment would violate valence requirements. Likewise, the cycloalkenyl groups may include one or more non-hydrogen substituents unless such substitution would violate valence requirements. Useful substituents include alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, alkoxycarbonyl, alkanoyl, and halo, as defined above, and hydroxy, mercapto, nitro, and amino.

"Cycloalkanoyl" and "cycloalkenoyl" refer to cycloalkyl-C(O)- and cycloalkenyl-C(O)-, respectively, where cycloalkyl and cycloalkenyl are defined above. References to cycloaikanoyl and cycloalkenoyl generally include a specified number of carbon atoms, excluding the carbonyl carbon. Examples of cycloalkanoyl groups include cyclopropanoyl, cyclobutanoyl, cyclopentanoyl, cyclohexanoyl, cycloheptanoyl, 1- cyclobutenoyl, 2-cyclobutenoyl, 1-cyclopentenoyl, 2-cyclopentenoyl, 3-cyclopentenoyl, 1-cyclohexenoyl, 2- cyclohexenoyl, and 3-cyclohexenoyl.

"Cycloalkoxy" and "cycloalkoxycarbonyl" refer, respectively, to cycioalkyl-O- and cycloalkenyl-0 and to cycloalkyl-O-C(O)- and cycloalkenyl-O-C(O)-, where cycloalkyl and cycloalkenyl are defined above. References to cycloalkoxy and cycloalkoxycarbonyl generally include a specified number of carbon atoms, excluding the carbonyl carbon. Examples of cycloalkoxy groups include cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy, 1-cyclobutenoxy, 2-cyclobutenoxy, 1-cyclopentenoxy, 2- cyclopentenoxy, 3-cyclopentenoxy, 1-cyclohexenoxy, 2-cyclohexenoxy, and 3-cyclohexenoxy. Examples of cycloalkoxycarbonyl groups include cyclopropoxycarbonyl, cyclobutoxycarbonyl, cyclopentoxycarbonyl, cyclohexoxycarbonyl, 1-cyclobutenoxycarbonyl, 2-cyclobutenoxycarbonyl, 1-cyclopentenoxycarbonyl, 2- cyclopentenoxycarbonyl, 3-cyclopentenoxycarbonyl, 1-cyclohexenoxycarbonyl, 2-cyclohexenoxycarbonyl, and 3-cyclohexenoxycarbonyl,.

"Aryl" and "arylene" refer to monovalent and divalent aromatic groups, respectively, including 5- and 6- membered monocyclic aromatic groups that contain 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Examples of monocyclic (and monovalent) aryl groups include phenyl, pyrrolyl, furanyl, thiopheneyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, 1 ,2,3- triazolyl, 1,3,4-triazolyl, 1-oxa-2,3-diazolyl, 1-oxa-2,4-diazolyl, 1-oxa-2,5-diazolyl, 1-oxa-3,4-diazolyl, 1- thia-2,3-diazolyl, 1-thia-2,4-diazolyl, 1-thia-2,5-diazolyl, 1-thia-3,4-diazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl.

Aryl and arylene groups also include bicyclic groups, tricyclic groups, etc., including fused 5- and 6- membered rings described above. Examples of multicyclic (and monovalent) aryl groups include naphthyl, biphenyl, anthracenyl, pyrenyl, carbazolyl, benzofuranyl, benzothiopheneyl, indolyl, benzoxazolyl, benzodioxazolyl, benzimidazolyl, indazolyl, benzotriazolyl, pyrrolo[2,3-6]pyridinyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrrolo[3,2-ό]pyridinyi, imidazo[4,5-jb]pyridinyl, imidazo[4,5- c]pyridinyl, pyrazolo[4,3-c/]pyridinyl, pyrazolo[4,3-c]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[3,4- ό]pyridinyl, isoindolyl, indazolyl, purinyl, indolizinyl, imidazo[1 ,2-a]pyridinyl, imidazo[1 ,5-a]pyridinyl, pyrazolo[1 ,5-a]pyridinyl, pyrrolo[1 ,2-ό]pyridinyl, and imidazo[1 ,2-c]pyridinyl. Other examples include quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, 1 ,6-naphthyridinyl, 1 ,7- naphthyridinyl, 1 ,8-naphthyridinyl, 1 ,5-naphthyridinyl, 2,6-naphthyridinyl, 2,7-naphthyridinyl, pyrido[3,2- cdpyrimidinyl, pyrido[4,3-cflpyrimidinyl, pyrido[3,4-tf|pyrimidinyl, pyrido[2,3-c/]pyrimidinyl, pyrido[2,3- jbjpyrazinyl, pyrido[3,4-jfc>]pyrazinyl, pyrimido[5,4-c/|pyrimidinyl, pyrazino[2,3-i£>]pyrazinyl, and pyrimido[4,5- cflpyrimidinyl.

The aryl and arylene groups may be attached to a parent group or to a substrate at any ring atom, unless such attachment would violate valence requirements. Likewise, aryl and arylene groups may include one or more non-hydrogen substituents unless such substitution would violate valence requirements. Useful substituents include alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, cycloalkyl, cycloalkenyl, alkoxy, cycloalkoxy, alkanoyl, cycloalkanoyl, cycloalkenoyl, alkoxycarbonyl, cycloalkoxycarbonyl, and halo, as defined above, and hydroxy, mercapto, nitro, amino, and alkylamino.

"Heterocycle" and "heterocyclyl" refer to saturated, partially unsaturated, or unsaturated monocyclic or bicyclic rings having from 3 to 7 or from 7 to 11 ring members, respectively. These groups have ring

members made up of carbon atoms and from 1 to 4 heteroatoms that are each independently selected from nitrogen, oxygen or sulfur, and may include any bicyclic group in which any of the above-defined monocyclic heterocycles are fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be attached to a parent group or to a substrate at any heteroatom or carbon atom unless such attachment would violate valence requirements. Likewise, any of the carbon or nitrogen ring members may include a non-hydrogen substituent unless such substitution would violate valence requirements. Useful substituents include alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, cycloalkyl, cycloalkenyl, alkoxy, cycloalkoxy, alkanoyl, cycloalkanoyl, cycloalkenoyl, alkoxycarbonyl, cycloalkoxycarbonyl, and halo, as defined above, and hydroxy, mercapto, nitro, amino, and alkylamino.

Examples of heterocycles include the aryl groups listed above which contain at least one heteroatom. Other examples include oxiranyl, thiaranyl, aziridinyl, oxetanyl, thiatanyl, azetidinyl, tetrahydrothiopheneyl, tetrahydropyran, tetrahydrothiopyran, 1 ,4-dioxanyl, 1 ,4-oxathianyl, 1 ,4-dithianyl, 1 ,4-azathianyl, oxepanyl, thiepanyl, azepanyl, 1 ,4-dioxepanyl, 1 ,4-oxathiepanyl, 1,4-oxaazepanyl, 1 ,4-dithiepanyl, 1 ,4-thiazepanyl, 1 ,4-diazepanyl, 3,4-dihydro-2H-pyranyl, 5,6-dihydro-2/7-pyranyl, 2/V-pyranyl, 1 ,2,3,4-tetrahydropyridinyl, 1 ,2,5,6-tetrahydropyridinyl, acridinyl, azocinyl, benzothiofuranyl, benzothiazolyl, benzotetrazolyl, benzoisoxazolyl, benzoisothiazolyl, benzoimidazolinyl, 4a/7-carbazolyl, carbolinyl, chromanyl, chromenyl, decahydroquinolinyl, 2H,6AV-1 ,5,2-dithiazinyl, dihydrofuro[2,3-ib]tetrahydrofuranyl, furazanyl, imidazolidinyl, imidazolinyl, indolenyl, indolinyl, 3/7-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, morpholinyl, octahydroisoquinolinyl, oxazolidinyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazolidinyl, pyrazolinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridyl, pyrrolidinyl, pyrrolinyl, 2/7-pyrrolyl, 4H-quinolizinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6/7-1 ,2,5-thiadiazinyl, thianthrenyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, triazinyl, 1 ,2,4-triazolyl, 1 ,2,5-triazolyl, and xanthenyl.

"Heteroaryl" and "heteroarylene" refer, respectively, to monovalent and divalent heterocycles or heterocyclyl groups, as defined above, which are aromatic. Heteroaryl and heteroarylene groups represent a subset of aryl and arylene groups, respectively.

"Arylalkyl" and "heteroarylalkyl" refer, respectively, to aryl-alkyl and heteroaryl-alkyl, where aryl, heteroaryl, and alkyl are defined above. Examples include benzyl, fluorenylmethyl, and imidazol-2-yl- m ethyl.

"Arylalkanoyl," "heteroarylalkanoyl," "arylalkenoyl," "heteroarylalkenoyl," "arylalkynoyl," and "heteroarylalkynoyl" refer, respectively, to aryl-alkanoyl, heteroaryl-alkanoyl, aryl-alkenoyl, heteroarylalkenoyl, aryl-alkynoyl, and heteroaryl-alkynoyl, where aryl, heteroaryl, alkanoyl, alkenoyl, and alkynoyl are defined above. Examples include benzoyl, benzylcarbonyl, fluorenoyl, fluorenylmethylcarbonyl, imidazol-2-oyl, imidazol-2-yl-methylcarbonyl, phenylethenecarbonyl, 1-phenylethenecarbonyl, 1-phenyl- propenecarbonyl, 2-phenyl-propenecarbonyl, 3-phenyl-propenecarbonyl, imidazol-2-yl-ethenecarbonyl, 1- (imidazol-2-yl)-ethenecarbonyi, 1-(imidazol-2-yl)-propenecarbonyl, 2-(imidazol-2-yl)-propenecarbonyl, 3-

(imidazol-2-yl)-propenecarbonyl, phenylethynecarbonyl, phenylpropyπecarbonyl, (imidazol-2-yl)- ethynecarbonyl, and (imidazol-2-yl)-propynecarbonyl.

"Arylalkoxy" and "heteroarylalkoxy" refer, respectively, to aryl-alkoxy and heteroaryl-alkoxy, where aryl, heteroaryl, and alkoxy are defined above. Examples include benzyloxy, fluorenylmethyloxy, and imidazol- 2-yl-methyloxy.

"Aryloxy" and "heteroaryloxy" refer, respectively, to aryl-O- and heteroaryl-O-, where aryl and heteroaryl are defined above. Examples include phenoxy and imidazol-2-yloxy.

"Aryloxycarbonyl," "heteroaryloxycarbonyl," "arylalkoxycarbonyl," and "heteroarylalkoxycarbonyl" refer, respectively, to aryloxy-C(O)-, heteroaryloxy-C(O)-, arylalkoxy-C(O)-, and heteroarylalkoxy-C(O)-, where aryloxy, heteroaryloxy, arylalkoxy, and heteroarylalkoxy are defined above. Examples include phenoxycarbonyl, imidazol-2-yloxycarbonyl, benzyloxycarbonyl, fluorenylmethyloxycarbonyl, and imidazol-2-yl-methyloxycarbonyl.

"Leaving group" refers to any group that leaves a molecule during a fragmentation process, including substitution reactions, elimination reactions, and addition-elimination reactions. Leaving groups may be nucleofugal, in which the group leaves with a pair of electrons that formerly served as the bond between the leaving group and the molecule, or may be electrofugal, in which the group leaves without the pair of electrons. The ability of a nucleofugal leaving group to leave depends on its base strength, with the strongest bases being the poorest leaving groups. Common nucleofugal leaving groups include nitrogen (e.g., from diazonium salts); sulfonates, including alkylsulfonates (e.g., mesylate), fluoroalkylsulfonates (e.g., triflate, hexaflate, nonaflate, and tresylate), and arylsulfonates (e.g., tosylate, brosylate, closylate, and nosylate). Others include carbonates, halide ions, carboxylate anions, phenolate ions, and alkoxides. Some stronger bases, such as NH ₂ ^" and OH ^' can be made better leaving groups by treatment with an acid. Common electrofugal leaving groups include the proton, CO ₂ , and metals.

Opposite enantiomer" refers to a molecule that is a non-superimposable mirror image of a reference molecule, which may be obtained by inverting all of the stereogenic centers of the reference molecule. For example, if the reference molecule has S absolute stereochemical configuration, then the opposite enantiomer has R absolute stereochemical configuration. Likewise, if the reference molecule has S ₁ S absolute stereochemical configuration, then the opposite enantiomer has R ₁ R stereochemical configuration, and so on.

"Stereoisomers" of a specified compound refer to the opposite enantiomer of the compound and to any diastereoisomers, including geometrical isomers (ZIE) of the compound. For example, if the specified compound has S ₁ R ₁ Z stereochemical configuration, its stereoisomers would include its opposite enantiomer having R ₁ S ₁ Z configuration, and its diastereomers having S ₁ S ₁ Z configuration, R ₁ R ₁ Z configuration, S ₁ R ₁ E configuration, R ₁ S ₁ E configuration, S ₁ S ₁ E configuration, and R ₁ R ₁ E configuration.

"Enantiomeric excess" or "ee" is a measure, for a given sample, of the excess of one enantiomer over a racemic sample of a chiral compound and is expressed as a percentage. Enantiomeric excess is defined

as 100 x (er - 1) / (er + 1), where "er" is the ratio of the more abundant enantiomer to the less abundant enantiomer.

"Diastereomeric excess" or "de" is a measure, for a given sample, of the excess of one diastereomer over a sample having equal amounts of diastereomers and is expressed as a percentage. Diastereomeric excess is defined as 100 x (dr - 1 ) / (dr + 1 ), where "dr" is the ratio of a more abundant diastereomer to a less abundant diastereomer.

"Stereoselective," "enantioselective," "diastereoselective," and variants thereof, refer to a given process (e.g., hydrogenation) that yields more of one stereoisomer, enantiomer, or diastereoisomer than of another, respectively.

"High level of stereoselectivity," "high level of enantioselectivity," "high level of diastereoselectivity," and variants thereof, refer to a given process that yields products having an excess of one stereoisomer, enantiomer, or diastereoisomer, which comprises at least about 90% of the products. For a pair of enantiomers or diastereomers, a high level of enantioselectivity or diastereoselectivity would correspond to an ee or de of at least about 80%.

"Stereoisomerically enriched," "enantiomerically enriched," "diastereomerically enriched," and variants thereof, refer, respectively, to a sample of a compound that has more of one stereoisomer, enantiomer or diastereomer than another. The degree of enrichment may be measured by % of total product, or for a pair of enantiomers or diastereomers, by ee or de.

"Substantially pure stereoisomer," "substantially pure enantiomer," "substantially pure diastereomer," and variants thereof, refer, respectively, to a sample containing a stereoisomer, enantiomer, or diastereomer, which comprises at least about 95% of the sample. For pairs of enantiomers and diastereomers, a substantially pure enantiomer or diastereomer would correspond to samples having an ee or de of about 90% or greater.

A "pure stereoisomer," "pure enantiomer," "pure diastereomer," and variants thereof, refer, respectively, to a sample containing a stereoisomer, enantiomer, or diastereomer, which comprises at least about 99.5% of the sample. For pairs of enantiomers and diastereomers, a pure enantiomer or pure diastereomer" would correspond to samples having an ee or de of about 99% or greater.

"Subject" refers to a mammal, including a human.

"Pharmaceutically acceptable" substances refers to those substances which are within the scope of sound medical judgment suitable for use in contact with the tissues of subjects without undue toxicity, irritation, allergic response, and so on, commensurate with a reasonable benefit-to-risk ratio, and effective for their intended use.

"Treating" refers to reversing, alleviating, inhibiting the progress of, or preventing a disorder or condition to which such term applies, or to reversing, alleviating, inhibiting the progress of, or preventing one or more symptoms of such disorder or condition.

"Treatment" refers to the act of "treating," as defined immediately above.

"Drug," "drug substance," "active pharmaceutical ingredient," and the like, refer to a compound (e.g., compounds of Formula 1 , Formula 1A, Formula 1B, and compounds specifically named above) that may be used for treating a subject in need of treatment.

"Therapeutically effective amount" of a drug refers to the quantity of the drug that may be used for treating a subject and may depend on the weight and age of the subject and the route of administration, among other things.

"Excipient" or "adjuvant" refers to any substance that may influence the bioavailability of a drug, but is otherwise pharmacologically inactive.

"Pharmaceutical composition" refers to the combination of one or more drug substances and one or more excipients.

"Drug product," "pharmaceutical dosage form," "dosage form," "final dosage form" and the like, refer to a pharmaceutical composition that is administered to a subject in need of treatment and generally may be in the form of tablets, capsules, sachets containing powder or granules, liquid solutions or suspensions, patches, films, and the like.

Table 1 lists abbreviations used throughout the specification.

TABLE 1. List of Abbreviations

Abbreviation Description

Ac acetyl

ACN acetonitrile

APCI atmospheric pressure chemical ionization

API active pharmaceutical ingredient aq aqueous

Boc f-butoxycarbonyl

CHO Chinese hamster ovary

CNS central nervous system de diastereomeric excess

CRF corticotropin releasing factor

DIPEA diisopropylethylamine (Hϋnig's Base)

DMSO dimethylsulfoxide ee enantiomeric excess

EPS extrapyramidal side effects eq equivalents er enantiomeric ratio

ESI electrospray ionization

Abbreviation Description

Et ethyl

Et ₃ N triethyl-amine

Et ₃ SiH triethyl-silane

EtOAc ethyl acetate

EtOH ethyl alcohol

GC gas chromatography h, min, s hour(s), minute(s), second(s)

HEK human embryonic kidney

HEPES 4-(2-hydroxyethyl)piperazine-1 -ethanesulfonic acid hSERT human serotonin transporter

HPLC high performance liquid chromatography

IC ₅₀ concentration at 50% inhibition

Ki inhibition constant

LCMS liquid chromatography mass spectrometry

MAOI monoamine oxidase inhibitor

Me methyl

MEK methylethylketone or butan-2-one

MeOH methyl alcohol mp melting point

MTBE methyl tertiary butyl ether

NK neurokinin

NMR, s, d, t, q, m, br nuclear magnetic resonance, singlet, doublet, triplet, quartet, multiplet, broad

NRI norepinephrine reuptake inhibitor

PEI polyethyleneimine

PGLA poly(DL-lactic-coglycolic)acid

Ph phenyl

Pr propyl

/-Pr isopropyl psig pounds per square inch (gauge)

RaNi Raney nickel

Rf response factor

RIMA reversible inhibitor of monoamine oxidase

RT room temperature (approximately 20°C to 25°C)

SNRI serotonin and noradrenaline reuptake inhibitor

SSRI selective serotonin reuptake inhibitor

TFA trifluoroacetic acid

THF tetrahydrofuran

TLC thin-layer chromatography

Abbreviation Description

Tris buffer 2-amino-2-hydroxymethyl-propane-1 ,3-diol buffer wt% weight (mass) percent

This disclosure concerns compounds of Formula 1 , which include compounds represented by Formula 1A, Formula 1 B, compounds specifically named above, and their pharmaceutically acceptable complexes, salts, solvates and hydrates. This disclosure also concerns materials and methods for preparing compounds of Formula 1, pharmaceutical compositions containing them, and their use for treating a variety of CNS disorders such as schizophrenia, bipolar disorder, depression, or anxiety.

Compounds of Formula 1 include those in which: (a) Z ¹ is selected from bond, methylene, and ethan-1 ,2- diyl, or is selected from bond and methylene; (b) Z ² is selected from methylene and ethan-1 ,2-diyl; (c) L is selected from methylene, ethan-1 ,2-diyl, and propan-1 ,3-diyl, or is selected from methylene and ethan- 1 ,2-diyl; (d) R ¹ , R ² , R ³ , and R ⁴ are each independently selected from H, halogeno, cyano, C _1-6 alkyl, halo- Ci _-6 alkyl, and carbamoyl, or from H, fluorine, chlorine, and methyl; (e) R ⁵ , R ⁶ , and R ⁷ are each independently selected from H and C _1-6 alkyl, or from H and methyl; (f) R ⁸ and R ⁹ are each independently selected from H, C _1-6 alkyl, carbamoyl, and cyano, or from H and methyl; (g) R ¹⁰ is a hydrogen atom; and any combination of (a) to (g) along with the substituent definitions provided above in connection with Formula 1.

Compounds of Formula 1 also include those in which Z ¹ is a bond or methylene, Z ² is methylene or ethan- 1 ,2-diyl, and L is methylene or ethan-1 ,2-diyl; R ¹ , R ² , R ³ , and R ⁴ are each independently selected from H, fluorine, chlorine, and methyl; R ⁵ , R ⁶ , and R ⁷ are each independently selected from H and methyl; R ⁸ and R ⁹ are each independently selected from H and methyl; and R ¹⁰ is a hydrogen atom.

Generally, and unless stated otherwise, when a particular substituent identifier (e.g., R ¹ , R ² , R ³ , etc.) is described in connection with a first formula (e.g., Formula 1 ) the same substituent identifier, when used in a subsequent formula (e.g., Formula 1A, Formula 1 B, etc.) will have the same definition as in the earlier formula. Thus, for example, if R ¹ , R ² , R ³ , and R ⁴ are each independently selected from H, halogeno, cyano, Ci _-6 alkyl, halo-C-|. ₆ alkyl, and carbamoyl, or from H, fluorine, chlorine, and methyl Fn Formula 1 , then, unless stated differently or otherwise clear from the context, R ¹ , R ² , R ³ , and R ⁴ are each independently selected from H, halogeno, cyano, C ₁ ^ alkyl, halo-C _1-6 alkyl, and carbamoyl, or from H, fluorine, chlorine, and methyl in Formula 1A, Formula 1B, and so on.

As described above, the compounds of Formula 1 may be used to treat CNS disorders, including schizophrenia and other psychotic disorders, mood disorders, anxiety disorders, sleep disorders, and cognitive disorders, such as delirium, dementia, and amnestic disorders. The standards for diagnosis of these disorders may be found in the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders (4th ed., 2000), which is commonly referred to as the DSM Manual.

For the purposes of this disclosure, schizophrenia and other psychotic disorders include schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder,

psychotic disorder due to general medical condition, and substance-induced psychotic disorder, as well as medication-induced movement disorders, such as neuroleptic-induced Parkinsonism, neuroleptic malignant syndrome, neuroleptic-induced acute dystonia, neuroleptic-induced acute akathisia, neuroleptic-induced tardive dyskinesia, and medication-induced postural tremor.

Mood disorders include depressive disorders, such as major depressive disorder, dysthymic disorder, premenstrual dysphoric disorder, minor depressive disorder, recurrent brief depressive disorder, postpsychotic depressive disorder of schizophrenia, and major depressive episode with schizophrenia; bipolar disorders, such as bipolar I disorder, bipolar Il disorder, cyclothymia, and bipolar disorder with schizophrenia; mood disorders due to general medical condition; and substance-induced mood disorders.

Anxiety disorders include panic attack, agoraphobia, panic disorder without agoraphobia, agoraphobia without history of panic disorder, specific phobia, social phobia (social anxiety disorder), obsessive- compulsive disorder, posttraumatic stress disorder, acute stress disorder, generalized anxiety disorder, anxiety disorder due to general medical condition, substance-induced anxiety disorder, and mixed anxiety-depressive disorder.

Sleep disorders include primary sleep disorders, such as dyssomnias (primary insomnia, primary hypersomnia, narcolepsy, breathing-related sleep disorder, circadian rhythm sleep disorder, sleep deprivation, restless legs syndrome, and periodic limb movements) and parasomnias (nightmare disorder, sleep terror disorder, sleepwalking disorder, rapid eye movement sleep behavior disorder, and sleep paralysis); sleep disorders related to another mental disorder, including insomnia related to schizophrenia, depressive disorders, or anxiety disorders, or hypersomnia associated with bipolar disorders; sleep disorders due to a general medical condition; and substance-induced sleep disorders,

Delirium, dementia, and amnestic and other cognitive disorders, includes delirium due to a general medical condition, substance-induced delirium, and delirium due to multiple etiologies; dementia of the Alzheimer's type, vascular dementia, dementia due to general medical conditions, dementia due to human immunodeficiency virus disease, dementia due to head trauma, dementia due to Parkinson's disease, dementia due to Huntington's disease, dementia due to Pick's disease, dementia due to Creutzfeldt-Jakob disease, dementia due to other general medical conditions, substance-induced persisting dementia, dementia due to multiple etiologies; amnestic disorders due to a general medical condition, and substance-induced persisting amnestic disorder.

Substance-induced disorders refer to those resulting from the using, abusing, dependence on, or withdrawal from, one or more drugs or toxins, including alcohol, amphetamines or similarly acting sympathomimetics, caffeine, cannabis, cocaine, hallucinogens, inhalants, nicotine, opioids, phencyclidine or similarly acting arylcyclohexylamines, and sedatives, hypnotics, or anxiolytics, among others.

The compounds of Formula 1 may be prepared using the techniques described below. Some of the schemes and examples may omit details of common reactions, including oxidations, reductions, and so on, separation techniques, and analytical procedures, which are known to persons of ordinary skill in the art of organic chemistry. The details of such reactions and techniques can be found in a number of

treatises, including Richard Larock, Comprehensive Organic Transformations (1999), and the multi- volume series edited by Michael B. Smith and others, Compendium of Organic Synthetic Methods (1974 et seq.). Starting materials and reagents may be obtained from commercial sources or may be prepared using literature methods. Some of the reaction schemes may omit minor products resulting from chemical transformations (e.g., an alcohol from the hydrolysis of an ester, CO ₂ from the decarboxylation of a diacid, etc.). In addition, in some instances, reaction intermediates may be used in subsequent steps without isolation or purification (i.e., in situ).

In some of the reaction schemes and examples below, certain compounds can be prepared using protecting groups, which prevent undesirable chemical reaction at otherwise reactive sites. Protecting groups may also be used to enhance solubility or otherwise modify physical properties of a compound. For a discussion of protecting group strategies, a description of materials and methods for installing and removing protecting groups, and a compilation of useful protecting groups for common functional groups, including amines, carboxylic acids, alcohols, ketones, aldehydes, and so on, see T. W. Greene and P. G. Wuts, Protecting Groups in Organic Chemistry (1999) and P. Kocienski, Protective Groups (2000).

Generally, the chemical transformations described throughout the specification may be carried out using substantially stoichiometric amounts of reactants, though certain reactions may benefit from using an excess of one or more of the reactants. Additionally, many of the reactions disclosed throughout the specification may be carried out at about room temperature (RT) and ambient pressure, but depending on reaction kinetics, yields, and so on, some reactions may be run at elevated pressures or employ higher temperatures (e.g., reflux conditions) or lower temperatures (e.g., -70°C to 0°C). Any reference in the disclosure to a stoichiometric range, a temperature range, a pH range, etc., whether or not expressly using the word "range," also includes the indicated endpoints.

Many of the chemical transformations may also employ one or more compatible solvents, which may influence the reaction rate and yield. Depending on the nature of the reactants, the one or more solvents may be polar protic solvents (including water), polar aprotic solvents, non-polar solvents, or some combination. Representative solvents include saturated aliphatic hydrocarbons (e.g., n-pentane, n- hexane, π-heptane, π-octane); aromatic hydrocarbons (e.g., benzene, toluene, xylenes); halogenated hydrocarbons (e.g., methylene chloride, chloroform, carbon tetrachloride); aliphatic alcohols (e.g., methanol, ethanol, propan-1-ol, propan-2-ol, butan-1-ol, 2-methyl-propan-1-ol, butan-2-ol, 2-methyl- propan-2-ol, pentan-1-ol, 3-methyl-butan-1-ol, hexan-1-ol, 2-methoxy-ethanol, 2-ethoxy-ethanol, 2-butoxy- ethanol, 2-(2-methoxy-ethoxy)-ethanol, 2-(2-ethoxy-ethoxy)-ethanol, 2-(2-butoxy-ethoxy)-ethanol); ethers (e.g., diethyl ether, di-isopropyl ether, dibutyl ether, 1 ,2-dimethoxy-ethane, 1,2-diethoxy-ethane, 1- methoxy-2-(2-methoxy-ethoxy)-ethane, 1-ethoxy-2-(2-ethoxy-ethoxy)-ethane, tetrahydrofuran, 1 ,4- dioxane); ketones (e.g., acetone, methyl ethyl ketone); esters (methyl acetate, ethyl acetate); nitrogen- containing solvents (e.g., formamide, λ/,λ/-dimethylformamide, acetonitrile, λ/-methyl-pyrrolidone, pyridine, quinoline, nitrobenzene); sulfur-containing solvents (e.g., carbon disulfide, dimethyl sulfoxide, tetrahydro- thiophene-1,1, -dioxide); and phosphorus-containing solvents (e.g., hexamethylphosphoric triamide).

Scheme I shows a process for preparing compounds of Formula 1. The process includes reacting a 2,3- dihydro-1 H-indole or 1,2,3,4-tetrahydro-quinoline (Formula 2) with a first acylating agent (Formula 3 or Formula 4). The resulting amide (Formula 5 or Formula 6) is treated with a Lewis acid to form a fused tricyclic heterocycle (not shown), which is subsequently acylated in situ via reaction with a second acylating agent (Formula 7). Selective reduction of the resulting arylketone (Formula 8) yields a fused tricyclic heterocycle (Formula 9) having an activated alkyl side group, which is subsequently reacted with a 1-/7-indol-3-yl-piperidine or 1-/-/-indol-3-yl-1,2,5,6-tetrahydropyridine (Formula 10) to give the desired compound of Formula 1. The 1 -/-/-indol-3-yl-piperidine or 1-W-indol-3-yl-1 ,2,5,6-tetrahydropyridine (Formula 10) may be prepared as shown in Scheme II, below. In Scheme I, substituents R ¹ to R ¹⁰ , L, Z ¹ , and Z ² are as defined above for Formula 1 and substituents X ¹ to X ⁴ are leaving groups, such as halogeno (e.g., chlorine or bromine).

Scheme I

As shown in Scheme |, acylation of the starting compound (Formula 2) using an alkylcarbonyl compound (Formula 3) or an α.β-unsaturated carbonyl compound (Formula 4) gives an amide of Formula 5 or Formula 6, respectively. The acylation may be carried out in one or more polar aprotic solvents such as acetone, methylethylketone (MEK), and dimethylsulfoxide (DMSO), at a temperature of about RT to reflux The reaction generally employs a stoichiometric excess (e.g., about 1.1 equivalents (eq) to about 1.5 eq) of the acylating agent (Formula 3 or Formula 4). Useful acylating agents include carboxylic acid halides,

such as chloro-acetyl chloride, 3-chloro-propionyl chloride, 4-chloro-butyryl chloride, 3-methyl-but-2-enoyl chloride, 3-methyl-pent-2-enoyl chloride, and 3-ethyl-pent-2-enoyl chloride. Useful starting compounds (Formula 2) include 2, 3-dihydro-1 H-indole, 4-fluoro-2,3-dihydro-1 /-/-indole, 1 ,2,3,4-tetrahydro-quinoline, and 5-fluoro-1 ,2,3,4-tetrahydro-quinoline.

Following acylation, the amide (Formula 5 or Formula 6) is treated with a Lewis acid to form a fused tricyclic intermediate, which is subsequently reacted in situ with a second acylating agent (Formula 7) to give an arylketone (Formula 8). The ring-closure reaction is carried out neat or in an inert solvent, such as CS ₂ or nitrobenzene, at a temperature in a range of from about 5O ⁰ C to about 120 ⁰ C or from about 70 ⁰ C to about 110°C. The subsequent acylation is typically carried out in one or more non-polar solvents, such as CS ₂ , CH ₂ CI ₂ , and CHCI ₃ , at a temperature in a range of from about RT to reflux. The ring closure reaction and the acylation generally employ a stoichiometric excess of the Lewis acid (e.g., about 2.1 eq to about 4 eq) and the acylating agent (e.g., about 1.1 eq to about 1.5 eq). Useful Lewis acids may include AIBr ₃ , AICI ₃ , GaCI ₃ , FeCI ₃ , ZnCI ₂ , SbCI ₅ , TiCI ₄ , ZrCI ₄ , SnCI ₄ , BCI ₃ , BF ₃ , or SbCI ₃ ; useful acylating agents may include chloro-acetyl chloride, 3-chloro-propionyl chloride, or 4-chloro-butyryl chloride.

After ring closure and acylation, the arylketone (Formula 8) is selectively reduced via reaction with a reducing agent, such as triethyl-silane (Et ₃ SiH) in trifluoroacetic acid (TFA). The selective reduction using Et ₃ SiH in TFA may be carried out at a temperature of about RT or less with a stoichiometric excess of both the trialkylsilane (e.g., about 2.1 eq to about 4 eq) and the acid (e.g., about 5 eq to about 15 eq). Although the reaction may be run neat, it may employ one or more solvents such as MeNO ₂ , CH ₂ CI ₂ , CHCI ₃ , and CCI ₄ .

As shown in Scheme I, the fused tricyclic heterocycle (Formula 9) is reacted with a 1-/-/-indol-3-yl- piperidine or 1-/7-indol-3-yl -1 ,2,5,6-tetrahydropyridine (Formula 10) to give the desired compound of Formula I. The reaction, which is run in an inert solvent and in the presence of a hindered or non- nucleophilic base, may employ a catalyst such as NaI or Kl. The reaction may be run at a temperature that ranges from about RT to reflux with a stoichiometric excess of the indole derivative (e.g., about 1.2 eq to about 1.5 eq), base (about 2 eq to about 5 eq) and catalyst (2 eq to about 5 eq). Useful inert solvents include water, acetonitrile (ACN), dioxane, benzene, toluene, tetrahydrofuran (THF) or mixtures thereof; useful bases include K ₂ CO ₃ , Na ₂ CO ₃ , triethyl-amine (Et ₃ N), or diisopropylethylamine (DIPEA).

Scheme Il shows a method for preparing 1-/Y-indol-3-yl-piperidines (Formula 10B) and 1-/-/-indol-3-yl- tetrahydropyridines (Formula 10A). The method includes reacting an indole (Formula 11) with an N- protected piperidinone (Formula 12) in a basic alcohol solution (e.g., KOH in MeOH) to give a 1-H-indol-3- yl-λ/-protected tetrahydropyridine (Formula 13). The reaction is typically carried out under reflux conditions in excess base (e.g., 2 eq to 4 eq) and with excess λ/-protected piperidinone (1.5 eq to 2.5 eq). Deprotection of the tetrahydropyridine moiety (Formula 13) gives a 1-/-/-indol-3-yl-tetrahydropyridine (Formula 10A), which may undergo hydrogenation to give a 1-/-/-indol-3-yl-piperidine (Formula 10B). Substituents R ¹ , R ² , R ⁷ , and R ¹⁰ in Formula 1OA, 1OB, 11, and 13, and substituents R ⁸ and R ⁹ in Formula 1OA, 1OB, 12, and 13, are as defined above for Formula 1. Substituent R ¹¹ in Formula 12 and 13 is an amine protecting group, such as f-butoxycarbonyl (Boc), triphenylmethyl, and the like. In

Formula 12, substituent Z ³ is methanediyl or ethanediyl and substituent Z ⁴ is a bond or methanediyl, provided that Z ³ , Z ⁴ , and the atoms to which they are attached form a 6-member heterocycle (piperidinone).

Scheme Il

The conditions in Scheme Il for deprotection of the tetrahydropyridine moiety (Formula 13) will depend on the nature of the protecting group (R ¹¹ ). For example, when R ¹¹ is Boc, the protecting group may be removed by treating the λ/-protected tetrahydropyridine (Formula 13) with an acid (e.g., 4N HCI in 1 ,4- dioxane) at RT. Hydrogenation of the resulting 1-H-indol-3-yl-tetrahydropyridine (Formula 10A) may be carried out in the presence of a catalyst and one or more polar solvents, such as MeOH, EtOH, /-PrOH, THF, EtOAc, and so on. Useful catalysts include heterogeneous catalysts containing from about 0.1% to about 20%, and more typically, from about 1 % to about 10%, by weight, of Pd, Pt, Rh, Ru, Ir, and combinations thereof, which are supported on various materials, including C, Ai ₂ O ₃ , CaCO ₃ , SrCO ₃ , BaSO ₄ , MgO, SiO ₂ , TiO ₂ , ZrO ₂ , and the like. Many of these metals, including Pd, may be doped with an amine, sulfide, or a second metal, such as Pb, Cu, or Zn. Useful catalysts thus include palladium catalysts such as Pd/C, Pd/SrCO ₃ , Pd/AI ₂ O ₃ , Pd/MgO, Pd/CaCO ₃ , Pd/BaSO ₄ , and the like, containing from about 1% to about 10% Pd, based on weight. The hydrogenation may be carried out at a

temperature in the range of about 5 ⁰ C to about 100 ⁰ C (e.g., at about RT). Generally, the substrate-to- catalyst ratio may range from about 1:1 to about 1000:1, based on weight, and H ₂ pressure may range from about atmospheric pressure, 0 psig, to about 1500 psig. Typically, the substrate-to-catalyst ratios range from about 4:1 to about 20:1, and H ₂ pressures range from about 25 psig to about 100 psig.

All references to compounds, including compounds of Formula 1, Formula 1A ₁ Formula 1B, and compounds named in the specification, generally include all complexes, salts, solvates, hydrates, and liquid crystals of the compounds. Likewise, all references to compounds include all complexes, solvates, hydrates, and liquid crystals of the salts of the compounds.

Compounds of Formula 1, which include compounds represented by Formula 1A, Formula 1B, and compounds specifically named above, may form pharmaceutically acceptable complexes, salts, solvates and hydrates. These salts include acid addition salts (including di-acids) and base salts. Pharmaceutically acceptable acid addition salts include nontoxic salts derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, and phosphorous acids, as well nontoxic salts derived from organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Such salts include acetate, adipate, aspartate, benzoate, besylate, bicarbonate, carbonate, bisulfate, sulfate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate, hydrogen phosphate, dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinofoate salts.

Pharmaceutically acceptable base salts include nontoxic salts derived from bases, including metal cations, such as an alkali or alkaline earth metal cation, as well as amines. Examples of suitable metal cations include sodium (Na ⁺ ), potassium (K ⁺ ), magnesium (Mg ²⁺ ), calcium (Ca ²⁺ ), zinc (Zn ²⁺ ), and aluminum (Al ³⁺ ). Examples of suitable amines include arginine, λ/,λ/'-dibenzylethylenediamine, chloroprocaine, choline, diethylamine, diethanolamine, dicyclohexylamine, ethylenediamine, glycine, lysine, λ/-methylglucamine, olamine, 2-amino-2-hydroxymethyl-propane-1 ,3-diol, and procaine. For a discussion of useful acid addition and base salts, see S. M. Berge et al., "Pharmaceutical Salts," 66 J. Pharm. ScL, 1-19 (1977); see also Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection, and Use (2002).

Pharmaceutically acceptable salts may be prepared using various methods. For example, one may react a compound of Formula 1 with an appropriate acid or base to give the desired salt. One may also react a precursor of the compound of Formula 1 with an acid or base to remove an acid- or base-labile protecting group or to open a lactone or lactam group of the precursor. Additionally, one may convert a salt of the compound of Formula 1 to another salt through treatment with an appropriate acid or base or through contact with an ion exchange resin. Following reaction, one may then isolate the salt by filtration if it

precipitates from solution, or by evaporation to recover the salt. The degree of ionization of the salt may vary from completely ionized to almost non-ionized.

Compounds of Formula 1 may exist in a continuum of solid states ranging from fully amorphous to fully crystalline. The term "amorphous" refers to a state in which the material lacks long range order at the molecular level and, depending upon temperature, may exhibit the physical properties of a solid or a liquid. Typically such materials do not give distinctive X-ray diffraction patterns and, while exhibiting the properties of a solid, are more formally described as a liquid. Upon heating, a change from solid to liquid properties occurs which is characterized by a change of state, typically second order ("glass transition"). The term "crystalline" refers to a solid phase in which the material has a regular ordered internal structure at the molecular level and gives a distinctive X-ray diffraction pattern with defined peaks. Such materials when heated sufficiently will also exhibit the properties of a liquid, but the change from solid to liquid is characterized by a phase change, typically first order ("melting point").

Compounds of Formula 1 may also exist in unsolvated and solvated forms. The term "solvate" describes a molecular complex comprising the compound and one or more pharmaceutically acceptable solvent molecules (e.g., EtOH). The term "hydrate" is a solvate in which the solvent is water. Pharmaceutically acceptable solvates include those in which the solvent may be isotopically substituted (e.g., D ₂ O, d ₆ - acetone, d ₆ -DMSO).

A currently accepted classification system for solvates and hydrates of organic compounds is one that distinguishes between isolated site, channel, and metal-ion coordinated solvates and hydrates. See, e.g., K. R. Morris (H. G. Brittain ed.) Polymorphism in Pharmaceutical Solids (1995). Isolated site solvates and hydrates are ones in which the solvent (e.g., water) molecules are isolated from direct contact with each other by intervening molecules of the organic compound. In channel solvates, the solvent molecules lie in lattice channels where they are next to other solvent molecules. In metal-ion coordinated solvates, the solvent molecules are bonded to the metal ion.

When the solvent or water is tightly bound, the complex will have a well-defined stoichiometry independent of humidity. When, however, the solvent or water is weakly bound, as in channel solvates and in hygroscopic compounds, the water or solvent content will depend on humidity and drying conditions. In such cases, non-stoichiometry will be the norm.

Compounds of Formula 1 may also exist as multi-component complexes (other than salts and solvates) in which the compound (drug) and at least one other component are present in stoichiometric or non- stoichiometric amounts. Complexes of this type include clathrates (drug-host inclusion complexes) and co-crystals. The latter are typically defined as crystalline complexes of neutral molecular constituents which are bound together through non-covalent interactions, but could also be a complex of a neutral molecule with a salt. Co-crystals may be prepared by melt crystallization, by recrystallization from solvents, or by physically grinding the components together. See, e.g., O. Almarsson and

M. J. Zaworotko, Chem. Commun., 17:1889-1896 (2004). For a general review of multi-component complexes, see J. K. Haleblian, J. Pharm. ScL 64(8): 1269-88 (1975).

When subjected to suitable conditions, compounds of Formula 1 may exist in a mesomorphic state (mesophase or liquid crystal). The mesomorphic state lies between the true crystalline state and the true liquid state (either melt or solution). Mesomorphism arising as the result of a change in temperature is described as "thermotropic" and mesomorphism resulting from the addition of a second component, such as water or another solvent, is described as "lyotropic." Compounds that have the potential to form lyotropic mesophases are described as "amphiphilic" and include molecules which possess a polar ionic moiety (e.g., -COO-Na ⁺ , -COO-K ⁺ , -SO ₃ -Na ⁺ ) or polar non-ionic moiety (such as -N ^" N ⁺ (CH ₃ ) ₃ ). See, e.g., N. H. Hartshorne and A. Stuart, Crystals and the Polarizing Microscope (4th ed, 1970).

All references to compounds, including compounds of Formula 1 , Formula 1A, Formula 1B, and compounds named in the specification, generally include all polymorphs and crystal habits, prodrugs, metabolites, stereoisomers, and tautomers thereof, as well as all isotopically-labeled compounds thereof.

"Prodrugs" refer to compounds having little or no pharmacological activity that can, when metabolized in vivo, undergo conversion to compounds having desired pharmacological activity. Prodrugs may be prepared by replacing appropriate functionalities present in pharmacologically active compounds with "pro-moieties" as described, for example, in H. Bundgaar, Design of Prodrugs (1985). Examples of prodrugs include ester, ether or amide derivatives of compounds of Formula 1 having carboxylic acid, hydroxy, or amino functional groups, respectively. For further discussions of prodrugs, see e.g., T. Higuchi and V. Stella "Pro-drugs as Novel Delivery Systems," ACS Symposium Series 14 (1975) and E. B. Roche ed., Bioreversible Carriers in Drug Design (1987).

"Metabolites" refer to compounds formed in vivo upon administration of pharmacologically active compounds. Examples include hydroxymethyl, hydroxy, secondary amino, primary amino, phenol, and carboxylic acid derivatives of compounds of Formula 1 having methyl, alkoxy, tertiary amino, secondary amino, phenyl, and amide groups, respectively.

Certain compounds described herein may have stereoisomers. Some of these compounds may exist as single enantiomers (enantiopure compounds) or mixtures of enantiomers (enriched and racemic samples), which depending on the relative excess of one enantiomer over another in a sample, may exhibit optical activity. Such stereoisomers, which are non-superimposable mirror images, possess a stereogenic axis or one or more stereogenic centers (i.e., chirality). Other compounds may be stereoisomers that are not mirror images. Such stereoisomers, which are known as diastereoisomers, may be chiral or achiral (contain no stereogenic centers). They include molecules containing an alkenyl or cyclic group, so that cis/trans (or ZIE) stereoisomers are possible, or molecules containing two or more stereogenic centers, in which inversion of a single stereogenic center generates a corresponding diastereoisomer. Unless stated or otherwise clear (e.g., through use of stereobonds, stereocenter descriptors, etc.) the scope of the invention and disclosure generally includes the reference compound and its stereoisomers, whether they are each pure (e.g., enantiopure) or mixtures (e.g., enantiomerically enriched or racemic).

Geometrical (cisltrans) isomers may be separated by conventional techniques such as chromatography and fractional crystallization.

Individual enantiomers of compounds may be prepared via chiral synthesis from a suitable optically pure precursor or isolated via resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral HPLC. Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable enantiomerically pure compound (e.g., acid or base) to yield a pair of diastereoisomers, each composed of a single enantiomer, which are separated via, say, fractional recrystallization or chromatography. The desired enantiomer is subsequently regenerated from the appropriate diastereoisomer. Often, the desired enantiomer may be further enriched by recrystallization in a suitable solvent (e.g., ACN) when it is it available in sufficient quantity (e.g., typically not much less than about 85% ee, and in some cases, not much less than about 90% ee). For a further discussion of techniques for separating stereoisomers, see E. L. Eliel and S. H. Wilen, Stereochemistry of Organic Compounds (1994).

"Tautomers" refer to structural isomers that are interconvertible via a low energy barrier. Tautomeric isomerism (tautomerism) may take the form of proton tautomerism in which the compound contains, for example, an imino, keto, or oxime group, or valence tautomerism in which the compound contains an aromatic moiety.

Compounds described herein also include all pharmaceutically acceptable isotopic variations, in which at least one atom is replaced by an atom having the same atomic number, but an atomic mass different from the atomic mass usually found in nature. Isotopes suitable for inclusion in compounds of Formula 1 include, for example, isotopes of hydrogen, such as ² H and ³ H; isotopes of carbon, such as ¹¹ C, ¹³ C and ¹⁴ C; isotopes of nitrogen, such as ¹³ N and ¹⁵ N; isotopes of oxygen, such as ¹⁵ 0, ¹⁷ O and ¹⁸ O; isotopes of sulfur, such as ³⁵ S; isotopes of fluorine, such as ¹⁸ F; isotopes of chlorine, such as ³⁶ CI, and isotopes of iodine, such as ¹²³ I and ¹²⁵ I. Use of isotopic variations (e.g., deuterium, ² H) may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements. Additionally, certain isotopic variations of the disclosed compounds may incorporate a radioactive isotope (e.g., tritium, ³ H, or ¹⁴ C), which may be useful in drug and/or substrate tissue distribution studies. Substitution with positron emitting isotopes, such as ¹¹ C, ¹⁸ F, ¹⁵ O and ¹³ N, may be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled compounds may be prepared by processes analogous to those described elsewhere in the disclosure using an appropriate isotopically-labeled reagent in place of a non-labeled reagent.

Compounds of Formula 1, which include compounds represented by Formula 1A, Formula 1B, compounds named above, and their pharmaceutically acceptable complexes, salts, solvates and hydrates, should be assessed for their biopharmaceutical properties, such as solubility and solution stability across pH, permeability, and so on, to select an appropriate dosage form and route of administration. Compounds that are intended for pharmaceutical use may be administered as crystalline or amorphous products, and may be obtained, for example, as solid plugs, powders, or films by methods

such as precipitation, crystallization, freeze drying, spray drying, evaporative drying, microwave drying, or radio frequency drying.

Compounds of Formula 1 may be administered alone or in combination with one another or with one or more pharmacologically active compounds which are different than the compounds of Formula 1. Generally, one or more these compounds are administered as a pharmaceutical composition (a formulation) in association with one or more pharmaceutically acceptable excipients. The choice of excipients depends on the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form, among other things. Useful pharmaceutical compositions and methods for their preparation may be found, for example, in A. R. Gennaro (ed.), Remington: The Science and Practice of Pharmacy (20th ed . , 2000).

Compounds of Formula 1 may be administered orally. Oral administration may involve swallowing in which case the compound enters the bloodstream via the gastrointestinal tract. Alternatively or additionally, oral administration may involve mucosal administration (e.g., buccal, sublingual, supralingual administration) such that the compound enters the bloodstream through the oral mucosa.

Formulations suitable for oral administration include solid, semi-solid and liquid systems such as tablets; soft or hard capsules containing multi- or nano-particulates, liquids, or powders; lozenges which may be liquid-filled; chews; gels; fast dispersing dosage forms; films; ovules; sprays; and buccal or mucoadhesive patches.

Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be employed as fillers in soft or hard capsules (made, for example, from gelatin or hydroxypropylmethylcellulose) and typically comprise a carrier (e.g., water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil) and one or more emulsifying agents, suspending agents or both. Liquid formulations may also be prepared by the reconstitution of a solid (e.g., from a sachet).

Compounds of Formula 1 may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Liang and Chen, Expert Opinion in Therapeutic Patents, 11(6):981-986 (2001).

For tablet dosage forms, depending on dose, the active pharmaceutical ingredient (API) may comprise from about 1 wt% to about 80 wt% of the dosage form or more typically from about 5 wt% to about 60 wt% of the dosage form. In addition to the API, tablets may include one or more disintegrants, binders, diluents, surfactants, glidants, lubricants, anti-oxidants, colorants, flavoring agents, preservatives, and taste-masking agents. Examples of disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, C-|. ₆ alkyl-substituted hydroxypropylcellulose, starch, pregelatinized starch, and sodium alginate. Generally, the disintegrant will comprise from about 1 wt% to about 25 wt% or from about 5 wt% to about 20 wt% of the dosage form.

Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropylcellulose and hydroxypropylmethylcellulose. Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.

Tablets may also include surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When present, surface active agents may comprise from about 0.2 wt% to about 5 wt% of the tablet, and glidants may comprise from about 0.2 wt% to about 1 wt% of the tablet.

Tablets may also contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulfate. Lubricants may comprise from about 0.25 wt% to about 10 wt% or from about 0.5 wt% to about 3 wt% of the tablet.

Tablet blends may be compressed directly or by roller compaction to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tableting. If desired, prior to blending one or more of the components may be sized by screening or milling or both. The final dosage form may comprise one or more layers and may be coated, uncoated, or encapsulated. Exemplary tablets may contain up to about 80 wt% of API, from about 10 wt% to about 90 wt% of binder, from about 0 wt% to about 85 wt% of diluent, from about 2 wt% to about 10 wt% of disintegrant, and from about 0.25 wt% to about 10 wt% of lubricant. For a discussion of blending, granulation, milling, screening, tableting, coating, as well as a description of alternative techniques for preparing drug products, see A. R. Gennaro (ed.), Remington: The Science and Practice of Pharmacy (20th ed., 2000); H. A. Lieberman et al. (ed.), Pharmaceutical Dosage Forms: Tablets, Vol. 1-3 (2d ed., 1990); and D. K. Parikh & C. K. Parikh, Handbook of Pharmaceutical Granulation Technology, Vol. 81 (1997).

Consumable oral films for human or veterinary use are pliable water-soluble or water-swellable thin film dosage forms which may be rapidly dissolving or mucoadhesive. In addition to the API, a typical film includes one or more film-forming polymers, binders, solvents, humectants, plasticizers, stabilizers or emulsifiers, viscosity-modifying agents, and solvents. Other film ingredients may include anti-oxidants, colorants, flavorants and flavor enhancers, preservatives, salivary stimulating agents, cooling agents, co- solvents (including oils), emollients, bulking agents, anti-foaming agents, surfactants, and taste-masking agents. Some components of the formulation may perform more than one function.

In addition to dosing requirements, the amount of API in the film may depend on its solubility. If water soluble, the API would typically comprise from about 1 wt% to about 80 wt% of the non-solvent components (solutes) in the film or from about 20 wt% to about 50 wt% of the solutes in the film. A less soluble API may comprise a greater proportion of the composition, typically up to about 88 wt% of the non-solvent components in the film.

The film-forming polymer may be selected from natural polysaccharides, proteins, or synthetic hydrocolloids and typically comprises from about 0.01 wt% to about 99 wt% or from about 30 wt% to about 80wt% of the film.

Film dosage forms are typically prepared by evaporative drying of thin aqueous films coated onto a peelable backing support or paper, which may carried out in a drying oven or tunnel (e.g., in a combined coating-drying apparatus), in lyophilization equipment, or in a vacuum oven.

Useful solid formulations for oral administration may include immediate release formulations and modified release formulations. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted-, and programmed-release. For a general description of suitable modified release formulations, see US Patent No. 6,106,864. For details of other useful release technologies, such as high energy dispersions and osmotic and coated particles, see Verma et al, Pharmaceutical Technology On-line (2001) 25(2):1-14.

Compounds of Formula 1 may also be administered directly into the blood stream, muscle, or an internal organ of the subject. Suitable techniques for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial, and subcutaneous administration. Suitable devices for parenteral administration include needle injectors, including microneedle injectors, needle-free injectors, and infusion devices.

Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (e.g., pH of from about 3 to about 9). For some applications, however, compounds of Formula 1 may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water. The preparation of parenteral formulations under sterile conditions (e.g., by lyophilization) may be readily accomplished using standard pharmaceutical techniques.

The solubility of compounds which are used in the preparation of parenteral solutions may be increased through appropriate formulation techniques, such as the incorporation of solubility-enhancing agents. Formulations for parenteral administration may be formulated to be immediate or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, targeted, and programmed release. Thus, compounds of Formula 1 may be formulated as a suspension, a solid, a semi-solid, or a thixotropic liquid for administration as an implanted depot providing modified release of the active compound. Examples of such formulations include drug-coated stents and semi-solids and suspensions comprising drug-loaded poly(DL-lactic-coglycolic)acid (PGLA) microspheres.

Compounds of Formula 1 may also be administered topically, intradermal^, or transdermal^ to the skin or mucosa. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions. Liposomes may also be used. Typical carriers may include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol.

Topical formulations may also include penetration enhancers. See, e.g., Finnin and Morgan, J. Pharm. Sci. 88(10):955-958 (1999).

Other means of topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free (e.g. POWDERJECT and BIOJECT) injection. Formulations for topical administration may be formulated to be immediate or modified release as described above.

Compounds of Formula 1 may also be administered intranasally or by inhalation, typically in the form of a dry powder, an aerosol spray, or nasal drops. An inhaler may be used to administer the dry powder, which comprises the API alone, a powder blend of the API and a diluent, such as lactose, or a mixed component particle that includes the API and a phospholipid, such as phosphatidylcholine. For intranasal use, the powder may include a bioadhesive agent, e.g., chitosan or cyclodextrin. A pressurized container, pump, sprayer, atomizer, or nebulizer, may be used to generate the aerosol spray from a solution or suspension comprising the API, one or more agents for dispersing, solubilizing, or extending the release of the API (e.g., EtOH with or without water), one or more solvents (e.g., 1 ,1,1,2-tetrafluoroethane or 1,1,1, 2,3, 3,3-heptafluoropropane) which serve as a propellant, and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid. An atomizer using electrohydrodynamics may be used to produce a fine mist.

Prior to use in a dry powder or suspension formulation, the drug product is usually comminuted to a particle size suitable for delivery by inhalation (typically 90% of the particles, based on volume, having a largest dimension less than 5 microns). This may be achieved by any appropriate size reduction method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing, high pressure homogenization, or spray drying.

Capsules, blisters and cartridges (made, for example, from gelatin or hydroxypropylmethyl cellulose) for use in an inhaler or insufflator may be formulated to contain a powder mixture of the active compound, a suitable powder base such as lactose or starch, and a performance modifier such as L-leucine, mannitol, or magnesium stearate. The lactose may be anhydrous or monohydrated. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose.

A suitable solution formulation for use in an atomizer using electrohydrodynamics to produce a fine mist may contain from about 1 μg to about 20 mg of the API per actuation and the actuation volume may vary from about 1 μl_ to about 100 μl_. A typical formulation may comprise one or more compounds of

Formula 1, propylene glycol, sterile water, EtOH, and NaCI. Alternative solvents, which may be used instead of propylene glycol, include glycerol and polyethylene glycol.

Formulations for inhaled administration, intranasal administration, or both, may be formulated to be immediate or modified release using, for example, PGLA. Suitable flavors, such as menthol and levomenthol, or sweeteners, such as saccharin or sodium saccharin, may be added to formulations intended for inhaled/intranasal administration.

In the case of dry powder inhalers and aerosols, the dosage unit is determined by means of a valve that delivers a metered amount. Units are typically arranged to administer a metered dose or "puff containing from about 10 μg to about 1000 μg of the API. The overall daily dose will typically range from about 100 μg to about 10 mg which may be administered in a single dose or, more usually, as divided doses throughout the day.

The active compounds may be administered rectally or vaginally, e.g., in the form of a suppository, pessary, or enema. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate. Formulations for rectal or vaginal administration may be formulated to be immediate or modified release as described above.

Compounds of Formula 1 may also be administered directly to the eye or ear, typically in the form of drops of a micronized suspension or solution in isotonic, pH-adjusted, sterile saline. Other formulations suitable for ocular and aural administration include ointments, gels, biodegradable implants (e.g. absorbable gel sponges, collagen), non-biodegradable implants (e.g. silicone), wafers, lenses, and particulate or vesicular systems, such as niosomes or liposomes. The formulation may include one or more polymers and a preservative, such as benzalkonium chloride. Typical polymers include crossed- linked polyacrylic acid, polyvinylalcohol, hyaluronic acid, cellulosic polymers (e.g., hydroxypropylmethylcellulose, hydroxyethylcellulose, methyl cellulose), and heteropolysaccharide polymers (e.g., gelan gum). Such formulations may also be delivered by iontophoresis. Formulations for ocular or aural administration may be formulated to be immediate or modified release as described above.

To improve their solubility, dissolution rate, taste-masking, bioavailability, or stability, compounds of Formula 1 may be combined with soluble macromolecular entities, including cyclodextrin and its derivatives and polyethylene glycol-containing polymers. For example, API-cyclodextrin complexes are generally useful for most dosage forms and routes of administration. Both inclusion and non-inclusion complexes may be used. As an alternative to direct complexation with the API, the cyclodextrin may be used as an auxiliary additive, i.e. as a carrier, diluent, or solubilizer. Alpha-, beta- and gamma- cyclodextrins are commonly used for these purposes. See, e.g., WO 91/11172, WO 94/02518, and WO 98/55148.

As noted above, one or more compounds of Formula 1 , including compounds of Formula 1A, Formula 1B, compounds specifically named above, and their pharmaceutically active complexes, salts, solvates and hydrates, may be combined with each other or with one or more other active pharmaceutically active compounds to treat various diseases, conditions and disorders. In such cases, the active compounds may be combined in a single dosage form as described above or may be provided in the form of a kit which is suitable for coadministration of the compositions. The kit comprises (1) two or more different pharmaceutical compositions, at least one of which contains a compound of Formula 1; and (2) a device for separately retaining the two pharmaceutical compositions, such as a divided bottle or a divided foil packet. An example of such a kit is the familiar blister pack used for the packaging of tablets or capsules. The kit is suitable for administering different types of dosage forms (e.g., oral and parenteral) or for administering different pharmaceutical compositions at separate dosing intervals, or for titrating the

different pharmaceutical compositions against one another. To assist with patient compliance, the kit typically comprises directions for administration and may be provided with a memory aid.

For administration to human patients, the total daily dose of the claimed and disclosed compounds is typically in the range of about 0.1 mg to about 3000 mg depending on the route of administration. For example, oral administration may require a total daily dose of from about 1 mg to about 3000 mg, while an intravenous dose may only require a total daily dose of from about 0.1 mg to about 300 mg. The total daily dose may be administered in single or divided doses and, at the physician's discretion, may fall outside of the typical ranges given above. Although these dosages are based on an average human subject having a mass of about 60 kg to about 70 kg, the physician will be able to determine the appropriate dose for a patient (e.g., an infant) whose mass falls outside of this weight range.

The claimed and disclosed compounds may be combined with one or more other pharmacologically active compounds for the treatment of one or more CNS-related disorders, including schizophrenia and other psychotic disorders, mood disorders, anxiety disorders, sleep disorders, and cognitive disorders. For example, compounds of Formula 1, which include compounds represented by Formula 1A, Formula 1 B, compounds specifically named above, and their pharmaceutically acceptable complexes, salts, solvates and hydrates, may be administered simultaneously, sequentially or separately in combination with one or more atypical antipsychotics, antidepressants, or anxiolytics. Such combinations may offer significant therapeutic advantages, including fewer side effects, improved ability to treat underserved patient populations, or synergistic activity.

Representative atypical antipsychotics include D ₂ dopamine receptor antagonists, such as clozapine, olanzapine, risperidone, quetiapine, sertindole, and ziprasidone. For the purposes of this disclosure, any reference to a pharmacologically active compound includes its pharmaceutically acceptable complexes, salts, solvates, and hydrates, any polymorphic forms, including crystalline and amorphous forms, and any stereoisomers or tautomeric forms, whether pure, substantially pure, or a mixture.

Representative antidepressants include norepinephrine reuptake inhibitors (NRIs), selective serotonin reuptake inhibitors (SSRIs), neurokinin 1 (NK-1) receptor antagonists, monoamine oxidase inhibitors (MAOIs), reversible inhibitors of monoamine oxidase (RIMAs), serotonin and noradrenaline reuptake inhibitors (SNRIs), corticotropin releasing factor (CRF) antagonists, α-adrenoreceptor antagonists, and atypical antidepressants. Suitable NRIs may include tertiary amine tricyclics and secondary amine tricyclics, such as amitriptyline, clomipramine, doxepin, imipramine, trimipramine, dothiepin, butripyline, iprindole, lofepramine, nortriptyline, protriptyline, amoxapine, desipramine and maprotiline. Suitable SSRIs may include fluoxetine, fluvoxamine, paroxetine, citalopram and sertraline. Suitable MAOIs may include isocarboxazid, phenelzine, and tranylcyclopramine. Suitable RIMAs may include moclobemide. Suitable SNRIs may include venlafaxine, duloxetine, and milnacipran. Suitable CRF antagonists may include those compounds described in published patent applications WO 94/13643, WO 94/13644, WO 94/13661 , WO 94/13676 and WO 94/13677. Suitable atypical antidepressants may include ^' bupropion, lithium, nefazodone, trazodone and viloxazine. Suitable NK-1 receptor antagonists may include those described in published patent application WO 01/77100.

Representative anxiolytics may include benzodiazepines and 5-HT-IA agonists or antagonists, especially 5- HTIA partial agonists, and CRF antagonists. Suitable benzodiazepines may include alprazolam, chlordiazepoxide, clonazepam, chlorazepate, diazepam, halazepam, lorazepam, oxazepam, and prazepam. Suitable 5-HT _1A receptor agonists or antagonists may include buspirone, flesinoxan, gepirone, and ipsapirone.

EXAMPLES

The following examples are intended to be illustrative and non-limiting, and represent specific embodiments of the present invention.

¹ H Nuclear magnetic resonance (NMR) spectra were obtained for many of the compounds in the following examples. Characteristic chemical shifts (δ) are given in parts-per-million downfield from tetramethylsilane using conventional abbreviations for designation of major peaks, including s (singlet), d (doublet), t (triplet), q (quartet); m (multiplet), and br (broad). The mass spectra (m/z) were recorded using either electrospray ionization (ESI) or atmospheric pressure chemical ionization (APCI). The following abbreviations may be used for common solvents: CDCI ₃ (deuterochloroform), DMSOd ₆ (deuterodimethylsulfoxide), CD ₃ OD (deuteromethanol), and THF-d ₈ (deuterotetrahydrofuran). "Ammonia" refers to a concentrated solution of ammonia in water possessing a specific gravity of 0.88. Where thin layer chromatography (TLC) has been used it refers to silica gel TLC using silica gel 60 F _2S4 plates; the response factor (R _f ) is the distance traveled by a compound divided by the distance traveled by the solvent front on a TLC plate.

EXAMPLE 1. Preparation of 3-chloro-1 -(3,4-dihydro-2W-quinolin-1 -yl)-propan-1 -one

To a solution of 1 ,2,3,4-tetrahydro-quinoline (5.0 g, 0.037 mol) in acetone (100 mL) was added 3-chloro- propionyl chloride (5.1 g, 0.040 mol). After heating the mixture at 70 ⁰ C for 3 h, the solvent was removed in vacuo. The resulting residue was dissolved in CH ₂ CI ₂ and washed with water and with brine. The organic layer was dried over Na ₂ SO ₄ , filtered, and concentrated to give the title compound as a brown solid (8.2 g, 98.8%). ¹ H NMR 400 MHz (CDCI ₃ ) δ 7.22 - 7.10 (4H, m), 3.92 - 3.80(4H, m), 2.99 (2H, t), 2.75 (2H, t), 2.00 (2H, m).

EXAMPLE 2. Preparation of 9-(3-chloro-propionyl)-1 ,2,6,7-tetrahydro-5H-pyrido[3,2,1-/y]quinolin-3-one

3-Chloro-1-(3,4-dihydro-2/-/-quinolin-1-yl)-propan-1-one (5.0 g, 0.022 mol) and AICI ₃ (8.96 g, 0.067 mol) were mixed under nitrogen and heated at 100 ⁰ C for 1 h. The reaction mixture was cooled. Carbon disulfide (20 mL), followed by 3-chloro-propionyl chloride (2.58 mL, 0.027 mol) were added and the reaction mixture was stirred overnight at RT. The reaction mixture formed two distinct layers. The upper, colorless layer (CS ₂ ) was decanted off. The lower viscous layer was hydrolyzed by the addition of crushed ice in small portions until gas evolution ceased, and was subsequently extracted with EtOAc, washed with water and brine, dried over Na ₂ SO ₄ , and concentrated to provide the title compound as a brown solid (6.0 g, 96.6%). ¹ H NMR 400 MHz (CDCI ₃ ) δ 7.65 (1 H, s), 7.62 (1 H, s), 4.00 - 3.80 (4H, m), 3.40 (2H, t), 3.00 (2H, t), 2.85 (2H ₁ 1), 2.70 (2H, t), 2.00 (2H, m).

EXAMPLE 3. Preparation of 9-(3-chloro-propy|)-i ,2,6,74etrahydro-5H-pyrido[3,2,1-/y]quinolin-3-one

To a solution of 9-(3-chloro-propionyl)-1 ,2,6,7-tetrahydro-5H-pyrido[3,2,1-/y]quinolin-3-one (3.0 g, 0.011 mol) in TFA (50 mL) under nitrogen was added Et ₃ SiH (3.78 g, 0.032 mol). The resulting reaction mixture was stirred at RT overnight. The volatile solvent was subsequently removed in vacuo, and the residue was dissolved in EtOAc, washed with saturated NaHCO ₃ and with brine, dried over Na ₂ SO ₄ , and concentrated. The residue was suspended in hexane, sonicated for 5 min, and filtered. The solid was washed with hexane and dried. Purification by column chromatography (silica gel, 2% MeOH in CH ₂ CI ₂ ) afforded the title compound as a white solid (1.5 g, 63%). ¹ H NMR 400 MHz (CDCI ₃ ) δ 6.82 (1 H, s), 6.80 (1 H, s), 3.85 (2H, t), 3.75 (1H, t), 2.85 (2H, t), 2.79 (2H, t), 2.70 (2H, t), 2.65 (2H, t), 2.05(2H, m), 1.95 (2H, m).

EXAMPLE 4. Preparation of 9-{3-[4-(5-fluoro-1 H-indol-3-yl)-3,6-dihydro-2W-pyridin-1 -yl]-propyl}-1 ,2,6,7- tetrahydro-5H-pyrido[3,2, 1 -/y]quinolin-3-one

A solution of 9-(3-chloro-propyl)-1,2,6,7-tetrahydro-5W-pyrido[3,2,1-/y]qu inolin-3-one (500 mg, 1.90 mmol), 5-fluoro-3-(1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indole (492 mg, 2.28 mmol), NaI (570 mg, 3.8 mmol) and Na ₂ CO ₃ (604 mg, 5.7 mmol) in 10% dioxane/H ₂ O (20 mL) was heated to reflux overnight. After cooling the reaction mixture, EtOAc was added, and the mixture was washed with water and with brine, dried over Na ₂ SO ₄ , and concentrated. The residue was purified by column chromatography (silica gel, 10% MeOH in CH ₂ CI ₂ ) to afford the title compound as a yellow solid (280 mg, 33%). MS m/z 444 (M+1), HPLC (area) purity 95.69%, mp 186.9°C; ¹ H NMR 400 MHz (CDCI ₃ ) δ 8.26 (1 H, br s), 7.52 (1 H, dd), 7.32 - 7.26 (1 H, m), 7.20 (1 H, d), 6.98 - 6.92 (1H, m), 6.86 (2H ₁ m), 6.10 (1H, m), 3.86 (2H, t), 3.24 (2H, t), 2.86 (2H, t), 2.82 - 2.74 (4H, m), 2.68 - 2.54 (8H, m), 2.00 - 1.90 (4H, m); anal, calc'd for C ₂₈ H ₃₀ FN ₃ O ^« 1.5 H ₂ O: C 71.47, H 7.07, N 8.93; found: C 71.32, H 6.50, N 9.07.

EXAMPLE 5. Preparation of 9-{3-[4-(5-fluoro-1H-indol-3-yl)-piperidin-1-yl]-propyl}-1 ,2,6,7-tetrahydro-5H- pyrido[3,2, 1 -/y]quinolin-3-one

A solution of 9-(3-chloro-propyl)-1 ,2,6,7-tetrahydro-5H-pyrido[3,2,1-/y]quinolin-3-one (500 mg, 1.90 mmol), 5-fluoro-3-piperidin-4-yl-1H-indole (497 mg, 2.28 mmol), NaI (570 mg, 3.8 mmol) and Na ₂ CO ₃ (604 mg, 5.7 mmol) in 10% dioxane/H ₂ O (20 mL) was heated to reflux overnight. After cooling the reaction mixture, EtOAc was added, and the mixture was washed with water and with brine, dried over Na ₂ SO ₄ , and concentrated. The residue was purified by column chromatography (silica gel, 10% MeOH in CH ₂ CI ₂ ) to afford the title compound as a white solid (460 mg, 54%). MS m/z 446 (M+1), HPLC (area) purity 94.45%, mp 99.9 ⁰ C; ¹ H NMR 400 MHz (CDCI ₃ ) δ 8.00 (1 H, br s), 7.30 - 7.24 (2H, m), 7.20 (1 H, d), 6.96 - 6.90(1 H, m), 6.84 (2H, m), 3.86 (2H, t), 3.10 (2H, d), 2.86 (2H, t), 2.80 - 2.72 (3H, m), 2.64 (2H, m), 2.58 (2H, t), 2.46 (2H, t), 2.15 (2H, t), 2.08 - 2.00 (2H, m), 1.98 - 1.86 (2H, m), 1.85 - 1.80 (4H, m); anal, calc'd for C ₂₈ H ₃₂ FN ₃ O ^« 0.33 H ₂ O: C 74.47, H 7.29, N 9.30; found: C 74.41, H 7.40, N 9.93.

EXAMPLE 6. Preparation of 9-{2-[4-(5-fluoro-1 H-indol-3-yl)-3,6-dihydro-2H-pyridin-1 -yl]-ethyl}-1 ,2,6,7- tetrahydro-5H-pyrido[3,2,1-/)]quinolin-3-one

The title compound is prepared in a manner similar to EXAMPLES 1 to 4 in which chloro-acetyl chloride replaces 3-chloro-propionyl chloride in EXAMPLE 2. ¹ H NMR (400 MHz, DMSOd ₆ ) δ 11.47 (1H, d, J=2.0 Hz), 9.79 (1H, s), 8.71 (1H ₁ m), 7.62 (2H, m), 7.42 (1H, dd, J=8.9, 4.8 Hz), 7.00 (3H, m), 6.15 (1H, s), 4.07 (1 H, s), 3.89 (1 H, s), 3.73 (3H, m), 2.99 (1 H, s), 2.96 (1 H, d, J=I .8 Hz), 2.83 (3H, d, J=6.6 Hz), 2.80 (1 H, s), 2.71 (3H, m), 2.54 (1H, s), 1.83 (3H, m).

EXAMPLE 7. Preparation of 9-{2-[4-(5-fluoro-1 H-indol-3-yl)-piperidin-1 -yl]-ethyl}-1 ,2,6,7-tetrahydro-5tf- pyrido[3,2,1-//]quinolin-3-one

The title compound is prepared in a manner similar to EXAMPLES 1 to 3 and 5 in which chloro-acetyl chloride replaces 3-chloropropionyl chloride in EXAMPLE 2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.00 (1 H, s), 9.77 (1 H, s), 7.39 (1H, d, J=9.0 Hz), 7.32 (2H, dd, J=8.8, 4.5 Hz), 7.21 (1H, s), 6.89 (3H, m), 3.67 (4H, m), 3.09 (2H, s), 3.00 (1H, s), 2.92 (2H, m), 2.78 (2H, t, J=7.1 Hz), 2.69 (2H, t, J=5.4 Hz), 2.47 (2H, d, J=7.2 Hz), 2.12 (2H, d, J=13.3 Hz), 1.94 (2H, d, J=12.7 Hz), 1.79 (2H, s).

EXAMPLE 8. Preparation of 9-{2-[4-(1 H-indol-3-yl)-3,6-dihydro-2H-pyridin-1 -yl]-ethyl}-1 ,2,6,7-tetrahydro- 5H-pyrido[3,2,1-/y]quinolin-3-one

The title compound is prepared in a manner similar to EXAMPLES 1 to 4 in which chloro-acetyl chloride replaces 3-chloro-propionyl chloride in EXAMPLE 2 and 3-(1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indole replaces 5-fluoro-3-(1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indole in EXAMPLE 4. MS m/z 412 (M+1), HPLC @ 254 nm (area) purity 92%.

EXAMPLE 9. Preparation of 9-{2-[4-(1 H-lndol-3-yl)-piperidin-1 -yl]-ethyl}-1 ,2,6,7-tetrahydro-5H- pyrido[3,2,1-/y]quinolin-3-one

The title compound is prepared in a manner similar to EXAMPLES 1 to 4 in which chloro-acetyl chloride replaces 3-chloro-propionyl chloride in EXAMPLE 2 and 3-piperidin-4-yl-1H-indole replaces 5-fluoro-3- (1 ,2,3,6-tetrahydro-pyridin-4-yl)-1 H-indole in EXAMPLE 4. LCMS 100% purity @ 254 nm; (APCI) MS m/z 414 (M+1).

EXAMPLE 10. Preparation of 9-{2-[4-(4,6-difluoro-1 H-indol-3-yl)-piperidin-1 -yl]-ethyl}-1 ,2,6,7-tetrahydro- 5H-pyrido[3,2, 1 -/y]quinolin-3-one

The title compound is prepared in a manner similar to EXAMPLES 1 to 4 in which chloro-acetyl chloride replaces 3-chloro-propionyl chloride in EXAMPLE 2 and 4,6-difluoro-3-pjperidin-4-yl-1H-indole replaces 5- fluoro-3-(1 ,2,3,6-tetrahydro-pyridin-4-yl)-1H-indole in EXAMPLE 4. MS m/z 450 (M+1).

EXAMPLE 11. Preparation of 9-{2-[4-(6-chloro-5-fluoro-1H-indol-3-yl)-piperidin-1-yl]-et hyl}-1 ,2,6,7- tetrahydro-5H-pyrido[3,2, 1 -//]quinolin-3-one

The title compound is prepared in a manner similar to EXAMPLES 1 to 4 in which chloro-acetyl chloride replaces 3-chloro-propionyl chloride in EXAMPLE 2 and 6-chloro-5-fluoro-3-piperidin-4-yl-1 /-/-indole replaces 5-fluoro-3-(1 ,2,3,6-tetrahydro-pyridin-4-yl)-1 H-indole in EXAMPLE 4. ¹ H NMR (400 MHz, DMSO- dβ) δ 11.00 (1 H ₁ s), 8.22 (1 H, s), 7.48 (1 H, m), 7.44 (1 H, s), 7.19 (1 H, s), 6.85 (2H, d, J=7.0 Hz), 3.68 (2H, s), 3.03 (2H ₁ d, J=WA Hz), 2.77 (1H, s), 2.74 (2H, d, J=7A Hz), 2.66 (3H, d, J=5.8 Hz), 2.63 (1 H, s), 2.55 (2H, m), 2.46 (4H, s), 2.18 (2H, t, J=10.9 Hz), 1.89 (2H, d, J=12.1 Hz), 1.78 (2H, s), 1.68 (1 H, s), 1.64 (1 H, d, J=10.9 Hz).

EXAMPLE 12. Preparation of 9-{2-[4-(2,6-dimethyl-1 H-indol-3-yl)-3,6-dihydro-2H-pyridin-1 -yl]-ethyl}- 1 ,2,6,7-tetrahydro-5H-pyrido[3,2,1-/y]quinolin-3-one

The title compound is prepared in a manner similar to EXAMPLES 1 to 4 in which chloro-acetyl chloride replaces 3-chloro-propionyl chloride in EXAMPLE 2 and 2,6-dimethyl-3-(1 ,2,3,6-tetrahydro-pyridin-4-yl)- 1 H-indole replaces 5-fluoro-3-(1 ,2,3,6-tetrahydro-pyridin-4-yl)-1 H-indole in EXAMPLE 4. MS m/z 440 (M+1).

EXAMPLE 13. Preparation of 9-{2-[4-(2,6-dimethyl-1H-indol-3-yl)-piperidin-1-yl]-ethyl}- 1 ,2,6,7-tetrahydro- 5H-pyrido[3,2,1-/y]quinolin-3-one

The title compound is prepared in a manner similar to EXAMPLES 1 to 4 in which chloro-acetyl chloride replaces 3-chloro-propionyl chloride in EXAMPLE 2 and 2, 6-dimethyl-3-piperidin-4-yl-1 /-/-indole replaces 5-fluoro-3-(1 ,2,3,6-tetrahydro-pyridin-4-yl)-1 H-indole in EXAMPLE 4. MS m/z 443 (M+1 ).

EXAMPLE 14. Preparation of 9-{2-[4-(2,4-dimethyl-iH-indol-3-yl)-3,6-dihydro-2H-pyridin- 1-yl]-ethyl}- 1 ,2,6,7-tetrahydro-5H-pyrido[3,2,1 -#]quinolin-3-one

The title compound is prepared in a manner similar to EXAMPLES 1 to 4 in which chloro-acetyl chloride replaces 3-chloro-propionyl chloride in EXAMPLE 2 and 2,4-dimethyl-3-(1,2,3,6-tetrahydro-pyridin-4-yl)- 1 H-indole replaces 5-fluoro-3-(1 ,2,3,6-tetrahydro-pyridin-4-yl)-1 H-indole in EXAMPLE 4. MS m/z 440 (M+1 ).

EXAMPLE 15. Preparation of 3-{1-[2-(3-oxo-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-/y]quin olin-9-yl)-ethyl]- piperidin-4-yl}-1/-/-indole-5-carboxylic acid amide

The title compound is prepared in a manner similar to EXAMPLES 1 to 4 in which chloro-acetyl chloride replaces 3-chloropropionyl chloride in EXAMPLE 2 and 3-piperidin-4-yl-1H-indole-5-carboxylic acid amide replaces 5-fluoro-3-(1 ,2,3,6-tetrahydro-pyridin-4-yl)-1 H-indole in EXAMPLE 4. ¹ H NMR (400 MHz, DMSO- d _β ) δ 11.09 (1 H, s), 8.24 (1H, s), 7.84 (1H, s), 7.65 (1H, d, J=7.8 Hz), 7.35 (1H, d, J=8.2 Hz), 7.23 (1H, s), 7.11 (1 H, s), 6.95 (2H ₁ d, J=2.7 Hz), 3.47 (3H, d, J=9.0 Hz), 3.09 (2H, s), 3.02 (2H, s), 2.84 (5H, d, J=10.5 Hz), 2.81 (2H, s), 2.72 (3H, s), 2.14 (2H, d, J=11.3 Hz), 1.91 (2H, d, J=11.3 Hz), 1.82 (2H, s).

EXAMPLE 16. Preparation of 3-chloro-1-(2,3-dihydro-indol-1-yl)-propan-1-one

To a solution of 2,3-dihydro-1H-indole (4.0 g, 0.034 mol) in acetone (100 mL) was added 3-chloro- propionyl chloride (4.7 g, 0.037 mol). After heating the mixture at 70 ⁰ C for 3 h, the solvent was removed in vacuo. The resulting residue was dissolved in CH ₂ CI ₂ and washed with water and with brine. The organic layer was dried over Na ₂ SO ₄ , filtered, and concentrated to give the title compound as a brown solid (7.0 g, quantitative). ¹ H NMR 400 MHz (CDCI ₃ ) δ 8.22 (1 H, d), 7.20 (2H, m), 7.02 (1 H, t), 4.05 (2H, t), 3.92 (2H ₁ 1), 3.20 (2H, t), 2.90 (2H, t).

EXAMPLE 17. Preparation of 8-(3-chloro-propionyl)-1 ,2,5,6-tetrahydro-pyrrolo[3,2,1-//]quinolin-4-one

3-Chloro-1-(2,3-dihydro-indol-1-yi)-propan-1-one (2.0 g, 0.0095 mol) and AICI ₃ (3.8 g, 0.028 mol) were mixed under nitrogen and heated at 100 ⁰ C overnight. The reaction mixture was cooled. Carbon disulfide (20 mL), followed by 3-chloro-propionyl chloride (1.09 mL, 0.0114 mol) were added and the reaction mixture was stirred overnight at RT. The reaction mixture formed two distinct layers. The upper, colorless layer (CS ₂ ) was decanted off. The lower viscous layer was hydrolyzed by the addition of crushed ice in small portions until gas evolution ceased, and was subsequently extracted with EtOAc, washed with water and brine, dried over Na ₂ SO ₄ , and concentrated to provide the title compound as a light green solid (2.2 g, 88%). ¹ H NMR 400 MHz (DMSO-d ₆ ) δ 7.76 - 7.72 (2H, m), 4.00 (2H, t), 3.92 (2H, t), 3.48 (2H, t), 3.19 (2H, t), 3.00 (2H, t), 2.60 (2H, t).

EXAMPLE 18. Preparation of 8-(3-chloro-propyl)-1 ,2,5,6-tetrahydro-pyrrolo[3,2,1-/)]quinolin-4-one

To a solution of 8-(3-chloro-propionyl)-1 ,2,5,6-tetrahydro-pyrrolo[3,2,1-/y]quinolin-4-one (2.2 g, 0.0084 mol) in TFA (50 mL) under nitrogen was added Et ₃ SiH (2.92 g, 0.0251 mol). The resulting reaction mixture was stirred at RT overnight. The volatile solvent was subsequently removed in vacuo, and the residue was dissolved in EtOAc, washed with saturated NaHCO ₃ and with brine, dried over Na ₂ SO ₄ , and concentrated. The residue was suspended in hexane, sonicated for 5 min, and filtered. The solid was washed with hexane and dried to afford the title compound as a brown solid (1.7 g, 81%). ¹ H NMR 400 MHz (CDCI ₃ ) δ 6.92 (1 H, s), 6.83 (1 H, s), 4.06 (2H, t), 3.54 (2H, t), 3.16 (2H, t), 2.94 (2H, t), 2.72 (2H, t), 2.66 (2H, t), 2.10 - 2.00 (2H, m).

EXAMPLE 19. Preparation of 8-{3-[4-(5-fluoro-1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-yl ]-propyl}-1 , 2,5,6- tetrahydro-pyrrolo[3,2,1-/)]quinolin-4-one

A solution of 8-(3-chloro-propyl)-1,2,5,6-tetrahydro-pyrrolo[3,2,1-/;]quin olin-4-one (500 mg, 2.00 mmol), 5- fluoro-3-(1 ,2,3,6-tetrahydro-pyridin-4-yl)-1 /-/-indole (520 mg, 2.41 mmol), NaI (600 mg, 4.00 mmol) and Na ₂ CO ₃ (636 mg, 6.00 mmol) in 10% dioxane/H ₂ O (20 mL) was heated to reflux overnight. After cooling the reaction mixture, EtOAc was added, and the mixture was washed with water and with brine, dried over Na ₂ SO ₄ , and concentrated. The residue was purified by column chromatography (silica gel, 10% MeOH in CH ₂ CI ₂ ) to afford the title compound as a yellow solid (450 mg, 52%). MS m/z 430 (M+1), HPLC (area) purity 92.83%, mp 221.1 - 222.5°C; ¹ H NMR 400 MHz (DMSO-d ₆ ) δ 11.25 (1 H, br s), 7.52 (1 H, dd), 7.46 (1 H, d), 7.37 (1 H, dd), 6.99 - 6.92 (2H, m), 6.88 (1 H, s), 6.10 - 6.00 (1 H, m), 3.90 (2H, t), 3.20 - 3.06 (4H,

m), 2.86 (2H, t), 2.70 - 2.60 (2H, m), 2.56 (2H ₁ 1), 2.54 - 2.52 (4H ₁ m), 2.48 - 2.40 (2H ₁ m), 1.84 - 1.72 (2H ₁ m); anal, calc'd for C ₂₇ H ₂₈ FN ₃ O-LO H ₂ O: C 72.46, H 6.76, N 9.39; found: C 72.10, H 6.41 , N 9.31.

EXAMPLE 20. Preparation of 8-{3-[4-(5-fluoro-1 W-indol-3-yl)-piperidin-1 -yl]-propyl}-1 ,2,5,6-tetrahydro- pyrrolo[3,2,1-/;]quinolin-4-one

A solution of 8-(3-chloro-propyl)-1 ,2,5,6-tetrahydro-pyrrolo[3,2,1-/y]quinolin-4-one (500 mg, 2.00 mmol), 5- fluoro-3-piperidin-4-yl-1H-indole (520 mg, 2.41 mmol), NaI (600 mg, 4.00 mmol) and Na ₂ CO ₃ (636 mg, 6.00 mmol) in 10% dioxane/H ₂ O (20 mL) was heated to reflux overnight. After cooling the reaction mixture, EtOAc was added, and the mixture was washed with water and with brine, dried over Na ₂ SO ₄ , and concentrated. The residue was purified by column chromatography (silica gel, 10% MeOH in CH ₂ CI ₂ ) to afford the title compound as a light yellow solid (450 mg, 52%). MS m/z 432 (M+1 ), HPLC (area) purity 95.58%, mp 98 ⁰ C; ¹ H NMR 400 MHz (CDCI ₃ ) δ 8.13 (1 H, br s), 7.30 - 7.24 (2H, m), 7.02 (1 H, d), 6.96 - 6.90 (2H, m), 6.84 (1 H, s), 4.07 (2H, t), 3.16 (2H, t), 3.08 (2H, d), 2.94 (2H, t), 2.82 - 2.72 (1 H, m), 2.66 (2H, t), 2.60 (2H, t), 2.44 (2H, t), 2.16 (2H, t), 2.04 (2H, d), 1.90 - 1.76 (4H, m); anal, calc'd for C ₂₇ H ₃₀ FN ₃ O ^« 0.33 H ₂ O: C 74.12, H 7.06, N 9.60; found: C 74.01 , H 7.06, N 9.40.

EXAMPLE 21. Preparation of 8-(2-chloro-acetyl)-1 ,2,5,6-tetrahydro-pyrrolo[3,2,1-/y]quinolin-4-one

3-Chloro-1-(2,3-dihydro-indol-1-yl)-propan-1-one (2.0 g, 0.0095 mol) and AICI ₃ (3.8 g, 0.028 mol) were mixed under nitrogen and heated at 100 ⁰ C overnight. The reaction mixture was cooled. Carbon disulfide (20 mL), followed by chloro-acetyl chloride (0.9 mL, 0.0114 mol) were added and the reaction mixture was stirred at 50 ⁰ C for 3 h. The reaction mixture formed two distinct layers. The upper, colorless layer (CS ₂ ) was decanted off. The lower viscous layer was hydrolyzed by the addition of crushed ice in small portions until gas evolution ceased, and was subsequently extracted with EtOAc, washed with water and brine, dried over Na ₂ SO ₄ , and concentrated to provide the title compound as a light green solid (1.7 g, 42%). ¹ H NMR 400 MHz (CDCI ₃ ) δ,7.75 (1 H, s), 7.70 (1 H, s) 4.62 (2H, s), 4.18 (2H, t), 3.20(2H, t), 3.00 (2H, t), 2.70 (2H, t).

EXAMPLE 22. Preparation of 8-(2-chloro-ethyl)-1 ,2,5,6-tetrahydro-pyrrolo[3,2,1-/y]quinolin-4-one

To a solution of 8-(2-chloro-acetyl)-1 ,2,5,6-tetrahydro-pyrrolo[3,2,1-/y]quinolin-4-one (1.7 g, 0.0068 mol) in TFA (20 mL) under nitrogen was added Et ₃ SiH (3.27 mL, 0.0205 mol). The resulting reaction mixture was stirred at RT overnight. The volatile solvent was subsequently removed in vacuo, and the residue was dissolved in EtOAc, washed with saturated NaHCO ₃ and with brine, dried over Na ₂ SO ₄ , and concentrated. The residue was suspended in hexane, sonicated for 5 min, and filtered. The solid was washed with hexane and dried to afford the title compound as a dark green solid (1.3 g, 86.6%). ¹ H NMR 400 MHz (CDCI ₃ ) δ 6.95 (1 H, s), 6.85 (1 H, s), 4.10 (2H, t), 3.68 (2H, t), 3.18 (2H, t), 3.02 (2H, t), 2.99 (2H, t), 2.70 (2H, t).

EXAMPLE 23. Preparation of 8-{2-[4-(5-fluoro-1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-yl ]-ethyl}-1 ,2,5,6- tetrahydro-pyrrolo[3,2,1-/y]quinolin-4-one

A solution of 8-(2-chloro-ethyl)-1 ,2,5,6-tetrahydro-pyrrolo[3,2,1-//]quinolin-4-one (500 mg, 2.13 mmol), 5- fluoro-3-(1 ,2,3,6-tetrahydro-pyridin-4-yl)-1 W-indole (552 mg, 2.55 mmol), NaI (639 mg, 4.26 mmol) and Na ₂ CO ₃ (677 mg, 6.39 mmol) in 10% dioxane/H ₂ O (20 ml.) was heated to reflux overnight. After cooling the reaction mixture, EtOAc was added, and the mixture was washed with water and with brine, dried over Na ₂ SO ₄ , and concentrated. The residue was purified by column chromatography (silica gel, 10% MeOH in CH ₂ CI ₂ ) to afford the title compound as a yellow solid (370 mg, 42%). MS m/z 416 (M+1), HPLC (area) purity 95.61%, mp 174.6 - 175.9 ⁰ C; ¹ H NMR 400 MHz (DMSO-d ₆ ) δ 11.22 (1H, br s), 7.54 (1 H, dd), 7.46 (1 H, d), 7.38 (1 H, dd), 7.00 - 6.94 (2H, m), 6.90 (1 H, s), 6.10 - 6.04 (4H, m), 3.92 (2H, t), 3.20 (2H, m), 3.10 (2H, t), 2.87 (2H, t), 2.78 - 2.68 (4H, m), 2.65 - 2.60 (2H, m), 2.58 - 2.48 (4H, m); anal, calc'd for C ₂₆ H ₂₆ FN ₃ O ^« 0.33 CH ₂ CI ₂ : C 71.27, H 6.06, N 9.47; found: C 71.36, H 6.43, N 9.60.

EXAMPLE 24. Preparation of 8-{2-[4-(5-fluoro-1 H-indol-3-yl)-piperidin-1 -yl]-ethyl}-1 ,2,5,6-tetrahydro- pyrrolo[3,2, 1 -/y]quinolin-4-one

A solution of 8-(2-chloro-ethyl)-1 ,2,5,6-tetrahydro-pyrrolo[3,2,1-//]quinolin-4-one (500 mg, 2.13 mmol), 5- fluoro-3-piperidin-4-yl-1H-indole (555 mg, 2.55 mmol), NaI (639 mg, 4.26 mmol) and Na ₂ CO ₃ (677 mg, 6.39 mmol) in 10% dioxane/H ₂ O (20 mL) was heated to reflux overnight. After cooling the reaction mixture, EtOAc was added, and the mixture was washed with water and with brine, dried over Na ₂ SO ₄ , and concentrated. The residue was purified by column chromatography (silica gel, 10% MeOH in CH ₂ CI ₂ ) to afford the title compound as an off white solid (370 mg, 42%). MS m/z 418 (M+1 ), HPLC (area) purity 92.87%, mp 150.1 ⁰ C; ¹ H NMR 400 MHz (CDCI ₃ ) δ 8.20 (1H, br s), 7.30 - 7.24 (2H, m), 7.04 (1 H, d), 6.96 (1 H, s), 6.92 (1 H, dd), 6.88 (1 H, s), 4.07 (2H, t), 3.24 (2H, d), 3.16 (2H, t), 2.95 (2H, t), 2.92 - 2.80 (3H, m), 2.76 - 2.60 (4H, m), 2.34 (2H, t), 2.10 (2H, d), 2.02 - 1.88 (2H, m); anal, calc'd for C ₂₆ H ₂₈ FN ₃ O-1.5 H ₂ O: C 70.25, H 7.03, N 9.45; found: C 70.52, H 6.78, N 9.24.

EXAMPLE 25. Preparation of 8-{2-[4-(5-fluoro-1 λ/-indol-3-yl)-3,3-dimethyl-3,6-dihydro-2H-pyridin-1 -yl]- ethyl}-1 ,2,5,6-tetrahydro-pyrrolo[3,2,1-/y]quinolin-4-one

A solution of 8-(2-chloro-ethyl)-1 ,2,5,6-tetrahydro-pyrrolo[3,2,1-/y]quinolin-4-one (289 mg, 1.23 mmol), 3- (3,3-dimethyl-1 ,2,3,6-tetrahydro-pyridin-4-yl)-5-fluoro-1H-indole (250 mg, 1.02 mmol), NaI (368 mg, 2.46 mmol) and Na ₂ CO ₃ (391 mg, 3.68 mmol) in 10% dioxane/H ₂ 0 (20 mL) was heated to reflux overnight. After cooling the reaction mixture, CH ₂ CI ₂ was added, and the mixture was washed with water and with brine, dried over Na ₂ SO ₄ , and concentrated. The residue was purified by column chromatography (silica gel, 5% MeOH in CH ₂ CI ₂ ) to afford the title compound as a yellow solid (120 mg, 26.6%). MS m/z 444(M+1), HPLC (area) purity 90.20%, mp 130.4°C; ¹ H NMR 400 MHz (CDCI ₃ ) δ 8.12 (1 H, br s), 7.30 - 7.22 (2H, m), 7.10 (1 H, d), 7.00 (1 H, s), 6.93 (1 H, dd), 6.90 (1 H, s), 5.66 (1 H, t), 4.08 (2H, t), 3.22 - 3.12 (4H, m), 2.96 (2H, t), 2.82 (2H, t), 2.72 - 2.64 (4H, m), 2.50 (2H, s), 1.15 (6H, s); anal, calc'd for C ₂₈ H ₃₀ FN ₃ OO^ CH ₂ CI ₂ : C 73.54, H 6.65, N 9.12; found: C 73.87, H 6.51 , N 9.27.

EXAMPLE 26. Preparation of 8-{2-[4-(5-fluoro-1H-indol-3-yl)-3,3-dimethyl-piperidin-1-yl ]-ethyl}-1 , 2,5,6- tetrahydro-pyrrolo[3,2,1-/y]quinolin-4-one

A solution of 8-(2-chloro-ethyl)-1 ,2,5,6-tetrahydro-pyrrolo[3 _l 2,1-//]quinolin-4-one (276 mg, 1.17 mmol), 3- (3,3-dimethyl-piperidin-4-yl)-5-fluoro-1H-indole (240 mg, 0.979 mmol), NaI (353 mg, 2.35 mmol) and Na ₂ CO ₃ (374 mg, 3.5 mmol) in 10% dioxane/H ₂ O (20 ml_) was heated to reflux overnight. After cooling the reaction mixture, CH ₂ CI ₂ was added, and the mixture was washed with water and with brine, dried over Na ₂ SO ₄ , and concentrated. The residue was purified by column chromatography (silica gel, 5% MeOH in CH ₂ CI ₂ ) to afford the title compound as a light yellow solid (160 mg, 36.7%). MS m/z 446 (M+1), HPLC (area) purity 93.79%, mp 146.3°C; ¹ H NMR 400 MHz (CDCI ₃ ) δ 8.18 (1 H, br s), 7.30 - 7.22 (2H, m), 7.02 (1 H, d), 6.98 (1 H, s), 6.93 (1 H, dd), 6.89 (1 H, s), 4.10 (2H, t), 3.20 (2H, t), 3.10 (1 H, m), 2.90 (2H, t), 2.85 - 2.73 (2H, m), 2.68 (2H, t), 2.65 (2H, m), 2.55 - 2.45 (1 H, m), 2.20 - 2.10 (2H, m), 1.68 (2H, m), 1.60 (1 H, m), 1.00 (1 H, s), 0.80 (3H, s); anal, calc'd for C ₂₈ H ₃₂ FN ₃ O: C 75.48, H 7.24, N 9.43; found: C 75.04, H 7.17, N 9.14.

EXAMPLE 27. Preparation of 1-(2,3-dihydro-indol-1-yl)-3-methyl-but-2-en-1-one

To a solution of 2,3-dihydro-1 AV-indole (2.0 g, 0.0168 mol) in CH ₂ CI ₂ (100 mL) was added 3-methyl-but-2- enoyl chloride (2.19 g, 0.0185 mol). After stirring at RT overnight, the reaction mixture was extracted with CH ₂ CI ₂ and washed with water and with brine. The organic layer was dried over Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by column chromatography (silica gel, 1 % MeOH in CH ₂ CI ₂ ) to afford the title compound as a white solid (1.5 g, 45%). ¹ H NMR 400 MHz (CDCI ₃ ) δ 8.24 (1 H, d), 7.19 (2H, m), 7.00 (1 H, t), 5.98 (1H, s), 4.10 (2H, t), 3.18 (2H, t), 2.18 (3H, s), 1.95 (3H, s).

EXAMPLE 28. Preparation of 8-(3-chloro-propionyl)-6,6-dimethyl-1 ,2,5,6-tetrahydro-pyrrolo[3,2,1- /y]quinolin-4-one

1-(2,3-Dihydro-indol-1-yl)-3-methyl-but-2-en-1-one (1.5 g, 0.0075 mol) and AICI ₃ (2.98 g, 0.0224 mol) were mixed under nitrogen and heated at 100 ⁰ C for 15 min. The reaction mixture was cooled. Carbon disulfide (20 mL), followed by 3-chloro-propionyl chloride (0.79 mL, 0.00825 mol) were added and the reaction mixture was heated at 50 ⁰ C for 2 h. The reaction mixture formed two distinct layers. The upper, colorless layer (CS ₂ ) was decanted off. The lower viscous layer was hydrolyzed by the addition of crushed ice in small portions until gas evolution ceased. Water (50 mL) and 1N HCI (50 mL) were added, and the mixture was stirred for 30 min. The precipitate was filtered off and washed with water, then dried to constant weight to provide compound the title compound as a yellow solid (1.8 g, 82.5%). ¹ H NMR 400 MHz (CDCI ₃ ) δ 7.80 (1 H, s), 7.75 (1 H, s), 4.20 (2H, t), 3.95 (2H, t), 3.42 (2H, t), 3.25 (2H, t), 2.60 (2H, s), 1.38 (6H, s).

EXAMPLE 29. Preparation of 8-(3-chloro-propyl)-6,6-dimethyl-1 ,2,5,6-tetrahydro-pyrrolo[3,2,1-//]quinolin- 4-one

To a solution of 8-(3-chloro-propionyl)-6,6-dimethyl-1 ,2,5,6-tetrahydro-pyrrolo[3,2,1-//]quinolin-4-one

(1.8 g, 0.062 mol) in TFA (50 mL) under nitrogen was added Et ₃ SiH (2.15 g, 0.0185 mol). The resulting

reaction mixture was stirred at RT overnight. The volatile solvent was subsequently removed in vacuo, and the residue was dissolved in EtOAc, washed with saturated NaHCO ₃ and with brine, dried over Na ₂ SO ₄ , and concentrated. The residue was suspended in hexane, sonicated for 5 min, and filtered. The solid was washed with hexane and dried to afford the title compound as a brown solid (0.8 g, 45%). ¹ H NMR 400 MHz (CDCI ₃ ) δ 6.95 (1 H, s), 6.90 (1 H, s), 4.10 (2H, t), 3.58 (2H, t), 3.20 (2H, t), 2.75 (2H, t), 2.50 (2H, s), 2.05 (2H, m).

EXAMPLE 30. Preparation of 8-{3-[4-(5-fluoro-1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-yl ]-propyl}-6,6- dimethyl-1 ,2,5,6-tetrahydro-pyrrolo[3,2,1-/y]quinolin-4-one

A solution of 8-(3-chloro-propyl)-6,6-dimethyl-1 ,2,5,6-tetrahydro-pyrrolo[3,2,1-//]quinolin-4-one (400 mg, 1.44 mmol), 5-fluoro-3-(1 ,2,3,6-tetrahydro-pyridin-4-yl)-1 H-indole (374 mg, 1.73 mmol), NaI (432 mg, 2.88 mmol) and Na ₂ CO ₃ (458 mg, 4.32 mmol) in 10% dioxane/H ₂ O (20 ml.) was heated to reflux overnight. After cooling the reaction mixture, EtOAc was added, and the mixture was washed with water and with brine, dried over Na ₂ SO ₄ , and concentrated. The residue was purified by column chromatography (silica gel, 10% MeOH in CH ₂ CI ₂ ) to afford the title compound as a yellow solid (280 mg, 42.5%). MS m/z 458 (M+1), HPLC (area) purity 90.72%, mp 146.8°C; ¹ H NMR 400 MHz (CDCI ₃ ) δ 8.16 (1 H, br s), 7.53 (1 H, dd), 7.28 (1 H, m), 7.20 (1 H, d), 6.96 - 6.92 (3H ₁ m), 6.12 (1 H, m), 4.08 (2H, t), 3.26 (2H, d), 3.20 (2H, t), 2.76 (2H, t), 2.66 (2H, t), 2.62 (2H, m), 2.54 (2H ₁ 1), 2.50 (2H, s), 1.98 - 1.88 (2H, m), 1.30 (6H, s); anal, calc'd for C ₂₉ H ₃₂ FN ₃ O-0.33 H ₂ O: C 75.13, H 7.10, N 9.06; found: C 74.98, H 7.06, N 9.25.

EXAMPLE 31. Preparation of 8-{3-[4-(5-fluoro-1 H-indol-3-yl)-piperidin-1 -yl]-propyl}-6,6-dimethyl-1 ,2,5,6- tetrahydro-pyrrolo[3,2,1-//]quinolin-4-one

A solution of 8-(3-chloro-propyl)-6,6-dimethyl-1 ,2,5,6-tetrahydro-pyrrolo[3,2,1-/y]quinolin-4-one (400 mg, 1.44 mmol), 5-fluoro-3-piperidin-4-yl-1H-indole (377 mg, 1.73 mmol), NaI (432 mg, 2.88 mmol) and Na ₂ CO ₃ (458 mg, 4.32 mmol) in 10% dioxane/H ₂ O (20 mL) was heated to reflux overnight. After cooling the reaction mixture, CH ₂ CI ₂ was added, and the mixture was washed with water and with brine, dried over Na ₂ SO ₄ , and concentrated. The residue was purified by column chromatography (silica gel, 7% MeOH in CH ₂ CI ₂ ) to afford the title compound as a white solid (480 mg, 72%). MS m/z 460 (M+1 ), HPLC (area) purity 95.29%, mp 128.2°C; ¹ H NMR 400 MHz (CDCI ₃ ) δ 8.16 (1 H, br s), 7.30 - 7.24 (2H, m), 7.02 (1 H, d), 6.96 - 6.92 (3H, m), 4.08 (2H, t), 3.20 (2H, t), 3.10 (2H, d), 2.82 - 2.72 (1 H, m), 2.64 (2H, t), 2.50 (2H, s), 2.46 (2H, d), 2.18 (2H, t), 2.06 (2H, d), 1.90 - 1.80 (4H, m), 1.30 (6H, s); anal, calc'd for C ₂₉ H ₃₄ FN ₃ O-O-S H ₂ O: C 74.33, H 7.53, N 8.97; found: C 74.43, H 7.87, N 9.16.

EXAMPLE 32. Preparation of 8-{2-[4-(5-fluoro-1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-yl ]-ethyl}-6,6- dimethyl-1 ,2,5,6-tetrahydro-pyrrolo[3,2,1-/y]quinolin-4-one

The title compound is prepared in a manner similar to EXAMPLES 27 to 30 in which chloro-acetyl chloride replaces 3-chloro-propionyl chloride in EXAMPLE 28. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.47 (1 H, d, J=2.0 Hz), 9.82 (1 H, s), 7.65 (1 H, m), 7.42 (1 H, dd, J=8.9, 4.8 Hz), 7.07 (1 H, d, J=2.0 Hz), 7.01 (1 H, td,

J=9.0, 2.4 Hz), 6.15 (1 H, s), 3.95 (1 H, t, J=8λ Hz), 3.75 (1 H, s), 3.35 (1OH, s), 3.15 (2H, t, J=8.4 Hz), 3.03 (2H, d, J=8.0 Hz), 2.84 (1 H, s), 2.42 (2H, s), 1.24 (4H ₁ s).

EXAMPLE 33. Preparation of 8-{2-[4-(5-fluoro-1 A7-indol-3-yl)-piperidin-1 -yl]-ethyl}-6,6-dimethyl-1 ,2,5,6- tetrahydro-pyrrolo[3,2,1-/y]quinolin-4-one

The title compound is prepared in a manner similar to EXAMPLES 27 to 29 and 31 in which chloro-acetyl chloride replaces 3-chloro-propionyl chloride in EXAMPLE 28. ¹ H NMR (400 MHz, DMSOd ₆ ) δ 11.00 (1 H, s), 9.46 (1 H, s), 7.43 (1 H, dd, J=10.3, 2.4 Hz), 7.35 (1 H, dd, J=8.9, 4.6 Hz), 7.24 (1 H, d, J=2.3 Hz), 7.05 (2H, s), 6.92 (1 H, td, J=9A , 2.4 Hz), 3.95 (2H, t, J=8.4 Hz), 3.66 (2H, s), 3.13 (4H, d, J=8.4 Hz), 3.01 (3H, m), 2.41 (2H, m), 2.14 (2H, s), 1.98 (2H, m), 1.22 (7H, m).

EXAMPLE 34. Preparation of 8-{2-[4-(1H-indol-3-yl)-3,6-dihydro-2f7-pyridin-1-yl]-ethyl} -6,6-dimethyl- 1 ,2,5,6-tetrahydro-pyrrolo[3,2,1-//]quinolin-4-one

The title compound is prepared in a manner similar to EXAMPLES 27 to 30 in which chloro-acetyl chloride replaces 3-chloro-propionyl chloride in EXAMPLE 28 and 3-(1 ,2,3,6-tetrahydro-pyridin-4-yl)-1 H-indole replaces 5-fluoro-3-(1 ,2,3,6-tetrahydro-pyridin-4-yl)-1H-indole in EXAMPLE 30. LCMS 100% purity @ 254 nm; (APCI) MS m/z 428 (M+1 ).

EXAMPLE 35. Preparation of 8-{2-[4-(1H-indol-3-yl)-piperidin-1-yl]-ethyl}-6,6-dimethyl- 1 ,2,5,6-tetrahydro- pyrrolo[3,2,1-//]quinolin-4-one

The title compound is prepared in a manner similar to EXAMPLES 27 to 30 in which chloro-acetyl chloride replaces 3-chloro-propionyl chloride in EXAMPLE 28 and 3-piperidin-4-yl-1 /-/-indole replaces 5-fluoro-3- (1 ,2,3,6-tetrahydro-pyridin-4-yl)-1 W-indole in EXAMPLE 30. MS m/z 428 (M+1 ), HPLC @ 254 nm (area) purity 100%.

EXAMPLE 36. Preparation of 8-{2-[4-(7-chloro-1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-yl ]-ethyl}-6,6- dimethyl-1 ,2,5,6-tetrahydro-pyrrolo[3,2,1-/y]quinolin-4-one

The title compound is prepared in a manner similar to EXAMPLES 27 to 30 in which chloro-acetyl chloride replaces 3-chloro-propionyl chloride in EXAMPLE 28 and 7-chloro-3-(1 ,2,3,6-tetrahydro-pyridin-4-yl)-1 W- indole replaces 5-fluoro-3-(1 ,2,3,6-tetrahydro-pyridin-4-yl)-1 W-indole in EXAMPLE 30. MS m/z 460.2 (M+1 ).

EXAMPLE 37. Preparation of 8-{2-[4-(7-chloro-1W-indol-3-yl)-piperidin-1-yl]-ethyl}-6,6- dimethyl-1 ,2,5,6- tetrahydro-pyrrolo[3,2,1-/;]quinolin-4-one

The title compound is prepared in a manner similar to EXAMPLES 27 to 30 in which chloro-acetyl chloride replaces 3-chloro-propionyl chloride in EXAMPLE 28 and 7-chloro-3-piperidin-4-yl-1 W-indole replaces 5- fluoro-3-(1 ,2,3,6-tetrahydro-pyridin-4-yl)-1 W-indole in EXAMPLE 30. MS m/z 462.2 (M+1).

EXAMPLE 38. Preparation of 8-{2-[4-(6-chloro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-6,6- dimethyl-1 ,2,5,6- tetrahydro-pyrrolo[3,2,1-/;]quinolin-4-one

The title compound is prepared in a manner similar to EXAMPLES 27 to 30 in which chloro-acetyl chloride replaces 3-chloro-propionyl chloride in EXAMPLE 28 and 6-chloro-3-piperidin-4-yl-1 /-/-indole replaces 5- fluoro-3-(1 ,2,3,6-tetrahydro-pyridin-4-yl)-1 H-indole in EXAMPLE 30. MS m/z 462 (M+1 ).

EXAMPLE 39. Preparation of 8-{2-[4-(4,6-difluoro-1 H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-yl]-ethyl}-6,6- dimethyl-1 ,2,5,6-tetrahydro-pyrrolo[3,2,1-//]quinolin-4-one

The title compound is prepared in a manner similar to EXAMPLES 27 to 30 in which chloro-acetyl chloride replaces 3-chloro-propionyl chloride in EXAMPLE 28 and 4,6-difluoro-3-(1 ,2,3,6-tetrahydro-pyridin-4-yl)- 1 H-indole replaces 5-fluoro-3-(1 ,2,3,6-tetrahydro-pyridin-4-yl)-1 H-indole in EXAMPLE 30. MS m/z 462 (M+1 ).

EXAMPLE 40. Preparation of 8-{2-[4-(4,6-difluoro-1 H-indol-3-yl)-piperidin-1 -yl]-ethyl}-6,6-dimethyl- 1 ,2,5,6-tetrahydro-pyrro!o[3,2,1-/y]quino!in-4-one

The title compound is prepared in a manner similar to EXAMPLES 27 to 30 in which chloro-acetyl chloride replaces 3-chloro-propionyl chloride in EXAMPLE 28 and 4,6-difluoro-3-piperidin-4-yl-1 /-/-indole replaces 5-fluoro-3-(1 ,2,3,6-tetrahydro-pyridin-4-yl)-1 H-indole in EXAMPLE 30. MS m/z 464 (M+1 ).

EXAMPLE 41. Preparation of 8-{2-[4-(2,4-dimethyl-1 H-indol-3-yl)-3,6-dihydro-2H-pyridin-1 -yl]-ethyl}-6,6- dimethyl-1 ,2,5,6-tetrahydro-pyrrolo[3,2,1-//]quinolin-4-one

The title compound is prepared in a manner similar to EXAMPLES 27 to 30 in which chloro-acetyl chloride replaces 3-chloro-propionyl chloride in EXAMPLE 28 and 2,4-dimethyl-3-(1 ,2,3,6-tetrahydro-pyridin-4-yl)- 1 H-indole replaces 5-fluoro-3-(1 ,2,3,6-tetrahydro-pyridin-4-yl)-1 H-indole in EXAMPLE 30. MS m/z 454 (M+1 ).

EXAMPLE 42. Preparation of 8-{2-[4-(2,6-dimethyl-1H-indol-3-yl)-piperidin-1-yl]-ethyl}- 6,6-dimethyl- 1 ,2,5,6-tetrahydro-pyrrolo[3,2,1-//|quinolin-4-one

The title compound is prepared in a manner similar to EXAMPLES 27 to 30 in which chloro-acetyl chloride replaces 3-chloro-propionyl chloride in EXAMPLE 28 and 2,6-dimethyl-3-piperidin-4-yl-1 H-indole replaces 5-fluoro-3-(1 ,2,3,6-tetrahydro-pyridin-4-yl)-1 H-indole in EXAMPLE 30. MS m/z 456 (M+1).

EXAMPLE 43. Preparation of 9-fluoro-8-{2-[4-(1 H-indol-3-yl)-piperidin-1-yl]-ethyl}-1 ,2,5,6-tetrahydro- pyrrolo[3,2,1-/y]quinolin-4-one

3-Piperidin-4-yl-1 H-indole acetate salt (102.6 g, 394 mmol) was added to a solution of K ₂ CO ₃ (103 g, 985 mmol) and water (1000 mL). To this solution was added 8-(2-chloro-ethyl)-9-fluoro-1 ,2,5,6-tetrahydro- pyrrolo[3,2,1-/y]quinolin-4-one (100 g, 394 mmol), and the resulting slurry was heated to 98 ⁰ C and was allowed to stir overnight. The reaction mixture was allowed to RT and filtered. The resulting filter cake

was washed with water and acetone, resuspended in water (1000 mL), and filtered. The cake was slurried in acetone (1000 mL), filtered, and dried under vacuum at 70°C overnight to give the title compound as a white solid (143.6 g, 87%). HPLC (area) purity 96.8%; ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 8.06 (1 H, s), 7.61 (1 H, d, J=5.6 Hz), 7.32 (1 H, d, J=5.6 Hz), 7.15 (1 H, dt, J=7.0, 1.1 Hz), 7.06 (1 H, dt, J=I.2, 1.1 Hz), 6.95 (1 H, d, J=1.9 Hz), 6.82 (1 H, d, J=6.4 Hz), 4.07 (2H, m), 3.14 (4H, m), 2.85 (5H, m), 2.61 (4H, m), 2.22 (2H, m), 2.07 (2H, m), 1.84 (2H, m).

EXAMPLE 44. Preparation of 9-fluoro-8-{2-[4-(6-fluoro-1 H-indol-3-yl)-piperidin-1 -yl]-ethyl}-1 ,2,5,6- tetrahydro-pyrrolo[3,2,1-/y]quinolin-4-one

A mixture of 8-(2-chloro-ethyl)-9-fluoro-1 ,2,5,6-tetrahydro-pyrrolo[3,2,1-/)]quinolin-4-one (0.25 g, 0.98 mmol), 6-fluoro-3-piperidin-4-yl-1H-indole (0.33 g, 1.28 mmol), NaI (0.15 g, 0.98 mmol), Na ₂ CO ₃

(0.31 g, 2.95 mmol), dioxane (5 mL), and water (10 mL) was refluxed for three days. After cooling to RT, the reaction mixture was diluted with CHCI ₃ , refluxed for 5 min to dissolve a white solid, and then extracted with CHCI ₃ . The combined organic layers were dried over Na ₂ SO ₄ , filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, 3% MeOH in CH ₂ CI ₂ ) to give the title compound as a white solid (0.17 g, 40%). HPLC (area) purity 98.05%, mp 267-270 ⁰ C; ¹ H NMR (400 MHz, CDCI ₃ ) δ 7.95 (1 H, br s), 7.54 (1 H, dd), 7.04 (1 H, dd), 6.96 (1 H, s), 6.95-6.84 (2H, m), 4.11 (2H, t), 3.22-3.13 (4H, m), 2.93-2.81 (5H, m), 2.68-2.59 (4H, m), 2.24 (2H, t), 2.09-2.06 (2H, m), 1.90-1.75 (2H, m); anal, calc'd for C ₂₆ H ₂₇ F ₂ N ₃ OOJS H ₂ O: C 69.78, H 6.38, N 9.39; found: C 69.66, H 6.11 , N 9.34.

EXAMPLE 45. Preparation of 9-fluoro-8-{2-[4-(5-fluoro-1 H-indol-3-yl)-piperidin-1 -yl]-ethyl}-1 ,2,5,6- tetrahydro-pyrrolo[3,2, 1 -/y]quinolin-4-one

A mixture of 8-(2-chloro-ethyl)-9-fluoro-1 ,2,5,6-tetrahydro-pyrrolo[3,2,1-/y]quinolin-4-one (0.25 g, 0.98 mmol 5-fluoro-3-piperidin-4-yl-1H-indole (0.28 g, 1.28 mmol), NaI (0.15 g, 0.98 mmol), Na ₂ CO ₃ (0.31 g, 2.95 mmol), dioxane (5 mL), and water (10 mL) was refluxed for three days. After cooling to RT, the reaction mixture was diluted with CHCI ₃ , refluxed for 5 min to dissolve a white solid, and then extracted with CHCI ₃ . The combined organic layers were dried over Na ₂ SO ₄ , filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, 3% MeOH in CH ₂ CI ₂ ) to give the title compound as a white solid (0.19 g, 45%). HPLC (area) purity 97.49%, mp 220-225 ⁰ C; ¹ H NMR (400 MHz, CDCI ₃ ) δ 7.97 (1 H, br s), 7.32-7.24 (2H, m), 7.04 (1 H, s), 6.92 (1 H, t), 6.85 (1H, d), 4.11 (2H, t), 3.25-3.12 (4H, m), 2.91 (2H, t), 2.88-2.72 (3H, m), 2.68-2.54 (4H, m), 2.25 (2H, t), 2.08 (2H, d), 1.88-1.75 (2H, m); anal, calc'd for C ₂₆ H ₂₇ F ₂ N ₃ O ^« 0.65 H ₂ O: C 69.83, H 6.38, N 9.40; found: C 69.82, H 6.04, N 9.31.

EXAMPLE 46. Preparation of 7,9-difluoro-8-{2-[4-(1 λ/-indol-3-yl)-piperidin-1 -yl]-ethyl}-1 ,2,5,6-tetrahydro- pyrrolo[3,2,1-/y]quinolin-4-one

A mixture of 8-(2-chloro-ethyl)-7,9-difluoro-1 ,2,5,6-tetrahydro-pyrrolo[3,2,1-//]quinolin-4-one (100 mg, 0.368 mmol), 3-piperidin-4-yl-1H-indole (73 mg, 0.364 mmol), Kl (61 mg, 0.367 mmol), K ₂ CO ₃ (61 mg,

0.441 mmol) and water (5 ml_) was stirred at 10O ⁰ C for 16 h. After completion of the reaction, the mixture was allowed to cool to RT and was filtered. The filtered solid was triturated in acetone and filtered to obtain the title compound as a yellowish white solid (109 mg, 68%). ¹ H NMR (400 MHz, DMSOd ₆ ) δ iθ.75 (1 H, s), 10.75 (1 H, s), 7.52 (1 H, d, J=8.0 Hz), 7.32 (1 H, d, J=8.2 Hz), 7.07 (1 H, d, J=2.1 Hz), 7.03 (1 H, m), 6.94 (1 H, m), 3.98 (2H, t, J=8λ Hz), 3.31 (2H, s), 3.13 (1 H, t, J=8.2 Hz), 2.88 (2H, t, J=7.7 Hz), 2.74 (2H, s), 2.56 (2H, t, J=7.8 Hz), 2.51 (7H, d, J=I .9 Hz), 2.14 (1 H, s), 1.92 (1 H, s), 1.68 (1 H, s).

EXAMPLE 47. Preparation of 7-fluoro-8-{2-[4-(1 H-indol-3-yl)-piperidin-1 -yl]-ethyl}-1 ,2,5,6-tetrahydro- pyrrolo[3,2,1-/)]quinolin-4-one

A mixture of 8-(2-chloro-ethyl)-7-fluoro-1 ,2,5,6-tetrahydro-pyrrolo[3,2,1-//|quinolin-4-one (100 mg, 0.394 mmol), 3-piperidin-4-yl-1 H-indole (79 mg, 0.394 mmol), Kl (65 mg, 0.392 mmol), K ₂ CO ₃ (65 mg,

0.470 mmol) and water (5 ml_) was stirred at 100 ⁰ C for 16 h. After completion of the reaction, the mixture was allowed to cool to RT and was filtered. The filtered solid was triturated in acetone and filtered to obtain title compound as a yellowish white solid (130 mg, 79%). ¹ H NMR (400 MHz, DMSOd ₆ ) δ 10.74 (1 H, s), 7.53 (1 H, d, J=7.8 Hz), 7.32 (1 H, d, J=8.0 Hz), 7.05 (3H, m), 6.94 (1 H, m), 3.94 (2H, t, J=8.5 Hz), 3.31 (3H, s), 3.07 (2H, t, J=8.5 Hz), 3.02 (2H, d, J=11.5 Hz), 2.90 (2H, t, J=7.8 Hz), 2.70 (2H, m), 2.55 (2H, t, J=7.8 Hz), 2.13 (2H, s), 1.92 (2H, s), 1.67 (1 H, dd, J=12.3, 3.1 Hz).

EXAMPLE 48. Preparation of 2-chloro-1-(2,3-dihydro-indol-1-yl)-ethanone

To a cooled (0°C) solution of 2,3-dihydro-1 /-/-indole (10.0 g, 83.9 mmol) in acetone (100 mL) was added chloro-acetyl chloride (14.2 g, 126 mmol) dropwise. The resulting mixture was stirred at RT for one-half h, subsequently diluted with water, and extracted with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ and filtered. The solvent was evaporated under reduced pressure to obtain the title compound as a white solid (15.1 g) which was used without purification. ¹ H NMR (400 MHz, CDCI ₃ ) δ 8.21 (1 H, d), 7.29-7.20 (2H, m), 7.08 (1 H, t), 4.30-4.02 (4H, m), 3.21 (2H, t).

EXAMPLE 49. Preparation of 4,5-dihydro-1H-pyrrolo[3,2,1-/7/]indol-2-one

2-Chloro-1-(2,3-dihydro-indol-1-yl)-ethanone (5.0 g, 25.6 mmol) and AICI ₃ (10.2 g, 76.7 mmol) were combined and heated at 270 ⁰ C on a sand bath in small batches (about 1.5 g each). The resulting black residue was hydrolyzed by the addition of crushed ice in small portions until gas evolution ceased and was extracted with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ , filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, 3:1 ratio of EtOAc and hexane) to give the title compound as a white solid (0.62 g, 15.2%). ¹ H NMR (400 MHz, CDCI ₃ ) δ 7.08 (1 H, d), 7.02 (1 H, d), 6.92 (1 H, t), 4.08 (2H, t), 3.78 (2H, s), 3.58 (2H, t).

EXAMPLE 50. Preparation of 7-(2-chloro-acetyl)-4,5-dihydro-1H-pyrrolo[3,2,1-/7/]indol-2 -one

4,5-Dihydro-1H-pyrrolo[3,2,1-/7/]indol-2-one (0.70 g, 4.40 mmol) and AICI ₃ (2.93 g, 22.0 mmol) were mixed under nitrogen in CS ₂ (20 mL) followed by the dropwise addition of chloro-acetyl chloride (0.63 mL, 7.91 mmol). The reaction was stirred at RT for two hours. The resulting mixture formed two distinct

layers. The upper colorless layer (CS ₂ ) was decanted off. The lower layer was hydrolyzed by the addition of crushed ice in small portions until the gas evolution ceased and was extracted with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ , filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, 2:1 ratio of EtOAc and hexane) to give the title compound as a white solid (0.61 g, 58.3%). ¹ H NMR (400 MHz, CDCI ₃ ) δ 7.78 (1 H, s), 7.72 (1 H, s), 4.60 (2H, s), 4.16 (2H, t), 3.83 (2H, s), 3.62 (2H, t).

EXAMPLE 51. Preparation of 7-(2-chloro-ethyl)-4,5-dihydro-1 H-pyrrolo[3,2,1 -λ/]indol-2-one

To a cooled solution (0 ⁰ C) of 7-(2-chloro-acetyl)-4,5-dihydro-1H-pyrrolo[3,2,1-/7/]indol-2 -one (0.61 g, 2.59 mmol) in TFA (4 ml_) was added Et ₃ SiH (0.69 g, 5.95 mmol). The resulting mixture was stirred at RT over night. After evaporation of the solvent under reduced pressure, the residue was dissolved in EtOAc, washed with water and with brine, dried over Na ₂ SO ₄ , and filtered. Following evaporation of the solvent under reduced pressure, the resulting residue was dissolved in EtOAc (1 mL) and mixed with hexane to precipitate the title compound as a white solid (0.52 g, 91 %). ¹ H NMR (400 MHz, CDCI ₃ ) δ 6.98 (1 H, s), 6.95 (1 H, s), 4.15 (2H, t), 3.95 (2H, s), 3.69 (2H, t), 3.62 (2H, t), 3.06 (2H ₁ 1).

EXAMPLE 52. Preparation of 7-{2-[4-(5-fluoro-3a,7a-dihydro-1 H-indol-3-yl)-piperidin-1 -yl]-ethyl}-4,5- dihydro-1 H-pyrrolo[3,2,1 -λ/]indol-2-one

A mixture of 7-(2-chloro-ethyi)-4,5-dihydro-1 H-pyrrolo[3,2,1-/?/|indol-2-one (0.40 g, 1.80 mmol), 5-fuoro-3- piperidin-4-yl-1H-indole (0.59 g, 2.71 mmol), Na ₂ CO ₃ (0.57 g, 5.40 mmol), NaI (0.27 g, 1.80 mmol), dioxane (3.6 mL) and water (14.4 mL) was refluxed for four hours. After cooling to RT, the reaction mixture was diluted with CHCI ₃ , refluxed for 30 min to dissolve a white solid, and then extracted with CHCI ₃ . The combined organic layers were dried over Na ₂ SO ₄ , filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, 3% MeOH in CH ₂ CI ₂ ) to give the title compound as a white solid (0.18 g, 24.8%). HPLC (area) purity 98.07%, mp 149-152°C; ¹ H NMR (400 MHz, CDCI ₃ ) δ 7.98 (1 H, br s), 7.34 (1 H, t), 7.02 (1 H, s), 6.99-6.84 (3H, m), 4.05 (2H, t), 3.74 (2H, s), 3.55 (2H, t), 3.18-3.12 (2H, m), 2.86-2.70 (3H, m), 2.62-2.55 (2H ₁ m), 2.24 (2H, t), 2.12-2.00 (2H, m), 1.92-1.78 (2H, m); anal, calc'd for C ₂₅ H ₂₆ FN ₃ O ^« 1.7 H ₂ O: C 69.17, H 6.87, N 9.68; found: C 69.10, H 6.63, N 9.57.

EXAMPLE 53. Preparation of 7-{2-[4-(5-fluoro-3a,7a-dihydro-1 H-indol-3-yl)-piperidin-1 -yl]-ethyl}-4,5- dihydro-1/-/-pyrrolo[3,2,1-/7/]indol-2-one methanesulfonic acid

To a cooled solution (O ⁰ C) of 7-{2-[4-(5-fluoro-3a,7a-dihydro-1 H-indol-3-yl)-piperidin-1 -yl]-ethyl}-4,5- dihydro-1H-pyrrolo[3,2,1-/7/]indol-2-one (120 mg, 0.297 mmol) in THF (10 mL) was added a solution of methanesulfonic acid (0.052 mL, 0.802 mmol) in THF (0.75 mL). The resulting mixture was stirred at 0 ⁰ C for 30 min, warmed to RT, and then diluted with dry diethyl ether. The white solid was filtered and washed several times with diethyl ether and dried overnight in a vacuum oven at 30 ⁰ C to give the title compound as a white solid (165 mg, quantitative). HPLC (area) purity 96.19%, mp 50-54 ⁰ C; ¹ H NMR (400 MHz, CD ₃ OD) δ 7.34-7.23 (2H, m), 7.14 (1 H, s), 7.08 (1 H, s), 7.03 (1 H, s), 6.86 (1 H, t), 4.06 (2H, t), 3.74 (2H,

d), 3.56 (2H, t), 3.39-3.28 (5H, m), 3.19 (2H, t), 3.18-3.06 (2H ₁ m), 2.72 (8H, s), 2.26 (2H, d), 2.18- 2.02 (2H, m); anal, calc'd for C ₂₅ H ₂₆ FN ₃ O ^« 2.7 MeSO ₃ H«2.0 H ₂ O: C 47.60, H 5.88, N 6.01 ; found: C 47.53, H 5.85, N 5.81.

EXAMPLE 54. Preparation of 7-{2-[4-(6-fluoro-3a,7a-dihydro-1 H-indol-3-yl)-piperidin-1-yl]-ethyl}-4,5- dihydro-1 H-pyrrolo[3,2,1 -/7/]indol-2-one

A mixture of 7-(2-chloro-ethyl)-4,5-dihydro-1H-pyrrolo[3,2,1-/7/]indol-2- one (0.40 g, 1.80 mmol), 6-fluoro-3- piperidin-4-yl-1 /-/-indole (0.69 g, 2.71 mmol), Na ₂ CO ₃ (0.67 g, 6.31 mmol), NaI (0.27 g, 1.80 mmol), dioxane (3.6 ml_) and water (14.4 mL) was refluxed for 4 h. After cooling to RT, the reaction mixture was diluted with CHCI ₃ , refluxed for 30 min to dissolve a white solid, and then extracted with CHCI ₃ . The combined organic layers were dried over Na ₂ SO ₄ , filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, 3% MeOH in CH ₂ CI ₂ ) to give the title compound as a white solid (0.18 g, 25.1 %). HPLC (area) purity 95.50%; mp 225-230 ⁰ C; ¹ H NMR (400 MHz, CDCI ₃ ) δ 8.00 (1 H, br s), 7.55 (1 H, t), 7.06 (1 H, d), 6.99-6.78 (4H, m), 4.09 (1 H, t), 3.76 (2H, s), 3.55 (2H, t), 3.15 (2H, t), 2.86-2.70 (3H, m), 2.63-2.55 (2H, m), 2.26 (2H, t), 2.10-2.01 (2H, m), 1.94-1.76 (2H, m); anal, calc'd for C ₂₅ H ₂₆ FN ₃ O-1.0 H ₂ O: C 71.24, H 6.69, N 9.97; found: C 71.20, H 6.52, N 9.62.

EXAMPLE 55. Preparation of 7-{2-[4-(6-fluoro-3a,7a-dihydro-1H-indol-3-yl)-piperidin-1-y l]-ethyl}-4,5- dihydro-1 H-pyrrolo[3,2,1-/7/]indol-2-one methanesulfonic acid

To a cooled solution (0 ⁰ C) of 7-{2-[4-(6-fluoro-3a,7a-dihydro-1 H-indol-3-yl)-piperidin-1-yl]-ethyl}-4,5- dihydro-1 H-pyrrolo[3,2,1-/7/]indol-2-one (123 mg, 0.31 mmol) in THF (6 mL) was added a solution of methanesulfonic acid (0.04 mL, 0.62 mmol) in THF (0.58 mL). The resulting mixture was stirred at 0 ⁰ C for 30 min, warmed to RT, and then diluted with dry diethyl ether. The white solid was filtered and washed several times with dry diethyl ether and dried overnight in a vacuum oven at 30°C to obtain the title compound as a white solid (153 mg, quantitative). HPLC (area) purity 92.04%, mp 55-58°C; ¹ H NMR (400 MHz, CD ₃ OD) δ 7.60-7.54 (1 H, m), 7.08 (1 H, s), 7.06-6.99 (3H, m), 6.80 (1 H, t), 4.04 (2H, t), 3.76- 3.67 (2H, m), 3.58 (2H, t), 3.36-3.29 (4H, m), 3.28-3.16 (5H, m), 3.13-3.07 (2H, m), 2.72 (6H, s), 2.34-2.26 (2H, m), 2.14- 1.90 (2H, m); anal, calc'd for C ₂₅ H ₂₆ FN ₃ O ^« 2.0 MeSO ₃ H ^« 2.0 H ₂ O: C 51.33, H 6.06, N 6.65; found: C 51.35, H 5.97, N, 6.02.

EXAMPLE 56. Preparation of 9-fluoro-8-{2-[4-(1 H-indol-3-yl)-piperidin-1 -yl]-ethyl}-1 ,2,5,6-tetrahydro- pyrrolo[3,2,1-/)]quinolin-4-one methanesulfonic acid

9-Fluoro-8-{2-[4-(1/-/-indol-3-yl)-piperidin-1-yl]-ethyl}-1 ,2,5,6-tetrahydro-pyrrolo[3,2,1-/)]quinolin-4-one (165 g, 395 mmol) was slurried in acetone (450 mL) and water (350 mL). The slurry was heated to 5O ⁰ C. Methanesulfonic acid (49.4 g, 514 mmol) was added and the reaction mixture was heated to reflux. Water (1200 mL) was added while keeping the reaction above 52°C. The reaction mixture was cooled to 20 ⁰ C to give a slurry which was filtered. The filter cake was washed with acetone (750 mL) and the solid was dried under vacuum at 7O ⁰ C overnight. The solid was subsequently allowed to sit at RT overnight to give a solid product (158.8 g, 78%). Part of the product (124 g, 241 mmol) was slurried in acetone (2000 mL)

and allowed to stir for 2 d. The reaction mixture was filtered and dried overnight under vacuum at 60 ⁰ C to give the above-title compound (122.8 g, 99%). HPLC (area) purity 99.6%; ¹ H NMR (CD ₃ OD ₁ 300 MHz) δ 2.03 (2H, m), 2.2 (2H, m), 2.62 (2H, t, J=7.8 Hz), 2.69 (3H, s), 2.91 (2H, t, J=7.8 Hz), 3.05 (2H, m), 3.19 (4H, m), 3.30 (2H, m), 3.69 (2H, br s), 4.03 (2H, t, J=8λ Hz), 7.13 (3H, s), 7.37 (2H, d, J=8.0 Hz), 7.61 (2H, d, J=8.0 Hz); anal, calc'd for C ₂₇ H ₃₂ FN ₃ O ₄ S: C 63.07, H 6.40, N 8.10; found: C 63.14, H 6.28, N 8.18.

The biological activities of certain compounds described in the above examples were determined using the following radioligand receptor binding assays. The inhibition constant (Ki) may be calculated from the concentration at 50% inhibition (IC ₅₀ ) using a method described in Y.C. Cheng & W. H. Prusoff, Biochemical Pharmacology, 22:3099-3108 (1973).

DOPAMINE D ₂ RECEPTOR BINDING

D ₂ receptor binding was carried out using methods similar to those described in the literature. See A. W. Schmidt et al., Euro. J. Pharmacol. 425:197-201 (2001). In accordance with Schmidt et al., [ ³ H]- spiperone binding to membranes prepared from Chinese hamster ovary (CHO) cells stably expressing the human D ₂ L receptor was carried out in 250 μL of 50 mM Tris-HCI buffer containing 100 mM NaCI, 1 mM MgCI ₂ and 1 % DMSO at pH 7.4. Duplicate samples containing (in order of addition) the test compounds, 0.4 nM [ ³ H]-spiperone and approximately 12 μg protein were incubated for 60 minutes at RT. Bound radioligand was separated by rapid filtration under reduced pressure through Whatman GF/B glass fiber filters previously treated with 0.3% polyethyleneimine (PEI). Non-specific binding was determined in the presence of 10 μM haloperidol. Radioactivity retained on the filter was determined by liquid scintillation spectrophotometry.

TABLE 2, below, lists D ₂ receptor binding for many of the compounds described in the examples. Most of the compounds exhibited Ki values of less than 150 nM. Preferred compounds exhibited Ki values of about 100 nM or less, about 50 nM or less, about 25 nM or less, or about 10 nM or less.

5-HT _2A RECEPTOR BINDING

5-HT _2A receptor binding was carried out using methods similar to those described in the literature. See A. W. Schmidt et al., Euro. J. Pharmacol. 425:197-201 (2001 ). In accordance with Schmidt et al., [ ³ H]- ketanserin binding to membranes prepared from cells Swiss 3T3 stably expressing human 5-HT _2A receptors was carried out in 250 μL of 50 mM Tris-HCI buffer containing 1 % DMSO at pH 7.4. Triplicate samples containing (in order of addition) the test compounds, 2 nM [ ³ H]-ketanserin and approximately 40 μg protein were incubated for 120 minutes at RT. Bound radioligand was separated by rapid filtration under reduced pressure through Whatman GF/B glass fiber filters previously treated with 0.5% polyethyleneimine. Non-specific binding was determined in the presence of 10 μM methiothepin. Radioactivity retained on the filter was determined by liquid scintillation spectrophotometry.

TABLE 2, below, lists 5-HT _2A receptor binding for many of the compounds described in the examples. All of the compounds exhibited Ki values of less than 250 nM. Preferred compounds exhibited Ki values of

about 100 nM or less, about 50 nM or less, about 25 nM or less, about 10 nM, about 1 nM or less, or about 0.5 nM or less.

hSERT RECEPTOR BINDING

[ ¹²⁵ l]-RTI-55 binding to membranes prepared from human embryonic kidney (HEK) cells stably expressing the human serotonin transporter was carried out in Krebs-HEPES assay buffer containing 25 mM HEPES, 122 m M NaCI, 3 m M KCI, 1.2 m M MgSO ₄ , 1.3 m M CaCI ₂ , and 11 mM glucose at pH 7.4. Assays were set up in FlashPlates pre-coated with 0.1 % PEI in a total volume of 250 μl_ containing: test compounds (10 ^'5 M to 10 ^"12 M), cell membranes, and 50 pM [ ¹²⁵ l]-RTI-55 (Perkin Elmer, NEX-272; specific activity 2200 Ci/mmol). The reaction was incubated and gently agitated for 90 minutes at RT, and terminated by removal of assay volume. Plates were covered, and bound [ ¹²⁵ l]-RTI-55 was determined using a Wallac Triiux Beta Plate Counter. Test compounds were run in duplicate, and specific binding was defined as the difference between binding in the presence and absence of 10 μM Citalopram.

TABLE 2, below, lists hSERT receptor binding for many of the compounds described in the examples. All of the compounds exhibited Ki values of less than 650 nM. Preferred compounds exhibited Ki values of about 100 nM or less, about 50 nM or less, about 25 nM or less, about 10 nM, about 1 nM or less, or about 0.5 nM or less.

TABLE 2. D ₂ , 5-HT _2A and hSERT Binding

(2) 5-HT _2A % Inhibition

(3) hSERT % Inhibition

As used in this specification and the appended claims, singular articles such as "a," "an," and "the," may refer to a single object or to a plurality of objects unless the context clearly indicates otherwise. Thus, for example, reference to a composition containing "a compound" may include a single compound or two or more compounds. It is to be understood that the above description is intended to be illustrative and not restrictive. Many embodiments will be apparent to those of skill in the art upon reading the above description. Therefore, the scope of the invention should be determined with reference to the appended claims and includes the full scope of equivalents to which such claims are entitled. The disclosures of all articles and references, including patents, patent applications and publications, are herein incorporated by reference in their entirety and for all purposes.