MXPA01006853A - Arylpiperazinyl-cyclohexyl indole derivatives for the treatment of depression - Google Patents

Arylpiperazinyl-cyclohexyl indole derivatives for the treatment of depression

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Publication number
MXPA01006853A
MXPA01006853A MXPA/A/2001/006853A MXPA01006853A MXPA01006853A MX PA01006853 A MXPA01006853 A MX PA01006853A MX PA01006853 A MXPA01006853 A MX PA01006853A MX PA01006853 A MXPA01006853 A MX PA01006853A
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Mexico
Prior art keywords
cyclohexyl
indole
piperazin
cis
fluoro
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MXPA/A/2001/006853A
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Spanish (es)
Inventor
Richard Eric Mewshaw
Dahui Zhou
Ping Zhou
Kristin Lynne Meagher
Magda Asselin
Deborah Ann Evrard
Adam Matthew Gilbert
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Wyeth
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Abstract

Compounds are provided which are useful for the treatment of serotonin-affected neurological disorders which comprise (I) wherein:Ra, R1, R2 and R3 are each, independently, hydrogen, or a substituent selected from halogen, CF3, alkyl, alkoxy, MeSO2, amino or aminocarbonyl (each optionally substituted by one or two groups selected from alkyl and benzyl) carboxy, or alkoxycarbonyl;or two adjacent of Ra and R1-4 together can form a 5-7 membered carbocyclic or heterocyclic ring which is optionally substituted by a substituent defined above;R4 is hydrogen, halogen, or alkyl;R5 is hydrogen, alkyl, arylalkyl, or aryl;R6 is hydrogen, halogen, CF3, CN, carbamide, alkoxy or benzyloxy;X1, X2 and X3 are each carbon or one of X1, X2 or X3 may be nitrogen;Y is CH or nitrogen;and Z is carbon or nitrogen;or pharmaceutically acceptable salts thereof.

Description

DERIVATIVES OF ARILPIPERAZINIL-CICLOHEXIL INDEXES FOR THE TREATMENT OF DEPRESSION FIELD OF THE INVENTION This invention relates to compounds useful for the treatment of diseases affected by disorders of systems affected by serotonin, such as depression and anxiety. More specifically, the present invention is directed to arylpiperazinyl-cyclohexyl derivatives useful for the treatment of such disorders.
BACKGROUND OF THE INVENTION Pharmacists who increase the neuro-transmission of serotonin (5-HT) are useful for the treatment of many psychiatric disorders, including depression and anxiety. The first generation of non-selective drugs that affect serotonin are made to work through a variety of physiological means that cause them to possess numerous unwanted side effects. The most recently prescribed drugs, Selective Serotonin Reuptake Inhibitors (SSRIs), act predominantly by inhibiting 5-HT, which is released at the synapse, from which it is eliminated.
REF: 130898 actively from the synaptic cleft via a transporter carrier of presynaptic serotonin. Since SSRIs require several weeks before they exert their full therapeutic effect, this mechanism of blocking 5-HT can not fully explain its therapeutic activity. It is speculated that these two weeks of induction that occur before a total antidepressant effect is observed, is due to the commitment of the 5-HT1A autoreceptors that suppress the detonating activity of the 5-HT neurons, causing a decrease in the therapeutic effect. Studies suggest that after several weeks of SSRI administration, a 5-HT autoreceptor desensitization occurs that allows a complete antidepressant effect in most patients. (See, for example, Le Poul et al., Arch. Pharmacol., 352: 141 (1995)). Therefore, it is believed that the predominance of this negative feedback using 5HT1A antagonists would potentially increase and accelerate the clinical antidepressant reaction. Recent studies by Artigas et al., Trends Neurosci., 19: 378-383 (1996), suggest a combination of 5-HT1A activity and inhibition of 5HT uptake within a simple molecular entity can achieve a stronger antidepressant effect and act faster.
The present invention relates to a new class of molecules that have the ability to act on the autoreceptors of 5-HT1A and concomitantly with the 5-HT transporter. Such compounds are therefore potentially useful for the treatment of depression as well as other serotonin disorders. U.S. Patent No. 5,468,767 reports a series of substituted characters of the following formula for the treatment of disorders associated with dysfunction in serotonergic neurotransmission, including depression wherein Ri is hydrogen or alkyl of 1 to 4 carbon atoms and R2 is alkyl of 1 to 4 carbon atoms or (CH2) pAr. , WO 9415928 describes a series of piperazine derivatives of the following formula for the treatment of CNS disorders, including depression wherein R is hydrogen or alkyl; Ri and R2 are each aryl or mono- or bicyclic heteroaryl radicals; R3 is hydrogen, alkyl, or a spirocycloalkyl group; Y n is 1 or 2 and m is from 1 to 3. WO 93/10092 describes a series of cyclohexanes of the following formula for the treatment of dopaminergic disorders.
BRIEF DESCRIPTION OF THE INVENTION The compounds of this invention are arylpiperazinyl-cyclohexyl derivatives represented by Formula I: wherein: Ra, Ri, R2 and R3 are each, independently, hydrogen, or a substituent selected from halogen, CF3, alkyl, alkoxy, MeS02, amino or aminocarbonyl (each optionally substituted by one or two groups selected from alkyl and benzyl) carboxy, or alkoxycarbonyl; or two adjacent groups of Ra and R? - together can form a 5-7 membered carbocyclic or heterocyclic ring which is optionally substituted by a substituent defined therein; R 4 is hydrogen, halogen, or alkyl; R5 is hydrogen, alkyl, arylalkyl, or aryl; Rβ is hydrogen, halogen, CF3, CN, carbamide, alkoxy or benzyloxy; Xi / X2 and X3 are each carbon or one of Xi, X2 or X3 can be nitrogen; And it is CH or nitrogen; and Z is carbon or nitrogen; or pharmaceutically acceptable salts thereof. Preferably, the compounds of the present invention are those represented by Formula I, wherein Ra, Ri, R2 and R3 are each, independently, hydrogen, halogen, alkyl, alkoxy or together form a carbocyclic or heterocyclic ring of 7 members; R 4 is hydrogen or halogen; and / or R5 is hydrogen, alkyl or alkylaryl; and / or R6 is hydrogen, halogen, CN or alkoxy; and / or Xi / 2 X3 Y and Z are each carbon; or a pharmaceutically acceptable salt thereof. More preferably, the compounds of the present invention are selected from the following: 3- [cis-4- [4- (lH-Indol-4-yl) -1-piperazinyl] cyclohexyl] -IH-indole; 3- [trans -4- [4- (lH-Indol-4-yl) -1-piperazinyl] cyclohexyl] -lH-indole; 4-Fluoro-3- [cis -4- [4- (lH-indol-4-yl) -1-piperazinyl] -cyclohexyl] -lH-indole; 4-Fluoro-3- [trans -4- [4- (lH-indol-4-yl) -1-piperazinyl] -cyclohexyl] -lH-indole; 5-Fluoro-3- [cis -4- [4- (lH-indol-4-yl) -1-piperazinyl] -cyclohexyl] -lH-indole; 5-Fluoro-3- [trans -4- [4- (lH-indol-4-yl) -1-piperazinyl] -cyclohexyl] -lH-indole; 6-Fluoro-3- [cis -4- [4- (lH-indol-4-yl) -1-piperazinyl] -cyclohexyl] -IH-indole; 6-Fluoro-3- [trans -4- [4- (lH-indol-4-yl) -1-piperazinyl] -cyclohexyl] -lH-indole; 5-Bromo-3- [cis -4- [4- (lH-indol-4-yl) -1-piperazinyl] -cyclohexyl] -lH-indole; -Bromo-3- [trans -4- [4- (lH-indol-4-yl) -1-piperazinyl] -cyclohexyl] -lH-indole; -Cloro-3- [cis-4- [4- (lH-indol-4-yl) -1-piperazinyl] -cyclohexyl] -lH-indole; -Cloro-3- [trans -4- [4- (lH-indol-4-yl) -1-piperazinyl] -cyclohexyl] -lH-indole; -. { 4 - [(1,4-cis) -4- (1H-indol-4-yl) -1-piperazinyl-1-yl] cycloalkyl} - lH-indole-5-carbonitrile; -. { 4 - [(1, 4-trans) -4- (1 H -indol-4-yl) -l-piperazinyl-1-yl] cyclohexyl) -lH-indole-5-carbonitrile; -Metoxy-3- [cis -4- [4- (lH-indol-4-yl) -1-piperazinyl] -cyclohexyl] -lH-indole; -Metoxy-3- [trans -4- [4- (lH-indol-4-yl) -1-piperazinyl] -cyclohexyl] -lH-indole; - [cis-4- [4- (lH-Indol-4-yl) -1-piperazinyl] cyclohexyl] -2-methyl-lH-indole; - [trans -4- [4- (lH-indol-4-yl) -1-piperazinyl] cyclohexyl] -2-methyl-lH-indole; -. { (1, 4 -cis) -4- [4-lH-Indol-4-yl) -piperazin-1-yl] -cyclohexyl} -lH-pyrrolo [2,3-b] pyridine; -. { (1, 4-trans) -4- [4-ÍH-Indol--i 1) -piperazin-1-yl] -cyclohexyl) -lH-pyrrolo [2,3-b] pyridine; -Fluoro-l-methyl-3-. { cis-4- [4- (l-methyl-lH-indol-4-yl) -1-piperazinyl] cyclohexyl} -lH-indole; 3-. { (1, 4-cis) -4- [4- (1H-indol-4-yl) -piperazin-1-yl] -cyclohexyl} -l-methyl-lH-indole-5-carbonitrile; 3-. { (1, 4-trans) -4- [4- (lH-indol-4-yl) -piperazin-1-yl] -cyclohexyl} -l-methyl-lH-indole-5-carbonitrile; I-Ethyl-3-. { (1, 4-cis) -4- [4- (1H-indol-4-yl) -piperazin-1-yl] -cyclohexyl} -lH-indole-5-carbonitrile; 3-. { (1, 4-cis) -4- [4- (1H-indol-4-yl) -piperazin-1-yl] -cyclohexyl} -l-propyl-lH-indole-5-carbonitrile; 3-. { (1, 4-trans) -4- [4- (1H-indol-4-yl) -piperazin-1-yl] -cyclohexyl} -l-propyl-lH-indole-5-carbonitrile; 3-. { (1, 4-cis) -4- [4- (1H-indol-4-yl) -piperazin-1-yl] -cyclohexyl) -l-isopropyl-1H-indole-5-carbonitrile; 3-. { (1, 4-trans) -4- [4- (1H-indol--yl) -piperazin-1-yl] -cyclohexyl) -1-i-sopropyl-1H-indo-1-5-carbonitrile; l-Benzyl-3-. { (1, 4-cis) -4- [4- (1H-indol-4-yl) -piperazin-1-yl] -cyclohexyl} - lH-indol- 5 -carbonitri lo; l-Benzyl-3-. { (1, 4-trans) -4- [4- (1H-indol-4-yl) -piperazin-1-yl] -cyclohexyl} -lH-indole-5-carbonitrile; l-Methyl-3-. { (1, 4-cis) -4- [4- (1-met yl-lH-i dol -4 -i 1) -piperazin-1-yl] -cyclohexyl} -lH-indole-5-carbonitrile; 5-Fluoro-3-. { (cis) - A - [A - (2-methoxy-phenyl) -piperazin-1-yl] -cyclohexyl} -lH-indole; 5-Fluoro-3-. { (1, 4-cis) - A - [4- (2-methoxy-phenyl) -piperidin-1-yl] -cyclohexyl} -lH-indole; -Fluoro-3-. { (1, 4-trans) -4- [4- (2-methoxy-phenyl) -piperidin-1-yl] -cyclohexyl} -lH-indole; 5-Metoxy-3-. { (1, 4-cis) -4- [4- (2-methoxy-phenyl) -piperazinyl-1-yl] -cyclohexyl} -lH-indole; 5-Metoxy-3-. { (1, 4-trans) -4- [4- (2-methoxy-phenyl) -piperidin-1-yl] -cyclohexyl} -lH-indole; 3- . { (1, -cis) -4- [4- (2-methoxy-phenyl) -piperazin-1-yl] -cyclohexyl} -lH-pyrrolo [2, 3-b] piperidine; 5-Fluoro-3-. { (cis) - A - [A - (5-fluoro-2-methoxy-phe yl) -piperazin-1-yl] -cyclohexyl} -lH-indole; 5-Fluoro-3-. { (trans) -4- [4- (5-Fluoro-2-methoxy-phenyl) -piperazin-1-yl] -cyclohexyl} -lH-indole; 3-. { (1,4-cis) - A - Í - [(2,3-Dihydro-benzo [1,4] dioxin-5-yl) -piperazin-1-yl] -cyclohexyl} -4-fluoro-lH-indole; 3-. { (1, 4-trans) -4- [4- (2,3-Dihydro-benzo [1,4] dioxin-5-yl) -piperazin-1-yl] -cyclohexyl} -4-fluoro-lH-indole; 3-. { (1, 4-cis) -4- [4- (2, 3-Dihydro-benzo [1,4] gave in-5-yl) -piperazin-1-yl] -cyclohexyl} -5-fluoro-lH-indole; 3-. { (1, 4-trans) -4- [4- (2,3-Dihydro-benzo [1,4] dioxin-5-yl) -piperazin-1-yl] -cyclohexyl} -5-fluoro-lH-indole; 3-. { (1, 4-cis) -4- [4- (2, 3-Dihydro-benzo [1,4] gave in-5-yl) -piperazin-1-yl] -cyclohexyl} -6-fluoro-lH-indole; 3-. { (1, 4-trans) -4- [4- (2,3-Dihydro-benzo [1,4] dioxin-5-yl) -piperazin-1-yl] -cyclohexyl} -6-fluoro-lH-indole; -. { (1, 4-trans) -4- [4- (2, 3-Dihydro-benzo [1,4] dioxin-5-yl) -piperazin-1-yl] -cyclohexyl} -6- fluoro-H-indole; -. { (1,4-cis) - A - [A - (2,3-Dihydro-benzo [1,4] dioxin-5-yl) -piperazin-1-yl] -cyclohexyl} -lH-indole-5-carbonitrile; -. { (1, 4-trans) -4- [4- (2,3-Dihydro-benzo [1,4] dioxin-5-yl) -piperazin-1-yl] -cyclohexyl} -lH-indole-5-carbonitrile; -. { 4- [(1,4-cis) -4- (5-Fluoro-IH-indol-3-yl) -cyclohexyl] -piperazin-1-yl} -quinoline; -. { 4- [(1, 4-trans) -4- (5-Fluoro-1H-indol-3-yl) -cyclohexyl] -piperazin-1-yl} -quinoline, • -. { 4- (1, 4-cis) -4- [4- (5-Fluoro-1-methyl-1H-indol-3-yl) -cyclohexyl] -piperazin-1-yl} -quinoline; - [(1, -cis) - A - (4-Quinolin-8-yl-piperazin-1-yl) -cyclohexyl] -lH-indole-5-carbonyl trile; - [(1,4-trans) -4- (4-Quinolin-8-yl-piperazin-1-yl) -cyclohexyl] -lH-indole-5-carbonitrile; -Met il-3- [(1,4-cis) - A - (4 -quinolin-8-yl-piperazin-1-yl) -cyclohexyl] -lH-indole-5-carbonitrile; -Fluoro-3-. { (1, -cis) -4- [4- (6-f1uoro-chroman-8-yl) -piperazin-1-yl] -cyclohexyl} -lH-indole; -Fluoro-3-. { (1, -trans) -4- [4- (6-fluoro-chroman-8-yl) -piperazin-1-yl] -cyclohexyl} -lH-indole; - . 5 -Fluoro-3-. { (1, 4-cis) -4- [4- (5-fluoro-2,3-dihydro-benzofuran-7-yl) -piperazin-1-yl] -cyclohexyl} - 1H- indole; 5-Fluoro-3 - [(1,4-trans) -4- [4- (5-fluoro-2,3-dihydro-benzofuran-7-yl) -piperazin-1-yl] -cyclohexyl} -lH- indole; 3- . { (1,4-cis) -4- [4- (5-Fluoro-2,3-dihydro-benzofuran-7-yl) -piperazin-1-yl] -cyclohexyl} -lH-indole-5-carbonitrile; 3-. { (1, -trans) -4- [4- (5-Fluoro-2, 3-dihydro-benzofuran-7-yl) -piperazin-1-yl] -cyclohexyl} -lH-indole-5-carbonitrile; 3- . { (1,4-cis) - A - [A - (5-Fluoro-2,3-dihydro-benzofuran-7-yl) -piperazin-1-yl] -cyclohexyl} -l-methyl-lH-indole-5-carbonyl trile; 3- [(1, -cis) -4- [4- (Benzofuran-7-yl-piperazin-1-yl) -cyclohexyl] -lH-indol-5-carbonyl tri; 3- [(1, 4-trans) -4- [4- (Benzofuran-7-yl-piperazin-1-yl) -cyclohexyl] -lH-indole-5-carbonitrile; 5-Fluoro-3-. { 4- [4- (2-methoxy-phenyl) -piperazin-1-yl] -cyclohex-l-enyl} -lH-indole; 3- [4- [4- (lH-Indol-4-yl) -piperazin-1-yl] -cyclohex-1-enyl} -lH-indole-5-carbonitrile; 5-Fluoro-3-. { (1,4-cis) - A - [A - (2-methoxy-phenyl) -piperazin-1-yl] -cyclohexyl} -l, 3-dihydro-indol-2-one; -Fluoro-3-. { cis-4- [4- (lH-indol-4-yl) piperazinyl] -cyclohexyl} - 1-methyl-1H-indole; 8-. { (1, 4-cis) -4- [4- (5-Fluoro-lH-indol-3-yl) -cyclohexyl] -piperazin-1-yl} -6-methoxy-quinoline; 8-. { (1, 4-trans) -4- [4- (5-Fluoro-lH-indol-3-yl) -cyclohexyl] -piperazin-1-yl} -6-methoxy-quinoline; 3- . { (1,4-cis) -4- [4- (6-Methoxy-quinolin-8-yl) -piperazin-1-yl] -cyclohexyl} -lH-indole-5-carbonitrile; 3- . { (1, 4-trans) -4- [4- (6-Methoxy-quinolin-8-yl) -piperazin-1-yl] -cyclohexyl} -lH-indole-5-carbonitrile; 6-Chloro-8-. { 4- [1,4-cis) -4- (5-fluoro-1H-indol-3-yl) -cyclohexyl] -piperazin-1-yl} quinoline; 6-Chloro-8-. { 4- [1, 4-trans) -4- (5-fluoro-lH-indol-3-yl) -cyclohexyl] -piperazin-1-yl} quinol ina; 3-. { (1, 4-cis) -4 - [(4- (6-chloroquino-lin-8-yl) -piperazin-1-yl] -cyclohexyl] -lH-indole-5-carbonitrile; {1,4-trans) -4- [4- (6-Chloro-quinolin-8-yl) -piperazin-1-yl] -cyclohexyl} -lH-indole-5-carbonitrile; 5-Chloro -8-. {4- [(1,4-cis) -4- (5-fluoro-lH-indol-3-yl) -cyclohexyl] -piperazin-1-yl} quinoline; (1, 4-cis) - A - [A - (5-Chloro-quinolin-8-yl) -piperazin-1-yl] -cyclohexyl} -lH-indole-5-carbonitrile; 8- {(1,4-cis) -4- (6-fluoro-1H-indol-3-yl) -cyclohexyl] -piperazin-1-yl}. Quinoline; -Fluoro-8-. { 4 - [(1, 4-trans) -4- (6-fluoro-lH-indol-3-yl) -cyclohexyl] -piperazin-1-yl} quinoline; -. { (1,4-cis) - A - [A - (2-Methyl-quinolin-8-yl) -piperazin-1-yl] -cyclohexyl} -lH-indol-5 -carboni ryl; -. { (1, 4-trans) -4- [4- (2-Methyl-quinolin-8-yl) -piperazin-1-yl] -cyclohexyl} -lH-indole-5-carbonitrile; -. { 4 - [(1,4-cis) -4- (5-Fluoro-lH-indol-3-yl) -cyclohexyl] -piperazin-1-yl} -2- trifluoromet i 1- qui ol a; -. { 4- [(1, 4-trans) -4- (5-Fluoro-lH-indol-3-yl) -cyclohexyl] -piperazin-1-yl} -2-trifluoromethyl-quinoline; -. { (1,4-cis) - A - [A - (2-Trif luoromethyl-quinolin-4-y1) -piperazin-1-yl] -cyclohexyl} -lH-indole-5-carbonitrile; -. { (1, 4-trans) -4- [4- (2 -Tri f luorome til -qui nol in- 4- il) -piperazin-1-yl] -cyclohexyl} -lH-indole-5-carbonyl trile; -. { 4- [(1,4-cis) -4- (5-Fluoro-lH-indol-3-yl) -cyclohexyl] -piperazin-1-yl} -6-me toxi -quino lina; -. { 4- [(1, 4-trans) -4 - (5-Fluoro-lH-indol-3-yl) -cyclohexyl] -piperazin-1-yl} -6-methoxy-quinoline; -. { (1,4-cis) -4- [4- (6-Me-t-oxy-quinolin-4-yl) -piperazin-1-yl] -cyclohexyl} - lH-indole-5-carbonyl trile; Y -. { (1, 4-trans) -4- [4- (6-Methoxy-quinolin-4-yl) -piperazin-1-yl] -cyclohexyl} -lH-indole-5-carbonitrile.
As used herein, the terms "alkyl" and "alkoxy" are intended to include both linear and branched carbon chains containing 1-6 carbon atoms. The term "aryl" is intended to include aromatic radicals of 6-12 carbon atoms. The term "halogen" is intended to include fluorine, chlorine, bromine and iodine. Heterocyclic groups have one to three heteroatoms selected from oxygen, nitrogen and sulfur. The compounds of this Formula I can also be used in the form of a pharmaceutically acceptable acid addition salt having the utility of the free base. Such salts, prepared by methods well known to those skilled in the art, are formed with both inorganic or organic acids, for example: fumaric, maleic, benzoic, ascorbic, pamoic, succinic, bismethylene-salicylic, methanesulfonic, ethanedisulfonic, acetic acids, oxalic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, hydrochloric, hydrobromic, sulfuric, cyclohexylsulfamic, phosphoric and nitric.
The compounds of the present invention can be prepared by any suitable method that will be recognized by those skilled in the art. Accordingly, this invention provides a process for the preparation of compounds of formula I: (D as defined above or a pharmaceutically acceptable salt thereof, comprising one of the following: a) reacting a compound of the formula (II) where Ra, R? -3, Y and X? -3 are as defined in the above, with a compound of the formula (IV) (TV) wherein Z, R4, R5 and Rβ are as defined in the foregoing; or b) reducing a compound of the formula: (V) wherein the variables are as defined in the above to give a compound of the formula (I); or c) acidifying a basic compound of formula I with a pharmaceutically acceptable acid to a pharmaceutically acceptable salt; or d) separating a mixture of the cis and trans isomers of a compound of the formula (I) to isolate an isomer substantially free of the other isomer; or e) reacting a compound of the formula (I) having a reactive substituent group to give a compound of the formula (I) having a different substituent group; f) reacting a compound of the formula (I) having a reactive site (for example NH) to give a compound of the formula (I) having a substituent group at the site. With respect to process a) the reaction can be carried out by reductive alkylation, for example using a reducing agent such as sodium triacetoxyborohydride in a suitable solvent for example acetic acid. With respect to process b) the reduction can be conveniently carried out using palladium on carbon and hydrogen as exemplified herein. The compounds of formula I can be isolated in the form of a salt of a pharmaceutically acceptable acid, for example an organic or inorganic acid by treatment with an acid as described above.
Geometric isomers (cis and trans) are possible and such isomers can be separated by standard techniques, for example, chromatography. Examples of process e) involving the conversion of substituents to other substituents are the conversion of a halo substituent to an amino substituent Rx, the esterification of a carboxy to an ester, the hydrolysis of an ester to a carboxy group; and the amination of an ester group to give an amide. Examples of process f) involving substitution at sites are the alkylation at a size of NH in the compound of formula (I) to give N-alkyl or N-benzyl. The initial materials / reagents used in the above processes are known or can be made by methods known in the art from readily available materials by processes known or readily apparent to those skilled in the art. In any of the above processes the reactive substituent groups or sites can be protected with protecting groups before the reaction and therefore the protecting group is removed. Nevertheless, the present compounds can be advantageously prepared according to any of Reaction Schemes 1-6 set forth below. In the Reaction Schemes, the intermediate compounds exemplified hereinafter are identified in parentheses. The compound produced in each of Reaction Schemes 1-6 is identified with reference to the appropriate Example set forth below.
Reaction Scheme 1 OS) (5) (6) R * CH3, Et, n-Pr, i-Pr, Benzyl Reaction Scheme 2 , 5-CN.5-OMe ? NH (6a-d) to ° Ex.12-1 ° 6 # NC R = 4-F, 5-F, 6-F, 5-CN Reaction Scheme 3 Reaction Scheme 4 Reaction Scheme 5 Reaction Scheme 6 Reaction Scheme 7 (34) Ex. 3 Reaction Scheme 8 Ar-OH / - ^ Ar-OTf »- Ar- N N-Boc Ar-N NH \ - (35) (36) (37) oligomer, 5-isoquinolyl, 1-naphthyl Ex. 40-43 Reaction Scheme 9 JL J Quinoline termediary 39 Intermediary 6 Ex. 44 when R3es6-MeO NaBH (? Ac) 3, HOAc Ex.45 when R3 is 6-Cl DCE, 23 0. 12 h Rl esH R2es5-F, 5-CN Reaction Scheme 10 Reaction Scheme 11 piperazine Middleman 41 Intermediary 39 Intermediary 6 NaBH (OAc) 3, HOAc Ex.49 when Rj is 2-CF3 DCE, 23"C, 12 h Ex.50 when R3 is 6-McO R, esH R2e 5-F, 6-F, 5-CN Reaction Scheme 12 Example 51 Reaction Scheme 13 Example 52 Reaction Scheme 14 Example 54 R "CH3 Example 55 R = CF3 Reaction Scheme 15 Reaction Scheme 16 Reaction Scheme 17 Reaction Scheme 18 Example Reaction Scheme 19 Example 62 Reaction Scheme 20 Reaction Scheme 21 Reaction Scheme 22 (61) (82) (63) Reaction Scheme 23 Reaction Scheme 24 Reaction Scheme 25 (Example 69) the cis and trans compounds were not separated Reaction Scheme 26 (Examples 70-75) Reaction Scheme 27 (Example 76) Reaction Scheme 28 (Example 77) Reaction Scheme 29 Reaction Scheme 30 Reaction Scheme 31 Reaction Scheme 32 Reaction Scheme 33 Reaction Scheme 34 Reaction Scheme 35 Reaction Scheme 36 The following Reaction Schemes 37-39 were used to obtain the compounds of Examples 86-114.
Reaction Scheme 37 NaBHfOAc) ^ HOAc DCE, 23 «C, 12 h R3 is 5-MeO, 5-CF3-, 6-OCF3, 6-0, 6-F, -6-CH3 Reaction Scheme 38 when R, it is 5-C! when R3 is S-F R, is H, CH3 R i is S-F, * -F.5-C Reaction Scheme 39 INTERMEDIARY 1 3- (1, 4-Dioxa-spiro [4, 5] dec-7-en-8-yl) -1H-indole (la) It was heated to indole reflux (4.69 g, 40 mmoles), 1.4 cyclohexanedione monoethylene ketal (6.3 g, 40 mmol) and potassium hydroxide (13.2 g, 200 mmol) in 70 ml of methanol for 6 hours. The reaction was cooled and the product was isolated by filtration and washed with water to give 9.1 g (89%) of product. 3- (1, 4-Dioxa-spiro [4.5] dec-7-en-8-yl) -4-fluoro-1H-indole (lb) This compound was prepared in a similar manner described above by replacing indole with 4-fluoroindole (3 g, 22 mmol) to yield the title compound in a quantitative yield as a white solid: mp at 140 ° C (sublimated). 3- (1, 4-Dioxa-spiro [4.5] dec-7-en-8-yl) -5-fluoro-1H-indole (lc) 5-fluoroindole (4.96 g, 0. 036 moles), 1,4-cyclohexanedione monoethylene ketal (7.17 g, 0.046 moles) and potassium hydroxide (6 g, 91 mmol) in 70 ml of methanol for 6 hours. The reaction was cooled and the product was isolated by filtration and washed with water to give 8.59 g (86%) of product as a white solid: m.p. 153-155 ° C. 3- (.1, 4-Dioxa-spiro [4.5] dec-7-en-8-yl) -6-fluoro-1H-indole (Id) This compound was prepared in the manner described by the intermediate replace indole with 6-fluoroindole (5.14 g, 38 mmol) to produce 10 g (96.3%) of the title compound as a white solid: m.p. 196-197 ° C. Elemental analysis for Ci6Hi6FN02 Calculated: C, 70.32; H, 5.90; N, 5.13 Found: C, 70.62; H, 5.91; N, 5.08 3- (1, 4-Dioxa-spiro [4.5] dec-7-en-8-yl) -5-bromo-lH-indole (le) This compound was prepared in the manner described above by the intermediate replacing indole with 5-bromoindole (7.84 g, 40 mmol) to yield 10.5 g (78%) of the title compound as a white solid; MS The m / e 333 (M +). 3- (1, 4-Dioxa-spiro [4.5] dec-7-en-8-yl) -5-chloro-lH-indole (lf) This compound was prepared in the manner described above by the intermediate replace indole with 5-chloroindole (5 g, 33 mmol) to produce 9. 14 g (96%) of the title compound as a white solid: m.p. 178-181 ° C; MS The m / e 273 (M +). 3- (1, 4-Dioxa-spiro [4.5] dec-7-en-8-yl) -5-cyano-1H-indole (lg) This compound was prepared in the manner described above by the intermediate replace indole with 5-cyanoindole (29.98 g, 0.21 mol) to yield 29.32 g (50%) of the title compound as a white solid: mp 158-160 ° C. 3- (1, 4-Dioxa-espi or [4,5] dec-7-en-8-yl) -5-methoxy-1H-indole (lh) This compound was prepared in the manner described above by the intermediate when replacing indole with 5-methoxyindole (5 g, 34 mmol) in a yield of 82% (7.95 g) as a white solid: mp 161-16-2 ° C. 3- (1, -Dioxa-spiro [4.5] dec-7-en-8-yl) -2-methyl-1H-indole (li) A solution of 2-methyl-indole (2.0) was refluxed. g, 15.2 mmol), 1-monoethylene ketal cyclohexanedione (4.76 g, 30.4 mmol) and potassium hydroxide (10 g, 0.18 mol) in 50 ml of methanol for 48 hours. The mixture was poured into water (150 ml) and extracted with methylene chloride (2 x 200 ml). The organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvent removed under vacuum. Chromatography (25% ethyl acetate-hexanes) yielded a light brown solid which was washed with C20 ml ethyl ether) to yield 2.35 g (62%) of product as a white solid: m.p. 136-137 ° C. Elemental analysis for C? H? G N02 Calculated: C, 75.81; H, 7.11; N, 5.70 Found: C, 75.47; H, 7.26; N, 5.13 3- (1, 4 -Diox-spiro [4.5] dec-7-en-8-yl) -lH-azaindole dj) This compound was prepared in the manner described above by the la intermediary when replacing indole with 7- azaindol (3.65 g, 31 mmol) in a yield of 68% (5.42 g) as a white solid: mp 162-165 ° C; MS The m / e 256 (M +).
INTERMEDIARY 2 3- (1, 4-Dioxa-spiro [4.5] dec-8-yl) -1H-indole (2a) A mixture of 3- (1,4-dioxa-spiro [4, 5] was hydrogenated dec-7-en-8-yl) -lH-indole (8.0 g, 31.3 mmol) and 10% palladium on carbon (1.3 g) in ethanol (700 ml) for 18 hours. The catalyst was removed by filtration and the solvent was removed under vacuum to yield 8.01 g (99%) of product as a white solid. 3- (1, -Dioxa-spiro [4.5] dec-8-yl) -4-fluoro-1H-indole (2b) This compound was prepared in the manner described above by intermediate 2a by replacing 3- (1 , 4-dioxa-spiro [4, 5] dec-7-en-8-yl) -lH-indole with 3- (1,4-dioxa-spiro [4, 5] dec-7-en-8-il ) -4-fluoro-IH-indole (6.3 g) to yield 4.44 g (70%) of the title compound as a white solid: mp 161-162CC. Elemental analysis for Ci6H? 8FN02 Calculated: C, 69.08; H, 6.59; N, 5.09 Found: C, 69.05; H, 6.56; N, 4.87 3- (1, -Dioxa-spiro [4.5] dec-8-yl) -5-fluoro-1H-indole (2c) A mixture of 3- (1,4-dioxa-spiro [4, 5]) was hydrogenated. ] dec-7-en-8-yl) -5-fluoro-lH-indole (8.5 g) and 10% palladium on carbon (2.72 g) in ethanol (200 ml) for 5 hours. The catalyst was removed by filtration and the solvent was removed under vacuum. Chromatography (methanol-methylene chloride) afforded 7.55 g (82%) of product as a white solid: m.p. 183-185 ° C. 3- (1, 4-Dioxa-spiro [4.5] dec-8-yl) -6-fluoro-lH-indole (2d) This compound was prepared in the manner described above by intermediate 2a by replacing 3- ( 1, 4-dioxa-spiro [4, 5] dec-7-en-8-yl) - lH-indole with 3- (1,4-dioxa-spiro [4, 5] dec-7-en-8- il) -6- fluoro-IH-indole (9.54 g) to yield 5.83 g (60%) of the title compound as a white solid: mp 158-159 ° C. Elemental analysis for Ci6H? SF 02 Calculated: C, 69.80; H, 6.59; N, 5.09 Found: C, 69.74; H, 6.48; N, 5.13 3- (1, 4-Dioxa-spiro [4.5] dec-8-yl) -5-bromo-lH-indole (2e) A mixture of 3- (1,4-dioxa-spiro) was hydrogenated overnight. [4, 5] dec-7-en-8-yl) -5-bromo-1H-indole (6.8 g, 20.34 mmoles) and 5% palladium on carbon (5.0 g) in ethanol (500 ml). The catalyst was removed by filtration and the solvent was removed under reduced pressure. Chromatography (30% ethyl acetate-hexanes) yielded 5.0 g (73%) of product as a solid; MS The m / e 336 (M +). 3- (1, -Dioxa-spiro [4.5] dec-8-yl) -5-chloro-lH-indole (2f) - A mixture of 3- (1,4-dioxa-spiro) is hydrized overnight. [4, 5] dec-7-en-8-yl) -5-chloro-lH-indole (0.18 g) and platinum oxide (0.02 g) in ethanol (20 ml) with ten drops of acetic acid. The catalyst was removed by filtration and the solvent was removed under vacuum. Chromatography (25% ethyl acetate-hexanes) yielded 0.16 g (88%) of product as a white solid: mp 205-206.5 ° C. 3- (1, 4-Dioxa-spiro [4.5] dec-8-yl) -5-cyano-1H-indole (2g) This compound was prepared in the manner described above by intermediate 2a by replacing 3- ( 1, 4-dioxa-spiro [4, 5] dec-7-en-8-yl) -lH-indole with 3- (1,4-dioxa-spiro [4, 5] dec-7-en-8- il) -5-cyano-lH-indole (54.6 g) to yield 52.11 g (95%) of the title compound as a white solid in a 95% yield (52.12 g) as a white solid: mp 153-155 ° C. 3- (1, 4-Dioxa-spiro [4.5] dec-8-yl) -5-me oxy-lH-indole (2h) This compound was prepared in the manner described above by intermediate 2a by replacing 3- (1,4-dioxa-spiro [4, 5] dec-7-en-8-yl) -lH-indole with 3- (1,4-dioxa-spiro [4, 5] dec-7-en-8 -yl) -5-methoxy-lH-indole to yield 7.18 g (96%) of the title compound as a white solid: mp 153-155 ° C. 3- (1, 4-Dioxa-spiro [4.5] dec-8-yl) -2-methyl-1H-indole (2i) A mixture of 3- (1,4-dioxa-spiro) was hydrogenated for 3 hours. [4, 5] dec-7-en-8-yl) -2-met il-lH-indole (2.39 g, 8.9 mmol) and 10% palladium on carbon (0.35 g) in ethanol (80 ml). The catalyst was removed by filtration and then a methylene-methanol solution (80 ml) was used to dissolve any solids within the celite. The solvent was removed under vacuum to yield 2.34 g (97%) of product as an off-white solid, which was triturated with ethyl ether (40 ml) to yield a white solid: mp 166-168 ° C. The mother liquor was concentrated to produce another 1.2 g of product as a yellow solid. Elemental analysis for C? 7H2? N02 Calculated: C, 75.25; H, 7.80; N, 5.16 Found: C, 75.17; H, 7.99; N, 5.12 3- (1,4-Dioxa-spi or [4,5] dec-8-yl) -lH-azaindole (2j) This compound was prepared in the manner described above by intermediate 2a by replacing 3- (1, 4) -dioxa-spiro [4, 5] dec-7-en-8-yl) -IH-indole (7.18 g) with 3- (1,4-dioxa-spiro [4, 5] dec-7-en-8 -yl) -lH-azaindole (4.02 g) to yield 2.7 g (67%) of the title compound as a white solid: mp 204-207 ° C. Elemental analysis for C? 3H? 4N20 Calculated: C, 72.87; H, 6.59; N, 13.07 Found: C, 72.44; H, 6.75; N, 12.81 INTERMEDIARY 3 4- (ÍH-Indolyl) -ciciohexanone (3a) a solution of 3- (1,4-dioxa-spiro [4, 5] dec-8-yl) -lH-indole (2.57 g, 10 mmol) in 200 ml of tetrahydrofuran-hydrochloric acid (1: 1) (IN) was allowed to stir at room temperature for 16 hours. The solvent was evaporated under vacuum. The crude product was dissolved in ethyl acetate, washed with IN sodium hydroxide (3 x 150 ml). The organic layer was dried over anhydrous sodium sulfate, and filtered. Chromatography (40% ethyl acetate-hexanes) yielded 1.9 g (89%) of product. 4- (4-Fluoro-lH-3-indolyl) -cycothexanone (3b) This compound was prepared in the manner described above by 3a by replacing 3- (1,4-dioxa-spiro [4, 5] dec-8- il) -lH-indole with 3- (1,4-dioxa-spiro [4, 5] ec-8-yl) -4-fluoro-lH-indole (4.0 g) to yield 3.7 g (63%) of the compound of the title as a white solid: pf 104-106 ° C. 4- (5-Fluoro-lH-3-indolyl) -cidiohexanone (3c) A solution of 3- (1,4-dioxa-spiro [4,5] dec-8-yl) -5-fluoro-lH-indol (2.8 g, 10 mmol) in 200 ml of tetrahydrofuran-hydrochloric acid (1: 1) (IN) was allowed to stir at room temperature for 16 hours. The solvent was evaporated under vacuum. The crude product was dissolved in ethyl acetate, washed with IN sodium hydroxide (3 x 150 ml). The organic layer was dried over anhydrous sodium sulfate, and filtered. Chromatography (40% ethyl acetate-hexanes) yielded 2.1 g (91%) of product as yellow solid: m.p. 112-114 ° C. 4- (6-Fluoro-lH-3-indolyl) -cycothexanone (3d) This compound was prepared in the manner described above by intermediate 3a by replacing 3- (1,4-dioxa-spiro [4, 5] dec- 8-yl) -lH-indole with 3- (1,4-dioxa-spiro [4, 5] dec-8-yl) -6-fluoro-lH-indole (5.4 g) to yield 19.29 g (99%) of the title compound as a white solid: mp 102-105 ° C. Elemental analysis for C? H? 4NOF Calculated: C, 72.71; H, 6.10; N, 6.06 Found: C, 72.77; H, 5.98; N, 5.96 4- (5-Bromo-lH-3-indolyl) -cycothexanone (3e) This compound was prepared in the manner described above by intermediate 3a by replacing 3- (1,4-dioxa-spiro [4, 5] dec- 8-yl) -lH-indole with 3- (1,4-dioxa-spiro [4, 5] dec-8-yl) -5-bromo-lH-indole (4.5 g) to yield 3.3 g (84%) of the title compound as a white solid: MS m / e 291 (M +). Calculated: C, 75.25; H, 7.80; N, 5.16 Found: C, 75.17; H, 7.99; N, 5.12 4- (5-Chloro-lH-3-indolyl) -cycothexanone (3f) This compound was prepared in the manner described above by intermediate 3a by replacing 3- (1,4-dioxa-spiro [4, 5] dec- 8-yl) -lH-indole with 3- (1,4-dioxa-spiro [4, 5] dec-8-yl) -5-chloro-lH-indole (2.12 g) to yield 1.13 g (60%) of the title compound as a clear oil: MS FAB m / e 248 (M + H)? 4- (5-Cyano-lH-3-indolyl) -cycothexanone (3g) This compound was prepared in the manner described above by intermediate 3a by replacing 3- (1,4-dioxa-spiro [4, 5] dec- 8-yl) -lH-indole with 3- (1, 4-dioxa-spiro [4, 5] dec-8-yl) -5-cyano-lH-indole (6 g) to yield 4.03 g (81%) of the title compound as a white solid: mp 162.5-164 ° C. Elemental analysis for C? 5H? 4N20 Calculated: C, 75.61; H, 5.92; N, 11.76 Found: C, 75.82; H, 6.06; N, 11.72 4- (5-Methoxy-lH-3-indolyl) -cycothexanone (3h) This compound was prepared in the manner described above by intermediate 3a by replacing 3- (1,4-dioxa-spiro [4, 5] dec- 8-yl) -lH-indole with 3- (1,4-dioxa-spiro [4, 5] dec-8-yl) -5-methoxy-1 H-indole (5.85 g) to yield 4.2 g (85%) of the title compound as a white solid: mp 103-106 ° C. 4- (2-Methyl-lH-3-indolyl) -cycothexanone (3i) This compound was prepared in the manner described above by intermediate 3a by replacing 3- (1,4-dioxa-spiro [4, 5] dec- 8-yl) -lH-indole with 3- (1,4-dioxa-spiro [4, 5] dec-8-yl) -2-methyl-lH-indole (2.2 g) to yield 1.62 g (88%) of the title compound as a thick yellow oil: MS m / e 227 (M +). 4- (1H-3-pyrrolo [2, 3-b] pyridyl) -cydohexanone (3j) -This compound was prepared in the manner described above by intermediate 3a by replacing 3- (1, -dioxa-spiro [4, 5] dec-8-yl) -IH-indole with 3- (1, 4-dioxa-spiro [4, 5] dec-8-yl) -lH-azaindole (2.48 g) to yield 1.96 g (95%) of the title compound as a white solid: mp 162-164 ° C.
INTERMEDIARY 4 3- (1, 4-Dioxa-spiro [4.5] dec-7-en-8-yl) -5-cyano-1-methyl-indole To a suspension of sodium hydride (60%, 1.74 g , 0.073 moles) in anhydrous N, N-dimethylformamide (100 mL) was added 3- (1,4-dioxa-spiro [4, 5] dec-7-en-8-yl) -5-cyano-lH-indole (9.9 g, 0.035 mole) at room temperature. The mixture was stirred for 30 minutes at room temperature, then methyl iodide (9 ml, 0.14 moles) was added at room temperature. The reaction was allowed to stir for 1 hour, then quenched with water (50 ml). The mixture was extracted with methylene chloride (3 x 150 ml) and water (3 x 150 ml). The organic layer was dried over anhydrous magnesium sulfate and filtered. The solvent was removed under vacuum. Chromatography (5% methanol-methylene chloride) yielded 2.54 g (24%) of product as a light yellow solid: m.p. 65-67 ° C. Elemental analysis for C? 8H? 8N202 Calculated: C, 73.45; H, 6.16; N, 9.52 Found: C, 73.17; H, 6.24; N, 9.43 INTERMEDIARY 5- (1, 4-Dioxa-spiro [4.5] dec-8-yl) -5-cyano-1-methyl-indole (5a) A mixture of 3- (1,4-dioxazole) was hydrogenated. spiro [4, 5] dec-7-en-8-yl) -5-bromo-lH-indole (3.77 g) and 10% palladium on carbon (0.99 g) in ethanol-tetrahydrofuran (200: 80 ml) per 5 hours. The catalyst was removed by filtration and the solvent was removed under vacuum to yield a white powder which was washed with ethane-hexanes (1: 1) and dried under vacuum for 4 hours to yield 2.75 g (12%) of product: m.p. 170-172 ° C. Elemental analysis for Ci8H20N2O2 Calculated: C, 72.95; H, 6.80; N, 9.45 Found C, 72.79; H, 6.82; N, 9.35 3- (1, 4-Dioxa-spiro [4.5] dec-8-yl) -5-cyano-l-ethyl-indole (5b) To a suspension of sodium hydride (60%, 1. 63 g, 0.068 moles) in anhydrous N, N-dimethylformamide (150 ml) was added 3- (1,4-dioxa-spiro [4, 5] dec-8-yl) -5-cyano-lH-indole (9.0 g, 0.032 mole) at room temperature. The mixture was stirred for 30 minutes at room temperature, then ethyl bromide was added (14.6 g, 0.13 moles) at temperature. The reaction was allowed to stir overnight, then quenched with water (50 ml.) The mixture was extracted with methylene chloride (3 x 150 ml) and water (3 x 150 ml).
The organic layer was dried over anhydrous magnesium sulfate and filtered. The solvent was removed under vacuum. Chromatography (hexanes) yielded 5.5 g (69%) of product as a white solid: m.p. 124-126 ° C. Aná l i s i the balance for C? 9H22N202 Calculated: C, 73.52; H, 7.14; N, 9.02 Found: C, 73.56; H, 6.93; N, 8.95 3- (1, 4-Dioxa-spxro [4,5] dec-8-yl) -5-cyano-ln-propyl-indole (5c) This compound was prepared in the manner described above by intermediate 5b by replacing bromide of ethyl with n-propyl bromide (13.1 g, 11 mmol) to yield 4.33 g (75%) of the title compound as an oil: MS m / e 324 (M +). 3- (1, 4-Dioxa-spiro [4.5] dec-8-yl) -5-cyano-1-isopropyl-indole (5d) This compound was prepared in the manner described above by intermediate 5b to replace ethyl bromide with isopropyl bromide (10.2 g, 83 mmol) in 62% yield (6.44 g) as a white solid: mp 114.5-116 ° C; MS M / e 324 (M +). 3- (1, 4-Dioxa-spiro [4.5] dec-8-yl) -5-cyano-1-benzyl-indole (5e) This compound was prepared in the manner described above by intermediate 5b by replacing bromide of ethyl with benzyl bromide (14.3 g, 84 mmol) to yield 6.04 g (57%) of the title compound as a white solid: mp 129-130 ° C. Elemental analysis for C23H24N202 Calculated: C, 77.39; H, 6.50; N, 7.52 Found: C, 76.59; H, 6.28; N, 7.47 INTERMEDIARY 6 4- (5-Cyano-l-methyl-3-indolyl) -cciohexanone (6a) A solution of 3- (1,4-dioxa-spiro [4, 5] dec-8-yl) - 5-cyano-l-methyl-indole (5.5 g) in 150 ml of tetrahydrofuran-hydrochloric acid (1: 1) (1N) was allowed to stir at room temperature for 16 hours, followed by the addition of 4.49 g of sodium bicarbonate . The mixture was extracted with methylene chloride (3 x 100 ml), washed with brine (3 x 150 ml). The organic layer was dried over anhydrous magnesium sulfate and filtered. The solvent was removed to yield a light brown solid which was boiled in ethyl acetate-hexanes (1: 1) The mixture was cooled to room temperature and the solid was collected and dried under vacuum to yield 2.06 g of the title compound as a solid: m.p. 150-152 ° C. Elemental analysis for Ci5H? SN20 Calculated: C, 76.16; H, 6.39; N, 11.10 Found: C, 75.84; H, 6.34; N, 10.92 4- (5-Cyano-l-ethyl-3-indolyl) -cycothexanone (6b) This compound was prepared in the manner described above by intermediate 6a by replacing 3- (1,4-dioxa-spiro [4, 5] dec-8-yl) -5-cyano-1-methyl-indole with 3- (1,4-dioxa-spiro [4, 5] -dec-8-yl) -5-cyano-l-ethyl-indole ( 6.77 g, 22 mmol) to yield 4.33 g (75%) of the title compound as a white solid: mp 124C. Elemental analysis for C? 7H? 8N20 Calculated: C, 76.66; H, 6.81; N, 10.52 Found: C, 76.30; H, 6.82; N, 10.25 4- (5-Cyano-ln-propyl-3-indolyl) -cciohexanone (6c) This compound was prepared in the manner described above by intermediate 6a by replacing 3- (1,4-dioxa-spiro [4, 5] dec-8-yl) -5-cyano-1-methyl-indole with 3- (1,4-dioxa-spiro [4, 5] -dec-8-yl) -5-cyano-ln-propyl-indole (2.64 g, 8.2 mmoles) to produce 1.67 g (73%) of the title compound as a white solid: m.p. 103-104 ° C; MS The m / e 280 (M +). 4- (5-Cyano-l-benzyl-3-indolyl) -cycothexanone (6d) This compound was prepared in the manner described above by intermediate 6a by replacing 3- (1, -dioxa-spiro [4, 5] dec -8-yl) -5-cyano-1-methyl-indole with 3- (1,4-dioxa-spiro [4.5] -dec-8-yl) -5-cyano-l-benzyl-indole (6.43 g, 20 mmol) to yield 3.49 g (63%) of the title compound as a white solid: mp 115-126 ° C. Elemental analysis for C22H20N20 Calculated: C, 80.46; H, 6.14; N, 8.53 Found: C, 80.42; H, 6.07; N, 8.49 4- (5-Cyano-l-isopropyl-3-indolyl) -cycothexanone (6e) This compound was prepared in the manner described above by intermediate 6a by replacing 3- (1,4-dioxa-spiro [4.5] dec-8-yl) -5-cyano-1-methyl-indole with 3- ( 1,4-dioxa-spiro [4, 5] -dec-8-yl) -5-cyano-l-iso-propyl-indole (5.86 g, 16 mmol) to yield 3.46 g (63%) of the title compound as a white solid: pf 106-107 ° C. Elemental analysis for C? 8H2rjN20 Calculated: C, 77.11; H, 7.19; N, 9. Found: C, 76.85; H, 7.16; N, 9 INTERMEDIARY 7 8- (4-Benzyl-piperazin-1-yl) quinoline A solution of 8-amino-quinoline (12.91 g, 89 mmol) and bis (2-chloroethyl) -benzylamine (25.95 g, 112 mmol) in n -butanol (65 ml) was allowed to warm to 85 ° C for 11 hours. The mixture was poured into 50% sodium hydroxide, extracted with methylene chloride and water. The organic layer was dried over anhydrous magnesium sulfate, and filtered. The solvent was removed under vacuum. Chromatography (methanol-methylene chloride) yielded 12.34 g of product as a solid m.p. 116.5-118 ° C. The HCl salt was prepared in ethyl acetate: m.p. 209-210 ° C. Elemental analysis for C20H2? N3 »2HCl» 0.5H20 Calculated: C, 62.34; H, 6.28; N, 10.91 Found: C, 62.37; H, 6.55; N, 10.80 INTERMEDIARY 8 8- (Piperazin-1-yl) -quinoline To a solution of 8- (4-benzyl-piperazin-1-yl) -quinoline (2.63 g, 8.7 mmol) in methylene chloride (30 ml) Vinyl chloroformate (1.1 ml, 13 mmol) was added at room temperature slowly. The reaction mixture was brought to reflux for 2 hours, and then concentrated under vacuum. The residue was dissolved in 12N hydrochloric acid (20 ml) and stirred at room temperature for 1 hour. The mixture was concentrated, the residue was extracted with 40 ml of ethanol and heated to 50 ° C for 2 hours. The solvent is The residue was removed under vacuum, the residue was dissolved in 1 N sodium hydroxide-ethyl acetate and extracted with ethyl acetate and washed with water. The organic layer was dried over anhydrous sodium sulfate. The solvent was removed under vacuum. Chromatography (10-30% methanol-methylene chloride plus ammonium hydroxide) yielded 1.86 g (90%) of a yellow oil; EM The m / e 213 (M)? INTERMEDIARY 9 6-Fluorochroman A mixture of 6-fluoro-4-oxo-chroman (2 g, 12 mmol) and 10% palladium on carbon (1 g) in concentrated hydrochloric acid (20 ml) and ethanol was hydrogenated for 20 hours. (30 ml). The catalyst was filtered and the solvent was removed under vacuum. The residue was dissolved in ethyl acetate (100 ml), washed with 1 N NaOH (6 x 200 ml) and water (3 x 150 ml), dried over anhydrous sodium sulfate, filtered and the solvent removed under empty. Chromatography (20% ethyl acetate-hexanes) yielded 1.41 g (77%) of product as a clear oil; MS The m / e 152 (M +).
INTERMEDIARY 10 6-Fluoro-8-ni rocroman A mixture of nitric acid (100%, 7.8 ml, 0. 16 moles) in acetic anhydride was maintained at room temperature for 0.5 hours. This mixture was added to a solution of 6-fluorochroman (11.9 g, 0.078 mol) in 40 ml of acetic anhydride at 0 ° C. The reaction mixture was stirred at room temperature for 2 hours, then poured into ice water. The mixture was extracted with methylene chloride (3 x 60 ml) and washed with saturated sodium carbonate (8 x 150 ml). The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was removed under vacuum to yield a yellow solid: m.p. 48-50 ° C. Elemental analysis for C9H8FN03 Calculated: C, 54.83; H, 4.09; N, 7.10 Found: C, 54.78; H, 3.93; N, 6.09 INTERMEDIARY 11 6-Fluoro-8-aminocroman A mixture of 6-fluoro-8-ni trochroman (14.4 g) and 10% palladium on carbon (2 g) in ethanol (160 ml) was hydrogenated for 2 hours. The catalyst was removed by filtration and the solvent was removed under vacuum. Chromatography (30% ethyl acetate-hexanes) yielded 12.12 g (100%) of product as a clear oil; MS The m / e 167 (M +).
INTERMEDIARY 12 l-Benzyl-4- (6-fluoro-chroman-8-yl) -piperazine A solution of 6-fluoro-8-aminocroman (1.24 g, 7.4 mmol) and bis (2-chloroethyl) -benzylamine (2.58 g) , 11 mmol) in butanol (20 ml) was stirred at 100 ° C for 10 hours. The mixture was poured into saturated sodium carbonate (950 ml) and extracted with ethyl acetate (3 x 60 ml). The organic layer was dried over anhydrous sodium sulfate and filtered. Chromatography (20% ethyl acetate-hexanes) yielded 1.64 g (68%) of product as an oil; EM The m / e 326 (M)? INTERMEDIARY 13 4- (6-Fluoro-8-chroman-8-yl) -piperazine A mixture of l-benzyl-4- (6-fluoro-chroman-8-yl) -piperazine (1.64 g, 5 mmol), % of palladium on carbon (0.4 g) and ammonium formate (0.64 g, 10 mmol) in ethanol (20 ml) was allowed to reflux for 2 hours. The catalyst was removed by filtration and the solvent was removed under vacuum. Chromatography (10-20% methanol-methylene chloride plus ammonium hydroxide) yielded 1.0 g (84%) of product as a yellow oil; MS The m / e 296 (M +).
INTERMEDIARY 14 2- (4-fluorophenoxy) -acetaldehyde diethylacetal To a suspension of sodium hydride (5.4 g, 0. 134 moles) in anhydrous N, N-dimethylformamide (100 ml) was added 4-fluorophenol (10 g, 0.089 mol) at 0 ° C. After evolution of hydrogen ceased, acetaldehyde bromo-diethylacetal (16 ml, 0.11 mol) was added. The reaction was heated to 160-170 ° C for 18 hours. The mixture was poured into ice water, extracted with ethyl acetate (3 x 150 ml), washed with 1 N sodium hydroxide (3 x 100 ml), and brine (3 x 100 ml). The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was removed under vacuum. Chromatography (25% ethyl acetate-hexanes) yielded 16.36 g (80%) of product as a clear oil: MS m / e 228 (M +).
INTERMEDIARY 15 5-Fluorobenzofuran To a mixture of benzene ^ 200 ml) containing polyphosphoric acid (7.9 g, 0.035 mole) was added 2- (4-fluoro-phenoxy) -acetaldehyde diethyl acetal (8 g, 0. 035 moles). The mixture was stirred vigorously while heating to reflux for 2.5 hours. The reaction mixture was cooled to room temperature and decanted from the polyphosphoric acid. The solvent was removed under vacuum. Chromatography (5% ethyl acetate-hexanes) yielded 3.4 g (45%) of product as a clear oil: 1 H NMR (CDC13) d 6.74 (dd, 1H, J = 2.0, 0.6 Hz), 7.01 (td, 1H, J = 9, 2.7 Hz), 7.25 (dd, 1H, J = 8.4, 2.7 Hz), 7.43 (dd, 1H, J = 9 , 3.9 Hz), 7.65 (d, 1H, J = 1.8 Hz).
INTERMEDIARY 16 5-Fluoro-2, 3-dihydrobenzofuran A solution of 5-fluorobenzofuran and 10% palladium on carbon was hydrogenated in acetic acid (25 ml) under 50 psi for 12 hours. The catalyst was filtered through celite and the celite was washed with methylene chloride (200 ml). The organic layer was washed sequentially with 1 N NaOH (3 x 100 ml), brine (3 x 100 ml) and dried over anhydrous sodium sulfate and filtered. The solvent was removed under vacuum to yield 2.59 g (85%) of product as a clear oil: XH NMR (300 MHz, CDC13): d 3.12 (t, 2H, J = 8.7 Hz), 4.58 (t, 2H, J = 8.7 Hz), 6.68 (dd, 1H, J = 8.7, 4.2 Hz), 6.79 (tm, 1H, J = 8.7 Hz), 6.89 (dm, 1H, J = 8.1 Hz).
INTERMEDIARY 17 5-Fluoro-7-nitro-2, 3-dihydrobenzo urane A mixture of nitric acid (100%, 1.5 ml, 36 mmol) in acetic anhydride (18 ml) was maintained at room temperature for 0.5 hours. The mixture was added to a solution of 5-fluoro-2,3-dihydrobenzofuran (2.5 g, 18 mmol) in 10 ml of acetic anhydride at 10 ° C. The reaction mixture was stirred at room temperature for 2 hours then poured into ice water. The mixture was extracted with methylene chloride (3 x 60 ml), washed with 1 N sodium hydroxide (5 x 100 ml) and brine (200 ml). The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was removed under vacuum to yield a yellow solid: p. f. '113- 114 ° C. Elemental analysis for C8H6N03 Calculated: C, 52.47; H, 3.30; N, 7.65 Found: C, 52.40; H, 3.21; N, 7.39 INTERMEDIARY lß 5-Fluoro-7-amino-2,3-dihydrobenzofuran A mixture of 5-fluoro-7-ni tro-2, 3-dihydrobenzofuran (2.65 g) and 10% palladium on carbon was hydrogenated for 3 hours (0.5 g) in ethanol (100 ml). The catalyst was removed by filtration and the solvent was removed under vacuum. Chromatography (30% ethyl acetate-hexanes) yielded 1.38 g (62%) of product as a white solid: m.p. 68-70 ° C. Elemental analysis for C8H8NO Calculated: C, 62.74; H, 5.27; N, 9.15 Found: C, 62.76; H, 5.32; N, 9.13 INTERMEDIARY 19 l-Benzyl-4- (5-fluoro-2,3-dihydro-benzofuran-7-yl) -piperazine A solution of 5-fluoro-7-amino-2,3-dihydro-benzofuran (1.38) g, 9 mmol) and bis (2-chloroethyl) -benzylamine (3.14 g, 14 mmol) in butanol (20 ml) was stirred at 100 ° C for 10 hours. The salt was extracted by filtration, washed with ethyl ether (30 ml) and dried under vacuum: m.p. 232-233.5 ° C. The salt became the free base to yield 2.06 g (73%) of the title compound. Elemental analysis for C? 9H2? FN2O * HCl »0.25H20 Calculated: C, 64.58; H, 6.42; N, 7.93 Found: C, 64.43; H, 6.27; N, 7.86 INTERMEDIARY 20 4- (5-Fluoro-2, 3-dihydro-benzofuran-7-yl) -piperazine A mixture of l-benzyl-4- (5-fluoro-2,3-dihydro-benzofuran-7-yl) - piperazine (2.06 g, 6.6 mmol), 10% palladium on carbon (0.6 g) and ammonium formate (0.83 g, 13 mmol) in ethanol (20 ml) was allowed to reflux for 2 hours. The catalyst was removed by filtration and the solvent was removed under vacuum. Chromatography (10-30% methanol-methylene chloride plus ammonium hydroxide) yielded 1.10 g (75%) of product as a yellow oil; EM The m / e 222 (M)? INTERMEDIARY 21 7-Ni robenzof ran-2-ethyl carboxylate A stirred mixture of 2-hydroxy-3-ni tro-benzaldehyde (4.8 g, 59 mmol), diethyl bromomalonate (16.8 g, 71 mmol), potassium carbonate (12.1 g, 88 mmol) and N, '-terephtalylidenebis (4-butylaniline) (1.9 g, 5.9 mmol) in toluene (100 ml) was refluxed with a trap or Dean-Stark harvester for 24 hours. Another 12.1 g of potassium carbonate was added to the above reaction mixture and the resulting mixture was refluxed for another 3 days. The reaction was quenched with water, extracted with (3 x 200 ml) and washed with 2.0 N sodium hydroxide (100 ml). The organic layer was dried over anhydrous sodium sulfate and filtered. Chromatography (30% ethyl acetate-hexanes) yielded a yellow solid: m.p. 86.5-87.5 ° C (lit1: p.p. 88-89 ° C).
INTERMEDIARY 22 7 -Nitrobenzofuran To a suspension of ethyl 7-n-trobenzofuran-2-carboxylate in ethanol was added 2 N potassium hydroxide (60 ml). After it was refluxed for 0.5 hours, the solution was cooled to room temperature and concentrated to an average volume. Concentrated hydrochloric acid was added to the above mixture and filtered. The solid was washed with water and dried under vacuum with phosphorus phosphorus overnight. The dried solid was mixed with quinoline (75 ml) and copper oxide (CuO, 0.4 g). The mixture was heated to 220 ° C for 3 hours. The mixture was filtered and the filtrate was concentrated. Chromatography (20% ethyl acetate-hexanes) yielded 5.3 g (91%) of product as a yellow solid: m.p. 92-94 ° C. (lit1: p.f. 95.5-97 ° C).
INTERMEDIARY 23 7-Aminobenzofuran Hydrochloride A stirred suspension of 7-N-trobenzofuran (5.3 g, 32 mmol) and Raney nickel (0.1 g) in methanol (70 ml) was heated to 50 ° C. Then hydrazine monohydrate (98%, 4.8 ml, 97 mmol) in methanol (10 ml) was slowly added to the above solution at a temperature of 50-60 ° C. When the addition was complete, the mixture was refluxed for 2 hours. The Raney nickel was filtered off and the solution was concentrated.
The residue was dissolved in ethyl acetate and converted into its HCl salt 3.68 g (66%) (lit1: mp 212-213 ° C).
INTERMEDIARY 24 1- (7-Benzofuranyl) piperazine A solution of 7-amino-benzofuran hydrochloride (3.66 g, 22 mmol) and bis (2-chloroethyl) amine hydrochloride (3.84 g, 22 mmol) in chloro-benzene (80 ml) was heated to reflux for 72 hours. The solvent was removed under vacuum, the residue was dissolved in 2.5 N methylene chloride-sodium hydroxide and extracted with methylene chloride (3 x 100 ml). The organic layer was dried over anhydrous sodium sulfate and filtered. Chromatography (10-20% methanol-methylene chloride plus ammonium hydroxide) yielded 0.66 g, (15%) of product as a brown-yellow oil; (lit1: p.f. 194.5-195 ° C for the HCl salt).
INTERMEDIARY 25 4- (5-Fluoro-lH-3-indolyl) -cyclohex-3-enone This compound was prepared in the manner described above by intermediate 3c by replacing 4- (5-fluoro-lH-3-indolyl) - Ethylene ketal cyclohexanone with 4- (5-fluoro-lH-3-indolyl) -cyclohex-3-enone-ethylene ketal (1.37 g) to yield 1.01 g (88%) of the title compound.
INTERMEDIARY 26 1- (2-Methoxy-phenyl) -4- (1,4-dioxa-spiro [4.5] dec-8-yl) -piperazine A solution of 1,4-cyclohexanedione mono-ethylene ketal (4.68 g, 30 mmol), 1 - (2-methoxy-phenyl) -piperazine (5.8 g, 30 mmol), sodium triacetoxyborohydride (9 g, 42 mmol) and acetic acid (1.8 ml, 30 mmol) in 1,2-dichloroethane (8 ml) was allowed to stir at room temperature for 12 hours. The reaction was quenched with 1N sodium hydroxide (pH> 9), and extracted with methylene chloride (3 x 100 ml). The organic layer was dried over anhydrous sodium sulfate and filtered. Chromatography (10% of ethyl methanol-aceta to) yielded 9.0 g (90%) of product as a semi-solid.
INTERMEDIARY 27 4- [4- (2-Methoxy-phenyl) -piperazin-1-yl] -cydohexanone This compound was prepared in the manner described above by intermediate 3a by replacing 3- (1,4-dioxa-spiro [4]). , 5] dec-8-yl) -lH-indole with l- (2-methoxy-phenyl) -4- (1,4-dioxa-spiro [4, 5] dec-8-yl) -piperazine (5.0 g , 15 mmol) to yield 4.0 g (93%) of the title compound.
INTERMEDIARY 28 5-Fluoro-3-. { 4- [4- (2-methoxy-phenyl) -piperazin-1-yl] -cyclohex-1-enyl} -lH-indole This compound was prepared in the manner described above by intermediate lc by replacing 1,4-cyclohexanedione monoethylene ketal with 4- [4- (2-methoxy-phenyl) -piperazin-1-yl] -cidiohexanone (1.44 g , 5 mmol). The crude mixture was used in the next step without further purification.
INTERMEDIARY 29 5-Fluoro-3-. { 4- [4- (2-methoxy-phenyl) -piperazin-1-yl] -cyclohexyl} -1H-indole This compound was prepared in the manner described above by intermediate 2c by replacing 4- (5-fluoro-lH-3-indolyl) -cyclohex-3-en-ethylene ketal with 5-fluoro-3-. { 4- [4- (2-methoxy-phenyl) -piperazin-1-yl] -cyclohex-1-enyl} -lH-indole (2.0 g) to yield 1.77 g (84%) of product as a mixture of the cis and trans isomer.
INTERMEDIARY 30 4- (5-Fluoro-l-methyl-3-indolyl) -cciohexanone To a suspension of sodium hydride (60%, 0.18 g, 4.5 mmol) in anhydrous N, N-dimethylformamide (10 ml) was added 4- (5-fluoro-lH-indol-3-yl) -cyclohexanone (0.7 g, 3.0 mmol) at room temperature. The mixture was stirred for 0.5 hours, then iodomethane (0.21 ml, 3.3 mmol) was added to the previous solution at room temperature. The resulting mixture was stirred for another 0.5 hour and cooled rapidly with water. The mixture was extracted with methylene chloride (3 x 50 ml) and the organic layer was dried over anhydrous sodium sulfate and filtered. Chromatography (30% ethyl acetate-hexanes) yielded 0.35 g (46%) of product as a yellow oil: MS m / e 245 (M +).
INTERMEDIARY 31 5-Nitro-quinoxaline To a room temperature solution of 3-nitro-o-phenylenediamine (10 g, 65.3 mmol) in EtOH (50 ml) was added glyoxal (40% in H20, 22.47 ml). The reaction mixture was refluxed 1 hour, then diluted with H20 (100 mL). The cooled mixture was extracted with CH2C12 (2 x 300 ml) and the organic layers were combined and washed again with H20 (500 ml), dried over Na2SO4 and concentrated to yield a bright orange solid which was recrystallized from EtOAc / hexanes to give 10.96 g (96%) of a brown solid: mp 90-92 ° C. Elemental analysis for C8H5N302 Calculated: C, 54.86; H, 2.88; N, 23.99 Found: C, 55.12; H, 3.05; N, 24.05.
INTERMEDIARY 32 5-Amino-quinoxaline To a 250 ml three-necked round bottom flask equipped with a reflux condenser and a nitrogen inlet was added 5-nit ro-quinoxaline (4 g, 22.8 mmol) dissolved in HOAc (60 ml). The mixture was heated to boiling, removed from the heat, and solid Fe powder (3.83 g, 68.6 mmol) was added. Vigorous boiling was observed. The reaction mixture was refluxed for 10 minutes and then poured into H20. (100 ml) and ice. The aqueous solution was filtered and basified to pH > 10 with 1M NaOH, and extracted into EtOAc (3 x 200 ml). The organic layers were combined, dried over Na2SO4, and concentrated. The resulting oil was purified by column chromatography (40% EtOAc / hexanes) yielding 2.03 g (61%) of an orange solid: m.p. 87-90 ° C. Elemental analysis for C8H7N3 Calculated: C, 66.19; H, 4.86; N, 28.95 Found: C, 66.25; H, 4.96; N, 29.26 INTERMEDIARY 33 l-Benzyl-4- (quinoxalin-yl) -piperazine To a solution of 5-amino-quinoxaline (2.8 g, 19.3 mmol) in BuOH (50 ml) was added bis (2-chloroethyl) -benzylamine (8.42 g, 38.6 mmoles) and Et3N (5.34 ml, 38.6 mmoles). The reaction was stirred at 100 ° C overnight. A second portion of Et3N (5.34 ml, 38.6 mmol) was added and the reaction was stirred at 100 ° C in an additional 24 hours. The cooled solution was made alkaline with 2.5 N NaOH (500 ml) and extracted into EtOAc (3 x 200 ml). The organic fractions were combined, dried over Na S0, concentrated and chromated (40% EtOAc / hexanes) yielding 1.0 g (17%) of a golden oil.
INTERMEDIARY 34 5- (1-Piperazinyl) -quinoxaline To a room temperature solution of 1-benzyl-4- (quinoxalin-yl) -piperazine (1.0 g, 3.3 mmol) in anhydrous CH2C12 under nitrogen was added vinyl chloroformate (0.34). ml, 3.9 mmol) dropwise. The reaction mixture was refluxed for 2 hours. The reaction was cooled, concentrated to dryness and concentrated HCl (25 mL) and 1,4-dioxane (25 mL) were added. The resulting solution was stirred at room temperature overnight. The solution was basified with 2.5 N NaOH (300 mL) and extracted into EtOAc (3 x 200 mL). The organic layers were combined, dried over Na2SO4, concentrated and subjected to chromatography "(10% MeOH / CH2Cl2 / NH40H) to give 450 mg (64%) of an orange solid: mp 106-108 ° C: MS (+) ESI m / e 215 [M + H]? INTERMEDIARY 35th 5- (Tri-loromethylsulphonyloxy) -quinoline A solution of 5-hydroxy quinoline (8 g, 55 mmol) and K2CO3 (15.2 g, 110 mmol) in anhydrous pyridine (60 ml) under nitrogen was cooled to -20 ° C . Tf20 (13.97 ml, 83 mmol) was added dropwise via syringe. The reaction mixture was stirred 1 hour at -20 ° C then warmed to 0 ° C for 1 hour then stirred at room temperature for 48 hours. The reaction mixture was then poured into H20 (200 ml) and extracted into CH2C12 (2 x 200 ml). The aqueous layer was acidified with 1 N HCl (100 mL) and extracted again with CH2C12 (2 x 200 mL). The organic fractions were dried over Na 2 SO 4, concentrated and purified by column chromatography (40% EtOAc / hexanes) to yield 13.97 g (90%) of the product as a pink oil: MS m / e 277 (M +).
INTERMEDIARY 35b 5- (Trifluoromethylsulfonyloxy) -isoquinoline This compound was prepared in the manner described above by Intermediate 35a by replacing 5-hydroxy-quinoline with 5-hydroxy-isoquinoline (5 g) to yield 7.71 g (79%) of the compound of title as a waxy beige solid: EM ESI m / e 278 (M +).
INTERMEDIARY 35c 5- (Trifluoromethylsulfonyloxy) -isoquinoline This compound was prepared in the manner described above by Intermediary 35a by replacing -hydroxy quinoline with isocarbastoryl (8 g) to yield 9.74 g (64%) of the title compound as a clear oil: MS m / e 277 (M +).
INTERMEDIARY 36a L-butyl-4- (5-quinolinyl) iperazine Carboxylate To a 100 ml oven-dried flask was added Cs2C03 (19.87 g, 61 mmol), Pd (0Aa) 2 (0.49 g, 2.2 mmol), and BINAP (1183 g, 1.9 mmol). The solids were washed with N2 for 10 minutes. A solution of 5- (trifluoromethylsulfonyloxy) -quinoline (12 g, 43 mmol) and 1-t-butyl-4-piperazine carboxylate (9.67 g, 52 mmol) in THF was then slowly added to the reaction flask. The reaction mixture was stirred at room temperature for 0.5 hours, then at 65 ° C overnight. The resulting solution was diluted with ether, filtered through a pad of celite, washed with Et20 (50 mL) and EtOAc (50 mL). The organic fractions were combined, dried over Na 2 SO, filtered, and chromatographed 3 times (10% MeOH / CH 2 Cl 2) yielding 1.57 g (12%) of pure product as a beige solid: m.p. 116-118 ° C. Elemental Analysis for C? 8H23N302: Calculated C, 68.98; H, 7.40; N, 13.41 Found C, 69.09; H, 7.33; N, 13.08 INTERMEDIARY 36c l-t-Butyl-4- (1-isoquinolinyl) piperazine Carboxylate This compound was prepared in the manner described above by Intermediary 36a when replacing - (trifluoromethylsulfonyloxy) -quinoline with 1- (trifluoromethylsulfonyloxy) -isoquinoline (9 g, 32.5 mmol) yielding 2.33 g (25%) of a beige waxy solid: m.p. 69-71 ° C.
INTERMEDIARY 37a 5- (1-Piperazinyl) -quinoline To a solution of lt-butyl-4- (5-quinolinyl) piperazine carboxylate (1.57 g, 5 mmol) in CH2C12 (2 mL) at 0 ° C was added a solution of pre-mixed, pre-cooled TFA (10 ml), CH2C12 (20 ml) and MeOH (10 drops). The reaction was slowly warmed to room temperature and allowed to stir overnight. The resulting solution was concentrated, dissolved in H20 (5 mL) and CH2C12 (5 mL) and made alkaline with NaHCO3 to pH 9. The aqueous portion was extracted with 6 x 100 mL EtOAc and concentrated to yield 1.0 g (100%). ) of a yellow oil that solidified firmly and was not purified further.INTERMEDIARY 37c 1- (1-piperazinyl) -isoquinoline This compound was prepared in the form as Intermediary 37a by replacing 1-t-butyl-4- (5-quinolini-1) piperazine carboxylate with 1-t-butylcarboxylate. 4- (1-isoquinolinyl) piperazine (2.33 g, 7.4 mmol) yielding 1.5 g (95%) of a beige solid: mp 127-130 ° C.
INTERMEDIARY 38a 6-Methoxy, 8-Amino-quinoline To a warm suspension of 6-methoxy, 8-nitro-quinoline in 100 ml of a mixture of ethanol: acetic acid: water (2: 2: 1) were added in portions 3.0 g of iron powder. The reaction was brought to reflux for about 2 h hours, the mixture was cooled, filtered over celite and basified with sodium bicarbonate. The product was extracted with ether, dried and the solvent removed under vacuum to give 3.2 g of the title compound. MS (ES) m / z (relative intensity): 175 (M + H + 100).
INTERMEDIARY 38b 6-Methoxy, 8-Amino-quinoline To a hot suspension of (0.800 g) of 6-chloro, 8-nitro-quinoline in 25 ml of a mixture of ethanol: acetic acid: water (2: 2: 1) 0.5 g of iron powder was added in portions. The reaction was refluxed for approximately 1 H hours, the mixture was cooled, filtered over celite and basified with sodium bicarbonate. The product was extracted with ether, dried and the solvent removed under vacuum to give 0.5 g of the title compound. P.f. 70-73 ° C. MS (ES) m / z (relative intensity): 179 (M + H +). Elemental analysis for C9 H7 Cl N2 Calculated: C: 60.52; H: 3.95; N: 15.68 Found: C: 60.82; H: 3.77; N: 15.96 INTERMEDIARY 39a 6-Methoxy, 8-piperazine-quinoline 6-methoxy, 8-amino-quinoline (8.2 g) and bis (chloroethyl) amine hydrochloride (9.0 g) were taken in 70 ml of chlorobenzene and heated to about 135 ° C with vigorous stirring for 3 days. The reaction was not until the termination. The mixture was cooled. Water was added and extracted with ether. The aqueous phase was basified with sodium carbonate and extracted with ethyl acetate, dried and the solvent was removed. The crude product was filtered through 300 ml of silica gel using 10% MeOH / CH2Cl2, 20% MeOH / CH2Cl2, then 1 NH4OH / 80% MeOH / 19% CH2C12, to give 1.5 g of the product wanted. MS (ES) m / z (relative intensity): 244 (M + H +, 100).
INTERMEDIARY 39b 6-Chlorine, 8-Piperazine-Quinoline 8-amino, 6-chloro-quinoline (0.980 g) and bis (chloroethyl) amine hydrochloride (0.980 g) were taken in 13 ml of chlorobenzene and heated to approximately 135 °. C with vigorous shaking for 5 days. The reaction was taken up in water and extracted with ether. The aqueous phase was basified with sodium carbonate and re-extracted with ether, dried and the solvent removed to give 0.400 g of the title compound. MS (ES) m / z (relative intensity): 248 (M + H +).
INTERMEDIARY 39c 5-Chloro-8-piperazine-quinoline To a solution of 5-chloro, 8- (trifluoromethyl-sulfonyloxy) -quinoline (1.0 g) in 15 ml of chlorobenzene was added an excess of piperazine (1.0 g). The mixture was heated at 120 ° C for 2 H days. The reaction was cooled, poured into water and the product was extracted with ether, dried over magnesium sulfate to give 0.480 g of product. MS (ES) m / z (relative intensity): 248 (M + H +, 100).
INTERMEDIARY 39d 5-Fluoro-8-piperazino-quinoline To a solution of 5-fluoro, 8- (trifluoromethylsulphonyloxy) -quinoline (1.0 g) in 5 ml of chlorobenzene was added an excess of piperazine (2.0 g). The mixture was heated at 120 ° C for 2 days. The reaction was cooled, poured into water and the product was extracted with ethyl acetate, the organic phase was washed with dilute NaOH, then with water, dried and the solvent was removed. The product was chromatographed on silica gel using 15% methanol / methylene chloride, then methanol: methylene chloride: NH 4 OH 79: 20: 1 to give 0.240 g of product. MS (ES) m / z (relative intensity): 232 (M + H +, 100).
INTERMEDIARY 39e 8-pipe azino-quinaldine To a solution of 8- (trifluoromethylsulfonyloxy) -quinaldine (7 g) in 25 ml of chlorobenzene, K2C03 and an excess of piperazine (10.0 g) were added. The mixture was heated at 130 ° C for 3 days. The reaction was cooled, poured into water and the product extracted with ethyl acetate, dried over magnesium sulfate. The product was chromatographed on silica gel using 20% methanol / methylene chloride then methanol: methylene chloride: NH40H 70: 20: 1 to give 3.2 g of product. MS (ES) m / z (relative intensity): 228 (M + H +, 100).
INTERMEDIARY 39f 6-MeO, 4-piperazine-quinoline To a solution of 6-MeO, 4- (trifluoromethylsulphonyloxy) -quinoline (2 g) in 10 ml of acetonitrile, an excess of piperazine (2 g) was added. The mixture was heated to about 70 ° C for 1 H hours. Water was added and the product was extracted with ethyl acetate, dried and the solvent was removed to give (2.5 g) of product. MS (ES) m / z (relative intensity): 308 (M + H +).
INTERMEDIARY 40a 6-Chlorine, 8-Nitro-Quinoline A solution of 1.0 g of 6-Chloro-quinoline in 5 ml of fuming nitric acid was heated almost to reflux for 2 days. The reaction was cooled, poured into ice water and neutralized with concentrated ammonium hydroxide at about a pH of 5. The formed precipitate was filtered and dried to give 0.600 g of the desired product. P.f. 149-155 ° C. MS (ES) m / z (relative intensity): 209 (M + H +).
INTERMEDIARY 40b 5-C1-8- (trifluoromethylsulfonyloxy) -quinoline To a solution of 5-chloro, 8-hydroxy-quinoline (8.95 g) in 100 ml of CH2C12, TEA (20 ml) was added. The suspension was dissolved, then cooled to -15 ° C. A solution of 21.1 g of triflic anhydride in 50 ml of CH2C12 was added drop by drop with eq. Friamiento. After the addition was complete, the reaction was stirred at -15 ° C for 1 hour. The reaction was diluted with CH2C12, washed with a solution of NaHCO3, then with dry water and the solvent was removed to give 15.0 g of product. P.f. 80-83 ° C. MS (ES) m / z (relative intensity): 312 (M + H +, 100). Elemental analysis for Cío H5 C1F N03 S Calculated: C: 38.54; H: 1.62; N: 4.49 Found: C: 38.3; H: 1.73; N: 4.5 INTERMEDIARY 40c 5-Fluoro-8- (trifluoromethylsulfonyloxy) -quinoline To a cold (-15 ° C) solution of 5-Fluoro, 8-hydroxy-quinoline (2.5 g) in 20 ml of CH2C12, TEA (6.3 ml) was added. . To the cold mixture was added a solution of 6.5 g of triflic anhydride in 10 ml of CH2C12, dropwise with cooling. After the addition was complete, the reaction was stirred at 0 ° C for 1 hour. The reaction was quenched with water, and the product was extracted with ether, dried and the solvent was removed to give 3.4 g of product. MS (ES) m / z (relative intensity): 296 (M + H +, 100).
INTERMEDIARY 40d 8- (trifluoromethylsul onyloxy) -quinaldine To a cold (-15 ° C) solution of 8-hydroxy-quinaldine (11.5 g) in 50 ml of CH2C12, TEA (29 ml) was added. To the cold mixture was added a solution of 29.6 g of triflic anhydride in 50 ml of CH2C12, dropwise with cooling. After the addition was complete, the reaction was stirred at -15 ° C for 1 hour. The reaction was quenched with water, and the product was extracted with ether, dried and the solvent was removed to give 20 g of product. MS (ES) m / z (relative intensity): 292 (M + H +).
INTERMEDIARY 41 6-MeO, 4- (trifluoromethylsulfonyloxy) -quinoline To a cold (-15 ° C) solution of 6-MeO, 4-hydroxy-quinoline (5 g) in 30 ml of CH2C12, TEA (12 ml) was added. . To the cold mixture was added a solution of 12 g of triflic anhydride in 15 ml of CH2C12, dropwise with cooling. After the addition was complete, the reaction was stirred at -15 ° C for 1 hour. The reaction was quenched with water, and the product was extracted with ether, dried and the solvent removed to give 7 g of product. MS (ES) m / z (relative intensity): 308 (M + H +).
INTERMEDIARY 42a l-Benzyl-4- (6-methoxy-2-methylquinolin-8-yl) piperazine A mecl of 8-amino-6-methoxy-2-methyl-quinoline 1. 75 g, 9. 30 mmoles), N-benzyl-bis-di-ethylene-ethane (8.9 g, 38.3 mmol), and triethylamine (6.5 mL, 46.6 mmol) in 1-butanol (25 mL) was heated at 100 ° C for 20 minutes. hours. After cooling to room temperature, the reaction was diluted with ethyl acetate (50 ml), and poured into saturated aqueous NaHCO3. The aqueous layer was extracted with ethyl acetate (3 x 50 ml). The organic layers were washed with saturated aqueous NaHCO3 (50 ml) and brine (50 ml), then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The excess of 1-butanol was azeotroped with hexane (2 x 500 ml). Flash chromatography on 5.5 x 18 cm of Si02 (25% EtOAc / hexane) yielded 1.15 g (36%) of a yellow oil, which crystallized firmly. Recrystallization from hexane produced 0.898 g (28%) of analytically pure product as yellow crystals: m.p. 83-85 ° C. Elemental analysis for C22H2sN30 Calculated: C, 76.05; H, 7.25; N, 12.09 Found: C, 75.88; H, 7.37; N, 12.05 INTERMEDIARY 42b l-benzyl-4- (6-methoxy-3-methylquinolin-8-yl) piperazine The title compound was prepared by the same method used for l-benzyl-4- (6-methoxy-2-methylinquinol- 8-yl) piperazine, except substituting 8-amino-6-methoxy-3-methylinquinoline (2.82 g, 15.0 mmol) for 8-amino-6-methoxy-2-methyl-quinoline. Flash chromatography on 6 x 20 cm of Si02 (25-30% EtOAc / hexane), with rechromatography of the mixed fractions, yielded 1.13 g (22%) of the title compound as a yellow gum- Crystallization from hexane produced 0.88 g of the analytically pure compound as yellow crystals: mp 112-113 ° C. Elemental analysis for C22H2sN30 Calculated: C, 76.05; H, 7.25; N, 12.09 Found: C, 75.83; H, 7.26; N, 12.07 INTERMEDIARY 42c l-benzyl-4- (6-methoxy-4-methylquinolin-8-yl) piperazine A mixture of 8-amino-6-methoxy-4-methylquinoline (3.0 g, 15.9 mmol), N-benzyl-1-bis-dichloroethane (11.1 g, 48. 0 mmol), triethylamine (4.8 g, 48 mmol) and 1-butanol was heated at 100 ° C for 24 hours. The reaction mixture was poured into 2.5 N aqueous NaOH and extracted with ethyl acetate (3 x 200 ml). The combined organic layers were washed with water (100 ml) and brine (100 ml), then dried over anhydrous sodium sulfate, filtered and concentrated to yield 12.0 g of a dark brown oil. Flash chromatography on silica gel (5% methanol / ethyl acetate) gave 2.3 g (42%) of the title compound as a thick oil, which solidified firmly: m.p. 154-155 ° C. Elemental analysis for C22H2sN30 Calculated: C, 76.05; H, 7.25; N, 12.09 Found: C, 75.92; H, 7.36; N, 11.96 INTERMEDIARY 43a 4- (6-Methoxy-2-methylquinolin-8-yl) piperazine A mixture of l-benzyl-4- (6-methoxy-2-methyl-quinolin-8-yl) piperazine (0.527 g, 1.52 mmol) , 10% Pd / C (0.20 g), and ammonium formate (0.96 g, 15.2 mmol) in methanol (10 ml) was heated to reflux under N2 for 3 hours. The TLC analysis (35% EtOAc / hexane) indicates only a hint of the remaining initial material. After cooling to room temperature, the reaction was filtered through celite, lavender with an excess of methanol. The filtrate was concentrated, diluted with CH2C12 (50 mL), and washed with saturated aqueous NaHCO3. The aqueous layer was extracted with CH2C12 (2 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to yield 0.37 g (95%) of the title compound as a yellow oil, which was used in the subsequent reaction without purification.
INTERMEDIARY 43b 4- (6-methoxy-3-methylquinolin-8-yl) piperazine The title compound was prepared by the same method used for the preparation of 4- (6-methoxy-2-methyquinolin-8-yl) piperazine , except that l-benzyl-4- (6-methoxy-3-methicholinolin-8-yl) piperazine (0.32 g, 0.92 mmol) was replaced by l-benzyl-4- (6-methoxy-2-methylquinoline- 8-yl) piperazine. The title compound was isolated in an almost quantitative yield and was used with purification in the subsequent reaction.
INTERMEDIARY 43c 4- (6-methoxy-4-methylquinolin-8-yl) piperazine A mixture of l-benzyl-4- (6-methoxy-4-methyl-quinolin-8-yl) piperazine (2.0 g, 5.76 mmol) , methylene chloride (50 ml) and vinyl chloroformate (0.8 ml, 8.64 mmol) were refluxed for 4 hours. The mixture was concentrated, then dissolved in a 1: 1 concentrated dioxane / HCl mixture and stirred at room temperature for 18 hours. The reaction mixture was made basic with 2.5 N aqueous NaOH and extracted with ethyl acetate (2 x 200 ml). The. Combined organic layers were washed with water (100 ml) and brine (100 ml), then dried over anhydrous sodium sulfate, filtered, and concentrated to give 0.6 g (47%) of the title compound: m.p. 208-209 ° C. Elemental analysis for C? 5H? 9N3O * HCl «0.5 H20 Calculated: C, 59.50; H, 6.99; N, 13.88 Found: C, 59.44; H, 7.09; N, 13.57 INTERMEDIARY 44a l-benzyl-4- (6-methoxy-5-methylquinolin-8-yl) piperazine This compound was prepared in a manner similar to that used for l-benzyl-4- (6-methoxy-4-methylquinoline- 8-yl) piperazine to give 3.0 g (56%) of the pure title compound: mp 129-133 ° C. Elemental analysis for C22H25N O Calculated: C, 76.05; H, 7.25; N, 12.09 Found: C, 75.61; H, 7.35; N, 11.97 INTERMEDIARY 44b 1-benzyl-4- (6-methoxy-5-chloro-quinolin-8-yl) piperazine This compound was prepared in a manner similar to that used by l-benzyl-4- (6-methoxy-4-methylquinolin-8-yl) piperazine to give 1.9 g (35%) of the pure title compound: m.p. 138-140 ° C.
Elemental analysis for C2? H22ClN30 Calculated: C, 68.56; H, 6.03; N, 11.42 Found: C, 68.26; H, 5.98; N, 11.45 INTERMEDIARY 45th 4- (6-methoxy-5-methylquinolin-8-yl) piperazine A mixture of methanol (15 ml), 10% Pd / C (0.12 g), l-benzyl-4- (6-methoxy-5-methicholinolin-8-yl) -piperazine (0.8 g, 2.3 mmol), and ammonium formate (0.88 g, 13.9 mmol) was brought to reflux for 45 minutes. The reaction mixture was filtered through celite and concentrated. The residue was diluted with IN aqueous NaOH (50 ml) and extracted with ethyl acetate. '(3 x 75 ml). The combined organic layers were washed with water (50 ml) and brine (50 ml), then dried over anhydrous Na 2 SO 4, filtered, and concentrated to give 0.52 g (61%) of the title compound as a thick oil. MS (ES) m / z: 258 (M + H +).
INTERMEDIARY 45b 4- (6-methoxy-5-chloro-quinolin-8-yl) piperazine This compound was prepared in a manner similar to that used by 4- (6-methoxy-5-methylquinolin-8-yl) piperazine for give 0.48 g (68%) of the pure title compound as a thick oil, MS (ES) m / z: 278 (M + H +).
INTERMEDIARY 46 5-Bromo-6-methoxy-quinoline To a solution of 6-methoxyquinoline (5 g, 31.4 mmol) in acetic acid (50 ml) was slowly added pure Br2 (1.62 ml, 31.4 mmol). The reaction mixture was stirred at room temperature for 1 hour and then poured into yarn. Saturated aqueous sodium bisulfite was added, and the resulting suspension was extracted into EtOAc (2 x 200 ml). The organic fractions were combined, dried over Na 2 SO 4, concentrated, and purified by column chromatography (5% MeOH / CH 2 Cl 2) to yield 4.39 g of the title compound as the acetate salt. The free base was prepared by washing the salt with 1 N NaOH (50 ml) and H20 (100 ml) and extract in CH2C12 (200 ml). The organic fractions were concentrated to yield 3.89 g (52%) of the title compound as a pink solid. Elemental analysis for C? OH8BrNO Calculated: C, 50.45; H, 3.39; N, 5.88 Found: C, 50.34; H, 3.25; N, 6-09 INTERMEDIARY 47 4-Bromo-2-nitrophenylamine To a solution of 2-nitro-phenylamine (13.8 g, 100 mmol) in HOAc (150 mL) was added NBS (18 g, 101 mmol). The reaction mixture was stirred and heated to reflux for 1 hour. The cooled reaction mixture was poured into H20 (1000 ml) and stirred for 15 minutes. The resulting orange suspension was filtered and washed with H20 (300 ml) yielding 20.26 g (93%) of the title compound as a bright orange solid. Elemental analysis for C6H5BrN202 Calculated: C, 33.21; H, 2.32; N, 12.91 Found: C, 33.15; H, 2.31; N, 12.75 Ref: Montash Chem IN 1994, 125 p. 723-730 INTERMEDIARY 48 6-Bromo-8-nitro-quinoline A solution of sulfuric acid was prepared by adding H2SO (50 ml) to a 250 ml flask containing H20 (20 ml) cooled in an ice bath. To this solution was added glycerol (12 ml, 16.5 mmol), sodium salt of m-nitrobenzenesulfonic acid (11.4 g, 5.06 mmol), and -bromo-2-nitrophenylamine (10 g, 4.6 mmol). The reaction mixture was heated at 135 ° C for 3 hours. The reaction mixture was heated, poured into H20 with ice (200 ml) and extracted in 50% MeOH / EtOAc (2 x 200 ml), dried over Na2SO4 and concentrated. The resulting brown solid was triturated with EtOH and filtered yielding 3.8 g (33%) of a pink solid: m.p. 172-174 ° C. Elemental analysis for CgH5BrN202 Calculated: C, 42.72; H, 1.99; N, 11.07 Found: C, 42.69; H, 1.85; N, 11.01 Ref: Mantash Chem IN 1994, 125 p. 723-730 INTERMEDIARY 49 6-Bromo-8-ammonno-quinolxna To a solution of 6-bromo-8-nitro-quinoline (4 g, 1.58 mmol) in EtOH / HOAc / H20 (50 mL / 50 mL / 25 mL) was added metal of iron (3.18 g, 5.69 mmoles). The resulting solution was heated to reflux for 3 hours.
The cooled reaction mixture was neutralized with NaOH 2. 5 N, filtered through celite to remove the iron solids and washed with EtOAc. The eluent was extracted into EtOAc (3 x 200 ml), combined, dried over Na 2 SO and concentrated. The resulting oil was purified by column chromatography (40% EtOAc / -hexanes) yielding 3.19 (91%) of a yellow solid: m.p. 142-145 ° C.
Elemental analysis for C9H7BrN2 Calculated: C, 48.46; H, 3.16; N, 12.56 Found: C, 48.04; H, 2.93; N, 12.36 INTERMEDIARY 50 8- (4-benzyl-piperazin-1-yl) -6-bromo-quinoline The free base of bis (2-chloroethyl) -benzylamine (5.12 g, 19.3 mmol) was prepared by washing the HCl salt with NaOH 1 M (200 ml) and extracting in EtOAc. The resulting organic phases were dried over Na 2 SO and concentrated. To this flask was added 6-bromo-8-amino-quinoline (2.15 g, 9.6 mmol), n-BuOH (100 ml), and Et3N (4 ml, 28.9 mmol). The resulting reaction mixture was stirred at 100 ° C overnight. The analysis of CCF shown of the amine is still present, therefore an additional portion of bis (2-chloroethyl) -benzylamine hydrochloride (5 g) was added. The reaction was heated an additional 72 hours. The cooled reaction mixture was quenched with 1 M NaOH (200 ml) and extracted into EtOAc (3 x 200 ml). The organic fractions were combined, dried over Na2SO4, and concentrated. The resulting golden oil was purified three times by column chromatography (40% EtOAc / hexanes) yielding 1.2 g (33%) of a viscous orange oil which solidified firmly: m.p. 65-68 ° C, MS (+) APCI m / z 382 [M + H]? Elemental analysis for C20H20BrN3 * 0.75H20 Calculated: C, 60.69; H, 5.48; N, 10.62 Found: C, 60.81; H, 5.02; N, 10.88 INTERMEDIARY 51 6-Bromo-8-piperazin-1-yl-quinoline To a solution of 8- (4-benzyl-piperazin-1-yl) -6-bromo-quinoline (1.6 g, 4.2 mmol) in dichloromethane (50 ml ) under an N 2 atmosphere chloroethyl chloroformate (1.26 ml, 12.6 mmol) was added and the reaction mixture was heated at 80 ° C for 4 hours, and at room temperature overnight. No reaction was observed by TLC, therefore, vinyl chloroformate (0.35 ml, 6.3 mmol) was added and the reaction was heated at 80 ° C for another 4 hours. The cooled reaction was poured into H20 and extracted into CH2C12 (2 x 100 mL) and EtOAc (100 mL). The organic fractions were combined, dried over Na 2 SO, and left in EtOAc overnight. The organic layer was concentrated and purified by column chromatography (10% MeOH / CH2Cl2 + NH40H) yielding 1.03 g (84%) of a brown foam. MS (+) APCI m / z 292 [M + H]? INTERMEDIARY 52 6-hydroxy-8-nitro-quinoline A solution of 6-methoxy-8-nitro-quinoline (9 g, 44.1 mmol) in HBr (100 mL) was heated at 110 ° C overnight. Additional HBr (80 ml) was added and the reaction was continued to heat for an additional 24 hours. The cooled reaction mixture was basified with 2.5 N NaOH (800 mL) and extracted into EtOAc (2 x 300 mL). The organic fractions were combined, dried over Na 2 SO and purified by column chromatography (50% EtOAc / hexane) to yield 2.71 g (32%) of the title compound as a white solid: m.p. previous discolourations 100 ° C, MS (-) ESI m / z 189 [M-H] ".
INTERMEDIARY 53 6-Ethoxy-8-nitro-quinoline A solution of 6-hydroxy-8-nitro-quinoline (2.5 g, 13.2 mmol), ethyl bromide (1.08 ml, 14.5 mmol), and K2C03 (4 g, 26.4 mmol) ) in DMF (50 ml) under a nitrogen atmosphere was heated at 40 ° C for 5 hours. The cooled reaction mixture was poured into H20 (200 ml) and extracted into EtOAc (2 x 200 ml). The organic fractions were combined, dried over Na 2 SO and concentrated. The resulting beige solid was triturated with 40% EtOAc / hexane to give 2.46 g (85%) of the title compound as beige crystals. Elemental analysis for CnH? 0N2? 3 Calculated: C, 60.55; H, 4.62; N, 12.84 Found: C, 60.15; H, 4.50; N, 12.75 INTERMEDIARY 54 8- (4-benzyl-piperazin-1-yl) -6-methoxy-l, 2,3,4-tetrahydroquinoline A solution of 8- (4-benzyl-piperazin-1-yl) -6-methoxy- Quinoline (1 g, 3 mmol) in HOAc (100 ml) was hydrogenated over Pt02 (300 mg) at 40 psi overnight. The reaction mixture was filtered through a pad of celite and washed with EtOAc (50 ml). The filtrate was concentrated. The resulting golden oil was purified by column chromatography (10% MeOH / CH2Cl2 + NH40H) yielding 330 mg (45%) of a viscous golden oil. An analytical sample was prepared as the HCl salt of EtOAc. EM The m / z 247 M +. Ref: J. Chem Soc Perkins I 1980 p. 1933-1939 INTERMEDIARY 55 [1,6] aftiridine A solution of sulfuric acid was prepared by adding H2SO (100 ml) to H20 (57 ml) cooled in an ice bath. To this solution was added glycerol (33 ml, 457 mmol), sodium salt of m-nitrobenzenesulfonic acid (48 g, 212 mmol) and 4-amino-pyridine (10 g, 106 mmol). The reaction mixture was heated at 135 ° C for 4 hours. The cooled reaction mixture was basified with 2.5 N NaOH (500 mL) with cooling in an ice bath, and extracted into CH2C12 (3 x 200 mL). The organic fractions were combined, dried over Na2SO4 and concentrated. The resulting oil was purified by column chromatography (5% MeOH / CH2Cl2) yielding 5.04 g (36%) as a dark orange oil. An analytical sample was prepared as the HCl salt of EtOAc yielding an orange, low melting solid. EM The m / z 130 M? Ref: Chem Pharm Bull. 1971, 19, 9, p. 1751-1755 INTERMEDIARY 56 8-Bromo- [1,6] -naphthyridine To a stirred solution of [1, 6] -naphthyridine (4.73 g, 36.4 mmoles) in CC14 (200 ml) was added- Br2 (2.25 ml, 43.7 mmol) in CC14 (35 ml) dropwise by means of an addition funnel. The resulting solution was heated to reflux for 1 hour. Pyridine (2.94 ml, 36.4 mmol) in CC1 (30 ml) was added dropwise to the refluxing solution, and the mixture was refluxed overnight. The cooled reaction mixture was filtered, and the solids were digested with 1 M NaOH (200 ml) for 1 hour. The basic solution was extracted into CH2C12 (2 x 200 ml), and the organic fractions were combined, dried over Na2SO and concentrated. The resulting oil was purified by column chromatography (10% EtOAc / CH2Cl2) yielding 2.03 g (27%) of the title compound as yellow crystals: m.p. 79-81 ° C. Elemental analysis for C8HsBrN2 Calculated: C, 45.97; H, 2.41; N, 13.40 Found: C, 45.72; H, 2.34; N, 13.36 Ref: JOC 1968, 33, 4, p. 1384-1387 INTERMEDIARY 57 8-piperazin-1-yl- [1,6] -naphthyridine To a 100 ml flask dried in an oven under a nitrogen atmosphere was added 8-bromo- [1,6] -naphthyridine (1.3 g, 6.2 mmol) ), piperazine (3.21 g, 37.3 mmol), and sodium t-butoxide (900 mg, 9.33 mmol). The solids were suspended in anhydrous o-xylenes (40 ml), and Pd (dba) (285 mg, 7 mol%) and P (t-Bu) 3 (0.31 ml, 1.24 mmol) were added. The reaction mixture was heated at 120 ° C for 3 hours. The cooled reaction mixture was poured into H20 (100 ml) and extracted into EtOAc (1 x 100 ml) and CH2C12 (2 x 100 ml). The organic fractions were combined, dried over Na 2 SO, concentrated, and the resulting oil was subjected to chromatography (10% MeOH / CH 2 Cl 2 + NH 4 OH) yielding 470 mg (35%) of the title compound as a dark golden oil. An analytical sample was prepared as the HCl salt of EtOAc to give a brown solid: m.p. 200 ° C decomposed previously. ME (+) APCI m / z 215 [M + H]? Ref: Tet. Lett. 1998. 39, p. 617-620 INTERMEDIARY 58 4- (6-Methylamino-quinolin-8-yl) -piperazine-1-carboxylic acid ethyl ester To a 25 ml round bottom flask dried in oven was added Cs2CO3 (1.55 g, 4.76 mmol), BINAP (300 mg, 3% in moles), Pd (Oac) 2 (100 mg, 3% in moles) and kept under vacuum overnight. To this reaction vessel was added under an atmosphere of nitrogen 8- (4-benzyl-piperazin-1-yl) -6-bromo-quinoline (1.3 g), 3.4 mmol), anhydrous toluene (12 ml) and benzylmethylamine (0.53 ml, 4.1 mmol). The reaction mixture was heated at 100 ° C overnight. The cooled reaction mixture was diluted with. Et20 (15 mL), filtered to remove solids, washed with EtOAc (10 mL) and concentrated. The resulting oil was purified by column chromatography (40% EtOAc / -hexane) yielding 830 mg (59%) of benzyl- [8- (4-benzyl-piperazin-1-yl) -quinolin-6-yl] - methylamine as an orange foam. To a solution of benzyl- [8- (4-benzyl-piperazin-1-yl) -quinolin-6-yl] -methylamine (800 mg, 1.89 mmol) in anhydrous CH2C12 (100 mL) was added vinyl chloroformate (0.48). ml, 5.68 mmol) and heated to reflux overnight. A second aliquot of vinyl chloroformate (0.48 ml) was added and the reaction was refluxed for a further 24 hours. The cooled reaction mixture was diluted with H20 (50 ml) and extracted into CH2C12 (2 x 50 ml). The combined organic phases were dried over Na 2 SO, filtered and concentrated. The resulting oil was purified by column chromatography (40% EtOAc / hexane) yielding 600 mg of a mono-debenzylated product. This material was dissolved in EtOH (100 ml) and 10% Pd / C (150 mg) and ammonium formate (244 mg, 4.5 mmol) were added. The reaction was heated to reflux overnight. Additional ammonium format (250 mg) was added and the reaction was refluxed for an additional 72 hours. The cooled reaction mixture was filtered through a celite pad and washed with EtOAc (200 ml), concentrated and purified by column chromatography (10% MeOH / CH2Cl2) yielding 400 mg of the title compound as an oil dark gold An analytical sample was prepared as the HCl salt of EtOAc as an orange solid: m.p. 85 ° C decomposed previously. MS '(+)' APCI m / z 315 [M + H].
INTERMEDIARY 59-methoxy-2,6-dinitro-phenylamine To a stirred solution of HN03 (65 ml) was added 4-methoxy-2-nitro-phenylamine (15 g, 89.3 mmoles). The reaction mixture was stirred at room temperature overnight. The dark red precipitate was filtered and washed with H20 (400 mL) yielding 10.01 g (53%) of the title compound.
INTERMEDIARY 60 7-Methoxy-quinoxalin-5-ylamine A solution of 4-methoxy-2,6-dinitro-phenylamine (5 g, 23.5 mmol) in EtOH (200 ml) was hydrogenated over 10% Pd / C (2 g ) at 40 psi for 1 hour.
After the H2 incorporation has ceased, the reaction was filtered through a pad of celite and washed with EtOAc (50 ml) and concentrated. Glioxal (8 ml, 704 mmol) and EtOH (50 ml) were added immediately and the reaction was heated to reflux for 2 hours. The cooled reaction was diluted with H20 (50 mL) and extracted into CH2C12 (3 x 100 mL). The organic phases were combined, dried over Na 2 SO 4, filtered and concentrated. The resulting oil was purified by column chromatography (10% MeOH / CH2Cl2) yielding 430 mg (10%) as a red oil. An analytical sample was prepared as the HCl salt of EtOAc yielding a red solid.
INTERMEDIARY 61 (l-Oxi-pyridin-3-yl) -acetonitrile A solution of 3-pyridylacetonitrile (11 g, 93. 1 mmol), HOAc (55 mL), and 30% H202 (17 mL) was heated at 95 ° C overnight, and H20 was added. (50 ml) at room temperature for 72 hours at the reaction mixture and the resulting solution was concentrated. This was repeated with additional H20 (100 ml). Toluene (2 x 100 ml) was used to remove the residual H20, and the resulting white solid was dried under vacuum overnight yielding a waxy white solid: m.p. 120-125 ° C; MS (+) APCI m / z 135 [M + H]? Ref: JACS 1959, 81 p. 740-743 INTERMEDIARY 62 3-Cyanomethyl-pyridine-2-carbonitrile To a suspension of (1-oxy-pyridin-3-yl) -acetonitrile (10 g, 75 mmol) in anhydrous CH 2 C 12 under a nitrogen atmosphere was added cyanide. trimethylsilyl (10.95 ml, 82 mmol) and dimethylcarbamoyl chloride (7.55 ml, 82 mmol). The reaction mixture was stirred at room temperature for 72 hours and then concentrated. EtOAc (100 ml) was added to the residue and the organic phase was washed with 1 M NaOH. (150 ml), dried over Na 2 SO 4, filtered and concentrated. The resulting solid was purified by column chromatography (50% EtOAc / hexanes) yielding 7.08 g (66%) of a yellow solid: m.p. 48-51 ° C; MS (+) APCI m / z 144 [M + H]? Ref: wO 9818796 INTERMEDIARY 63 6-Methoxy- [1,7] naphthyridin-8-ylamine To an oven-dried 250 ml flask under a nitrogen atmosphere was added anhydrous MeOH (200 ml). The metal Na (1.07 g, 44 mmol) was weighed into a small beaker containing hexane and then transferred to the reaction vessel. After dissolution of the sodium, 3-cyanomethyl-pyridine-2-carbonitrile (5.3 g, 37 mmol) dissolved in anhydrous MeOH (10 ml) was added to the reaction. The resulting solution was heated at 80 ° C for 3 hours, then stirred at room temperature overnight. The reaction mixture was concentrated to remove MeOH and extracted into CH2C12 (2 x 200 mL). The organic phases were combined, dried over Na 2 SO 4, filtered, concentrated and subjected to unsuccessful chromatography (2% MeOH / CH 2 Cl 2). The combined fractions were combined and recris talized from EtOAc / hexanes yielding 1.16 g (18%) of the title compound as a yellow solid. The mother liquor was subjected to rechromatography (50% EtOAc / hexanes) to yield an additional 560 mg (9%) of product: m.p. 110 ° C decomposed previously; MS (+) APCI m / z 176 [M + H]? Ref: Te. Lett. 1975 p. 173-174 INTERMEDIARY 64 6-Methoxy-8-piperazin-1-yl- [1,7] a tiridine A solution of 6-methoxy- [1,7-naphthyridin-8-ylamine (2.25 g, 12.8 mmol), bis (2- chloroethyl) -benzylamine (10.25 g, 38.6 mmol) and Et3N (5.34 mL, 38.6 mmol) in BuOH (100 mL) was heated at 100 ° C for 72 hours. The cooled reaction mixture was poured into H20 (100 ml) and 2.5 N NaOH (100 ml), and extracted into EtOAc (2 x 200 ml). The organic phases were combined, dried over Na 2 SO, filtered and concentrated. The resulting oil was purified twice by column chromatography (10% MeOH / CH2Cl2) producing a dark golden oil with BuOH impurity. This oil was dissolved in EtOH (50 ml) and 10% Pd / C (390 mg) and ammonium formate were added. The reaction mixture was heated at 80 ° C for 2.5 hours. The cooled reaction mixture was filtered through a celite pad and washed with EtOAc (50 ml). The organic phase was concentrated and purified by column chromatography (10% MeOH / CH2Cl2 + NH4OH) yielding 270 mg of the title compound as a dark orange oil. An analytical sample was prepared as the HCl salt of EtOAc.
INTERMEDIARY 65 4-Piperazin-l-yl-l, 3-dihydro-benzoimidazol-2-one To a solution of 4- (4-benzylpiperazin-1-yl) -1, 3-dihydro-benzoimidazol-2-one ( 1 g, 3.2 mmol) in Anhydrous CH2C12 (50 ml) was added vinyl chloroformate (0.41 ml, 4.87 mmol) under a nitrogen atmosphere. The reaction mixture was heated to reflux for 2 hours, and then a second aliquot of vinyl chloroformate (0.41 ml) was added. The reaction was refluxed an additional 3 hours. The cooled reaction mixture was concentrated, and dioxane was added (25 ml) and concentrated HCl (25 ml) to the residue. The resulting solution was stirred at room temperature for 72 hours. The reaction was basified with 2.5 N NaOH (300 ml) and extracted into MeOH / EtOAc (2 x 200 ml). The organic fractions were combined, dried over Na 2 SO and concentrated, and the resulting oil was purified by column chromatography producing 393 mg (46%) as the oxalate salt. EM (+) ESI m / z 219 [M + H] INTERMEDIARY 66 6-Methoxy-1H-indol-4-ylamine To a solution of 5-methoxy-2-methyl-1,3-dinium trobenzene (3.28 g, 15 mmol) in 15 ml of dry N, N-dimethylformamide was added N, N-dimethylformamide dimethylacetal (6.16 ml, 45 mmol) and pyrrolidine (1.3 ml, 15 mmol). The reaction mixture was heated to 120 ° C until the TLC analysis showed complete consumption of 5-methoxy-2-met il-1,3-dinitrobenzene. The N, N-dimethylformamide was removed under vacuum, yielding a dark red material, which was dissolved in dry benzene and hydrogenated at 50 psi with 10% Pd / C (0.1 g) for 4 hours. The catalyst was removed by filtration and the solvent was removed under vacuum. Chromatography (25% ethyl acetate / hexane) yielded 1.0 g (40%) of the desired product as a yellow solid: m.p. 83-86 ° C; EM The m / e 162.
INTERMEDIARY 67 4- (4-Benzyl-piperazin-1-yl) -6-methoxy-1H-indole A solution of 6-methoxy-1H-indol-4-ylamine (0.76 g, 4.7 mmol) and bis (2-chloroethyl) -benzylamine (2.72 g, 11.7 mmol) in 1-butanol (20 ml) was stirred at 100 ° C for 18 hours then poured into aqueous sodium carbonate solution. The mixture was extracted with ethyl acetate (3 x 60 ml). The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was removed under vacuum. Chromatography (30% ethyl acetate / hexane) yielded 0.60 g (40%) of product as a gray oil. EM (+) APCI (M + H) + m / e 322.
INTERMEDIARY 68 6-Methoxy-4-piperazin-1-yl-1H-indole A mixture of 4- (4-benzyl-piperazin-1-yl) -6-methoxy-1H-indole (0.37 g, 1.1 mmol), % of Pd / C (0.05 g) and ammonium formate (0.15 g, 2.2 mmol) in ethanol (20 ml) was allowed to reflux for 2 hours. The catalyst was removed by filtration and the solvent was removed under vacuum. Chromatography (10% methanol / methylene chloride plus ammonium hydroxide) yielded 0.2 g (75%) of product as a yellow foam. EM (El) m / e 231.
EXAMPLE 3- [cis-4- [4- (lH-Indol-4-yl) -1-piperazinyl] cyclohexyl] -lH-indole A solution of 4- (lH-indol-3-yl) -cycothexanone (0.53 g, 2.5 mmol), 1- (indol-4-yl) iperazine (0.5 g, 2.5 mmol), sodium triacetoxyborohydride (0.78 g, 3.5 mmol) and acetic acid (0.14 mL, 2.5 mmol) in 1, 2 Dichloroethane (11 ml) was allowed to stir at room temperature overnight. The reaction was quenched with 1 N sodium hydroxide (10 ml), extracted with methylene chloride (3 x 60 ml), and washed with brine (3 x 60 ml). The organic layer was dried over anhydrous sodium sulfate and filtered. Chromatography (10% methanol-ethyl acetate) yielded 0.52 g (53%) of product as a white solid: 85-87 ° C. The HCl salt was prepared in ethyl acetate: m.p. 198-200 ° C. Elemental analysis for C26H3oN4 *? Cl Calculated: C, 68.25; H, 7.38; N, 12.25 Found: C, 68.12; H, 7.16; N, 11.93 EXAMPLE lb 3- [trans-4- [4- (lH-indol-4-yl) -1-piperazinyl] -cyclohexyl] -lH-indole The trans compound was isolated at the same time as the cis isomer in 20% yield (0.21 g) as a white solid: mp 105-107 ° C. The HCl salt was prepared in ethyl acetate: m.p. 305 ° C (decomposed). Elemental analysis for C26H30N4 »Calculated HC1: C, 68.25; H, 7.38; N, 12.25 Found: C, 68.12; H, 7.16; N, 11.93 EXAMPLE 2a 4-Fluoro-3- [cis-4- [4- (lH-indol-4-yl) -1-piperazinyl] -cyclohexyl] -lH-indole A solution of 4- (4-fluoro-lH-indole -3-yl) -cyclohexanone (0.88 g, 3.8 mmol), 1- (indol-4-yl) -piperazine (0.7 g, 3.5 mmol), sodium t-butylacetoxyborohydride (1.1 g, 5.2 mmol) and acetic acid (0.4 ml, 7 mmol) in 1,2-dichloroethane (20 ml) was allowed to stir at room temperature overnight. The reaction was quenched with 1 N sodium hydroxide (10 ml), extracted with methylene chloride (3 x 60 ml), and washed with brine (3 x 60 ml). The organic layer was dried over anhydrous sodium sulfate and filtered. Chromatography (5-7% methanol-ethyl acetate) yielded 1.14 g (79%) of product as a white foam. The HCl salt was prepared in ethanol: m.p. 283-285 ° C. Elemental analysis for C26H29FN4 «HC1» 0.25H20 Calculated: C, 68.26; H, 6.72; N, 12.25 Found: C, 68.16; H, 6.74; N, 12.04 EXAMPLE 2b 4-Fluoro-3- [trans-4- [4- (lH-indol-4-yl) -1-piperazinyl] -cyclohexyl] -lH- ndol The trans compound was isolated at the same time as the cis isomer in 17% yield (0.24 g) as a white solid: mp 206-208 ° C. The HCl salt was prepared in ethanol: m.p. 297-299 ° C. Elemental analysis for C26H29N4 »HC1» H20 Calculated: C, 66.30; H, 6.85; N, 11.90 Found: C, 66.17; H, 6.51; N, 11.70 EXAMPLE 3a-Fluoro-3- [cis-4- [4- (lH-indol-4-yl) -1-piperazinyl] -cyclohexyl] -lH-indole This compound was prepared in the manner described above by Example 2 by replacing 4- (4-fluoro-lH-indol-3-yl) -cciohexanone with 4- (5-fluoro-lH-indol-3-yl) -cycothexanone (0.56 g, 2.5 mmol) to yield 0.54 g (52 %) of product as a white solid: mp 108-110 ° C. The HCl salt was prepared in ethyl acetate: m.p. 215-217 ° C. Elemental analysis for C26H29FN4 »HC1« O .36C4H802 Calculated: C, 67.37; H, 6.88; N, 11.45 Found: C, 67.18; H, 6.72; N, 11.18 EXAMPLE 3b 5-Fluoro-3- [trans-4- [4- (lH-indol-4-yl) -1-piperazinyl] -cyclohexyl] -lH-indole The trans compound was isolated at the same time as the cis isomer in 30% yield (0.31 g) as a white solid: mp 112-114 ° C. The HCl salt was prepared in ethanol: m.p. 280 ° C (decomposed). Elemental analysis for C26H29FN4 * HC1 Calculated: C, 66.81; H, 6.81; N, 11.99 Found: C, 66.44; H, 6.66; N, 11.74 EXAMPLE 4a 6-Fluoro-3- [cis -4- [4- (lH-indol-4-yl) -1-piperazinyl] -cyclohexyl] -IH-indole This compound was prepared in the manner described above by Example 2 by replacing 4- (4-fluoro-lH-indol-3-yl) -cydohexanone with 4- (6-fluoro-lH-indol-3-yl) -cydohexanone (1.15 g, 5.0 mmol) to yield 1.06 g (51%) of product as a white foam. The HCl salt was prepared in ethanol: m.p. 250-252 ° C (decomposed). Elemental analysis for C26H29FN4 «Calculated HC1: C, 67.37; H, 6.88; N, 11.45 Found: C, 67.18; H, 6.72; N, 11.18 EXAMPLE 4b 6-Fluoro-3- [trans-4- [4- (lH-indol-4-yl) -1-piperazinyl] -cyclohexyl] -IH-indole The trans compound was isolated at the same time as the cis isomer in 27% yield (0.55 g) as a white foam. The HCl salt was prepared in ethanol: m.p. 319-320 ° C (decomposed). Elemental analysis for C26H29FN4 »Calculated HC1: C, 66.81; H, 6.81; N, 11.99 Found: C, 66.44; H, 6.66; N, 11.74 EXAMPLE 5a-Bromo-3- [cis-4- [4- (lH-indol-4-yl) -1-piperazinyl] -cyclohexyl] -lH-indole This compound was prepared in the manner described above by Example 2 by replacing 4- (4-fluoro-lH-indole-3-yl) -cydohexanone with 4- (5-bromo-lH-indol-3-yl) -cydohexanone (0.75 g, 2.5 mmol) to yield 0.81 g (68%) of product. The HCl salt was prepared in ethyl acetate: m.p. 276 ° C. Elemental Analysis for C26H2gBrN4 »Calculated HCl: C, 60.23; H, 5.93; N, 10.81 Found: C, 59.95; H, 5.83; N, 10.64 EXAMPLE 5b 5-Bromo-3- [trans-4- [4- (lH-indol-4-yl) -1-piperazinyl] -cyclohexyl] -lH-indole The trans compound was isolated at the same time as the cis isomer in 24% yield (0.29 g). The HCl salt was prepared in ethyl acetate: m.p. > 300 ° C. Elemental analysis for C26H29BrN * HCl Calculated: C, 60.75; H, 5.88; N, 10.90 Found: C, 60.38; H, 5.89; N, 10.61 EXAMPLE 6a 5-Chloro-3 ~ [cis-4- [4- (lH-indol-4-yl) -1-piperazinyl] -cyclohexyl] -lH-indole A solution of 4- (5-chloro- lH-indol-3-yl) -cydohexanone (0.78 g, 3.1 mmol), 1- (indol-4-yl) -piperazine (0.6 g, 3 mmol), sodium triacetoxyborohydride (0.95 g, 4.5 mmol) and acetic acid (0.34 ml, 6 mmol) in 1,2-dichloroethane (20 ml) was allowed to stir at room temperature overnight. The reaction was quenched with 1 N sodium hydroxide (10 ml), extracted with methylene chloride (3 x 60 ml) and washed with brine (3 x 60 ml). The organic layer was dried over anhydrous sodium sulfate and filtered. Chromatography (5% methanol-ethyl acetate) yielded 0.84 g (65%) of product as a white foam. The HCl salt was prepared in ethanol: m.p. 283-285 ° C. Elemental analysis for C26H29C1N4 * HC1 »0.25H20 Calculated: C, 65.46; H, 6.69; N, 11.45 Found: C, 65.14; H, 6.73; N, 11.33 EXAMPLE 6b 5-Chloro-3- [trans-4- [4- (lH-indol-4-yl) -1-piperazinyl] -cyclohexyl] -lH-indole The trans compound was isolated at the same time as the cis-isomer in 24% yield (0.32 g) as a white foam. The HCl salt was prepared in ethanol: m.p. 314-315.5 ° C. Elemental analysis for C26H29C1N4 * HC1 »0.25H20 Calculated: C, 65.65; H, 6.60; N, 11.62 Found: C, 65.50; H, 6.50; N, 11.30 EXAMPLE 7a 3-. { 4 - [(1,4-cis) -4- (1 H -indol-4-yl) -1-piperazinyl-1-yl] cyclohexyl} -lH-indole-5-carbonitrile This compound was prepared in the manner described above by Example 2 by replacing 4- (4-fluoro-l-indol-3-yl) -cydohexanone with 4- (5-cyano-1H- indol-3-yl) -cycothexanone (0.71 g, 3.0 mmol) to yield 0.38 g (30%) of product. The HCl salt was prepared in ethyl acetate: m.p. 216-218 ° C. Elemental analysis for C27H29N5 * HC1 »0.33C4H802 Calculated: C, 66.25; H, 6.94; N, 13.64 Found: C, 66.05; H, 6.54; N, 13.28 EXAMPLE 7b 3-. { 4- [(1, 4-trans) -4- (1 H -indol-4-yl) -1-piperazinyl-1-yl] cyclohexyl} -lH-indole-5-carbonitrile The trans compound was isolated at the same time as the cis isomer in 25% yield (0.32 g). The HCl salt was prepared in ethyl acetate: m.p. > 310 ° C. Aná lis is elementary for C2 H29N5 »Calculated HC1: C, 68.48; H, 6.71; N, 14.79 Found: C, 68.43; H, 6.54; N, 14.63 EXAMPLE 8a 5-Methoxy-3- [cis-4- [4- (lH-indol-4-yl) -1-piperazinyl] -cyclohexyl] -lH-indole A solution of 4- (5-methoxy-1H-indole -3-yl) -cyclohexanone (1.2 g, 5 mmol), 1- (indol-4-yl) -piperazine (1 g, 5 mmol), sodium triacetoxyborohydride (1.47 g, 6.2 mmol) and acetic acid (0.28 ml). , 4 mmol) in 1,2-dichloroethane (20 ml) was allowed to stir at room temperature overnight. The reaction was quenched with 1 N sodium hydroxide (10 ml), extracted with methylene chloride (3 x 60 ml) and washed with brine (3 x 60 ml). The organic layer was dried over anhydrous sodium sulfate and filtered. Chromatography (2.5% methanol-ethyl acetate) yielded 1.18 g (55%) of product as a white solid: m.p. 105-108 ° C.
The HCl salt was prepared in ethyl acetate: mp 283-285 ° C. Elemental analysis for C27H32N40 «HC1» 0.5H20 Calculated: C, 68.55; H, 7.03; N, 11.85 Found: C, 68.86; H, 7.29; N, 11.76 EXAMPLE 8b 5-Methoxy-3- [trans-4- [4- (lH-indol-4-yl) -1-piperazinyl] -cyclohexyl] -lH-indole The trans compound was isolated at the same time as the cis isomer in 20% yield (0.43 g) as a white foam. The HCl salt was prepared in ethyl acetate: m.p. 194-196 ° C. Elemental analysis for C27H32N 0 «HC1« 1.5H20 Calculated: C, 66.65; H, 7.15; N, 11.52 Found: C, 66.65; H, 7.06; N, 11.44 EXAMPLE 9a 3- [cis-4- [4- (lH-Indol-4-yl) -1-piperazinyl] -cyclohexyl] -2-methyl-lH-indole A solution of 4- (lH-indol-3-yl) ) -cydohexanone (1.44 g, 6.33 mmol), 1- (indole-4-yl) -piperazine (1.27 g, 6.33 mmol), sodium triacetoxyborohydride (1.88 g, 8.86 mmol) and acetic acid (0.76 mg, 12.6 mmol) in 1,2-dichloroethane (100 ml) was allowed to stir at room temperature overnight. The reaction was quenched with 1 N sodium hydroxide (80 ml), extracted with methylene chloride (3 x 300 ml) and washed with brine (150 ml). The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was removed under vacuum to yield an off-white solid. Trituration of the solid with hot methylene chloride (80 ml) followed by filtration yielded 0.88 g of white solid. The mother liquor was concentrated and subjected to chromatography (2% methanol-methylene chloride) to give another 0.18 g (total yield of 40.7%) of product as a white solid: m.p. 279-280 ° C. The HCl salt was prepared in ethanol: m.p. 200-203 ° C. Elemental Analysis for C27H32N »2HC1 Calculated: C, 64.99; H, 7.17; N, 11.23 Found: C, 65.05; H, 7.07; N, 11.23 EXAMPLE 9b 3- [trans -4- [4- (lH-Indol-4-yl) -1-piperazinyl] -cyclohexyl] -2-methyl-lH-indole The trans compound was isolated at the same time as the cis isomer in 25.7% yield (0.67 g) as a white foam.
The HCl salt was prepared in ethanol: m.p. > 310 ° C. Anal i s i elemental for C2 H32N4 »2 HC 1 Calculated: C, 66.80; H, 7.06; N, 11.54 Found: C, 66.84; H, 6.87; N, 11.37 EXAMPLE 10a 3-. { (1, 4-cis) -4- [4- (1H-indol-4-yl) -1-piperazin-1-yl] cyclohexyl} -1H-pyrrolo [2, 3-b] pyridine This compound was prepared in the manner described above by Example 2 by replacing 4- (5-fluoro-lH-indol-3-yl) -cidiohexanone with 4- (lH- 3-pyrrolo [2, 3-b] pyridyl) -cycothexanone (1.52 7.1 mmoles) in 27 3 0.79 g) of yield as a white solid. • The HCl salt was prepared in ethanol: p.f > 250 ° C (decomposition.) Elemental analysis for C 25 H 29 Ns »3 HCl Calculated: C, 58.49; H, 6.38; N, 13.64 Found: C, 58.47; H, 6.52; N, 12.91 EXAMPLE 10b 3-. { (1, 4-trans) -4- [4- (lH-Indol-4-yl) -1-piperazin-1-yl] cyclohexyl} -1H-pyrrolo [2, 3-b] pyridine The trans compound was isolated at the same time as the cis isomer in 9% yield (0.26 g) as a white solid: m.p. > 228 ° C. The HCl salt was prepared in ethanol: m.p. > 250 ° C (decomposition.) Aná l i s elemental for C25H29N5 «3 HC 1 Calculated: C, 56.50; H, 6.54; N, 13.18 Found: C, 56.45; H, 6.63; N, 12.98 EXAMPLE 11 6-Fluoro-l-methyl-3-. { cis-4- [4- (1-methyl-1H-indol-4-yl) -1-piperazinyl] cyclohexyl} -lH-indole To a solution of 3- [ci s-4- [4- (lH-indol-4-yl) -1-piperazinyl] cyclohexyl] -lH-indole (0.27 g, 0.65 mmole) in N, N anhydrous dimethylformamide (4 ml) was added 60% sodium hydride (33.7 mg, 0.84 mmol) at room temperature. The mixture was allowed to stir for 30 minutes at room temperature, then iodomethane was added to the above solution. The resulting mixture was stirred for another 0.5 hour and then poured into water (80 ml) and extracted with ethyl acetate (2 x 80 ml). The organic layer was dried over anhydrous magnesium sulfate and filtered. Chromatography (20% acetone-hexanes) yielded 0.93 g (55%) of product as an oil which was heated in ethanol to yield a white solid: m.p. 188-190 ° C.
The HCl salt was prepared in ethanol: m.p. 253-254 ° C. Aná l i s i elementa l for C28H33N4 F »HC1» 0. 5 H20 Calculated: C, 68.62; H, 7.20; N, 11.43 Found: C, 68.98; H, 6.80; N, 11.47 EXAMPLE 12a 3-. { (1,4-cis) -4- [4- (lH-indol-4-yl) -piperazin-1-yl] -cyclohexyl} -1-methyl-lH-indole-5-carbonitrol A solution of 4- (5-cyano-l-methyl-3-indolyl) -cycothexanone (0.75 g, 3 mmol), 1- (indole-4-yl) Piperazine (0.6 g, 3 mmol), sodium triacetoxyborohydride (0.95 g, 4.5 mmol) and acetic acid (0.76 mg, 12.6 mmol) in 1,2-dichloroethane (20 mL) was allowed to stir at room temperature overnight . The reaction was quenched with 1 N sodium hydroxide (10 ml), extracted with methylene chloride (3 x 60 ml) and washed with brine (3 x 60 ml). The organic layer was dried over anhydrous sodium sulfate and filtered. Chromatography (10% methanol-ethyl acetate) yielded 0.73 g (56%) of product as a white solid: m.p. 274-275 ° C. The HCl salt was prepared in ethyl acetate: m.p. 285.5-288 ° C.
Analysis for C28H3? N5 * 2 HCl »H20 Calculated: C, 68.35; H, 6.97; N, 14.23 Found: C, 68.51; H, 6.65; N, 14.06 EXAMPLE 12b 3-. { (1, 4-trans) -4- [4- (lH-indol-4-yl) -piperazin-1-yl] -c-clohexyl} -1-methyl-1H-indole-5-carbonitrile The trans compound was isolated at the same time as the cis isomer in 33% yield (0.42 g) as a white solid: m.p. 239-240 ° C. The HCl salt was prepared in ethyl acetate: m.p. 286-288 ° C. Elemental analysis for C28H3? N5 »2HCl * 0.5H20 Calculated: C, 64.73; H, 6.60; N, 13.65 Found: C, 64.55; H, 6.42; N, 13.41 EXAMPLE 13a-Ethyl-3-. { (1,4-cis) -4- [4- (lH-Indol-4-yl) -piperazin-1-yl] -cyclohexyl} -lH-indole-5-carbonitrile A solution of 4- (5-cyano-l-ethyl-indol-3-yl) -cydohexanone (1.5 g, 5.6 mmol), 1- (indol-4-yl) -piperazine ( 1.19 g, 5.9 mmol), sodium triacetoxyborohydride (1.73 g, 8.2 mmol) and acetic acid (0.9 mg, 15 mmol) in 1,2-dichloroethane (30 ml) was allowed to stir at room temperature overnight. The reaction was quenched with 1 N sodium hydroxide (10 ml), extracted with methylene chloride (3 x 80 ml) and washed with brine (3 x 80 ml). The organic layer was dried over anhydrous sodium sulfate and filtered. Chromatography (2.5% methanol-ethyl acetate) yielded 0.98 g (39%) of product as a white solid: m.p. 226 ° C (decomposition.) The HCl salt was prepared in ethyl acetate: m.p. 245 ° C. Elemental analysis for C29H33N5 «2HC1« 0.25H20 Calculated: C, 65.84; H, 6.76; N, 13.24 Found: C, 65.97; H, 6.74; N, 13.40 EXAMPLE 13b l-Ethyl-3-. { (1, 4-trans-) -4- [4- (lH-Indol-4-yl) -perazinyl-1-yl] -cyclohexyl} -1H-Indole-5-carbonitrile The trans compound was isolated at the same time as the cis isomer in 19% yield (0.48 g) as a light brown solid: m.p. decomposed at 110 ° C. The HCl salt was prepared in ethyl acetate: m.p. 250 ° C (decomposed). Elemental analysis for C29H33N5 »2HC1 Calculated: C, 66.40; H, 6.73; N, 13.35 Found: C, 66.32; H, 6.67; N, 13.10 EXAMPLE 14a 3-. { (1,4-cis) -4- [4- (1H-indol-4-yl) -piperazin-1-yl-cyclohexyl} -1-propyl-1H-indole-5-carbonitrile A solution of 4- (5-cyano-ln-propyl-indol-3-yl) -cydohexanone (1.68 g, 6 mmol), 1- (indole-4-yl) ) -piperazine (1.27 g, 6.3 mmol), sodium triacetoxyborohydride (1.84 g, 8.9 mmol) and acetic acid (0.94 mL, 16 mmol) in 1,2-dichloroethane (80 mL) was allowed to stir at room temperature overnight . The reaction was quenched with 1 N sodium hydroxide (20 ml), extracted with methylene chloride (3 x 100 ml) and washed with brine (3 x 100 ml). The organic layer was dried over anhydrous sodium sulfate and filtered. Chromatography (10% methanol-ethyl acetate) yielded 0.42 g (15%) of product as a white powder. The HCl salt was prepared in ethanol: m.p. 200-206 ° C. Elemental analysis for C3oH35N5 * 2HCl »0.75H20 Calculated: C, 65.27; H, 7.03; N, 12.69 Found: C, 65.18; H, 6.97; N, 12.68 EXAMPLE 14b 3-. { (1,4-trans-) -4- [4- (lH-Indol-4-yl) -perazinyl-1-yl] -cyclohexyl} -1-propyl-1H-indole-5-carbonitrile The trans compound was isolated at the same time as the cis isomer in 14% yield (0.39 g) as a white foam. The HCl salt was prepared in ethanol: m.p. > 245 ° C. Anal is is elemental for C3oH35N5 * 2HCl Calculated: C, 66.90; H, 6.93; N, 13.00 Found: C, 66.68; H, 6.97; N, 12.96 EXAMPLE 15a 3-. { (1, 4-cis) -4- [4- (1H-indol-4-yl) -piperazin-1-yl] -cyclohexyl} -1-isopropyl-1H-indole-5-carbonitrile A solution of 4- (5-cyano-ln-propyl-indol-3-yl) -cydohexanone (1.68 g, 6 mmol), 1- (indole-4-yl) ) -piperazine (1.27 g, 6.3 mmol), sodium triacetoxyborohydride (1.84 g, 8.9 mmol) and acetic acid (0.94 mL, 16 mmol) in 1,2-dichloroethane (80 mL) was allowed to stir at room temperature overnight . The reaction was quenched with 1 N sodium hydroxide (20 ml), extracted with methylene chloride (3 x 100 ml) and washed with brine (3 x 100 ml). The organic layer was dried over anhydrous sodium sulfate and filtered. Chromatography (10% methanol-ethyl acetate) yielded 0.49 g (18%) of product as a white powder. The HCl salt was prepared in ethanol: m.p. 285-286 ° C.
Elemental analysis for C3oH35N5 »HCl« 0. 5H20 Calculated: C, 70.50; H, 7.30; N, 13.70 Found: C, 70.65; H, 7.16; N, 13.45 EXAMPLE 15b 3-. { (1, -trans-) -4- [4- (1H-indol-4-yl) -perazinyl-1-yl] -cyclohexyl} -1-isopropyl-1H-indole-5-carbonitrile The trans compound was isolated at the same time as the cis isomer in 12% yield (0.34 g) as a white foam. The HCl salt was prepared in ethanol: m.p. > 245 ° C. Elemental analysis for C3oH35N5 * HCl Calculated: C, 66.90; H, 6.93; N, 13.00 Found: C, 66.68; H, 6.97; N, 12.96 EXAMPLE 16a 1-Benzyl-3-. { (1,4-cis) -4- [4- (lH-indol-4-yl) -piperazin-1-yl] -cyclohexyl} -1H-indole-5-carbonitrile A solution of 4- (5-cyano-benzyl-indol-3-yl) -cydohexanone (2.97 g, 9 mmol), 1- (indol-4-yl) -piperazine ( 1.94 g, 9.6 mmol), sodium triacetoxyborohydride (2.7 g, 13 mmol) and acetic acid (1 mL, 24 mmol) in 1,2-dichloroethane (50 mL) was allowed to stir at room temperature overnight. The reaction was quenched with 1 N sodium hydroxide (20 ml), extracted with methylene chloride (3 x 100 ml) and washed with brine (3 x 100 ml). The organic layer was dried over anhydrous sodium sulfate and filtered. Chromatography (25-50% ethyl acetate-hexanes) yielded 1.71 g (37%) of product as a white powder. The HCl salt was prepared in ethanol: m.p. decomposition > 245 ° C. Elemental analysis for C34H35N5 * HC1 * 0.5H20 Calculated: C, 68.56; H, 6.43; N, 11.76 Found: C, 68.93; H, 6.55; N, 11.52 EXAMPLE 16b 1-Benzyl-3-. { (1,4-trans-) -4- [4- (1H-indol-4-yl) -perazinyl-1-yl] -cyclohexyl} -1H-Indole-5-carbonitrile The trans compound was isolated at the same time as the cis isomer in 15% yield (0.68 g) as a white foam. The HCl salt was prepared in ethanol: m.p. > 240 ° C (decomposition) Anál is is elementa l pa ra C3 H35N5 »2 HC 1 * 0. 25H20 Calculated: C, 69.08; H, 6.40; N, 11.85 Found: C, 69.09; H, 6.17; N, 11.80 EXAMPLE 17 l-Methyl-3-. { (1,4-cis) -4- [4- (l-methyl-lH-indol-4-yl) -pi? Erazin-1-yl] -cyclohexyl) -lH-indole-5-carbonitrile To a suspension of Sodium hydride (60%, 95 mg, 2.4 mmol) in anhydrous N, N-dimethylformamide was added a solution of 3-. { (1,4-cis) -4- [4 - (1H-indol-4-yl) -piperazin-1-yl] cyclohexyl} -l-methyl-lH-indole-5-carbonitrile (0.52 g, 1.2 mmol) in 10 ml of N, N-dimethylformamide. The mixture was allowed to stir at room temperature for 30 minutes. Then iodomethane (0.17 g, 2.4 mmol) was added to the above reaction mixture. The mixture was allowed to stir at room temperature for another 30 minutes, then rapidly cooled with wire-water. The mixture was extracted with methylene chloride (150 ml), and dried over anhydrous sodium sulfate. Chromatography (methanol-methylene chloride-ethyl acetate; 1: 1: 8) yielded 0.53 g (99%) of product as a pink foam. The HCl salt was prepared in ethanol: m.p. 252-255 ° C. Elemental analysis for C29H33N5 * 2HC1 Calculated: C, 66.40; H, 6.73; N, 13.35 Found: C, 66.64; H, 6.82; N, 13.21 EXAMPLE 18 5-Fluoro-3-. { (cis) -4- [4- (2-methoxy-phenyl) -piperazin-1-yl] -cyclohexyl} -lH-indole A solution of 4- (5-fluoro-indol-3-yl) -cydohexanone (0.35 g, 1.5 mmol), 1- (2-methoxy-phenyl) -piperazine (0.29 g, 1.5 mmol) Sodium triacetoxyborohydride (0.47 g, 2.1 mmol) and acetic acid (0.05 ml, 1.5 mmol) in 1,2-dichloroethane (8 ml) was allowed to stir at room temperature for 12 hours. The reaction was quenched with 1 N sodium hydroxide (pH >)9) and extracted with methylene chloride (3 x 50 ml). The organic layer was dried over anhydrous sodium sulfate and filtered. Chromatography (10% methanol-ethyl acetate) yielded 0.34 g (56%) of product as a white solid. The HCl salt was prepared in ethyl acetate: m.p. 170-172 ° C. Elemental analysis for C25H30FN3O »Calculated HCl: C, 66.95; H, 7.08; N, 9.37 Found: C, 66.93; H, 7.08; N, 9.29 EXAMPLE 19a 5-Fluoro-3-. { (1, 4-cis) -4- [4- (2-methoxy-phenyl) -piperidin-1-yl] -cyclohexyl} -lH-indole This compound was prepared in the manner described above by Example 18 by replacing l- (2-methoxy-phenyl) piperazine with 1- (2-methoxy-pheny1) piperidine (1.0 g, 5.2 mmoles) to produce 1.34 g of product in 63% yield.
The HCl salt was prepared in ethyl acetate: mp 245-250 ° C. Elemental analysis for C26H3? FN2O * HCl »0.09C H802. Calculated: C, 69.09; H, 7.36; N, 6.20 Found: C, 66.19; H, 7.18; N, 6.08 EXAMPLE 19b 5-Fluoro-3-. { (1, 4-trans) -4- [4- (2-methoxy-phenyl) -piperidin-1-yl] -cyclohexyl} -1H-indole The trans compound was isolated at the same time as the cis isomer in 20% yield (0.43 g). The HCl salt was prepared in ethyl acetate: m.p. 297-299 ° C. Elemental analysis for C26H3? FN2O «HCl« 0.08C4H8O2 Calculated: C, 70.49; H, 7.28; N, 6.32 Found: C, 70.17; H, 7.30; N, 6.10 EXAMPLE 20a 5-Methoxy-3-. { (1,4-cis) -4- [4- (2-methoxy-phenyl) -piperazin-1-yl] -cyclohexyl} -lH-indole This compound was prepared in the manner described above by Example 18 by replacing 4- (5-fluoro-l-indol-3-yl) -cydohexanone with 4- (5-methoxy-l-indole-3-) il) -cydohexanone (1.2 g, 5 mmol) to yield 1.18 g (55%) of the title compound as a white solid: mp 105-108 ° C. The HCl salt was prepared in ethyl acetate: m.p. 198- 199 ° C. Elemental analysis for C26H33N302 »Calculated HC1: C, 68.48; H, 7.52; N, 9.21 Found: C, 68.31; H, 7.54; N, 9.08 EXAMPLE 20b 5-Methoxy-3-. { (1, 4-trans) -4- [4- (2-methoxy-phenyl) -piperazin-1-yl] -cyclohexyl} -1H-indole The trans compound was isolated at the same time as the cis isomer in 20% yield (0.43 g) as a white foam. The HCl salt was prepared in ethyl acetate: m.p. 195-197 ° C. Elemental analysis for C26H33N302 * HC1 Calculated: C, 68.48; H, 7.52; N, 9.21 Found: C, 68.18; H, 7.50; N, 9.11 EXAMPLE 21 3-. { (1,4-cis) -4- [4- (2-methoxy-phenyl) -piperazin-1-yl] -cyclohexyl} -1H-pyrrolo [2, 3-b] pyridine This compound was prepared in the manner described above by Example 18 by replacing 4- (5-fluoro-lH-indol-3-yl) -cydohexanone with 4 - (IH- pyrrolo- [2, 3-b] -3-pyridyl) -cyclohexanone (1.71 g, 7.9 mmol) in 42% yield (1.34 g) as a white solid: mp 170-172 ° C. The HCl salt was prepared in ethanol: m.p. 259-261 ° C. Elemental analysis for C24H30ON4 * HC1 Calculated: C, 65.44; H, 7.44; N, 12.72 Found: C, 65.60; H, 7.36; N, 12.22 EXAMPLE 22a 5-Fluoro-3-. { (cis) -4- [4- (5-fluoro-2-methoxy-phenyl) -piperazin-1-yl] -cyclohexyl} -1H-indole A solution of 4- (5-fluoro-l-indol-3-yl) -cydohexanone (1.1 g, 4.8 mmol), 1- (2-methoxy-5-fluoro-phenyl-1) -piperazine (1.0 g, 4.8 mmol), sodium triacetoxyborohydride (1.5 g, 7.1 mmol) and acetic acid (0.27 ml, 4.7 mmol) in 1,2-dichloroethane (20 ml) was allowed to stir at room temperature for 12 hours. The reaction was quenched with 1 N sodium hydroxide (pH> 9), extracted with methylene chloride (3 x 50 ml). The organic layer was dried over anhydrous sodium sulfate and filtered. Chromatography (10% methanol-ethyl acetate) yielded 1.16 g (53%) of product as a white solid: m.p. 152-153 ° C.
The HCl salt was prepared in ethyl acetate m.p. 171- 174 ° C. Aná l i s elemental for C25H29F2N3 «2 HC l Calculated: C, 59.17; H, 6.36; N, 8.28 Found: C, 59.20; H, 6.33; N, 8.09 EXAMPLE 22b 5 -Fluoro-3-. { (trans) -4- [4- (5-fluoro-2-methoxy-phenyl) -piperazin-1-yl] -cyclohexyl} -1H-indole The trans compound was isolated at the same time as the cis isomer in 12% yield (0.25 g) as a white solid: m.p. 64-67 ° C. The HCl salt was prepared in ethyl acetate: m.p. 272-273.5 ° C. «Elemental analysis for C25H29F2ON3 * HCl Calculated: C, 63.75; H, 6.64; N, 8.92 Found: C, 63.77; H, 6.41; N, 8.75 EXAMPLE 23a 3-. { (1,4-cis) -4- [4- (2,3-Dihydro-benzo [1,4] dioxin-5-yl) -piperazin-1-yl] -cyclohexyl} -4-fluoro-lH-indole A solution of 4- (4-fluoro-l-indol-3-yl) -cycothexanone (0.71 g, 3.1 mmol), 5- (1-piperazinyl) -benzodioxane (0.77 g, 3.5 mmol), sodium t-butylacetoxyborohydride (0.98 g, 4.6 mmol) and acetic acid (0.28 g, 4.6 mmol) in 1,2-dichloroethane ( 70 ml) was allowed to stir at room temperature for 12 hours. The reaction was quenched with 1 N sodium hydroxide (100 ml), extracted with methylene chloride (3 x 100 ml). The organic layer was dried over anhydrous magnesium sulfate and filtered. Chromatography (1% methanol-ethyl acetate) yielded 0.8 g (53%) of product as a white foam which was dissolved in hot ethanol (15 ml) and crystallized to yield a white solid: m.p. 194-195.5 ° C. The HCl salt was prepared in ethanol: m.p. 215-220 ° C. Elemental analysis for C26H3oFN302 «? Cl Calculated: C, 61.42; H, 6.34; N, 8.62 Found: C, 61.15; H, 6.29; N, 8.04 EXAMPLE 23b 3-. { (1, 4-trans-) -4- [4- (2,3-Dihydro-benzo [1,4] dioxin-5-yl) -piperazin-1-yl] -cyclohexyl} -4-fluoro-lH-indole The trans compound was isolated at the same time as the cis isomer in 14% yield (0.21 g) as a white foam which is in recrystallization from ethanol to produce a white solid: m.p. 188-190 ° C. Elemental analysis for C2eH3oF02N3 Calculated: C, 71.70; H, 6.94; N, 9.65 Found: C, 71.33; H, 7.03; N, 9.55 EXAMPLE 24a 3-. { (1, 4-cis) -4- [4- (2,3-Dihydro-benzo [1,4] dioxin-5-yl) -piperazin-1-yl] -cyclohexyl} -5-fluoro-1H-indole A solution of 4- (5-fluoro-1-indol-3-yl) -cydohexanone (1.06 g, 4.6 mmol), 5- (1-piperazinyl) -benzodioxane (1.14 g, 5.2 mmoles), sodium triacetoxyborohydride (1.46 g, 6.9 mmol) and acetic acid (0.41 g, 6.9 mmol) in 1,2-dichloroethane (80 ml) was allowed to stir at room temperature for 12 hours. The reaction was rapidly cooled with saturated sodium bicarbonate (100 ml), extracted with methylene chloride (3 x 100 ml). The organic layer was dried over anhydrous magnesium sulfate and filtered. Chromatography (1% methanol-ethyl acetate) yielded 1.06 g (53%) of product as a solidified oil to yield a white solid: m.p. 104-106 ° C. The HCl salt was prepared in ethanol: m.p. 222-225 ° C. Elemental analysis for C26H30FN3? 2 * HCl4 > 0.2H20 Calculated: C, 60.88; H, 6.39; N, 8.19 Found: C, 60.85; H, 6.03; N, 8.13 EXAMPLE 24b 3-. { (1, 4 -trans-) -4- [4- (2,3-Dihydro-benzo [1,4] dioxin-5-yl) -piperazin-1-yl] -cyclohexyl} -5-fluoro-lH-indole The trans compound was isolated at the same time as the cis isomer in 27% yield (0.53 g) as a white solid: m.p. 206-210 ° C. The HCl salt in ethanol was prepared: m.p. 295-297 ° C. Elemental analysis for C 26 H 3 OF02 N 3 »2 HCl Calculated: C, 61.42; H, 6.34; N, 8.26 Found: C, 61.22; H, 6.19; N, 8.13 ' EXAMPLE 25a 3-. { (1,4-cis) -4- [4- (2,3-Dihydro-benzo [1,4] dioxin-5-yl) -piperazin-1-yl] -cyclohexyl} -6-fluoro-1H-indole A solution of 4- (5-fluoro-l-indol-3-yl) -cydohexanone (0.77 g, 3.0 mmol), 5- (1-piperazinyl) -benzodioxane (0.78 g, 3.0 mmoles), sodium cyanoborohydride (0.2 g, 3.0 mmol) in methanol (100 ml) was allowed to stir at room temperature for 48 hours. The reaction was quenched with potassium hydroxide (0.4 g). The methanol was removed under vacuum, the residue was extracted with ethyl acetate (3 x 100 ml) and washed with water. The organic layer was dried over anhydrous magnesium sulfate and filtered. Chromatography (1% methanol-ethyl acetate) yielded 0.24 g (18%) of product as a yellow solid. The HCl salt was prepared in ethanol: m.p. 228-230 ° C. Elemental analysis for C26H3oFN302 * 2HCl * 0.6C2H60 Calculated: C, 61.37; H, 6.38; N, 8.22 Found: C, 61.19; H, 6.32; N, 8.29 EXAMPLE 25b 3-. { (1, 4-trans-) -4- [4- (2,3-Dihydro-benzo [1,4] dioxin-5-l) -piperazin-1-yl] -cyclohexyl} -6-fluoro-lH-indole The trans compound was isolated at the same time as the cis isomer in 8% yield (0.11 g) as an oil. The HCl salt was prepared in ethanol: m.p. 309-310 ° C. Elemental analysis for C26H3oF02N3 «> 2HCl * 0.08C4H8O2 Calculated: C, 61.42; H, 6.34; N, 8.26 Found: C, 61.22; H, 6.19; N, 8.13 EXAMPLE 26a 3-. { (1, 4-cis) -4- [4- (2, 3-Dihydro-benzo [1,4] dioxin-5-yl) -piperazin-1-yl] -cyclohexyl} -1H-Indole-5-carbonitrile A solution of 4- (5-cyano-l-indol-3-yl) -cydohexanone (0.60 g, 2.5 mmol), 5- (1-piperazinyl) -benzodioxane (0.55 g, 2.5 mmoles), sodium triacetoxyborohydride (0.78 g, 3.5 mmol) and acetic acid (0.14 g, 2.5 mmol) in 1,2-dichloroethane (11 ml) was allowed to stir at room temperature for 12 hours. The reaction was quenched with sodium hydroxide (100 ml), extracted with methylene chloride (3 x 100 ml). The organic layer was dried over anhydrous magnesium sulfate and filtered. Chromatography (1% methanol-ethyl acetate) yielded 0.46 g (41%) of product. The HCl salt was prepared in ethyl acetate: m.p. 300 ° C. Elemental analysis for C27H30N4O2 »HCl * 0.07C4H8O2 Calculated: C, 65.84; H, 6.65; N, 11.38 Found: C, 65.65; H, 6.47; N, 11.11 EXAMPLE 26b 3-. { (1,4-trans-) -4- [4- (2,3-Dihydro-benzo [1,4] dioxin-5-yl) -piperazin-1-yl] -cyclohexyl} -lH-indole-5-carbonitrile The trans compound was isolated at the same time as the cis isomer in 31% yield (0.34 g). The HCl salt was prepared in ethyl acetate: m.p. 300 ° C (decomposed). Elemental analysis for C27H3o02N4 »HCl * 0.08C H8O2 Calculated: C, 66.43; H, 6.69; N, 11.34 Found: C, 66.57; H, 7.02; N, 10.85 EXAMPLE 27a 8-. { 4- [(1,4-cis) -4- (5-Fluoro-lH-indol-3-yl) -cyclohexyl] -piperazin-1-yl} -quinoline A solution of 4- (5-fluoro-l-indol-3-yl) -cycothexanone (0.54 g, 2.3 mmol), 8- (piperazin-1-yl) -quinoline (0.5 g, 2.3 mmol), triacetoxyborohydride Sodium (0.75 g, 3.5 mmol) and acetic acid (0.27 ml, 4.7 mmol) in 1,2-dichloroethane (20 ml) was allowed to stir at room temperature overnight. The reaction was quenched with sodium hydroxide (20 ml), extracted with methylene chloride (3 x 100 ml) and washed with brine (3 x 100 ml). The organic layer was dried over anhydrous sodium sulfate and filtered. Chromatography (5% methanol-ethyl acetate) yielded 0.46 g (46%) of product as a white solid: m.p. 122-125 ° C. The HCl salt was prepared in ethanol: m.p. 209-212 ° C. Elemental analysis for C2 H29FN4 * 3HCl Calculated: C, 66.28; H, 6.00; N, 10.42 Found: C, 60.23; H, 6.29; N, 10.21 EXAMPLE 27b 8-. { 4- [(1, 4-trans-) -4- (5-Fluoro-lH-indol-3-yl) -cyclohexyl] -piperazin-1-yl} -quinoline The trans compound was isolated at the same time as the cis isomer in 25% yield (0.25 g) as a white solid: m.p. 207.5-209 ° C. The HCl salt was prepared in ethanol: m.p. 286-288 ° C. Elemental analysis for C27H29FN4 «Calculated HC1: C, 64.67; H, 6.23; N, 11.17 Found: C, 64.74; H, 6.27; N, 11.06 EXAMPLE 28 8-. { 4- (1,4-cis) -4- [4- (5-Fluoro-l-methyl-lH-indol-3-yl) -cyclohexyl] -piperazin-1-yl} -quinoline To a suspension of sodium hydride (60%, 0.03 g, 0.76 mmol) in anhydrous N, N-dimethylformamide (4 ml) was added 8-. { 4 - [(1, 4-cis) -4 - (5-fluoro-lH-indol-3-yl) -cyclohexyl] -piperazin-1-yl} -quinoline (0.25 g, 0.58 mmole ') in 6 ml of anhydrous N, N-dimethylformamide at room temperature. The mixture was stirred at room temperature for 30 minutes, then iodomethane (0.044 ml, 0.7 mmol) was added to the previous solution. The resulting mixture was stirred at room temperature for 30 minutes, and quenched with water. The mixture was extracted with ethyl acetate and the organic layer was dried over anhydrous sodium sulfate. The solvent was removed under vacuum. Chromatography (50% methylene-ethyl acetate plus 5% methanol) yielded 0.22 g (85%) of product as a yellow solid: m.p. > 200 ° C. The HCl salt was prepared in ethanol: m.p. 261-263.5 ° C. Elemental analysis for C28H3? FN »2HCl * H20 Calculated: C, 63.03; H, 6.61; N, 10.50 Found: C, 63.39; H, 6.43; N, 10.21 EXAMPLE 29a 3- [(1,4-cis) -4- (4-Quinolin-8-yl-piperazi? -l-yl) -cyclohexyl] -lH-indole-5-carbonitrile A solution of 4- (5-cyano-l-indol-3-yl) -cydohexanone (1.47 g, 6.2 mmol), 8- (piperazin-1-yl) -quinoline (1.32 g, 6.2 mmol), sodium triacetoxyborohydride (2.0 g, 7.2 mmoles) and acetic acid (0.71 ml, 12 mmol) in 1,2-dichloroethane (40 ml) was allowed to stir at room temperature overnight. The reaction was quenched with sodium hydroxide (20 ml), extracted with methylene chloride (3 x 100 ml) and washed • with brine (3 x 100 ml). The organic layer was dried over anhydrous sodium sulfate and filtered. Chromatography (5% methanol-ethyl acetate) afforded 1.48 g (55%) of product as a white solid: m.p. 149-151 ° C. The HCl salt was prepared in ethanol: m.p. 209-212 ° C. Elemental analysis for C27H29FN4 * 2HC1 »0.75H20 Calculated: C, 64.43; H, 6.28; N, 13.58 Found: C, 64.46; H, 6.29; N, 13.37 EXAMPLE 29b 3- [(1, 4-trans-) -4- (4-Quinolin-8-yl-piperazin-1-yl) -cyclohexyl] -1H-indol-5-carbonitrile The trans compound was isolated at the same time as the cis isomer in 26% yield (0.55 g) as a white solid: mp 276-278 ° C. The HCl salt in ethanol was prepared: m.p. 286-288 ° C. Elemental analysis for C27H29FN4 »2HC1« 0.5H20 Calculated: C, 64.98; H, 6.23; N, 13.53 Found: C, 65.28; H, 5.96; N, 13.30 EXAMPLE 30 1 -Methyl-3- [(1,4-cis) -4- (4-quinolin-8-yl-piperazin-1-yl) -cyclohexyl] -lH-indole-5-carbonitrile To a hydride suspension Sodium (60%, 0.06 g, 1.4 mmol) in anhydrous N, -dimethylformamide (8 ml) was added 3- [(1,4-cis) -4- (4-quinolin-8-yl-piperazin-1) -yl) -cyclohexyl] -lH-indole-5-carbonitrile (0.30 g, 0.69 mmol) in 4 ml of anhydrous N, N-dimethylformamide at room temperature. The mixture was stirred at room temperature for 30 minutes, followed by the addition of iodomethane (0.051 mL, 0.83 mmol) to the above solution. The resulting mixture was stirred at room temperature for 30 minutes and quenched with water. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was removed under vacuum. Chromatography (50% methylene-ethyl acetate plus 5% methanol) yielded 0.27 g (90%) of product as a light yellow solid: m.p. 208-209 ° C. The HCl salt was prepared in ethanol: m.p. 288-289 ° C. Elemental analysis for C29H3? N5 * 2HCl »0.15C4H10O Calculated: C, 66.62; H, 6.52; N, 13.12 Found: C, 66.79; H, 6.74; N, 12.81 EXAMPLE 31a 5-Fluoro-3-. { (1,4-cis) -4- [4- (6-fluoro-chroman-8-yl) -piperazin-1-yl] -cyclohexyl} -lH-indole A solution of 4- (5-fluoro-l-indol-3-yl) -cydohexanone (0.49 g, 2.1 mmol), 4- (6-fluoro-chroman-8-yl) -piperazine (0.5 g) , 2.1 mmol), sodium triacetoxyborohydride (0.67 g, 3.2 mmol) and acetic acid (0.24 mL, 4.2 mmol) in 1,2-dichloroethane (20 mL) was allowed to stir at room temperature overnight. The reaction was quenched with sodium hydroxide (20 ml), extracted with methylene chloride (3 x 100 ml) and washed with brine (3 x 100 ml). The organic layer was dried over anhydrous sodium sulfate and filtered. Chromatography (5% methanol-ethyl acetate) yielded 0.42 g (44%) of product as a white foam. The HCl salt was prepared in ethanol: m.p. 199-200.5 ° C. Elemental analysis for C27H3? F2ON3 »HCl * 0.5H20 Calculated: C, 65.25; H, 6.69; N, 8.45 Found: C, 65.04; H, 6.61; N, 8.29 EXAMPLE 31b 5-Fluoro-3-. { (1, 4-trans) -4- [4- (6-fluoro-chroman-8-yl) -piper zin-1-yl] -cyclohexyl} -1H-indole The trans compound was isolated at the same time as the cis isomer in 35% yield (0.33 g) as a clear oil. The HCl salt was prepared in ethanol: m.p. 286-288 ° C. Elemental analysis for C27H3? F2ON3 «HCl * 0.5H20 Calculated: C, '65.25; H, 6.69; N, 8.45 Found: C, 65.09; H, 6.63; N, 8.29 EXAMPLE 32a 5-Fluoro-3-. { (1, 4-cis) -4- [4- (5-fluoro-2, 3-dihydro-benzo-uran-7-yl) -piperazin-1-yl] -cyclohexyl} -lH-indole A solution of 4- (5-fluoro-l-indol-3-yl) -cydohexanone (0.52 g, 2.2 mmol), 4- (5-fluoro-2,3-dihydro-benzofuran-7-yl) -piperazine ( 0.5 g, 2.2 mmol), sodium triacetoxyborohydride (0.72 g, 3.4 mmol) and acetic acid (0.26 mL, 4.5 mmol) in 1,2-dichloroethane (20 mL) was allowed to stir at room temperature overnight. The reaction was quenched with sodium hydroxide (20 ml), extracted with methylene chloride (3 x 100 ml) and washed with brine (3 x 100 ml). The organic layer was dried over anhydrous sodium sulfate and filtered. Chromatography (5% methanol-ethyl acetate) yielded 0.37 g (38%) of product as a white solid: m.p. 182-183.5 ° C. The HCl salt was prepared in ethanol: m.p. 196-198 ° C. Elemental analysis for C26H29F2ON3 * HC1 «0.5H20 Calculated: C, 64.65; H, 6.47; N, 8.70 Found: C, 64.45; H, 6.20; N, 8.60 EXAMPLE 32b 5-Fluoro-3-. { (1, 4-trans) -4- [4- (5-fluoro-2,3-dihydrobenzo-uran-7-yl) -piperazin-1-yl] -cyclohexyl} -lH-indole The trans compound was isolated at the same time as the cis isomer in 34% yield (0.34 g) as a clear oil. The HCl salt was prepared in ethanol: m.p. 303-305 ° C. Elemental analysis for C26H29F2ON3 «HC1« 0.5H20 Calculated: C, 64.65; H, 6.47; N, 8.70 Found: C, 64.86; H, 6.40; N, 8.36 EXAMPLE 33a 3-. { (1,4-cis) -4- [4- (5-Fluoro-2,3-dihydro-benzofuran-7-yl) -piperazin-1-yl] -cyclohexyl} -lH-indole-5-carboni trilo A solution of 4- (5-cyano-l-indol-3-yl) -cycothexanone (0.46 g), 1.9 mmol), 4- (5-fluoro-2, 3-dihydro-benzofuran-7-yl) -piperazine (0.43 g, 1.9 mmol), sodium triacetoxyborohydride (0.62 g, 2.9 mmol) and acetic acid (0.22 ml. , 3.9 mmol) in 1,2-dichloroethane (20 ml) was allowed to stir at room temperature overnight. The reaction was quenched with sodium hydroxide (20 ml), extracted with methylene chloride (3 x 100 ml) and washed with brine (3 x 100 ml). The organic layer was dried over anhydrous sodium sulfate and filtered. Chromatography (5% methanol-ethyl acetate) yielded 0.35 g (41%) of product as a white foam. The HCl salt was prepared in ethanol: m.p. 298-301 ° C. Elemental analysis for C27H29FON4 «HC1 * 0.75H20 Calculated: C, 65.58; H, 6.42; N, 11.33 Found: C, 65.38; H, 6.22; N, 11.14 EXAMPLE 33b 3-. { (1, -trans) -4- [4- (5-Fluoro-2, 3-dihydro-benzofuran-7-yl) -piperazin-1-yl] -cyclohexyl} -lH-indole-5-carbonitrile The trans compound was isolated at the same time as the cis isomer in 23% yield (0.20 g) as a white foam.
The HCl salt was prepared in ethanol: m.p. 330-331 ° C. Elemental analysis for C27H29FON * HC1 »0.75H20 Calculated: C, 65.58; H, 6.42; N, 11.33 Found: C, 65.17; H, 6.14; N, 10.97 EXAMPLE 33c 3- [(1, 4-cis) -4- [4- (5-Fluoro-2, 3-dihydro-benzofuran-7-yl) -piperazin-1-yl] -cyclohexyl} -l-methyl-lH-indole-5-carbonitrile To a suspension of sodium hydride (60%, 0. 036 g, 0.9 mmol) in N, N-dimethyl-formamide anhydrous (2 ml) was added 3-. { (1,4-cis) -4- [4- (5-fluoro-2,3-dihydro-benzofuran-7-yl) -piperazin-1-yl] -cyclohexyl] -lH-indole-5-carbonitrile (0.2 g, 0.45 mmole) in 6 ml of anhydrous N, N-dimethylformamide at room temperature. The mixture was stirred at room temperature for 30 minutes, followed by the addition of iodomethane (0.034 ml, 0.54 mmole) to the previous solution. The resulting mixture was stirred at room temperature for 30 minutes and quenched with water. The mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. The solvent was removed under vacuum. Chromatography (5% methanol-ethyl acetate) yielded 0.18 g (87%) of product as a white solid: m.p. 207-208 ° C.
The HCl salt was prepared in ethanol: m.p. 282-284 ° C Elemental analysis for C28H3? FON4 * HCl Calculated: C, 67.94; H, 6.52; N, 11.32 Found: C, 67.61; H, 6.39; N, 10.98 EXAMPLE 34a 3- [(1,4-cis) -4- [4- (Benzofuran-7-yl-piperazin-1-yl) -cyclohexyl] -lH-indole-5-carbonitrile A solution of 4- (5- fluoro-l-indol-3-yl) -cydohexanone (0.72 g, 3.1 mmol), 1- (7-benzo-furanyl) -piperazine (0.55 g, 2.8 mmol), sodium triacetoxyborohydride (0.84 g, 3.9 mmol) and Acetic acid (0.18 ml, 2.8 mmol) in 1,2-dichloroethane (80 ml) was allowed to stir at room temperature overnight. The reaction was quenched with 0.5 N sodium hydroxide (100 ml), extracted with methylene chloride (2 x 100 ml). The organic layer was dried over anhydrous magnesium sulfate and filtered. The solvent was removed, after 1 hour crystals appeared. The crystals were triturated with ethyl ether (80 ml) to yield 0.47 g (35%) of product as a white solid: m.p. 158-159 ° C. The HCl salt was prepared in ethanol: m.p. 295-296 ° C. Elemental analysis for C27H28? N »HCl * 0.25H20 Calculated: C, 6.9.66; H, 6.39; N, 12.04 Found: C, 69.56; H, 6.38; N, 12.12 EXAMPLE 34b 3- [(1, 4-trans) -4- [4- (Benzofuran-7-yl-piperazin-1-yl) -cyclohexyl] -1H-indole-5-carbonitrile The remaining residue of the The above reaction was purified by chromatography (acetone-methane-hexanes: 3: 5: 3) to yield 0.17 g (12%) of product as a glass. The HCl salt was prepared in ethanol: m.p. 330-331 ° C. Elemental analysis for C27H28F0N «? C1« O.75H20 Calculated: C, 65.58; H, 6.42; N, 11.32 Found: C, 65.17; H, 6.14; N, 10.97 EXAMPLE 35 5-Fluoro-3-. { 4- [4- (2-methoxy-phenyl) -piperazxn-1-yl] -cyclohex-1-enyl} -1H-indole This compound was prepared in the manner described above by Example 18 by replacing 4- (5-fluoro-l-indol-3-yl) -cydohexanone (1.71 g, 7.9 mmol) with 4- (5-fluoro) -l-indol-3-yl) -cyclohex-3-enone in a yield of 32% (0.26 g). The HCl salt was prepared in ethyl acetate: m.p. 250 ° C. Elemental analysis for C25H280FN3 * HC1 Calculated: C, 67.94; H, 6.61; N, 9.51 Found: C, 66.47; H, 6.58; N, 9.38 EXAMPLE 36 3-. { 4- [4- (lH-Indol-4-yl) -piperazin-1-yl] -cyclohex-1-enyl} -lH-indole-5-carbonitrile This compound was prepared in the manner described above by Example 18 by replacing it with 4- (5-cyano-lH-3-indolyl) -cyclohex-3-enone in 62% yield ( 0.78 g). The HCl salt was prepared in ethyl acetate: m.p. 199-201 ° C. Elemental analysis for C27H27N5 * 2HC1 Calculated: C, 66.25; H, 6.49; N, 14.31 Found: C, 66.43; H, 6.24; N, 14.27 EXAMPLE 38 5-Fluoro-3-. { cis-4- [4- (lH-indol-4-yl) -piperazinyl] -cyclohexyl} -1-methyl-lH-indole This compound was prepared in the manner described above by Example 18 by replacing 4- (5-fluoro-lH-3-indolyl) -cyclohexone with 4- (5-fluoro-1-methyl- 3-indolyl) -cyclohexone in (0.34 g, 1.4 mmol) in a yield of 34% (0.24 g) as a clear oil. The HCl salt was prepared in ethanol: m.p. 247-249 ° C. Elemental analysis for C27H3? FN4 * 2HCl »0.25H20 Calculated: C, 63.84; H, 6.65; N, 11.03 Found: C, 63.88; H, 6.51; N, 10.77 EXAMPLE 39a 3-. { (1,4-cis) -4- [4- (Quinoxalin-yl) -piperazin-1-yl] -cyclohexyl} -1-methyl-1H-indole-5-carbonitrile A solution of 4- (5-cyano-lH-3-indolyl) -cycothexanone (443 mg, 1.87 mmol), Intermediate 34 (400 mg, 1.87 mmol), acetic acid (0.22 ml, 3.7 mmol), and sodium triacetoxyborohydride (590 mg, 2.8 mmol) in dichloroethane (50 ml) was stirred at room temperature overnight. The reaction was quenched with 1 M NaOH (100 mL) and extracted into CH2C12 (3 x 100 mL). The organic fractions were combined, dried over Na 2 SO, and filtered. The resulting oil was purified by column chromatography (5% MeOH / EtOAc) yielding 130 mg (16%) of the product as a yellow solid: m.p. 223-225 ° C. Elemental analysis for C27H28N6 * 1H20 Calculated: C, 71.34; H, 6.65; N, 18.49 Found: C, 71.02; H, 6.33; N, 18.03 EXAMPLE 39b 3-. { (1,4-trans) -4- [4- (Quinoxalin-yl) -piperazin-1-yl] -cyclohexyl} -1-methyl-1H-indole-5-carbonitrile The trans isomer was isolated at the same time as the cis isomer yielding 240 mg (29%) of a pale yellow solid: m.p. 257-259 ° C.
Elemental analysis for C27H28N6 * 1H20 Calculated: C, 71.34; H, 6.65; N, 18.49 Found: C, 71.63; H, 6.38; N, 18.39 EXAMPLE 40a 3- [(1, 4-trans) -4- (Quinolin-5-yl-piperazin-1-yl) -cyclohexyl] -1H-indol-5-carbonitrile A 'a solution of 5- (1-piperazinyl) ) -quinoline (500 mg, 2.35 mmol), 4- (5-cyano-lH-3-indolyl) -cycothexanone (540 mg, 2.35 mmol), and sodium triacetoxyborohydride (740 mg, 3.5 mmol) in dichloroethane (20 ml) Acetic acid (0.27 ml, 4.7 mmol) was added and stirred overnight at room temperature. The reaction was quenched with 1 M NaOH (50 mL) and extracted into CH2C12 (3 x 100 mL). The organic fractions were combined, dried over Na 2 SO, concentrated, filtered and subjected to chromatography (5% MeOH / EtOAc) yielding 410 mg (41%) of the cis isomer as a white solid. The HCl salt was generated from EtOAc yielding a white solid: m.p. 220-223 ° C. Elemental analysis for C28H29N5 * HC1 »1H20 Calculated: C, 68.62; H, 6.58; N, 14.29 Found: C, 68.99; H, 6.54; N, 14.06 EXAMPLE 40b 3- [(1, 4-trans) -4- (4-Quinolin-5-yl) -piperazin-1-yl) -cyclohexyl] -1H-indole-5-carbonitrile The trans isomer was isolated at the same time as the cis isomer in Example 40a yielding 180 mg (18%) as a beige solid: The HCl salt was generated from EtOAc yielding a white solid: mp 210-211 ° C. Elemental analysis for C28H29N5 »HC1» 0.4H20 Calculated: C, 70.17; H, 6.48; N, 14.62 Found: C, 70.23; H, 6.21; N, 14.45 EXAMPLE 40c 5-. { 4- [(1,4-cis) -4- (5-Fluoro-lH-indol-3-yl) -cyclohexyl] -piperazin-1-yl} -quinoline This compound was prepared in the same manner as the compound in Example 40a by replacing 4- (5-cyano-lH-3-indolyl) -cycothexanone with 4- (5-fluoro-lH-3-indolyl) -cycothexanone. (540 mg, 2.35 mmol) to yield 410 mg (41%) of a pale yellow solid: mp 220-223 ° C; MS (+) ESI m / e 429 [M + H]? EXAMPLE 40d 5-. { 4- [(1,4-trans) -4- (5-Fluoro-lH-indol-3-yl) -cyclohexyl] -piperazin-1-yl} Isoquinoline The trans isomer was isolated at the same time as the cis isomer of Example 40c as the cis isomer of Example 40c yielding 180 mg (18%) as a white solid: m.p. 210-211 ° C; MS (+) ESI m / e 429 [M + H]? EXAMPLE 40e 5-. { 4- [(1,4-cis) -4- (5-Fluoro-l-methyl-lH-indol-3-yl) -cyclohexyl] -piperazin-1-yl} -quinoline To a solution of NaH (38 mg, 0.94 mmole) in anhydrous DMF (4 ml) under a nitrogen atmosphere was added a solution of 5-. { 4 - [(1,4-cis) - A - (5-fluoro-lH-indol-3-yl) -cyclohexyl] -piperazin-1-yl} -quinoline (200 mg, 0.47 mmol) in DMF (6 ml). The mixture was stirred at room temperature 0.5 hours after Mel (0.035 ml, 0.56 mmole) was added via syringe. The reaction mixture was stirred an additional 0.5 hours and then quenched with H20 (50 ml) and extracted with EtOAc (3 x 50 ml). The organic fractions were combined, dried over Na 2 SO and concentrated to yield 190 mg (92%) of a clear oil. The HCl salt was made of EtOAc yielding a pale yellow solid: m.p. decomposed >270 ° C. Elemental analysis for C28H3? FN4 »HCl * 0.75H20 Calculated: C, 68.28; H, 6.86; N, 11.37 Found: C, 68.34; H, 6.56; N, 11.26 EXAMPLE 41a 5-Fluoro-3- [(1,4-cis) -4- (4-naphthalen-1-yl-piperazin-1-yl) -cyclohexyl] -lH-indole This compound was prepared in the same form as the compound of Example 40a by replacing 4- (5-cyano-lH-3-indolyl) -cciohexanone with 4- (5-fluoro-lH-3-indolyl) -cidiohexanone (437 mg, 1.9 mmol) and - (1-piperazinyl) -quinoline with 1- (1-naphthyl) piperazine (410 mg, 1.9 mmol) yielding 240 mg (29%) of the product as a white solid: mp 195-197 ° C. Elemental analysis for C28H30FN3 Calculated: C, 78.66; H, 7.07; N, 9.83 Found: C, 78.24; H, 7.06; N, 9.59 EXAMPLE 41b 5-Fluoro-3- [(1,4-trans) -4- (4-naphthalen-1-yl-piperazin-1-yl) -cyclohexyl] -lH-indole The trans isomer was isolated at the same time as the cis isomer of Example 41a yielding 70 mg (9%) of a white solid: mp 179-181 ° C. Elemental analysis for C28H3oFN3 Calculated: C, 78.66; H, 7.07; N, 9.83 Found: C, 78.28; H, 7.05; N, 9.79 EXAMPLE 42a 5-. { 4- [(1,4-cis) -4- (5-fluoro-lH-indol-3-yl) -cyclohexyl] piperazin-1-yl} Isoquinoline This compound was prepared in the same manner as described by the compound of Example 36a by replacing 5- (trifluoromethylsulfonyloxy) -quinoline with 5- (trifluoromethylsulfonyloxy) -isoquinoline (12 g, 43.3 mmol) to produce an inseparable mixture of the product desired and impurities. The mixture was treated with TFA (10 ml), MeOH (10 drops), and CH2C12 (20 ml) at 0 ° C and was warmed to room temperature overnight. The resulting solution was concentrated and then redissolved in CH2C12 and neutralized with NaHCO3. The aqueous layer was extracted into CH2C12 (3 x 100 ml) and EtOAc (3 x 100 ml), dried over Na2SO4, filtered and concentrated to give a bright orange oil. The oil was purified twice by column chromatography (10% MeOH / CH2Cl2 / NH OH) but a very high color impurity is persisted. 5- (1-piperazinyl) -isoquinoline (450 mg, 2.1 mmol), 4- (5-fluoro-lH-3-indolyl) -cycothexanone (485 mg, 2.1 mmol) and sodium triacetoxyborohydride (672 mg, 3.2 mmol) ) were dissolved in dichloroethane (30 ml). Acetic acid (0.25 ml, 4.2 mmol) was added and the resulting solution was stirred at room temperature overnight. The reaction mixture was quenched with 1 M NaOH (40 ml) and extracted into CH2C12 (4 x 100 ml). The organic fractions were combined, dried over Na 2 SO 4 and concentrated to yield a yellow oil which was purified by column chromatography (5% MeOH / EtOAc) yielding 300 mg (33% of 5- (1-piperazinyl) isoquinoline) of the compound of the title as a beige solid: pf 209-211 ° C. Elemental analysis for C27H29FN4 Calculated: C, 75.67; H, 6.82; N, 13.07 Found: C, 75.40; H, 6.83; N, 12.89 EXAMPLE 42b 5-. { 4 [(1, -trans) -4- (5-luoro-lH-indol-3-yl) -cyclohexyl] piperazin-1-yl} Isoquinoline The trans isomer was isolated at the same time as the cis isomer of Example 42a yielding 110 mg (12%) of a pale pink solid: m.p. 218-221 ° C. Elemental analysis for C27H29FN4 «> 0.25H20 Calculated: C, 74.89; H, 6.87; N, 12.94 Found: C, 74.79; H, 6.79; N, 12.85 EXAMPLE 43a l. { 4- [(1,4-cis) -4- (5-Fluoro-1H-indol-3-yl) -cyclohexyl] -piperazin-1-yl} Isoquinoline This compound was prepared in the same manner as the compound of Example 40a by replacing 4- (5-cyano-lH-3-indolyl) -cycothexanone with 4- (5-fluoro-lH-3-indolyl) -cycothexanone ( 530 mg, 2.3 mmol) and 5- (l-piperazinyl) -quinoline with 1- (1-piperazinyl) -isoquinoline (500 mg, 2.3 mmol) yielding 260 mg (27%) of the product as a pale yellow solid: mp 180-18'3 ° C. Elemental analysis for C2 H29FN4 * 0.5H20 Calculated: C, 74.11; H, 6.91; N, 12.81 Found: C, 74.13; H, 6.58; N, 12.60 EXAMPLE 43b l-. { 4- [(1, -trans) -4- (5-Fluoro-1H-indol-3-yl) -cyclohexyl] -piperazin-1-yl} Isoquinoline The trans isomer was isolated at the same time as the cis isomer of Example 43a yielding 180 mg (18%) of a white solid: m.p. 232-235 ° C. Elemental analysis for C2 H2gFN »0.25H20 Calculated: C, 74.89; H, 6.87; N, 12.94 Found: C, 74.68; H, 6.88; N, 12.64 EXAMPLE 43c l-. { 4- [(1,4-cis) -4- (5-Cyano-lH-indol-3-yl) -cyclohexyl] -piperazin-1-yl} Isoquinoline This compound was prepared in the same manner as the compound of Example 40a by replacing 5- (l-piperazinyl) -quinoline with 1- (1-piperazinyl) -isoquinoline (500 mg, 2.3 mmol) yielding 230 mg (23%) ) of the product as a pale yellow solid: mp 107-109 ° C; EMAR The m / e 435.2431 (M +).
EXAMPLE 43d l-. { 4- [(1,4-trans) -4- (5-Cyano-lH-indol-3-yl) -cyclohexyl] -piperazin-1-yl} Isoquinoline The trans isomer was isolated at the same time as the cis isomer of Example 43c yielding 170 mg (17%) of a white solid: m.p. 252-255 ° C; MS (+) APCI m / e 436 (M + H)? EXAMPLE 44a 8-. { (1,4-cis) -4- [4- (5-Fluoro-lH-indol-3-yl) -cyclohexyl] -piperazin-1-yl} -6-methoxy-quinoline To a solution of 0.360 g of 6-methoxy, 8-piperazino-quinoline in 10 ml of CH2C12, (0.285 g of 4- (5-fluoro-lH-3-indolyl) -cycothexanone was added. by 0.625 g of sodium triacetoxyborohydride and 0.09 ml of acetic acid.The reaction was stirred at room temperature overnight.It was rapidly cooled with 1 N NaOH, and the product was extracted with CH2C12.The organic phase was washed with water and dried over magnesium sulfate The product was filtered through 75 ml of silica gel using 50% ethyl acetate / hexanes, 75% ethyl acetate / hexanes, and finally 100% ethyl acetate to give 0.053 g of the desired product: mp 226-227 ° C; MS (ES) m / z (relative intensity): 459 (M + H +, 100).
EXAMPLE 44b l-. { (1,4-trans) -4- [4- (5-Fluoro-lH-indol-3-yl) -cyclohexyl] -piperazin-1-yl} -6-methoxy-quinoline The trans isomer of the compound of Example 44a was isolated at the same time as the cis isomer as an off-white solid (0.013 g), m.p. 207-215 ° C. MS (ES) m / z (relative intensity): 459 (M + H +, 100).
EXAMPLE 44c 3-. { (1, 4-cis) -4- [4- (6-Methoxy-quinolin-8-yl) -piperazin-1-yl] -cyclohexyl} -1H-Indole-5-carbonitrile To a solution of 1.0 g of 6-methoxy, 8-piperazino-quinoline in 20 ml of CH2C12, 0.979 g of 3- (4-oxo-cyclohexyl) -lH-indole-5 was added. -carboni trilo followed by 1.3 g of sodium triacetoxyborohydride and 0.246 ml of acetic acid. The reaction was stirred at room temperature overnight. It was quenched with 1N NaOH, and the product was extracted with CH2C12. The organic phase was washed with water and dried over magnesium sulfate. The product was filtered through 300 ml of silica gel using 2.5% MeOH / CH2Cl2 to give 0.550 g of the desired product: m.p. 183-185 ° C; MS (ES) m / z (relative intensity): 466 (M + H +, 100). The hydrochloride was also prepared to give a yellow solid, m.p. 183-185 ° C.
EXAMPLE 44d 3-. { (1, 4-trans) -4- [4- (6-Methoxy-quinolin-8-yl) -piperazin-1-yl] -cyclohexyl} -1H-Indole-5-carbonitrile The trans isomer of the compound of Example 44c was isolated at the same time as the cis isomer as an off-white solid (0.170 g), m.p. 148-152 ° C. MS (ES) m / z (relative intensity): 466 (M + H +, 100). The maleic acid salt was prepared to give an off-white solid (0.129 g). p.f. 160-165 ° C.
EXAMPLE 45a 6-Chloro-8-. { 4- [(1,4-cis) -4- (5-luoro-lH-indol-3-yl) -cyclohexyl] -piperazin-1-yl} -quinoline To a solution of 0.200 g of 6-chloro, 8-piperazino-quinoline in 10 ml of CH2C12, 0.266 g of 4- (5-fluoro-lH-3-indolyl) -cidiohexanone was added followed by 0.430 g of triacetoxyborohydride. of sodium and 0.09 ml of acetic acid. The reaction was stirred at room temperature overnight. It was quenched with 1N NaOH, and the product was extracted with CH2C12. The organic phase was washed with water and dried over magnesium sulfate. The product was filtered through 75 ml of silica gel using 50% ethyl acetate / hexanes, and then 75% ethyl acetate / hexanes, to give 0.119 g of the desired product: m.p. 166-176 ° C; MS (ES) m / z (relative intensity): 464 (M + H +, 100). Elemental analysis for C27 H28 Cl F N4 Calculated: C: 70.04; H: 6.1; N: 12.1 Found: C: 70.07; H: 6.33; N: 11.87 EXAMPLE 45b 6-Chloro-8-. { 4- [(1, 4-trans) -4- (5-fluoro-lH-indol-3-yl) -cyclohexyl] -piperazin-1-yl} -quinoline The trans isomer of the compound of Example 45a _ was isolated at the same time as the cis isomer as an off-white solid (0.026 g), m.p. 209-210 ° C. MS (ES) m / z (relative intensity): 464 (M + H + 100). Elemental analysis for C2 H28 Cl F N Calculated: C: 70.04; H: 6.1; N: 12.1 Found: C: 70.23; H: 6.33; N: 11.94 EXAMPLE 45c 3-. { (1,4-cis) -4- [4- (6-Chloro-quinolin-8-yl) -piperazin-1-yl] -cyclohexyl} -lH-indole-5-carbonitrile To a solution of 0.250 g of 6-chloro, 8-piperazino-quinoline in 10 ml of CH2C12, 0.240 g of 3- (4-oxo-cyclohexyl) -lH-indole-5 was added. -carboni trilo followed by 0.532 g of sodium triacetoxyborohydride and 0.09 ml of acetic acid. The reaction was stirred at room temperature overnight. It was quenched with 1 N NaOH, and the product was extracted with ether. The organic phase was washed with water and dried. The product was filtered through 75 ml of silica gel using 25% ethyl acetate / hexanes, and then 75% ethyl acetate / hexanes, to give 0.123 g of the desired product: m.p. 152-160 ° C; MS (ES) m / z (relative intensity): 471 (M + H +, 100).
EXAMPLE 45d 3-. { (1, 4-trans) -4- [4- (6-Chloro-quinolin-8-yl) -piperazin-1-yl] -cyclohexyl} -lH-indole-5-sarbonitrile The trans isomer of the compound of Example 45c was isolated at the same time as the cis isomer as an off-white solid (0.032 g), m.p. 144-152 ° C. MS (ES) m / z (relative intensity): 471 (M + H + 100).
EXAMPLE 46a 5-Chloro-8-. { 4- [(1,4-cis) -4- (5-luoro-lH-indol-3-yl) -cyclohexyl] -piperazin-1-yl} -quinoline To a solution of 0.250 g of 5-chloro, 8-piperazino-quinoline in 10 ml of CH2C12, 0.200 g of 4- (5-fluoro-lH-3-indolyl) -cidiohexanone was added followed by 0.533 g of triacetoxyborohydride. of sodium and 0.09 ml of acetic acid. The reaction was stirred at room temperature overnight. It was quenched with 1 N NaOH, and the product was extracted with ether. The organic phase was washed with water and dried over magnesium sulfate. The product was filtered through 75 ml of silica gel using 25% ethyl acetate / hexanes, 75% ethyl acetate / hexanes, to give 0.074 g of the desired product: m.p. 101-104 ° C; MS (ES) m / z (relative intensity): 464 (M + H +, 100).
EXAMPLE 45b 3-. { (1,4-cis) -4- [4- (5-Chloro-quinolin-8-yl) -piperazin-1-yl] -cyclohexyl} -lH-indole-5-carbonitrile To a solution of 0.300 g of 5-chloro, 8-piperazino-quinoline in 10 ml of CH2C12, was added 0. 230 g of 3- (4-oxo-cyclohexyl) -lH-indole-5-carbonitrile followed by 0.550 g of sodium triacetoxyborohydride and 0.09 ml of acetic acid. The reaction was stirred at room temperature overnight. It was quenched with 1N NaOH, and the product was extracted with CH2C12. The organic phase was washed with water and dried over magnesium sulfate. The product was filtered through 75 ml of silica gel using 50% ethyl acetate / hexanes, 75% ethyl acetate / hexanes and finally 100% ethyl acetate to give 0.051 g of the desired product: m.p. 135-144 ° C; MS (ES) m / z (relative intensity): 471 (M + H +, 100).
EXAMPLE 47a 5-Fluoro-8-. { 4- [(1,4-cis) -4- (6-fluoro-lH-indol-3-yl) -c-clohexyl] -piperazin-1-yl} -quinoline To a solution of 0.231 g of 5-fluoro, 8-piperazino-quinoline in 10 ml of CH2C12, 0.230 g of 4- (6-fluoro-lH-3-indolyl) -cidiohexanone was added followed by 0.530 g of triacetoxyborohydride. of sodium and 0.09 ml of acetic acid. The reaction was stirred at room temperature overnight. It was quenched with 1N NaOH, and the product was extracted with CH2C12. The organic phase was washed with water and dried over magnesium sulfate. The product was filtered through 100 ml of silica gel using 50% ethyl acetate / hexanes, 100% ethyl acetate, then 6% MeOH / ethyl acetate to give 0.049 g of the desired product: m.p. 172-174 ° C; MS (ES) m / z (relative intensity): 447 (M + H +, 100).
EXAMPLE 47b 5-Fluoro-8-. { 4- [(1, 4-trans-4- (6-fluoro-lH-indol-3-yl) -cyclohexyl] -piperazin-1-yl}. -quinoline The trans isomer of the compound of Example 47a was isolated at same time as the cis isomer as an off-white solid (0.055 g) mp 173-175 ° C. MS (ES) m / z (relative intensity): 447 (M + H +, 100).
EXAMPLE 48a 3-. { (1, 4-cis) -4- [4- (2-Methyl-quinolin-8-yl) -piperazin-1-yl] -cyclohexyl} -lH-indole-5-carbonitrile To a solution of 0.230 g of 8-piperazino-quinaldine in 10 ml of CH2C12, 0.238 g of 3- (4-oxo-cyclohexyl) -lH-indole-5-carbonyl trity was added. for 0.527 g of sodium triacetoxyborohydride and 0.09 ml of acetic acid. The reaction was stirred at room temperature overnight. It was quenched with 1N NaOH, and the product was extracted with CH2C12. The organic phase was washed with water and dried over magnesium sulfate. The product was filtered through 100 ml of silica gel using 50% ethyl acetate / hexanes, 100% ethyl acetate and finally 10% MeOH / ethyl acetate to give 0.089 g of the desired product: m.p. 197-199 ° C; MS (ES) m / z (relative intensity): 450 (M + H +, 100).
EXAMPLE 48b 3-. { (1, 4-trans-4- [4- (2-Methyl-quinolin-8-yl) -piperazin-1-yl] -cyclohexyl] -lH-indole-5-carbonitrile The trans-isomer of the compound of Example 48a was isolated at the same time as the cis isomer as an off-white solid (0.058 g) mp 268-280 ° C. MS (ES) m / z (relative intensity): 450 (M + H +, 100).
EXAMPLE 49a 4-. { 4- [(1,4-cis) -4- (5-Fluoro-lH-indol-3-yl) -cyclohexyl] -piperazin-1-yl} -2-trifluoromethyl-quinoline To a solution of 0.281 g of l- [2-trifluoromethyl) quinol-4-yl] piperazine in 10 ml of CH2C12, 0.231 g of 4- (5-fluoro-lH-3-indolyl) -cciohexanone was added followed by 0.528 g of sodium triacetoxyborohydride and 0.09 ml of acetic acid. The reaction was stirred at room temperature overnight. It was quenched with 1 N NaOH, and the product was extracted with ether. The organic phase was washed with water and dried over magnesium sulfate. The product was filtered through 100 ml of silica gel using 25% ethyl acetate / hexanes, 50% ethyl acetate / hexanes, to give 0.089 g of the desired product: m.p. 235-239 ° C; MS (ES) m / z (relative intensity): 497 (M + H +, 100).
EXAMPLE 49b 4-. { 4- [(1, 4-trans-4- (5-Fluoro-lH-indol-3-yl) -cyclohexyl] -piperazin-1-yl) -2-trifluoromethyl-quinoline The trans isomer of the compound of Example 49a was isolated at the same time as the cis isomer as an off-white solid (0.110 g) m.p. 218-223 ° C. MS (ES) m / z (relative intensity): 497 (M + H +, 100).
EXAMPLE 49c 3-. { (1, 4-cis) -4- [4- (2-Trifluoromethyl-quinolin-4-yl) -piperazin-1-yl] -cyclohexyl} -1H-Indole-5-carbonitrile This compound was prepared in the same manner as in Example 49a by replacing 4- (5-fluoro-1-H-3-indolyl) -cydohexanone with 3- (4-oxo-cyclohexyl) -1H-indole-5-carbonitrile to yield 0.137 g of a white solid. P.f. 235-239 ° C; MS (ES) m / z (relative intensity): 504 (M + H +, 100). Elemental analysis for C2g H28 F3 N5 Calculated: C: 69.17; H: 5.6; N: 13.91 Found: C: 68.96; H: 5.37; N: 13.8 EXAMPLE 49d 3-. { (1, 4-trans-4- [4- (2-Trifluoromethyl-quinolin-4-yl) -piperazin-1-yl] -cyclohexyl} -1 H -indole-5-carbonitrile The trans-isomer of the compound of Example 49c was isolated at the same time as the cis isomer as an off-white solid (0.036 g) mp 259-264 ° C. MS (ES) m / z (relative intensity): 504 (M + H +, 100).
EXAMPLE 50a 4-. { 4- [(1,4-cis) -4- (5-Fluoro-IH-indol-3-yl) -cyclohexyl] -piperazin-1-yl} -6-methoxy-quinoline To a solution of 0.280 g of 6-methoxy-4-piperazino-quinoline in 10 ml of CH2C12, 0.230 g of 4- (5- fluoro-1H-3-indolyl) -cycothexanone was added. followed by 0.530 g of sodium triacetoxyborohydride and 0.09 ml of acetic acid. The reaction was stirred at room temperature overnight. It was quenched with 1N NaOH, and the product was extracted with CH2C12. The organic phase was washed with water and dried over magnesium sulfate. The product was filtered through 100 ml of silica gel using 100% ethyl acetate then 10% MeOH / ethyl acetate, to give 0.036 g of the desired product: m.p. 222-227 ° C; MS (ES) m / z (relative intensity): 459 (M + H +, 100).
EXAMPLE 50b 4-. { 4- [(1,4-trans -4- (5-Fluoro-l-indol-3-yl) -cyclohexyl] -piperazin-1-yl) -6-methoxy-quinoline The trans-isomer of the compound of Example 50a is isolated at the same time as the cis isomer as an off-white solid (0.027 g) pf 249-251 ° C. MS (ES) m / z (relative intensity): 459 (M + H +, 100).
EXAMPLE 50c 3-. { (1,4-cis) -4- [4- (6-Methoxy-quinolin-4-yl) -piperazin-1-yl] -cyclohexyl} -lH-indole-5-carbonitrile This compound was prepared in the same manner as in Example 50a by replacing 4- (5-f luoro-1-H-3-indolyl) -cycothexanone with 3- (4-oxo-cyclohexy) 1) - 1H-indole-5-carbonyl trity to yield 0.016 g of a white solid. P.f. 271-272 ° C; MS (ES) m / z (relative intensity): 466 (M + H +, 100).
EXAMPLE 50d 3-. { (1, 4-trans-4- [4- (6-Methoxy-quinolin-4-yl) -piperazin-1-yl] -cyclohexyl] -lH-indole-5-carbonitrile The trans-isomer of the compound of Example 50c was isolated at the same time as the cis isomer as an off-white solid (0.014 g) mp 288-292 ° C. MS (ES) m / z (relative intensity): 466 (M + H +, 100).
EXAMPLE 51a (cis) -3-. { 4- [4- (6-methoxy-2-methylquinolin-8-yl) piperazin-1-yl] cyclohexyl} -l-methyl-lH-indole-5-carbonitrile To a mixture of 4- (6-methoxy-2-methylquinolin-8-yl) piperazine (300 mg, 1.16 mmol), 3- (1-met il-lH- indole-5-carbonitrile) cyclohexan-4-one (440 mg, 1.75 mmol), and sodium triacetoxyborohydride (495 mg, 2. 34 mmoles) in 5 ml of anhydrous THF was added 70 μl (73 mg, 1.22 mmol) of glacial acetic acid. The resulting mixture was stirred at room temperature under N2 for 24 hours. The reaction was treated with saturated aqueous sodium bicarbonate (50 ml), and the aqueous mixture was extracted with CH2C12 (3 x 50 ml). The organic layers were combined, dried over anhydrous Na 2 SO 4, filtered, and concentrated in vacuo. Flash chromatography on 4 x 15 cm Si02 (gradient elution, 50% EtOAc / hex at 100% EtOAc then 5% MeOH / EtOAc) yielded the impure distillation title compound. A second chromatography using the same eluent in 2 x 20 cm of SiO2 yielded 190 mg (33%) of clean product and 140 mg of an impure distillation product. Recrystallization of the clean product from EtOAc / hexane produced 100 mg (17%) of the title compound: m.p. 201-203 ° C. Anál is i s e l l l for C3 j.H35N5O * 0. 1 C4H802 Calculated: C, 75.06; H, 7.18; N, 13.94 Found: C, 75.00; H, 7.32; N, 13.83 EXAMPLE 51b (cis) -3-. { 4- [4- (6-methoxy-3-methylquinolin-8-yl) piperazin-1-yl] cyclohexyl} -1-methyl-1H-indole-5-carbonitrile To a mixture of 4- (6-methoxy-3-methylquinolin-8-yl) piperazine (210 mg, 0.82 mmol), 3- (1-methyl-1H-indole -5-carbonitrile) cyclohexan-4-one (330 mg, 1.31 mmol), and sodium triacetoxyborohydride (435 mg, 2. 05 mmoles) in 5 ml of anhydrous THF was added 55 μl (68 mg, 0.96 mmol) of glacial acetic acid. The resulting mixture was stirred at room temperature under N2 for 24 hours. The reaction was treated with saturated aqueous sodium bicarbonate (50 ml), and the aqueous mixture was extracted with CH2C12 (3 x 50 ml). The organic layers were combined, dried over anhydrous Na 2 SO 4, filtered, and concentrated in vacuo. Flash chromatography on 2 x 20 cm of Si02 (5% MeOH / EtOAc) afforded the title compound, which was slightly impure. Recrystallization from EtOAc / hexane afforded 0.26 g (64%) of the title compound: m.p. 190-191 ° C. Elemental analysis for C3? H35NsO Calculated: C, 75.43; H, 7.15; N, 14.19 Found: C, 75.13; H, 7.25; N, 14.01 EXAMPLE 51c (cis) -3-. { 4- [4- (6-methoxy-4-methylquinolin-8-yl) piperazin-1-yl] cyclohexyl} -l-methyl-lH-indole-5-carbonitrile To a mixture of 4- (6-methoxy-4-methylquinolin-8-yl) piperazine (0.2 g, 0.78 mmol), 3- (1-methyl-lH-indole -5-carbonitrile) cyclohexan-4-one (0.215 g, 0.85 mmole), dichloroethane (10 ml) and glacial acetic acid (0.12 ml) sodium triacetoxyborohydride was added (0.25 g, 1.16 mmol). The reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with dichloromethane (60 ml) and washed with 1 N aqueous sodium hydroxide (2 x 50 ml), water (50 ml) and brine (50 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give 0.43 g of crude product. Flash chromatography on 50 g of silica gel (5% methanol / ethyl acetate) yielded 0.15 g (40%) of the title compound. Recrystallization from ethyl acetate / hexane gave 0.085 g (23%) of pure product: m.p. 210-212 ° C. Aná l i s i s elementa l pa ra C3? H35N5O * 0. 25 H20 Calculated: C, 74.74; H, 7.18; N, 14.06 Found: C, 74.82; H, 7.12; N, 14.11 EXAMPLE 5Id (trans) -3-. { 4- [4- (6-methoxy-4-methylquinolin-8-yl) piperazin-1-yl] cyclohexyl} -1-methyl-1H-indole-5-carbonitrol The trans-isomer was isolated at the same time as the cis-isomer in a yield of 16% (0.062 g). Trituration with ethyl acetate / hexane yielded 0.058 g (15%) of the pure title compound: m.p. 230-232 ° C. Elemental analysis for C3? H35N5O »0.5 H20 Calculated: C, 74.07; H, 7.22; N, 13.93 Found: C, 74.12; H, 7.10; N, 13.95 EXAMPLE 52a (cis) -3-. { 4- [4- (6-methoxy-5-methylquinolin-8-yl) piperazin-1-yl] cyclohexyl} -1-methyl-1H-indole-5-carbonitrile The above compound was prepared using the same method as that used for the preparation of (cis) -3-. { 4- [4- (6-methoxy-4-methylquinolin-8-yl) piperazin-1-yl] -cyclohexyl} 1-methyl-1H-indo-1-5-carbonitrile to give 0.25 g of the title compound. Recrystallization from ethyl acetate yielded 0.125 g (20%) of pure product: m.p. 227-22 ~ 8 ° C. Elemental analysis for C3? H35N5O »0.25 H20 Calculated: C, 74.74; H, 7.18; N, 14.06 Found: C, 74.61; H, 7.20; N, 13.71 EXAMPLE 52b (trans) -3-. { 4- [4- (6-methoxy-5-methylquinolin-8-yl) piperazin-1-yl] cyclohexyl} -l-methyl-lH-indole-5-carbonitrile The trans isomer (0.15 g) was isolated at the same time as the cis compound. Trituration from ethyl acetate yielded 0.110 g (18%) of crude product: m.p. 212-213 ° C. Elemental analysis for C? H3sN5? »0.25 H20 Calculated: C, 75.43; H, 7.15; N, 14.19 Found: C, 75.09; H, 7.10; N, 13.96 EXAMPLE 52c (cis) -5-chloro-8-. { 4- [- (5-fluoro-l-methyl-lH-indol-3-yl) cyclohexyl] piperazin-1-yl} -6-methoxyquinoline The above compound was prepared using the same method as that used for the preparation of (cis) -3-. { 4- [4- (6-methoxy-4-methicholinolin-8-yl) piperazin-1-yl-cyclohexyl} -l-methyl-lH-indole-5-carbonitrile to give 0.13 g of the title compound. Trituration from ethyl acetate yielded 0.120 g (29%) of pure product. Elemental analysis for C29H32C1FN 0 Calculated: C, 68.70; H, 6.36; N, 11.05 Found: C, 68.45; H, 6.24; N, 10.89 EXAMPLE 52d (trans) -5-chloro-8-. { 4- [- (5-fluoro-1-methyl-1H-indol-3-yl) cyclohexyl] piperazin-1-yl} -6-methoxyquinoline The trans isomer was isolated in a yield of 19% (0.075 g) at the same time as the cis compound. Trituration from ethyl acetate yielded 0.070 g (17%) of pure product: m.p. 170-171 ° C. Elemental analysis for C29H32C1FN40 Calculated: C, 68.70; H, 6.36; N, 11.05 Found: C, 68.44; H, 6.32; N, 11.02 EXAMPLE 52e (cis) -3-. { 4- [4- (5-chloro-6-methylquinolin-8-yl) piperazin-1-yl] cyclohexyl} -1-methyl-1H-indol-5-carbonitrile The above compound was prepared using the same method as that used for the preparation of (cis) -3-. { 4- [4- (6-methoxy-4-methyl-lquinolin-8-yl) piperazin-1-yl] -cyclohexyl} -1-methyl-lH-indo 1-5 -carbonitrile to give 0.1 g (24%) of the title compound. Recrystallization from ethyl acetate yielded 0.080 g (20%) of pure product: m.p. 231-231 ° C. Elemental analysis for C30H32ClN5O »0.25 H20 Calculated: C, 69.48; H, 6.32; N, 13.50 Found: C, 69.49; H, 6.31; N, 13.29 EXAMPLE 52f (trans) -3-. { 4- [4- (5-chloro-6-methoxyquinolin-8-yl) piperazin-1-yl] -cyclohexyl} -1-methyl-1H-indole-5-carbonitrile The trans isomer was isolated in a yield of 22% (0.095 g) at the same time as the cis compound. The "trituration from ethyl acetate yielded 0.070 g (17%) of pure product: mp 215-216 ° C Elemental analysis for C30H32ClN5O" 0.25 H20 Calculated: C, 69.48; H, 6.36; N, 13.50 Found: C , 69.36; H, 6.28; N, 13.27 EXAMPLE 53a 4-. { 4- [(1,4-cis) -4- (lH-indol-3-yl) -cyclohexyl] -piperazin-1-yl} -2- (trifluoromethyl) -lH-benzimidazole To a solution of 4-piperazin-1-yl-2-trifluoromethyl-1H-benzimidazole (400 mg, 1.48 mmol), 4- (lH-3-indolyl) -cycothexanone (315 mg, 1.48 mmol), and sodium triacetoxyborohydride (470 mg, 2.22 mmol) in dichloroethane (30 ml) was added acetic acid (0.20 ml, 2.96 mmol) and stirred overnight at room temperature. The reaction was quenched with 1 M NaOH (50 mL) and extracted into CH2C12 (2 x 100 mL) and 50% EtOAc / MeOH (3 x 100 mL). The organic fractions were combined, dried over Na 2 SO 4, concentrated, filtered and chromatographed twice (5% MeOH / EtOAc) to yield 170 mg (25%) of the cis isomer as a white solid. The HCl salt was generated from EtOAc yielding a white solid: m.p. previous foams of 207 ° C. Elemental analysis for C26H2sF3N5 »HCl«? 0 Calculated: C, 59.82; H, 5.99; N, 13.42 Found: C, 60.18; H, 5.84; N, 13.29 EXAMPLE 53b 4-. { 4- [(1, 4-trans -4- (lH-indol-3-yl) -cyclohexyl] -piperazin-1-yl) -2- (trifluoromethyl) -lH-benzimidazole The trans isomer was isolated at the same time producing 180 mg (9%) as a beige solid. The HCl salt was generated from EtOAc yielding a white solid: m.p. decomposed previous 200 ° C. Elemental analysis for C26H28F3N5 »HC1 * 0.75H20 Calculated: C, 60.34; H, 5.94; N, 13.53 Found: C, 60.37; H, 5.68; N, 13.43 EXAMPLE 54a 4-. { 4- [(1,4-cis) -4- (1H-indol-3-yl) -cyclohexyl] -piperazin-1-yl} -1H-benzimidazole This compound was prepared as described by replacing 4-piperazin-l-yl-2-trifluoro-methyl-lH-benzoimidazole with 4-piperazin-1-yl-lH-benzo-imidazole (510 mg, 2.5 mmol) to yield 350 mg (34%) of the title compound as a yellow foam which was triturated with Et20 to give a white solid: mp 217-219 ° C. Elemental analysis for C25H29N5 Calculated: C, 75.16; H, 7.32; N, 17.53 Found: C, 74.82; H, 7.21; N, 17.05 EXAMPLE 54b 4-. { 4- [(1, 4-trans-4- (lH-indol-3-yl) -cyclohexyl] -piperazin-1-yl) -lH-benzimidazole The trans isomer was isolated at the same time yielding 200 mg (20%) as a white solid. The HCl salt was generated from Et20 / EtOH to give a white solid: m.p. decomposed previous 215 ° C. Elemental analysis for C25H29N5 * 2HC1 «H20 Calculated: C, 61.22; H, 6.78; N, 14.28 Found: C, 61.24; H, 6.97; N, 14.09 EXAMPLE 55a 4-. { 4- [(1,4-cis) -4- (lH-indol-3-yl) -cyclohexyl] piperazin-1-yl} -2-methyl-1H-benzimidazole This compound was prepared as described by 53a by replacing 4-piperazin-1-yl-2-trifluoro-methyl-1H-benzoimidazole with 4-piperazin-1-yl-2-methyl-1H -benzoimidazole (340 mg, 1.57 mmol) to yield 350 mg (54%) of the title compound as a white foam. The HCl salt was generated from EtOAc to give a white solid: m.p. decomposed previous 190 ° C. Elemental analysis for C26H3? N5 * 2HCl »H2? Calculated: C, 61.90; H, 6.99; N, 13.88 Found: C, 62.26; H, 7.18; N, 13.46 EXAMPLE 55b 4-. { 4- [(1, 4-trans-4- (lH-indol-3-yl) -cyclohexyl] -pyrazzln-1-yl) -2-methyl-1H-benzimidaz l The trans isomer was isolated at the same time yielding 110 mg (17%) as a white solid. The HCl salt was generated from EtOH / Et20 to give a white solid: m.p. decomposed previous 220 ° C. Elemental analysis for C25H2gN5 * 2HCl * 1 .5H20 Calculated: C, 60.81; H, 7.07; N, 13.64 Found: C, 60.84; H, 7.04; N, 13.31 EXAMPLE 56 3-. { 4- [(1,4-cis) -4- (6-me oxyquinolin-5-yl) piperazin-1-yl] cyclohexyl} -1H-Indole-5-carbonitrile To a 100 ml flask oven-dried under an N 2 atmosphere was added 5-bromo-6-methoxyquinoline (3 g, 12.6 mmol), piperazine (6.5 g, 75.6 mmol), Pd ( dba) 2 (570 mg, 5% in moles), P (t-Bu) 3 (0.628 ml, 5% in moles) and sodium t-butoxide (1.82 g, 18.9 mmol). 50 ml of dry o-xylene was added and the reaction mixture was stirred and heated at 120 ° C for 3 hours, then at room temperature overnight. The reaction mixture was poured into H20 (100 ml) and extracted into EtOAc (3 x 100 ml). The organic fractions were combined, dried over Na 2 SO, concentrated and purified by column chromatography 710% MeOH / CH 2 Cl 2 + NH 4 OH) yielding 170 mg (6%) of 6-methoxy-5-piperazin-1-yl-quinoline. This material was used without further purification (combined with another batch) in the next step. (Ref: Tet Lett, 1998, 39, pp. 617-620). To a solution of 6-methoxy-5-piperazin-1-yl-quinoline (220 mg, 0.9 mmol), 4 - (5-cyano-1 H -3-indolyl) -cycothexanone (215 mg, 0.9 mmol), and triacetoxyborohydride Sodium (288 mg, 1.36 mmol) in dichloroethane (20 ml) was added acetic acid (0.10 ml, 1.75 mmol) and stirred overnight at room temperature. The reaction was quenched with 2.5 M NaOH (20 ml) and H20 (150 ml), then extracted into CH2C12 (2 x 100 ml) and 5% MeOH / Et'OAc (3 x 100 ml). The organic fractions were combined, dried over Na 2 SO, concentrated, filtered and subjected to chromatography (5% MeOH / EtOAc) yielding 140 mg (33%) of the cis isomer as a yellow glass. The HCl salt was generated from EtOAc yielding a yellow solid: m.p. previous discolourations of 85 ° C. Elemental analysis for C26H3? N5 »3HCl * H20 Calculated: C, 58.74; H, 6.12; N, 11.81 Found: C, 58.67; H, 6.34; N, 11.47 EXAMPLE 57 2-. { 4- (1, 4-trans) - [4- (6-Bromoquinolin-8-yl) piperazin-1-yl] cyclohexyl} -1-methyl-1H-indole-5-carbonitrile To a solution of 6-bromo-8-piperazin-1-yl-quinoline (1 g, 3.4 mmol), 4- (5-cyano-lH-3-indolyl) Cyclohexanone (857 mg, 3.4 mmol), and sodium triacetoxyborohydride (1.08 g, 5.1 mmol) in dichloroethane (40 mL) were added with acetic acid (0.40 mL, 6.8 mmol) and stirred overnight at room temperature. The reaction was quenched with 2.5 M NaOH (20 ml) and H20 (150 ml), then extracted into CH2C12 (2 x 100 ml) and 5% MeOH / EtOAc (3 x 100 ml). The organic fractions were combined, dried over Na 2 SO 4, concentrated, filtered and subjected to chromatography (5% MeOH / EtOAc), yielding 360 mg (20%) of the trans isomer as a white foam. The HCl salt was generated from EtOAc to give a white solid: m.p. previous decompositions of 85 ° C. Elemental analysis for C2gH30BrN5 * HCl * 0.75H20 Calculated: C, 60.21; H, 5.66; N, 12.11 Found: C, 60.17; H, 5.44; N, 11.99 EXAMPLE 58a (Cis) -6-bromo-8-. { 4- [4- (5-fluoro-l-methyl-lH-indol-3-yl) -cyclohexyl] piperazin-1-yl} quinoline To a solution of 6-bromo-8-piperazin-1-yl-quinoline (610 mg, 2.09 mmol), 4- (5-fluoro-1-methyl-lH-3-indol-3-yl) -cycothexanone ( 510 mg, 2.09 mmol), and sodium triacetoxyborohydride (660 mg, 3.14 mmol) in dichloroethane (40 ml) was added acetic acid (0.24 ml, 4.18 mmol) and stirred overnight at room temperature. The reaction was quenched with 1 M NaOH (50 mL) and H20 (100 mL), then extracted into CH2C12 (100 mL) and EtOAc (100 mL). The organic fractions were combined, dried over Na 2 SO 4, concentrated, filtered and subjected to chromatography (5% MeOH / EtOAc). The majority of the cis compound is precipitated from 5% MeOH / EtOAc before application to the column and purified by filtration yielding 510 mg (47%) of the cis isomer as a pale yellow solid: m.p. 215-217 ° C. Elemental analysis for C28H30BrFN4 »0.5H20 Calculated: C, 60.21; H, 5.66; N, 12.11 Found: C, 60.17; H, 5.44; N, 11.99 EXAMPLE 58b (Trans) -6-bromo-8-. { 4- [4- (5-fluoro-1-methyl-lH-indol-3-yl) cyclohexyl] piperazin-1-yl} quinoline The trans isomer was isolated by chromatography yielding 210 mg (19%) as a pale yellow foam. The HCl salt was generated from EtOAc to give a gray solid: m.p. previous decomposed 225 ° C. Elemental analysis for C28H30BrFN4 * HCl «0.5H20 Calculated: C, 59.32; H, 5.69; N, 9.88 Found: C, 59.36; H, 5.47; N, 9.79 EXAMPLE 59a 3-. { 4- (1, 4-cis) -4- (6-ethoxyquinolin-8-yl) piperazin-1-yl] cyclohexyl} -1-methyl-1H-indole-5-carbonitrile To a solution of 6-ethoxy-8-piperazin-1-yl-quinoline (500 mg, 1.95 mmol), 4 - (5-cyano-1-methyl-1-yl) 3-indol-3-yl) -cyclohexanone (490 mg, 1.95 mmol), and sodium triacetoxyborohydride (620 mg, 2.93 mmol) in dichloroethane (40 ml) was added acetic acid (0.25 ml, 3.9 mmol) and stirred overnight at room temperature. The reaction was quenched with 1 M NaOH (100 mL) and H20 (50 mL), then extracted into CH2C12 (50 mL) and 5% MeOH / EtOAc (2 x 100 mL). The organic fractions were combined, dried over Na 2 SO 4, concentrated, filtered and subjected to chromatography (5% MeOH / EtOAc). The majority of the cis compound is precipitated from 5% MeOH / EtOAc before application to the column and purified by filtration and combined with the column fractions yielding 450 mg (47%) of the cis isomer as an off-white solid: m.p. decomposed previous 215 ° C. Analysis for the C3? H35N50 * l. 25 H20 Calculated: C, 72.14; H, 7.32; N, 13.57 Found: C, 72.23; H, 7.06; N, 13.35 EXAMPLE 59b 3-. { 4- (1, 4-trans) -4- (6-ethoxyquinolin-8-yl) piperazin-1-yl] cyclohexyl} -1-methyl-1H-indole-5-carbonitrile The trans isomer was isolated at the same time by chromatography yielding 210 mg (22%) as a yellow foam which was triturated with Et20 to yield a pale yellow solid: m.p. 225-228 ° C. Aná l is i s e l l l for C3? H35NsO * H20 Calculated: C, 72.77; H, 7.29; N, 13.69 Found: C, 72.79; H, 7.07; N, 13.41 EXAMPLE 60 3- [4- (4-. {6- [benzyl (methyl) amino] quinolin-8-yl.] Piperazin-1-yl) -cyclohexyl] -l-methyl-1H-indol-5 carbonitrile To a 10 ml round bottom flask oven dried under an N2 atmosphere was added Cs2CO3 (173 mg, 0.53 mmole), BINAP (15 mg, 3% mole), Pd (0Ac) 3 (5 mg, 3 % in moles) and 2 -. { 4- (1, 4-trans) - [4 - (6-bromoquinolin-8-yl) piperazin-1-yl] cyclohexyl} - 1-methyl-lH-indole-5-carbonitrile (200 mg, 0.38 mmol). Toluene (1 ml) and benzylmethylamine (0.06 ml, 0.45 mmol) were added via syringe, and the reaction mixture was heated at 100 ° C overnight. The cooled reaction mixture was diluted with Et20 (15 mL), filtered to remove solids, and concentrated. The resulting oil is purified by column chromatography (5% MeOH / EtOAc + NH 4 OH) to give 60 mg of the title compound as a brown solid. The HCl salt was generated from EtOAc / Et20 yielding an orange solid: m.p. Decomposed previous 90 ° C. Elemental analysis for C3 H40N6 »3HC1 Calculated: C, 65.53; H, 6.39; N, 12.39 Found: C, 65.36; H, 6.71; N, 12.39 EXAMPLE 61a 1-Methyl-3- [(1,4-cis) -4- (4-quinolin-5-ylpiperazin-1-yl) cyclohexyl] -lH-indole-5-carbonitrile To a solution of 5-piperazin- l-il-quinoline (300 mg, 1.4 mmol), 4- (5-cyano-l-met yl-lH-indol-3-yl) -cidiohexanone (350 mg, 1.4 mmol), and sodium triacetoxyborohydride (450 mg, 2.1 mmol) in dichloroethane (40 ml) was added acetic acid (0.25 ml, 3.4 mmol) and stirred overnight at room temperature. The reaction was quenched with 1 M NaOH (25 mL) and H20 (100 mL), then extracted into CH2C12 (100 mL) and EtOAc (2 x 100 mL). The organic fractions were combined, dried over Na 2 SO 4, concentrated, filtered and subjected to chromatography (5% MeOH / EtOAc) yielding 190 mg (30%) of the cis isomer as a white foam. The HCl salt was generated from EtOAc to give a white solid: m.p. decomposed previous 235 ° C. Elemental analysis for C29H31N5 »HC1 * 0.5H20 Calculated: C, 70.36; H, 6.72; N, 14.15 Found: C, 70.43; H, 6.57; N, 13.83 EXAMPLE 61b l-Methyl-3- [(1, -trans) -4- (4-quinolin-5-ylpiperazin-1-yl) cyclohexyl] -lH-indole-5-carbonitrile The trans isomer was isolated at the same time producing 140 mg (22%) as a pale yellow solid: mp Previous discolours 200 ° C. Elemental analysis for C29H3? N5 »0.5H20 Calculated: C, 75.95; H, 7.03; N, 15.27 Found: C, 75.82; H, 6.72; N, 15.09 EXAMPLE 62a 3-. { (1,4-cis) -4- [4- (6-methoxy-1,2, 3,4-tetrahydroquinolin-8-yl) piperazin-1-yl] cyclohexyl} -1- ethyl-1H-indole-5-carbonitrile To a solution of 6-methoxy-5-piperazin-1-yl-1,2,3,4-tetrahydroquinoline (300 mg, 1.2 mmol), 4- (5- cyano-l-met il-lH-3-indol-3-yl) -cciohexanone (306 mg, 1.2 mmol), and sodium triacetoxyborohydride (254 mg, 1.8 mmol) in dichloroethane (50 mL) was added acetic acid (0.15). ml, 2.4 mmol) and stirred overnight at room temperature. The reaction was quenched with 1 M NaOH (50 mL) and H20 (50 mL), then extracted into CH2C12 (100 mL) and EtOAc (2 x 100 mL). The organic fractions were combined, dried over Na 2 SO 4, concentrated, filtered and chromatographed twice (5% MeOH / EtOAc) to yield 140 mg (24%) of the cis isomer as a white foam. The HCl salt was generated from EtOAc to give a white solid: m.p. decomposed previous 170 ° C. Elemental analysis for C30H37N5O "HCl" H2O Calculated: C, 66.96; H, 7.49; N, 13.01 Found: C, 66.71; H, 7.28; N, 12.50 EXAMPLE 62b 3-. { (1,4-trans) -4- [4- (6-methoxy-1, 2,3,4-tetrahydroquinolin-8-yl) pipßrazin-1-yl] cyclohexyl) -l-ethyl-1H-indol-5 -carbonitrile The trans isomer was isolated at the same time yielding 80 mg (22%) as a white foam. The HCl salt was generated from EtOAc yielding a white solid: m.p. previous decomposed 225 ° C. Elemental analysis for C30H37N5O * HCl »0.5H20 Calculated: C, 68.10; H, 7.43; N, 13.24 Found: C, 68.17; H, 7.30; N, 13.17 EXAMPLE 63a l-Methyl-3- [(1,4-cis) -4- (4- [1,6] naphthyridin-8-ylpiperazin-1-yl) cyclohexyl] -lH-indole-5-carbonitrile To a solution of 8 -piperazin-l-yl-naphthyridine (470 mg, 2.19 mmol), 4- (5-cyano-1-methyl-lH-3-indol-3-yl) -cydohexanone (550 mg, 2.19 mmol), and triacetoxyborohydride sodium (700 mg, 3.28 mmol) in dichloroethane (40 ml) was added acetic acid (0.25 ml, 4.38 mmol) and stirred overnight at room temperature. The reaction was quenched with 1 M NaOH (45 mL) and H20 (20 mL), then extracted into CH2C12 (50 mL) and EtOAc (2 x 100 mL). The organic fractions were combined, dried over Na 2 SO 4, concentrated, filtered and chromatographed three times (5% MeOH / EtOAc) yielding 490 mg (50%) of the cis isomer as a pale yellow solid: m.p. decomposed previous 215 ° C, then fusions of 227-230 ° C. Elemental analysis for C28H30N6 * 0.5H20 Calculated: C, 73.90; H, 6.76; N, 18.47 Found: C, 73.90; H, 6.76; N, 18.61 EXAMPLE 63b l-Methyl-3- [(1,4-trans) -4- (4- [1,6] naphthyridin-8-yl-piperazin-1-yl) cyclohexyl] -lH-indole-5-carbonitrile The trans isomer was isolated at the same time yielding 120 mg (12%) as a pale yellow solid: mp decomposed previous 195 ° C.
Elemental analysis for C3oH3 N50 «0. 5 H20 Calculated: C, 73.90; H, 6.76; N, 18.47 Found: C, 73.87; H, 6.75; N, 18.66 EXAMPLE 64 l-Methyl-3- ((1,4-cis) -4-. {4- [6- (methylamino) quinolin-8-yl] piperazin-1-yl}. Cyclohexyl) -1H-indole -5-carbonitrile To a solution of 6- (methylamino) -8-piperazin-1-yl-quinoline (100 mg, 0.43 mmol), 4- (5-cyano-1-methyl-lH-indol-3-yl) -cycothexanone ( 100 mg, 0.43 mmol), and sodium triacetoxyborohydride (130 mg, 0.62 mmol) in dichloroethane (30 mL) was added acetic acid (0.1 mL, 0.86 mmol) and stirred overnight at room temperature. The reaction was quenched with 1 M NaOH (50 mL) and H20 (50 mL), then extracted into CH2C12 (100 mL) and EtOAc (2 x 100 mL). The organic fractions were combined, dried over Na 2 SO, concentrated, filtered and subjected to chromatography (10% MeOH / EtOAc) yielding 60 mg (30%) of the cis isomer as a golden oil. The HCl salt was generated from EtOAc yielding a yellow solid: m.p. decomposed previous 170 ° C. Elemental analysis for C3oH34N6 »HCl» H20 Calculated: C, 67.59; H, 7.00; N, 15.76 Found: C, 67.58; H, 6.86; N, 15.65 EXAMPLE 65a (Cis) -3-. { 4- [4- (7-methoxyquinolalin-5-yl) piperazin-1-yl] cyclohexyl} -l-methyl-lH-indole-5-carbonitrile To a solution of 7-methoxy-5-piperazin-1-yl-quinoxaline (160 mg, D.66 mmol), 4- (5-cyano-1-methyl) lH-indol-3-yl) -cydohexanone (170 mg, 0.66 mmol), and sodium triacetoxyborohydride (210 mg, 0.98 mmol) in dichloroethane (30 mL) was added acetic acid (0.1 mL, 1.3 mmol) and stirred for the night at room temperature. The reaction was quenched with 1 M NaOH (100 mL) then extracted into CH2C12 (75 mL) and 'EtOAc (100 mL). The organic fractions were combined, dried over Na 2 SO 4, concentrated, filtered and subjected to chromatography (5% MeOH / EtOAc) yielding 120 mg (38%) of the cis isomer as a bright yellow solid: m.p. 226-229 ° C. Elemental analysis for C2gH32N60 «H 0 Calculated: C, 69.86; H, 6.87; N, 16.85 Found: C, 69.94; H, 6.71; N, 16.60 EXAMPLE 65b (Trans) -3-. { 4- [4- (7-methoxyquinolalin-5-yl) piperazin-1-yl] cyclohexyl} -l-methyl-lH-indole-5-carbonitrile The trans isomer was isolated at the same time yielding 80 mg (12%) as a yellow solid: m.p. 230-233 ° C. Elemental analysis for C29Ha2N6O »0.5H20 Calculated: C, 71.14; H, 6.79; N, 17.16 Found: C, 71.29; H, 6.69; N, 17.16 EXAMPLE 66a (Cis) -3-. { 4- [4- (6-methoxy [1,7] naphthyridin-8-yl) piperazin-1-yl] cyclohexyl} -l-methyl-lH-indole-5-carbonitrile To a solution of 6-methoxy-8-piperazin-1-yl- [1,7] naphthyridine (250 mg, 1.02 mmol), 4 - (5-cyano-1) -methyl-lH-indol-3-yl) -cidiohexanone (260 mg, 1.02 mmol), and sodium triacetoxyborohydride (320 mg, 1.53 mmol) in dichloroethane (50 ml) were added acetic acid (0.12 ml, 2.04 mmol) and it was stirred overnight at room temperature. The reaction was quenched with 1 M NaOH (50 mL) then extracted into CH2C12 (1 x 50 mL) and EtOAc (75 mL). The organic fractions were combined, dried over Na2SO4, concentrated, filtered and subjected to chromatography (5% MeOH / EtOAc + NHOH) yielding 160 mg (33%) of the cis isomer as a yellow foam: m.p. 235-238 ° C. Elemental analysis for C29H32N60 «HC1 * H20 Calculated: C, 65.10; H, 6.59; N, 15.71 Found: C, 65.09; H, 6.77; N, 15.60 EXAMPLE 66b (Cis) -3-. { 4- [4- (6-methoxy [1,7] naphthyridin-8-yl) piperazin-1-yl] cyclohexyl} -l-methyl-lH-indole-5-carbonitrile The trans isomer was isolated at the same time yielding 90 mg (18%) as a pale yellow foam: m.p. 230-233 ° C. Elemental analysis for C2gH32N6O * HCl »0.5H20 Calculated: C, 66.21; H, 6.51; N, 15.97 Found: C, 66.26; H, 6.37; N, 15.91 EXAMPLE 67a 3-. { (1,4-cis) 4- [4- (2-Oxo-2,3-dihydro-lH-benzimidazol-4-yl) -piperazin-1-yl] -cyclohexyl} -lH-indole-5-carbonitrile To a solution of 4-piperazin-1-yl-1,3-dihydro-benzoimidazol-2-one (400 mg, 1.8 mmol), 4- (5-cyano-1 H-indole- 3-yl) -cycothexanone (430 mg, 1.8 mmol), and sodium triacetoxyborohydride (590 mg, 2.8 mmol) in dichloroethane (50 ml) was added acetic acid (0.21 ml, 3.7 mmol) and stirred overnight at room temperature. The reaction was quenched with 2.5 M NaOH (100 mL) then extracted into MeOH / CH2Cl2 (2 x 100 mL). The organic fractions were combined, dried over Na 2 SO 4, concentrated, filtered and chromatographed twice (10% MeOH / EtOAc) yielding 185 mg (23%) of the cis isomer as a beige solid: m.p. decomposed previous 235 ° C. Elemental analysis for C26H28N60 »HC1« 1.5H20 Calculated: C, 61.96; H, 6.40; N, 16.67 Found: C, 61.97; H, 6.26; N, 16.28 EXAMPLE 67b 3-. { (1, 4-trans) 4- [4- (2-Oxo-2,3-dihydro-lH-benzimidazol-4-yl) -piperazin-1-yl] -cyclohexyl} -1H-Indole-5-carbonitrile The trans isomer was isolated at the same time yielding 90 mg (18%) as a white solid. The HCl salt was generated from EtOAc yielding a white solid: m.p. decomposed 265 ° C. Elemental analysis for C26H28N60 * HC1 * 1.5H20 Calculated: C, 61.96; H, 6.40; N, 16.67 Found: C, 61.98; H, 6.25; N, 16.38 EXAMPLE 68a 3- [cis-4- [4- (6-Methoxy-lH-indol-4-yl) -1- piperazinyl] cyclohexyl] lH-indole-5-carbonitrile To a solution of 4- (5-cyano- l-methyl-3-indolyl) -cidiohexanone (0.43 g, 1.8 mmol), 6-methoxy-4-piperazin-1-yl-lH-indole (0.4 g, 1.8 mmol), sodium triacetoxyborohydride (0.77 g, 2.7 mmol) ) and acetic acid (0.21 ml, 3.6 mmol) in 1,2-dichloroethane (20 ml) was allowed to stir at room temperature overnight. The reaction was quenched with 1N aqueous sodium hydroxide (10 ml), and extracted with methylene chloride (3 x 50 ml). The combined organic layers were washed with brine (2 x 50 ml), then dried over anhydrous sodium sulfate and filtered. Chromatography (5% methanol / ethyl acetate) gave 0.38 g (48%) of the title compound as a white solid: m.p. 182-185 ° C. The HCl salt was prepared in ethyl acetate: m.p. 225-226 ° C. Elemental analysis for C28H3? N5O »2HCl« 0.25H2O «-0.40C4H8O2 Calculated: C, 62.79; H, 6.53; N, 12.37 Found: C, 62.28; H, 6.44; N, 12.97 EXAMPLE 68b 3- (trans -4- [4- (6-Methoxy-lH-indol-4-yl) -1-piperazinyl] -cyclohexyl}.-LH-indole-5-carbonitrile The trans compound was isolated at the same time as the cis isomer in a 33% yield (0.26 g) as a white solid: mp 157-160 ° C. The HCl salt was prepared in ethyl acetate: mp> 210 ° C. Elemental analysis for C28H3? N50 »HCl« 1 .5H20 Calculated: C, 64.82; H, 6.58; N, 13.94 Found: C, 65.04; H, 6.82; N, 13.54 EXAMPLE 69 5-Fluoro-3-. { 4- [4- (6-Me-oxy-na-talen-2-yl) -piperazin-1-yl] -cyclohexyl} -1H-indole To 400 mg (1.66 mmoles) of 1- (6-methoxy-naphthalen-2-yl) -piperazine in 40 ml of CH2C12 and 100 mg of glacial HOAc at 23 ° C was added 384 mg (1.66 mmoles) of 4- (5-fluoro-l-indol-3-yl) -cyclohex-3-enone followed by 216 mg, (1.89 mmol) of Na (OAc) 3BH. After stirring at 23 ° C for 12 hours, the reaction mixture was transferred to a separatory funnel and partitioned between water and CH2C12. The organic materials were washed with brine, dried over MgSO4, and chromatographed on silica gel eluting with EtOAc: 2: NH 2 20: 1 in MeOH. The product fractions were deposited, washed, and treated with 115 mg (1.3 mmol) of (C02H) 2 in absolute EtOH to give 640 mg (1.40 mmol, an 84% yield) of the oxalate salt of the title compound as a white crystalline solid. P.f. 200-203 ° C; MS (ES) m / z 458 (MH)? Elemental analysis for C2gH32FN30 Calculated: C, 67.95; H, 6.25; N, 7.67. Found: C, 66.64; H, 6.71; N, 7.11.
EXAMPLE 70a 3- [4 - [(Cis) -4- (6- [l, 3] dioxolan-2-yl-quinolin-8-yl) -piperazin-1-yl] -cyclohexyl-lH-xndol-5- carbonitrile 6- [1,3-Dioxolan-2-yl-8-piperazinyl-quinoline 1.36 g (4.8 mmol) was combined with 1-methyl-3- (4-oxo-cyclohexyl) -1H-indole-5-carboni trio, 1.53 g (7.2 mmol), 0.43 g (7.2 mmol) CH3C02H, and 100 ml of CH2C12 by the process described by Example 1. The crude product was chromatographed on silica gel in a gradient of CH2C12 to CH2Cl2: MeOH 10: 1, and the cis compound was isolated, (Rf = 0.39, CH 2 Cl 2: MeOH 10: 1). The product fractions were deposited, washed and treated with 0.09 g (1.0 mmol) of (C02H) 2 in absolute EtOH to give 1.0 g (1.9 mmol, a yield of 40%) of the oxalate salt of the cis isomer of the compound of the title as a yellow crystalline solid. P.f .: 105 ° C; MS (ES) m / z 522 (MH)? Elemental analysis for C32H35N502 Calculated: C, 73.68; H, 6.76; N, 13.43 Found: C, 73.67; H, 6.82; N, 13.23 EXAMPLE 70b 3 - [4- [(Trans) -4- (6- [1, 3] dioxolan-2-yl-quinolin-8-yl) -piperazin-1-yl] -cyclohexyl-lH-indole-5- carbonitrile The trans compound was also obtained, (Rf = 0.24, CH2Cl2: MeOH 10: 1). The product fractions were deposited, washed, and treated with 0.07 g (0.8 mmol) of (C02H) 2 in absolute EtOH to give 0.80 g (1.5 mmol, a yield of 31%) m.p .: 160 ° C; EM ES m / z 522 (MH)? Elemental analysis for C32H35 5? 2 Calculated: C, 73.68; H, 6.76; N, 13.43. Found: C, 67.05; H, 6.27; N, 12.03.
EXAMPLE 72 8- [4- [(Trans) -4- (5-Cyano-l-methyl-lH-indol-3-yl) -cyclohexyl] -piperazin-1-yl] -6-quinolinecarbaldehxdo The trans compound was obtained by the process described by Example 4 by combining 0.750 mg (1.4 mmol) of 3- [4- [(trans) -4- (6- [1,3] dioxolan-2-yl-quinolin-8-yl) - piperazinyl] cyclohexyl-lH-indole-5-carbonitrile, 0.6 ml of 6N HCl, 7 ml of THF, 7 ml of glacial HOAc. The product fractions were deposited, washed and treated with 85 mg (0.9 mmol) of (C02H) 2 in absolute EtOH to give 450 mg (0.76 mmol, a yield of 42%) P.f .: 201-203 ° C; MS (ES) m / z 478 (MH)? Elemental analysis for C30H33.N5O Calculated: C, 75.44; H, 6.54; N, 14.66. Found: C, 72.10; H, 6.80; N, 12.64.
EXAMPLE 73 8- [4- [(Cis) -4- (5-Cyano-l-methyl-lH-indol-3-yl) -cyclohexyl] -1-piperazinyl] -6-quinolinecarboxylic acid A 750 mg (1.6 mmol) ) of 8- [4- [(Cis) -4- (5-cyano-l-methyl-lH-indol-3-yl) cyclohexyl] -1-piperazinyl] -6-quinolinecarbaldehyde in 60 ml of t-BuOH and 8 ml of CH3CHC (CH3) 2 at 23 ° C was added a solution of 1.3 mg (14.4 mmoles) of NaCl02, 1.3 g (10.8 mmoles) of NaH2P04 in 3 ml of water. After stirring at 23 ° C for 12 hours, the volatile materials were removed by rotary evaporation. The reaction mixture was transferred to a separatory funnel and partitioned between water and CH2C12. The organic materials were washed with brine, dried over MsSO4, and chromatographed on silica gel eluting with CH2Cl2: MeOH 20: 1 containing 5% glacial HOAc. The product fractions were deposited, washed and treated with 75 mg (0.83 mmoles) of (C02H) 2 in absolute EtOH to give 390 mg (0.6 mmol, a 38% yield) of the oxalate salt of the title compound as a brown crystalline solid. P.f .: 230 ° C; MS (ES) m / z: 494 (MH)? Elemental analysis for C30H3? N5O Calculated: C, 73.00; H, 6.33; N, 14.19. Found: C, 50.91; H, 4.92; N, 7.70 EXAMPLE 74 8- [4- [(Trans) -4- (5-Cyano-l-methyl-lH-indol-3-yl) cyclohexyl] -1-piperazinyl] -6-quinolinecarboxylic acid The trans compound was obtained by the process described by Example 73 by combining 0.30 g (0.60 mmoles) of 8- [4 - [(Trans) -4- (5-cyano-l-methyl-lH-indol-3-yl) cyclohexyl] -l-piperazinyl ] -6-guinolincarbaldehyde, 0.48 g (5.5 mmoles) of NaC102, 0.48 g (4.1 mmoles) of NaH2P04, 24 ml of t-BuOH; 3 ml of CH3CHC (CH3) 2, and 6 ml of water. The product fractions were deposited, washed, and treated with 54 mg (0.60 mmol) of (C02H) 2 in absolute EtOH to give 97 mg (0.16 mmol, a yield of 10%) m.p .: 275 ° C; MS (ES) m / z: 494 (MH)? Elemental analysis for C3oH3? NsO Calculated: C, 75.44; H, 6.54; N, 14.66. Found: C, 50.42; H, 4.66; N, 8.82.
EXAMPLE 75 8- [4- [(Cis) -4- (5-cyano-l-methyl-lH-indol-3-yl) -cyclohexyl] -1-piperazinyl] -6-quinolinecarboxylic acid methyl ester 50 mg (0.1 mmoles) of 8- [4- [(Cis) -4- (5-cyano-l-methyl-lH-indol-3-yl) cyclohexyl] -1-piperazinyl] -6-quinolinecarboxylic acid in 1 ml of MeOH and 3 ml of C6H5CH3 at 23 ° C was added 0.9 ml (0.39 mmol) of a solution of 10% (CH3) 3SiCHN2 in hexanes. After stirring at 23 ° C for 12 hours, the volatile materials were removed by rotary evaporation. The crude product was chromatographed on silica gel eluting with CH2Cl2: MeOH 20: 1. The product fractions were deposited, washed and treated with 5 mg (0.05 mmol) of (C02H) 2 in absolute EtOH to give 20 mg (0.04 mmol, a yield of 40%) of the oxalate salt of the title compound as a brown crystalline solid. P.f .: 153-155 ° C; MS (ES) m / z: 599 (MH)? Elemental analysis for C3? H33N502 Calculated: C, 66.28; H, 5.90; N, 11.71. Found: C, 61.49; H, 5.85; N, 10.35.
EXAMPLE 76a 3- [4- [(Cis) -4- (7-methoxy-8-quinolinyl) -1-piperazinyl] -cyclohexyl] -1-methyl-1H-indole-5-carbonitrile The 7-methoxy-8- (1-piperazinyl) quinoline 400 mg (1.6 mmole.s) was combined with 404 mg (1.6 mmoles) of l-methyl-3- (4-oxo-cyclohexyl) -lH-indole-5-carbonitrile, 510 mg (2.4 mmol) of Na (OAc) 3BH, 143 mg (2.4 mmol) of glacial HOAc, in 30 mL of CH2C12 by the process described by Example 69. The crude product was chromatographed on silica gel eluting with CH2Cl2: MeOH 20: 1, the cis compound was isolated (Rf = 0.34, EtOAc: MeOH 10: 1). The product fractions were deposited, washed, and treated with 27 mg (0.30 mmol) of (C02H) 2 in absolute EtOH to give 179 mg (0.37 mmol, 23% yield) of the oxalate salt of the title compound as a yellow crystalline solid. P.f .: 183-186 ° C; MS (ES) / z 480 (MH)? Elemental analysis for C3oH33NsO Calculated: C, 67.43; H, 6.19; N, 12.29. Found: C, 65.38; H, 6.34; N, 11.83.
EXAMPLE 76b 3- [4- [(Trans) -4- (7-methoxy-8-quinolin) -1- piperazinyl] cyclohexyl] -l-methyl-lH-indole-5-carbonitrile The trans compound was obtained at the same time (Rf = 0.17, EtOAc: MeOH 10: 1). The product fractions were deposited, washed, and treated with 12 mg (0.13 mmol) of (C02H) 2 in absolute EtOH to give 80 mg (0.17 mmol, a yield of 11%) m.p .: 144-148 ° C; MS (ES) m / z: 480 (MH)? Elemental analysis for C30H33N5O Calculated: C, 67.43; H, 6.19; N, 12.29. Found: C, 64.17; H, 6.37; N, 11.68.
EXAMPLE 77a 8- [4- [(Cis) -4- (5-cyano-l-methyl-lH-indol-3-yl) cyclohexyl] -1-piperazinyl] -N, N-dimethyl-6-quinolinecarboxamide Combined N, N-Dimethyl-8- (1-piperazinyl) -6-quinolinecarboxamide 300 mg (1.1 mmol) with 267 mg (1.1 mmol) of 1-methyl-3- (4-oxo-cyclohexyl) -lH-indole -5-carbonitrile, 339 mg (1.6 mmol) of Na (OAc) 3BH, 96 mg (1.6 mmol) of glacial HOAc in 20 ml of CH2C12 by the process described by Example 69. The crude product was subjected to gel chromatohy. of silica in a ient from EtOAc to EtOAc: MeOH 10: 1, and the cis compound was isolated (Rf = 0.43, EtOAc: NH3 2M 10: 1 in MeOH). The product fractions were deposited, washed and treated with 35 mg (0.39 mmol) of (C02H) 2 in absolute EtOH to give 210 mg (0.40 mmol, 36% yield) of the oxalate salt of the cis isomer of the title compound as a pale yellow crystalline solid. P.f .: 163-165 ° C; MS (ES) m / z 521 (MH)? Elemental analysis for C32H36NeO Calculated: C, 66.83; H, 6.27; N, 13.75. Found: C, 59.62; H, 6.15; N, 11.33.
EXAMPLE 77b 8- [4- [(Trans) -4- (5-cyano-l-methyl-lH-indol-3-yl) cyclohexyl] -1-piperazinyl] -N, N-dimethyl-6-quinolinecarboxamide The compound trans was obtained at the same time (Rf = 0.33, EtOAc: 2M NH 3 10: 1 in MeOH). The product fractions were deposited, washed, and treated with 15 mg (0.17 mmol) of (C02H) 2 in absolute EtOH to give 80 mg (0.15 mmol, a yield of 14%) m.p .: 160-163 ° C; MS (ES) m / z 521 (MH)? Elemental analysis for C32H3e 6? Calculated: C, 66.83; H, 6.27; N, 13.75. Found: C, 62.7; H, 6.52; N, 12.33.
EXAMPLE 78 6-Methoxy-8-. { cis-4- [4- (1H-pi [2, 3-b] pyridin-3-yl) -cyclohexyl] -1-piperazinyl} quinoline To a stirred solution of 195 mg (0.80 mmol) of 6-methoxy-8- (1-piperazinyl) quinoline in 10 ml of 1,2-dichloroethane at 23 ° C was added 177.9 mg (0.83 mmoles) of 4- ( IH-pyrrolo [2, 3-b] pyridin-3-yl) ciciohexanone, 254 mg (1.2 mmoles) of sodium triacetoxyborohydride, and 78 mg (1.3 mmoles) of glacial acetic acid. The reaction was monitored by TLC on a silica gel plate eluted with CH2Cl2 / MeOH (10: 1). After stirring at 23 ° C for 64 hours, the reaction was quenched with 10 ml of 1 N NaOH, and extracted with CH2C12 (2 x 25 ml). The aqueous layer was adjusted to pH 10 with AcOH, and further extracted with CH2C12 (2 x 75 mL). The combined organic layers were washed with brine (2 x 75 mL), dried over MgSO4 filtered and evaporated to a brown solid. The crude product was purified by flash chromatohy on silica gel using a ient elution of CH2Cl2 / MeOH (40: 1 to 10: 1 to 4: 1). The appropriate fractions were combined and evaporated to yield 94.8 mg (0.21 mmol, a 27% yield) of the title compound as a brown crystalline solid. The oxalate salt of the title compound was prepared by adding 19 mg (0.21 mmoles) of oxalic acid to 92 mg (0.21 mmoles) of the title compound in 1 ml of ethanol at 23 ° C. After stirring at 23 ° C for 64 hours, a solid was precipitated from the solution. Diethyl ether (5 ml) was added to the suspension and cooled to 0 ° C, to further crystallize the product. The precipitated solid was collected and washed with ether to yield 79.5.mg (15 mmol, a 71% yield) of the oxalate salt. P.f .: 216-220 ° C; MS (ES) m / z: 442.3 (MH) +, 221.6 (M / 2 + H)? Elemental Analysis For C2 H33 5? 5 Calculated: C, 65.48; H, 6.25; N, 13.17. Found: C, 62.66; H, 5.95; N, 11.67.
EXAMPLE 79 6-Methoxy-8-. { cis-4- [4- (1-methyl-1 H -pyrrolo [2, 3-b] pyridin-3-yl) cyclohexyl] -1-piperazinyl} quinoline The title compound was prepared by the procedure described in Example 78 using 4- (1-methyl-lH-pyrrolo [2, 3-b] pyridin-3-yl) -cydohexanone (204.7 mg, 0.89 mmol) in place of 4- (IH-pyrrolo [2, 3-b] -pyridin-3-yl) ciciohexanone. Yield: 30% (108.5 mg, 0.24 mmol); viscous yellow oil. The oxalate salt was prepared in the manner previously described in Example 78 using 108.5 mg (0.24 mmol) of the title compound. Yield: 30% (39.2 mg, 0.072 mmol). P.f .: 105-110 ° C; MS (ES) m / z: 456.3 (MH) +, 228.8 (M / 2 + H)? Elemental Analysis for C30H35N5? 5 Calculated: C, 66.00; H, 6.46; N, 12.83. Found: C, 58.43; H, 6.31; N, 10.57.
EXAMPLE 80 8-. { cis-4- [4- (6-fluoro-lH-indol-3-yl) cyclohexyl] -1- piperazinyl} -6-methoxyquinoline The title compound was prepared by the procedure described in Example 78 using 4- (6-fluoro-lH-indol-3-yl) -cydohexanone (401 mg, 1.87 mmol) instead of 4- (lH -pyrrolo [2, 3-b] -pyridin-3-yl) ciciohexanone. Yield: 28% (243 mg, 0.53 mmol); white crystalline solid. The oxalate salt was prepared in the manner previously described in Example 78 using 78.0 mg (0.24 mmol) of the title compound. Yield: 66% (61.1 mg, 0.11 mmol) as a white solid. P.f .: 239-243 ° C; MS (ES) m / z: 459.3 (MH) +, 230.1 (M / 2 + H). Elemental Analysis for C3oH33FN? 5 Calculated: C, 65.64; H, 6.06; N, 10.21. Found: C, 65.16; H, 6.40; N, 9.86.
EXAMPLE 81 8-. { cis-4- [4- (6-fluoro-l-methyl-lH-indol-3-yl) cyclohexyl] -1-piperazinyl} -6-methoxyquinoline The title compound was prepared by the procedure described in Example 78 using 4- (6-fluoro-1-met yl-lH-indol-3-yl) -cycothexanone (230 mg, 0. 94 mmoles) instead of 4- (lH-pyrrolo [2, 3-b] -pyridin-3-yl) ciciohexanone. Yield: 30% (131.6 mg, 0.28 mmol); white crystalline solid. The oxalate salt was prepared in the manner previously described in Example 78 using 127.9 mg (0.27 mmol) of the title compound. Yield: 20% (30.1 mg, 0.054 mmol). P.f .: 219-223 ° C; EM (ES) m / z: 473.2 (MH)? Elemental Analysis for C3? H35FN4? 5 Calculated: C, 66.00; H, 6.46; N, 12.83. Found: C, 58.43; H, 6.31; N, 10.57.
EXAMPLE 82 6-Methoxy-8- (4- { (Cis) -4- [5- (trifluoromethyl) -lH-indol-3-yl) cyclohexyl} -1-piperazinyl) quinoline The title compound was prepared by the procedure described in Example 78 using cyclohexanone 4- (5-trifluoromethyl-lH-indol-3-yl) -cycothexanone (271.5 mg, 0.97 mmol) instead of 4 - (lH-pyrrolo- [2, 3-b] -pyridin-3-yl) ciciohexanone. Performance: 12% (57 mg, 0.12 mmol); whitish solid.
The oxalate salt was prepared in the manner previously described in Example 78 using 25.6 mg (0.050 mmol) of the title compound. Yield: 67% (20 mg, 0.033 mmol). P.f .: 143-147 ° C; MS (ES) m / z: 509.4 (MH)? Elemental Analysis for C3? H33F3N 0s Calculated: C, 62.17; H, 5.55; N, 9.35. Found: C, 57.55; H, 5.84; N, 8.63.
EXAMPLE 83a (Cis) -6-methoxy-8- (4-. {4- [l-methyl-5- (trifluoromethyl) -1H-indol-3-yl] cyclohexylpiperazinyl) quinoline The title compound was prepared by the procedure described in Example 78 using 4- (l-methyl-5-trifluoromethyl-lH-indol-3-yl) -cydohexanone (750.3 mg, 2.54 mmol) instead of 4- (lH-pyrrolo [2, 3- b] -pyridin-3-yl) ciciohexanone. Flash chromatography was performed using a gradient elution of ethyl acetate / MeOH (40: 1 to 10: 1 to 4: 1) instead of CH2Cl2 / MeOH; Rf = 0.36. Yield: 12% (162.1 mg, 0.30 mmol); Solid brown color. The oxalate salt was prepared in the manner previously described in Example 78 using 93.5 mg (0.18 mmol) of the title compound.
Yield: 29% (31.4 mg, 0.051 mmol). P.f., 101-104 ° C; MS (ES) m / z 523.2 (MH)? Elemental Analysis for C32H35F3N4? 5 Calculated: C, 62.70; H, 5.76; N, 9.14. Found: C, 55.43; H, 6.21; N, 7.75.
EXAMPLE 83b (Trans) -6-methoxy-8- (4-. {4- [l-methyl-5- (tr-fluorouoronyl) -lH-indol-3-yl] cyclohexyl} piperazinyl) quinoline The trans compound ( Rf = 0.26) was isolated at the same time as the cis isomer in an 11% yield (140 mg, 0.27 mmol) as a brown solid. The oxalate salt was prepared in the manner previously described in Example 78 using 100 mg (0.19 mmol) of the title compound. Yield: 86% (101 mg, 0.16 mmol). P.f .: 111-115 ° C; MS (ES) m / z 523.3 (MH)? Elemental Analysis for C32H35F3 4? 5 Calculated: C, 62.70; H, 5.76; N, 9.14. Found: C, 59.47; H, 5.80; N, 7.93.
EXAMPLE 84 3-. { (Cis) -4- [4- (6-methoxy-8-quinolinyl) -1- piperazinyl] cyclohexyl} -1-methyl-lH-carbonitrile The title compound was prepared in a similar manner described in Example 78 'using l-methyl-3- (4-oxo-cyclohexy-1) -lH-indole-6-carbonitrile (164 mg , 0.69 mmoles) instead of 4- (lH-pyrrolo [2, 3-b] -pyridin-3-yl) ciciohexanone. Flash chromatography was performed using a gradient elution of ethyl acetate / MeOH (40: 1 to 10: 1 to 4: 1) instead of CH2Cl2 / MeOH. Yield: 20% (80.4 mg, 0.17 mmol); solid yellow. The oxalate salt was prepared in the manner previously described in Example 78 using 80.4 mg (0.17 mmole) of the title compound and DMF in place of EtOH. Yield: 56% (53.4 mg, 0.094 mmol). P.f .: 111-114 ° C; MS (ES) m / z: 480.2 (MH) +, 240.7 (M / 2 + H)? Elemental Analysis for C32H35N5? 5 Calculated: C, 67.43; H, 6.19; N, 12.29. Found: C, 62.69; H, 5.98; N, 11.16.
EXAMPLE 85 3-. { 4- [4- (6-Methoxy-8-quinolinyl) -1- piperazinyl] cyclohexyl} -lH-indole-6-carbonitrile The title compound was prepared by the procedure described in Example 78 using 3- (4-oxo-cyclohexyl) -lH-indole-6-carbonitrile (404.8 mg, 1.7 mmol) instead of 4- (IH-pyrrolo [2, 3-b] -pyridin-3-yl) ciciohexanone. Flash chromatography was performed using a gradient elution of ethyl acetate / MeOH (40: 1 to 10: 1 to 4: 1) instead of CH2Cl2 / MeOH. Yield: 63% (493.7 mg, 1.06 mmol); Solid brown color. The oxalate salt was prepared in the manner previously described in Example 78 using 183.5 mg (0.39 mmol) of the title compound and DMF in place of EtOH. Yield: 43% (93 mg, 0.20 mmol). P.f .: 242-244 ° C; EM (ES) m / z: 466.2 (MH)? Elemental Analysis for C3? H33N505 Calculated: C, 66.97; H, 5 ~ .98; N, 12.60. Found: C, 67.56; H, 6.09; N, 13.15.
EXAMPLE 86a 8-. { 4- [(1,4-cis) -4- (5-Fluoro-1-methyl-lH-indol-3-yl) -cyclohexyl] -piperazin-1-yl} -6-methoxy-quinoline To a solution of 0.270 g of 6-methoxy, 8-piperazino-quinoline in 20 ml of CH2C12, 0.245 g of 4- (5-fluoro-l-methyl-lH-3-indolyl) was added. -ciciohexanone followed by 0.530 g of sodium triacetoxyborohydride and 0.09 ml of acetic acid. The reaction was stirred at room temperature overnight. It was rapidly cooled with 1 N NaOH, and the. The product was extracted with CH2C12. The organic phase was washed with water and dried over magnesium sulfate. The product was filtered through 75 ml of silica gel using 50% ethyl acetate / hexanes, 75% ethyl acetate / hexanes, and finally 100% ethyl acetate to give 0.115 g of the desired product: m.p. 216-218 ° C; MS (ES) m / z (relative intensity): 473 (M + + H, 100).
EXAMPLE 86b 8-. { 4- [(1, 4-trans) -4- (5-Fluoro-l-methyl-lH-indol-3-yl) -cyclohexyl] -piperazinyl-1-yl} -6-methoxy-quinoline The trans isomer was isolated at the same time as the cis isomer as an off-white solid (0.013020 g). p.f. 198-200 ° C. MS (ES) m / z (relative intensity): 473 (M + + H, 100).
EXAMPLE 87a 8-. { 4- [4- ((1,4-cis) -lH-Indol-3-yl) -cyclohexyl] -pipßrazin-1-yl} -6-methoxy-quinoline To a solution of 0.350 g of 6-methoxy, 8-piperazino-quinoline in 10 ml of CH2C12, 0.335 g of 4- (lH-3-indolyl) -cycothexanone was added followed by 0.840 g of triacetoxyborohydride. of sodium and 0.2 ml of acetic acid. The reaction was stirred at room temperature overnight. It was quenched with 1N NaOH, and the product was extracted with CH2C12. The organic phase was washed with water and dried over magnesium sulfate. The product was filtered through 125 ml of silica gel using 50% ethyl acetate / hexanes, 75% ethyl acetate / hexanes, and finally 100% ethyl acetate to give 0.041 g of the desired product: m.p. 165-171 ° C; MS (ES) m / z (relative intensity): 441 (M + + H, 100).
EXAMPLE 87b 8-. { 4- [4- ((1,4-trans) -lH-Indol-3-yl) -cyclohexyl] -piperazinyl-1-yl} -6-methoxy-quinoline The trans isomer was isolated at the same time as the cis isomer as an off-white solid (0.023 g). p.f. 118-122 ° C. MS (ES) m / z (relative intensity): 441 (M + + H, 100).
EXAMPLE 88a 3-. { (1,4-cis) -4- [4- (6-Methoxy-quinolin-8-yl) -piperazin-1-yl] -cyclohexyl} -l-methyl-lH-indole-5-carbonitrile To a solution of 0.243 g of 6-methoxy, 8-piperazino-quinoline in 10 ml of CH2C12, was added 0. 252 g of 3- (4-oxo-cyclohexyl) -1-met il-lH-indole-5-carbonitrile followed by 0.527 g of sodium triacetoxyborohydride and 0.2 ml of acetic acid. The reaction was stirred at room temperature overnight. It was quenched with 1N NaOH, and the product was extracted with CH2C12. The organic phase was washed with water and dried over magnesium sulfate. The product was filtered through 100 ml of silica gel using 50% ethyl acetate / hexanes, 75% ethyl acetate / hexanes, and finally 100% ethyl acetate to give 0.085 g of the desired product: m.p. 239-240 ° C; MS (ES) m / z (relative intensity): 480 (M + + H, 100).
EXAMPLE 88b 3-. { (1, 4-trans) -4- [4- (6-Methoxy-quinolin-8-yl) -piperazin-1-yl] -cyclohexyl} -l-methyl-lH-indole-5-carbonitrile The trans isomer was isolated at the same time as the cis isomer as an off-white solid (0.029 g). p.f. 225-228 ° C. MS (ES) m / z (relative intensity): 480 (M? H, 100).
EXAMPLE 89a 6-Methoxy-8-. { 4- (1,4-cis) - [4- (l-methyl-lH-indol-3-yl) -cyclohexyl] -piperazin-1-yl} -quinoline To a solution of 0.243 g of 6-methoxy, 8-piperazine-quinoline in 10 ml of CH2C12, 0.250 g of 4 - (l-methyl-lH-3-indolyl) -cycothexanone was added followed by 0.527 g of triacetoxyborohydride. of sodium and 0.2 ml of acetic acid. The reaction was stirred at room temperature overnight. It was quenched with 1N NaOH, and the product was extracted with CH2C12. The organic phase was washed with water and dried over magnesium sulfate. The product was filtered through 100 ml of silica gel using 50% ethyl acetate / hexanes, 75% ethyl acetate / hexanes, and finally 100% ethyl acetate to give 0.120 g of the desired product: m.p. 190-191 ° C; MS (ES) m / z (relative intensity): 455 (M + + H, 100).
EXAMPLE 89b 6-Methoxy-8-. { 4- (1,4-trans) [4- (1-methyl-lH-indol-3-yl) -cyclohexyl] -piperazinyl-1-yl} -quinoline The trans isomer was isolated at the same time as the cis isomer as an off-white solid (0.027 g). p.f. 208-210 ° C. MS (ES) m / z (relative intensity): 455 (? H, 100).
EXAMPLE 90a 8-. { 4- (1, 4-cis) -4- (5-Fluoro-1-methyl-1H-indol-3-yl) -cyclohexyl] -piperazin-1-yl} -6-methyl-quinoline To a solution of 0.275 g of 6-methyl, 8-piperazino-quinoline in 10 ml of CH2C12, 0.326 g of 4- (5-fluoro-l-methyl-lH-3-indolyl) was added. -ciciohexanone followed by 0.639 g of sodium triacetoxyborohydride and 0.2 ml of acetic acid. The reaction was stirred at room temperature overnight. It was quenched with 1N NaOH, and the product was extracted with CH2C12. The organic phase was washed with water and dried over magnesium sulfate. The product was filtered through 75 ml of silica gel using 50% ethyl acetate / hexanes, 75% ethyl acetate / hexanes, and finally 100% ethyl acetate to give 0.145 g of the desired product: m.p. 179-181 ° C; MS (ES) m / z (relative intensity): 457 (M + + H, 100).
EXAMPLE 90b 8-. { 4- (1, 4-trans) -4- (5-Fluoro-l-methyl-lH-indol-3-yl) -cyclohexyl] -piperazinyl-1-yl} -6-methyl-quinoline The trans isomer was isolated at the same time as the cis isomer as an off-white solid (0.043 g). p.f. 98-103 ° C. MS (ES) m / z (relative intensity): 457 (M? H, 100).
EXAMPLE 91a 8-. { (1,4-cis) -4- [4- (5-Cyano-1H-indol-3-yl) -cyclohexyl] -piperazin-1-yl} -6-methyl-quinoline To a solution of 0.300 g of 6-methyl, 8-piperazino-quinoline in 10 ml of CH2C12, was added 0. 280 g of 4- (l-H-3-indolyl) -cycothexanone followed by 0. 70 Q g of sodium triacetoxyborohydride and 0.2 ml of acetic acid. The reaction was stirred at room temperature overnight. It cooled quickly with NaOH 1 N, and the product was extracted with CH2C12. The organic phase was washed with water and dried over magnesium sulfate. The product was filtered through 100 ml of silica gel using 50% ethyl acetate / hexanes, 75% ethyl acetate / hexanes, and finally 100% ethyl acetate to give 0.125 g of the desired product: m.p. 132-135 ° C; MS (ES) m / z (relative intensity): 425 (M ++ H, 100).
EXAMPLE 91b 8-. { (1, 4-cis) -4- [4- (5-cyano-lH-indol-3-yl) -cyclohexyl] -piperazin-1-yl} -6-methyl-quinoline To a solution of 0.275 g of 6-methyl, 8-piperazino-quinoline in 10 ml of CH2C12, 0.315 g of 3- (4-oxo-cyclohexy-1) -lH-indole-5- was added. carbonitrile followed by 0.639 g of sodium triacetoxyborohydride and 0.2 ml of acetic acid. The reaction was stirred at room temperature overnight. It was quenched with 1N NaOH, and the product was extracted with CH2C12. The organic phase was washed with water and dried over magnesium sulfate. The product was filtered through 100 ml of silica gel using 50% ethyl acetate / hexanes, 75% ethyl acetate / hexanes, and finally 100% ethyl acetate to give 0.175 g of the desired product: m.p. 142-147 ° C; MS (ES) m / z (relative intensity): 450 (M + + H, 100).
EXAMPLE 92 8-. { (1,4-cis) -4- [4- (1-ethyl-5-Fluoro-1H-indol-3-yl) -cyclohexyl] -piperazin-1-yl} -6-methoxy-quinoline To a solution of 0.400 g of 6-methoxy, 8-piperazino-quinoline in 20 ml of CH2C12, 0.300 g of 4- (5-fluoro-l-ethyl-lH-3-indolyl) was added. -cyclohexanone followed by 0.651 g of sodium triacetoxyborohydride and 0.4 ml of acetic acid. The reaction was stirred at room temperature overnight. It was quenched with 1N NaOH, and the product was extracted with CH2C12. The organic phase was washed with water and dried over magnesium sulfate. The product was filtered through 100 ml of silica gel using 50% ethyl acetate / hexanes, 75% ethyl acetate / hexanes, and finally 100% ethyl acetate to give 0.041 g of the desired product: m.p. 203-205 ° C; MS (ES) m / z (relative intensity): 487 (M + + H, 100).
EXAMPLE 93a 8-. { (1, 4-cis) -4- [4- (5-methoxy-1-methyl-1H-indol-3-yl) -cyclohexyl] -piperazin-1-yl} -6-methoxy-quinoline To a solution of 0.500 g of 6-methoxy, 8-piperazino-quinoline in 20 ml of CH2C12, 0.565 g of 4- (5-methoxy-l-methyl-3-indolyl) -cycothexanone was added. followed by 1.1 g of sodium triacetoxyborohydride and 0.4 ml of acetic acid. The reaction was stirred at room temperature overnight. It was quenched with 1N NaOH, and the product was extracted with CH2C12. The organic phase was washed with water and dried over magnesium sulfate. The product was filtered through 200 ml of silica gel using 50% ethyl acetate / hexanes, 75% ethyl acetate / hexanes, and finally 100% ethyl acetate to give 0.077 g of the desired product: m.p. 170-172 ° C; MS (ES) m / z (relative intensity): 485 (M + + H, 100).
EXAMPLE 93b 8-. { (1,4-trans) -4- [4- (5-methoxy-lH-indol-3-yl) -cyclohexyl] -piperazin-1-yl} -6-methoxy-quinoline The trans isomer was isolated at the same time as the cis isomer as an off-white solid (0.039 g). p.f. 185-186 ° C. MS (ES) m / z (relative intensity): 485 (M + + H, 100).
EXAMPLE 94a 3-. { (1,4-cis) -4- [4- (6-isopropoxy-quinolin-8-yl) -piperazin-1-yl] -cyclohexyl} -1-methyl-lH-indole-5-carbonitrile To a solution of 0.350 g of 6-Isopropoxy, 8-piperazino-quinoline in 10 ml of CH2C12, 0.356 g of 3- (4-oxo-cyclohexyl) -l was added. -methyl-lH-indole-5-carbonitrile followed by 0.405 g of triacetoxyborohydride. of sodium and 0.08 ml of acetic acid. The reaction was stirred at room temperature overnight. It was rapidly cooled with 1 N NaOH, and the product was extracted with CH2C12. The organic phase was washed with water and dried over magnesium sulfate. The product was filtered through 100 ml of silica gel using 50% ethyl acetate / hexanes, 75% ethyl acetate / hexanes, and finally 100% ethyl acetate to give 0.141 g of the desired product: m.p. 223-226 ° C; MS (ES) m / z (relative intensity): 508 (M + + H, 100).
EXAMPLE 94b 3-. { (1,4-trans) -4- [4- (6-isopropoxy-quinolin-8-yl) -piperazin-1-yl] -cyclohexyl} -1-methyl-1H-indole-5-carbonitrol The trans-isomer was isolated at the same time as the cis-isomer as an off-white solid (0.087 g). p.f. 221-223 ° C. MS (ES) m / z (relative intensity 508 (M? H, 100).
EXAMPLE 95a 3-. { (1,4-cis) -4- [4- (6-fluoro-quinolin-8-yl) -piperazin-1-yl] -cyclohexyl} -l-methyl-lH-indole-5-carbonitrile To a solution of 0.300 g of 6-Fluoro, 8-piperazino-quinoline in 10 ml of CH2C12, 0.411 g of 3- (4-oxo-cyclohexyl) -l was added. -methyl-lH-indole-5-carbonitrile followed by 0.359 g of sodium triacetoxyborohydride and 0.1 ml of acetic acid. The reaction was stirred at room temperature overnight. It was quenched with 1N NaOH, and the product was extracted with CH2C12. The organic phase was washed with water and dried over magnesium sulfate. The product was filtered through 100 ml of silica gel using 50% ethyl acetate / hexanes, 75% ethyl acetate / hexanes, and finally 100% ethyl acetate to give 0.187 g of the desired product: m.p. 230 ° C; MS (ES) m / z (relative intensity): 468 (M + + H, 100).
EXAMPLE 95b 3-. { (1, 4-trans) -4- [4- (6-fluoro-quinolin-8-yl) -piperazin-1-yl] -cyclohexyl} -l-methyl-lH-indol-5-carbonitrile The trans isomer was isolated at the same time as the cis isomer as an off-white solid (0.039 g). p.f. 214-216 ° C. MS (ES) m / z (relative intensity): 468 (M? H, 100).
EXAMPLE 96a 3-. { (1, 4-cis) -4- [4- (6-trifluoromethoxy-quinolin-8-yl) -piperazin-1-yl] -cyclohexyl} -l-methyl-lH-indole-5-carbonitrile To a solution of 0.297 g of 6-trifluoromethoxy, 8-piperazine-quinoline in 10 ml of DCE, was added 0. 272 g of 3- (4-oxo-cyclohexyl) -l-methyl-1H-indole-5-carbonitrile followed by 0.316 g of sodium triacetoxyborohydride and 0.1 ml of acetic acid. The reaction was stirred at room temperature overnight. It was quenched with 1N NaOH, and the product was extracted with CH2C12. The organic phase was washed with water and dried over magnesium sulfate. The product was filtered through 100 ml of silica gel using 50% ethyl acetate / hexanes, 75% ethyl acetate / hexanes, and finally 100% ethyl acetate to give 0.166 g of the desired product: m.p. 206 ° C; EM (ES) m / z (relative intensity): 534 (M + + H, 100).
EXAMPLE 96b 3-. { (1, 4-trans) -4- [4- (6-trifluoromethoxy-quinolin-8-yl) -piperazin-1-yl] -cyclohexyl} -l-methyl-lH-indole-5-carbonitrile The trans isomer was isolated at the same time as the cis isomer as an off-white solid (0.064 g). p.f. 170 ° C. MS (ES) m / z (relative intensity): 534 (? H, 100).
EXAMPLE 97a 3-. { (1,4-cis) -4- [4- (5-methoxy-quinolin-8-yl) -piperazin-1-yl] -cyclohexyl} -l-methyl-lH-indole-5-carbonitrile To a solution of 0.500 g of 5-methoxy, 8-piperazino-quinoline in 10 ml of DCE, 0.544 g of 3- (4-oxo-cyclohexyl) -1 was added. -met il-lH-indole-5-carbonitrile followed by 0.633 g of sodium triacetoxyborohydride and 0.2 ml of acetic acid. The reaction was stirred at room temperature overnight. It was quenched with 1N NaOH, and the product was extracted with CH2C12. The organic phase was washed with water and dried over magnesium sulfate. The product was filtered through 100 ml of silica gel using 50% ethyl acetate / hexanes, 75% ethyl acetate / hexanes, and finally 100% ethyl acetate to give 0.310 g of the desired product: m.p. 221 ° C; MS (ES) m / z (relative intensity): 480 (M + + H, 100).
EXAMPLE 97b 3-. { (1, 4-trans) -4- [4- (5-methoxy-quinolin-8-yl) -piperazin-1-yl] -cyclohexyl} -l-methyl-lH-indole-5-carbonitrile The trans isomer was isolated at the same time as the cis isomer as an off-white solid (0.118 g). p.f. 206 ° C. MS (ES) m / z (relative intensity): 480 (M? H, 100).
EXAMPLE 98a 8-. { (1,4-cis) -4- [4- (5-Fluoro-lH-indol-3-yl) -cyclohexyl] -piperazin-1-yl} -6-Fluoro-qinoline To a solution of 0.300 g of 6-Fluoro, 8-piperazino-quinoline in 10 ml of DCE, 0.411 g of 4- (5-fluoro-1-met il-3-indolyl) was added. -ciciohexanone followed by 0.349 g of sodium triacetoxyborohydride and 0.1 ml of acetic acid. The reaction was stirred at room temperature overnight. It was quickly cooled with 1 N NaOH, and the product was extracted with CH2C12. The organic phase was washed with water and dried over magnesium sulfate. The product was filtered through 100 ml of silica gel using 50% ethyl acetate / hexanes, 75% ethyl acetate / hexanes, and finally 100% ethyl acetate to give 0.190 g of the desired product: m.p. 194.5 ° C; MS (ES) m / z (relative intensity): 461 (M + + H, 100).
EXAMPLE 98b 8-. { (1,4-trans) -4- [4- (5-Fluoro-lH-indol-3-yl) -cyclohexyl] -piperazin-1-yl} -6-Fluoro-quinoline The trans isomer was isolated at the same time as the cis isomer as an off-white solid (0.062 g). p.f. 171 ° C. MS (ES) m / z (relative intensity): 461 (M? H, 100).
EXAMPLE 99a 3-. { (1, 4-cis) -4- [4- (6-Benzyloxy-quinolin-8-yl) -piperazin-1-yl] -cyclohexyl} -l-methyl-lH-indole-5-carbonitrile To a solution of 0.300 g of 6-Benzyloxy, 8-piperazino-quinoline in 10 ml of DCE, 0.252 g of 3- (4-oxo-cyclohexyl) -1 was added. -met il-lH-indole-5-carbonitrile followed by 0.297 g of sodium triacetoxyborohydride and 0.1 ml of acetic acid. The reaction was stirred at room temperature overnight. It was quenched with 1N NaOH, and the product was extracted with CH2C12. The organic phase was washed with water and dried over magnesium sulfate. The product was filtered through 100 ml of silica gel using 50% ethyl acetate / hexanes, 75% ethyl acetate / hexanes, and finally 100% ethyl acetate to give 0.172 g of the desired product: m.p. 171 ° C; MS (ES) m / z (relative intensity): 556 (M + + H, 100).
EXAMPLE 99b 3-. { (1, 4-trans) -4- [4- (6-Benzyloxy-quinolin-8-yl) -piperazin-1-yl] -cyclohexyl} -l-methyl-lH-indol-5-carbonitrile The trans isomer was isolated at the same time as the cis isomer as an off-white solid (0.083 g). p.f. 118.5 ° C. MS (ES) m / z (relative intensity): 556 (M + + H, 100).
EXAMPLE 100 3-. { (1, 4-cis) -4- [4- (6-Hydroxy-quinolin-8-yl) -piperazin-1-yl] -cyclohexyl} -1-methyl-lH-indole-5-carbonitrile A solution of 0.100 g of 3-. { (1,4-cis) -4- [4- (6-Benzyloxy-quinolin-8-yl) -piperazin-1-yl] -cyclohexyl} -l-methyl-lH-indole-5-carbonyl trile in THF was added to a suspension of 0.015 g of 10% Pd / C in MeOH and hydrogenated by H hour. It was filtered and the solvent was evaporated to give 0.045 g of the desired product. P.f. 144 ° C. MS (ES) m / z (relative intensity): 466 (M + + H, 100).
EXAMPLE 101 3-. { (1,4-cis) -4- [4- (6-fluoro-8-quinolinyl) -1- piperazinyl] -cyclohexyl} -l-methyl-lH-indole-5-carboxamide To a solution of 0.100 g of 6-fluoro-8-. { 4- [4- (5-fluoro-l-methyl-lH-indol-3-yl) cyclohexyl] -1-? Piperazinyl} -quinoline in 5 ml (THF: MeOH), 1 ml of 5N NaOH was added followed by 2 ml of 30% H202. The mixture was stirred at AMBIENT TEMPERATURE for 24 hours. Water was added and the product was filtered to give 0.035 g of the desired product. P.f. 289 ° C. MS (ES) m / z (relative intensity): 486 (M + + H, 100).
EXAMPLE 102a 3-. { (1, 4-cis) -4- [4- (5-trifluoromethyl-quinolin-8-yl) -pipßrazin-1-yl] -cyclohexyl} -l-methyl-lH-indole-5-carbonitrile To a solution of 0.250 g of 5-trifluoromethyl, 8-piperazine-quinoline in 10 ml of DCE, was added 0. 224 g of 3- (4-oxo-cyclohexyl) -l-methyl-1H-indole-5-carbonitrile followed by 0.287 g of sodium triacetoxyborohydride and 0.2 ml of acetic acid. The reaction was stirred at room temperature overnight. It was quenched with 1N NaOH, and the product was extracted with CH2C12. The organic phase was washed with water and dried over magnesium sulfate. The product was filtered through 100 ml of silica gel using 50% ethyl acetate / hexanes, 75% ethyl acetate / hexanes, and finally 100% ethyl acetate to give 0.057 g of the desired product: m.p. 231 ° C; MS (ES) m / z (relative intensity): 518 (M + + H, 100).
EXAMPLE 102b 3-. { (1, 4-trans) -4- [4- (5-trifluoromethyl-quinolin-8-yl) -piperazxn-1-xl] -cyclohexyl} -l-methyl-lH-indole-5-carbonitrile The trans isomer was isolated at the same time as the cis isomer as an off-white solid (0.044 g). p.f. 194-197 ° C. MS (ES) m / z (relative intensity): 518 (M? H, 100).
EXAMPLE 103a 3-. { (1,4-cis) -4- [4- (6-chloro-quinolin-8-yl) -piperazin-1-yl] -cyclohexyl} -l-methyl-lH-indole-5-carbonitrile To a solution of 0.300 g of 6-chloro, 8-piperazino-quinoline in 10 ml of DCE, 0.305 g of 3- (4-oxo-cyclohexyl) -1 was added. -methyl-1H-indole-5-carbonitrile followed by 0.274 g of sodium triacetoxyborohydride and 0.2 ml of acetic acid. The reaction was stirred at room temperature overnight. It was quenched with 1N NaOH, and the product was extracted with CH2C12. The organic phase was washed with water and dried over magnesium sulfate. The product was filtered through 100 ml of silica gel using 50% ethyl acetate / hexanes, 75% ethyl acetate / hexanes, and finally 100% ethyl acetate to give 0.057 g of the desired product: m.p. 222 ° C; MS (ES) m / z (relative intensity): 485 (M + + H, 100).
EXAMPLE 103b 3-. { (1, 4-trans) -4- [4- (6-chloro-quinolin-8-yl) -piperazin-1-yl] -cyclohexyl} -l-methyl-lH-indole-5-carbonitrile The trans isomer was isolated at the same time as the cis isomer as an off-white solid (0.044 g). p.f. 229 ° C. MS (ES) m / z (relative intensity): 485 (M? H, 100).
EXAMPLE 104a 8-. { (1,4-cis) -4- [4- (5-Fluoro-l-methyl-lH-indol-3-yl) -cyclohexyl] -piperazin-1-yl} -6-chloro-quinoline To a solution of 0.247 g of 6-chloro, 8-piperazino-quinoline in 10 ml of DCE, 0.245 g of 4- (5-fluoro-l-methyl-3-indolyl) -cycothexanone was added. followed by 0.274 g of sodium triacetoxyborohydride and 0.2 ml of acetic acid. The reaction was stirred at room temperature overnight. It was quenched with 1N NaOH, and the product was extracted with CH2C12. The organic phase was washed with water and dried over magnesium sulfate. The product was filtered through 100 ml of silica gel using 50% ethyl acetate / hexanes, 75% ethyl acetate / hexanes, and finally 100% ethyl acetate to give 0.070 g of the desired product: m.p. 219 ° C; MS (ES) m / z (relative intensity): 478 (M + + H, 100).
EXAMPLE 104b 8-. { (1,4-trans) -4- [4- (5-Fluoro-l-methyl-lH-indol-3-yl) -cyclohexyl] -piperazin-1-yl} -6-chloro-quinoline The trans isomer was isolated at the same time as the cis isomer as an off-white solid (0.049 g). p.f. 193 ° C. MS (ES) m / z (relative intensity): 478 (M + + H, 100).
EXAMPLE 105a 3-. { (1,4-Cis) -4- [4- (5-chloro-quinolinyl) -piperazinyl] -cyclohexyl} -l-methyl-lH-indole-5-carbonitrile To a solution of 0.250 g of 5-chloro, 8-piperazino-quinoline in 10 ml of DCE, was added 0. 260 g of 3- (4-oxo-cyclohexyl) -l-methyl-1H-indole-5-carbonitrile followed by 0.274 g of sodium triacetoxyborohydride and 0.2 ml of acetic acid. The reaction was stirred at room temperature overnight. It was quenched with 1N NaOH, and the product was extracted with CH2C12. The organic phase was washed with water and dried over magnesium sulfate. The product was filtered through 100 ml of silica gel using 50% ethyl acetate / hexanes, 75% ethyl acetate / hexanes, and finally 100% ethyl acetate to give 0.080 g of the desired product: m.p. 243-248 ° C; MS (ES) m / z (relative intensity): 485 (M + + H, 100).
EXAMPLE 105b 3-. { (1, 4-trans) -4- [4- (5-chloro-quinolinyl) -piperazinyl] -cyclohexyl} -l-methyl-lH-indol-5'-carbonitrile The trans isomer was isolated at the same time as the cis isomer as an off-white solid (0.034 g). p.f. 192-196 ° C. MS (ES) m / z (relative intensity): 485 (M? H, 100).
EXAMPLE 106a 8-. { (1,4-cis) -4- [4- (5-Fluoro-l-methyl-lH-indol-3-yl) -cyclohexyl] -piperazin-1-yl} -5-chloro-quinoline To a solution of 0.250 g of 5-chloro, 8-piperazino-quinoline in 10 ml of DCE, 0.224 g of 4- (5-fluoro-l-methyl-3-indolyl) -cycothexanone was added. followed by 0.274 g of sodium triacetoxyborohydride and 0.1 ml of acetic acid. The reaction was stirred at room temperature overnight. It was quenched with 1N NaOH, and the product was extracted with CH2C12. The organic phase was washed with water and dried over magnesium sulfate. The product was filtered through 100 ml of silica gel using 50% ethyl acetate / hexanes, 75% ethyl acetate / hexanes, and finally 100% ethyl acetate to give 0.053 g of the desired product: m.p. 196 ° C; MS (ES) m / z (relative intensity): 478 (M + + H, 100).
EXAMPLE 106b 8-. { (1,4-trans) -4- [4- (5-Fluoro-l-methyl-lH-indol-3-yl) -cyclohexyl] -piperazin-1-yl} -5-Chloro-quinoline The trans isomer was isolated at the same time as the cis isomer as an off-white solid (0.025 g). p.f. 196 ° C. MS (ES) m / z (relative intensity): 478 (M? H, 100).
EXAMPLE 107a 8-. { (1,4-cis) -4- [4- (6-Fluoro-l-methyl-lH-indol-3-yl) -cyclohexyl] -piperazin-1-yl} -5-chloro-quinoline To a solution of 0.250 g of 5-chloro, 8-piperazino-quinoline in 10 ml of DCE, 0.250 g of 4- (6-fluoro-1-met il-3-indol il) was added. -ciciohexanone followed by 0.274 g of sodium triacetoxyborohydride and 0.2 ml of acetic acid. The reaction was stirred at room temperature overnight. It was quenched with 1N NaOH, and the product was extracted with CH2C12. The organic phase was washed with water and dried over magnesium sulfate. The product was filtered through 100 ml of silica gel using 50% ethyl acetate / hexanes, 75% ethyl acetate / hexanes, and finally 100% ethyl acetate to give 0.030 g of the desired product: m.p. 107-110 ° C; MS (ES) m / z (relative intensity): 478 (M + + H, 100).
EXAMPLE 107b 8-. { (1,4-trans) -4- [4- (6-Fluoro-l-methyl-lH-indol-3-yl) -cyclohexyl] -piperazin-1-yl} -5-chloro-quinoline The trans isomer was isolated at the same time as the cis isomer as an off-white solid (0.014 g). p.f. 228 ° C. MS (ES) m / z (relative intensity): 478 (M + + H, 100).
EXAMPLE 108a 8-. { (1,4-cis) -4- [4- (5-benzyloxy-1-methyl-lH-i? Dol-3-yl) -cyclohexyl] -piperazin-1-yl} -6-methoxy-quinoline To a solution of 0.650 g of 6-methoxy, 8-piperazino-quinoline in 15 ml of DCE, 0.959 g of 4- (5-benzyloxy-l-methyl-3-indolyl) -cycothexanone was added. followed by 0.790 g of sodium triacetoxyborohydride and 0.5 ml of acetic acid. The reaction was stirred at room temperature overnight. It was quenched with 1N NaOH, and the product was extracted with CH2C12. The organic phase was washed with water and dried over magnesium sulfate. The product was filtered through 100 ml of silica gel using 50% ethyl acetate / hexanes, 75% ethyl acetate / hexanes, and finally 100% ethyl acetate to give 0.175 g of the desired product: m.p. 168 ° C; MS (ES) m / z (relative intensity): 561 (M + + H, 100).
EXAMPLE 108b 8-. { (1,4-trans) -4- [4- (5-benzyloxy-l-methyl-lH-indol-3-yl) -cyclohexyl] -piperazin-1-yl} -6-methoxy-quinoline The trans isomer was isolated at the same time as the cis isomer as an off-white solid (0.055 g). p.f. 228 ° C. MS (ES) m / z (relative intensity): 561 (M + + H, 100).
EXAMPLE 109a 8-. { (1,4-cis) -4- [4- (6-Fluoro-l-methyl-lH-indol-3-yl) -cyclohexyl] -piperazin-1-yl} -5-fluoro-quinoline To a solution of 0.231 g of 5-Fluoro, 8-piperazino-quinoline in 10 ml of DCE, 0.245 g of 4- (6-fluoro-l-methyl-3-indolyl) -cycothexanone was added. followed by 0.274 g of sodium triacetoxyborohydride and 0.1 ml of acetic acid. The reaction was stirred at room temperature overnight. It was quenched with 1N NaOH, and the product was extracted with CH2C12. The organic phase was washed with water and dried over magnesium sulfate. The product was filtered through 100 ml of silica gel using 50% ethyl acetate / hexanes, 75% ethyl acetate / hexanes, and finally 100% ethyl acetate to give 0.030 g of the desired product: m.p. 112-115 ° C; MS (ES) m / z (relative intensity): 461 (M + + H, 100).
EXAMPLE 109b 8-. { (1, 4-trans) -4- [4- (6-fluoro-l-methyl-lH-indol-3-yl) -cyclohexyl] -piperazin-1-yl} -5-fluoro-quinoline The trans isomer was isolated at the same time as the cis isomer as an off-white solid (0.010 g). MS (ES) m / z (relative intensity): 461 (M + + H, 100).
EXAMPLE 110 3-. { (1,4-cis) -4- [4- (6-methoxy-8-quinolinyl) -1- piperazinyl] -cyclohexyl} -l-methyl-lH-indol-5-ol A solution of 0.120 g of 8-. { (1,4-cis) -4- [4- (5-benzyloxy-1-methyl-1H-indol-3-yl) -cyclohexyl] -piperazin-1-yl} -6-methoxy-quinoline in 10 ml of THF was added to a suspension of 0.100 g of 10% Pd / C in MeOH and hydrogenated for 1 hour. It was filtered and the solvent was evaporated to give 0.036 g of the desired product. P.f. 250 ° C. MS (ES) m / z (relative intensity): 471 (M + + H, 100).
EXAMPLE Illa 8-. { (1,4-cis) -4- [4- (5-fluoro-1-methyl-lH-indol-3-yl) -cyclohexyl] -piperazin-1-yl} -5-fluoro-quinoline To a solution of 0.200 g of 5-Fluoro, 8-piperazino-quinoline in 10 ml of DCE, 0.245 g of 4- (5-fluoro-1-methyl-3-indolyl) -cycothexanone was added. followed by 0.274 g of sodium triacetoxyborohydride and 0.1 ml of acetic acid. The reaction was stirred at room temperature overnight. It was quenched with 1N NaOH, and the product was extracted with CH2C12. The organic phase was washed with water and dried over magnesium sulfate. The product was filtered through 100 ml of silica gel using 50% ethyl acetate / hexanes, 75% ethyl acetate / hexanes, and finally 100% ethyl acetate to give 0.040 g of the desired product: m.p. 199-202 ° C; MS (ES) m / z (relative intensity): 461 (M + + H, 100).
EXAMPLE 111b 8-. { (1,4-trans) -4- [4- (5-fluoro-1-methyl-lH-indol-3-yl) -cyclohexyl] -piperazin-1-yl} -5-fluoro-quinoline The trans isomer was isolated at the same time as the cis isomer as an off-white solid (0.021 g). p.f. 197 ° C. MS (ES) m / z (relative intensity): 461 (M + + H, 100).
EXAMPLE 112a 8-Chloro-7-. { (1,4-cis) -4- [4- (5-fluoro-1-methyl-lH-indol-3-yl) -cyclohexyl] -1- 'piperazinyl} quinoline To a solution of 0.247 g of 8-chloro, 7-piperazino-quinoline in 10 ml of DCE, 0.245 g of 4- (5-fluoro-l-methyl-3-indolyl) -cidiohexanone was added followed by 0.274 g of sodium triacetoxyborohydride and 0.2 ml acetic acid. The reaction was stirred at room temperature overnight. It was quenched with 1N NaOH, and the product was extracted with CH2C12. The organic phase was washed with water and dried over magnesium sulfate. The product was filtered through 100 ml of silica gel using 50% ethyl acetate / hexanes, 75% ethyl acetate / hexanes, and finally 100% ethyl acetate to give 0.085 g of the desired product: m.p. 182-184 ° C; MS (ES) m / z (relative intensity): 478 (M + + H, 100).
EXAMPLE 112b 8-Chloro-7-. { (1,4-trans) -4- [4- (5-fluoro-1-methyl-lH-indol-3-yl) -cyclohexyl] -1- 'piperazinyl} quinoline The trans isomer was isolated at the same time as the cis isomer as an off-white solid (0.025 g). p.f. 181-182 ° C. MS (ES) m / z (relative intensity): 478 (M + + H, 100).
EXAMPLE 113a 3-. { (1, 4-cis) -4- [4- (8-chloro-7-quinolinyl) -1- piperazinyl] -cyclohexyl} -l-methyl-lH-indol-5- * carbonitrile To a solution of 0.247 g of 8-chloro, 7-piperazino-quinoline in 10 ml of DCE, was added 0. 252 g of 4- (5-fluoro-l-methyl-l-H-3-indolyl) -cciohexanone followed by 0.274 g of sodium triacetoxyborohydride and 0. 2 ml of acetic acid. The reaction was stirred at room temperature overnight. It was quenched with 1N NaOH, and the product was extracted with CH2C12. The organic phase was washed with water and dried over magnesium sulfate. The product was filtered through 100 ml of silica gel using 50% ethyl acetate / hexanes, 75% ethyl acetate / hexanes, and finally 100% ethyl acetate to give 0.075 g of the desired product: m.p. 240-242 ° C; MS (ES) m / z (relative intensity): 485 (M + + H, 100).
EXAMPLE 113b 3-. { (1, 4-trans) -4- [4- (8-chloro-7-quinolinyl) -1- piperazinyl] -cyclohexyl} -l-methyl-lH-indole-5-x carbonitrile The trans isomer was isolated at the same time as the cis isomer as an off-white solid (0.015 g). p.f. 233-237 ° C. MS (ES) m / z (relative intensity): 485 (M "? H, 100).
EXAMPLE 114a 3-. { (1,4-cis) -4- [4- (4-Fluoro-quinolin-8-yl) -piperazin-1-yl] -cyclohexyl} -lH-indole-5-carbonitrile To a solution of 0.310 g of 4-fluoro-8-piperazine-quinoline in 50 ml of CH2C12, was added 0. 319 g (1.34 mmol) of 3- (4-oxo-cyclohexyl) -lH-indole-5-carbonitrile followed by 0.402 g (1.5 equivalents) of sodium triacetoxyborohydride and 0.076 ml of acetic acid. The reaction was stirred at room temperature overnight. It was quenched with 1 N NaOH, and the product was extracted with ether. The organic phase was washed with water and dried. The product was filtered through 75 ml of silica gel using 25% ethyl acetate / hexanes, 75% ethyl acetate / hexanes, to give 0.185 g of the cis: p.p. 152-160 ° C; MS (ES) m / z (relative intensity): 454.3 (M? H, 100).
EXAMPLE 114b 3-. { (1, 4-trans) -4- [4- (4-fluoro-quinolin-8-yl) -piperazin-1-yl] -cyclohexyl} -lH-indole-5-carbonitrile The trans isomer (0.065 g) was isolated at the same time as the cis compound, as an off-white solid: m.p. 144-152 ° C. MS (ES) m / z (relative intensity): 454.4 (M + + H, 100).
The activity of the present compounds was demonstrated by the following standard pharmacological test procedures. PCR cloning of the human 5-H receptor subtype IA from a genomic library has been previously described by Chanda et al., Mol. Pharmacol. , 43: 516 (1993). A stable Chinese hamster ovary cell line expressing the human 5-HT? A receptor subtype (5-HT? A. CHO cells) was employed throughout this study. Cells were maintained in DMEM supplemented with 10% fetal bovine serum, non-essential amino acids and penicillin / streptomycin. The cells were grown to confluence of 95-100% as a monolayer before the membranes were harvested for binding studies. The cells were gently scraped from the culture plates, transferred to centrifuge tubes, and washed twice by centrifugation (2000 rpm for 10 minutes, 4 ° C) in buffer (50 mM Tris).; pH 7.5). The resulting pellets are aliquoted and maintained at -80 ° C. On the day of the test, the cells were melted on ice, and resuspended in buffer. The studies were conducted using [3 H] 8-OH-DPAT as the radioligand. The binding assay was performed in 96-well microtiter plates in a final total volume of 250 μl of buffer. The comparison experiments were performed using 7 unclassified drug concentrations and a final ligand concentration of 1.5 nM. No specific binding was determined in the presence of 10 μM 5HT. Saturation analysis was conducted using [3H] 8-OH-DPAT at concentrations varying from. 0.3-30 nM.
After an incubation of 30 minutes at room temperature, the reaction was terminated by the addition of ice-cooled buffer and rapid filtration using a Brandel M-96 Cell Harvester (Gaithersburg, MD) through a GF / B filter pre-moistened with 30 ml. minutes in 0.5% polyethyleneimine. A protocol similar to that used by Cheetham et al., Neuropharmacol. , 32: 737 (1993) to determine the affinity of the compounds for the serotonin transporter. Briefly, the frontal cortical membranes prepared from male Sprague-Dawley rats were incubated with 3 H-paroxetine (0.1 nM) for 60 minutes at 25 ° C. All tubes also contained any vehicle, test compounds (one to eight concentrations), or a saturating concentration of fluoxetine (10 μM) to define the specific binding. All reactions were terminated by the addition of ice-cooled Tris buffer followed by rapid filtration using. a Tom Tech filtration device to separate the free H3-paroxetine linkage. Linkage radioactivity was quantified using a Wallac 1205 Beta Píate counter. The non-linear regression analysis was used to determine the IC50 values that were converted to Ki values using the method established in Cheng and Prusoff, Biochem. Pharmacol., 22: 3099 (1973) (Ki = IC50 / ((Radioligand concentrate) / (1 + KD)). The [35S] -GTP? S binding assay was similar to that used by Lazareno and Birdsall, Br. J Pharmacol. 109: 1120 (1993): Briefly, membrane fragments of the cloned 5-HT? A receptor (as used by the 5-HT? A receptor binding assays) were stored at -70 ° C. , the membranes were thawed rapidly, centrifuged at 40,000 xg for 10 minutes in a test buffer (25 mM HEPES, 3 mM MgCl, 100 mM NaCl, 1 mM EDTA, 10 uM GDP, 500 mM DTT, pH 8.0). These membranes were then incubated for 30 minutes at 30 ° C with [35S] GTPgS (1 nM) in the presence of a vehicle, a test compound (one to eight concentrations), or an excess of 8-OH-DPAT to define the Maximal agonist response All reactions were terminated by the addition of an ice-cooled Tris buffer followed by rapid filtration using a Tom Tech® filtration device. to separate the binding of [35S] GTPgS free. The agonists produced an increase in the binding amount of [35S] GTPgS while the antagonists produced no increase in the binding. The binding radioactivity was counted and analyzed as in the above.
The following assays were performed by incubating the cells with DMEM containing 25 mM HEPES, 5 mM theophylline and 10 μM pargyline for a period of 20 minutes at 37 ° C. Functional activity was assessed by treating the cells with forskolin (final concentration of 1 uM) followed immediately by the test compounds (6 concentrations) for an additional 10 minutes at 37 ° C. In separate experiments, 6 concentrations of the antagonist were preincubated for 20 minutes before the addition of 10 nM 8-OH-DPAT and forskolin. The reaction was terminated by removing the medium and adding 0.5 ml of ice-cold assay buffer. The plates were stored at -20 ° C before the evaluation of cAMP formation by a cAMP SPA assay (Amersham). The compounds tested correspond to those prepared in Examples 1-13 above. The results of the procedures are set forth in Table 1.
Example ST GTP? S ED50 cAMP ED50 No. (Ki, nM) (Ks, nM,) (% EMax) ÍEMax) the 32.0 38.0 327 (0%) 631 (0%) lb 5.29 155 176 (32%) 17 (77%) 2a 117.3 27% 2b 22.3 0% 3a 36.7 5.4 650 (10%) 400 (0%) 3b 4.62 10.07 42.6 (51%) 155 (0%) 4a 33.5 12.7 278 (0%) 580 (0%) 4b 5.45 35% 85 (7.5%) 5a .0% 34% 5b 78.7% 14% 6a 325.7 28 84.6 (53%) 4.72 (80%) 6b 58.3 20% 7a 69.6 1.62 539 (0%) 87 (0%) 7b 3.51 4.19 8.9 (83%) 8a 60.3 25% 0% 357 (0%) 8b 2.87 0% 38.6 (32%) 8.9 (77%) 9a 87.1 4% 9b 13.0 12% 10a 15.81 18% 0% 209 (0%) 10b 7.78 0% 16.3 (14%) 3.9 (79%) 11 0% 40 12a 234 0.76 12b 53.2 35% 13 a 563.5 8.9 13b 827 40 14a 819.9 17 14b 0% 40 15a 694.2 28 15b 0% 16% 16a 0% 29.0 16b 0% ßl00nM 25% 100nM 17 0% 2.5 18 129.4 1.36 Example GTP? S ED50 cAMP ED50 5-OTIA ST No. < Ki, nM) (K,, nM,) (% EMax) (EMax) 19a 264.4 5.72 19b 26.2 24% 418 (74%) 14.9 (92%) 20a 631.2 29% 20b 14.9 0% 35.5 (33%) 3.05 (75.5%) 21 110.4 11% 22a 80.7 4.96 0% 101.3 (0%) 22b 11.6 36.5 4.5% 357 (0%) 23a 103.2 22% 23b 14.9 32% 24a 65.7 6.90 15.4% 52.1 (81%) 24b 11.3 36.0 73% 25a 67.7 63.0 9% 16.0 (0%) 25b 9.66 58.0 24 (46%) 26a 59.1 4.1 3960 (18%) 59.6 (0%) 26b 8.5 23.0 15 (39%) 27a 69.7 8.6 139 (20%) 212 (0%) 27b 6.54 28.0 26 (66%) 28 25.1 2.02 25 (0%) 95 (0%) 29th 43.9 2.25 23% 9.05 (0%) 29b 2.91 46.0% 34 (70%) 30 24.5 1.25 29.5 (95%) 31a 142.2 13 31b 32.4 17% 32a 245.6 14 32b 49.1 22% 33a 98.9 1.9 33b 19.2 45.0 33c 431.0 7.1 34a 185.4 1.49 34b 8.37 17.0 35 70.1 91 36 12.34 28 84.6 (53%) 4.72 (80%) 38 124 7.22 44c 21.0 1.5 556 (0%) 521 (0%) As demonstrated by the results set forth in the foregoing, the compounds of the present invention are active with respect to 5HT1 " " > receptors and generally elevate Serotonin levels by inhibiting 5-HT transport Accordingly, the compounds present should be useful in the treatment of disorders related to defects in serotonin concentration The compounds of this invention can be prepared orally or parenterally, pure or in combination with conventional pharmaceutical carriers Applicable solid carriers may include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or disintegrating agents of Tablets or an encapsulation material In powders, the carrier is a finely divided solid that is mixed with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the desired shape and size. The powders and tablets preferably contain up to 99% of the active ingredient. Any of the solid carriers known to those skilled in the art can be used with the compounds of this invention. Particularly suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, low melting waxes, and ion exchange resins. Liquid carriers can be used in the preparation of solutions, suspensions, emulsions, syrups and elixirs of the compounds of this invention. The compounds of this invention can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats. The liquid carrier may contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators. Suitable examples of liquid carriers for oral and parenteral administration include water (particularly containing additives as in the above, for example, cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, for example glycols) and their derivatives and oils (for example fractionated coconut oil and peanut oil). For parenteral administration, the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in compositions for parenteral administration. Liquid pharmaceutical compositions which are sterile solutions or suspensions may be used for example, by intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. The compositions for oral administration can be either in the form of liquid or solid composition. Preferably, the pharmaceutical compositions containing the compounds of this invention are in unit dosage form, for example, tablets or capsules. Thus, the compositions can be sub-divided into unit doses containing appropriate amounts of the present compounds. The unit dosage forms may be packaged compositions, for example, packaged powders, vials, ampoules, prefilled syringes or sachets containing liquids. Alternatively, the unit dosage form may be, for example, a capsule or tablet itself, or it may be the appropriate number of any such compositions in package form. The therapeutically effective amount of the compounds of this invention that are administered and the dosage regimen depends on a variety of factors, including the subject's weight, age, sex and medical condition, the severity of the disease, the route and frequency of administration , and the specific compound employed, and thus can vary widely. However, it is believed that the pharmaceutical compositions may contain the compounds of this invention in the range of about 0.1 to about 2000 mg, preferably in the range of about 0.5 to about 500 mg and more preferably between about 1 and about 100 mg . The projected daily doses of the active compound are from about 0.01 to about 100 mg / kg of body weight. Daily doses can be conveniently administered two to four times per day. The present invention may be expressed in other specific forms without departing from the spirit and essential attributes thereof and accordingly, reference is made to the appended claims, rather than to the preceding specification, as it indicates the scope of the invention. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (10)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:
1. A compound of the formula: ? characterized in that: Ra, Ri, R2 and R3 are each, independently, hydrogen, or a substituent selected from halogen, CF3, alkyl, alkoxy, MeS02, amino or aminocarbonyl (each optionally substituted by one or two groups selected from alkyl and benzyl) carboxy, or alkoxycarbonyl; or two adjacent groups of Ra and R? -4 together can form a 5-7 membered carbocyclic or heterocyclic ring which is optionally substituted by a substituent defined therein; R 4 is hydrogen, halogen, or alkyl; R5 is hydrogen, alkyl, arylalkyl, or aryl; R6 is hydrogen, halogen, CF3, CN, carbamide, alkoxy or benzyloxy; Xi /? 2 and? 3 are each carbon; And it is CH or nitrogen; and Z is carbon or nitrogen; or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1, characterized in that: Ra, Ri, R2 and R3 are each, independently, hydrogen, halogen, alkyl, alkoxy or together they can form a 5-7 membered carbocyclic or heterocyclic ring;
3. A compound according to claim 1 or claim 2, characterized in that R is hydrogen or halogen.
4. A compound according to any of claims 1 to 3, characterized in that R5 is hydrogen, alkyl or alkylaryl.
5. A compound according to any of claims 1 to 6, characterized in that Rβ is hydrogen, halogen, CN or alkoxy.
6. A compound according to any of claims 1 to 5, characterized in that Y and Z are each carbon.
7. A compound according to claim 1, characterized in that it is selected from the following: 3- [cis-4- [4- (lH-Indol-4-yl) -1-piperazinyl] cyclohexyl] -lH-indole; 3- [trans -4- [4- (lH-Indol-4-yl) -1-piperazinyl] cyclohexyl] -lH-indole; 4-Fluoro-3- [cis -4- [4- (lH-indol-4-yl) -1-piperazinyl] -cyclohexyl] -lH-indole; 4-Fluoro-3- [trans -4- [4- (lH-indol-4-yl) -1-piperazinyl] -cyclohexyl] -lH-indole; 5-Fluoro-3- [cis -4- [4- (lH-indol-4-yl) -1-piperazinyl] -cyclohexyl] -lH-indole; 5-Fluoro-3- [trans -4- [4- (lH-indol-4-yl) -1-piperazinyl] -cyclohexyl] -lH-indole; 6-Fluoro-3- [cis -4- [4- (lH-indol-4-yl) -1-piperazinyl] -cyclohexyl] -IH-indole; 6-Fluoro-3- [trans -4- [4- (lH-indol-4-yl) -1-piperazinyl] -cyclohexyl] -lH-indole; 5-Bromo-3- [cis-4- [4- (lH-indol-4-yl) -l-piperazinyl] -cyclohexyl] -lH-indole; 5-Bromo-3- [trans -4- [4- (lH-indol-4-yl) -1-piperazinyl] -cyclohexyl] -lH-indole; 5-Chloro-3- [cis -4- [4- (lH-indol-4-yl) -1-piperazinyl] -cyclohexyl] -lH-indole; 5-Chloro-3- [trans -4- [4- (lH-indol-4-yl) -1-piperazinyl] -cyclohexyl] -IH-indole; 3- . { 4- [(1,4-cis) -4- (1 H -indol-4-yl) -1-piperazinyl-1-yl] cyclohexyl} -1H- indol- 5 -carbonitrile; 3-. { 4- [(1, 4-trans) -4- (1H-indol-4-yl) -1-piperazinyl-1-yl] cyclohexyl} -lH-indole-5-carbonitrile; 5-Methoxy-3- [cis -4- [4- (lH-indol-4-yl) -1-piperazinyl] -cyclohexyl] -lH-indole; 5-Methoxy -3- [trans -4- [4- (lH-indol-4-yl) -1-piperazinyl] -cyclohexyl] -IH-indole; 3- [cis-4- [4- (lH-Indol-4-yl) -1-piperazinyl] cyclohexyl] -2-methyl-lH-indole; 3- [trans-4- [4- (lH-indol-4-yl) -1-piperazinyl] cyclohexyl] • 2-methyl-lH-indole; 3 - [(1, 4-cis) -4- [4-lH-Indol-4-yl) -piperazin-1-yl] -cyclohexyl} -lH-pyrrolo [2, 3-b] pyridine; 3-. { (1, 4-trans) -4- [4-1H-Indol-4-yl) -piperazin-1-yl] -cyclohexyl} -lH-pyrrolo [2, 3-b] pyridine; 6-Fluoro-l-methyl-3-. { cis-4- [4- (1-met il-lH-indol-4-yl) -1-piperazinyl] cyclohexyl} -lH-indole; 3-. { (1, 4-cis) -4- [4- (1H-indol-4-yl) -piperazin-1-yl] -cyclohexyl} -1-met il-lH-indol-5-carbonitrile; 3-. { (1, 4-trans) -4- [4- (1H-indol-4-yl) -piperazin-1-yl] -cyclohexyl} -1-methyl-lH-indole-5-carbonitrile; I-Ethyl-3-. { (1, 4-cis) -4- [4- (1H-indol-4-yl) -piperazin-1-yl] -cyclohexyl} - lH-indole-5-carbonitrile; 3-. { (1, 4-cis) -4- [4- (1H-indol-4-yl) -piperazin-1-yl] -cyclohexyl} -1-propyl-1H-indole-5-carbonitrile; 3-. { (1, 4-trans) -4- [4- (1H-indol-4-yl) -piperazin-1-yl] -cyclohexyl} -l-propyl-lH-indole-5-carbonitrile; 3-. { (1, 4-cis) -4- [4- (1H-indol-4-yl) -piperazin-1-yl] -cyclohexyl} -l-isopropyl-lH-indole-5-carbonitrile; 3-. { (1, 4-trans) - A - [A - (lH-indol-4-yl) -piperazin-1-yl] -cyclohexyl} -l-isopropyl-lH-indole-5-carbonitrile; l-Benzyl-3-. { (1,4-cis) -4- [4- (1H-indol-4-yl) -piperazin-1-yl] -cyclohexyl} -lH-indole-5-carbonitrile; l-Benzyl-3-. { (1,4-trans) -4- [4- (1H-indol-4-yl) -piperazin-1-yl] -cyclohexyl} -lH-indole-5-carbonitrile; l-Methyl-3-. { (1,4-cis) -4- [4- (1-methyl-1H-indol-4-yl) -piperazin-1-yl] -cyclohexyl} -lH-indole-5-carbonitrile; 5-Fluoro-3-. { (cis) -4- [4- (2-methoxy-phenyl) -piperazin-1-yl] -cyclohexyl} -lH-indole; 5-Fluoro-3-. { (1,4-cis) - A - [A - (2-methoxy-phenyl) -piperidin-1-yl] -cyclohexyl} -lH-indole; 5-Fluoro-3-. { (1, 4-trans) -4- [4- (2-methoxy-phenyl) -piperidin-1-yl] -cyclohexyl} -lH-indole; 5-Metoxy-3-. { (1,4-cis) -4- [4- (2-methoxy-phenyl) -piperazinyl-1-yl] -cyclohexyl} -lH-indole; 5-Metoxy-3-. { (1, 4-trans) -4- [4- (2-methoxy-phenyl) -piperidin-1-yl] -cyclohexyl} -lH-indole; 3- . { (1, 4-cis) -4- [4- (2-methoxy-phenyl) -piperazin-1-yl] -cyclohexyl} -lH-pyrroLo [2, 3-b] piperidine; 5-Fluoro-3-. { (cis) -4- [4- (5-fluoro-2-methoxy-phenyl) -piperazin-1-yl] -cyclohexyl} -lH-indole; 5-Fluoro-3-. { (trans) -4- [4- (5- Fluoro-2-methoxy-phenyl-1) -piperazin-1-yl] -cyclohexyl} -lH-indole; 3-. { (1, 4-cis) -4- [4- [(2,3-Dihydro-benzo [1,4] dioxin-5-yl) -piperazin-1-yl] -cyclohexyl} -4-fluoro-lH-indole; 3-. { (1, 4-cis) -4- [4- (2,3-Dihydro-benzo [1,4] dioxin-5-yl) -piperazin-1-yl] -cyclohexyl} -4-fluoro-lH-indole; 3-. { (1, 4-trans) -4- [4- (2,3-Dihydro-benzo [1,4] dioxin-5-yl) -piperazin-1-yl] -cyclohexyl} -5-fluoro-lH-indole; 3-. { (1, 4-trans) -4- [4- (2, 3-Dihydro-benzo [1,4] dioxin-5-yl) -piperazin-1-yl] -cyclohexyl} -5-fluoro-lH-indole; 3-. { (1, 4-cis) -4- [4- (2,3-Dihydro-benzo [1,4] dioxin-5-yl) -piperazin-1-yl] -cyclohexyl} -6-fluoro-lH-indole; 3-. { (1, 4-trans) -4- [4- (2,3-Dihydro-benzo [1,4] dioxin-5-yl) -piperazin-1-yl] -cyclohexyl} -6-fluoro-lH-indole; 3-. { (1, 4-cis) -4- [4- (2, 3-Dihydro-benzo [1,4] dioxin-5-yl] -cyclohexyl] -lH-indole-5-carbonitrile; (1, 4-cis) -4- [4- (2, 3-Dihydro-benzo [1,4] dioxin-5-yl) ~ piperazin-1-yl] -cyclohexyl] -lH-indole 5- carbonitrile; 3- ({1,4-trans) -4- [4- (2,3-Dihydro-benzo [1,4] dioxin-5-yl) -piperazin-1-yl] -cyclohexyl .}.-lH-indole-5-carbonitrile; 8- { 4 - [(1,4-cis) -4- (5-Fluoro-lH-indol-3-yl) -cyclohexyl] -piperazin-1 -yl.}. -quinoline; 8-. {4 - [(1, 4-trans) -4- (5-Fluoro-lH-indol-3-yl) -cyclohexyl] -piperazin-1-yl}. . -quinoline; 8-. {4- (1,4-cis) -4- [4- (5-Fluoro-l-methyl-lH-indol-3-yl) -cyclohexyl] -piperazin-1-yl .}. -quinoline; 3- [(1,4-cis) -4- (4-quinolin-8-yl-piperazin-1-yl) -cyclohexyl] -lH-indole-5-carbonitrile; 3- [( 1, 4 -trans) - A - (4-Quinolin-8-yl-piperazin-1-yl) -cyclohexyl] -lH-indole-5-carbonitrile; l-Methyl-3- [(1,4-cis) - A - (4-quinolin-8-yl-piperazin-1-yl) -cyclohexyl] -1H-indole-5-carbonitrile; 5-Fluoro-3-. { (1,4-cis) -4- [4- (6-fluoro-chroman-8-yl) -piperazin-1-yl] -cyclohexyl} -lH-indole; 5-Fluoro-3-. { (1, 4-trans) - A - [A - (6-fluoro-chroman-8-yl) -piperazin-1-yl] -cyclohexyl} -lH-indole; 5-Fluoro-3-. { (1,4-cis) -4- [4- (5-fluoro-2,3-dihydro-benzofuran-7-yl) -piperazin-1-yl] -cyclohexyl} -lH- indole; 5-Fluoro-3-. { (1,4-trans) -4- [4- (5-fluoro-2,3-dihydro-benzofuran-7-yl) -piperazin-1-yl] -cyclohexyl} -lH- indole; 3- . { (1,4-cis) -4- [4- (5-Fluoro-2,3-dihydro-benzofuran-7-yl) -piperazin-1-yl] -cyclohexyl} -lH-indole-5-carbonitrile; 3- . { (1, 4-trans) -4- [4- (5-Fluoro-2, 3-dihydro-benzofuran-7-yl) -piperazin-1-yl] -cyclohexyl} -lH-indole-5-carbonitrile; 3- . { (1, 4-trans) -4- [4- (5-Fluoro-2, 3-dihydro-benzofuran-7-yl) -piperazin-1-yl] -cyclohexyl} - 1-methyl-1H-indole-5-carbonitrile; 3- [(1,4-cis) - A - [A - (Benzofuran-7-yl-piperazin-1-yl) -cyclohexyl] -lH-indole-5-carbonitrile; 3- [(1, 4-trans) -4- [4- (Benzofuran-7-yl-piperazin-1-yl) -cyclohexyl] -lH-indole-5-carbonitrile; 5-Fluoro-3-. { 4- [4- (2-methoxy-phenyl) -piperazin-1-yl] -cyclohex-1-enyl} -lH-indole; 3- . { 4- [4- (lH-Indol-4-yl) -piperazin-1-yl] -cyclohex-1-enyl} -lH-indole-5-carbonitrile; 5-Fluoro-3-. { cis-4- [4- (lH-indol-4-yl) piperazinyl] -cyclohexyl} -1-methyl-lH-indole; 3-. { (1,4-cis) -4- [4- (6-Methoxy-quinolin-8-yl) -piperazin-1-yl] -cyclohexyl} -lH-indole-5-carbonitrile; or a pharmaceutically acceptable salt thereof.
8. A pharmaceutical composition, characterized in that it comprises a compound of the formula (I) according to any of claims 1 to 7 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
9. A method for the treatment of depression in a patient in need thereof, characterized in that it comprises administering to the patient, an effective antidepressant amount of a compound of the formula (I) according to any of claims 1 to 7 or a pharmaceutically salt acceptable of it.
10. A process for the preparation of a compound of the formula (I) according to claim 1, characterized in that it comprises one of the following: a) reacting a compound of the formula wherein Ra, R? -3, Y and X? -3 are as defined in the above, with a compound of the formula (IV): (IV) wherein Z, R, R5 and Rβ are as defined in the above; or b) reducing a compound of the formula: (V) wherein the variables are as defined in the above to give a compound of the formula (I); or c) acidifying a basic compound of formula I with a pharmaceutically acceptable acid to a pharmaceutically acceptable salt; or d) separating a mixture of the cis and trans isomers of a compound of the formula (I) to isolate an isomer substantially free of the other isomer; or e) reacting a compound of the formula (I) having a reactive substituent group to give a compound of the formula (I) having a different substituent group; or f) reacting a compound of the formula (I) having a reactive site (for example NH) to give a compound of the formula (I) having a substituent group at the site.
MXPA/A/2001/006853A 1999-01-07 2001-07-04 Arylpiperazinyl-cyclohexyl indole derivatives for the treatment of depression MXPA01006853A (en)

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