Substituted-3-indolyl-4-piperidino-alkyl heterocycles for the treatment of depression

This application is a divisional of U.S. application Ser. No. 10/652,424, filed Aug. 29, 2003 (now U.S. Pat. No. 6,939,870), which claims the benefit of U.S. Provisional Application No. 60/408,376 filed Sep. 5, 2002, the entire disclosures of which are incorporated herein by reference.

Pharmaceuticals which enhance serotonergic neurotransmission are useful for the treatment of many psychiatric disorders, including depression and anxiety. The first generation of non-selective serotonin-affecting drugs operated through a variety of physiological functions which endowed them with several side effect liabilities. The more currently prescribed drugs, the selective serotonin reuptake inhibitors (SSRIs), act predominately by inhibiting 5-HT, which is released at the synapses, from being actively removed from the synaptic cleft via a presynaptic serotonin transport carrier.

SSRI's currently available suffers from a serious drawback in that several weeks of treatment is necessary to produce the therapeutic effect. The delayed onset of action is a significant problem, especially in the treatment of patients with severe depression.

It has been shown by Arborelius et. al (Arborelius, L. et al., Naunyn-Schmiedeberg's Arch. Pharmacol. 1995, 352, 157) that acute administration of SSRI's reduces firing of 5-HT neurons of dorsal raphe nucleus in the rodent brain and sustained treatment of SSRI's leads to normalization of the firing activity of the 5-HT neurons. Further more it has been shown by others that the recovery of firing activity of 5-HT neurons is linked to desentization of somatodendritic 5-HT 1A autoreceptors. (Invernizzi, R. et al, Eur. J. Pharmacol. 1994, 260, 243.) Hence it has been suggested that simultaneous administration of SSRI's and a 5-HT 1A receptor antagonist would lead to rapid onset of antidepressive effect. (Artigas, F. et al, Trends Neurosci. 1996, 19, 378).

Jean-Luc Malleron et. al (Jean-Luc Malleron et. al J. Med. Chem. 1993, 36, 1194) published a series of naphthalenesultam derivatives of formula 1 as selective serotonin uptake inhibitors, but nothing has been mentioned about the 5HT-1A activity. In the same paper the naphthalene sultam was replaced by different heterocycles such as 2 to 7. These compounds were evaluated for serotonin uptake inhibiton.

Wustrow et al. have disclosed a series of 3-[[4-aryl-1-piperazinyl)alkyl]cyclohexyl]-1H-indoles as dopamine D 2 partial agonists in J. Med. Chem. 1997, 40, 250.

Cipollina et al. have disclosed a series of indolylcycloalkylamines as serotonergic vasoconstrictors for the treatment of vascular or migraine headaches in European Patent Application EP 666258.

The present invention comprises a compound represented by the formula I:

wherein A represents the following heterocycles:

R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are independently, hydrogen, straight chain alkyls of 1 to 4 carbon atoms, branched alkyls of 3 to 6 carbon atoms or cycloalkyls of 3 to 10 carbon atoms, halogens such as F, Cl, Br and I, alkoxy group of 1 to 4 carbon atoms, heteroaryloxy, cycloalkoxy (where the cyclic moiety is 3 to 6 membered cyclic system with or with out heteroatom such as O, S, N—R 9 , hydroxy, nitro, nitrile, amino, carboxy, alkoxycarbonyl of 1 to 4 carbon atoms, alkylcarbonyl of 1 to 4 carbon atoms, aminocarbonyl and alkylaminocarbonyl of 1 to 12 carbon atoms, C1 to C4 fluorinated alkyl (straight and branched), aryl, aryloxy, alkylaryl of C-7 to C-12 carbon atoms, heteroaryl, saturated cycloalkyl with or with out any hetero atom such as N, N—R 9 , O and S;

R 9 is C 1 –C 6 alkyl optionally substituted with R 10 , C 3 –C 6 alkenyl with the proviso that the carbon bearing the double bond is not bonded directly to the heteroatoms such as O, S or N—R 9 optionally substituted with R 10 , C 3 –C 6 alkynyl with the proviso that the carbon bearing the triple bond is not bonded directly to the heteroatoms such as O, S or N—R 9 optionally substituted with R 10 , C 6 –C 10 aryl optionally substituted with R 10 , C 7 –C 10 alkyl aryl optionally substituted with R 10 , heteroaryl optionally substitued with R 10 , alkyl heteroaryl optionally substituted with R 10 , SO 2 -aryl, or SO 2 -alkyl;

n is 2 to 4;

R 10 is halogen, nitrile, alkoxy, aryloxy, aryl, heteroaryl, cycloalkyl with or with a hetero atom such as N, O or S;

and all crystalline forms or a pharmaceutically acceptable salt thereof.

The present invention relates to a new class of molecules that have the ability to act at the 5-HT-1A receptor as well as serotonin uptake inhibitors. Such compounds are therefore potentially useful for the treatment of depression as well as other serotonin disorders.

The present invention relates to compounds containing a heterocycle group (8 to 11) connected to a 3-piperidino indole derivative via —(CH 2 ) n —, where n=2 to 4, and derivatives having pharmacological activity, and to their use in the treatment of diseases affected by disorders of the serotonin affected neurological systems, such as depression and anxiety.

In accordance with this invention there, is provided a group of compounds represented by the formula I, as defined above.

Alkyl, whether used alone or as part of another group includes straight and branched chain alkyl groups containing from 1 to 4 carbon atoms. For example, methyl, ethyl, propyl, isopropyl, butyl, i-butyl and t-butyl are encompassed by the term alkyl. In some embodiments of the present invention alkyl may refer to substituted or unsubstituted alkyl. Carbon number refers to carbon backbone and does not include carbon atoms of substituents such as alkoxy substitutions and the like.

Halogen, as used herein means chlorine, bromine, iodine and fluorine.

Aryl, as used herein refers to single or multiple 4 to 10 membered aromatic ring radicals including but not limited to phenyl, benzyl, naphthalene, indene and indacene. Preferred are phenyl, benzyl and naphthalene. In some embodiments of the present invention, the aryl group may be substituted by R 10 , which is defined as above.

Heteroaryl as used herein refers to single or multiple 4 to 10 membered aromatic ring radicals having from 1 to 3 heteroatoms selected from S, O or N including, but not limited to, furan, thiophene, pyrrole, imidazole, oxazole, thiazole, isoxazole, pyrazole, isothiazole, oxadiazole, triazole, thiadiazole, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, napthyridine, pteridine, pyridine, pyrazine, pyrimidine, pyridazine, pyran, triazine, indole, isoindole, indazole, indolizine, and isobenzofuran. Preferred heteroaryls include furan, thiophene, pyrrole, imidazole, oxazole, thiazole, isoxazole, pyrazole, isoxazole, isothiazole, oxadiazole, triazole, thiadiazole, quinolizine, quinoline, and isoquinoline. More preferred heteroaryls include furan, thiophene, imidazole, isoxazole, quinoline, pyridine and pyrazole. In some embodiments of the present invention, the heteroaryl group is substituted.

Preferably, the substituted aryl group is substituted with from 1 to 3 groups. The substituted heteroaryl group is preferably substituted with 1 to 3 groups and more preferably 1 to 2 groups. Alkyl and cycloalkyl groups may also be substituted. Suitable substitutions include, but are not limited to halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, nitro, nitrile, amino, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, alkoxycarbonylalkyl and alkylcarbonyloxy.

Highly preferred embodiments of the present invention include:

3-[2-(4-(1H-indol-3-yl)-3,6-dihydro-1(2H)-pyridinyl)ethyl]-6-7-dimethoxy-4(3H)quinazolinone or a pharmaceutically acceptable salt thereof; 3-[2-(4-(1H-indol-3-yl)-1-piperidinyl)ethyl]-6-7-dimethoxy-4(3H)-quinazolin or a pharmaceutically acceptable salt thereof; 3-[2-(4-(5-fluoro-1H-indol-3-yl)-3,6-dihydro-1 (2H)-pyridinyl)ethyl]-6-7 4(3H)-quinazolinone or a pharmaceutically acceptable salt thereof; 3-[4-(4-(1H-indol-3-yl)-3,6-dihydro-1(2H)-pyridinyl)butyl]-6-7-dimethoxy-4(3H)-quinazolinone or a pharmaceutically acceptable salt thereof; 3-[4-(4-(1H-indol-3-yl)-1-piperdinyl)butyl]-6-7-dimethoxy-4(3H) -quinazolinone or a pharmaceutically acceptable salt thereof; 3-[3-(4-(1H-indol-3-yl)-3,6-dihydro-1(2H)-pyridinyl)propyl]-6-7-dimethoxy-4(3H)-quinazolinone or a pharmaceutically acceptable salt thereof; 3-[3-(4-(1H-indol-3-yl)-1-piperidinyl)propyl]-6-7-dimethoxy-4(3H) -quinazolinone or a pharmaceutically acceptable salt thereof; 3-[3-(4-(5-fluoro-1H-indol-3-yl)-3,6-dihydro-1(2H)-pyridinyl)propyl]-6-7dimethoxy-4(3H)-quinazolinone or a pharmaceutically acceptable salt thereof; 8-bromo-6-chloro-3-[3-(4-(5-(1H-indol-3-yl)-3,6-dihydro-1(2H) -pyridinyl)propyl]-4(3H)-quinazolinone)-quinoline or a pharmaceutically acceptable salt thereof; 6-Chloro-3-[3-(4-(1H-indol-3-yl)-3,6-dihydro-1(2H)-pyridinyl)propyl]-4(3H)-quinazolinone or a pharmaceutically acceptable salt thereof; 6-Chloro-3-[2-(4-(1H-indol-3-yl)-piperidinyl)propyl]-4(3H)-quinazolinone or a pharmaceutically acceptable salt thereof; 3-[2-(4-(1H-indol-3-yl)-3,6-dihydro-1(2H)-pyridinyl)ethyl]-4(3H)quinazolinone or a pharmaceutically acceptable salt thereof; 3-[2-(4-(1H-indol-3-yl)-1-piperidinyl)ethyl]-4(3H)-quinazolinone or a pharmaceutically acceptable salt thereof; 3-[2-(4-(1-methyl-1H-indol-3-yl)-1-piperidinyl)ethyl]-4-(3H)-quinazolinone or a pharmaceutically acceptable salt thereof; 6-Fluoro-3-[2-(4-(1H-indol-3-yl)-3,6-dihydro-1(2H)-pyridinyl)ethyl]-4(3H)- quinazolinone or a pharmaceutically acceptable salt thereof; 3-[2-(4-(1H-indol-3-yl)-3,6-dihydro-1(2H)-pyridinyl)ethyl]-1,2,3-benzotriazin-4(3H)- quinazolinone or a pharmaceutically acceptable salt thereof; 3-[2-(4-(1H-indol-3-yl)-1-piperidinyl)ethyl]-1,2,3-benzotriazin-4(3H)-one or a pharmaceutically acceptable salt thereof; 3-[2-(4-(1-methyl-1H-indol-3-yl)-1-piperidinyl)ethyl]-1,2,3-benzotriazin-4(3H)-one or a pharmaceutically acceptable salt thereof; 3-[2-(4-(1H-indol-3-yl)-3,6-dihydro-1(2H)-pyridinyl)propyl]-1,2,3-benzotriazin-4(3H)-one or a pharmaceutically acceptable salt thereof; 3-[2-4-(1H-indol-3-yl)-1-piperidinyl)propyl]-1,2,3-benzotriazin-4(3H)-one or a pharmaceutically acceptable salt thereof; 3-[2-(4-(1-methyl-1H-indol-3-yl)-1-piperidinyl)propyl]-1,2,3-benzotriazin-4(3H)-one or a pharmaceutically acceptable salt thereof; 2-{3-[4-(1H-Indol-3-yl)-3,6-dihydro-2H-pyridin-1-yl]-propyl}-2H-[1,2,4]triazolo[4,3-a]pyridin-3-one or a pharmaceutically acceptable salts there of; 2-{3-[4-(1H-Indol-3-yl)-piperidin-1-yl]-propyl}-2H-[1,2,4]triazolo[4,3-a]pyridin-3-one or a pharmaceutically acceptable salts there of; 2-{2-[4-(1H-Indol-3-yl)-3,6-dihydro-2H-pyridin-1-yl]-ethyl}-2H-[1,2,4]triazolo[4,3-a]pyridin-3-one or a pharmaceutically acceptable salts there of; 2-{2-[4-(1H-Indol-3-yl)-piperidin-1-yl]-ethyl}-2H-[1,2,4]triazolo[4,3-a ]pyridin -3-one or a pharmaceutically acceptable salts there of; 2-{4-[4-(1H-Indol-3-yl)-3,6-dihydro-2H-pyridin-1-yl]-butyl}-2H-[1,2, 4]triazolo[4,3-a]pyridin-3-one or a pharmaceutically acceptable salts there of;

It is understood that the definition of the compounds of formula I, when R 1 , R 2 or R 3 contain asymmetric carbons, encompasses all possible stereoisomers and mixtures thereof which possess the activity discussed below. In particular, it encompasses racemic modifications and any optical isomers which possess the indicated activity. Optical isomers may be obtained in pure form by standard separation techniques.

Pharmaceutically acceptable salts are those derived from such organic and inorganic acids as: lactic, citric, acetic, tartaric, succinic, maleic, malonic, oxalic, fumaric, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, and similarly known acceptable acids. Where R 1 , R 2 or R 4 contain a carboxyl group, salts of the compounds of this invention may be formed with bases such as alkali metals (Na, K, Li) or the alkaline earth metals (Ca or Mg).

The compounds of this invention have been found to have affinity for the 5-HT reuptake transporter. They are, therefore, useful in the treatment of diseases affected by disorders of the serotonin affected neurological systems, such as depression and anxiety.

The present invention includes a pharmaceutical composition which comprises a compound of this invention in combination or association with a pharmaceutically acceptable carrier. The composition preferably is adapted for oral or subcutaneous administration. However, it may be adapted for other modes of administration.

In order to obtain consistency of administration, it is preferred that a composition of the invention is in the form of a unit dose. Suitable unit dose forms include tablets, capsules and powders in sachets or vials. Such unit dose forms may contain from 0.1 to 100 mg of a compound of the invention and preferably from 2 to 50 mg. Still further preferred unit dosage forms contain 5 to 25 mg of a compound of the present invention. The compounds of the present invention can be administered orally at a dose range of about 0.01 to 100 mg/kg or preferably at a dose range of 0.1 to 10 mg/kg. Such compositions may be administered from 1 to 6 times a day, more usually from 1 to 4 times a day.

The compositions of the invention may be formulated with conventional excipients, such as a filler, a disintegrating agent, a binder, a lubricant, a flavoring agent and the like. They are formulated in conventional manner, for example, in a manner similar to that use for known antihypertensive agents, diuretics and β-blocking agents.

The present invention further provides a compound of the invention for use as an active therapeutic substance. Compounds of formula (I) are of particular use in the treatment of diseases affected by disorders of the serotonin.

The present invention further provides a method of treating depression and anxiety in mammals including man, which comprises administering to the afflicted mammal an effective amount of a compound or a pharmaceutical composition of the invention.

The present invention provides a process for the preparation of a compound of general formula I. The core heterocycles 8, 9, 10 and 11 were prepared by the well established literature procedure. (Advances in Heterocyclic Chemistry, Edited by A. R. Katritzky and A. J. Boulton, Academic Press, R. J. Kobylecki and A. Mc Killop, Vol. 19, 215 (1976); W. L. F. Armarego, J. Appl. Chem, 11, 70, (1961); A. Abdulqader; A. M. Atef; L. Eric J, J. Med. Chem. 28, 1394–8, (1985)).

In accordance with the present invention, compounds of formula I, having the heterocyles 9 to 11, may be prepared to the following Scheme I.

Thus, compound of formula II (where in X═N; Y═CH; A═C═O, heterocycle 9, X═Y═N; A═C═O, heterocycle 10, X═N; Y═CH; A═SO 2 heterocycle 11) is reacted with compound of formula III, Hunig's base in DMSO at 80° C. to give a compound of formula I.

The compound of formula I can be further hydrogenated using catalytic Pd/C and hydrogen pressure in a parr apparatus to give the saturated piperdinyl

product I a .

Compounds of formula I or I a can be alkylated at the indole nitrogen using sodium hydride and and an appropriately substituted alkyl iodide at 0° C. to give the substituted product I b .

In accordance with the present invention, compounds of formula II may be prepared to the following Scheme II.

Thus compounds of formula IV are reacted with p-toulene sulfonyl chloride in pyridine to give compounds of formula II. Compounds of formula V are reacted with the appropriate bromo-alcohol using potassium carbonate in acetone at reflux to give compounds of formula IV. Similar reactions may be carried out to synthesize compounds based on 1,2,4-triazolo pyridinone, 8.

The following examples are presented to illustrate certain embodiments of the present invention, but should not be construed as limiting the scope of this invention.

3-[2-(4-(1H-indol-3-yl)-3,6-dihydro-1(2H)-pyridinyl)ethyl]-6-7-dimethoxy-4(3H)-quinazolinone

3-(2-hydroxyethyl)-6,7-dimethoxy-4(3H)-quinazolinone was prepared from 6,7-dimethoxy-4(3H)-quinazolinone (3 g, 14.6 mmol). The quinazolinone was combined with 2-bromoethanol (1.14 mL, 16 mmol), an excess of potassium carbonate (10 g) and heated at reflux in 200 mL acetone. The salts were filtered off and the reaction mixture was concentrated. The residue was dissolved in chloroform and washed with water. The organic layer was dried over Na 2 SO 4 , filtered and concentrated, 1.39 g (38%); light brown powder; m.p. 130° C., MS: 250.9 (M+H) +

2-(6,7-dimethoxy-4-oxo-3(4H)-quinazolinyl)ethyl 4-methyl benzenesulfonate

2-(6,7-dimethoxy-4-oxo-3(4H)-quinazolinyl)ethyl 4-methyl benzenesulfonate was prepared from 3-(2-hydroxyethyl)-6,7-dimethoxy-4(3H)-quinazolinone (1.39 g, 5.56 mmol). The quinazolinone was diluted in pyridine (10 mL) and cooled to 0° C. in an ice water bath. p-Toulene sulfonyl chloride (1.17 g, 6.12 mmol) was added and the mixture stirred at 0° C. then warmed to room temperature overnight. The reaction was quenched with water and the product crashed out and was collected, then washed with water, ether and ethyl acetate and dried, 1.21 g (54%); light brown powder; m.p. 170° C., MS: 404.7 (M+H) +

3-[2-(4-(1H-indol-3-yl)-3,6-dihydro-1(2H)-pyridinyl)ethyl]-6-7-dimethoxy-4(3H)-quinazolinone

A mixture of 2-(6,7-dimethoxy-4-oxo-3(4H)-quinazolinyl)ethyl 4-methyl benzenesulfonate (0.5 g, 1.24 mmol), 3-(1,2,3,6-tetrahydro-4-pyridinyl)1-H-indole (0.244 g, 1.24 mmol) and diisopropyl ethylamine (3 ml, excess) was heated in DMSO (50 ml) at 100° C. for 24 hrs. At the end reaction mixture was quenched with water and extracted with chloroform. The organic layer was dries over anhydrous MgSO 4 ; filtered and concentrated. The brown gum obtained was purified by SiO 2 column chromatography by eluting it with ethyl acetate; hexane (3:1) and 0.16 g of 3-[2-(4-(1H-indol-3-yl)-3,6-dihydro-1 (2H)-pyridinyl)ethyl]-6-7-dimethoxy-4(3H)-quinazolinone was isolated as a yellow powder. Yield 30%; mp 219° C.; MS: 430.9 (M+H) + ; 1 H NMR (300 MHz, DMSO-d 6 ): δ 2.51 (m, 2H), 2.73 (d, J=4.02 Hz, 4H), 3.19 (s, 2H), 3.88 (s, 3H), 3.91 (s, 3H) 4.16 (t, J=4.47 Hz, 2H), 6.02 (t, 1H), 6.99 (m, 1H), 709 (m, 2H), 7.37 (m, 2H), 7.47 (s, 1H), 7.78 (d, 1H), 8.25 (s, 1H), 11.1 (s, 1H).

3-(4-chlorobutyl)-6,7-dimethoxy-4(3H)-quinazolinone

3-(4-chlorobutyl)-6,7-dimethoxy-4(3H)-quinazolinone was prepared starting from 6,7-dimethoxy-4(3H)-quinazolinone (1.65 g, 8 mmol). The quinazolinone was combined with 1-chloro-4-iodobutane (1.08 mL, 8.8 mmol), an excess of potassium carbonate (10 g) and stirred in 30 mL DMF overnight. The salts were filtered off and the reaction mixture was dilluted with water. The solid that formed was collected via vacuum filtration, washed with water and dried, 1.55 g (65%); gray solid; m.p. 117° C., MS: 296.8 (M+H) +

3-[4-(4-(1H-indol-3-yl)-3,6-dihydro-1(2H)-pyridinyl)butyl]-6-7-dimethoxy-

Starting from 3-(4-chlorobutyl)-6,7-dimethoxy-4(3H)-quinazolinone (0.5 g, 1.69 mmol) and 3-(1,2,3,6-tetrahydro-4-pyridinyl)1-H-indole (0.330 g, 1.69 mmol), following the same procedure as in example 1, step 3; 0.23 g of 3-[4-(4-(1H-indol-3-yl)-3,6-dihydro-1 (2H)-pyridinyl)butyl]-6-7-dimethoxy-4(3H)-quinazolinone was isolated as a yellow powder. Yield 30%; mp 136° C.; MS: 458.8 (M+H) + ; 1 H NMR (300 MHz, DMSO-d 6 ): δ 1.52 (m, 2H), 1.74 (m, 2H), 2.50 (d, J=1.35 Hz, 4H), 2.62 (m, 2H), 3.10 (m, 2H), 3.87 (s, 3H), 3.90 (s, 3H) 4.01 (t, J=5.34 Hz, 2H), 6.10 (t, 1H), 7.02 (m, 1H), 7.08 (m, 1H), 7.14 (s, 1H), 7.37 (m, 2H), 7.48 (s, 1H), 7.78 (d, 1H), 8.31 (s, 1H), 11.1 (s, 1H).

3-{4-[4-(1H-indol-3-yl)-1-piperdinyl]butyl}-6,7-dimethoxy-4(3H)-quinazolinone

Starting from 3-[4-(4-(1H-indol-3-yl)-3,6-dihydro-1(2H)-pyridinyl)butyl]-6-7-dimethoxy-4(3H)-quinazolinone (0.16 g, 0.35 mmol), following the same procedure as in example 2, 0.023 g of 3-{4-[4-(1H-indol-3-yl)-1-piperdinyl]butyl}-6-7-dimethoxy-4(3H)-quinazolinone was isolated as an off white powder. Yield 14%; mp 148° C.; MS: 460.9 (M+H) + ; 1 H NMR (300 MHz, CDCl 3 ): δ 1.72 (m, 2H), 1.84 (m, 4H), 2.06 (m, 4H), 2.22 (m, 1H), 2.56 (m, 2H), 3.13 (m, 2H), 4.00 (s, 6H) 4.04 (t, J=5.37 Hz, 2H), 6.99 (t, 1H), 7.12 (m, 2H), 7.16 (t, 1H), 7.30 (d, 1H), 7.63 (d, 2H), 7.96 (s, 1H).

3-[3-(4-(1H-indol-3-yl)-3,6-dihydro-1(2H)-pyridinyl)propyl]-6-7-dimethoxy-4(3H)-quinazolinone

3-(3-chloropropyl)-6,7-dimethoxy-4(3H)-quinazolinone

3-(3-chloropropyl)-6,7-dimethoxy-4(3H)-quinazolinone was prepared starting from 6,7-dimethoxy-4-(3H)quinazolinone (1.61 g, 8 mmol). The quinazolinone was combined with 1-chloro-3-iodopropane (1.9 mL, 8 mmol), an excess of potassium carbonate (10 g) and stirred in 30 mL DMF overnight. The salts were filtered off and the reaction mixture dilluted with water. The solid that formed was collected via vacuum filtration, washed with water and dried, 0.70 g (31%); brown solid; m.p. 143° C., MS: 282.8 (M+H) +

3-[3-(4-(1H-indol-3-yl)-3,6-dihydro-1(2H)-pyridinyl)propyl]-6-7-dimethoxy-4(3H)-quinazolinone

Starting from 3-(3-chloropropyl)-6,7-dimethoxy-4(3H)-quinazolinone (0.5 g, 1.77 mmol) and 3-(1,2,3,6-tetrahydro-4-pyridinyl)1-H-indole (0.349 g, 1.77 mmol), following the same procedure as in example 1, step 3, 0.30 g of 3-[3-(4-(1H-indol-3-yl)-3,6-dihydro-1(2H)-pyridinyl)propyl]-6-7-dimethoxy-4(3H)-quinazolinone was isolated as an orange solid. Yield 38%; mp 120° C.; MS: 444.9 (M+H) + ; 1 H NMR (300 MHz, CDCl 3 ): δ 2.08 (t, 2H), 2.53 (t, J=4.98 Hz, 2H), 2.62 (m, 2H), 2.73 (t, J=4.38 Hz, 2H), 3.21 (m, 2H), 3.95 (s, 3H), 4.00 (s, 3H), 4.15 (t, 2H), 6.20 (t, 1H), 7.09 (s, 1H), 7.17 (m, 3H), 7.37 (d, 1H), 7.64 (s, 1H), 7.89 (d, 1H), 8.10 (s, 1H).

8-Bromo-6-chloro-4(3H)quinazolinone

8-Bromo-6-chloro-4(3H)quinazolinone was prepared from 2-amino-3-bromo-5-chlorobenzoic acid (10 g, 40 mmol). The acid was heated in excess formamide (50 mL) at reflux overnight. The mixture was cooled and quenched with water. The solid that formed was washed with acetonitrile, 6.7 g crude (65%); MS: 260.8 (M+H) +

3-(4-chloropropyl)-(8-bromo-6-chloro)-4(3H)-quinazolinone

3-(4-chloropropyl)-(8-bromo-6-chloro)-4(3H)-quinazolinone was prepared according to the procedure outlined in example 6, step 1. Starting from 8-bromo-6-chloro-4(3H)-quinazolinone (5 g, 19.3 mmol) and 1-chloro-3-iodopropane (2.07 mL, 21.2 mmol), 3.45 g (53%); white powder, MS: 336.9 (M+H) +

8-bromo-6-chloro-3-[3-(4-(1H-indol-3-yl)-3,6-dihydro-1(2H)-pyridinyl)propyl]-4(3H)-quinazolinone

Starting from 3-(4-chloropropyl)-(8-bromo-6-chloro)-4(3H)-quinazolinone (2 g, 5.97 mmol) and 3-(1,2,3,6-tetrahydro-4-pyridinyl)1-H-indole (1.18 g, 5.97 mmol), following the same procedure as in example 1, step 3; 2.13 g of 8-bromo-6-chloro-3-[3-(4-(1H-indol-3-yl)-3,6-dihydro-1(2H)-pyridinyl)propyl]-4(3H)-quinazolinone was isolated as a yellow powder. Yield 72%; mp 192° C.; MS: 499.3 (M+H) + ; 1 H NMR (300 MHz, DMSO-d 6 ): δ 1.95 (t, J=5.07 Hz, 2H), 2.47 (m, 4H), 2.60 (m, 2H), 3.09 (m, 2H), 4.08 (t, J=5.22 Hz, 2H), 6.06 (t, 1H), 6.99 (t, J=5.22 Hz, 1H), 7.09 (t, J=5.25 Hz, 1H), 7.34 (m, 1H), 7.75 (d, 1H), 8.10 (d, J=1.77 Hz, 1H), 8.18 (d, J=1.8 Hz, 1H), 8.54 (s, 1H), 11.1 (s, 1H).

3-[2-(4-(1-methyl-1H-indol-3-yl)-3,6-dihydro-1(2H)-pyridinyl)ethyl]-4-(3H)-quinazolinone

A dried flask under nitrogen was loaded with sodium hydride (0.015 g, 0.37 mmol) and THF (10 mL). At 0° C. 3-[2-(4-(1H-indol-3-yl)-3,6-dihydro-1(2H) -pyridinyl)ethyl]-4(3H)-quinazolinone (0.80 g, 2.16 mmol), was added and the mixture stirred for 15 minutes. Keeping the reaction temperature at 0° C., the iodomethane was added dropwise (0.14 mL, 2.16 mmol). This was allowed to warm to room temperature and stir overnight. Water was slowly added to the mixture to quench and the organics were extracted in chloroform, washed with water and dried over Na 2 SO 4 , filtered and concentrated. The residue was chromatograhed using silica (2% methanol:chloroform system); 0.52 g of 3-[2-(4-(1-methyl-1H-indol-3-yl)-3,6-dihydro-1(2H)-pyridinyl)ethyl]-4(3H)-quinazolinone was isolated as an orange solid. Yield 63%; MS: 384.9 (M+H) + ; 1 H NMR (300 MHz, CDCl 3 ): δ 2.79 (m, 2H), 3.17 (m, 4H), 3.20 (m, 2H), 3.61 (m, 2H), 3.76 (s, 3H), 4.44 (t, 2H), 6.12 (t, 1H), 7.00 (t, 1H), 7.37 (m, 1H), 7.53 (m, 1H), 7.45 (m, 2H), 7.81 (m, 1H), 8.17 (d, 1H), 8.35 (s, 1H).

3-{2-[4-(1-methyl-1H-indol-3-yl)-1-piperidinyl]ethyl}-4-(3H)-quinazolinone

Starting from 3-[2-(4-(1-methyl-1H-indol-3-yl)-3,6-dihydro-1 (2H)-pyridinyl)ethyl]-4(3H)-quinazolinone (0.430 g, 1.12 mmol), following the same procedure as in example 2, 0.044 g of 3-{2-[4-(1-methyl-1H-indol-3-yl)-1-piperidinyl]ethyl}-4-(3H)-quinazolinone was isolated as an orange solid. Yield 10%; mp 78° C.; MS: 386.9 (M+H) + ; 1 H NMR (300 MHz, CDCl 3 ): δ 1.62 (m, 4H), 2.08 (m, 2H), 2.53 (m, 1H), 2.92 (m, 2H), 3.22 (m, 2H), 3.75 (s, 3H), 4.29 (m, 2H), 6.79 (s, 1H), 7.11 (m, 1H), 7.21 (m, 1H), 7.27 (m, 2H), 7.50 (m, 1H), 7.59 (d, 1H), 7.76 (m, 2H), 8.32 (d, 1H).

6-fluoro-3-{2-[4-(1H-indol-3-yl)-3,6-dihydro-1(2H)-pyridinyl]ethyl}-4

Starting from 3-(4-chloroethyl)-6-fluoro-4(3H)-quinazolinone (0.56 g, 2.5 mmol) and 3-(1,2,3,6-tetrahydro-4-pyridinyl)1-H-indole (0.49 g, 2.5 mmol), following the same procedure as in example 1, step 3; 0.035 g of 6-fluoro-3-{2-[4-(1H-indol-3-yl)-3,6-dihydro-1(2H)-pyridinyl]ethyl}-4(3H)-quinazolinone was isolated as a tan powder. Yield 4%; mp 138° C.; MS: 388.9 (M+H) + ; 1 H NMR (300 MHz, DMSO-d 6 ): δ 2.49 (m, 2H), 2.74 (m, 4H), 3.19 (m, 2H), 4.18 (t, J=4.53 Hz, 2H), 6.09 (t, 1H), 7.00 (t, J=5.4 Hz, 1H), 7.09 (t, J=5.4 Hz, 1H), 7.37 (m, 2H), 7.70–7.86 (band, 4H), 8.36 (s, 1H), 11.1 (s, 1H).

3-[2-(4-(1H-indol-3-yl)-3,6-dihydro-1(2H)-pyridinyl)ethyl]-1,2,3-benzotriazin-4(3H)-one

3-(2-hydroxyethyl)-1,2,3-benzotriazin-4(3H)one

3-(2-hydroxyethyl)-1,2,3-benzotriazin-4(3H)one was prepared according to the general procedure outlined in example 1, step 1. Starting from 1,2,3-benzotriazin-4(3H)one (1.5 g, 10 mmol) and 2-bromoethanol (1.68 mL, 20 mmol), 1.20 g (63%); off white solid; m.p. 114° C., MS: 191.9 (M+H) +

2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl-4-methyl benzenesulfonate

2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl-4-methyl benzenesulfonate was prepared according to the general procedure outlined in example 1, step 2. Starting from 3-(2-hydroxyethyl)-1,2,3-benzotriazin-4(3H)one (0.5 g, 2.6 mmol) and p-toulene sulfonyl chloride (0.55 g, 2.9 mmol), 0.81 g (90%); white crystals; m.p. 161° C., MS: 345.7 (M+H) +

3-[2-(4-(1H-indol-3-yl)-3,6-dihydro-1(2H)-pyridinyl)ethyl]-1,2,3-benzotriazin-4(3H)-one

Starting from 2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl-4-methyl benzenesulfonate (0.68 g, 1.97 mmol) and 3-(1,2,3,6-tetrahydro-4-pyridinyl)1-H-indole (0.39 g, 1.97 mmol), following the same procedure as in example 1, step 3; 0.45 g of 3-[2-(4-(1H-indol-3-yl)-3,6-dihydro-1(2H)-pyridinyl)ethyl]-1,2,3-benzotriazim-4(3H)-one was isolated as a yellow powder. Yield 62%; mp 230° C.; MS: 371.9 (M+H) + ; 1 H NMR (300 MHz, DMSO-d 6 ): δ 2.46 (s, 2H), 2.75 (m, 2H), 2.92 (m, 2H), 3.23 (m, 2H), 4.61 (t, J=4.86 Hz, 2H), 6.09 (t, 1H), 6.98 (t, J=5.1 Hz, 1H), 7.09 (t, J=5.1 Hz, 1H), 7.36 (m, 2H), 7.77 (t, 1H), 7.93 (t, 1H), 8.08 (t, 1H), 8.20 (d, 1H), 8.28 (d, 1H), 11.1 (s, 1H).

3-(3-chloropropyl)-1,2,3-benzotriazin-4(3H)one

3-(3-chloropropyl)-1,2,3-benzotriazin-4(3H)one was prepared according to the general procedure outlined in example 6, step 1. Starting from 1,2,3-benzotriazin-4(3H)one (2 g, 13.6 mmol) and 1-chloro-3-iodopropane (1.6 mL, 14.95 mmol), 1.57 g (52%); yellow solid; m.p. 69° C., MS: 223.9 (M+H) +

3-[3-(4-(1H-indol-3-yl)-3,6-dihydro-1(2H)-pyridinyl)propyl]-1,2,3-benzotriazin-4(3H)-one

Starting from 3-(3-chloropropyl)-1,2,3-benzotriazin-4(3H)one (1.49 g, 6.68 mmol) and 3-(1,2,3,6-tetrahydro-4-pyridinyl)1-H-indole (1.32 g, 6.68 mmol), following the same procedure as in example 1, step 3; 2.03 g of 3-[3-(4-(1H-indol-3-yl)-3,6-dihydro-1(2H)-pyridinyl)propyl]-1,2,3-benzotriazin-4(3H)-one was isolated as an off white solid. Yield 79%; mp 189° C.; MS: 386.2 (M+H) + ; 1 H NMR (300 MHz, CDCl 3 ): δ 2.20 (m, 2H), 2.57 (m, 2H), 2.66 (t, 2H), 2.72 (t, 2H), 3.21 (m, 2H), 4.61 (t, J=5.34 Hz, 2H), 6.15 (t, 1H), 7.12–7.21 (band, 2H), 7.26 (s, 1H), 7.35 (d, 1H), 7.75 (t, 1H), 7.87 (m, 2H), 8.13 (d, 1H), 8.36 (d, 1H).