Piperazino[1,2-a]indol-1-ones and [1,4]diazepino[1,2-a]indol-one

Abstract

The present invention relates to compounds of general formula I wherein R.sup.1, R.sup.2, R.sup.3 and X are as defined ##STR00001##
herein, or to a pharmaceutically acceptable acid addition salt or optical isomers thereof, which are useful to treat CNS disorders.

Claims

1. A compound of formula I ##STR00119## wherein R.sup.1 is halogen, lower alkyl, lower alkoxy, lower alkyl substituted by halogen, lower alkoxy substituted by halogen or cyano; R.sup.2 is hydrogen, CF.sub.3 or lower alkyl; R.sup.3 is lower alkyl, lower alkenyl, lower alkynyl, heterocycloalkyl, lower alkyl substituted by cyano, cyano, benzyl substituted by halogen, 2-oxa-6-aza-spiro[3.3]hept-6-yl or is lower alkoxy substituted by halogen; X is CH.sub.2 or CH.sub.2CH.sub.2; or a pharmaceutically acceptable acid addition salt, an enantiomer, diastereomer or a mixture of enantiomers or diastereomers.

2. The compound of claim 1 which compound has formula IA ##STR00120## wherein R.sup.1 is halogen, lower alkyl, lower alkoxy, lower alkyl substituted by halogen, lower alkoxy substituted by halogen or cyano; R.sup.2 is hydrogen, CF.sub.3 or lower alkyl; R.sup.3 is lower alkyl, lower alkenyl, lower alkynyl, heterocycloalkyl, lower alkyl substituted by cyano, cyano, benzyl substituted by halogen, 2-oxa-6-aza-spiro[3.3]hept-6-yl or is lower alkoxy substituted by halogen; or a pharmaceutically acceptable acid addition salt an enantiomer, diastereomer or a mixture of enantiomers or diastereomers thereof.

3. The compound of claim 2, wherein the compound is: 8-Fluoro-6-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one, 8-Fluoro-6-isobutyl-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one, 8-Fluoro-6,10-dimethyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one, 8-Fluoro-10-methyl-6-morpholin-4-yl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one, 8-Chloro-6,10-dimethyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one, 6-Ethyl-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one, 6-(1,1-Dioxo-1.sup.6-thiomorpholin-4-yl)-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one, 8-Chloro-6-ethyl-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one, 6-Allyl-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one, 8-Fluoro-10-methyl-6-(3-methyl-butyl)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one, 4-(8-Fluoro-10-methyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indol-6-yl)-butyronitrile, 8-Chloro-6-isobutyl-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one, 8-Fluoro-6-(4-fluoro-benzyl)-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one, 8-Fluoro-10-methyl-6-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one, 8-Chloro-6-(1,1-dioxo-1.sup.6-thiomorpholin-4-yl)-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one, 8-Chloro-10-methyl-6-morpholin-4-yl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one, 6-(1,1-Dioxo-1.sup.6-thiomorpholin-4-yl)-10-methyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile, 6-Ethynyl-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one, 6-Isobutyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile, 8-Fluoro-6-(2-methylpropyl)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one, 8-Fluoro-10-methyl-6-(2,2,2-trifluoroethoxy)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one, 8-Chloro-6-(2-methylpropyl)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one, 8-Chloro-6-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one, 8-Fluoro-10-methyl-1-oxo-3,4-dihydro-2H-pyrazino[1,2-a]indole-6-carbonitrile, 10-Methyl-1-oxo-6-(trifluoromethoxy)-3,4-dihydro-2H-pyrazino[1,2-a]indole-8-carbonitrile, 8-Methyl-6-(2-methylpropyl)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one, 6,8-Dimethyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one, 8-Methoxy-6-(2-methylpropyl)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one, 6-(2-Methylpropyl)-8-(trifluoromethoxy)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one, 10-Methyl-6-morpholin-4-yl-1-oxo-3,4-dihydro-2H-pyrazino[1,2-a]indole-8-carbonitrile, 6-Morpholin-4-yl-1-oxo-3,4-dihydro-2H-pyrazino[1,2-a]indole-8-carbonitrile, or a pharmaceutically acceptable salt, an enantiomer, diastereomer or a mixture of enantiomers or diastereomers thereof.

4. The compound of claim 1 which compound has formula IB, ##STR00121## wherein R.sup.1 is halogen, lower alkyl, lower alkoxy, lower alkyl substituted by halogen, lower alkoxy substituted by halogen or cyano; R.sup.2 is hydrogen, CF.sub.3 or lower alkyl; R.sup.3 is lower alkyl, lower alkenyl, lower alkynyl, heterocycloalkyl, lower alkyl substituted by cyano, cyano, benzyl substituted by halogen, 2-oxa-6-aza-spiro[3.3]hept-6-yl or is lower alkoxy substituted by halogen; or a pharmaceutically acceptable acid addition salt, an enantiomer, diastereomer or a mixture of enantiomers or diastereomers.

5. The compound of claim 4, wherein the compound is 9-Fluoro-7-methyl-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indol-1-one, 9-Fluoro-7-isobutyl-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indol-1-one, 9-Chloro-7-(2-methylpropyl)-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indol-1-one, 9-Chloro-7-methyl-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indol-1-one, 9-Methyl-7-(2-methylpropyl)-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indol-1-one, 11-Methyl-7-(2-methylpropyl)-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile, 7,11-Dimethyl-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile, 9-Chloro-11-methyl-7-(2-methylpropyl)-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indol-1-one, 9-Chloro-7,11-dimethyl-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indol-1-one, 7-(2-Methylpropyl)-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile, 7-(1,1-Dioxo-1,4-thiazinan-4-yl)-11-methyl-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile, 7-(1,1-Dioxo-1,4-thiazinan-4-yl)-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile, 11-Methyl-7-morpholin-4-yl-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile, or 7-Morpholin-4-yl-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile, or a pharmaceutically acceptable salt, an enantiomer, diastereomer or a mixture of enantiomers or diastereomers thereof.

6. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutical acceptable carrier and/or adjuvant useful for stimulating neurogenesis in a patient in need thereof.

7. A process for the manufacture of a compound of formula I as defined in claim 1 which process comprises reacting a compound of formula ##STR00122## with a compound of formula ##STR00123## or in case of formation of a nitrogen carbon bond by Buchwald coupling reaction to a compound of formula ##STR00124## wherein the substituents are as described in claim 1, and, optionally, converting the compounds obtained into pharmaceutically acceptable acid addition salts.

8. A compound manufactured by a process according to claim 7.

Description

EXAMPLE 1

9-Fluoro-7-methyl-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indol-1-one

(1) ##STR00073##

(2) A mixture of 7-bromo-9-fluoro-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indol-1-one (intermediate 2) (74.3 mg, 0.25 mmol), tetrakis triphenylphosphine palladium (28.9 mg, 25.0 mol) and potassium carbonate (104 mg, 0.75 mmol) in DMF (1.66 ml) was allowed to stir at room temperature for 5 min under argon atmosphere. Then commercially available 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (71.4 l, 0.25 mmol) was added and the reaction mixture was allowed to stir at 110 C. for 15 h. Afterwards the reaction mixture was cooled to room temperature, poured into water (20 ml) and extracted with ethyl acetate (220 ml). The combined organic layers were washed with brine (120 ml), dried (MgSO.sub.4) and evaporated. The crude material (90 mg) was purified by flash chromatography on silica gel [dichloromethane-dichloromethane/MeOH 9:1 (20-80%)] and trituration with diethyl ether (1 ml) and heptane (10 ml) to yield the title compound as a white solid (58 mg, 44%), MS (ISP) m/z=233.2 [(M+H).sup.+], mp 198 C.

EXAMPLE 2

8-Fluoro-6-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one

(3) ##STR00074##

(4) The title compound, light yellow solid (44 mg, 81%), MS (ISP) m/z=219.2 [(M+H).sup.+], mp 250.5 C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 1) (70.8 mg, 0.25 mmol) and commercially available 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (71.4 l, 0.25 mmol).

EXAMPLE 3

8-Fluoro-6-isobutyl-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one

(5) ##STR00075##

(6) To a mixture of 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 11) (74.3 mg, 0.25 mmol) and commercially available isobutylboronic acid (102 mg, 1.0 mmol) in toluene (3 ml), was added at room temperature potassium phosphate, tribasic (106 mg, 0.5 mmol), and the reaction mixture was purged with argon in an ultrasonic bath during 5 min. Afterwards tetrakis(triphenylphosphine)palladium(0) (14.4 mg, 12.5 mol) was added and the reaction mixture was heated for 5 h under reflux conditions. The reaction mixture was cooled to room temperature, poured into water (20 ml) and extracted with diethyl acetate (220 ml). The combined organic layers were washed with brine (20 ml), dried (MgSO.sub.4) and evaporated. The crude product (120 mg) was further purified by flash chromatography on silica gel (heptane/ethyl acetate, 20-100%) and crystallization from dichloromethane/heptane to yield the title compound as an off-white solid (33 mg, 48%), MS (ISP) m/z=275.5 [(M+H).sup.+], mp 189 C.

EXAMPLE 4

8-Fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one

(7) ##STR00076##

(8) The title compound, white solid (16 mg, 29%), MS (ISP) m/z=219.5 [(M+H).sup.+], mp 230 C., was obtained by the reaction of 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 11) (74.3 mg, 0.25 mmol) and commercially available isopropylboronic acid (87.9 mg, 1.0 mmol) in accordance with the general method of example 3 instead of the desired product.

EXAMPLE 5

8-Fluoro-6,10-dimethyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one

(9) ##STR00077##

(10) The title compound, white solid (34 mg, 59%), MS (ISP) m/z=233.5 [(M+H).sup.+], mp 208 C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 11) (74.3 mg, 0.25 mmol) and commercially available 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (71.4 l, 0.25 mmol).

EXAMPLE 6

8-Fluoro-10-methyl-6-morpholin-4-yl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one

(11) ##STR00078##

(12) A mixture of 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 11) (149 mg, 0.5 mmol), sodium tert-butoxide (72.1 mg, 0.75 mmol), (R)-2,2-bis(diphenylphosphino)-1,1-binaphthyl (24.9 mg, 40.0 mol), tris(dibenzylideneacetone)-dipalladium(0) (18.3 mg, 20.0 mol) and morpholine (87.1 mg, 87.1 l, 1.0 mmol) in toluene (2 ml) was allowed to stir for 21 h at 100 C. Afterwards, the reaction mixture was filtered through Dicalite, the collected solid was washed with diethylacetate and the organic phase was evaporated. The crude product (140 mg) was purified by flash chromatography on silica gel (dichloromethane/MeOH, 0-20%) to yield the title compound as a white solid (22 mg, 14%), MS (ISP) m/z=304.6 [(M+H).sup.+], mp 226 C.

EXAMPLE 7

8-Chloro-6,10-dimethyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one

(13) ##STR00079##

(14) The title compound, white solid (43 mg, 69%), MS (ISP) m/z=249.4 [(M+H).sup.+], mp 251 C., was prepared in accordance with the general method of example 1 from 7-bromo-9-chloro-11-methyl-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indol-1-one (intermediate 9) (78.4 mg, 0.25 mmol) and commercially available 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (71.4 l, 0.25 mmol).

EXAMPLE 8

6-Ethyl-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one

(15) ##STR00080##

(16) The title compound, white solid (35 mg, 57%), MS (ISP) m/z=247.5 [(M+H).sup.+], mp 177 C., was prepared in accordance with the general method of example 3 from 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 11) (74.3 mg, 0.25 mmol) and commercially available ethylboronic acid (73.9 mg, 1.0 mmol).

EXAMPLE 9

6-(1,1-Dioxo-16-thiomorpholin-4-yl)-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one

(17) ##STR00081##

(18) The title compound, white solid (18 mg, 10%), MS (ISP) m/z=352.5 [(M+H).sup.+], mp 387 C., was prepared in accordance with the general method of example 6 from 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 11) (149 mg, 0.50 mmol) and commercially available thiomorpholine 1,1-dioxide (135 mg, 1.0 mmol).

EXAMPLE 10

8-Chloro-6-ethyl-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one

(19) ##STR00082##

(20) The title compound, off-white solid (40 mg, 61%), MS (ISP) m/z=263.5 [(M+H).sup.+], mp 191 C., was prepared in accordance with the general method of example 3 from 7-bromo-9-chloro-11-methyl-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indol-1-one (intermediate 9) (78.4 mg, 0.25 mmol) and commercially available ethylboronic acid (22.2 mg, 0.3 mmol).

EXAMPLE 11

6-Allyl-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one

(21) ##STR00083##

(22) The title compound, white solid (43 mg, 67%), MS (ISP) m/z=259.4 [(M+H).sup.+], mp 172 C., was prepared in accordance with the general method of example 3 from 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 11) (74.3 mg, 0.25 mmol) and commercially available allylboronic acid (85.9 mg, 1.0 mmol).

EXAMPLE 12

8-Fluoro-10-methyl-6-(3-methyl-butyl)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one

(23) ##STR00084##

(24) The title compound, white solid (47 mg, 65%), MS (ISP) m/z=289.5 [(M+H).sup.+], mp 161 C., was prepared in accordance with the general method of example 3 from 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 11) (74.3 mg, 0.25 mmol) and commercially available isopentylboronic acid (116 mg, 1.0 mmol).

EXAMPLE 13

4-(8-Fluoro-10-methyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indol-6-yl)-butyronitrile

(25) ##STR00085##

(26) The title compound, white solid (20 mg, 28%), MS (ISP) m/z=286.4 [(M+H).sup.+], mp 194 C., was prepared in accordance with the general method of example 3 from 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 11) (74.3 mg, 0.25 mmol) and commercially available 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butanenitrile (195 mg, 1.0 mmol).

EXAMPLE 14

8-Chloro-6-isobutyl-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one

(27) ##STR00086##

(28) The title compound, white solid (32 mg, 44%), MS (ISP) m/z=291.6 [(M+H).sup.+], mp 199 C., was prepared in accordance with the general method of example 3 from 7-bromo-9-chloro-11-methyl-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indol-1-one (intermediate 9) (78.4 mg, 0.25 mmol) and commercially available isobutylboronic acid (102 mg, 1.0 mmol).

EXAMPLE 15

8-Fluoro-6-(4-fluoro-benzyl)-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one

(29) ##STR00087##

(30) The title compound, white solid (58 mg, 71%), MS (ISP) m/z=327.5 [(M+H).sup.+], mp 178 C., was prepared in accordance with the general method of example 3 from 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 11) (74.3 mg, 0.25 mmol) and commercially available 2-(4-fluorobenzyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (76.7 mg, 0.325 mmol).

EXAMPLE 16

8-Fluoro-10-methyl-6-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one

(31) ##STR00088##

(32) The title compound, off-white solid (20 mg, 13%), MS (ISP) m/z=316.5 [(M+H).sup.+], mp 237 C., was prepared in accordance with the general method of example 6 from 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 11) (149 mg, 0.50 mmol) and commercially available 2-oxa-6-azaspiro[3.3]heptane oxalate (189 mg, 1.0 mmol).

EXAMPLE 17

8-Chloro-6-(1,1-dioxo-16-thiomorpholin-4-yl)-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one

(33) ##STR00089##

(34) The title compound, white solid (8 mg, 4%), MS (ISP) m/z=368.5 [(M+H).sup.+], mp 386 C., was prepared in accordance with the general method of example 6 from 7-bromo-9-chloro-11-methyl-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indol-1-one (intermediate 9) (157 mg, 0.5 mmol) and commercially available thiomorpholine 1,1-dioxide (135 mg, 1.0 mmol).

EXAMPLE 18

8-Chloro-10-methyl-6-morpholin-4-yl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one

(35) ##STR00090##

(36) The title compound, white solid (6 mg, 4%), MS (ISP) m/z=320.6 [(M+H).sup.+], mp 207 C., was prepared in accordance with the general method of example 6 from 7-bromo-9-chloro-11-methyl-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indol-1-one (intermediate 9) (157 mg, 0.5 mmol) and commercially available morpholine (87.1 mg, 87.1 l, 1.0 mmol).

EXAMPLE 19

6-(1,1-Dioxo-16-thiomorpholin-4-yl)-10-methyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile

(37) ##STR00091##

(38) The title compound, white solid (10 mg, 6%), MS (ISP) m/z=359.5 [(M+H).sup.+], mp 400 C., was prepared in accordance with the general method of example 6 from 6-bromo-10-methyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 13) (152 mg, 0.50 mmol) and commercially available thiomorpholine 1,1-dioxide (135 mg, 1.0 mmol).

EXAMPLE 20

6-Ethynyl-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one

(39) ##STR00092##
Step A

(40) To a stirred mixture of triphenylphosphine (17.7 mg, 67.3 mol), palladium(II)acetate (7.56 mg, 33.7 mol) and copper(I)iodide (8.01 mg, 42.1 mol) in tetrahydrofurane (1 ml), was added at room temperature triethylamine (579 mg, 797 l, 5.72 mmol), 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 11) (0.25 g, 0.84 mmol) and commercially available ethynyltrimethylsilane (124 mg, 175 l, 1.26 mmol), and the reaction mixture was allowed to stir at 70 C. for 23 h. The reaction mixture was poured into water (30 ml) and extracted with ethyl acetate (240 ml). The combined organic layers were washed with brine (30 ml), dried (MgSO.sub.4) and evaporated. The crude product (150 mg dark brown solid) was further purified by flash chromatography on silica gel (heptane/ethyl acetate 50-100%) to yield 8-fluoro-10-methyl-6-trimethylsilanylethynyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one as a brown solid (43 mg, 16%), MS (ISP) m/z=315.5 [(M+H).sup.+], mp 194 C.

(41) Step B

(42) To a stirred solution of 8-fluoro-10-methyl-6-trimethylsilanylethynyl-3,4-dihydro-2H-pyrazino[1,2-c]indol-1-one (Step A) (43 mg, 137 mol) in methanol (1 ml) and tetrahydrofurane (1 ml) was added at 0 C. potassium carbonate (9.45 mg, 68.4 mol) and the reaction mixture was allowed to stir at 0 C. for 2 h. The reaction mixture was diluted with tetrahydrofurane (5 ml), filtered and evaporated. The crude product was purified by flash chromatography on silica gel (diethyl acetate) and trituration (diethyl ether) to yield the title compound as a light brown solid (21 mg, 63%), MS (ISP) m/z=243.5 [(M+H).sup.+], mp 259 C.

EXAMPLE 21

6-Isobutyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile

(43) ##STR00093##

(44) The title compound, off-white solid (78 mg, 58%), MS (ISP) m/z=268.5 [(M+H).sup.+], mp 260.5 C., was prepared in accordance with the general method of example 3 from 6-bromo-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 12) (145 mg, 0.5 mmol) and commercially available isobutylboronic acid (204 mg, 2.0 mmol).

EXAMPLE 22

9-Fluoro-7-isobutyl-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indol-1-one

(45) ##STR00094##

(46) The title compound, white solid (33 mg, 48%), MS (ISP) m/z=275.6 [(M+H).sup.+], mp 157 C., was prepared in accordance with the general method of example 3 from 7-bromo-9-fluoro-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indol-1-one (intermediate 2) (74.3 mg, 0.25 mmol) and commercially available isobutylboronic acid (38.2 mg, 0.375 mmol).

EXAMPLE 23

8-Fluoro-6-(2-methylpropyl)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one

(47) ##STR00095##

(48) The title compound, white solid (33 mg, 51%), MS (ISP) m/z=261.5 [(M+H).sup.+], mp 229 C., was prepared in accordance with the general method of example 3 from 6-bromo-8-fluoro-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 1) (70.8 mg, 0.25 mmol) and commercially available isobutylboronic acid (38.2 mg, 0.375 mmol).

EXAMPLE 24

8-Fluoro-10-methyl-6-(2,2,2-trifluoroethoxy)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one

(49) ##STR00096##

(50) A mixture of 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 11) (149 mg, 0.5 mmol), copper(I)iodide (9.52 mg, 50.0 mol), cesium carbonate (228 mg, 0.7 mmol), ethyl 2-cyclohexanonecarboxylate (18.9 mg, 17.7 l, 0.1 mmol) and 2,2,2-trifluoroethanol (700 mg, 506 l, 7.0 mmol) was heated in a sealed microwave tube for 24 h at 110 C. The reaction mixture was cooled to room temperature, filtered (Dicalite) and washed with ethyl acetate. The organic layer was evaporated, and the crude product was purified by flash chromatography on silica gel (heptane/ethyl acetate 20-80%) and crystallization (dichloromethane/methanol/heptane) to yield the title compound as a white solid (31 mg, 20%), MS (ISP) m/z=317.4 [(M+H).sup.+], mp 239 C.

EXAMPLE 25

9-Chloro-7-(2-methylpropyl)-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indol-1-one

(51) ##STR00097##

(52) The title compound, off-white solid (28 mg, 39%), MS (ISP) m/z=291.4 [(M+H).sup.+], mp 186 C., was prepared in accordance with the general method of example 3 from 7-bromo-9-chloro-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indol-1-one (intermediate 5) (78.4 mg, 0.25 mmol) and commercially available isobutylboronic acid (38.2 mg, 0.375 mmol).

EXAMPLE 26

8-Chloro-6-(2-methylpropyl)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one

(53) ##STR00098##

(54) The title compound, white solid (32 mg, 46%), MS (ISP) m/z=277.4 [(M+H).sup.+], mp 236 C., was prepared in accordance with the general method of example 3 from 6-bromo-8-chloro-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 6) (74.9 mg, 0.25 mmol) and commercially available isobutylboronic acid (38.2 mg, 0.375 mmol).

EXAMPLE 27

8-Chloro-6-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one

(55) ##STR00099##

(56) The title compound, white solid (22 mg, 37%), MS (ISP) m/z=235.5 [(M+H).sup.+], mp 263 C., was prepared in accordance with the general method of example 1 from 6-bromo-8-chloro-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 6) (74.9 mg, 0.25 mmol) and commercially available 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (71.4 l, 0.25 mmol).

EXAMPLE 28

9-Chloro-7-methyl-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indol-1-one

(57) ##STR00100##

(58) The title compound, white solid (21 mg, 34%), MS (ISP) m/z=249.4 [(M+H).sup.+], mp 207 C., was prepared in accordance with the general method of example 1 from 7-bromo-9-chloro-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indol-1-one (intermediate 5) (78.4 mg, 0.25 mmol) and commercially available 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (71.4 l, 0.25 mmol).

EXAMPLE 29

8-Fluoro-10-methyl-1-oxo-3,4-dihydro-2H-pyrazino[1,2-a]indole-6-carbonitrile

(59) ##STR00101##

(60) To a solution of 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 11) (0.1 g, 337 mol) in DMF (1.5 ml) zinc cyanide (45.9 mg, 390 mol) was added at room temperature, and the reaction mixture was purged with argon for 5 min in an ultrasonic bath. Afterwards tetrakis(triphenylphosphine)palladium(0) (26 mg, 22.5 mol) was added and the reaction mixture was allowed to stir for 90 min at 90 C. The reaction mixture was poured into 2M potassium carbonate solution (20 ml) and extracted with ethyl acetate (240 ml). The combined organic layers were washed with brine (20 ml), dried (MgSO.sub.4) and evaporated. The crude product was further purified by flash chromatography on silica gel (ethyl acetate) and trituration (diethyl ether) to yield the title compound as a white solid (67 mg, 82%), MS (ISP) m/z=244.4 [(M+H).sup.+], mp 265 C.

EXAMPLE 30

10-Methyl-1-oxo-6-(trifluoromethoxy)-3,4-dihydro-2H-pyrazino[1,2-a]indole-8-carbonitrile

(61) ##STR00102##
Step A

(62) 4-Hydrazinyl-3-trifluoromethoxy-benzonitrile, light green solid (0.8 g, 75%), MS (ISP) m/z=218.2 [(M+H).sup.+], mp 127 C., was prepared in accordance with the general method of intermediate 4, step A, from commercially available 4-amino-3-trifluoromethoxy-benzonitrile (1.0 g, 4.95 mmol).

(63) Step B

(64) Methyl (2Z)-2-[4-cyano-2-trifluoromethoxy-phenyl)-hydrazinylidene]-butanoate (1.14 g, 98%) as a brown oil, MS (ISP) m/z=316.4 [(M+H).sup.+], was prepared in accordance with the general method of intermediate 9, step B, from 4-hydrazinyl-3-trifluoromethoxy-benzonitrile (step A) (0.8 g, 3.68 mmol).

(65) Step C

(66) Methyl 5-cyano-3-methyl-7-(trifluoromethoxy)-1H-indole-2-carboxylate, light yellow solid (0.46 g, 43%), MS (ISN) m/z=299.5 [(M+H).sup.+], mp 184 C., was prepared in accordance with the general method of intermediate 9, step C, from methyl (2Z)-2-[4-cyano-2-trifluoromethoxy-phenyl)-hydrazinylidene]-butanoate (step B) (1.14 g, 3.62 mmol).

(67) Step D

(68) Methyl 5-cyano-3-methyl-1-{2-[(2-methylpropan-2-yl)-oxycarbonylamino]-ethyl}-7-trifluoromethoxy-indole-2-carboxylate, light yellow solid (0.45 g, 92%), MS (ISP) m/z=442.5 [(M+H).sup.+], mp 133 C., was prepared in accordance with the general method of intermediate 1, step A, from methyl 5-cyano-3-methyl-7-(trifluoromethoxy)-1H-indole-2-carboxylate (step C) (0.33 g, 1.11 mmol) and commercially available 2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester [CAS No. 459817-82-4] (0.3 g, 1.33 mmol).

(69) Step E

(70) The title compound, white solid (245 mg, 79%), MS (ISP) m/z=310.5 [(M+H).sup.+], mp 253 C., was prepared in accordance with the general method of intermediate 1, step B, from methyl 5-cyano-3-methyl-1-{2-[(2-methylpropan-2-yl)-oxycarbonylamino]-ethyl}-7-trifluoromethoxy-indole-2-carboxylate (step D) (445 mg, 1.01 mmol).

EXAMPLE 31

8-Methyl-6-(2-methylpropyl)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one

(71) ##STR00103##

(72) The title compound, white solid (39 mg, 61%), MS (ISP) m/z=257.6 [(M+H).sup.+], mp 182 C., was prepared in accordance with the general method of example 3 from 6-bromo-8-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 7) (69.8 mg, 0.25 mmol) and commercially available isobutylboronic acid (38.2 mg, 0.375 mmol).

EXAMPLE 32

9-Methyl-7-(2-methylpropyl)-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indol-1-one

(73) ##STR00104##

(74) The title compound, white solid (40 mg, 59%), MS (ISP) m/z=271.6 [(M+H).sup.+], mp 160 C., was prepared in accordance with the general method of example 3 from 7-bromo-9-methyl-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indol-1-one (intermediate 8) (73.3 mg, 0.25 mmol) and commercially available isobutylboronic acid (38.2 mg, 0.375 mmol).

EXAMPLE 33

6,8-Dimethyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one

(75) ##STR00105##

(76) The title compound, white solid (21 mg, 39%), MS (ISP) m/z=215.5 [(M+H).sup.+], mp 253 C., was prepared in accordance with the general method of example 1 from 6-bromo-8-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 7) (69.8 mg, 0.25 mmol) and commercially available 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (71.4 l, 0.25 mmol).

EXAMPLE 34

11-Methyl-7-(2-methylpropyl)-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile

(77) ##STR00106##

(78) The title compound, white solid (41 mg, 56%), MS (ISP) m/z=296.5 [(M+H).sup.+], mp 235 C., was prepared in accordance with the general method of example 3 from 7-bromo-11-methyl-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 14) (79.5 mg, 0.25 mmol) and commercially available isobutylboronic acid (38.2 mg, 0.375 mmol).

EXAMPLE 35

7,11-Dimethyl-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile

(79) ##STR00107##

(80) The title compound, white solid (53 mg, 84%), MS (ISP) m/z=254.5 [(M+H).sup.+], mp 255 C., was prepared in accordance with the general method of example 1 from 7-bromo-11-methyl-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 14) (79.5 mg, 0.25 mmol) and commercially available 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (85.7 l, 0.30 mmol).

EXAMPLE 36

8-Methoxy-6-(2-methylpropyl)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one

(81) ##STR00108##

(82) The title compound, white solid (35 mg, 51%), MS (ISP) m/z=273.5 [(M+H).sup.+], mp 175 C., was prepared in accordance with the general method of example 3 from 6-bromo-8-methoxy-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 15) (73.8 mg, 0.25 mmol) and commercially available isobutylboronic acid (38.2 mg, 0.375 mmol).

EXAMPLE 37

6-(2-Methylpropyl)-8-(trifluoromethoxy)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one

(83) ##STR00109##

(84) The title compound, white solid (41 mg, 50%), MS (ISP) m/z=327.4 [(M+H).sup.+], mp 166 C., was prepared in accordance with the general method of example 3 from 6-bromo-8-(trifluoromethoxy)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 16) (87.3 mg, 0.25 mmol) and commercially available isobutylboronic acid (38.2 mg, 0.375 mmol).

EXAMPLE 38

9-Chloro-11-methyl-7-(2-methylpropyl)-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indol-1-one

(85) ##STR00110##

(86) The title compound, white solid (42 mg, 55%), MS (ISP) m/z=305.6 [(M+H).sup.+], mp 176 C., was prepared in accordance with the general method of example 3 from 7-bromo-9-chloro-11-methyl-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indol-1-one (intermediate 10) (81.9 mg, 0.25 mmol) and commercially available isobutylboronic acid (38.2 mg, 0.375 mmol).

EXAMPLE 39

9-Chloro-7,11-dimethyl-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indol-1-one

(87) ##STR00111##

(88) The title compound, white solid (49 mg, 75%), MS (ISP) m/z=263.5 [(M+H).sup.+], mp 198 C., was prepared in accordance with the general method of example 1 from 7-bromo-9-chloro-11-methyl-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indol-1-one (intermediate 10) (81.9 mg, 0.25 mmol) and commercially available 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (85.7 l, 0.30 mmol).

EXAMPLE 40

7-(2-Methylpropyl)-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile

(89) ##STR00112##

(90) The title compound, light yellow solid (38 mg, 54%), MS (ISP) m/z=282.5 [(M+H).sup.+], mp 199 C., was prepared in accordance with the general method of example 3 from 7-bromo-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 17) (76.0 mg, 0.25 mmol) and commercially available isobutylboronic acid (38.2 mg, 0.375 mmol).

EXAMPLE 41

10-Methyl-6-morpholin-4-yl-1-oxo-3,4-dihydro-2H-pyrazino[1,2-a]indole-8-carbonitrile

(91) ##STR00113##

(92) The title compound, light yellow solid (4 mg, 4%), MS (ISP) m/z=311.5 [(M+H).sup.+], mp 276 C., was prepared in accordance with the general method of example 6 from 6-bromo-10-methyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 13) (100 mg, 0.33 mmol) and commercially available morpholine (31.5 mg, 31.1 l, 0.36 mmol).

EXAMPLE 42

7-(1,1-Dioxo-1,4-thiazinan-4-yl)-11-methyl-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile

(93) ##STR00114##

(94) The title compound, off-white solid (15 mg, 8%), MS (ISP) m/z=373.5 [(M+H).sup.+], mp 393 C., was prepared in accordance with the general method of example 6 from 7-bromo-11-methyl-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 14) (159 mg, 0.5 mmol) and commercially available thiomorpholine 1,1-dioxide (135 mg, 1.0 mmol).

EXAMPLE 43

7-(1,1-Dioxo-1,4-thiazinan-4-yl)-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile

(95) ##STR00115##

(96) The title compound, off-white solid (13 mg, 7%), MS (ISP) m/z=359.5 [(M+H).sup.+], mp 404.5 C., was prepared in accordance with the general method of example 6 from 7-bromo-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 17) (152 mg, 0.5 mmol) and commercially available thiomorpholine 1,1-dioxide (135 mg, 1.0 mmol).

EXAMPLE 44

11-Methyl-7-morpholin-4-yl-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile

(97) ##STR00116##

(98) The title compound, off-white solid (16 mg, 10%), MS (ISP) m/z=325.5 [(M+H).sup.+], mp 227 C., was prepared in accordance with the general method of example 6 from 7-bromo-11-methyl-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 14) (159 mg, 0.5 mmol) and commercially available morpholine (87.1 mg, 87.1 l, 1.0 mmol).

EXAMPLE 45

7-Morpholin-4-yl-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile

(99) ##STR00117##

(100) The title compound, light yellow solid (34 mg, 22%), MS (ISP) m/z=311.1 [(M+H).sup.+], mp 221 C., was prepared in accordance with the general method of example 6 from 7-bromo-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 17) (152 mg, 0.5 mmol) and commercially available morpholine (87.1 mg, 87.1 l, 1.0 mmol).

EXAMPLE 46

6-Morpholin-4-yl-1-oxo-3,4-dihydro-2H-pyrazino[1,2-a]indole-8-carbonitrile

(101) ##STR00118##

(102) The title compound, light grey solid (28 mg, 32%), MS (ISP) m/z=297.1 [(M+H).sup.+], mp 280 C., was prepared in accordance with the general method of example 6 from 6-bromo-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 12) (85 mg, 0.29 mmol) and commercially available morpholine (51.1 mg, 51.1 l, 0.58 mmol).