 Arylpiperazinyl-cyclohexyl indole derivatives for the treatment of depression
专利摘要:
There is provided a compound useful in the treatment of serotonin-affected neurological disorders comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof. Formula 1 In this formula, R a , R 1 , R 2 and R 3 are each independently selected from the group consisting of hydrogen or halogen, CF 3 , alkyl, alkoxy, MeSO 2 , amino or aminocarbonyl (each optionally substituted with one or two groups selected from alkyl and benzyl) Optionally substituted by hydroxy, carboxy, or alkoxycarbonyl; Two adjacent R a and R 1-4 together may form a 5-7 membered carbocyclic or heterocyclic ring optionally substituted by a substituent as defined above; R 4 is hydrogen, halogen, or alkyl; R < 5 > is hydrogen, alkyl, arylalkyl, or aryl; R 6 is hydrogen, halogen, CF 3, CN, cover imide, alkoxy or benzyloxy, and; X 1 , X 2 and X 3 are each carbon or one of X 1 , X 2 or X 3 may be nitrogen; Y is CH or nitrogen; Z is carbon or nitrogen. 公开号:KR20010086163A 申请号:KR1020017008567 申请日:2000-01-06 公开日:2001-09-08 发明作者:뮤쇼리처드에릭；쪼우핑；쪼우다후이；미거크리스틴린；애슬린매그다；에브러드데보라앤；길버트애덤매튜 申请人:이곤 이 버그；아메리칸 홈 푸로닥츠 코포레이션； IPC主号:
专利说明:
[0001] ARYLPIPERAZINYL-CYCLOHEXYL INDOLE DERIVATIVES FOR THE TREATMENT OF DEPRESSION [0002] [2] Agents that promote neurotransmission of serotonin (5-HT) are useful in the treatment of a number of psychiatric disorders, including depression and anxiety. The first generation of non-selective serotonin-influencing agents worked through various physiological means leading to the possession of a large number of undesired side effects. A more recent prescription drug, selective serotonin reuptake inhibitor (SSRI), works by largely inhibiting synaptic release of 5-HT from the synaptic cleft through the synaptic serotonin transport carrier. These 5-HT blockade mechanisms do not fully account for their therapeutic activity, as SSRIs require several weeks for them to exert their full therapeutic effect. These two-week induction, which occurs before complete antidepressant effect is observed, is presumed to be due to the intervention of the 5-HT1A autoreceptor, which suppresses the aerobic activity of 5-HT neurons and damages the therapeutic effect. Studies suggest that desensitization of the 5-HT autoreceptors occurs several weeks after SSRI administration, allowing complete antidepressant effects in most patients. (See, for example, Le Poul et al., Arch. Pharmacol., 352: 141 (1995)). Thus, overriding this negative feedback by the use of 5HT1A antagonists is likely to potentially increase and promote clinical antidepressant response. A recent study by Artigas et al., Trends Neurosci., 19: 378-383 (1996) showed that the combination of 5-HT1A activity and 5-HT uptake inhibition in a single molecular sieve achieved a more potent and rapid antidepressant effect It is possible to do. [3] The present invention relates to molecules of nephropathies having the ability to cooperate with 5-HT1A autoreceptors and with 5-HT transporters. Thus, such compounds are potentially useful in the treatment of depression and other serotonin disorders. [4] US Pat. 5,468, 767 reports a substituted indole series of the formula: EMI2.1 for the treatment of dysfunction associated with dysfunction in serotonin neurotransmitter neurotransmission, including depression. [5] The [6] [7] In this formula, [8] R 1 is hydrogen or C 1-4 alkyl, [9] R 2 is C 1-4 alkyl or (CH 2 ) 2 pAr. [10] WO 9415928 discloses a series of piperazine derivatives of the following formula for the treatment of CNS disorders, including depression. [11] The [12] [13] In this formula, [14] R is hydrogen or alkyl; [15] R 1 and R 2 are each a mono- or bicyclic aryl or heteroaryl radical; [16] R 3 is hydrogen, alkyl, or a spirocycloalkyl group; [17] n is 1 or 2 and m is 1 to 3. [18] WO 93/10092 discloses cyclohexene series of the formula for the treatment of dopamine action over treatment. [19] The [20] [1] The present invention relates to compounds useful in the treatment of diseases caused by abnormalities of serotonin-affected neurological systems such as depression and anxiety. More specifically, the present invention relates to arylpiperazinyl cyclohexyl derivatives useful in the treatment of such disorders. [21] SUMMARY OF THE INVENTION [22] The compound of the present invention is an arylpiperazinyl-cyclohexyl indole derivative represented by the following formula (1): Or a pharmaceutically acceptable salt thereof. [23] [24] In this formula, [25] R a , R 1 , R 2 and R 3 are each independently selected from the group consisting of hydrogen or halogen, CF 3 , alkyl, alkoxy, MeSO 2 , amino or aminocarbonyl (each optionally substituted with one or two groups selected from alkyl and benzyl) Optionally substituted by hydroxy, carboxy, or alkoxycarbonyl; Two adjacent R a and R 1-4 together may form a 5-7 membered carbocyclic or heterocyclic ring optionally substituted by a substituent as defined above; [26] R 4 is hydrogen, halogen, or alkyl; [27] R < 5 > is hydrogen, alkyl, arylalkyl, or aryl; [28] R 6 is hydrogen, halogen, CF 3, CN, cover imide, alkoxy or benzyloxy, and; [29] X 1 , X 2 and X 3 are each carbon or one of X 1 , X 2 or X 3 may be nitrogen; [30] Y is CH or nitrogen; [31] Z is carbon or nitrogen. [32] Preferably, the compounds of the present invention are those wherein R a , R 1 , R 2 and R 3 are each independently hydrogen, halogen, alkyl, alkoxy or together form a 5-7 membered carbocyclic or heterocyclic ring; [33] R < 4 > is hydrogen or halogen; And / or [34] R < 5 > is hydrogen, alkyl or alkylaryl; And / or [35] R < 6 > is hydrogen, halogen, CN or alkoxy; And / or [36] Those represented by the formula (1) wherein X 1 , X 2 , X 3 , Y and Z are each carbon; Or a pharmaceutically acceptable salt thereof. [37] More preferably, the compounds of the present invention are selected from the following compounds: [38] 3- [cis-4- [4- (1H-Indol-4-yl) -1-piperazinyl] cyclohexyl] -1H-indole; [39] 3- [trans-4- [4- (1H-indol-4-yl) -1-piperazinyl] cyclohexyl] -1H-indole; [40] 4-Fluoro-3- [cis-4- [4- (1H-indol-4-yl) -1-piperazinyl] cyclohexyl] -1H-indole; [41] 4-Fluoro-3- [trans-4- [4- (1H-indol-4-yl) -1-piperazinyl] cyclohexyl] -1H-indole; [42] 5-Fluoro-3- [cis-4- [4- (1H-indol-4-yl) -1-piperazinyl] cyclohexyl] -1H-indole; [43] 5-Fluoro-3- [trans-4- [4- (1H-indol-4-yl) -1-piperazinyl] cyclohexyl] -1H-indole; [44] 6-Fluoro-3- [cis-4- [4- (1H-indol-4-yl) -1-piperazinyl] cyclohexyl] -1H-indole; [45] 6-Fluoro-3- [trans-4- [4- (1H-indol-4-yl) -1-piperazinyl] cyclohexyl] -1H-indole; [46] 5-Bromo-3- [cis-4- [4- (lH-indol-4-yl) -1-piperazinyl] cyclohexyl] -lH-indole; [47] 5-Bromo-3- [trans-4- [4- (1H-indol-4-yl) -1-piperazinyl] cyclohexyl] -1H-indole; [48] 5-Chloro-3- [cis-4- [4- (1H-indol-4-yl) -1-piperazinyl] cyclohexyl] -1H-indole; [49] 5-chloro-3- [trans-4- [4- (1H-indol-4-yl) -1-piperazinyl] cyclohexyl] -1H-indole; [50] 3- {4 - [(1,4-cis) -4- (1H-indol-4-yl) -1-piperazinyl-1-yl] cyclohexyl} -1H-indole-5-carbonitrile; [51] 3- {4 - [(1,4-trans) -4- (1H-indol-4-yl) -1-piperazinyl-1-yl] cyclohexyl} -1H-indole-5-carbonitrile; [52] 5-Methoxy-3- [cis-4- [4- (1H-indol-4-yl) -1-piperazinyl] cyclohexyl] -1H-indole; [53] 5-Methoxy-3- [trans-4- [4- (1H-indol-4-yl) -1-piperazinyl] cyclohexyl] -1H-indole; [54] 3- [cis-4- [4- (1H-Indol-4-yl) -1-piperazinyl] cyclohexyl] -2-methyl-1H-indole; [55] 3- [trans-4- [4- (1H-indol-4-yl) -1-piperazinyl] cyclohexyl] -2-methyl-1H-indole; [56] 3 - {(l, 4-cis-4- [4- (lH-indol-4-yl) -piperazin-l-yl] -cyclohexyl} -lH- pyrrolo [2,3-b] pyridine; [57] 3 - {(1,4-trans-4- [4- (1H-indol-4-yl) -piperazin-1-yl] -cyclohexyl} -IH- pyrrolo [2,3-b] pyridine; [58] 6-Fluoro-l-methyl-3- {cis-4- [4- (l-methyl-lH-indol-4-yl) -1-piperazinyl] cyclohexyl} -1H-indole; [59] 3 - {(l, 4-cis) -4- [4- (lH-indol-4-yl) -piperazin-l-yl] cyclohexyl} -l-methyl-lH-indole-5-carbonitrile; [60] 3 - {(1,4-trans) -4- [4- (1H-indol-4-yl) -piperazin-1-yl] cyclohexyl} -1-methyl-1H-indole-5-carbonitrile; [61] 1-yl] -cyclohexyl} -lH-indole-5-carbonitrile < / RTI >; [62] 1-yl] -cyclohexyl} -l-propyl-lH-indole-5-carbonitrile < / RTI >; [63] 1-yl] -cyclohexyl} -l-propyl-lH-indole-5-carbonitrile < / RTI >; [64] 4-yl) -piperazin-l-yl] -cyclohexyl} -l-isopropyl-lH-indole-5-carbo Nitrile; [65] 1-yl] cyclohexyl} -l-isopropyl-lH-indole-5-carbonitrile < / RTI >; [66] 1-yl] -cyclohexyl} -lH-indole-5-carbonitrile < / RTI >; [67] L-Benzyl-3 - {(1,4-trans) -4- [4- (lH-indol-4-yl) -piperazin-l-yl] cyclohexyl} -lH-indole-5-carbonitrile; [68] 1-yl] -piperazin-1-yl] -cyclohexyl} -1H-indole- 5-carbonitrile; [69] 5-Fluoro-3 - {(cis) -4- [4- (2-methoxy-phenyl) -piperazin-1-yl] -cyclohexyl} -1H-indole; [70] 5-Fluoro-3 - {(l, 4-cis) -4- [4- (2-methoxy-phenyl) -piperidin- l-yl] -cyclohexyl} -lH-indole; [71] 5-Fluoro-3 - {(1,4-trans) -4- [4- (2-methoxy-phenyl) -piperidin- l-yl] -cyclohexyl} -1H-indole; [72] 5-Methoxy-3 - {(l, 4-cis) -4- [4- (2-methoxy-phenyl) -piperazinyl- l-yl] -cyclohexyl} -lH-indole; [73] 5-Methoxy-3 - {(1,4-trans) -4- [4- (2-methoxy-phenyl) -piperidin-l-yl] -cyclohexyl} -1H-indole; [74] LH-pyrrolo [2,3-b] piperidine-lH-pyrrolo [2,3-b] Dean; [75] 5-Fluoro-3 - {(cis) -4- [4- (5-fluoro-2-methoxy-phenyl) -piperazin-1-yl] -cyclohexyl} -1H-indole; [76] 5-Fluoro-3 - {(trans) -4- [4- (5-fluoro-2-methoxy-phenyl) -piperazin-1-yl] -cyclohexyl} -1H-indole; [77] Yl) -piperazin-1-yl] -cyclohexyl} -piperazin-1-yl) -4-fluoro-lH-indole < / RTI > [78] Yl) -piperazin-1-yl] -cyclohexyl} - (2, 3-dihydro-benzo [ 4-fluoro-lH-indole; [79] Yl) -piperazin-1-yl] -cyclohexyl} - (3, 4-dihydro- 5-fluoro-lH-indole; [80] Yl) -piperazin-1-yl] -cyclohexyl} - (2, 3-dihydro-benzo [ 5-fluoro-lH-indole; [81] Yl) -piperazin-1-yl] -cyclohexyl} - (3, 4-dihydro- 6-fluoro-lH-indole; [82] Yl) -piperazin-1-yl] -cyclohexyl} - (2, 3-dihydro-benzo [ 6-fluoro-lH-indole; [83] Yl) -piperazin-1-yl] -cyclohexyl} - (2, 3-dihydro-benzo [ 6-fluoro-lH-indole; [84] Yl) -piperazin-1-yl] -cyclohexyl} - (3, 4-dihydro- 1H-indole-5-carbonitrile; [85] Yl) -piperazin-1-yl] -cyclohexyl} - (2, 3-dihydro-benzo [ 1H-indole-5-carbonitrile; [86] 8- {4 - [(1,4-cis) -4- (5-fluoro-lH-indol-3-yl) -cyclohexyl] -piperazin-1-yl} quinoline; [87] 8- {4 - [(1,4-trans) -4- (5-fluoro-lH-indol-3-yl) -cyclohexyl] -piperazin-1-yl} -quinoline; [88] 8- {4- (l, 4-cis) -4- [4- (5-fluoro-l-methyl-lH-indol-3-yl) -cyclohexyl] -piperazin-l- yl} quinoline; [89] 3 - [(l, 4-cis) -4- (4-quinolin-8-yl-piperazin-l-yl) -cyclohexyl] -lH-indole-5-carbonitrile; [90] 3 - [(1,4-trans) -4- (4-quinolin-8-yl-piperazin-1-yl) -cyclohexyl] -1H-indole-5-carbonitrile; [91] L-Methyl-3 - [(l, 4-cis) -4- (4-quinolin-8-yl-piperazin-l-yl) -cyclohexyl] -lH-indole-5-carbonitrile; [92] Yl) -piperazin-l-yl] -cyclohexyl} -1H-indole < / RTI >; [93] Yl) -piperazin-l-yl] -cyclohexyl} -lH-indole < / RTI >; [94] Yl) -piperazin-1-yl] - (4-fluoro-benzyl) -piperazin-1- Cyclohexyl} -1H-indole; [95] Yl) -piperazin-1-yl] - (4-fluoro-benzyl) Cyclohexyl} -1H-indole; [96] Yl) -piperazin-l-yl] -cyclohexyl} - lH- (l, 4-dihydro- - indole-5-carbonitrile; [97] Yl) -piperazin-l-yl] -cyclohexyl} - lH-pyrrolo [2,3-d] pyrimidin- - indole-5-carbonitrile; [98] Yl) -piperazin-1-yl] -cyclohexyl} - 1, 3-dihydro-benzofuran- Methyl-lH-indole-5-carbonitrile; [99] 3 - [(l, 4-cis) -4- [4- (benzofuran-7-yl-piperazin-l-yl) -cyclohexyl] -lH-indole-5-carbonitrile; [100] 3 - [(1,4-trans) -4- [4- (benzofuran-7-yl-piperazin-1-yl) -cyclohexyl] -1H-indole-5-carbonitrile; [101] 5-Fluoro-3- {4- [4- (2-methoxy-phenyl) -piperazin-1-yl] -cyclohex-1-enyl} -1H-indole; [102] 3- {4- [4- (1H-Indol-4-yl) -piperazin-1-yl] -cyclohex-1-enyl} -1H-indole-5-carbonitrile; [103] 1-yl] -cyclohexyl} -1,3-dihydro-indole < RTI ID = 0.0 >Gt; [104] 5-Fluoro-3- {cis-4- [4- (1H-indol-4-yl) piperazinyl] -cyclohexyl} -1-methyl-1H-indole; [105] 8 - {(l, 4-cis) -4- [4- (5-fluoro-lH-indol-3-yl) -cyclohexyl] -piperazin-l-yl} -6-methoxy-quinoline; [106] 8 - {(1,4-trans) -4- [4- (5-fluoro-lH-indol-3-yl) -cyclohexyl] -piperazin-1-yl} -6-methoxy-quinoline; [107] 3 - {(l, 4-cis) -4- [4- (6-methoxy-quinolin-8-yl) -piperazin-l-yl] -cyclohexyl} -lH-indole-5-carbonitrile; [108] 3 - {(1,4-trans) -4- [4- (6-methoxy-quinolin-8-yl) -piperazin-1-yl] -cyclohexyl} -1H-indole-5-carbonitrile; [109] 6-chloro-8- {4- [l, 4-cis) -4- (5-fluoro-lH-indol-3-yl) -cyclohexyl] -piperazin-1-yl} quinoline; [110] 6-Chloro-8- {4- [1,4-trans) -4- (5-fluoro-lH-indol-3-yl) -cyclohexyl] -piperazin-1-yl} quinoline; [111] 3 - {(1,4-cis) -4 - [(4- (6-Chloro-quinolin-8-yl) -piperazin-1-yl] -cyclohexyl} -1H-indole-5-carbonitrile; [112] 3 - {(1,4-trans) -4- [4- (6-chloro-quinolin-8-yl) -piperazin-1-yl] -cyclohexyl} -1H-indole-5-carbonitrile; [113] 5-Chloro-8- {4 - [(l, 4-cis) -4- (5-fluoro-lH-indol-3-yl) -cyclohexyl] -piperazin-1-yl} -quinoline; [114] 3 - {(l, 4-cis) -4- [4- (5-Chloro-quinolin-8-yl) -piperazin-l-yl] -cyclohexyl} -lH-indole-5-carbonitrile; [115] 5-Fluoro-8- {4 - [(1,4-cis) -4- (6-fluoro-lH-indol-3-yl) -cyclohexyl] -piperazin-1-yl} -quinoline; [116] 5-Fluoro-8- {4 - [(1,4-trans) -4- (6-fluoro-lH-indol-3-yl) -cyclohexyl] -piperazin-1-yl} -quinoline; [117] 3 - {(l, 4-cis) -4- [4- (2-methyl-quinolin-8-yl) -piperazin-l-yl] -cyclohexyl} -lH-indole-5-carbonitrile; [118] 3 - {(1,4-trans) -4- [4- (2-methyl-quinolin-8-yl) -piperazin-1-yl] -cyclohexyl} -1H-indole-5-carbonitrile; [119] 1-yl} -2-trifluoromethyl-pyrimidin-4-yl) -piperazin-1- Quinoline; [120] 1-yl} -2-trifluoromethyl-pyrimidin-4-yl) -piperazin-1- Quinoline; [121] - (l, 4-cis) -4- [4- (2-Trifluoromethyl-quinolin-4-yl) -piperazin- 1-yl] -cyclohexyl} -lH- indole-5-carbonitrile ; [122] 1-yl] -cyclohexyl} -lH-indole-5-carbonitrile < / RTI >; [123] 4- {4 - [(l, 4-cis) -4- (5-fluoro-lH-indol-3-yl) -cyclohexyl] -piperazin-1-yl} -6-methoxy-quinoline; [124] 4- {4 - [(1,4-trans) -4- (5-fluoro-lH-indol-3-yl) -cyclohexyl] -piperazin-1-yl} -6-methoxy-quinoline; [125] 3 - {(l, 4-cis) -4- [4- (6-methoxy-quinolin-4-yl) -piperazin-l-yl] -cyclohexyl} -lH-indole-5-carbonitrile; And [126] 3 - {(1,4-trans) -4- [4- (6-methoxy-quinolin-4-yl) -piperazin-1-yl] -cyclohexyl} -1H-indole-5-carbonitrile. [127] The term " alkyl " used herein is meant to include both straight and branched carbon chains of 1 to 6 carbon atoms. The term " aryl " means containing an aromatic radical having from 6 to 12 carbon atoms. The term " halogen " means containing fluorine, chlorine, bromine and iodine. The heterocyclic group has 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur. [128] In addition, the compound of formula (I) may be used in the form of a pharmaceutically acceptable acid addition salt having the use of a free base. Such salts prepared by methods well known to those skilled in the art can be prepared by reacting a compound of formula I with an inorganic or organic acid such as, for example, fumaric acid, maleic acid, benzoic acid, ascorbic acid, pamoic acid, succinic acid, bismethylene salicylic acid, methanesulfonic acid, Examples of the organic acid include acetic acid, oxalic acid, propionic acid, tartaric acid, salicylic acid, citric acid, gluconic acid, lactic acid, malic acid, mandelic acid, cinnamic acid, citraconic acid, aspartic acid, stearic acid, palmitic acid, itaconic acid, Benzoic acid, glutamic acid, benzene-sulfonic acid, hydrochloric acid, bromic acid, sulfuric acid, cyclohexylsulfamic acid, phosphoric acid and nitric acid. [129] The compounds of the present invention may be prepared by any suitable method known to those skilled in the art. [130] Therefore, [131] a) reacting a compound of formula 2 with a compound of formula 4; or [132] b) reducing the compound of formula 5 to yield a compound of formula 1; or [133] c) acidifying the basic compound of formula (I) with a pharmaceutically acceptable acid to obtain a pharmaceutically acceptable salt; or [134] d) separating a mixture of cis and trans isomers of the compound of formula (I) to isolate one isomer that is substantially free of the other isomer; or [135] e) reacting a compound of formula 1 having a reactive substituent group to yield a compound of formula 1 having a different substituent group; or [136] f) reacting a compound of formula (I) having a reactive moiety (e.g., NH) to obtain a compound of formula (1) having a substituent group at that site, or a compound of formula Lt; RTI ID = 0.0 > of: < / RTI > [137] Formula 1 [138] [139] [140] [141] [142] In this formula, [143] R a , R 1-6 , Y, Z and X 1-3 are as defined above. [144] In the case of step a), the reaction can be carried out, for example, by reduction alkylation using a reducing agent such as sodium triacetoxyborohydride in a suitable solvent, such as acetic acid. [145] For step b), reduction can conveniently be carried out using palladium on carbon and hydrogen as illustrated herein. [146] The compound of formula (I) may be isolated by treatment with an acid as described above to form a pharmaceutically acceptable acid, for example, an organic acid or a salt of an inorganic acid. [147] Geometric (cis and trans) isomers are possible, and these isomers can be separated by standard techniques, such as chromatography. [148] Examples of step e) involving the conversion of a substituent to another substituent include conversion from a halo substituent to an amino R 1 substituent, obtaining an ester by esterification of carboxy, obtaining a carboxy group by hydrolysis of the ester; And amidation of the ester group by amination. [149] An example of step f) involving substitution at a particular site is the yield of N-alkyl or N-benzyl by alkylation at the NH moiety in the compound of formula 1. [150] The starting materials / reactants used in the process are known or can be prepared from materials readily available by processes known or obvious to those skilled in the art by methods known in the art. In any of the above processes, a reactive substituent group or moiety can be protected with a protecting group before the reaction and subsequently the protecting group can be removed. [151] However, the present compounds can be advantageously prepared according to any one of the reaction schemes 1 to 6 described below. In the scheme, the intermediate compounds illustrated below are indicated in parentheses. The compounds produced in each of Schemes 1 to 6 are identified by reference to the appropriate examples described below. [152] The preparation of such compounds is shown in the following Schemes 1 to 6. [153] [154] [155] [156] [157] [158] [159] [160] [161] [162] [163] [164] [165] [166] [167] [168] [169] [170] [171] [172] [173] [174] [175] [176] [177] (Example 69) [178] [179] (Examples 70 to 75) [180] [181] [182] (Example 76) [183] [184] (Example 77) [185] [186] [187] [188] [189] [190] [191] [192] [193] [194] The compounds of Examples 86-114 were obtained using the following Reaction Schemes 37-39. [195] [196] [197] [198] Intermediate 1 [199] 3- (1,4-dioxa-spiro [4,5] dec-7-en-8-yl) [200] Indole (4.69 g, 40 mmol), 1,4-cyclohexanedione monoethylenecetane (6.3 g, 40 mmol) and potassium hydroxide (13.2 g, 200 mmol) were heated at reflux in 70 ml methanol for 6 hours. The reaction is cooled and the product is then filtered off and washed with water to give 9.1 g (89%) of the product. [201] 7-en-8-yl) -4-fluoro-1H-indole (1b) [202] This compound was prepared in a similar manner as described above, substituting indole with 4-fluoroindole (3 g, 22 mmol) to give the title compound in quantitative yield as a white solid: mp 140 deg. C (sublimation). [203] 7-en-8-yl) -5-fluoro-1H-indole (1c) [204] (7.1 g, 0.046 mol) and potassium hydroxide (6 g, 91 mmol) were dissolved in 70 ml methanol for 6 hours, Reflux is heated. The reaction is cooled and the product is then filtered off and washed with water to give 8.59 g (86%) of the product as a white solid: mp 153-155 < 0 > C. [205] 7-en-8-yl) -6-fluoro-lH-indole (1d) [206] This compound was prepared by the method described for intermediate 1a substituting indole for 6-fluoroindole (5.14 g, 38 mmol) to give 10 g (96.3%) of the title compound as a white solid: mp 196-197 & . [207] Elemental analysis: C 16 H 16 FNO 2 [208] Calculated: C 70.32; H 5.90; N 5.13 [209] Found: C 70.62; H 5.91; N 5.08 [210] 7-en-8-yl) -5-bromo-1H-indole (1e) [211] This compound was prepared as described above for Intermediate Ia by substituting indole with 5-bromoindole (7.84 g, 40 mmol) to give 10.5 g (78%) of the title compound as a white solid: MS EI m / e 333 (M < + & gt ; ). [212] 4-dioxa-spiro [4,5] dec-7-en-8-yl) -5- [213] This compound was prepared as described above for Intermediate 1a by substituting indole with 5-chloroindole (5 g, 33 mmol) to give 9.14 g (96%) of the title compound as a white solid: mp 178-181 [deg.] C; MS EI m / e 273 (M < + & gt ; ). [214] 7-en-8-yl) -5-cyano-1H-indole (1 g) [215] This compound was prepared as described above for Intermediate 1a by replacing the indole with 5-cyanoindole (29.98 g, 0.21 mol) to give 29.32 g (50%) of the title compound as a white solid: mp 158-160 < . [216] 7-en-8-yl) -5-methoxy-lH-indole (lh) [217] This compound was prepared as described above for intermediate 1a by substituting indole with 5-methoxyindole (5 g, 34 mmol) to give the title compound as a white solid in 82% yield (7.95 g): mp 161- 162 ° C. [218] 7-en-8-yl) -2-methyl-1H-indole (1i) [219] A solution of 2-methyl-indole (2.0 g, 15.2 mmol), 1,4-cyclohexanedione monoethylene ketal (4.76 g, 30.4 mmol) and potassium hydroxide (10 g, 0.18 mol) Lt; / RTI > The mixture is poured into water (150 ml) and extracted with methylene chloride (2 x 200 ml). The organic layer is dried over anhydrous magnesium sulfate, filtered and the solvent is removed in vacuo. Chromatography (25% ethyl acetate-hexanes) gave a pale tan solid which was washed with ethyl ether (20 ml) to give 2.35 g (62%) of the product as a white solid: mp 136-137 [deg.] C. [220] Elemental analysis: C 17 H 19 NO 2 [221] Calculated: C 75.81; H 7.11; N 5.70 [222] Found: C 75.47; H 7.26; N 5.13 [223] 3- (1,4-dioxa-spiro [4,5] dec-7-en-8-yl) -1H-azaindole (1j) [224] This compound was prepared as described above for intermediate 1a by substituting indole with 7-azaindole (3.65 g, 31 mmol) to give 68% yield (5.42 g) as a white solid: mp 162-165 [deg.] C; MS EI m / e 256 (M < + & gt ; ). [225] Intermediate 2 [226] 3- (1,4-dioxa-spiro [4,5] dec-8-yl) [227] 7-en-8-yl) -1H-indole (8.0 g, 31.3 mmol) and 10% palladium on carbon 1.3 g) is hydrogenated for 18 h. The catalyst is filtered off and the solvent is removed in vacuo to give 8.01 g (99%) of the product as a white solid. [228] 4-fluoro-lH-indole < / RTI > (2b) [229] This compound was prepared by reacting 3- (1,4-dioxa-spiro [4,5] dec-7-en-8-yl) 7-en-8-yl) -4-fluoro-1H-indole (6.3 g) to give 4.44 g (70%) of the title compound as a white solid : mp 161-162 [deg.] C. [230] Elemental analysis: C 16 H 18 FNO 2 [231] Calculated: C 69.08; H 6.59; N 5.09 [232] Found: C 69.05; H 6.56; N 4.87 [233] 3- (1, 4-dioxa-spiro [4,5] dec-8-yl) -5-fluoro-lH- indole (2c) [234] 5-fluoro-lH-indole (8.5 g) and 10% palladium-on-carbon in ethanol (200 ml) A mixture of palladium (2.72 g) is hydrogenated for 5 hours. The catalyst is filtered off and the solvent is removed in vacuo. Chromatography (methanol-methylene chloride) gave 7.55 g (82%) of the product as a white solid: mp 183-185 [deg.] C. [235] 3- (1,4-dioxa-spiro [4,5] dec-8-yl) -6-fluoro-lH- indole (2d) [236] This compound was prepared by reacting 3- (1,4-dioxa-spiro [4,5] dec-7-en-8-yl) 7-ene-8-yl) -6-fluoro-1H-indole (9.54 g) to give 5.83 g (60%) of the title compound as a white solid : mp 158-159 [deg.] C. [237] Elemental analysis: C 16 H 18 FNO 2 [238] Calculated: C 69.80; H 6.59; N 5.09 [239] Found: C 69.74; H 6.48; N 5.13 [240] 3- (1,4-dioxa-spiro [4,5] dec-8-yl) -5-bromo-1H- indole (2e) [241] 5-bromo-1H-indole (6.8 g, 20.34 mmol) and a solution of carbon < RTI ID = 0.0 & 5% palladium on carbon (5.0 g) is hydrogenated over night. The catalyst is filtered off and the solvent is removed in vacuo. Chromatography (30% ethyl acetate-hexanes) gave 5.0 g (73%) of the product as a solid: MS EI m / e 336 (M + ). [242] Spiro [4,5] dec-8-yl) -5-chloro-lH-indole (2f) [243] 5-chloro-lH-indole (0.18 g) and platinum oxide (0.02 g, 0.14 mmol) in ethanol (20 ml) ) Is hydrogenated overnight with 10 drops of acetic acid. The catalyst is filtered off and the solvent is removed in vacuo. Chromatography (25% ethyl acetate-hexanes) afforded 0.16 g (88%) of the product as a white solid: mp 205-206.5 [deg.] C. [244] 3- (1,4-dioxa-spiro [4,5] dec-8-yl) -5-cyano- [245] This compound was prepared by reacting 3- (1,4-dioxa-spiro [4,5] dec-7-en-8-yl) 7-en-8-yl) -5-cyano-1H-indole (54.6 g) to give Intermediate 2a as a white solid, which was obtained in 95% yield (52.12 g) g (95%): mp 153-155 [deg.] C. [246] 3- (1,4-dioxa-spiro [4,5] dec-8-yl) -5-methoxy- [247] This compound was prepared by reacting 3- (1,4-dioxa-spiro [4,5] dec-7-en-8-yl) 7-en-8-yl) -5-methoxy-1H-indole to give 7.18 g (96%) of the title compound as a white solid: mp 153- 155 ° C. [248] 4-dioxa-spiro [4,5] dec-8-yl) -2-methyl-lH- indole (2i) [249] 7-en-8-yl) -2-methyl-lH-indole (2.39 g, 8.9 mmol) and carbon on carbon (80 ml) A mixture of 10% palladium (0.35 g) is hydrogenated for 3 hours. The catalyst is filtered off and the solids are dissolved in Celite using a solution of methylene-methanol (80 ml). The solvent was removed in vacuo to give 2.34 g (97%) of the product as an off-white solid which was triturated with ethyl ether (40 ml) to give a white solid: mp 166-168 [deg.] C. The mother liquor is concentrated to give 1.2 g of the product as a yellow solid. [250] Elemental analysis: C 17 H 21 NO 2 [251] Calculated: C 75.25; H 7.80; N 5.16 [252] Found: C 75.17; H 7.99; N 5.12 [253] 3- (1, 4-dioxa-spiro [4,5] dec-8-yl) -1H-azaindole (2j) [254] This compound is prepared by reacting 3- (1,4-dioxa-spiro [4,5] dec-7-en-8-yl) 7-en-8-yl) -1H-azaindole (4.02 g) to give Intermediate 2a as described above to give 2.7 g (67%) of the title compound as a white solid : mp 204-207 [deg.] C. [255] Elemental analysis: C 13 H 14 N 2 O [256] Calculated: C 72.87; H 6.59; N 13.07 [257] Found: C 72.44; H 6.75; N 12.81 [258] Intermediate 3 [259] 4- (1H-3-indolyl) -cyclohexanone (3a) [260] A solution of 3- (1,4-dioxa-spiro [4,5] dec-8-yl) -1H-indole (2.57 g, 10 mmol) in 200 ml (1: 1) tetrahydrofuran- The solution is stirred at room temperature for 16 hours. The solvent is evaporated under vacuum. The crude product is dissolved in ethyl acetate and washed with 1 N sodium hydroxide (3 x 150 ml). The organic layer is dried over anhydrous sodium sulfate and filtered. Chromatography (40% ethyl acetate-hexane) gave 1.9 g (89%) of the product. [261] 4- (4-fluoro-1H-3-indolyl) -cyclohexanone (3b) [262] This compound is prepared by reacting 3- (1,4-dioxa-spiro [4,5] dec-8-yl) 4-fluoro-lH-indole (4.0 g) to give 3.7 g (63%) of the title compound as a white solid: mp 104-106 [deg.] C. [263] 4- (5-fluoro-lH-3-indolyl) -cyclohexanone (3c) [264] A solution of 3- (1,4-dioxa-spiro [4,5] dec-8-yl) -5-fluoro-lH-indole (2.8 g, , 10 mmol) in dichloromethane (10 ml) was stirred at room temperature for 16 hours. The solvent is evaporated under vacuum. The crude product is dissolved in ethyl acetate and washed with 1 N sodium hydroxide (3 x 150 ml). The organic layer is dried over anhydrous sodium sulfate and filtered. Chromatography (40% ethyl acetate-hexane) gave 2.1 g (91%) of the product as a yellow solid: mp 112-114 [deg.] C. [265] 4- (6-fluoro-lH-3-indolyl) -cyclohexanone (3d) [266] This compound is prepared by reacting 3- (1,4-dioxa-spiro [4,5] dec-8-yl) Yl) -6-fluoro-lH-indole (5.4 g) to give 19.29 g (99%) of the title compound as a white solid: mp 102-105 [deg.] C. [267] Elemental analysis: C 14 H 14 NOF [268] Calculated: C 72.71; H 6.10; N 6.06 [269] Found: C 72.77; H 5.98; N 5.96 [270] 4- (5-bromo-1H-3-indolyl) -cyclohexanone (3e) [271] This compound is prepared by reacting 3- (1,4-dioxa-spiro [4,5] dec-8-yl) (84%) of the title compound as a white solid: MS EI m / e 291 < RTI ID = 0.0 > M + ). [272] Calculated: C 75.25; H 7.80; N 5.16 [273] Found: C 75.17; H 7.99; N 5.12 [274] 4- (5-chloro-lH-3-indolyl) -cyclohexanone (3f) [275] This compound is prepared by reacting 3- (1,4-dioxa-spiro [4,5] dec-8-yl) (60%) of the title compound as a clear oil: MS FAB m / e 248 (M < RTI ID = 0.0 > + H) + . [276] 4- (5-cyano-lH-3-indolyl) -cyclohexanone (3 g) [277] This compound is prepared by reacting 3- (1,4-dioxa-spiro [4,5] dec-8-yl) 4-yl) -5-cyano-1H-indole (6 g) to give 4.03 g (81%) of the title compound as a white solid: 162.5-164 ° C. [278] Elemental analysis: C 15 H 14 N 2 O [279] Calculated: C 75.61; H 5.92; N 11.76 [280] Found: C 75.82; H 6.06; N 11.72 [281] 4- (5-methoxy-lH-3-indolyl) -cyclohexanone (3h) [282] This compound is prepared by reacting 3- (1,4-dioxa-spiro [4,5] dec-8-yl) 5-methoxy-lH-indole (5.85 g) to give the title compound 4.2 g (85%) as a white solid: 103-106 [deg.] C. [283] 4- (2-methyl-1H-3-indolyl) -cyclohexanone (3i) [284] This compound is prepared by reacting 3- (1,4-dioxa-spiro [4,5] dec-8-yl) (88%) of the title compound as a dark yellow oil: MS EI m / e 227 < RTI ID = 0.0 > (M + ). [285] (1H-3-pyrrolo [2,3-b] pyridyl) -cyclohexanone (3j) [286] This compound is prepared by reacting 3- (1,4-dioxa-spiro [4,5] dec-8-yl) Yl) -1H-azaindole (2.48 g) to give 1.96 g (95%) of the title compound as a white solid: 162-164 占 폚. [287] Intermediate 4 [288] 3- (1,4-dioxa-spiro [4,5] dec-7-en-8-yl) -5-cyano- [289] To a suspension of sodium hydride (60%, 1.74 g, 0.073 mol) in anhydrous N, N-dimethylformamide (100 ml) at room temperature was added 3- (1,4- dioxa-spiro [4,5] -En-8-yl) -5-cyano-lH-indole (9.9 g, 0.035 mol). The mixture is stirred at room temperature for 30 minutes and then methyl iodide (9 ml, 0.14 mol) is added at room temperature. The reaction is stirred for 1 hour and then quenched with water (50 ml). The mixture is extracted with methylene chloride (3 x 150 ml) and water (3 x 150 ml). The organic layer is dried over anhydrous magnesium sulfate and filtered. The solvent is removed under vacuum. Chromatography (5% methanol-methylene chloride) affords 2.54 g (24%) of the product as a pale yellow solid: mp 65-67 [deg.] C. [290] Elemental analysis: C 18 H 18 N 2 O 2 [291] Calculated: C 73.45; H 6.16; N 9.52 [292] Found: C 73.17; H 6.24; N 9.43 [293] Intermediate 5 [294] Spiro [4,5] dec-8-yl) -5-cyano-1-methyl-indole (5a) [295] 7-en-8-yl) -5-bromo-lH-indole (3.77 g, ) And 10% palladium on carbon (0.99 g) is hydrogenated for 5 hours. The catalyst was filtered off and the solvent was removed in vacuo to give a white powder which was washed with ethanol-hexane (1: 1) and dried under vacuum for 4 hours to give 2.75 g (12%) of product: mp 170 -172 ° C. [296] Elemental analysis: C 18 H 20 N 2 O 2 [297] Calculated: C 72.95; H 6.80; N 9.45 [298] Found: C 72.79; H 6.82; N 9.35 [299] Spiro [4,5] dec-8-yl) -5-cyano-1-ethyl-indole (5b) [300] To a suspension of sodium hydride (60%, 1.63 g, 0.068 mol) in anhydrous N, N-dimethylformamide (150 ml) at room temperature was added 3- (1,4- dioxa-spiro [4,5] -Yl) -5-cyano-lH-indole (9.0 g, 0.032 mol) is added. The mixture is stirred at room temperature for 30 minutes and then methyl bromide (14.6 g, 0.13 mol) is added at room temperature. The reaction is stirred overnight and then quenched with water (50 ml). The mixture is extracted with methylene chloride (3 x 150 ml) and water (3 x 150 ml). The organic layer is dried over anhydrous magnesium sulfate and filtered. The solvent is removed under vacuum. Chromatography (hexane) gave 5.5 g (69%) of the product as a white solid: mp 124-126 [deg.] C. [301] Elemental analysis: C 19 H 22 N 2 O 2 [302] Calculated: C 73.52; H 7.14; N 9.02 [303] Found: C 73.56; H 6.93; N 8.95 [304] 5-cyano-1-n-propyl-indole (5c) [305] This compound was prepared as described above for Intermediate 5b by replacing ethyl bromide with n-propyl bromide (13.1 g, 11 mmol) to give 4.33 g (75%) of the title compound as an oil: MS EI m / e 324 (M + ). [306] Spiro [4,5] dec-8-yl) -5-cyano-1-iso-propyl-indole (5d) [307] This compound was prepared as described above for Intermediate 5b, substituting ethyl bromide with isopropyl bromide (10.2 g, 83 mmol) to give 62% yield (6.44 g) as a white solid: mp 114.5-116 [deg.] C; MS EI m / e 324 (M < + & gt ; ). [308] Spiro [4,5] dec-8-yl) -5-cyano-1-benzyl-indole (5e) [309] This compound was prepared as described above for Intermediate 5b by replacing ethyl bromide with benzyl bromide (14.3 g, 84 mmol) to give 6.04 g (57%) of the title compound as a white solid: mp 129-130 < 0 > C. [310] Elemental analysis: C 23 H 24 N 2 O 2 [311] Calculated: C 77.39; H 6.50; N 7.52 [312] Found: C 76.59; H 6.28; N 7.47 [313] Intermediate 6 [314] 4- (5-cyano-1-methyl-3-indolyl) -cyclohexanone (6a) [315] Dioxa-spiro [4,5] dec-8-yl) -5-cyano-1-methyl-indole (prepared as described above) in 150 ml (1: 1) tetrahydrofuran- 5.5 g) in dichloromethane is stirred at room temperature for 16 hours and then 4.49 g of sodium bicarbonate is added. The mixture is extracted with methylene chloride (3 x 100 ml) and washed with brine (3 x 150 ml). The organic layer is dried over anhydrous magnesium sulfate and filtered. Solvent is removed to give a light brown solid which is boiled in ethyl acetate-hexane (1: 1). The mixture was cooled to room temperature and the solid collected and dried in vacuo to give 2.06 g of the title compound as a solid: mp 150-152 < 0 > C. [316] Elemental analysis: C 15 H 15 N 2 O [317] Calculated: C 76.16; H 6.39; N 11.10 [318] Found: C 75.84; H 6.34; N 10.92 [319] 4- (5-cyano-1-ethyl-3-indolyl) -cyclohexanone (6b) [320] This compound was prepared by reacting 3- (1,4-dioxa-spiro [4,5] dec-8-yl) -5-cyano- , 5] -dec-8-yl) -5-cyano-1-ethyl-indole (6.77 g, 22 mmol) to afford Intermediate 6a as described above to afford the title compound as a white solid, 4.33 g %): Mp 124 [deg.] C. [321] Elemental analysis: C 17 H 18 N 2 O [322] Calculated: C 76.66; H 6.81; N 10.52 [323] Found: C 76.30; H 6.82; N 10.25 [324] 4- (5-cyano-l-propyl-3-indolyl) -cyclohexanone (6c) [325] This compound was prepared by reacting 3- (1,4-dioxa-spiro [4,5] dec-8-yl) -5-cyano- , 5] -dec-8-yl) -5-cyano-1-n-propyl-indole (2.64 g, 8.2 mmol) to afford Intermediate 6a as described above to afford 1.67 g (73%): mp 103-104 [deg.] C; MS EI m / e 280 (M < + & gt ; ). [326] 4- (5-cyano-1-benzyl-3-indolyl) -cyclohexanone (6d) [327] This compound was prepared by reacting 3- (1,4-dioxa-spiro [4,5] dec-8-yl) -5-cyano- , 5] -dec-8-yl) -5-cyano-1-benzyl-indole (6.43 g, 20 mmol) to afford Intermediate 6a as described above to afford 3.49 g %): Mp 115-126 [deg.] C. [328] Elemental analysis: C 22 H 20 N 2 O [329] Calculated: C 80.46; H 6.14; N 8.53 [330] Found: C 80.42; H 6.07; N 8.49 [331] 4- (5-cyano-1-isopropyl-3-indolyl) -cyclohexanone (6e) [332] This compound was prepared by reacting 3- (1,4-dioxa-spiro [4,5] dec-8-yl) -5-cyano- , 5] -dec-8-yl) -5-cyano-1-isopropyl-indole (5.86 g, 16 mmol) to afford Intermediate 6a as described above to afford 3.46 g 63%): mp 106-107 [deg.] C. [333] Elemental analysis: C 18 H 20 N 2 O [334] Calculated: C 77.11; H 7.19; N 9 [335] Found: C 76.85; H 7.16; N 9 [336] Intermediate 7 [337] 8- (4-Benzyl-piperazin-1-yl) quinoline [338] 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 heated at 85 <0> C for 11 h. The mixture is poured into 50% sodium hydroxide and extracted with methylene chloride and water. The organic layer is dried over anhydrous magnesium sulfate and filtered. The solvent is removed under vacuum. Chromatography (methanol-methylene chloride) gave 12.34 g of the product as a solid: mp 116.5-118 [deg.] C. [339] HCl salt is prepared in ethyl acetate: mp 209-210 [deg.] C. [340] Elemental analysis: C 20 H 21 N 3 · 2HCl · 0.5H 2 O [341] Calculated: C 62.34; H 6.28; N 10.91 [342] Found: C 62.37; H 6.55; N 10.80 [343] Intermediate 8 [344] 8- (Piperazin-1-yl) -quinoline [345] To a solution of 8- (4-benzyl-piperazin-1-yl) quinoline (2.63 g, 8.7 mmol) in methylene chloride (30 ml) was slowly added vinyl chloroformate (1.1 ml, 13 mmol) at room temperature. The reaction mixture is refluxed for 2 hours and then concentrated in vacuo. The residue is dissolved in 12 N hydrochloric acid (20 ml) and stirred at room temperature for 1 hour. The mixture is concentrated and the residue is taken up in 40 ml of ethanol and then heated to 50 < 0 > C for 2 hours. The solvent is removed in vacuo and the residue is dissolved in 1 N sodium hydroxide-ethyl acetate, extracted with ethyl acetate and washed with water. The organic layer is dried over anhydrous sodium sulfate. The solvent is removed under vacuum. 1.86 g (90%) of a yellow oil is obtained by chromatography (10-30% methanol-methylene chloride + ammonium hydroxide): MS EIm / e 213 (M + ). [346] Intermediate 9 [347] 6-fluorochroman [348] 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 (30 ml) was hydrogenated for 20 hours. The catalyst is filtered off and the solvent is removed in vacuo. The residue was dissolved in ethyl acetate (10 ml), washed with 1N NaOH (6 x 200 ml) and water (3 x 150 ml), dried over anhydrous sodium sulfate, filtered and the solvent removed in vacuo. Chromatography (20% ethyl acetate-hexane) gave 1.41 g (77%) of the product as a clear oil: MS EI m / e 152 (M + ). [349] Intermediate 10 [350] 6-Fluoro-8-nitrochroman [351] A mixture of nitric acid (100%, 7.8 ml, 0.16 mmol) in acetic anhydride is maintained at room temperature for 0.5 h. This mixture is added at 0 < 0 > C to a solution of 6-fluorochroman (11.9 g, 0.078 mol) in 40 ml acetic anhydride. The reaction mixture is stirred at room temperature for 2 hours and then poured into cold water. The mixture is extracted with methylene chloride (3 x 60 ml) and washed with saturated sodium carbonate (8 x 150 ml). The organic layer is dried over anhydrous sodium sulfate and then filtered. The solvent was removed in vacuo to give a yellow solid: mp 48-50 [deg.] C. [352] Elemental analysis: C 9 H 8 FNO 3 [353] Calculated: C 54.83; H 4.09; N 7.10 [354] Found: C 54.78; H 3.93; N 6.09 [355] Intermediate 11 [356] 6-fluoro-8-aminocroman [357] A mixture of 6-fluoro-8-nitrochroman (14.4 g) and 10% palladium on carbon (2 g) in ethanol (160 ml) is hydrogenated for 2 hours. The catalyst is filtered off and the solvent is removed in vacuo. Chromatography (30% ethyl acetate-hexane) gave 12.12 g (100%) of the product as a clear oil: MS EI m / e 167 (M + ). [358] Intermediate 12 [359] L-Benzyl-4- (6-fluoro-chroman-8-yl) -piperazine [360] 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) Lt; / RTI > The mixture is poured into saturated sodium carbonate (950 ml) and extracted with ethyl acetate (3 x 60 ml). The organic layer is dried over anhydrous sodium sulfate and filtered. 1.64 g (68%) of the product as an oil is obtained by chromatography (20% ethyl acetate-hexane): MS EI m / e 326 (M) + . [361] Intermediate 13 [362] 4- (6-Fluoro-chroman-8-yl) -piperazine [363] Piperazine (1.64 g, 5 mmol), 10% palladium on carbon (0.4 g) and ammonium formate (1.00 g, 5 mmol) in ethanol (20 ml) 0.64 g, 10 mmol) is refluxed for 2 hours. The catalyst is filtered off and the solvent is removed in vacuo. 1.0 g (84%) of the product as a yellow oil is obtained by chromatography (10-20% methanol-methylene chloride + ammonium hydroxide): MS EI m / e 296 (M + ). [364] Intermediate 14 [365] 2- (4-Fluorophenoxy) -acetaldehyde-diethyl acetal [366] To a solution of sodium hydride (5.4 g, 0.134 mol) in anhydrous N, N-dimethylformamide (100 ml) was added 4-fluorophenol (10 g, 0.089 mol) at 0 ° C. After nitrogen evolution ceases, bromo-acetaldehyde diethyl acetal (16 ml, 0.11 mol) is added. The reaction is heated at 160-170 < 0 > C for 18 hours. The mixture is poured into cold 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 is dried over anhydrous sodium sulfate and then filtered. The solvent is removed under vacuum. Chromatography (25% ethyl acetate-hexane) gave 16.36 g (80%) of the product as a clear oil: MS EI m / e 228 (M + ). [367] Intermediate 15 [368] 5-fluorobenzofuran [369] 2- (4-Fluoro-phenoxy) -acetaldehyde diethyl acetal (8 g, 0.035 mol) was added to a mixture of benzene (200 ml) containing polyphosphoric acid (7.9 g, 0.035 mol). The mixture is vigorously stirred under reflux for 2.5 hours. The reaction mixture is cooled to room temperature and then tilted from polyphosphoric acid. The solvent is removed under vacuum. 3.4 g (45%) of the product as a clear oil are obtained by chromatography (5% ethyl acetate-hexane): 1 H NMR (CDCl 3 ) 6.74 (dd, 1H, J = 2.0, 0.6 Hz), 7.01 (dd, 1H, J = 9, 3.9 Hz), 7.65 (d, 1H, J = 1.8 Hz), 7.25 (dd, 1H, J = Hz). [370] Intermediate 16 [371] 5-fluoro-2,3-dihydrobenzofuran [372] A solution of 5-fluorobenzofuran and 10% palladium on carbon in acetic acid (25 ml) is hydrogenated at 50 psi for 12 h. The catalyst is filtered through celite and the celite is washed with methylene chloride (200 ml). The organic layer is washed sequentially with 1N NaOH (3 x 100 ml), brine (3 x 100 ml), then dried over anhydrous sodium sulfate and filtered. To give the product 2.59 g (85%) as a clear oil and the solvent removed in vacuo: 1 H NMR (300 MHz, CDCl 3): δ3.12 (t, 2H, J = 8.7 Hz), 4.58 (t, 2H 1H, J = 8.7 Hz), 6.68 (dd, 1H, J = 8.7,4.2 Hz), 6.79 (tm, 1H, J = 8.7 Hz) [373] Intermediate 17 [374] 5-fluoro-7-nitro-2,3-dihydrobenzofuran [375] A mixture of nitric acid (100%, 1.5 ml, 36 mmol) in acetic anhydride (18 ml) is maintained at room temperature for 0.5 h. The mixture is added at 10 [deg.] C to a solution of 5-fluoro-2,3-dihydrobenzofuran (2.5 g, 18 mmol) in 10 ml acetic anhydride. The reaction mixture is stirred at room temperature for 2 hours and then poured into cold water. The mixture is extracted with methylene chloride (3 x 60 ml) and washed with 1 N sodium hydroxide (5 x 100 ml) and brine (200 ml). The organic layer is dried over anhydrous sodium sulfate and then filtered. The solvent was removed in vacuo to give a yellow solid: mp 113-114 [deg.] C. [376] Elemental analysis: C 8 H 6 NO 3 [377] Calculated: C 52.47; H 3.30; N 7.65 [378] Found: C 52.40; H 3.21; N 7.39 [379] Intermediate 18 [380] 5-fluoro-7-amino-2,3-dihydrobenzofuran [381] A mixture of 5-fluoro-7-nitro-2,3-dihydrobenzofuran (2.65 g) and 10% palladium on carbon (0.5 g) in ethanol (100 ml) is hydrogenated for 3 hours. The catalyst is filtered off and the solvent is removed in vacuo. Chromatography (30% ethyl acetate-hexanes) afforded 1.38 g (62%) of the product as a white solid: mp 68-70 [deg.] C. [382] Elemental analysis: C 8 H 8 NO [383] Calculated: C 62.74; H 5.27; N 9.15 [384] Found: C 62.76; H 5.32; N 9.13 [385] Intermediate 19 [386] Benzyl-4- (5-fluoro-2,3-dihydro-benzofuran-7-yl) -piperazine [387] To a solution of 5-fluoro-7-amino-2,3-dihydrobenzofuran (1.38 g, 9 mmol) and bis (2-chloroethyl) -benzylamine (3.14 g, 14 mmol) in butanol (20 ml) Is stirred at 100 < 0 > C for 10 hours. The salt is filtered off, washed with ethyl ether (30 ml) and dried under vacuum: mp 232-233.5 [deg.] C. Conversion of the salt to the free base afforded 2.06 g (73%) of the title compound. [388] Elemental analysis: C 19 H 21 FN 2 O.HCl 0.25H 2 O [389] Calculated: C 64.58; H 6.42; N 7.93 [390] Found: C 64.43; H 6.27; N 7.86 [391] Intermediate 20 [392] 4- (5-Fluoro-2,3-dihydro-benzofuran-7-yl) -piperazine [393] Piperazine (2.06 g, 6.6 mmol), 10% palladium on carbon (0.6 mL), and triethylamine (0.2 mL) were added to a solution of 1-benzyl-4- (5- fluoro-2, 3- dihydro-benzofuran- g) and ammonium formate (0.83 g, 13 mmol) is refluxed for 2 hours. The catalyst is filtered off and the solvent is removed in vacuo. 1.10 g (75%) of the product as a yellow oil are obtained by chromatography (10-30 methanol-methylene chloride + ammonium hydroxide): MS EI m / e 222 (M) + . [394] Intermediate 21 [395] Ethyl 7-nitrobenzofuran-2-carboxylate [396] A solution of 2-hydroxy-3-nitrobenzaldehyde (4.8 g, 59 mmol), diethyl bromomalonate (16.8 g, 71 mmol), potassium carbonate (12.1 g, 88 mmol) N, N'-terephthalylidene bis (4-butyl aniline) (1.9 g, 5.9 mmol) is refluxed in a Dean-Stark trap for 24 hours. Again, 12.1 g of potassium carbonate is added to the reaction mixture and the resulting mixture is refluxed for another 3 days. The reaction is quenched with water, extracted with (3 x 200 ml) and then washed with 2.0 N sodium hydroxide (100 ml). The organic layer is dried over anhydrous sodium sulfate and then filtered. Chromatography (30% ethyl acetate-hexanes) affords a yellow solid: mp 86.5-87.5 C (lit 1 : mp 88-89 C). [397] Intermediate 22 [398] 7-Nitrobenzofuran [399] To a suspension of ethyl 7-nitrobenzofuran-2-carboxylate in ethanol was added 2N potassium hydroxide (60 ml). After heating to reflux for 0.5 h, the solution is cooled to room temperature and concentrated to half volume. Concentrated hydrochloric acid is added to the reaction mixture and filtered. The solids are washed with water and dried in vacuo under vacuum with an < RTI ID = 0.0 > pentoxide. ≪ / RTI > The dried solid is mixed with quinoline (75 ml) and copper oxide (CuO, 0.4 g). The mixture is heated to 220 < 0 > C for 3 hours. The mixture is filtered and the filtrate is concentrated. Chromatography (20% ethyl acetate-hexanes) afforded 5.3 g (91%) of the product as a yellow solid: mp 92-94 [deg.] C. (lit 1 : mp 95.5-97 [deg.] C). [400] Intermediate 23 [401] 7-aminobenzofuran hydrochloride [402] A stirred suspension of 7-nitrobenzofuran (5.3 g, 32 mmol) and Raney nickel (0.1 g) in methanol (70 ml) is heated to 50 < 0 > C. Hydrazine monohydrate (98%, 4.8 ml, 97 mmol) in methanol (10 ml) is then slowly added to the solution at a temperature of 50-60 < 0 > C. When the addition is complete, the mixture is refluxed for 2 hours. The Raney nickel is filtered off and the solution is concentrated. The residue is dissolved in ethyl acetate and converted to 3.68 g (66%) of its HCl salt (lit 1 : mp 212-213 [deg.] C). [403] Intermediate 24 [404] 1- (7-benzofuranyl) piperazine [405] A solution of 7-aminobenzofuran hydrochloride (3.66 g, 22 mmol) and bis (2-chloroethyl) amine hydrochloride (3.84 g, 22 mmol) in chlorobenzene (80 ml) was heated at reflux for 72 h. The solvent is removed in vacuo and the residue is dissolved in 2.5 N sodium hydroxide-methylene chloride and extracted with methylene chloride (3 x 100 ml). The organic layer is dried over anhydrous sodium sulfate and filtered. Chromatography (10-20% methanol-methylene chloride + ammonium hydroxide) gave 0.66 g (15%) of the product as a tan oil: mp 194.5-195 ° C for lit 1 : HCl salt. [406] Intermediate 25 [407] 4- (5-Fluoro-lH-indolyl) -cyclohex-3-enone [408] This compound was prepared by reacting 4- (5-fluoro-1H-3-indolyl) -cyclohexanone ethylene ketal with 4- (5-fluoro-lH-3-indolyl- cyclohex- 1.37 g) to give Intermediate 3c as described above to give 1.01 g (88%) of the title compound. [409] Intermediate 26 [410] 4- (1,4-dioxa-spiro [4,5] dec-8-yl) -piperazine [411] (4.68 g, 30 mmol), l- (2-methoxy-phenyl) piperazine (5.8 g, 30 mmol) and sodium cyanoborohydride monoethylenecetal in 8 ml of 1,2- A solution of triacetoxyborohydride (9 g, 42 mmol) and acetic acid (1.8 ml, 30 mmol) is stirred at room temperature for 12 hours. The reaction is quenched with 1 N sodium hydroxide (pH > 9) and extracted with methylene chloride (3 x 100 ml). The organic layer is dried over anhydrous sodium sulfate and filtered. Chromatography (10% methanol-ethyl acetate) gives 9.0 g (90%) of the product as a semisolid. [412] Intermediate 27 [413] 4- [4- (2-methoxy-phenyl) -piperazin-1-yl] -cyclohexanone [414] The present compounds are prepared by reacting 3- (1,4-dioxa-spiro [4,5] dec-8-yl) -1H- indole with 1- (2-methoxy- -Spiro [4,5] dec-8-yl) -piperazine (5.0 g, 15 mmol) to give 4.0 g (93%) of the title compound. [415] Intermediate 28 [416] 5-Fluoro-3- {4- [4- (2-methoxy-phenyl) -piperazin- 1-yl] -cyclohex- 1-enyl} -1H-indole [417] This compound was prepared by replacing 1,4-cyclohexanedione monoethylene ketal with 4- [4- (2-methoxy-phenyl) -piperazin-1-yl] -cyclohexanone (1.44 g, 1c. ≪ / RTI > The crude mixture is used in the next step without further purification. [418] Intermediate 29 [419] 5- Fluoro-3- {4- [4- (2-methoxy-phenyl) -piperazin-1-yl] -cyclohexyl} -1H-indole [420] This compound is prepared by the same procedure as described for 4- (5-fluoro-lH-3-indolyl) -cyclohex-3-ene- 1-yl] cyclohex-1-enyl} -1H-indole (2.0 g) to give 1.77 g (84%) of the product as a mixture of cis and trans isomers, ≪ / RTI > [421] Intermediate 30 [422] 4- (5-fluoro-1-methyl-3-indolyl) -cyclohexanone [423] 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- The rice paddy (0.7 g, 3.0 mmol) is added. The mixture is stirred for 0.5 h and then iodomethane (0.21 ml, 3.3 mmol) is added to the solution at room temperature. The resulting mixture is stirred again for 0.5 h and quenched with water. The mixture is extracted with methylene chloride (3 x 50 ml) and the organic layer is dried over anhydrous sodium sulfate and filtered. Chromatography (30% ethyl acetate-hexane) gave 0.35 g (46%) of the product as a yellow oil: MS EI m / e 245 (M + ). [424] Intermediate 31 [425] 5-nitro-quinoxaline [426] In EtOH (50 ml) 3- nitro -o- exerts a phenylenediamine glyoxal (40% in H 2 O, 22.47 ml) at room temperature, a solution of (10 g, 65.3 mmol). The reaction mixture is heated to reflux for 1 h and then diluted with H 2 O (100 ml). The cooling solution was extracted with CH 2 Cl 2 (2 x 300 ml) and the combined organic layers were washed again with H 2 O (500 ml), dried over Na 2 SO 4 and concentrated to a light orange solid which was purified by chromatography on EtOAc / Recrystallization from hexane gave a tan solid: mp 90-92 [deg.] C. [427] Elemental analysis: C 8 H 5 N 3 O 2 [428] Calculated: C 54.86; H 2.88; N; 23.99 [429] Found: C 55.12; H 3.05; N 24.05 [430] Intermediate 32 [431] 5-Amino-quinoxaline [432] Nitro-quinoxaline (4 g, 22.8 mmol) dissolved in HOAc (60 ml) was added to a 3-neck 250 ml round bottom flask equipped with a reflux condenser and a nitrogen inlet. The mixture is boiled heated and removed from the heat, and solid Fe powder (3.83 g, 68.6 mmol) is added. Active boiling is observed. The reaction mixture is heated to reflux for 10 minutes and then poured into ice with H 2 O (100 ml). The aqueous solution is filtered, basified to pH > 10 with 1 M NaOH and extracted into EtOAc (3 x 200 ml). The organic layers are combined, which is concentrated, dried over Na 2 SO 4. The resulting oil was purified by column chromatography (40% EtOAc / hexanes) to give 2.03 g (61%) of orange solid mp 87-90 [deg.] C. [433] Elemental analysis: C 8 H 7 N 3 [434] Calculated: C 66.19; H 4.86; N 28.95 [435] Found: C 66.25; H 4.96; N 29.26 [436] Intermediate 33 [437] 1-Benzyl-4- (quinoxalin-yl) -piperazine [438] Benzylamine (8.42 g, 38.6 mmol) and Et 3 N (5.34 ml, 38.6 mmol) - BuOH of 5-amino (50 ml) - bis (2-chloroethyl) To a solution of quinoxaline (2.8 g, 19.3 mmol) . The reaction is stirred overnight at 100 < 0 > C. A second portion of Et 3 N (5.34 ml, 38.6 mmol) is added and the reaction is stirred at 100 ° C for a further 24 hours. The cold solution is made alkaline with 2.5 N NaOH (500 ml) and extracted with EtOAc (3 x 200 ml). Combine the organic fractions, dry Na 2 SO 4 and concentrated on to give the purified by chromatography (40% EtOAc / Hex) to gold oil 1.0 g (17%). [439] Intermediate 34 [440] 5- (1-Piperazinyl) -quinoxaline [441] To a room temperature solution of 1-benzyl-4- (quinoxalin-yl) -piperazine (1.0 g, 3.3 mmol) in anhydrous CH 2 Cl 2 under nitrogen was added vinyl chloroformate (0.34 ml, 3.9 mmol). The reaction mixture is heated to reflux for 2 hours. The reaction is cooled, concentrated to dryness and concentrated hydrochloric acid (25 ml) and 1,4-dioxane (25 ml) are added. The resulting solution is stirred overnight at ambient temperature. The solution is basified with 2.5 N NaOH (300 ml) and then extracted into EtOAc (3 x 200 ml). The organic layers were combined, dried over Na 2 sikimyeo SO 4, and concentrated to afford chromatography (10% MeOH / CH 2 Cl 2 / NH 4 OH) to orange gocheeul: mp 106-108 ℃: MS (+ ) ESI m / e 215 [M + H] < + >. [442] Intermediate 35a [443] 5- (Trifluoromethylsulfonyloxy) -quinoline [444] Cool a solution of 5-hydroxy-quinoline (8 g, 55 mmol) and K 2 CO 3 (15.2 g, 110 mmol) in anhydrous pyridine (60 ml) under nitrogen at -20 ° C. Tf 2 O (13.97 ml, 83 mmol) is added dropwise via syringe. The reaction mixture is stirred at -20 < 0 > C for 1 hour, then for 1 hour at 0 < 0 > C and at ambient temperature for 48 hours. The reaction mixture is then poured into H 2 O (200 ml) and extracted into CH 2 Cl 2 (2 x 200 ml). The aqueous layer is acidified with 1N HCl (100 ml) and then extracted with CH 2 Cl 2 (2 x 200 ml). The organic fraction is dried over Na 2 SO 4, concentrated and purified by column chromatography (40% EtOAc / hexanes) to give 13.97 g (90%) of the product as a pink oil: MS EI m / e 277 (M + ). [445] Intermediate 35b [446] 5- (Trifluoromethylsulfonyloxy) -isoquinoline [447] This compound was prepared as described above for intermediate 35a by replacing 5-hydroxy-quinoline with 5-hydroxy-isoquinoline (5 g) to give 7.71 g (79%) of the title compound as a waxy beige solid MS: ESI m / e 278 (M < + & gt ; ). [448] Intermediate 35c [449] 1- (Trifluoromethylsulfonyloxy) -isoquinoline [450] This compound was prepared as described above for Intermediate 35a by replacing 5-hydroxy-quinoline with isocarbastyryl (8 g) to give 9.74 g (64%) of the title compound as a clear oil: MS EI m / e 277 (M < + & gt ; ). [451] Intermediate 36a [452] 1-t-butyl-4- (5-quinolinyl) piperazinecarboxylate [453] Apply the Cs 2 CO 3 (19.87 g, 61 mmol), Pd (OAc) 2 (0.49 g, 2.2 mmol), and BINAP (1.183 g, 1.9 mmol) in a dried 100 ml flask oven. The solid is flushed with N 2 for 10 minutes. A solution of 5- (trifluoromethylsulfonyloxy) -quinoline (12 g, 43 mmol) and 1-tert-butyl-4-piperazinecarboxylate (9.67 g, 52 mmol) in THF was slowly added to the reaction flask do. The reaction mixture is stirred at room temperature for 0.5 h, then at 65 < 0 > C overnight. Dilute the resulting solution with ether, washed, filtered through a Celite layer to the next, Et 2 O (50 ml) and EtOAc (50 ml). The organic fractions were combined, dried over Na 2 SO 4 , filtered and chromatographed three times (10% MeOH / CH 2 Cl 2 ) to give 1.57 g (12%) of pure product as a beige solid: mp 116-118 ℃. [454] Elemental analysis: C 18 H 23 N 3 O 2 [455] Calculated: C 68.98; H 7.40; N 13.41 [456] Found: C 69.09; H 7.33; N 13.08 [457] Intermediate 36c [458] 1-t-butyl-4- (1-isoquinolinyl) piperazinecarboxylate [459] This compound was prepared by replacing 5- (trifluoromethylsulfonyloxy) -quinoline with 1- (trifluoromethyl-sulfonyloxy) -isoquinoline (9 g, 32.5 mmol) To give a beige solid on wax: mp 69-71 [deg.] C. [460] Intermediate 37a [461] 5- (1-Piperazinyl) -quinoline [462] To a solution of 1-t-butyl-4- (5-quinolinyl) piperazinecarboxylate (1.57 g, 5 mmol) in CH 2 Cl 2 (2 ml) at 0 ° C was added TFA (10 ml), CH 2 Cl 2 (20 ml) and MeOH (10 drops) is added to the pre-cooled, pre-mixed solution. The reaction is slowly warmed to room temperature and stirred overnight. The resulting solution is concentrated to a pH of 9 by dissolving in H 2 O (5 ml) and CH 2 Cl 2 (5 ml) and making it alkaline with NaHCO 3 . The aqueous portion is extracted with 6 x 100 ml EtOAc and concentrated to give 1.0 g (100%) of a yellow oil which solidifies on standing without further purification. [463] Intermediate 37c [464] 1- (1-Piperazinyl) -isoquinoline [465] This compound is prepared by reacting 1-t-butyl-4- (5-quinolinyl) piperazinecarboxylate with 1-tert-butyl- 4- (1- isoquinolinyl) piperazinecarboxylate (2.33 g, 7.4 mmol) To give 1.5 g (95%) of a beige solid: mp 127-130 < 0 > C. [466] Intermediate 38a [467] 6-methoxy, 8-amino-quinoline [468] 3.0 g of iron powder was added to a hot suspension of 6-methoxy, 8-nitro-quinoline in 100 ml of a mixture of ethanol: acetic acid: water (2: 1: 1). The reaction is refluxed for about 2.5 hours, the mixture is cooled, filtered over celite and basified with sodium bicarbonate. The product is extracted with ether and dried, and the solvent is removed in vacuo to yield 3.2 g of the title compound. MS (ES) m / z (relative intensity): 175 (M + H < + >, 100). [469] Intermediate 38b [470] 8-amino, 6-chloro-quinoline [471] 0.5 g of iron powder was added to a hot suspension of 6-chloro, 8-nitro-quinoline in 25 ml of a mixture of ethanol: acetic acid: water (2: 1: 1). The reaction is refluxed for about 1.5 hours, the mixture is cooled, filtered over celite, and basified with sodium carbonate. The product is extracted with ether and dried, and the solvent is removed in vacuo to give 0.5 g of the title compound. mp 70-73 [deg.] C. MS (ES) m / z (relative intensity): 179 (M + H < + >). [472] Elemental analysis: C 9 H 7 ClN 2 [473] Calculated: C 60.52; H 3.95; N 15.68 [474] Found: C 60.82; H 3.77; N 15.96 [475] Intermediate 39a [476] 6-methoxy, 8-piperazino-quinoline [477] 8.2 g of 6-methoxy, 8-amino-quinoline and 9.0 g of bis (chloroethyl) amine hydrochloride are taken up in 70 ml of chlorobenzene and heated at about 135 ° C for 3 days under vigorous stirring. The reaction was never complete. Cool the mixture. Add water and extract with ether. The aqueous phase is basified with sodium carbonate and extracted with ethyl acetate, dried and the solvent is removed. The crude product was filtered through 300 ml of silica gel using 10% MeOH / CH 2 Cl 2 , 20% MeOH / CH 2 Cl 2 followed by 1% NH 4 OH / 80% MeOH / 19% CH 2 Cl 2 1.5 g of the product are obtained. MS (ES) m / z (relative intensity): 244 (M + H < + >, 100). [478] Intermediate 39b [479] 6-chloro-, 8-piperazino-quinoline [480] 8-amino, 6-chloro-quinoline (0.980 g) and bis (chloroethyl) amine hydrochloride (0.980 g) are taken in 13 ml of chlorobenzene and heated at about 135 캜 for 5 days under vigorous stirring. The reaction is cooled in water and then extracted with ether. The aqueous phase is basified with sodium carbonate, reextracted with ether, dried and then the solvent is removed to give 0.400 g of the title compound. MS (ES) m / z (relative intensity): 248 (M + H < + >). [481] Intermediate 39c [482] 5-chloro-, 8-piperazino-quinoline [483] To a solution of 5-chloro, 8- (trifluoromethylsulfonyloxy) -quinoline (1.0 g) in 15 ml of chlorobenzene is added excess piperazine (1.0 g). The mixture is heated at 120 < 0 > C for 2.5 days. The reaction is cooled, poured into water, the product is extracted with ether and dried over magnesium sulphate to give 0.480 g of product. MS (ES) m / z (relative intensity): 248 (M + H < + >, 100). [484] Intermediate 39d [485] 5-fluoro, 8-piperazino-quinoline [486] An excess of piperazine (2.0 g) is added to a solution of 5-fluoro, 8- (trifluoromethylsulfonyloxy) -quinoline (1 g) in 5 ml of chlorobenzene. The mixture is heated at 120 < 0 > C for 2.5 days. The reaction is cooled and poured into water and the product is extracted with ethyl acetate and the organic phase is washed with dilute NaOH, then with water, dried and the solvent is removed. The product of 15% methanol / methylene chloride, then 79: 20: 1 methanol: methylene chloride: NH 4 OH by using chromatography on silica gel to afford the product 0.240 g. MS (ES) m / z (relative intensity): 232 (M + H < + >, 100). [487] Intermediate 39e [488] 8-piperazino-quailandine [489] To a solution of 8- (trifluoromethylsulfonyloxy) -quinoline (7 g) in 25 ml of chlorobenzene is added K 2 CO 3 (3.3 g) and excess piperazine (10.0 g). The mixture is heated at 130 DEG C for 3 days. The reaction is cooled and poured into water and the product is extracted with ethyl acetate and dried over magnesium sulphate. The product of 20% methanol / methylene chloride, then 79: 20: 1 methanol: methylene chloride: NH 4 OH by using chromatography on silica gel to give the product 3.2 g. MS (ES) m / z (relative intensity): 228 (M + H < + >, 100). [490] Intermediate 39f [491] 6-MeO, 4-piperazino-quinoline [492] An excess of piperazine (2 g) is added to a solution of 6-MeO, 4- (trifluoromethylsulfonyloxy) -quinoline (2 g) in 10 ml acetonitrile. The mixture is heated at about 70 < 0 > C for 1.5 hours. Water is added and the product is extracted with ethyl acetate, dried and then the solvent is removed to give the product (2.5 g). MS (ES) m / z (relative intensity): 308 (M + H < + & [493] Intermediate 40a [494] 6-chloro, 8-nitro-quinoline [495] A solution of 1.0 g of 6-chloro-quinoline in 5 ml of fuming nitric acid is heated under reflux for approximately 2 days. The reaction is cooled, poured into cold water and neutralized with concentrated ammonium hydroxide to about pH 5. The precipitate formed is filtered and dried to give 0.600 g of the desired product. mp 149-155 [deg.] C. MS (ES) m / z (relative intensity): 209 (M + H < + >). [496] Intermediate 40b [497] 5-Cl-8- (trifluoromethylsulfonyloxy) -quinoline [498] To a suspension of 5-chloro, 8-hydroxy-quinoline (8.95 g) in 100 ml CH 2 Cl 2 is added TEA (20 ml). The suspension is dissolved and then cooled to -15 < 0 > C. A solution of 21.1 g of triflic anhydride in 50 ml of CH 2 Cl 2 is added dropwise under cooling. After complete addition, the reaction is stirred at -15 [deg.] C for 1 hour. The reaction is diluted with CH 2 Cl 2 , washed with NaHCO 3 solution, then with water, dried and then the solvent is removed to give 15.0 g of product. mp 80-83 [deg.] C. MS (ES) m / z (relative intensity): 312 (M + H < + >, 100). [499] Elemental analysis: C 10 H 5 ClF 3 NO 3 S [500] Calculated: C 38.54; H 1.62; N 4.49 [501] Found: C 38.3; H 1.73; N 4.5 [502] Intermediate 40c [503] 5-Fluoro-8- (trifluoromethylsulfonyloxy) -quinoline [504] TEA (6.3 ml) is added to a cooled solution (-15 ° C) of 5-fluoro, 8-hydroxy-quinoline (2.5 g) in 20 ml CH 2 Cl 2 . To the cooled mixture is added dropwise a solution of 6.5 g of triflic anhydride in 10 ml of CH 2 Cl 2 under cooling. After complete addition, the reaction is stirred at 0 < 0 > C for 1 hour. The reaction is quenched with water, the product is extracted with ether, dried and then the solvent is removed to give 3.4 g of product. MS (ES) m / z (relative intensity): 296 (M + H < + >, 100). [505] Intermediate 40d [506] 8- (Trifluoromethylsulfonyloxy) -quinidane [507] To the cooled solution of 8-hydroxy-quinalde (11.5 g) in 50 ml CH 2 Cl 2 is added TEA (-29 ° C) (-15 ° C). To the cooled solution is added dropwise a solution of 29.6 g of triflic anhydride in 50 ml of CH 2 Cl 2 under cooling. After complete addition, the reaction is stirred at -15 [deg.] C for 1 hour: the reaction is quenched with water, the product is extracted with ether, dried and then the solvent is removed to give 20 g of product. MS (ES) m / z (relative intensity): 292 (M + H < + >). [508] Intermediate 41 [509] 6-MeO, 4- (trifluoromethylsulfonyloxy) -quinoline [510] TEA (12 ml) is added to a cold solution (-15 ° C) of 6-MeO, 4-hydroxy-quinoline (5 g) in 30 ml CH 2 Cl 2 . To the cooled mixture is added dropwise a solution of 12 g of triflic anhydride in 15 ml of CH 2 Cl 2 under cooling. After the addition is complete, the reaction is stirred at -15 [deg.] C for 1 hour. The reaction is quenched with water, the product is extracted with ether and dried to remove the solvent, yielding 7 g of product. MS (ES) m / z (relative intensity): 308 (M + H < + >). [511] Intermediate 42a [512] Benzyl-4- (6-methoxy-2-methylquinolin-8-yl) piperazine [513] Methyl-quinoline (1.75 g, 9.30 mmol), N-benzyl-bis-dichloroethane (8.9 g, 38.3 mmol), and triethylamine ( 6.5 ml, 46.6 mmol) is heated at 100 < 0 > C for 20 h. After cooling to room temperature the reaction was diluted with ethyl acetate (50 ml), poured into saturated aqueous NaHCO 3. The aqueous layer is extracted with ethyl acetate (3 x 50 ml). The combined organic layers are washed with saturated aqueous NaHCO 3 (50 ml) and brine (50 ml), then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Excess 1-butanol is azeotroped with hexane (2 x 500 ml). Flash chromatography on 5.5 x 18 cm SiO 2 (25% EtOAc / hexanes) gave 1.15 g (36%) of a yellow oil which crystallized on standing. Recrystallization from hexane gave 0.898 g (28%) of the analytically pure product as yellow crystals: mp 83-85 [deg.] C. [514] Elemental analysis: C 22 H 25 N 3 O [515] Calculated: C 76.05; H 7.25; N 12.09 [516] Found: C 75.88; H 7.37; N 12.05 [517] Intermediate 42b [518] 1-Benzyl-4- (6-methoxy-3-methylquinolin-8-yl) piperazine [519] Benzyl-4- (6-methoxy-2-methyl-quinolinone) was obtained, except that 8-amino-6-methoxy- -Methoxy-2-methylquinolin-8-yl) piperazine, the title compound is prepared. Flash chromatography on 6 x 20 cm SiO 2 (25-30% EtOAc / hexanes) and re-chromatography of the combined fractions yielded 1.13 g (22%) of the title compound as a yellow gum. Crystallization from hexane gave 0.88 g of analytically pure compound as yellow crystals: mp 112-113 [deg.] C. [520] Elemental analysis: C 22 H 25 N 3 O [521] Calculated: C 76.05; H 7.25; N 12.09 [522] Found: C 75.83; H 7.26; N 12.07 [523] Intermediate 42c [524] L-Benzyl-4- (6-methoxy-4-methylquinolin-8-yl) piperazine [525] N-benzyl-bis-dichloroethane (11.1 g, 48.0 mmol), triethylamine (4.8 g, 48 mmol), and 1- (2-methoxy- Butanol is heated to 100 < 0 > C for 24 hours. The reaction mixture is poured into 2.5 N aqueous NaOH and extracted with ethyl acetate (3 x 200 ml). The combined organic layers are washed with water (100 ml) and brine (100 ml), then dried over anhydrous sodium sulfate, filtered and concentrated to give 12.0 g of a dark brown oil. Flash chromatography on silica gel (5% methanol / ethyl acetate) provided 2.3 g (42%) of the title compound as a thick oil which solidified upon standing: mp 154-155 [deg.] C. [526] Elemental analysis: C 22 H 25 N 3 O [527] Calculated: C 76.05; H 7.25; N 12.09 [528] Found: C 75.92; H 7.36; N 11.96 [529] Intermediate 43a [530] 4- (6-methoxy-2-methylquinolin-8-yl) piperazine [531] To a solution of 1-benzyl-4- (6-methoxy-2-methylquinolin-8-yl) piperazine (0.527 g, 1.52 mmol), 10% Pd / c (0.20 g) the mixture of formate (0.96 g, 15.2 mmol) and heated under reflux for 3 hours under N 2. TLC analysis (35% EtOAc / hexane) shows only trace amounts of starting material remaining. After cooling to room temperature, the reaction is filtered through celite and washed with excess methanol. The filtrate is concentrated, diluted with CH 2 Cl 2 (50 ml) and washed with saturated aqueous NaHCO 3 . The aqueous layer is extracted with CH 2 Cl 2 (2 x 50 ml). The combined organic layers are dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford 0.37 g (95%) of the title compound as a yellow oil which is used in the subsequent reaction without purification. [532] Intermediate 43b [533] 4- (6-methoxy-3-methylquinolin-8-yl) piperazine [534] Benzyl-4- (6-methoxy-2-methylquinolin-8-yl) piperazine was reacted with l-benzyl- 4- , 0.92 mmol), the title compound was prepared in a similar manner as used for the preparation of 4- (6-methoxy-2-methylquinolin-8-yl) piperazine. The title compound is isolated in near quantitative yield and used in a subsequent reaction. [535] Intermediate 43c [536] 4- (6-Methoxy-4-methylquinolin-8-yl) piperazine [537] (2.0 g, 5.76 mmol), methylene chloride (50 ml) and vinyl chloroformate (0.8 ml, 8.64 mmol) were added to a solution of 1-benzyl-4- (6-methoxy- The mixture is refluxed for 4 hours. The mixture is concentrated and then dissolved in a 1: 1 mixture of dioxane / concentrated hydrochloric acid and stirred at ambient temperature for 18 hours. The reaction mixture is basified 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 the title compound: mp 208-209 [deg.] C. [538] Elemental analysis: C 15 H 19 N 3 O.HCl .0.5H 2 O [539] Calculated: C 59.50; H 6.99; N 13.88 [540] Found: C 59.44; H 7.09; N 13.57 [541] Intermediate 44a [542] L-Benzyl-4- (6-methoxy-5-methylquinolin-8-yl) piperazine [543] This compound was prepared in a manner analogous to that for 1-benzyl-4- (6-methoxy-4-methylquinolin-8-yl) piperazine to give 3.0 g (56%) pure title compound: mp 129 -133C. [544] Elemental analysis: C 22 H 25 N 3 O [545] Calculated: C 76.05; H 7.25; N 12.09 [546] Found: C 75.61; H 7.35; N 11.97 [547] Intermediate 44b [548] L-Benzyl-4- (6-methoxy-5-chloro-quinolin-8-yl) piperazine [549] This compound was prepared in a similar manner to that for 1-benzyl-4- (6-methoxy-4-methylquinolin-8-yl) piperazine to give 1.9 g (35%) of pure title compound: mp 138 -140 ° C. [550] Elemental analysis: C 21 H 22 ClN 3 O [551] Calculated: C 68.56; H 6.03; N 11.42 [552] Found: C 68.26; H 5.98; N 11.45 [553] Intermediate 45a [554] 4- (6-methoxy-5-methylquinolin-8-yl) piperazine [555] Methanol (15 ml), 10% Pd / C (0.12 g), 1-benzyl-4- (6-methoxy-5-methylquinolin-8-yl) piperazine (0.8 g, 2.3 mmol) Mate (0.88 g, 13.9 mmol) is refluxed for 45 minutes. The reaction mixture is filtered through celite and then concentrated. The residue is diluted with 1N 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), and then to obtain a was then concentrated to give the title compound 0.52 g (61%) as a thick oil dried over anhydrous Na 2 SO 4. MS (ES) m / z: 258 (M + H < + >). [556] Intermediate 45b [557] 4- (6-Methoxy-5-chloro-quinolin-8-yl) piperazine [558] This compound was prepared by a method similar to that of 4- (6-methoxy-5-methylquinolin-8-yl) piperazine to give 0.48 g (68%) of pure title compound as a thick oil. MS (ES) m / z: 278 (M + H < + >). [559] Intermediate 46 [560] 5-Bromo-6-methoxy-quinoline [561] To a solution of 6-methoxyquinoline (5 g, 31.4 mmol) in acetic acid (50 ml) was added Br 2 nitrate (1.62 ml, 31.4 mmol). The reaction mixture is stirred for 1 hour at ambient temperature and then poured into ice. Saturated aqueous sodium bisulfite is added and the resulting slurry is extracted into EtOAc (2 x 200 ml). The organic fractions are combined, dried over Na 2 SO 4 , concentrated and purified by column chromatography (5% MeOH / CH 2 Cl 2 ) to give 4.39 g of the title compound as the acetate salt. The salt is washed with 1 N NaOH (50 ml) and H 2 O (100 ml) and extracted into CH 2 Cl 2 (200 ml) to give the free base. The organic fraction was concentrated to give 3.89 g (52%) of the title compound as a pink solid. [562] Elemental analysis: C 10 H 8 BrNO [563] Calculated: C 50.45; H 3.39; N 5.88 [564] Found: C 50.34; H 3.25; N 6.09 [565] Intermediate 47 [566] 4-Bromo-2-nitrophenylamine [567] To a solution of 2-nitro-phenylamine (13.8 g, 10 mmol) in HOAc (150 ml) was added NBS (18 g, 101 mmol). The reaction mixture is stirred and heated to reflux over 1 hour. The cooled reaction mixture is poured into H 2 O (1000 ml) and stirred for 15 minutes. The resulting orange slurry was filtered and washed with H 2 O (300) to give 20.56 g (93%) of the title compound as a light orange solid. [568] Elemental analysis: C 6 H 5 BrN 2 O 2 [569] Calculated: C 33.21; H 2.32; N 12.91 [570] Found: C 33.15; H 2.31; N 12.75 [571] Reference: Montash Chem EN 1994, 125 p. 723-730 [572] Intermediate 48 [573] 6-Bromo-8-nitro-quinoline [574] H 2 SO 4 (50 ml) was added to a 250 ml flask containing H 2 O (20 ml) cooled in an ice bath to prepare a sulfuric acid solution. To this solution was added glycerol (12 ml, 16.5 mmol), m-nitrobenzenesulfonic acid sodium salt (11.4 g, 5.06 mmol) and 4-bromo-2-nitrophenylamine (10 g, 4.6 mmol). The reaction mixture is heated at 135 < 0 > C for 3 hours. The warm reaction mixture is poured into ice H 2 O (200 ml) and extracted into 50% MeOH / EtOAc (2 x 200 ml), dried over Na 2 SO 4 and concentrated. The resulting brown solid was triturated with EtOH and filtered to give 3.8 g (33%) of a pink solid: mp 172-174 [deg.] C. [575] Elemental analysis: C 9 H 5 BrN 2 O 2 [576] Calculated: C 42.72; H 1.99; N 11.07 [577] Found: C 42.69; H 1.85; N 11.01 [578] Reference: Mantash Chem EN 1994, 125 p. 723-730 [579] Intermediate 49 [580] 6-Bromo-8-amino-quinoline [581] And the quinoline iron metal (3.18 g, 5.69 mmol) to a solution of (4 g, 1.58mmol) - 6- bromo-8-amino of EtOH / HOAc / H 2 O ( 50 ml / 50 ml / 25 ml) . The resulting solution is heated to reflux for 3 hours. The cooled reaction mixture is neutralized with 2.5 N NaOH, filtered through celite to remove iron solids, and washed with EtOAc. Were combined extracts eluate in EtOAc (3 x 200 ml), concentrated, and then dried over Na 2 SO 4. The resulting oil was purified by column chromatography (40% EtOAc / hexanes) to give 3.19 g (91%) of a yellow solid: mp 142-145 [deg.] C. [582] Elemental analysis: C 9 H 7 BrN 2 [583] Calculated: C 48.46; H 3.16; N 12.56 [584] Found: C 48.04; H 2.93; N 12.36 [585] Intermediate 50 [586] 8- (4-Benzyl-piperazin-1-yl) -6-bromo-quinoline [587] The HCl salt is washed with 1 M NaOH (200 ml) and extracted into EtOAc to give the free base of bis (2-chloroethyl) -benzylamine (5.12 g, 19.3 mmol). The resulting organic phase is dried over Na 2 SO 4 and concentrated. To this flask was added 6-bromo-8-amino-quinoline (2.15 g, 9.6 mmol), n-BuOH (100 ml), and Et 3 N (4 ml, 28.9 mmol). The resulting reaction mixture is stirred overnight at 100 < 0 > C. TLC analysis shows that the starting amine is still present, so an additional portion of bis (2-chloroethyl) -benzylamine hydrochloride (5 g) is added. The reaction is heated for an additional 72 hours. The cooled reaction mixture is quenched with 1 M NaOH (200 ml) and extracted into EtOAc (3 x 200 ml). Combine the organic fractions dried over Na 2 SO 4 then then concentrated. The resulting gold oil was purified three times with column chromatography (40% EtOAc / hexanes) to give 1.2 g (33%) of a viscous orange oil which solidified upon standing: mp 65-68 C, MS (+) APCI m / z 382 [M + H] < + >. [588] Elemental analysis: C 20 H 20 BrN 3 .0.75H 2 O [589] Calculated: C 60.69; H 5.48; N 10.62 [590] Found: C 60.81; H 5.02; N 10.88 [591] Intermediate 51 [592] 6-Bromo-8-piperazin-l-yl-quinoline [593] To a solution of 8- (4-benzyl-piperazin-l-yl) -6-bromo-quinoline (1.6 g, 4.2 mmol) in dichloroethane (50 ml) under N 2 atmosphere was added chloroethyl chloroformate , 12.6 mmol) and the reaction mixture is heated at 80 < 0 > C for 4 h, and at ambient temperature overnight. No reaction was observed by TLC, so vinyl chloroformate (0.35 ml, 6.3 mmol) was added and the reaction was heated at 80 < 0 > C for a further 4 hours. The cooled reaction is poured into H 2 O and extracted into CH 3 Cl 2 (2 x 100 ml) and EtOAc (100 ml). Combine the organic fractions were dried over Na 2 SO 4, and then, allowed to stand overnight in EtOAc. The organic layer was concentrated and purified by column chromatography (10% MeOH / CH 2 Cl 2 + NH 4 OH) to give 1.03 g (84%) of a brown foam. MS (+) APCI m / z 292 [M + H] < + >. [594] Intermediate 52 [595] 6-Hydroxy-8-nitro-quinoline [596] A solution of 6-methoxy-8-nitro-quinoline (9 g, 44.1 mmol) in HBr (100 ml) is heated at 110 <0> C overnight. Additional HBr (80 ml) is added and the reaction is continued heating for an additional 24 h. The cooled reaction mixture is basified with 2.5N NaOH (800 ml) and extracted into EtOAc (2 x 300 ml). The organic fractions were combined and dried over Na 2 SO 4 and then purified by column chromatography (50% EtOAc / hexanes) to give 2.71 g (32%) of the title compound as a white solid: mp, MS (-) ESI m / z 189 [MH] - . [597] Intermediate 53 [598] 6-Ethoxy-8-nitro-quinoline [599] (2.5 g, 13.2 mmol), ethyl bromide (1.08 ml, 14.5 mmol), and K 2 CO 3 (4 g, 26.4 mmol) in DMF (50 ml) The solution is heated at 40 < 0 > C for 5 hours. The cooled reaction mixture is poured into H 2 O (200 ml) and extracted into EtOAc (2 x 200 ml). The organic fractions are combined, dried over Na 2 SO 4 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. [600] Elemental analysis: C 11 H 10 N 2 O 3 [601] Calculated: C 60.55; H 4.62; N 12.84 [602] Found: C 60.15; H 4.50; N 12.75 [603] Intermediate 54 [604] 8- (4-Benzyl-piperazin-1-yl) -6-methoxy-1,2,3,4-tetrahydroquinoline [605] 8 in HOAc (100 ml) (4- benzyl-piperazin-1-yl) -6-methoxy-quinoline A solution of (1 g, 3 mmol) at 40 psi onto PtO 2 (300 mg) then hydrogenated overnight . The reaction mixture is filtered through a pad of celite and washed with EtOAc (50 ml). Concentrate the filtrate. The resulting gold oil was purified by column chromatography (10% MeOH / CH 2 Cl 2 + NH 4 OH) to give 330 mg (45%) of a viscous gold oil. Analytical samples are prepared as HCl salt from EtOAc. MS EI m / z 247 M < + >. [606] J. Chem Soc Perkins I 1980 p. 1933-1939 [607] Intermediate 55 [608] [1,6] naphthyridine [609] H 2 SO 4 (100 ml) was added to H 2 O (57 ml) cooled in an ice bath to prepare a sulfuric acid solution. To this solution was added glycerol (33 ml, 457 mmol), m-nitrobenzenesulfonic acid sodium salt (48 g, 212 mmol) and 4-amino-pyridine (10 g, 106 mmol). The reaction mixture is heated at 135 < 0 > C for 4 hours. The cooled reaction mixture is basified with 2.5 N NaOH (500 ml) in an ice bath and extracted into CH 2 Cl 2 (3 x 200 ml). Combine the organic fractions dried over Na 2 SO 4 then concentrated. The resulting oil was purified by column chromatography (5% MeOH / CH 2 Cl 2 ) to give 5.04 g (36%) of the product as a dark orange oil. Analytical sample is prepared from EtOAc to HCI salt to give an orange low melting point solid. MS EI m / z 130 M < + >. [610] See Chem Pharm Bull. 1971, 19, 9, p. 1751-1755 [611] Intermediate 56 [612] 8-Bromo- [l, 6] -naphthyridine [613] To a stirred solution of [1,6] -naphthyridine (4.73 g, 36.4 mmol) in CCl 4 (200 ml) was added Br 2 (2.25 ml, 43.7 mmol) in CCl 4 (35 ml) via an addition funnel. The resulting solution is heated to reflux for 1 hour. Pyridine (2.94 ml, 36.4 mmol) in CCl 4 (30 ml) is added dropwise to the refluxing solution and the mixture is refluxed overnight. The cooled reaction mixture is filtered and the solid is digested with 1 M NaOH (200 ml) for 1 h. The basic solution is extracted into CH 2 Cl 2 (2 x 200 ml) and the combined organic fractions are dried over Na 2 SO 4 and concentrated. The resulting oil was purified by column chromatography (10% EtOAc / CH 2 Cl 2 ) to give 2.03 g (27%) of the title compound as yellow crystals: mp 79-81 ° C. [614] Elemental analysis: C 8 H 5 BrN 2 [615] Calculated: C 45.97; H 2.41; N 13.40 [616] Found: C 45.72; H 2.34; N 13.36 [617] See JOC 1968, 33, 4, p. 1384-1387 [618] Intermediate 57 [619] 8-piperazin-1-yl- [l, 6] -naphthyridine [620] (1.3 g, 6.2 mmol), piperazine (3.21 g, 37.3 mmol), and sodium t-butoxide (900 mg) in a 100 ml oven-dried flask under nitrogen atmosphere. mg, 9.33 mmol). The solid was suspended in anhydrous o-xylene (40 ml) and Pd (dba) (285 mg, 5 mol%) and P (t-Bu) 3 (0.31 ml, 1.24 mmol) were added. The reaction mixture is heated at 120 < 0 > C for 3 hours. The cooled reaction mixture is poured into H 2 O (100 ml) and extracted into EtOAc (1 x 100 ml) and CH 2 Cl 2 (2 x 100 ml). The organic fractions were combined, dried over Na 2 SO 4, concentrated and the resulting oil was chromatographed (10% MeOH / CH 2 Cl 2 + NH 4 OH) to give 470 mg (35%) of the title compound as a dark golden oil do. Analytical sample was prepared as a HCl salt from EtOAc to give a brown solid: mp decomposed above 200 < 0 > C. MS (+) APCI m / z 215 [M + H] < + >. [621] See Tet. Lett. 1998, 39, P. 617-620 [622] Intermediate 58 [623] 4- (6-methylamino-quinolin-8-yl) -piperazine-1-carboxylic acid ethyl ester [624] Oven-on dry 25 ml round bottom flask was charged Cs 2 CO 3 (1.55 g, 4.76 mmol), BINAP (300 mg, 3 mol%), Pd (OAc) 2 was added (100 mg, 3 mol%) and kept under overnight vacuo . (1.3 g, 3.4 mmol), anhydrous toluene (12 ml), and benzylmethylamine (0.53 ml, 2.9 mmol) were added to the reaction vessel under a nitrogen atmosphere. 4.1 mmol). The reaction mixture is heated at 100 < 0 > C overnight. The cooled reaction mixture is diluted with Et 2 O (15 ml) and filtered to remove solids, washed with EtOAc (10 ml) and then concentrated. The resulting oil was purified by column chromatography (40% EtOAc / hexanes) to give 830 mg (yield) of benzyl- [8- (4- benzyl- piperazin- 1 -yl) -quinolin- 6-yl] -methylamine as an orange foam 59%). [625] To a solution of benzyl- [8- (4-benzyl-piperazin-l-yl) -quinolin-6-yl] -methylamine (800 mg, 1.89 mmol) in anhydrous CH 2 Cl 2 (100 ml) Mate (0.48 ml, 5.68 mmol) is added and the mixture is heated under reflux overnight. A second aliquot of chloroformate (0.48 ml) is added and the reaction is refluxed for an additional 24 h. The cooled reaction mixture is diluted with H 2 O (50 ml) and extracted into CH 2 Cl 2 (2 x 50 ml). Dry the combined organic phases over Na 2 SO 4, filtered and then concentrated. The resulting oil is purified by column chromatography (40% EtOAc / hexanes) to give 600 mg of mono-decabenzylated product. This material is dissolved in EtOH (100 ml) and 10% Pd / C (150 mg) and ammonium formate (244 mg, 4.5 mmol) are added. The reaction is heated to reflux overnight. Additional ammonium formate (250 mg) is added and the reaction is refluxed for a further 72 hours. The cooled reaction mixture was filtered through a pad of celite, washed with EtOAc (200 ml), concentrated and then purified by column chromatography (10% MeOH / CH 2 Cl 2 ) to give 400 mg of the title compound as a dark golden oil . Analytical sample is prepared as an HCl salt from EtOAc as an orange solid: mp decomposes above 85 캜. MS (+) APCI m / z 315 [M + H]. [626] Intermediate 59 [627] 4-Methoxy-2,6-dinitro-phenylamine [628] To a stirred solution of HNO 3 (65 ml) was added 4-methoxy-2-nitro-phenylamine (15 g, 89.3 mol). The reaction mixture is stirred at room temperature overnight. The dark red precipitate was filtered and washed with H 2 O (400 ml) to give 10.01 g (53%) of the title compound. [629] Intermediate 60 [630] 7-Methoxy-quinoxalin-5-ylamine [631] A solution of 4-methoxy-2,6-dinitro-phenylamine (5 g, 23.5 mmol) in EtOH (200 ml) is hydrogenated over 10% Pd / C (2 g) at 40 psi for 1 hour. After H 2 absorption is stopped, the reaction is filtered through a pad of celite, washed with EtOAc (50 ml) and concentrated. Glyoxal (8 ml, 704 mmol) and EtOH (50 ml) are immediately added and the reaction is heated to reflux for 2 hours. The cooling reaction is diluted with H 2 O (50 ml) and extracted into CH 2 Cl 2 (3 x 100 ml). The organic phases were combined, dried over Na 2 SO 4 then filtered and concentrated. The resulting oil was purified by column chromatography (10% MeOH / CH 2 Cl 2 ) to give 430 mg (10%) as a red oil. Analytical sample is prepared from EtOAc as the HCl salt to give a red solid. [632] Intermediate 61 [633] (L-oxy-pyridin-3-yl) -acetonitrile [634] A solution of 3-pyridyl acetonitrile (11 g, 93.1 mmol), HOAc (55 ml), and 30% H 2 O 2 (17 ml) is heated at 95 ° C overnight and at room temperature for 72 hours. H 2 O (50 ml) is added to the reaction mixture and the resulting solution is concentrated. This process is repeated with additional H 2 O (100 ml). The residual H 2 O was removed using toluene (2 x 100 ml) and the resulting white solid was dried under vacuum overnight to give a waxy white solid: mp 120-125 ° C; MS (+) APCI m / z 135 [M + H] < + >. [635] Reference literature: JACS 1959, 81 p. 740-743 [636] Intermediate 62 [637] 3-Cyanomethyl-pyridine-2-carbonitrile [638] To a suspension of (1-oxy-pyridin-3-yl) -acetonitrile (10 g, 75 mmol) in anhydrous CH 2 Cl 2 under a nitrogen atmosphere was added trimethylsilyl cyanide (10.95 ml, 82 mmol) and dimethylene carbamoyl chloride (7.55 ml, 82 mmol). The reaction mixture is stirred at room temperature for 72 hours and concentrated. The EtOAc washed with (100 ml) 1 M NaOH ( 150 ml) and the organic phase was added to the residue, filtered, dried over Na 2 SO 4 and then concentrated. The resulting solid was purified by column chromatography (50% EtOAc / hexanes) to give 7.08 g (66%) of a yellow solid: mp 48-51 DEG C; MS (+) APCI m / z 144 [M + H] < + >. [639] See WO 9818796 [640] Intermediate 63 [641] 6-Methoxy- [l, 7] naphthyridin-8-ylamine [642] Anhydrous MeOH (200 ml) is added to an oven-dried 250 ml flask under a nitrogen atmosphere. The Na metal (1.07 g, 44 mmol) is weighed into a small beaker containing hexane and transferred to the reaction vessel. After dissolving the sodium, 3-cyanomethyl-pyridine-2-carbonitrile (5.3 g, 37 mmol) dissolved in anhydrous MeOH (10 ml) is added to the reaction. The resulting solution is heated at 80 < 0 > C for 3 hours and then stirred overnight at room temperature. The reaction mixture is concentrated to remove MeOH and extracted into CH 2 Cl 2 (2 x 200 ml). The organic phases were combined, dried over Na 2 SO 4, filtered, concentrated and unsuccessfully chromatographed (2% MeOH / CH 2 Cl 2 ). The combined fractions were combined and recrystallized from EtOAc / hexanes to give 1.16 g (18%) of the title compound as a yellow solid. The mother liquor was rechromatographed (50% EtOAc / hexanes) to afford further 560 mg (9%) of the product: mp decomposed above 110 ° C: MS (+) APCI m / z 176 [M + H] + . [643] See Tet. Lett. 1975 p. 173-174 [644] Intermediate 64 [645] 6-Methoxy-8-piperazin-1-yl- [l, 7] naphthyridine [646] (2.25 g, 12.8 mmol), bis (2-chloroethyl) -benzylamine (10.25 g, 38.6 mmol) and Et (2-chloroethyl) 3 N (5.34 ml, 38.6 mmol) was heated at 100 < 0 > C for 72 hours. The cooled reaction mixture is poured into H 2 O (100 ml) and 2.5 N NaOH (100 ml) and extracted into EtOAc (2 x 200 ml). The organic phases were combined, dried sikimyeo filtered over Na 2 SO 4 then concentrated. The resulting oil was purified twice by column chromatography (10% MeOH / CH 2 Cl 2 ) to give a deep gold oil which was subjected to BuOH impurities. The oil is dissolved in EtOH (50 ml) and 10% Pd / C (390 mg) and ammonium formate (730 mg) are added. The reaction mixture is heated at 80 < 0 > C for 2.5 hours. The cooled reaction mixture is filtered through a pad of celite and washed with EtOAc (50 ml). The organic phase was concentrated and purified by column chromatography (10% MeOH / CH 2 Cl 2 + NH 4 OH) to give 270 mg of the title compound as a dark orange oil. Analytical samples are prepared from EtOAc as the HCl salt. [647] Intermediate 65 [648] 4-piperazin-1-yl-1,3-dihydro-benzoimidazol-2-one [649] To a solution of 4- (4-benzylpiperazin-1-yl) -1,3-dihydro-benzoimidazol-2-one (1 g, 3.2 mmol) in anhydrous CH 2 Cl 2 (50 ml) The formate (0.41 ml, 4.87 mmol) is added under a nitrogen atmosphere. The reaction mixture is heated to reflux for 2 hours and then a second aliquot of vinyl chloroformate (0.41 ml) is added. The reaction is refluxed for an additional 3 hours. The cooled reaction mixture is concentrated, and dioxane (25 ml) and concentrated hydrochloric acid (25 ml) are added to the residue. The resulting solution is stirred at room temperature for 72 hours. The reaction is basified with 2.5 N NaOH (300 ml) and extracted with MeOH / EtOAc (2 x 200 ml). Combine the organic fractions were dried and concentrated on Na 2 SO 4 and purify the oil that is generated by column chromatography to obtain 393 mg (46%) as the oxalate salt. MS (+) ESI m / z 219 [M + H] < + & gt ; . [650] Intermediate 66 [651] 6-Methoxy-lH-indol-4-ylamine [652] To a solution of 5-methoxy-2-methyl-1,3-dinitrobenzene (3.28 g, 15 mmol) in 15 ml 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 is heated at 120 <0> C until the TLC analysis shows complete consumption of 5-methoxy-2-methyl-1,3-dinitrobenzene. The N, N-dimethylformamide is removed in vacuo to give a dark red substance which is dissolved in dry benzene and hydrogenated at 50 psi with 10% Pd / C (0.1 g) for 4 hours. The catalyst is filtered off and the solvent is removed under vacuum. Chromatography (25% ethyl acetate / hexanes) gave 1.0 g (40%) of the desired product as a yellow solid: mp 83-86 [deg.] C; MS EI m / e 162. [653] Intermediate 67 [654] 4- (4-Benzyl-piperazin-1-yl) -6-methoxy-lH-indole [655] A solution of 6-methoxy- lH-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) Lt; 0 > C for 18 hours and then poured into aqueous sodium carbonate solution. The mixture is extracted with ethyl acetate (3 x 60 ml). The organic layer is dried over anhydrous sodium sulfate and filtered. The solvent is removed under vacuum. Chromatography (30% ethyl acetate / hexanes) afforded 0.60 g (40%) of the product as a gray oil. MS (+) APCI (M + H) < + & gt ; m / e 322. [656] Intermediate 68 [657] 6-Methoxy-4-piperazin-1-yl-lH-indole [658] (0.37 g, 1.1 mmol), 10% Pd / C (0.05 g), and ammonium formate (0.2 g) in ethanol (20 ml) (0.15 g, 2.2 mmol) is refluxed for 2 hours. The catalyst is filtered off and the solvent is removed in vacuo. Chromatography (10% methanol / methylene chloride + ammonium hydroxide) gives 0.2 g (75%) of the product as a yellow foam. [659] Example 1a [660] 3- [cis-4- [4- (1H-indol-4-yl) -1-piperazinyl] cyclohexyl] [661] (0.5 g, 2.5 mmol) and l- (indol-4-yl) piperazine (0.5 g, 2.5 mmol) in 1,2-dichloroethane (11 ml) mmol), sodium triacetoxyborohydride (0.78 g, 3.5 mmol) and acetic acid (0.14 ml, 2.5 mmol) in dichloromethane at room temperature overnight. The reaction was quenched with 1 N sodium hydroxide (10 ml), extracted with methylene chloride (3 x 60 ml) and then brine (3 x 60 ml). The organic layer is dried over anhydrous sodium sulfate and then filtered. Chromatography (10% methanol-ethyl acetate) gave 0.52 g (53%) of the product as a white solid: mp 85-87 [deg.] C. [662] HCl salt is prepared in ethyl acetate: mp 198-200 [deg.] C. [663] Elemental analysis: C 26 H 30 N 4 .HCl [664] Calculated: C 68.25; H 7.38; N 12.25 [665] Found: C 68.12; H 7.16; N 11.93 [666] Example 1b [667] 3- [trans-4- [4- (1H-indol-4-yl) -1-piperazinyl] cyclohexyl] [668] The trans compound was isolated as a white solid simultaneously with the cis isomer in 21% yield (0.21 g): mp 105-107 [deg.] C. [669] HCl salt is prepared in ethyl acetate: mp 305 [deg.] C (decomposition). [670] Elemental analysis: C 26 H 30 N 4 .HCl [671] Calculated: C 68.25; H 7.38; 12.25 [672] Found: C 68.12; H 7.16; N 11.93 [673] Example 2a [674] 4-fluoro-3- [cis-4- [4-1H-indol-4-yl) -1-piperazinyl] cyclohexyl] [675] (4-fluoro-lH-indol-3-yl) -cyclohexanone (0.88 g, 3.8 mmol), l- (indol- (0.7 g, 3.5 mmol), sodium triacetoxyborohydride (1.1 g, 5.2 mmol) and acetic acid (0.4 ml, 7 mmol) at room temperature overnight. The reaction was quenched with 1 N sodium hydroxide (10 ml), extracted with methylene chloride (3 x 60 ml) and then brine (3 x 60 ml). The organic phase is dried over anhydrous sodium sulfate and then filtered. Chromatography (5-7% methanol-ethyl acetate) affords 1.14 g (79%) of the product as a white foam. [676] HCl salt is prepared in ethanol: mp 283-285 [deg.] C. [677] Elemental analysis: C 26 H 29 FN 4揃 HCl 揃 0.25H 2 O [678] Calculated: C 68.26; H 6.72; N 12.25 [679] Found: C 68.16; H 6.74; N 12.04 [680] Example 2b [681] Fluoro-3- [trans-4- [4- (1H-indol-4-yl) -1-piperazinyl] cyclohexyl] [682] The trans compound was isolated as a white solid simultaneously with the cis isomer in 17% yield (0.24 g). [683] HCl salt is prepared in ethanol: mp 297-299 [deg.] C [684] Elemental analysis: C 26 H 29 FN 4揃 HCl 揃 H 2 O [685] Calculated: C 66.30; H 6.85; N 11.90 [686] Found: C 66.17; H 6.51; N 11.70 [687] Example 3a [688] 5- Fluoro-3- [cis-4- [4- (lH-indol-4-yl) -1-piperazinyl] cyclohexyl] [689] This compound is prepared by the same procedure as described for 4- (4-fluoro-lH-indol-3-yl) -cyclohexanone with 4- (5-fluoro- ) To give 0.54 g (52%) of the product as a white solid: mp 108-110 < 0 > C. [690] HCl salt is prepared in ethyl acetate: mp 215-217 [deg.] C. [691] Elemental analysis: C 26 H 29 FN 4揃 HCl 揃 0.36 C 4 H 8 O 2 [692] Calculated: C 67.37; H 6.88; N 11.45 [693] Found: C 67.18; H 6.72; N 11.18 [694] Example 3b [695] Fluoro-3- [trans-4- [4- (1H-indol-4-yl) -1-piperazinyl] cyclohexyl] [696] The trans compound was isolated as a white solid simultaneously with the cis isomer in 30% yield (0.31 g): mp 112-114 [deg.] C. [697] HCl salt is prepared in ethanol: mp 280 [deg.] C (decomposition) [698] Elemental analysis: C 26 H 29 FN 4 .HCl [699] Calculated: C 66.81; H 6.81; N 11.99 [700] Found: C 66.44; H 6.66; N 11.74 [701] Example 4a [702] 6-Fluoro-3- [cis-4- [4- (lH-indol-4-yl) -1-piperazinyl] cyclohexyl] [703] This compound was prepared in accordance with the general method of Example 1 from 4- (4-fluoro-lH-indol-3-yl) -cyclohexanone with 4- (6-fluoro-lH- ) To give 1.06 g (51%) of the product as a white foam. [704] HCl salt is prepared in ethanol: mp 250-252 [deg.] C (decomposition). [705] Elemental analysis: C 26 H 29 FN 4 .HCl [706] Calculated: C 67.37; H 6.88; N 11.45 [707] Found: C 67.18; H 6.72; N 11.18 [708] Example 4b [709] 6-Fluoro-3- [trans-4- [4- (1H-indol-4-yl) -1-piperazinyl] cyclohexyl] [710] The trans compound was isolated as a white foam simultaneously with the cis isomer in 27% yield (0.55 g). [711] HCl salt is prepared in ethanol: mp 319-320 [deg.] C (decomposition). [712] Elemental analysis: C 26 H 29 FN 4 .HCl [713] Calculated: C 66.81; H 6.81; N 11.99 [714] Found: C 66.44; H 6.66; N 11.74 [715] Example 5a [716] Cis-4- [4- (1H-indol-4-yl) -1-piperazinyl] cyclohexyl] [717] This compound was prepared in accordance with the general method of Example 1 from 4- (4-fluoro-lH-indol-3-yl) -cyclohexanone with 4- (5-bromo- ) To give 0.81 g (68%) of the product. [718] HCl salt is prepared in ethyl acetate: mp 276 [deg.] C. [719] Elemental analysis: C 26 H 29 BrN 4 .HCl [720] Calculated: C 60.23; H 5.93; N 10.81 [721] Found: C 59.95; H 5.83; N 10.64 [722] Example 5b [723] 5-Bromo-3- [trans-4- [4- (1H-indol-4-yl) -1-piperazinyl] cyclohexyl] [724] The trans compound was simultaneously separated with the cis isomer in 24% yield (0.29 g). [725] HCl salt is prepared in ethyl acetate: mp > 300 < 0 > C [726] Elemental analysis: C 26 H 29 BrN 4 .HCl [727] Calculated: C 60.75; H 5.88; N 10.90 [728] Found: C 60.38; H 5.89; N 10.61 [729] Found 6a [730] 5-Chloro-3- [cis-4- [4- (lH-indol-4-yl) -1- piperazinyl] cyclohexyl] [731] To a solution of 4- (5-chloro-lH-indol-3-yl) -cyclohexanone (0.78 g, 3.1 mmol), 1- (indol- 0.6 g, 3 mmol), sodium triacetoxyborohydride (0.95 g, 4.5 mmol) and acetic acid (0.34 ml, 6 mmol) at room temperature overnight. The reaction was quenched with 1 N sodium hydroxide (10 ml), extracted with methylene chloride (3 x 60 ml) and then brine (3 x 60 ml). The organic layer is dried over anhydrous sodium sulfate and filtered. Chromatography (5% methanol-ethyl acetate) affords 0.84 g (65%) of the product as a white foam. [732] HCl salt is prepared in ethanol: 283-285 [deg.] C. [733] Elemental analysis: C 26 H 29 ClN 4揃 HCl 揃 0.25H 2 O [734] Calculated: C 65.46; H 6.69; N 11.45 [735] Found: C 65.14; H 6.73; N 11.33 [736] Example 6b [737] Chloro-3- [trans-4- [4- (1H-indol-4-yl) -1-piperazinyl] cyclohexyl] [738] The trans compound was isolated as a white foam simultaneously with the cis isomer in 24% yield (0.32 g). [739] HCl salt is prepared in ethanol: mp 314-315.5 [deg.] C. [740] Elemental analysis: C 26 H 29 ClN 4揃 HCl 揃 0.25H 2 O [741] Calculated: C 65.65; H 6.60; N 11.62 [742] Found: C 65.50; H 6.50; N 11.30 [743] Example 7a [744] 3- {4 - [(1,4-cis) -4- (lH-indol-4-yl) -piperazinyl- l- yl] cyclohexyl} -lH- indole-5-carbonitrile [745] This compound was prepared by the same procedure for the preparation of 4- (4-fluoro-lH-indol-3-yl) -cyclohexanone with 4- (5-cyano- ) To give 0.38 g (30%) of the product. [746] HCl salt is prepared in ethyl acetate: mp 216-218 [deg.] C. [747] Elemental analysis: C 27 H 29 N 5 .HCl 0.33 C 4 H 8 0 2 [748] Calculated: C 66.25; H 6.94; N 13.64 [749] Found: C 66.05; H 6.54; N 13.28 [750] Example 7b [751] 3- {4 - [(1,4-trans) -4- (lH-indol-4-yl) -piperazinyl- l- yl] cyclohexyl} -lH- indole-5-carbonitrile [752] The trans compound was isolated simultaneously with the cis isomer in 25% yield (0.32 g). [753] HCl salt is prepared in ethyl acetate: mp > 310 [deg.] C. [754] Elemental analysis: C 27 H 29 N 5 .HCl [755] Calculated: C 68.48; H 6.71; N 14.79 [756] Found: C 68.43; H 6.54; N 14.63 [757] Example 8a [758] Cis-4- [4- (1H-indol-4-yl) -1-piperazinyl] cyclohexyl] -1H-indole [759] To a solution of 4- (5-methoxy-lH-indol-3-yl) -cyclohexanone (1.2 g, 5 mmol), 1- (indol- (1 g, 5 mmol), sodium triacetoxyborohydride (1.47 g, 6.2 mmol) and acetic acid (0.28 ml, 4 mmol) at room temperature overnight. The reaction was quenched with 1N sodium hydroxide (10 ml), extracted with methylene chloride (3 x 60 ml) and washed with brine (3 x 60 ml). The organic layer is dried over anhydrous sodium sulfate and filtered. Chromatography (2.5% methanol-ethyl acetate) gave 1.18 g (55%) of the product as a white solid: mp 105-108 [deg.] C. [760] HCl salt is prepared in ethyl acetate: mp 283-285 [deg.] C. [761] Elemental analysis: C 27 H 32 N 4 O · HCl · 0.5H 2 O [762] Calculated: C 68.55; H 7.03; N 11.85 [763] Found: C 68.86; H 7.29; N 11.76 [764] Example 8b [765] Methoxy-3- [trans-4- [4- (1H-indol-4-yl) -1-piperazinyl] cyclohexyl] [766] The trans compound was isolated as a white foam simultaneously with the cis isomer in 20% yield (0.43 g). [767] HCI salt is prepared in ethyl acetate: mp 194-196 [deg.] C. [768] Elemental analysis: C 27 H 32 N 4 O · HCl · 1.5H 2 O [769] Calculated: C 66.65; H 7.15; N 11.52 [770] Found: C 66.65; H 7.06; N 11.44 [771] Example 9a [772] 4- [4- (1H-indol-4-yl) -1-piperazinyl] cyclohexyl] -2-methyl- [773] (1.44 g, 6.33 mmol) and l- (indol-4-yl) piperazine (1.27 g, 6.33 mmol) in 1,2-dichloroethane (100 ml) mmol), sodium triacetoxyborohydride (1.88 g, 8.66 mmol) and acetic acid (0.76 mg, 12.6 mmol) in dichloromethane at room temperature overnight. The reaction is quenched with 1N sodium hydroxide (80 ml), extracted with methylene chloride (3 x 300 ml) and then brine (150 ml). The organic layer is dried over anhydrous sodium sulfate and filtered. The solvent is removed in vacuo to give an off-white solid. The solid was triturated with warmed methylene chloride (80 ml) and then filtered to give 0.88 g of a white solid. The mother liquor was concentrated and chromatographed (2% methanol-methylene chloride) to afford 0.18 g (total yield 40.7%) of additional product as a white solid: mp 279-280 [deg.] C. [774] HCl salt is prepared in ethanol: mp 200-203 < 0 > C. [775] Elemental analysis: C 27 H 32 N 4 .2HCl [776] Calculated: C 64.99; H 7.17; N 11.23 [777] Found: C 65.05; H 7.07; N 11.23 [778] Example 9b [779] 3- [trans-4- [4- (1H-indol-4-yl) -1-piperazinyl] cyclohexyl] -2- [780] The trans compound was isolated as a white foam simultaneously with the cis isomer in 25.7% yield (0.67 g). [781] HCl salt is prepared in ethanol: mp > 310 [deg.] C. [782] Elemental analysis: C 27 H 32 N 4 .2HCl [783] Calculated: C 66.80; H 7.06; N 11.54 [784] Found: C 66.84; H 6.87; N 11.37 [785] Example 10a [786] LH-pyrrolo [2,3-b] pyridine prepared in Step 2 of Example 1 was prepared in accordance with the general method of example 1 from 3 - {(l, 4-cis) -4- [4- [787] This compound was prepared by the same procedure as described in Example 1 but using 4- (5-fluoro-lH-indol-3-yl) -cyclohexanone with 4- (1H-3- pyrrolo [2,3- b] pyridyl) , 7.1 mmol) to give 27% (0.79 g) as a white solid. [788] HCl salt is prepared in ethanol: mp > 250 DEG C (decomposition). [789] Elemental analysis: C 25 H 29 N 5 .3HCl [790] Calculated: C 58.49; H 6.38; N 13.64 [791] Found: C 58.47; H 6.52; N 12.91 [792] Example 10b [793] LH-pyrrolo [2,3-b] pyridine prepared in step 2 of Example 1 was prepared in accordance with the general method of example 1 from 3 - {(l, 4-trans) -4- [4- [794] The trans compound was isolated as a white solid simultaneously with the cis isomer in 9% yield (0.26 g). [795] HCl salt is prepared in ethanol: mp > 250 [deg.] C (decomposition) [796] Elemental analysis: C 25 H 29 N 5 .3HCl [797] Calculated: C 56.50; H 6.54; N 13.18 [798] Found: C 56.45; H 6.63; N 12.98 [799] Example 11 [800] Methyl-1H-indole-4-yl) -1-piperazinyl] cyclohexyl} -1H-indole [801] Cis-4- [4- (lH-indol-4-yl) -1-piperazinyl] cyclohexyl] -lH- indole (0.27 g, 0.65 mmol) in dichloromethane (10 mL) at room temperature was added 60% sodium hydride (33.7 mg, 0.84 mmol). The mixture is stirred at room temperature for 30 minutes and then iodomethane is added to the solution. The resulting mixture is stirred again for 0.5 h, then poured into water (80 ml) and then extracted with ethyl acetate (2 x 80 ml). The organic layer is dried over anhydrous magnesium sulfate and filtered. 0.93 g (55%) of the product as an oil was obtained by chromatography (20% acetone-hexane) which was heated in ethanol to give a white solid: mp 188-190 [deg.] C. [802] HCl salt is prepared in ethanol: mp 253-254 [deg.] C. [803] Elemental analysis: C 28 H 33 N 4 F · HCl · 0.5H 2 O [804] Calculated: C 68.62; H 7.20; N 11.43 [805] Found: C 68.98; H 6.80; N 11.47 [806] Example 12a [807] L-yl] -cyclohexyl} -l-methyl-lH-indole-5-carbonitrile < / RTI > [808] Cyclohexanone (0.75 g, 3 mmol), 1- (indol-4-yl) piperazine-1- A solution of razine (0.6 g, 3 mmol), sodium triacetoxyborohydride (0.95 g, 4.5 mmol) and acetic acid (0.34 ml, 6 mmol) is stirred at room temperature overnight. The reaction was quenched with 1 N sodium hydroxide (10 ml), extracted with methylene chloride (3 x 60 ml) and then brine (3 x 60 ml). The organic layer is dried over anhydrous sodium sulfate and filtered. Chromatography (10% methanol-ethyl acetate) afforded 0.73 g (56%) of the product as a white solid: mp 274-275 [deg.] C. [809] HCl salt is prepared in ethyl acetate: mp 285.5-288 [deg.] C. [810] Elemental analysis: C 28 H 31 N 5 · 2HCl · H 2 O [811] Calculated: C 68.35; H 6.97; N 14.23 [812] Found: C 68.51; H 6.65; N 14.06 [813] Example 12b [814] L-yl] -cyclohexyl} -l-methyl-lH-indole-5-carbonitrile < / RTI > [815] The trans compound was isolated simultaneously with the cis isomer in 33% yield (0.42 g) as a white solid: mp 239-240 [deg.] C. [816] HCl salt is prepared in ethyl acetate: mp 286-288 [deg.] C. [817] Elemental analysis: C 28 H 31 N 5 · 2HCl · 0.5H 2 O [818] Calculated: C 64.73; H 6.60; N 13.65 [819] Found: C 64.55; H 6.42; N 13.41 [820] Example 13a [821] 1-yl] -cyclohexyl} -lH-indole-5-carbonitrile < / RTI > [822] (1.5 g, 5.6 mmol), l- (indol-4-yl) -cyclohexanone (1.5 g, A solution of piperazine (1.19 g, 5.9 mmol), sodium triacetoxyborohydride (1.73 g, 8.2 mmol) and acetic acid (0.9 ml, 15 mmol) is stirred at room temperature overnight. The reaction is quenched with 1N sodium hydroxide (10 ml), extracted with methylene chloride (3 x 80 ml) and then brine (3 x 80 ml). The organic layer is dried over anhydrous sodium sulfate and filtered. Chromatography (2.5% methanol-ethyl acetate) gave 0.98 g (39%) of the product as a white solid: mp 226 [deg.] C (decomposition). [823] HCl salt is prepared in ethyl acetate: mp 245 [deg.] C. [824] Elemental analysis: C 29 H 33 N 5 .2HCl. 0.25H 2 O [825] Calculated: C 65.84; H 6.76; N 13.24 [826] Found: C 65.97; H 6.74; N 13.40 [827] Example 13b [828] 1-yl] -cyclohexyl} -lH-indole-5-carbonitrile < / RTI > [829] The trans compound was isolated as a pale brown solid simultaneously with the cis isomer in 19% yield (0.48 g): mp decomposed at 110 < 0 > C. [830] HCl salt is prepared in ethyl acetate: mp 250 [deg.] C (decomposition). [831] Elemental analysis: C 29 H 33 N 5 .2 HCl [832] Calculated: C 66.40; H 6.73; N 13.35 [833] Found: C 66.32; H 6.67; N 13.10 [834] Example 14a [835] 1-yl] -cyclohexyl} -l-propyl-lH-indole-5-carbonitrile < / RTI > [836] (1.68 g, 6 mmol) and l- (indole-4-yl) -cyclohexanone (1.68 g, 6 mmol) in 1,2-dichloroethane A solution of piperazine (1.27 g, 6.3 mmol), sodium triacetoxyborohydride (1.84 g, 8.9 mmol) and acetic acid (0.94 ml, 16 mmol) is stirred overnight at room temperature. The reaction is quenched with 1 N sodium hydroxide (20 ml), extracted with methylene chloride (3 x 100 ml) and then brine (3 x 100 ml). The organic layer is dried over anhydrous sodium sulfate and filtered. Chromatography (10% methanol-ethyl acetate) afforded 0.42 g (15%) of the product as a white powder. [837] HCl salt is prepared in ethanol: mp 200-206 < 0 > C. [838] Elemental analysis: C 30 H 35 N 5 .2HCl. 0.75H 2 O [839] Calculated: C 65.27; H 7.03; N 12.69 [840] Found: C 65.18; H 6.97; N 12.68 [841] Example 14b [842] 1-yl] -cyclohexyl} -l-propyl-lH-indole-5-carbonitrile < / RTI > [843] The trans compound was isolated as a white foam simultaneously with the cis isomer in 14% yield (0.39 g). [844] HCl salt is prepared in ethanol: mp > 245 (decomposition). [845] Elemental analysis: C 30 H 35 N 5 .2HCl [846] Calculated: C 66.90; H 6.93; N 13.00 [847] Found: C 66.68; H 6.97; N 12.96 [848] Example 15a [849] 4-yl) -piperazin-l-yl] -cyclohexyl} -l-isopropyl-lH-indole-5-carbo Nitrile [850] (1.68 g, 6 mmol) and l- (indole-4-yl) -cyclohexanone (1.68 g, 6 mmol) in 1,2-dichloroethane A solution of piperazine (1.27 g, 6.3 mmol), sodium triacetoxyborohydride (1.84 g, 8.9 mmol) and acetic acid (0.94 ml, 16 mmol) is stirred overnight at room temperature. The reaction is quenched with 1 N sodium hydroxide (20 ml), extracted with methylene chloride (3 x 100 ml) and then brine (3 x 100 ml). The organic layer is dried over anhydrous sodium sulfate and filtered. Chromatography (10% methanol-ethyl acetate) afforded 0.49 g (18%) of the product as a white solid. [851] HCl salt is prepared in ethanol: mp 285-286 [deg.] C. [852] Elemental analysis: C 30 H 35 N 5 · HCl · 0.5H 2 O [853] Calculated: C 70.50; H 7.30; N 13.70 [854] Found: C 70.65; H 7.16; N 13.45 [855] Example 15b [856] 1-yl] -cyclohexyl} -l-isopropyl-lH-indole-5-carbo < / RTI > Nitrile [857] The trans compound was isolated as a white foam simultaneously with the cis isomer in 12% yield (0.34 g). [858] HCl salt is prepared in ethanol: mp > 245 DEG C (decomposition). [859] Elemental analysis: C 30 H 35 N 5 .HCl [860] Calculated: C 66.90; H 6.93; N 13.00 [861] Found: C 66.68; H 6.97; N 12.96 [862] Example 16a [863] 1-yl] -cyclohexyl} -lH-indole-5-carbonitrile < / RTI > [864] (2.97 g, 9 mmol), l- (indol-4-yl) -cyclohexanone (2.97 g, A solution of piperazine (1.94 g, 9.6 mmol), sodium triacetoxyborohydride (2.7 g, 13 mmol) and acetic acid (1 ml, 24 mmol) was stirred at room temperature overnight. The reaction is quenched with 1 N sodium hydroxide (20 ml), extracted with methylene chloride (3 x 100 ml) and then brine (3 x 100 ml). The organic layer is dried over anhydrous sodium sulfate and filtered. Chromatography (25-50% ethyl acetate-hexanes) afforded 1.71 g (37%) of the product as a white powder. [865] HCl salt is prepared in ethanol: mp > 245 DEG C (decomposition). [866] Elemental analysis: C 34 H 35 N 5 · HCl · 0.5H 2 O [867] Calculated: C 68.56; H 6.43; N 11.76 [868] Found: C 68.93; H 6.55; N 11.52 [869] Example 16b [870] 1-yl] -cyclohexyl} -lH-indole-5-carbonitrile < / RTI > [871] The trans compound was isolated as a white foam simultaneously with the cis isomer in 15% yield (0.68 g). [872] HCl salt is prepared in ethanol: mp > 240 [deg.] C (decomposition). [873] Elemental analysis: C 34 H 35 N 5 .2HCl. 0.25H 2 O [874] Calculated: C 69.08; H 6.40; N 11.85 [875] Found: C 69.09; H 6.17; N 11.80 [876] Example 17 [877] 1-yl] -piperazin-1-yl] -cyclohexyl} -1H-indole- 5-Carbonitrile [878] To a suspension of sodium hydride (60%, 95 mg, 2.4 mmol) in anhydrous N, N-dimethylformamide was added 3 - {(l, Yl) -piperazin-1-yl] -cyclohexyl} -1-methyl-1H-indole-5-carbonitrile (0.52 g, 1.2 mmol) The mixture is stirred at room temperature for 30 minutes. Iodomethane (0.17 g, 2.4 mmol) is then added to the reaction mixture. The mixture is stirred at room temperature for a further 30 minutes and then quenched with cold water. The mixture is extracted with methylene chloride (150 ml) and dried over anhydrous sodium sulfate. Chromatography (methanol-methylene chloride-ethyl acetate; 1: 1: 8) affords 0.53 g (99%) of the product as a pink foam. [879] HCl salt is prepared in ethanol: mp 252-255 [deg.] C. [880] Elemental analysis: C 29 H 33 N 5 .2 HCl [881] Calculated: C 66.40; H 6.73; N 13.35 [882] Found: C 66.64; H 6.82; N 13.21 [883] Example 18 [884] 5-Fluoro-3 - {(cis) -4- [4- (2-methoxy- phenyl) -piperazin- 1-yl] -cyclohexyl} [885] To a solution of 4- (5-fluoro-1-indol-3-yl) -cyclohexanone (0.35 g, 1.5 mmol), 1- (2-methoxy- phenyl) (0.29 g, 1.5 mmol), sodium triacetoxyborohydride (0.47 g, 2.1 mmol) and acetic acid (0.05 ml, 1.5 mmol) at room temperature for 12 hours. The reaction is quenched with 1 N sodium hydroxide (pH > 9) and extracted with methylene chloride (3 x 50 ml). The organic layer is dried over anhydrous sodium sulfate and filtered. Chromatography (10% methanol-ethyl acetate) afforded 0.34 g (56%) of the product as a white solid. [886] HCl salt is prepared in ethyl acetate: mp 170-172 < 0 > C. [887] Elemental analysis: C 25 H 30 FN 3 O.HCl [888] Calculated: C 66.95; H 7.08; N 9.37 [889] Found: C 66.93; H 7.08; N 9.29 [890] Example 19a [891] (4-methoxy-phenyl) -piperidin-l-yl] -cyclohexyl} -1H-indole [892] This compound was prepared as described above for Example 18 substituting 1- (2-methoxy-phenyl) piperazine for 1- (2-methoxy-phenyl) piperidine (1.0 g, 5.2 mmol) A yield of 63% yields 1.34 g of the product. [893] HCl salt is prepared in ethyl acetate: mp 245-250 < 0 > C. [894] Elemental analysis: C 26 H 31 FN 2 O.HCl 0.09 C 4 H 8 O 2 [895] Calculated: C 69.09; H 7.36; N 6.20 [896] Found: C 66.19; H 7.18; N 6.08 [897] Example 19b [898] 4-trans-4- [4- (2-methoxy-phenyl) -piperidin- l-yl] -cyclohexyl} -1H-indole [899] The trans compound was isolated simultaneously with the cis isomer in 20% yield (0.43 g). [900] HCl salt is prepared in ethyl acetate: mp 297-299 [deg.] C. [901] Elemental analysis: C 26 H 31 FN 2 O.HCl 0.08 C 4 H 8 O 2 [902] Calculated: C 70.49; H 7.28; N 6.32 [903] Found: C 70.17; H 7.30; N 6.10 [904] Example 20a [905] (4-methoxy-phenyl) -piperazin-l-yl] -cyclohexyl} -1H-indole [906] This compound is prepared by reacting 4- (5-fluoro-1-indol-3-yl) -cyclohexanone with 4- (5-methoxy- ) To give 1.18 g (55%) of the title compound as a white solid. [907] HCl salt is prepared in ethyl acetate: mp 198-199 < 0 > C. [908] Elemental analysis: C 26 H 33 N 3 O 2 .HCl [909] Calculated: C 68.48; H 7.52; N 9.21 [910] Found: C 68.31; H 7.54; N 9.08 [911] Example 20b [912] 1-yl] -cyclohexyl} -lH-indole < / RTI > < RTI ID = 0.0 & [913] The trans compound was isolated as a white foam simultaneously with the cis isomer in 20% yield (0.43 g). [914] HCl salt is prepared in ethyl acetate: mp 195-197 < 0 > C. [915] Elemental analysis: C 26 H 33 N 3 O 2 .HCl [916] Calculated: C 68.48; H 7.52; N 9.21 [917] Found: C 68.18; H 7.50; N 9.11 [918] Example 21 [919] LH-pyrrolo [2,3-b] pyridine hydrochloride The title compound, MS: m / e = [920] This compound was prepared by the same procedure for the synthesis of 4- (5-fluoro-lH-indol-3-yl) -cyclohexanone with 4- (lH- pyrrolo [2,3- b] g, 7.9 mmol) to give 42% yield (1.34 g) as a white solid, m.p. [921] HCl salt is prepared in ethanol: mp 259-261 [deg.] C. [922] Elemental analysis: C 24 H 30 ON 4揃 HCl [923] Calculated: C 65.44; H 7.44; N 12.72 [924] Found: C 65.60; H 7.36; N 12.22 [925] Example 22a [926] Fluoro-3 - {(cis) -4- [4- (5-fluoro-2-methoxy- phenyl) -piperazin- 1-yl] -cyclohexyl} [927] Cyclohexanone (1.1 g, 4.8 mmol), sodium triacetoxyborohydride (1.5 g, 4.8 mmol) in 1,2-dichloroethane (20 ml) 7.1 mmol) and acetic acid (0.27 ml, 4.7 mmol) in dichloromethane (10 ml) was stirred at room temperature for 12 hours. The reaction is quenched with 1 N sodium hydroxide (pH > 9) and extracted with methylene chloride (3 x 50 ml). The organic layer is dried over anhydrous sodium sulfate and filtered. Chromatography (10% methanol-ethyl acetate) gave 1.16 g (53%) of the product as a white solid: mp 152-153 [deg.] C. [928] HCl salt is prepared in ethyl acetate: mp 171-174 [deg.] C. [929] Elemental analysis: C 25 H 29 F 2 N 3 O · 2HCl [930] Calculated: C 59.17; H 6.36; N 8.28 [931] Found: C 59.20; H 6.33; N 8.09 [932] Example 22b [933] Fluoro-3 - {(trans) -4- [4- (5-fluoro-2-methoxy- phenyl) -piperazin- 1-yl] -cyclohexyl} -1H-indole [934] The trans compound was isolated as a white solid simultaneously with the cis isomer in 12% yield (0.25 g): mp 64-67 [deg.] C. [935] HCl salt is prepared in ethyl acetate: mp 272-273.5 [deg.] C. [936] Elemental analysis: C 25 H 29 F 2 ON 3 .HCl [937] Calculated: C 63.75; H 6.64; N 8.92 [938] Found: C 63.77; H 6.41; N 8.75 [939] Example 23a [940] Yl) -piperazin-1-yl] -cyclohexyl} - (3, 4-dihydro- 4-fluoro-lH-indole [941] To a solution of 4- (4-fluoro-1-indol-3-yl) -cyclohexanone (0.71 g, 3.1 mmol), 5- (1-piperazinyl) benzodioxane (0.77 g, 3.5 mmol), sodium triacetoxyborohydride (0.98 g, 4.6 mmol) and acetic acid (0.28 ml, 4.6 mmol) was stirred at room temperature for 12 hours. The reaction is quenched with 1N sodium hydroxide (100 ml) and extracted with methylene chloride (3 x 100 ml). The organic layer is dried over anhydrous sodium sulfate and filtered. Chromatography (1% methanol-ethyl acetate) gave 0.8 g (53%) of the product as a white foam which was dissolved in warm ethanol (15 ml) and crystallized to give a white solid: mp 194-195.5 [deg.] C. [942] HCl salt is prepared in ethanol: mp 215-220 [deg.] C. [943] Elemental analysis: C 26 H 30 FN 3 O 2 .HCl [944] Calculated: C 61.42; H 6.34; N 8.62 [945] Found: C 61.15; H 6.29; N 8.04 [946] Example 23b [947] Yl) -piperazin-1-yl] -cyclohexyl} - (2, 3-dihydro-benzo [ 4-fluoro-lH-indole [948] The trans compound was isolated as a white foam simultaneously with the cis isomer in 14% yield (0.21 g) which was recrystallized from ethanol to give a white solid: mp 188-190 [deg.] C. [949] Elemental analysis: C 26 H 30 FO 2 N 3 [950] Calculated: C 71.70; H 6.94; N 9.65 [951] Found: C 71.33; H 7.03; N 9.55 [952] Example 24a [953] Yl) -piperazin-1-yl] -cyclohexyl} - (3, 4-dihydro- 5-fluoro-lH-indole [954] To a solution of 4- (5-fluoro-1-indol-3-yl) -cyclohexanone (1.06 g, 4.6 mmol), 5- (1-piperazinyl) benzodioxane (1.14 g, 5.2 mmol), sodium triacetoxyborohydride (1.46 g, 6.9 mmol) and acetic acid (0.41 ml, 6.9 mmol) was stirred at room temperature for 12 hours. The reaction is quenched with saturated sodium bicarbonate (100 ml) and extracted with methylene chloride (3 x 100 ml). The organic layer is dried over anhydrous magnesium sulfate and filtered. Chromatography (1% methanol-ethyl acetate) affords 1.06 g (53%) of the product as an oil: mp 104-106 [deg.] C. [955] HCl salt is prepared in ethanol: mp 222-225 [deg.] C. [956] Elemental analysis: C 26 H 30 FN 3 O 2 .2HCl .0.2H 2 O [957] Calculated: C 60.88; H 6.39; N 8.19 [958] Found: C 60.85; H 6.03; N 8.13 [959] Example 24b [960] Yl) -piperazin-1-yl] -cyclohexyl} - (2, 3-dihydro-benzo [ 5-fluoro-lH-indole [961] The trans compound was isolated as a white solid simultaneously with the cis isomer in 27% yield (0.53 g): mp 206-210 [deg.] C. [962] HCl salt is prepared in ethanol: mp 295-297 [deg.] C. [963] Elemental analysis: C 26 H 30 FO 2 N 3 .2 HCl [964] Calculated: C 61.42; H 6.34; N 8.26 [965] Found: C 61.22; H 6.19; N 8.13 [966] Example 25a [967] Yl) -piperazin-1-yl] -cyclohexyl} - (3, 4-dihydro- 6-fluoro-lH-indole [968] To a solution of 4- (5-fluoro-1-indol-3-yl) -cyclohexanone (0.77 g, 3.0 mmol), 5- (1-piperazinyl) benzodioxane (0.78 g, 3.0 mmol) and sodium triacetoxyborohydride (0.2 g, 3.0 mmol) in DMF (5 mL) was stirred at room temperature for 48 h. The reaction was quenched with potassium hydroxide (0.4 g). The methanol is removed in vacuo and the residue is extracted with ethyl acetate (3 x 100 ml) and washed with water. The organic layer is dried over anhydrous magnesium sulfate and filtered. Chromatography (1% methanol-ethyl acetate) afforded 0.24 g (18%) of the product as a yellow solid. [969] HCl salt is prepared in ethanol: mp 228-230 < 0 > C. [970] Elemental analysis: C 26 H 30 FN 3 O 2 .2 HCl. 0.6 C 2 H 6 O [971] Calculated: C 61.37; H 6.38; N 8.22 [972] Found: C 61.19; H 6.32; N 8.29 [973] Example 25b [974] Yl) -piperazin-1-yl] -cyclohexyl} - (2, 3-dihydro-benzo [ 6-fluoro-lH-indole [975] The trans compound was isolated as an oil simultaneously with the cis isomer in 8% yield (0.11 g). [976] HCl salt is prepared in ethanol: mp 309-310 [deg.] C. [977] Elemental analysis: C 26 H 30 FO 2 N 3 .2 HCl 0.08 C 4 H 8 O 2 [978] Calculated: C 61.42; H 6.34; N 8.26 [979] Found: C 61.22; H 6.19; N 8.13 [980] Example 26a [981] Yl) -piperazin-1-yl] -cyclohexyl} - (3, 4-dihydro- 1H-indole-5-carbonitrile [982] To a solution of 4- (5-cyano-1-indol-3-yl) -cyclohexanone (0.60 g, 2.5 mmol), 5- (1-piperazinyl) benzodi A solution of oxane (0.55 g, 2.5 mmol), sodium triacetoxyborohydride (0.78 g, 3.5 mmol) and acetic acid (0.14 ml, 2.5 mmol) is stirred at room temperature for 12 hours. The reaction is quenched with 1N sodium hydroxide (100 ml) and extracted with methylene chloride (3 x 100 ml). The organic layer is dried over anhydrous magnesium sulfate and filtered. Chromatography (1% methanol-ethyl acetate) affords 0.46 g (41%) of the product. [983] HCl salt is prepared in ethyl acetate: mp 300 < 0 > C. [984] Elemental analysis: C 27 H 30 N 4 O 2 .HCl 0.07 C 4 H 8 O 2 [985] Calculated: C 65.84; H 6.65; N 11.38 [986] Found: C 65.65; H 6.47; N 11.11 [987] Example 26b [988] Yl) -piperazin-1-yl] -cyclohexyl} - (2, 3-dihydro-benzo [ 1H-indole-5-carbonitrile [989] The trans compound was isolated simultaneously with the cis isomer in 31% yield (0.34 g). [990] HCl salt is prepared in ethyl acetate: mp 300 [deg.] C (decomposition). [991] Elemental analysis: C 27 H 30 O 2 N 4 HCl 0.08 C 4 H 8 O 2 [992] Calculated: C 66.43; H 6.69; N 11.34 [993] Found: C 66.57; H 7.02; N 10.85 [994] Example 27a [995] Yl) -cyclohexyl] -piperazin-1-yl} - quinoline [996] To a solution of 4- (5-fluoro-1-indol-3-yl) -cyclohexanone (0.54 g, 2.3 mmol), 8- (piperazinyl- A solution of quinoline (0.5 g, 2.3 mmol), sodium triacetoxyborohydride (0.75 g, 3.5 mmol) and acetic acid (0.27 ml, 4.7 mmol) is stirred at room temperature overnight. The reaction is quenched with 1 N sodium hydroxide (20 ml), extracted with methylene chloride (3 x 100 ml) and then brine (3 x 100 ml). The organic layer is dried over anhydrous sodium sulfate and filtered. Chromatography (5% methanol-ethyl acetate) gave 0.46 g (46%) of the product as a white solid: mp 122-125 [deg.] C. [997] HCl salt is prepared in ethanol: mp 209-212 [deg.] C. [998] Elemental analysis: C 27 H 29 FN 4 .3HCl [999] Calculated: C 66.28; H 6.00; N 10.42 [1000] Found: C 60.23; H 6.29; N 10.21 [1001] Example 27b [1002] Yl) -cyclohexyl] -piperazin-1-yl} - quinoline [1003] The trans compound was isolated as a white solid simultaneously with the cis isomer in 25% yield (0.25 g): mp 207.5-209 [deg.] C. [1004] HCl salt is prepared in ethanol: mp 286-288 [deg.] C. [1005] Elemental analysis: C 27 H 29 FN 4 .HCl [1006] Calculated: C 64.67; H 6.23; N 11.17 [1007] Found: C 64.74; H 6.27; N 11.06 [1008] Example 28 [1009] Yl) -cyclohexyl] -piperazin-1-yl} - (4-fluoro- Quinoline [1010] To a suspension of sodium hydride (60%, 0.03 g, 0.76 mmol) in anhydrous N, N-dimethylformamide (4 ml) was added a solution of 8- {4 - [(1,4 1-yl} -quinoline (0.25 g, 0.58 mmol) at room temperature. The mixture is stirred at room temperature for 30 minutes and then iodomethane (0.044 ml, 0.7 mmol) is added to the solution. The resulting mixture is stirred at room temperature for 30 minutes and then quenched with water. The mixture is extracted with ethyl acetate and the organic layer is dried over anhydrous sodium sulfate. The solvent is removed under vacuum. Chromatography (50% methylene-ethyl acetate + 5% methanol) gave 0.22 g (85%) of the product as a yellow solid: mp> 200 [deg.] C. [1011] HCl salt is prepared in ethanol: mp 261-263.5 [deg.] C. [1012] Elemental analysis: C 28 H 31 FN 4 · 2HCl · H 2 O [1013] Calculated: C 63.03; H 6.61; N 10.50 [1014] Found: C 63.39; H 6.43; N 10.21 [1015] Example 29a [1016] 4 - (4-quinolin-8-yl-piperazin-1-yl) -cyclohexyl] -lH-indole-5-carbonitrile [1017] Cyclohexanone (1.47 g, 6.2 mmol), 8- (piperazin-1-yl) - cyclohexanone (1.47 g, 6.2 mmol) in 1,2- dichloroethane (40 ml) A solution of quinoline (1.32 g, 6.2 mmol), sodium triacetoxyborohydride (2.0 g, 7.2 mmol) and acetic acid (0.71 ml, 12 mmol) is stirred at room temperature overnight. The reaction is quenched with 1 N sodium hydroxide (20 ml), extracted with methylene chloride (3 x 100 ml) and then brine (3 x 100 ml). The organic layer is dried over anhydrous sodium sulfate and filtered. Chromatography (5% methanol-ethyl acetate) gave 1.48 g (55%) of the product as a white solid: mp 149-151 [deg.] C. [1018] HCl salt is prepared in ethanol: mp 209-212 [deg.] C. [1019] Elemental analysis: C 27 H 29 FN 4揃 2HCl 揃 0.75 H 2 O [1020] Calculated: C 64.43; H 6.28; N 13.58 [1021] Found: C 64.46; H 6.29; N 13.37 [1022] Example 29b [1023] 3 - [(1,4-trans) -4- (4-quinolin-8-yl-piperazin- 1 -yl) -cyclohexyl] -lH-indole- [1024] The trans compound was isolated simultaneously with the cis isomer in 26% yield (0.55 g) as a white solid: mp 276-278 [deg.] C. [1025] HCl salt is prepared in ethanol: mp 286-288 [deg.] C. [1026] Elemental analysis: C 27 H 29 FN 4揃 2HCl 揃 0.5H 2 O [1027] Calculated: C 64.98; H 6.23; N 13.53 [1028] Found: C 65.28; H 5.96; N 13.30 [1029] Example 30 [1030] 1-methyl-3 - [(1,4-cis) -4- (4-quinolin-8-yl-piperazin- 1 -yl) -cyclohexyl] -lH- indole-5-carbonitrile [1031] To a suspension of sodium hydride (60%, 0.06 g, 1.4 mmol) in anhydrous N, N-dimethylformamide (8 ml) was added a solution of 3 - [(l, 4-cis) Yl) -piperazin-l-yl) -cyclohexyl] -lH-indole-5-carbonitrile (0.30 g, 0.69 mmol) at room temperature. The mixture is stirred at room temperature for 30 minutes and then iodomethane (0.051 ml, 0.83 mmol) is added to the solution. The resulting mixture is stirred at room temperature for 30 minutes and then quenched with water. The mixture is extracted with ethyl acetate, dried over anhydrous sodium sulfate and the solvent is removed in vacuo. Chromatography (50% methylene-ethyl acetate + 5% methanol) gave 0.27 g (90%) of the product as a pale yellow solid: mp 208-209 [deg.] C. [1032] HCl salt is prepared in ethanol: mp 288-289 [deg.] C. [1033] Elemental analysis: C 29 H 31 N 5 .2 HCl. 0.15 C 4 H 10 O [1034] Calculated: C 66.62; H 6.52; N 13.12 [1035] Found: C 66.79; H 6.74; N 12.81 [1036] Example 31a [1037] Yl) -piperazin-l-yl] -cyclohexyl} -1H-indole < / RTI > [1038] To a solution of 4- (5-fluoro-1-indol-3-yl) -cyclohexanone (0.49 g, 2.1 mmol), 4- (6-fluoro- (0.5 g, 2.1 mmol), sodium triacetoxyborohydride (0.67 g, 3.2 mmol) and acetic acid (0.24 ml, 4.2 mmol) in dichloromethane at room temperature overnight. The reaction is quenched with 1 N sodium hydroxide (20 ml), extracted with methylene chloride (3 x 100 ml) and then brine (3 x 100 ml). The organic layer is dried over anhydrous sodium sulfate and filtered. Chromatography (5% methanol-ethyl acetate) afforded 0.42 g (44%) of the product as a white foam. [1039] HCl salt is prepared in ethanol: mp 199-200. [1040] Elemental analysis: C 27 H 31 F 2 ON 3 · HCl · 0.5H 2 O [1041] Calculated: C 65.25; H 6.69; N 8.45 [1042] Found: C 65.04; H 6.61; N 8.29 [1043] Example 31b [1044] Yl) -piperazin-l-yl] -cyclohexyl} -lH-indole < / RTI > [1045] The trans compound was isolated as a clear oil simultaneously with the cis isomer in 35% yield (0.33 g). [1046] HCl salt is prepared in ethanol: mp 286-288 [deg.] C. [1047] Elemental analysis: C 27 H 31 F 2 ON 3 · HCl · 0.5H 2 O [1048] Calculated: C 65.25; H 6.69; N 8.45 [1049] Found: C 65.09; H 6.63; N 8.29 [1050] Example 32a [1051] Yl) -piperazin-1-yl] - (4-fluoro-benzyl) -piperazin-1- Cyclohexyl} -1H-indole < / RTI > [1052] (0.52 g, 2.2 mmol), 4- (5-fluoro-2,3-dihydro-indol- (0.5 g, 2.2 mmol), sodium triacetoxyborohydride (0.72 g, 3.4 mmol) and acetic acid (0.26 ml, 4.5 mmol) in anhydrous tetrahydrofuran Lt; / RTI > The reaction is quenched with 1 N sodium hydroxide (20 ml), extracted with methylene chloride (3 x 100 ml) and then brine (3 x 100 ml). The organic layer is dried over anhydrous sodium sulfate and filtered. Chromatography (5% methanol-ethyl acetate) afforded 0.37 g (38%) of the product as a white solid: mp 182-183.5 [deg.] C. [1053] HCl salt is prepared in ethanol: mp 196-198 [deg.] C. [1054] Elemental analysis: C 26 H 29 F 2 ON 3揃 HCl 揃 0.5H 2 O [1055] Calculated: C 64.65; H 6.47; N 8.70 [1056] Found: C 64.45; H 6.20; N 8.60 [1057] Example 32b [1058] Yl) -piperazin-1-yl] - (4-fluoro-benzyl) Cyclohexyl} -1H-indole < / RTI > [1059] The trans compound was isolated as a clear oil simultaneously with the cis isomer in 34% yield (0.34 g). [1060] HCl salt is prepared in ethanol: mp 303-305 [deg.] C. [1061] Elemental analysis: C 26 H 29 F 2 ON 3揃 HCl 揃 0.5H 2 O [1062] Calculated: C 64.65; H 6.47; N 8.70 [1063] Found: C 64.86; H 6.40; N 8.36 [1064] Example 33a [1065] Yl) -piperazin-l-yl] -cyclohexyl} - lH- (l, 4-dihydro- - indole-5-carbonitrile [1066] To a solution of 4- (5-cyano-1-indol-3-yl) -cyclohexanone (0.46 g, 1.9 mmol), 4- (5- (0.43 g, 1.9 mmol), sodium triacetoxyborohydride (0.62 g, 2.9 mmol) and acetic acid (0.22 ml, 3.9 mmol) in dichloromethane Stir overnight. The reaction is quenched with 1 N sodium hydroxide (20 ml), extracted with methylene chloride (3 x 100 ml) and then brine (3 x 100 ml). The organic layer is dried over anhydrous sodium sulfate and filtered. Chromatography (5% methanol-ethyl acetate) afforded 0.35 g (41%) of the product as a white foam. [1067] HCl salt is prepared in ethanol: mp 298-301 [deg.] C. [1068] Elemental analysis: C 27 H 29 FON 4 HCl 0.75 H 2 O [1069] Calculated: C 65.58; H 6.42; N 11.33 [1070] Found: C 65.38; H 6.22; N 11.14 [1071] Example 33b [1072] Yl) -piperazin-l-yl] -cyclohexyl} - lH-pyrrolo [2,3-d] pyrimidin- - indole-5-carbonitrile [1073] The trans compound was isolated as a white foam simultaneously with the cis isomer in 23% yield (0.20 g). [1074] HCl salt is prepared in ethanol: mp 330-331 [deg.] C. [1075] Elemental analysis: C 27 H 29 FON 4 HCl 0.75 H 2 O [1076] Calculated: C 65.58; H 6.42; N 11.33 [1077] Found: C 65.17; H 6.14; N 10.97 [1078] Example 33c [1079] Yl) -piperazin-1-yl] -cyclohexyl] -1- (4-fluoro-benzyloxy) Methyl-lH-indole-5-carbonitrile < / RTI > [1080] To a suspension of sodium hydride (60%, 0.036 g, 0.9 mmol) in anhydrous N, N-dimethylformamide (2 ml) was added a solution of 3 - {(1,4- cis) Yl] -cyclohexyl} -lH-indole-5-carbonitrile (0.2 g, 0.10 mmol) was added to a stirred solution of 4-fluoro-2- , 0.45 mmol) at room temperature. The mixture is stirred at room temperature for 30 minutes and then iodomethane (0.034 ml, 0.54 mmol) is added to the solution. The resulting mixture is stirred at room temperature for 30 minutes and then quenched with water. The mixture is extracted with ethyl acetate and the organic layer is dried over anhydrous sodium sulfate. The solvent is removed under vacuum. Chromatography (5% methanol-ethyl acetate) afforded 0.18 g (87%) of the product as a white solid: mp 207-208 [deg.] C. [1081] HCl salt is prepared in ethanol: mp 282-284 [deg.] C. [1082] Elemental analysis: C 28 H 31 FON 4 .HCl [1083] Calculated: C 67.94; H 6.52; N 11.32 [1084] Found: C 67.61; H 6.39; N 10.98 [1085] Example 34a [1086] 1 - [(1,4-cis) -4- [4- (benzofuran-7-yl-piperazin- 1 -yl) -cyclohexyl] -lH- indole-5-carbonitrile [1087] To a solution of 4- (5-fluoro-1-indol-3-yl) -cyclohexanone (0.72 g, 3.1 mmol), 1- (7-benzofuranyl) 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 dichloromethane The reaction is quenched with 0.5N sodium hydroxide (100 ml) and extracted with methylene chloride (2 x 100 ml). The organic layer is dried over anhydrous magnesium sulfate and filtered. The solvent appears and crystals appear after 1 hour. The crystals were triturated with ethyl ether (80 ml) to yield 0.47 g (35%) of the product as a white solid: mp 158-159 [deg.] C. [1088] HCl salt is prepared in ethanol: mp 295-296 [deg.] C. [1089] Elemental analysis: C 27 H 28 ON 4揃 HCl 揃 0.25H 2 O [1090] Calculated: C 69.66; H 6.39; N 12.04 [1091] Found: C 69.56; H 6.38; N 12.12 [1092] Example 34b [1093] 3 - [(1,4-trans) -4- [4- (benzofuran-7-yl-piperazin- 1 -yl) -cyclohexyl] -lH- indole-5-carbonitrile [1094] The residue of the reaction was purified by chromatography (acetone-methanol-hexane: 3: 5: 3) to give 0.17 g (12%) of the product as a glassy substance. [1095] HCl salt is prepared in ethanol: mp 330-331 [deg.] C. [1096] Elemental analysis: C 27 H 28 FON 4 .HCl 0.75 H 2 O [1097] Calculated: C 65.58; H 6.42; N 11.33 [1098] Found: C 65.17; H 6.14; N 10.97 [1099] Example 35 [1100] 5-Fluoro-3- {4- [4- (2-methoxy-phenyl) -piperazin- 1 -yl] cyclohex- 1-enyl} -1H-indole [1101] This compound was prepared by the same procedure as described for 4- (5-fluoro-lH-indol-3-yl) -cyclohexanone (1.71 g, 7.9 mmol) 3-enone, which was prepared as described above for Example 18 and was obtained in 32% (0.26 g) yield. [1102] HCl salt is prepared in ethyl acetate: mp 250 [deg.] C. [1103] Elemental analysis: C 25 H 28 OFN 3 .HCl [1104] Calculated: C 67.94; H 6.61; N 9.51 [1105] Found: C 66.47; H 6.58; N 9.38 [1106] Example 36 [1107] 1-yl] cyclohex- 1-enyl} -lH-indole-5-carbonitrile < / RTI > [1108] The present compound is prepared by reacting 4- (5-fluoro-lH-3-indolyl) -cyclohex-3-enone with 4- (5-cyano- g, 2.96 mmol) to give the title compound in 62% yield (0.78 g). [1109] HCl salt is prepared in ethyl acetate: mp 199-201 [deg.] C. [1110] Elemental analysis: C 27 H 27 N 5 .2HCl [1111] Calculated: C 66.25; H 6.49; N 14.31 [1112] Found: C 66.43; H 6.24; N 14.27 [1113] Example 38 [1114] 5- Fluoro-3- {cis-4- [4- (lH-indol-4-yl) -piperazinyl] -cyclohexyl} -l-methyl- lH- indole [1115] This compound is prepared by reacting 4- (5-fluoro-1H-3-indolyl) -cyclohexane with 4- (5-fluoro- Prepared according to the procedure described above for Example 2, substituting to give 34% (0.24 g) as a clear oil. [1116] HCl salt is prepared in ethanol: mp 247-249 [deg.] C. [1117] Elemental analysis: C 27 H 31 FN 4揃 2HCl 揃 0.25H 2 O [1118] Calculated: C 63.84; H 6.65; N 11.03 [1119] Found: C 63.88; H 6.51; N 10.77 [1120] Example 39a [1121] 1-yl] -cyclohexyl} -l-methyl-lH-indole-5-carbonitrile < / RTI > [1122] (443 mg, 1.87 mmol), Intermediate 34 (400 mg, 1.87 mmol) and acetic acid (0.22 ml, 3.7 mmol) in dichloroethane (50 ml) mmol), and sodium triacetoxyborohydride (590 mg, 2.8 mmol) in dichloromethane at room temperature overnight. The reaction is quenched with 1 M NaOH (100 ml) and extracted with CH 2 Cl 2 (3 x 100 ml). The organic fractions are combined, dried over Na 2 SO 4 and filtered. The resulting oil was purified by column chromatography (5% MeOH / EtOAc) to give 130 mg (16%) of the product as a yellow solid: mp 223-225 [deg.] C. [1123] Elemental analysis: C 27 H 28 N 6 .1H 2 O [1124] Calculated: C 71.34; H 6.65; N 18.49 [1125] Found: C 71.02; H 6.33; N 18.03 [1126] Example 39b [1127] 1-yl] -cyclohexyl} -l-methyl-lH-indole-5-carbonitrile < / RTI > [1128] The trans isomers are separated simultaneously with the cis isomer to give 240 mg (29%) of light yellow solid: mp 257-259 [deg.] C. [1129] Elemental analysis: C 27 H 28 N 6 .1H 2 O [1130] Calculated: C 71.34; H 6.65; N 18.49 [1131] Found: C 71.63; H 6.38; N 18.39 [1132] Example 40a [1133] 3 - [(1,4-cis) -4- (4-quinolin-5-yl-piperazin- 1 -yl) -cyclohexyl] -lH-indole- [1134] (500 mg, 2.35 mmol) and 4- (5-cyano-lH-3-indolyl) -cyclohexanone (540 mg, 2.35 mmol) in dichloroethane (20 ml) mmol), and sodium triacetoxyborohydride (740 mg, 3.5 mmol) in dichloromethane (10 ml) was added acetic acid (0.27 ml, 34.7 mmol) and the mixture was stirred overnight at room temperature. The reaction is quenched with 1 M NaOH (50 ml) and extracted into CH 2 Cl 2 (3 x 100 ml). The organic fractions were combined, dried over Na 2 SO 4 , concentrated, filtered and chromatographed (5% MeOH / EtOAc) to give 410 mg (41%) of cis isomer as a white solid. HCl salt from EtOAc to give a white solid: mp 220-223 [deg.] C. [1135] Elemental analysis: C 28 H 29 N 5 · HCl · 1H 2 O [1136] Calculated: C 68.62; H 6.58; N 14.29 [1137] Found: C 68.99; H 6.54; N 14.06 [1138] Example 40b [1139] 3 - [(1,4-trans) -4- (4-quinolin-5-yl) -piperazin- 1 -yl) -cyclohexyl] -lH-indole- [1140] The trans isomer is isolated simultaneously with the cis isomer in example 40a to give 180 mg (18%) as a beige solid. HCl salt was generated from EtOAc to give a white solid: mp 210-211 [deg.] C. [1141] Elemental analysis: C 28 H 29 N 5 .HCl .0.4H 2 O [1142] Calculated: C 70.17; H 6.48; N 14.62 [1143] Found: C 70.23; H 6.21; N 14.45 [1144] Example 40c [1145] Yl) -cyclohexyl] -piperazin-1-yl} - quinolin-2-one [1146] This compound was prepared by reacting 4- (5-cyano-1H-3-indolyl) -cyclohexanone with 4- (5-fluoro-1H-3-indolyl) -cyclohexanone (540 mg, 2.35 mmol) Was prepared in the same manner as in the compound of Example 40a to give 410 mg (41%) of a pale yellow solid: mp 220-223 [deg.] C; MS (+) ESI m / e 429 [M + H] < + >. [1147] Example 40d [1148] Yl) -cyclohexyl] -piperazin-1-yl} -isoquinoline < / RTI > [1149] The trans isomer was isolated in the same manner as the cis isomer of Example 40c to give 180 mg (18%) as a white solid: mp 210-211 [deg.] C; MS (+) ESI m / e 429 [M + H] < + & gt ; . [1150] Example 40e [1151] Yl) -cyclohexyl] -piperazin-1-yl} - quinoline (prepared according to the procedure described for the synthesis of 5- (4-fluoro- [1152] To a solution of NaH (38 mg, 0.94 mmol) in anhydrous DMF (4 ml) under nitrogen atmosphere was added 5- {4 - [(l, 4-cis) -4- (5- - indol-3-yl) -cyclohexyl] -piperazin-1-yl} -quinoline (200 mg, 0.47 mmol). The mixture is stirred at room temperature for 0.5 h, after which MeI (0.035 ml, 0.56 mmol) is added via syringe. The reaction mixture is stirred for an additional 0.5 h, then quenched with H 2 O (50 ml) and extracted with EtOAc (3 x 50 ml). The organic fractions were combined, dried over Na 2 SO 4 and concentrated to give 190 mg (92%) of a clear oil. HCl was prepared from EtOAc to give a light yellow solid: mp > 270 DEG C (decomposition). [1153] C 28 H 31 FN 4揃 HCl 揃 0.75 H 2 O [1154] Calculated: C 68.28; H 6.86; N 11.37 [1155] Found: C 68.34; H 6.56; N 11.26 [1156] Example 41a [1157] 1-yl-piperazin-l-yl) -cyclohexyl] -lH-indole < / RTI > [1158] This compound was prepared by reacting 4- (5-cyano-1H-3-indolyl) -cyclohexanone with 4- (5-fluoro-1H-3-indolyl) -cyclohexanone (437 mg, 1.9 mmol) And 4- (1-piperazinyl) -quinoline was replaced with 1- (1-naphthyl) piperazine (410 mg, 1.9 mmol) to give 240 mg of the product as a white solid (29%): mp 195-197 < 0 > C. [1159] Elemental analysis: C 28 H 30 FN 3 [1160] Calculated: C 78.66; H 7.07; N 9.83 [1161] Found: C 78.24; H 7.06; N 9.59 [1162] Example 41b [1163] 1-yl-piperazin-l-yl) -cyclohexyl] -lH-indole < / RTI > [1164] The trans isomer is separated at the same time as the cis isomer of Example 41a to give 70 mg (9%) of a white solid: mp 179-181 [deg.] C. [1165] Elemental analysis: C 28 H 30 FN 3 [1166] Calculated: C 78.66; H 7.07; N 9.83 [1167] Found: C 78.28; H 7.05; N 9.79 [1168] Example 42a [1169] Yl) -cyclohexyl] -piperazin-1-yl} - isoquinoline The title compound was prepared from 5- {4 - [(1,4- [1170] This compound was prepared by replacing 5- (trifluoromethylsulfonyloxy) -quinoline with 5- (trifluoromethylsulfonyloxy) -isoquinoline (12 g, 43.3 mmol) to give the compound of Example 36a To obtain an indivisible mixture of the desired product and the impurity. The mixture is treated with TFA (10 ml), MeOH (10 drops), and CH 2 Cl 2 (20 ml) at 0 ° C and warmed to room temperature overnight. The resulting solution is concentrated, redissolved in CH 2 Cl 2 and neutralized with NaHCO 3 . The aqueous layer was extracted into CH 2 Cl 2 (3 x 100 ml) and EtOAc (3 x 100 ml), dried over Na 2 SO 4, filtered and concentrated to give a pale orange oil. The oil was purified twice by column chromatography (10% MeOH / CH 2 Cl 2 / NH 4 OH) but still highly colored impurities persisted. (450 mg, 2.1 mmol), 4- (5-fluoro-1H-3-indolyl) -cyclohexanone (485 mg, 2.1 mmol) and sodium triacetoxy (672 mg, 3.2 mmol) is dissolved in dichloroethane (30 ml). Acetic acid (0.25 ml, 4.2 mmol) is added and the resulting solution is stirred overnight at ambient temperature. The reaction mixture is quenched with 1 M NaOH (40 ml) and extracted into CH 2 Cl 2 (4 x 100 ml). The organic fractions were combined and dried over Na 2 SO 4 and concentrated to give a yellow oil which was purified by column chromatography (5% MeOH / EtOAc) to give 300 mg of the title compound as a beige solid (5- (1-piperazinyl ) ≪ / RTI > isoquinoline: mp 209-211 [deg.] C. [1171] Elemental analysis: C 27 H 29 FN 4 [1172] Calculated: C 75.67; H 6.82; N 13.07 [1173] Found: C 75.40; H 6.83; N 12.89 [1174] Example 42b [1175] Yl) -cyclohexyl] -piperazin-1-yl} -isoquinoline < / RTI > [1176] The trans isomer is separated at the same time as the cis isomer of Example 42a to give 110 mg (12%) of a pink solid: mp 218-221 [deg.] C. [1177] Elemental analysis: C 27 H 29 FN 4 .0.25 H 2 O [1178] Calculated: C 74.89; H 6.87; N 12.94 [1179] Found: C 74.79; H 6.79; N 12.85 [1180] Example 43a [1181] L- {4 - [(1,4-cis) -4- (5-fluoro-lH-indol-3- yl) -cyclohexyl] -piperazin- 1-yl] -isoquinoline [1182] This compound was prepared by reacting 4- (5-cyano-1H-3-indolyl) -cyclohexanone with 4- (5-fluoro-lH-3-indolyl) -cyclohexanone (530 mg, And substituting 5- (1-piperazinyl) -quinoline for 1- (1-piperazinyl) -isoquinoline (500 mg, 2.3 mmol) to give the product as a pale yellow solid 260 mg (27%) is obtained: mp 180-183 [deg.] C. [1183] Elemental analysis: C 27 H 29 FN 4 .0.5H 2 O [1184] Calculated: C 74.11; H 6.91; N 12.81 [1185] Found: C 74.13; H 6.58; N 12.60 [1186] Example 43b [1187] L- {4 - [(1,4-trans) -4- (5-fluoro-lH-indol-3- yl) -cyclohexyl] -piperazin- 1-yl] -isoquinoline [1188] The trans isomers were separated simultaneously with the cis isomer of Example 43a to give 180 mg (18%) of a white solid: mp 232-235 [deg.] C. [1189] Elemental analysis: C 27 H 29 FN 4 .0.25 H 2 O [1190] Calculated: C 74.89; H 6.87; N 12.94 [1191] Found: C 74.68; H 6.88; N 12.64 [1192] Example 43c [1193] L- {4 - [(1,4-cis) -4- (5-cyano-lH-indol-3- yl) -cyclohexyl] -piperazin- 1-yl] -isoquinoline [1194] This compound was prepared in the same manner as the compound of Example 40a, substituting 5- (1-piperazinyl) -quinoline with 1- (1-piperazinyl) -isoquinoline (500 mg, 2.3 mmol) To give 230 mg (23%) of the product: mp 107-109 [deg.] C; HRMS EI m / e 435.2431 (M + ). [1195] Example 43d [1196] L- {4 - [(1,4-trans) -4- (5-cyano-lH-indol-3- yl) -cyclohexyl] -piperazin- 1-yl] -isoquinoline [1197] The trans isomers were separated simultaneously with the cis isomer of Example 43c to give 170 mg (17%) of a white solid: mp 252-255 [deg.] C; MS (+) APCI m / e 436 (M + H) < + & gt ; . [1198] Example 44a [1199] - (l, 4-cis) -4- [4- (5-fluoro-lH-indol-3- yl) -cyclohexyl] -piperazin- 1 -yl] -6- methoxy-quinoline [1200] 0.25 g of 4- (5-fluoro-1H-3-indolyl) -cyclohexanone was added to a solution of 6-methoxy, 8-piperazino-quinoline 0.360 g in 10 ml of CH 2 Cl 2 , 0.625 g of cetoxyborohydride and 0.09 ml of acetic acid are added. The reaction is stirred overnight at room temperature. It is quenched with 1N NaOH and the product is extracted with CH 2 Cl 2 . The organic phase is washed with water and dried over magnesium sulphate. 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 yield 0.053 g of the desired product: mp 226-227 [deg.] C; MS (ES) m / z (relative intensity): 459 (M + H < + >, 100). [1201] Example 44b [1202] Yl) -6-methoxy-quinolin-1-yl] - (4-fluoro-4- [1203] Example 44a The trans isomer of the compound is isolated simultaneously with the cis isomer as an off-white solid (0.013 g): mp 207-215 [deg.] C. MS (ES) m / z (relative intensity): 459 (M + H < + >, 100). [1204] Example 44c [1205] - (l, 4-cis) -4- [4- (6-methoxy-quinolin-8-yl) -piperazin- l-yl] -cyclohexyl} -lH- indole-5-carbonitrile [1206] 0.979 g of 3- (4-oxo-cyclohexyl) -1H-indole-5-carbonitrile was added to a solution of 6-methoxy, 8-piperazino-quinoline 1.0 g in 20 ml of CH 2 Cl 2 , 1.3 g of cetoxyborohydride and 0.246 ml of acetic acid are added. The reaction is stirred overnight at room temperature. It is quenched with 1N NaOH and the product is extracted with CH 2 Cl 2 . The organic phase is washed with water and dried over magnesium sulphate. The product was filtered through 300 ml of silica gel using 2.5% MeOH / CH 2 Cl 2 to give 0.550 g of the desired product: mp 183-185 ° C; MS (ES) m / z (relative intensity): 466 (M + H < + >, 100). Hydrochloride was also prepared to give a yellow solid: mp 183-185 [deg.] C. [1207] Example 44d [1208] 1-yl] -cyclohexyl} -lH-indole-5-carbonitrile < / RTI > [1209] The trans isomer of Example 44c is isolated simultaneously with the cis isomer as an off-white solid (0.170 g): mp 148-152 [deg.] C. MS (ES) m / z (relative intensity): 466 (M + H < + >, 100). Maleate salt to give an off-white solid (0.129 g): mp 160-165 < 0 > C. [1210] Example 45a [1211] (4-fluoro-lH-indol-3-yl) -cyclohexyl] -piperazin-1-yl} - quinoline [1212] 0.266 g of 4- (5-fluoro-lH-indolyl) -cyclohexanone was added to a solution of 6-chloro, 8-piperazino-quinoline 0.200 g in 10 ml of CH 2 Cl 2 and then sodium triacetoxyborane 0.430 g of hydride and 0.09 ml of acetic acid are added. The reaction is stirred overnight at room temperature. It is quenched with 1N NaOH and the product is extracted with CH 2 Cl 2 . The organic phase is washed with water and dried over magnesium sulphate. The product was filtered through 75 ml of silica gel using 50% ethyl acetate / hexanes followed by 75% ethyl acetate / hexanes to yield 0.119 g of the desired product: mp 166-176 [deg.] C; MS (ES) m / z (relative intensity): 464 (M + H < + >, 100). [1213] Elemental analysis: C 27 H 28 ClFN 4 [1214] Calculated: C 70.04; H 6.1; N 12.1 [1215] Found: C 70.07; H 6.33; N 11.87 [1216] Example 45b [1217] (4-fluoro-lH-indol-3-yl) -cyclohexyl] -piperazin-1-yl} - quinoline [1218] Example 45a The trans isomer of the compound is isolated simultaneously with the cis isomer as an off-white solid (0.026 g): mp 209-210 [deg.] C. MS (ES) m / z (relative intensity): 464 (M + H < + >, 100). [1219] Elemental analysis: C 27 H 28 ClFN 4 [1220] Calculated: C 70.04; H 6.1; N 12.1 [1221] Found: C 70.23; H 6.33; N 11.94 [1222] Example 45c [1223] - (l, 4-cis) -4- [4- (6-chloro-quinolin-8-yl) -piperazin- 1- yl] -cyclohexyl} -lH- indole- [1224] 0.240 g of 3- (4-oxo-cyclohexyl) -1H-indole-5-carbonitrile was added to a solution of 0.250 g of 6-chloro, 8-piperazino-quinoline in 10 ml of CH 2 Cl 2 , 0.532 g of sodium hydride and 0.09 ml of acetic acid are added. The reaction is stirred overnight at room temperature. It is quenched with 1N NaOH and the product is extracted with ether. The organic phase is washed with water and dried. The product was filtered through 75 ml of silica gel using 25% ethyl acetate / hexanes followed by 75% ethyl acetate / hexanes to yield 0.123 g of the desired product: mp 152-160 [deg.] C; MS (ES) m / z (relative intensity): 471 (M + H < + >, 100). [1225] Example 45d [1226] - (l, 4-trans) -4- [4- (6-chloro-quinolin-8-yl) -piperazin- l-yl] -cyclohexyl} -lH- indole- [1227] Example 45c The trans isomer of the compound is isolated simultaneously with the cis isomer as an off-white solid (0.032 g): mp 144-152 [deg.] C. MS (ES) m / z (relative intensity): 471 (M + H < + >, 100). [1228] Example 46a [1229] (4-fluoro-lH-indol-3-yl) -cyclohexyl] -piperazin-1-yl} - quinoline [1230] To a solution of 0.250 g of 5-chloro, 8-piperazino-quinoline in 10 ml of CH 2 Cl 2 was added 0.200 g of 4- (5-fluoro-1H-3-indolyl) -cyclohexanone followed by sodium triacetoxy 0.533 g of sodium hydride and 0.09 ml of acetic acid are added thereto. The reaction is stirred overnight at room temperature. It is quenched with 1N NaOH and the product is extracted with ether. The organic phase is washed with water and dried over magnesium sulphate. The product was filtered through 75 ml of silica gel using 25% ethyl acetate / hexanes followed by 75% ethyl acetate / hexanes to afford 0.074 g of the desired product: mp 101-104 [deg.] C; MS (ES) m / z (relative intensity): 464 (M + H < + >, 100). [1231] Example 46b [1232] - (l, 4-cis) -4- [4- (5-chloro-quinolin-8-yl) -piperazin- l-yl] -cyclohexyl} -lH- indole-5-carbonitrile [1233] To a solution of 0.300 g of 5-chloro, 8-piperazino-quinoline in 10 ml of CH 2 Cl 2 was added 0.230 g of 3- (4-oxo-cyclohexyl) -1H-indole- 0.550 g of the Lohaiide and 0.09 ml of acetic acid are added. The reaction is stirred overnight at room temperature. It is quenched with 1N NaOH and the product is extracted with CH 2 Cl 2 . The organic phase is washed with water and dried over magnesium sulphate. 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 yield 0.051 g of the desired product: mp 135-144 [deg.] C; MS (ES) m / z (relative intensity): 471 (M + H < + >, 100). [1234] Example 47a [1235] - (4-fluoro-lH-indol-3-yl) -cyclohexyl] -piperazin-1-yl} - quinoline [1236] 0.230 g of 4- (6-fluoro-1H-3-indolyl) -cyclohexanone was added to a solution of 5-fluoro, 8-piperazino-quinoline 0.231 g in 10 ml of CH 2 Cl 2 , 0.530 g of cetoxyborohydride and 0.09 ml of acetic acid are added. The reaction is stirred overnight at room temperature. It is quenched with 1N NaOH and the product is extracted with CH 2 Cl 2 . The organic phase is washed with water and dried over magnesium sulphate. The product was filtered through 100 ml of silica gel using 50% ethyl acetate / hexanes, 100% ethyl acetate then 6% MeOH / ethyl acetate to yield 0.049 g of the desired product: mp 172-174 [deg.] C; MS (ES) m / z (relative intensity): 447 (M + H < + >, 100). [1237] Example 47b [1238] 4-r (4-trans-4- (6-fluoro-lH-indol-3-yl) -cyclohexyl] -piperazin- [1239] The trans isomer of Example 47a compound was isolated as an off-white solid (0.055 g) simultaneously with the cis isomer: mp 173-175 [deg.] C. MS (ES) m / z (relative intensity): 447 (M + H < + >, 100). [1240] Example 48a [1241] - (l, 4-cis) -4- [4- (2-methyl-quinolin-8-yl) -piperazin- l-yl] -cyclohexyl} -lH- indole-5-carbonitrile [1242] 0.238 g of 3- (4-oxo-cyclohexyl) -1H-indole-5-carbonitrile was added to a solution of 0.230 g of 8-piperazino-quinaldine in 10 ml of CH 2 Cl 2 and then sodium triacetoxyborohydride 0.09 g of rye and 0.09 ml of acetic acid are added. The reaction is stirred overnight at room temperature. It is quenched with 1N NaOH and the product is extracted with CH 2 Cl 2 . The organic phase is washed with water and dried over magnesium sulphate. 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 yield 0.089 g of the desired product: mp 197-199 [deg.] C; MS (ES) m / z (relative intensity): 450 (M + H < + >, 100). [1243] Example 48b [1244] Yl) -cyclohexyl} -lH-indole-5-carbonitrile < / RTI > [1245] The trans isomer of the compound of Example 48a is isolated simultaneously with the cis isomer as an off-white solid (0.058 g): mp 268-280 [deg.] C. MS (ES) m / z (relative intensity): 450 (M + H < + >, 100). [1246] Example 49a [1247] 1-yl} -2-trifluoromethyl-pyrimidin-4-yl) -piperazin-1- Quinoline [1248] To a solution of 1- [2- (trifluoromethyl) quinol-4-yl] piperazine 0.281 g in 10 mL of CH 2 Cl 2 was added 4- (5-fluoro-lH-3-indolyl) g, then 0.528 g of sodium triacetoxyborohydride and 0.09 ml of acetic acid are added. The reaction is stirred overnight at room temperature. It is quenched with 1N NaOH and the product is extracted with ether. The organic phase is washed with water and dried over magnesium sulphate. The product was filtered through 100 ml of silica gel using 25% ethyl acetate / hexanes and then 50% ethyl acetate / hexanes to afford 0.089 g of the desired product: mp 235-239 [deg.] C; MS (ES) m / z (relative intensity): 497 (M + H < + >, 100). [1249] Example 49b [1250] 1-yl} -2-trifluoromethyl-pyrimidin-4-yl) -piperazin-1- Quinoline [1251] Example 49a The trans isomer of the compound is isolated simultaneously with the cis isomer as an off-white solid (0.110 g): mp 218-223 [deg.] C. MS (ES) m / z (relative intensity): 497 (M + H < + >, 100). [1252] Example 49c [1253] 4-yl) -piperazin-1-yl} -cyclohexyl} -1H-indole-5-carbo Nitrile [1254] This compound was prepared in analogy to Example 49a, substituting 4- (5-fluoro-lH-3-indolyl) -cyclohexanone with 3- (4-oxo-cyclohexyl) Prepared in the same way, yielding 0.137 g white solid: mp 235-239 [deg.] C; MS (ES) m / z (relative intensity): 504 (M + H < + >, 100). [1255] Elemental analysis: C 29 H 28 F 3 N 5 [1256] Calculated: C 69.17; H 5.6; N 13.91 [1257] Found: C 68.96; H 5.37; N 13.08 [1258] Example 49d [1259] 4-yl) -piperazin-1-yl] -cyclohexyl} -1H-indole-5-carbo Nitrile [1260] Example 49c The trans isomer of the compound is isolated simultaneously with the cis isomer as an off-white solid (0.036 g): mp 259-264 [deg.] C. MS (ES) m / z (relative intensity): 504 (M + H < + >, 100). [1261] Example 50a [1262] 1-yl} -6-methoxy-quinolin-4-ylmethyl) -piperazin- [1263] 0.230 g of 4- (5-fluoro-1H-3-indolyl) -cyclohexanone was added to a solution of 0.280 g of 6-methoxy-4-piperazino-quinoline in 10 ml of CH 2 Cl 2, 0.530 g of cetoxyborohydride and 0.09 ml of acetic acid are added. The reaction is stirred overnight at room temperature. It is quenched with 1N NaOH and the product is extracted with CH 2 Cl 2 . The organic phase is washed with water and dried over magnesium sulphate. 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: mp 222-227 [deg.] C; MS (ES) m / z (relative intensity): 459 (M + H < + >, 100). [1264] Example 50b [1265] Yl) -pyrazin-1-yl} -6-methoxy-quinoline (prepared according to the method described for the synthesis of 4- (4-fluoro- [1266] The trans isomer of the compound of Example 50a is isolated simultaneously with the cis isomer as an off-white solid (0.027 g): mp 249-251 [deg.] C. MS (ES) m / z (relative intensity): 459 (M + H < + >, 100). [1267] Example 50c [1268] 4-yl) -piperazin-1-yl] -cyclohexyl} -1H-indole-5-carbonitrile [1269] This compound was prepared in analogy to Example 50a by substituting 4- (5-fluoro-lH-3-indolyl) -cyclohexanone with 3- (4-oxo-cyclohexyl) Lt; / RTI > to give 0.016 g of a white solid: mp 271-272 C; MS (ES) m / z (relative intensity): 466 (M + H < + >, 100). [1270] Example 50d [1271] 4-yl) -piperazin-1-yl] -cyclohexyl} -lH-indole-5-carbonitrile [1272] Example 50c The trans isomer of the compound is isolated simultaneously with the cis isomer as an off-white solid (0.014 g): mp 288-292 [deg.] C. MS (ES) m / z (relative intensity): 466 (M + H < + >, 100). [1273] Example 51a [1274] (Cis) -3- {4- [4- (6-methoxy-2-methylquinolin-8-yl) piperazin- 1 -yl] cyclohexyl} -1-methyl-1H-indole-5-carbonitrile [1275] (300 mg, 1.16 mmol) and 3- (l-methyl-lH-indole-5-carbonitrile) cyclohexane (73 mg, 1.22 mmol) of glacial acetic acid was added to a mixture of 4-amino-4-one (440 mg, 1.75 mol), and sodium triacetoxyborohydride (495 mg, 2.34 mmol). The resulting mixture is stirred under N 2 at ambient temperature for 24 hours. The reaction is treated with saturated aqueous sodium bicarbonate (50 ml) and the aqueous mixture is extracted with CH 2 Cl 2 (3 x 50 ml). The organic layers were combined, filtered, dried over anhydrous Na 2 SO 4 and then concentrated in vacuo. Flash chromatography (gradient elution, 50% EtOAc / hex to 100% EtOAc, then 5% MeOH / EtOAc) on 4 x 15 cm SiO 2 still yields the impure title compound. Secondary chromatography using the same eluant on 2 x 20 cm SiO 2 affords 190 mg (33%) of clean product and 140 mg of still impure product. The clear product was recrystallized from EtOAc / hexanes to give 100 mg (17%) of the title compound: mp 201-203 [deg.] C. [1276] Elemental analysis: C 31 H 35 N 5 O · 0.1 C 4 H 8 O 2 [1277] Calculated: C 75.06; H 7.18; N 13.94 [1278] Found: C 75.00; H 7.32; N 13.83 [1279] Example 51b [1280] (Cis) -3- {4- [4- (6-methoxy-3-methylquinolin-8-yl) piperazin- 1 -yl] cyclohexyl} [1281] (210 mg, 0.82 mmol) and 3- (l-methyl-lH-indole-5-carbonitrile) cyclohexane in 5 ml anhydrous THF were added to a solution of 4- (6-methoxy- (68 mg, 0.96 mmol) of glacial acetic acid was added to a mixture of diisopropylethylamine (330 mg, 1.31 mol), sodium triacetoxyborohydride (435 mg, 2.05 mmol) The resulting mixture is stirred under N 2 at ambient temperature for 24 hours. The reaction is treated with saturated aqueous sodium bicarbonate (50 ml) and the aqueous mixture is extracted with CH 2 Cl 2 (3 x 50 ml). The organic layers were combined, filtered, dried over anhydrous Na 2 SO 4 and then concentrated in vacuo. Flash chromatography on 2 x 20 cm SiO 2 (5% MeOH / EtOAc) gave slightly offensive title compound. Recrystallization from EtOAc / hexanes afforded 0.26 g (64%) of the title compound: mp 190-191. [1282] Elemental analysis: C 31 H 35 N 5 O [1283] Calculated: C 75.43; H 7.15; N 14.19 [1284] Found: C 75.13; H 7.25; N 14.01 [1285] Example 51c [1286] (Cis) -3- {4- [4- (6-methoxy-4-methylquinolin-8-yl) piperazin- 1 -yl] cyclohexyl} -1-methyl-1H- indole-5-carbonitrile [1287] (0.2 g, 0.78 mmol), 3- (l-methyl-lH-indole-5-carbonitrile) cyclohexan-4- Sodium triacetoxyborohydride (0.25 g, 1.16 mmol) is added to a mixture of dichloromethane (0.215 g, 0.85 mol), dichloroethane (10 mg) and glacial acetic acid (0.12 ml). The reaction mixture is stirred at ambient temperature for 24 hours. The reaction is diluted with dichloromethane (60 ml) and washed with 1N aqueous sodium hydroxide (2 x 50 ml), water (50 ml), and brine (50 ml). Filtered and the organic layer was dried over anhydrous Na 2 SO 4 then was concentrated to afford 0.43 g crude product. Flash chromatography on 50 g silica gel (5% methanol / ethyl acetate) yields 0.15 g (40%) of the title compound. Recrystallization from ethyl acetate / hexanes gave 0.85 g (23%) pure product: mp 210-212 [deg.] C. [1288] Elemental analysis: C 31 H 35 N 5 O · 0.25H 2 O [1289] Calculated: C 74.74; H 7.18; N 14.06 [1290] Found: C 74.82; H 7.12; N 14.11 [1291] Example 51d [1292] (Trans) -3- {4- [4- (6-methoxy-4-methylquinolin-8-yl) piperazin- 1 -yl] cyclohexyl} [1293] The trans isomer is simultaneously separated with the cis isomer to 16% yield (0.062 g). Trituration with ethyl acetate / hexanes afforded 0.058 g (15%) of pure title compound: mp 230-232 [deg.] C. [1294] Elemental analysis: C 31 H 35 N 5 O 0.5 H 2 O [1295] Calculated: C 74.07; H 7.22; N 13.93 [1296] Found: C 74.12; H 7.10; N 13.95 [1297] Example 52a [1298] 1-yl] cyclohexyl} -1-methyl-1H-indole-5-carbonitrile (100 mg) [1299] The compound was prepared from (cis) -3- {4- [4- (6-methoxy-4-methylquinolin-8-yl) piperazin- 1 -yl] cyclohexyl} - < / RTI > carbonitrile, 0.25 g of the title compound is obtained. Recrystallization from ethyl acetate gave 0.125 g (20%) of pure product: mp 227-228 [deg.] C. [1300] Elemental analysis: C 31 H 35 N 5 O · 0.25H 2 O [1301] Calculated: C 74.74; H 7.18; N 14.06 [1302] Found: C 74.61; H 7.20; N 13.71 [1303] Example 52b [1304] (Trans) -3- {4- [4- (6-methoxy-5-methylquinolin-8-yl) piperazin- 1 -yl] cyclohexyl} [1305] The trans isomer (0.15 g) was simultaneously separated from the cis compound. Trituration from ethyl acetate gave 0.110 g (18%) of pure product: mp 212-213 [deg.] C. [1306] Elemental analysis: C 31 H 35 N 5 O · 0.25H 2 O [1307] Calculated: C 75.43; H 7.15; N 14.19 [1308] Found: C 75.09; H 7.10; N 13.96 [1309] Example 52c [1310] (4-fluoro-1-methyl-1H-indol-3-yl) cyclohexyl] piperazin-1-yl} -6-methoxyquinoline [1311] The compound was prepared from (cis) -3- {4- [4- (6-methoxy-4-methylquinolin-8-yl) piperazin- 1 -yl] cyclohexyl} -Carbonitrile, 0.13 g of the title compound is obtained. Trituration from ethyl acetate gave 0.120 g (29%) pure product. [1312] Elemental analysis: C 29 H 32 ClFN 4 O [1313] Calculated: C 68.70; H 6.36; N 11.05 [1314] Found: C 68.45; H 6.24; N 10.89 [1315] Example 52d [1316] (Trans) -5-chloro-8- {4 - [- (5-fluoro-1 -methyl-1 H-indol-3-yl) cyclohexyl] piperazin- 1 -yl} -6-methoxyquinoline [1317] The trans isomer was simultaneously separated with the cis compound in a yield of 19% (0.075 g). Trituration from ethyl acetate gave 0.070 g (17%) of pure product: mp 170-171 < 0 > C. [1318] Elemental analysis: C 29 H 32 ClFN 4 O [1319] Calculated: C 68.70; H 6.36; N 11.05 [1320] Found: C 68.44; H 6.32; N 11.02 [1321] Example 52e [1322] (4-chloro-6-methoxyquinolin-8-yl) piperazin-1 -yl] cyclohexyl} -1-methyl-1H- indole-5-carbonitrile [1323] The compound was prepared from (cis) -3- {4- [4- (6-methoxy-4-methylquinolin-8-yl) piperazin- 1 -yl] cyclohexyl} -Carbonitrile, 0.1 g (24%) of the title compound is obtained. Recrystallization from ethyl acetate gave 0.080 g (20%) of pure product: mp 231-231 [deg.] C. [1324] Elemental analysis: C 30 H 32 ClN 5 O · 0.25H 2 O [1325] Calculated: C 69.48; H 6.32; N 13.50 [1326] Found: C 69.49; H 6.31; N 13.29 [1327] Example 52f [1328] (Trans) -3- {4- [4- (5-chloro-6-methoxyquinolin-8-yl) piperazin- 1 -yl] cyclohexyl} [1329] The trans isomer is separated at the same time as the cis compound in a yield of 22% (0.095 g). Trituration from ethyl acetate gave 0.070 g (17%) of pure product: mp 215-216 [deg.] C. [1330] Elemental analysis: C 30 H 32 ClN 5 O · 0.25H 2 O [1331] Calculated: C 69.48; H 6.32; N 13.50 [1332] Found: C 69.36; H 6.28; N 13.27 [1333] Example 53a [1334] Yl} -2- (trifluoromethyl) -1H-benzimidazole < / RTI > [1335] Benzoimidazole (400 mg, 1.48 mmol), 4- (lH-3-indolyl) -cyclohexanone in dichloromethane (30 ml) Acetic acid (0.20 ml, 2.96 mmol) was added to a solution of the title compound (3.15 mg, 1.48 mmol), and sodium triacetoxyborohydride (470 mg, 2.22 mol) and the mixture was stirred overnight at room temperature. The reaction is quenched with 1 M NaOH (50 ml) and extracted into CH 2 Cl 2 (2 x 100 ml) and 50% EtOAc / MeOH (3 x 100 ml). By filtration were combined organic fractions were dried over Na 2 SO 4 and concentrated and then twice chromatography (5% MeOH / EtOAc) to give the cis isomer 170 mg (25%) as a white solid. HCl salt was generated from EtOAc to give a white solid: mp foamed above 207 < 0 > C. [1336] Elemental analysis: C 26 H 28 F 3 N 5 · HCl · H 2 O [1337] Calculated: C 59.82; H 5.99; N 13.42 [1338] Found: C 60.18; H 5.84; N 13.29 [1339] Example 53b [1340] Yl} -2- (trifluoromethyl) -lH-benzimidazole < / RTI > [1341] The trans isomer is separated at the same time as the cis isomer to give 180 mg (9%) as a beige solid. HCl salt is generated from EtOAc to give a white solid: mp decomposes above 200 < 0 > C. [1342] Elemental analysis: C 26 H 28 F 3 N 5 .HCl 0.75 H 2 O [1343] Calculated: C 60.34; H 5.94; N 13.53 [1344] Found: C 60.37; H 5.68; N 13.43 [1345] Example 54a [1346] 4 - [(1,4-cis) -4- (1H-indol-3-yl) cyclohexyl] piperazin-1-yl} -1H-benzimidazole [1347] This compound was prepared by replacing 4-piperazin-1-yl-2-trifluoromethyl-1H-benzoimidazole with 4-piperazin-1-yl-1H-benzoimidazole (510 mg, 2.5 mmol) example 1a as a yellow foam prepared by the method described above for the to give the title compound 350 mg (34%) and pulverized it with Et 2 O to give a white solid: mp 217-219 ℃. [1348] Elemental analysis: C 25 H 29 N 5 [1349] Calculated: C 75.16; H 7.32; N 17.53 [1350] Found: C 74.82; H 7.21; N 17.05 [1351] Example 54b [1352] 4- {4 - [(1,4-trans) -4- (1H-indol-3-yl) cyclohexyl] piperazin-1-yl} -1H- [1353] The trans isomer is separated at the same time as the cis isomer to give 200 mg (20%) as a white solid. The HCl salt was generated from Et 2 O / EtOH to give a white solid: mp decomposed at the more than 250 ℃. [1354] Elemental analysis: C 25 H 29 N 5. 2HCl. H 2 O [1355] Calculated: C 61.22; H 6.78; N 14.28 [1356] Found: C 61.24; H 6.97; N 14.09 [1357] Example 55a [1358] Yl} -2-methyl-1H-benzimidazole < / RTI > [1359] Benzimidazole (340 mg, 1.57 mmol) was reacted with 4-piperazin-1-yl-2-trifluoromethyl- To give 350 mg (54%) of the title compound as yellow foam. HCl salt is generated from EtOAc to give a white solid: mp decomposes above 190 < 0 > C. [1360] Elemental analysis: C 26 H 31 N 5. 2HCl. H 2 O [1361] Calculated: C 61.90; H 6.99; N 13.88 [1362] Found: C 62.26; H 7.18; N 13.46 [1363] Example 55b [1364] Yl} -2-methyl-1H-benzimidazole < / RTI > [1365] The trans isomer is separated at the same time as the cis isomer to give 110 mg (17%) as a white solid. A HCl salt is produced from EtOH / Et 2 O to give a white solid: mp decomposes above 220 ° C. [1366] Elemental analysis: C 25 H 29 N 5 .2HCl. 1.5H 2 O [1367] Calculated: C 60.81; H 7.07; N 13.64 [1368] Found: C 60.84; H 7.04; N 13.31 [1369] Example 56 [1370] 3- {4 - [(1,4-cis) -4- (6-methoxyquinolin-5-yl) piperazin- 1 -yl] cyclohexyl} -1H- indole-5-carbonitrile [1371] Under N 2 atmosphere oven - to a dry 100 ml flask was charged 5-Bromo-6-methoxyquinoline (3 g, 12.6 mmol), piperazine (6.5 g, 75.6 mmol), Pd (dba) 2, (570 mg, 5 mol%), P (t -Bu) 3, (0.628 ml, 5 mol%) and a sodium t- butoxide (1.82 g, 18.9 mmol), the reaction mixture was added to 50 ml dry xylene, o- After stirring, the mixture is heated at 120 占 폚 for 3 hours and then at room temperature overnight. The reaction mixture is poured into H 2 O (100 ml) and extracted into EtOAc (3 x 100 ml). The organic fractions were combined, dried over Na 2 SO 4, concentrated and then purified by column chromatography (10% MeOH / CH 2 Cl 2 + NH 4 OH) to give 6-methoxy-5-piperazin- 170 mg (6%) is obtained. This material is used in the next step without further purification (combined with other batches). (Tet Lett 1998, 39, p 617-620). [1372] (220 mg, 0.9 mmol) and 4- (5-cyano-lH-3-indolyl) -cyclohexanone ( Acetic acid (0.10 ml, 1.75 mmol) was added to a solution of sodium triacetoxyborohydride (288 mg, 1.36 mmol) and the mixture was stirred overnight at room temperature. The reaction is quenched with 2.5 M NaOH (20 ml) and H 2 O (150 ml) and then extracted into CH 2 Cl 2 (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 chromatographed (5% MeOH / EtOAc) to give 140 mg (33%) of cis isomer as yellow glassy material. HCl salt is generated from EtOAc to give a yellow solid: mp discoloration above 85 < 0 > C. [1373] Elemental analysis: C 26 H 31 N 5 .3HCl. H 2 O [1374] Calculated: C 58.74; H 6.12; N 11.81 [1375] Found: C 58.67; H 6.34; N 11.47 [1376] Example 57 [1377] 1-yl] cyclohexyl} -l-methyl-lH-indole-5-carbonitrile < / RTI > [1378] To a solution of 6-bromo-8-piperazin-l-yl-quinoline (1 g, 3.4 mmol) and 4- (5-cyano- Acetic acid (0.40 ml, 6.8 mmol) was added to a solution of cyclohexanone (857 mg, 3.4 mmol), and sodium triacetoxyborohydride (1.08 g, 5.1 mmol) and the mixture was stirred at room temperature overnight. The reaction is quenched with 2.5 M NaOH (20 ml) and H 2 O (150 ml) and then extracted into CH 2 Cl 2 (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 chromatographed (5% MeOH / EtOAc) to give 360 mg of trans isomer as a white foam (20%). HCl salt is generated from EtOAc to give a white solid: mp decomposes above 85 < 0 > C. [1379] Elemental analysis: C 29 H 30 BrN 5 .HCl 0.75H 2 O [1380] Calculated: C 60.21; H 5.66; N 12.11 [1381] Found: C 60.17; H 5.44; N 11.99 [1382] Example 58a [1383] (4-fluoro-1-methyl-1H-indol-3-yl) cyclohexyl] piperazin-1-yl} quinoline [1384] (610 mg, 2.09 mmol) and 4- (5-fluoro-1-methyl-lH-indol-3-yl) -methanone in dichloroethane (40 ml) Acetic acid (0.24 ml, 4.18 mmol) was added to a solution of 4-amino-cyclohexanone (510 mg, 2.09 mmol), and sodium triacetoxyborohydride (660 mg, 3.14 mmol) and the mixture was stirred at room temperature overnight. The reaction is quenched with 1 M NaOH (50 ml) and H 2 O (100 ml) and then extracted into CH 2 Cl 2 (100 ml) and EtOAc (100 ml). Combine the organic fractions were concentrated dried over Na 2 SO 4, filtered, and purified by chromatography (5% MeOH / EtOAc). Most of the cis compounds precipitate in 5% MeOH / EtOAc before being applied to the column and are filtered to give 510 mg (47%) of the cis isomer as a pale yellow solid: mp 215-217 [deg.] C. [1385] Elemental analysis: C 28 H 30 BrFN 4 .0.5H 2 O [1386] Calculated: C 60.21; H 5.66; N 12.11 [1387] Found: C 60.17; H 5.44; N 11.99 [1388] Example 58b [1389] (Trans) -6- bromo-8- {4- [4- (5-fluoro-1 -methyl-1 H- indol- 3-yl) cyclohexyl] piperazin- [1390] The trans isomer is separated by chromatography to give 210 mg (19%) as a pale yellow foam. HCl salt is generated from EtOAc to give a gray solid: mp decomposes above 225 [deg.] C. [1391] Elemental analysis: C 28 H 30 BrFN 4揃 HCl 揃 0.5H 2 O [1392] Calculated: C 59.32; H 5.69; N 9.88 [1393] Found: C 59.36; H 5.47; N 9.79 [1394] Example 59a [1395] L-yl] cyclohexyl} -1-methyl-lH-indole-5-carbonitrile < / RTI > [1396] (500 mg, 1.95 mmol) and 4- (5-cyano-1-methyl-lH-indol-3-yl) -methanone in dichloroethane (40 ml) Acetic acid (0.25 ml, 3.9 mmol) was added to a solution of 4-amino-cyclohexanone (490 mg, 1.95 mmol), and sodium triacetoxyborohydride (620 mg, 2.93 mmol) and the mixture was stirred at room temperature overnight. The reaction is quenched with 1 M NaOH (100 ml) and H 2 O (50 ml) and then extracted into CH 2 Cl 2 (50 ml) and 5% MeOH / EtOAc (2 x 100 ml). Combine the organic fractions were concentrated dried over Na 2 SO 4, filtered, and purified by chromatography (5% MeOH / EtOAc). Most of the cis compounds were precipitated in 5% MeOH / EtOAc before being applied to the column, filtered and combined with the column fractions to give 450 mg (47%) of the cis isomer as an off-white solid: mp decomposed above 215 캜. [1397] Elemental analysis: C 31 H 35 N 5 O.1.25H 2 O [1398] Calculated: C 72.14; H 7.32; N 13.57 [1399] Found: C 72.23; H 7.06; N 13.35 [1400] Example 59b [1401] 1-yl] cyclohexyl} -l-methyl-lH-indole-5-carbonitrile < / RTI > [1402] The trans isomers are separated simultaneously by chromatography to give 210 mg (22%) as a yellow foam which is triturated with EtOAc to give a light yellow solid: mp 225-228 [deg.] C. [1403] Elemental analysis: C 31 H 35 N 5 O.H 2 O [1404] Calculated: C 72.77; H 7.29; N 13.69 [1405] Found: C 72.79; H 7.07; N 13.41 [1406] Example 60 [1407] Yl) piperazin-1-yl) cyclohexyl] -1-methyl-1H-indole-5-carbonitrile [1408] Under N 2 atmosphere oven - to a dry 10 ml round bottom flask was charged Cs 2 CO 3 (173 g, 0.53 mmol), BINAP (15 mg, 3 mol%), Pd (OAc) 3 (5 mg, 3 mol%) and 2 - {4- (1,4-trans) - [4- (6-bromoquinolin-8-yl) piperazin-1 -yl] cyclohexyl} -1-methyl-1H-indole- 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 < 0 > C overnight. The cooled reaction mixture is diluted with Et 2 O (15 ml) and filtered to remove solids and concentrate. Purification of the oil produced was purified by column chromatography (5% MeOH / EtOAc + NH 4 OH) to afford 60 mg title compound as a brown solid. HCl salt is generated from EtOAc / Et 2 O to give an orange solid: mp decomposes above 90 ° C. [1409] Elemental analysis: C 37 H 4 ON 6 .3HCl [1410] Calculated: C 65.53; H 6.39; N 12.39 [1411] Found: C 65.36; H 6.71; N 12.39 [1412] Example 61a [1413] 1-methyl-3 - [(1,4-cis) -4- (4-quinolin-5-yl-piperazin- 1 -yl) cyclohexyl] -lH- indole-5-carbonitrile [1414] (300 mg, 1.4 mmol) and 4- (5-cyano-1-methyl-lH-indol-3-yl) -cyclohexanone Acetic acid (0.2 ml, 3.4 mmol) was added to a solution of sodium triacetoxyborohydride (450 mg, 2.1 mmol), and the mixture was stirred at room temperature overnight. The reaction is quenched with 1 M NaOH (25 ml) and H 2 O (100 ml) and then extracted into CH 2 Cl 2 (100 ml) and EtOAc (2 x 100 ml). The organic fractions were combined, dried over Na 2 SO 4, concentrated, filtered and chromatographed (5% MeOH / EtOAc) to give 190 mg (30%) of cis isomer as a white foam. HCl salt is generated from EtOAc to give a white solid: mp decomposes above 235 캜. [1415] Elemental analysis: C 29 H 31 N 5 · HCl · 0.5H 2 O [1416] Calculated: C 70.36; H 6.72; N 14.15 [1417] Found: C 70.43; H 6.57; N 13.83 [1418] Example 61b [1419] 1-methyl-3 - [(1,4-trans) -4- (4-quinolin-5-yl-piperazin- 1 -yl) cyclohexyl] -lH- indole-5-carbonitrile [1420] Separation of the trans isomers simultaneously yields 140 mg (22%) as a pale yellow solid: mp is discolored above 200 < 0 > C. [1421] Elemental analysis: C 29 H 31 N 5 .0.5H 2 O [1422] Calculated: C 75.95; H 7.03; N 15.27 [1423] Found: C 75.82; H 6.72; N 15.09 [1424] Example 62a [1425] Yl) piperazin-1-yl] cyclohexyl} -1- (4-methylpiperazin-1- Methyl-lH-indole-5-carbonitrile < / RTI > [1426] To a solution of 6-methoxy-5-piperazin-1-yl-1,2,3,4-tetrahydroquinoline (300 mg, 1.2 mmol), 4- (5-cyano- Acetic acid (0.15 ml, 2.4 mmol) was added to a solution of sodium triacetoxyborohydride (254 mg, 1.8 mmol) and sodium triacetoxyborohydride (306 mg, 1.2 mmol) Stir at room temperature overnight. The reaction is quenched with 1 M NaOH (50 ml) and H 2 O (50 ml) and then extracted into CH 2 Cl 2 (100 ml) and EtOAc (2 x 100 ml). The organic fractions were combined, dried over Na 2 SO 4, concentrated, filtered and twice chromatographed (5% MeOH / EtOAc) to give 140 mg (24%) of cis isomer as a white foam. HCl salt is generated from EtOAc to give a white solid: mp decomposes above 170 < 0 > C. [1427] Elemental analysis: C 30 H 37 N 5 O.HCl.H 2 O [1428] Calculated: C 66.96; H 7.49; N 13.01 [1429] Found: C 66.71; H 7.28; N 12.50 [1430] Example 62b [1431] Yl) piperazin-1-yl] cyclohexyl} -1- (4-methylpiperazin-1 -yl) Methyl-lH-indole-5-carbonitrile < / RTI > [1432] The trans isomers were simultaneously removed to give 80 mg (22%) as a white foam. HCl salt is generated from EtOAc to give a white solid: mp decomposes above 225 < 0 > C. [1433] Elemental analysis: C 30 H 37 N 5 O.HCl .0.5H 2 O [1434] Calculated: C 68.10; H 7.43; N 13.24 [1435] Found: C 68.17; H 7.30; N 13.17 [1436] Example 63a [1437] Yl) piperazin-1-yl) cyclohexyl] -1H-indole-5-carbo (4- Nitrile [1438] (470 mg, 2.19 mmol) and 4- (5-cyano-1-methyl-lH-indol-3-yl) -cyclohexanone in dichloroethane (40 ml) Acetic acid (0.25 ml, 4.38 mmol) was added to a solution of the title compound (550 mg, 2.19 mmol), and sodium triacetoxyborohydride (700 mg, 3.28 mmol) The reaction is quenched with 1 M NaOH (40 ml) and H 2 O (20 ml) and then extracted into CH 2 Cl 2 (50 ml) and EtOAc (2 x 100 ml). Combine the organic fractions were concentrated dried over Na 2 SO 4 and filtered by three chromatography (5% MeOH / EtOAc) to give the cis isomer 490 mg (50%) as a pale yellow solid: mp 227-215 is ℃ Above, followed by melting at 227-230 ° C. [1439] Elemental analysis: C 28 H 30 N 6 .0.5H 2 O [1440] Calculated: C 73.90; H 6.76; N 18.47 [1441] Found: C 73.90; H 6.76; N 18.61 [1442] Example 63b [1443] 1-yl) piperazin-1-yl) cyclohexyl] -1H-indole-5-carbo Nitrile [1444] Separation of the trans isomers simultaneously yields 120 mg (12%) as a light yellow solid: mp decomposes above 195 [deg.] C. [1445] Elemental analysis: C 30 H 37 N 5 O · 0.5H 2 O [1446] Calculated: C 73.90; H 6.76; N 18.47 [1447] Found: C 73.87; H 6.75; N 18.66 [1448] Example 64 [1449] Yl) piperazin-1-yl} cyclohexyl) -1H-indole-5-carboxylic acid Carbonitrile [1450] To a solution of 6- (methylamino) -8-piperazin-l-yl-quinoline (100 mg, 0.43 mmol), 4- (5- Acetic acid (0.1 ml, 0.86 mmol) was added to a solution of sodium hydride (100 mg, 0.43 mmol), sodium triacetoxyborohydride (130 mg, 0.62 mmol) and the mixture was stirred overnight at room temperature. The reaction is quenched with 1 M NaOH (50 ml) and H 2 O (50 ml) and then extracted into CH 2 Cl 2 (100 ml) and EtOAc (2 x 100 ml). Combine the organic fractions were concentrated dried over Na 2 SO 4, filtered and purified by chromatography (10% MeOH / EtOAc) to give the cis-isomer 60 mg (30%) as a gold oil. HCl salt is generated from EtOAc to give a yellow solid: mp decomposes above 170 < 0 > C. [1451] Elemental analysis: C 30 H 34 N 6 · HCl · H 2 O [1452] Calculated: C 67.59; H 7.00; N 15.76 [1453] Found: C 67.58; H 6.86; N 15.65 [1454] Example 65a [1455] (Cis) -3- {4- [4- (7-methoxyquinoxalin-5-yl) piperazin- 1 -yl] cyclohexyl} -1-methyl-lH- indole-5-carbonitrile [1456] To a solution of 7-methoxy-5-piperazin-l-yl-quinoxaline (160 mg, 0.66 mmol), 4- (5-cyano- ) Acyclohexanone (170 mg, 0.66 mmol) and sodium triacetoxyborohydride (210 mg, 0.98 mmol) in acetic acid (0.1 ml, 1.3 mmol) was added and stirred at room temperature overnight. The reaction is quenched with 1 M NaOH (100 ml) and then extracted into CH 2 Cl 2 (75 ml) and EtOAc (100 ml). Combine the organic fractions were concentrated, dried over Na 2 SO 4 and filtered to give the purified by chromatography (5% MeOH / EtOAc) to cis-isomer 120 mg (38%) as a pale yellow solid: mp is 226-229 ℃. [1457] Elemental analysis: C 29 H 32 N 6 O.H 2 O [1458] Calculated: C 69.86; H 6.87; N 16.85 [1459] Found: C 69.94; H 6.71; N 16.60 [1460] Example 65b [1461] (Trans) -3- {4- [4- (7-methoxyquinoxalin-5-yl) piperazin- 1 -yl] cyclohexyl} -l-methyl-lH- indole-5-carbonitrile [1462] The trans isomers were separated simultaneously to give 80 mg (12%) as a yellow solid: mp 230-233 [deg.] C. [1463] Elemental analysis: C 29 H 32 N 6 O 0.5 H 2 O [1464] Calculated: C 71.14; H 6.79; N 17.16 [1465] Found: C 71.29; H 6.69; N 17.16 [1466] Example 66a [1467] Yl) piperazin-1-yl] cyclohexyl} -1-methyl-1H-indole-5-carboxylic acid (4- Carbonitrile [1468] To a solution of 6-methoxy-8-piperazin-l-yl- [l, 7] naphthyridine (250 mg, 1.02 mmol), 4- (5-cyano- Acetic acid (0.12 ml, 2.04 mmol) was added to a solution of the title compound (260 mg, 1.02 mmol) and sodium triacetoxyborohydride (320 mg, 1.53 mmol) . The reaction is quenched with 1 M NaOH (50 ml) and then extracted into CH 2 Cl 2 (1 x 50 ml) and EtOAc (75 ml). Combine the organic fractions were concentrated dried over Na 2 SO 4 and filtered to give the purified by chromatography (5% MeOH / EtOAc + NH 4 OH) and cis isomer 160 mg (33%) as a yellow foam. HCl salt from EtOAc to give a light yellow solid: mp 235-238 [deg.] C. [1469] Elemental analysis: C 29 H 32 N 6 O.HCl.H 2 O [1470] Calculated: C 65.10; H 6.59; N 15.71 [1471] Found: C 65.09; H 6.77; N 15.60 [1472] Example 66b [1473] (Trans) -3- {4- [4- (6-methoxy [1,7] naphthyridin-8-yl) piperazin- 1 -yl] cyclohexyl} Carbonitrile [1474] The trans isomers are separated at the same time to give 90 mg (18%) as a yellow foam. HCl salt from EtOAc to give a light yellow solid: mp 230-233 [deg.] C. [1475] Elemental analysis: C 29 H 32 N 6 O · HCl · 0.5H 2 O [1476] Calculated: C 66.21; H 6.51; N 15.97 [1477] Found: C 66.26; H 6.37; N 15.91 [1478] Example 67a [1479] Yl) -piperazin-l-yl] -cyclohexyl} -piperazin-l-yl) -1H-indole-5-carbonitrile [1480] 1-yl-1,3-dihydro-benzoimidazol-2-one (400 mg, 1.8 mmol), 4- (5-cyano-lH-indol- Acetic acid (0.21 ml, 3.7 mmol) was added to a solution of 3-yl-cyclohexanone (430 mg, 1.8 mmol), and sodium triacetoxyborohydride (590 mg, 2.8 mmol) and the mixture was stirred at room temperature overnight. The reaction is quenched with 1 M NaOH (100 ml) and then extracted into MeOH / CH 2 Cl 2 (2 x 100 ml). Combine the organic fractions were concentrated dried over Na 2 SO 4 and filtered to give the following twice chromatography (10% MeOH / EtOAc) to cis-isomer 185 mg (23%) as a beige solid. HCl salt is generated from EtOAc to give an off-white solid: mp decomposes above 235 [deg.] C. [1481] Elemental analysis: C 26 H 28 N 6 O · HCl · 1.5H 2 O [1482] Calculated: C 61.96; H 6.40; N 16.67 [1483] Found: C 61.97; H 6.26; N 16.28 [1484] Example 67b [1485] 1-yl] -cyclohexyl} -piperazin-1-yl) -piperazin-1 -yl] -1H-indole-5-carbonitrile [1486] The trans isomers are separated at the same time to give 90 mg (18%) as a white solid. HCl salt was generated from EtOAc to give a white solid: mp decomposed above 265 캜. [1487] Elemental analysis: C 26 H 28 N 6 O · HCl · 1.5H 2 O [1488] Calculated: C 61.96; H 6.40; N 16.67 [1489] Found: C 61.98; H 6.25; N 16.38 [1490] Example 68a [1491] 3- [cis-4- [4- (6-methoxy-lH-indol-4-yl) -1- piperazinyl] cyclohexyl] -lH- indole- [1492] To a solution of 4- (5-cyano-1-methyl-3-indolyl) -cyclohexanone (0.43 mg, 1.8 mmol), 6-methoxy- A solution of 1-yl-lH-indole (0.4 g, 1.8 mmol), sodium triacetoxyborohydride (0.77 g, 2.7 mmol) and acetic acid (0.21 ml, 36 mmol) was stirred overnight at room temperature. The reaction is quenched with 1N aqueous sodium hydroxide (10 ml) and extracted with methylene chloride (3 x 50 ml). The combined organic layers are washed with brine (2 x 50 ml), then dried over anhydrous sodium sulfate and filtered. Chromatography (5% methanol / ethyl acetate) afforded 0.38 g (48%) of the title compound as a white solid: mp 182-185 [deg.] C. [1493] HCl salt is prepared in ethyl acetate: mp 225-226 [deg.] C. [1494] Elemental analysis: C 28 H 31 N 5 O.2HCl 0.25H 2 O. 0.40C 4 H 8 O 2 [1495] Calculated: C 62.79; H 6.53; N 12.37 [1496] Found: C 62.28; H 6.44; N 12.97 [1497] Example 68b [1498] 3- [trans-4- [4- (6-methoxy-lH-indol-4-yl) -1- piperazinyl] cyclohexyl] -lH- indole-5-carbonitrile [1499] The trans isomer was separated at the same time as the cis isomer to give 33% yield (0.26 g) as a white solid: mp 157-160 < 0 > C. HCl salt is prepared in ethyl acetate: mp > 210 < 0 > C. [1500] Elemental analysis: C 28 H 31 N 5 O · HCl · 1.5H 2 O [1501] Calculated: C 64.82; H 6.58; N 13.94 [1502] Found: C 65.04; H 6.82; N 13.54 [1503] Example 69 [1504] 5- Fluoro-3- {4- [4- (6-methoxy-naphthalen-2-yl) -piperazin- 1-yl] -cyclohexyl} -1H-indole [1505] To a solution of 400 mg (1.66 mmol) of l- (6-methoxy-naphthalen-2-yl) -piperazine in 40 ml of CH 2 Cl 2 and 100 mg of ice HOAc was added 4- (5-fluoro- 3-enyl) -cyclohex-3-enone, followed by 216 mg (1.89 mmol) Na (OAc) 3 BH. After stirring at 23 [deg.] C for 12 hours, the reaction mixture is transferred to a separatory funnel and partitioned between water and CH 2 Cl 2 . The organics were washed with brine and was then dried over elution agent 20 MgSO 4: 1 EtOAc: using the 2 M NH 3 in MeOH and chromatographed on silica gel. The product fractions were collected and stripped and treated with 115 mg (1.3 mmol) of (CO 2 H) 2 in dry EtOH to give 640 mg (1.40 mmol, 84% yield) of the oxalate salt of the title compound as a white crystalline solid: mp 200 -203 C; MS (ES) m / z 458 (MH) < + & gt ; . [1506] Elemental analysis: C 29 H 32 FN 3 O [1507] Calculated: C 67.95; H 6.25; N 7.67 [1508] Found: C 66.64; H 6.71; N 7.11 [1509] Example 70a [1510] Yl] -piperazin-l-yl] -cyclohexyl-lH-indole-5-carboxylic acid - Carbonitrile [1511] 1.36 g (4.8 mmol) of 6- [1,3] dioxolan-2-yl-8-piperazinyl-quinoline was prepared from 1-methyl- hexyl) -1H- indole-5-carbonitrile, merges with 1.53 g (7.2 mmol), 0.43 g (7.2 mmol) CH 3 CO 2 H and 100 ml CH 2 Cl 2. The crude product is chromatographed on silica gel with a gradient of CH 2 Cl 2 to 10: 1 H 2 Cl 2 : MeOH to isolate the cis compound (R f = 0.39, 10: 1 CH 2 Cl 2 : MeOH). The product fractions were collected and stripped and treated with 0.09 g (1.0 mmol) (CO 2 H) 2 in dry EtOH to give 1.0 g (1.9 mmol, 40% yield) of the oxalate salt of the cis isomer of the title compound as a yellow crystalline solid . mp: 105 [deg.] C; MS (ES) m / z 522 (MH) < + & gt ; . [1512] Elemental analysis: C 32 H 35 N 5 O 2 [1513] Calculated: C 73.68; H 6.76; N 13.43 [1514] Found: C 73.67; H 6.82; N 13.23 [1515] Example 70b [1516] Yl] -piperazin-l-yl] -cyclohexyl-lH-indole-5-carboxylic acid - Carbonitrile [1517] A trans compound is also obtained. (R f = 0.24, 10: 1 CH 2 Cl 2 : MeOH). The product fractions were pooled and stripped and treated with 0.07 g (0.8 mmol) of (CO 2 H) 2 in dry EtOH to give 0.80 g (1.5 mmol, 31% yield): mp 160 [deg.] C; MS ES m / z 522 (MH) < + & gt ; . [1518] Elemental analysis: C 32 H 35 N 5 O 2 [1519] Calculated: C 73.68; H 6.76; N 13.43 [1520] Found: C 67.05; H 6.27; N 12.03 [1521] Example 71 [1522] -Cyclohexyl] -piperazin-1-yl] -6-quinolinecarbaldehyde (prepared as described in Example 1) [1523] To a solution of 3- [4 - [(cis) -4- (6- [1,3] dioxolan-2-yl-quinolin-8-yl) -piperazinyl] cyclohexyl -1H-indole-5-carbonitrile (920 mg, 1.8 mmol) at 23 < 0 > C is added 0.8 ml of 6N HCl. The reaction is heated at 40 < 0 > C for 5 hours. The volatiles were removed by rotary evaporation and the aqueous phase was neutralized with 5N NaOH. The organics are extracted into CH 2 Cl 2 , washed with brine, dried over MgSO 4 and then chromatographed on silica gel using 10: 1 CH 2 Cl 2 : MeOH as eluent. The product fractions were collected and stripped and treated with 147 mg (1.6 mmol) of (CO 2 H) 2 in dry EtOH to give 780 mg (1.3 mmol, 72% yield) of the oxalate salt of the title compound as a pale yellow crystalline solid: mp 172 -174 캜; MS (ES) m / z 478 (MH) < + & gt ; . [1524] Elemental analysis: C 30 H 31 N 5 O [1525] Calculated: C 75.44; H 6.54; N 14.66 [1526] Found: C 73.27; H 6.66; N 13.98 [1527] Example 72 [1528] - cyclohexyl] -piperazin-1-yl] -6-quinolinecarbaldehyde (prepared from 8- [4 - [(trans) -4- (5-cyano- [1529] 1-yl) -piperazinyl] cyclohexyl-lH-indole < / RTI > -5-carbonitrile, 0.6 ml of 6N HCl, 7 ml of THF, and 7 ml of ice-cold HOAc to give the trans compound. The product fractions were pooled and stripped and then treated with 85 mg (0.9 mmol) (CO 2 H) 2 in dry EtOH to give 450 mg (0.76 mmol, 42% yield): mp 201-203 ° C; MS (ES m / z 478 (MH) < + > [1530] Elemental analysis: C 30 H 31 N 5 O [1531] Calculated: C 75.44; H 6.54; N 14.66 [1532] Found: C 72.10; H 6.80; N 12.64 [1533] Example 73 [1534] - [4- (cis) -4- (5-cyano-l-methyl-lH-indol-3- yl) -cyclohexyl] -1- piperazinyl] -6- quinolinecarboxylic acid [1535] At 23 ℃ t-BuOH 60 ml and CH 3 CHC (CH 3) 2 8 750 mg (1.6 mmol) of ml 8- [4 - [(cis) -4- (5-cyano-1-methyl -1H- 3-yl) cyclohexyl] -1-piperazinyl] -6-quinolinecarbaldehyde was added a solution of 1.3 mg (14.4 mmol) NaClO 2 and 1.3 g (10.8 mmol) NaH 2 PO 4 in 3 ml water . After stirring at 23 [deg.] C for 12 hours, the volatiles are removed by rotary evaporation. The reaction mixture is transferred to a separatory funnel and partitioned between water and CH 2 Cl 2 . The organics are washed with brine, dried over MgSO 4 and then chromatographed on silica gel using 20: 1 CH 2 Cl 2 : MeOH containing 5% ice-cold HOAc as eluent. The product fractions were pooled and stripped and then treated with 75 mg (0.83 mmol) (CO 2 H) 2 in dry EtOH to give 390 mg (0.6 mmol, 38% yield) of the oxalate salt of the title compound as a tan crystalline solid: mp 230 DEG C; MS (ES m / z 494 (MH) < + > [1536] Elemental analysis: C 30 H 31 N 5 O 2 [1537] Calculated: C 73.00; H 6.33; N 14.19 [1538] Found: C 50.91; H 4.92; N 7.70 [1539] Example 74 [1540] Cyclohexyl] -1-piperazinyl] -6-quinolinecarboxylic acid < RTI ID = 0.0 > [1541] (0.60 mmol) of 8- [4 - [(trans) -4- (5-cyano- 1 -methyl-1 H-indol-3- yl) cyclohexyl] -1- piperazinyl] -6- quinoline carbaldehyde, 0.48 g (5.5 mmol) NaClO 2, 0.48 g (4.1 mmol) NaH 2 PO 4, 24 ml t-BuOH, 3 ml CH 3 CHC (CH 3) example 73 by blending the two, and 6 ml water, To obtain a trans compound. The product fractions were pooled and stripped and then treated with 54 mg (0.60 mmol) (CO 2 H) 2 in dry EtOH to give 97 mg (0.16 mmol, 10% yield): mp 275 ° C; MS (ES m / z 494 (MH) < + > [1542] Elemental analysis: C 30 H 31 N 5 O [1543] Calculated: C 75.44; H 6.54; N 14.66 [1544] Found: C 50.42; H 4.66; N 8.82 [1545] Example 75 [1546] Methyl 8- [4 - [(cis) -4- (5-cyano-l-methyl-lH-indol-3- yl) cyclohexyl] - 1- piperazinyl] -6- quinolinecarboxylate [1547] At 23 ℃ MeOH and 1 ml C 6 H 5 CH 3 3 ml of 8- [4 - [(cis) -4- (5-cyano-1-methyl -1H- indol-3-yl) -cyclohexyl} - 1-piperazinyl] -6-quinolinecarboxylic acid 50 mg exerts a hexanes (CH 3) 3 10% solution 0.8 ml (0.39 mmol) of 2 to SiCHN (0.1 mmol). After stirring at 23 [deg.] C for 12 hours, the volatiles are removed by rotary evaporation. The crude product is chromatographed on silica gel using 20: 1 CH 2 Cl 2 : MeOH as eluent. The product fractions were pooled, stripped and treated with 5 mg (0.05 mmol) of (CO 2 H) 2 in EtOH to afford 20 mg (0.04 mmol, 40% yield) of the oxalate salt of the title compound as a tan crystalline solid. mp: 153-155 [deg.] C; MS (ES) m / z: 599 (MH) < + & gt ; . [1548] Elemental analysis: C 31 H 33 N 5 O 2 [1549] Calculated: C 66.28; H 5.90; N 11.71 [1550] Found: C 61.49; H 5.85; N 10.35 [1551] Example 76a [1552] 3- [4 - [(cis) -4- (7-methoxy-8-quinolinyl) -1-piperazinyl] cyclohexyl] -1-methyl- lH- indole-5-carbonitrile [1553] 7-methoxy-8- (1-piperazinyl) quinoline 400 mg (1.6 mmol) from the Example, 30 ml CH 2 Cl 2 by the procedure described for 69, 1-methyl-3- (4 404 mg (1.6 mmol) of Na (OAc) 3 BH, 510 mg (2.4 mmol) of NaOH and 143 mg (2.4 mmol) of ice-cold HOAc. The crude product is chromatographed on silica gel using 20: 1 CH 2 Cl 2 : MeOH as eluent to isolate the cis compound (R f = 0.34, 10: 1 EtOAc: MeOH). The product fractions were pooled and stripped and treated with 27 mg (0.30 mmol) of (CO 2 H) 2 in dry EtOH to give 179 mg (0.37 mmol, 23% yield) of the oxalate salt of the title compound as a yellow crystalline solid. mp: 183-186 [deg.] C; MS (ES) m / z: 480 (MH) < + & gt ; . [1554] Elemental analysis: C 30 H 33 N 5 O [1555] Calculated: C 67.43; H 6.19; N 12.29 [1556] Found: C 65.38; H 6.34; N 11.83 [1557] Example 76b [1558] 3- [4 - [(trans) -4- (7-methoxy-8-quinolinyl) -1-piperazinyl] cyclohexyl] -1-methyl-1H- indole-5-carbonitrile [1559] The trans compound is obtained simultaneously (R f = 0.17, 10: 1 EtOAc: MeOH). The product fractions were pooled, stripped and treated with 12 mg (0.13 mmol) of (CO 2 H) 2 in dry EtOH to afford 80 mg (0.17 mmol, 11% yield). mp: 144-148 [deg.] C; MS (ES) m / z: 480 (MH) < + & gt ; . [1560] Elemental analysis: C 30 H 33 N 5 O [1561] Calculated: C 67.43; H 6.19; N 12.29 [1562] Found: C 64.17; H 6.37; N 11.68 [1563] Example 77a [1564] Yl) cyclohexyl] -1-piperazinyl] -N, N-dimethyl-6-quinoline Carboxamide [1565] N, N- dimethyl-8- (1-piperazinyl possess) quinoline-6-carboxamide 300 mg (1.1 mmol) of Example 69 by the procedure described for the, 20 ml CH 2 Cl 2 in a 1- methyl-3- (4-oxo-cyclohexyl) -1H- indole-5-carbonitrile 267 mg (1.1 mmol), Na (OAc) 3 BH 339 mg (1.6 mmol), ice-HOAc 96 mg (1.6 mmol) and . The crude product is chromatographed on silica gel with a gradient of EtOAc to 10: 1 EtOAc: MeOH to separate the cis compound (R f = 0.43 in 10: 1 EtOAc: 2 M NH 3 in MeOH). The product fractions were pooled and stripped and treated with 35 mg (0.39 mmol) of (CO 2 H) 2 in dry EtOH to afford 210 mg (0.40 mmol, 36% yield) of the oxalate salt of the title compound as light yellow crystalline solid. mp: 163-165 [deg.] C; MS (ES) m / z: 521 (MH) < + & gt ; . [1566] Elemental analysis: C 32 H 36 N 6 O [1567] Calculated: C 66.83; H 6.27; N 13.75 [1568] Found: C 59.62; H 6.15; N 11.33 [1569] Example 77b [1570] Indol-3-yl) cyclohexyl] -1-piperazinyl] -N, N-dimethyl-6-quinoline Carboxamide [1571] The trans compound is obtained simultaneously (R f = 0.33, 10: 1 EtOAc: 2M NH 3 in MeOH). The product fractions were pooled, stripped and treated with 15 mg (0.17 mmol) of (CO 2 H) 2 in dry EtOH to afford 80 mg (0.15 mmol, 14% yield). mp: 160-163 DEG C; MS (ES) m / z: 521 (MH) < + & gt ; . [1572] Elemental analysis: C 32 H 36 N 6 O [1573] Calculated: C 66.83; H 6.27; N 13.75 [1574] Found: C 62.7; H 6.52; N 12.33 [1575] Example 78 [1576] Cis-4- [4- (lH-pyrrolo [2,3-b] pyridin-3- yl) cyclohexyl] -1-piperazinyl} quinoline [1577] To a stirred solution of 195 mg (0.80 mmol) of 6-methoxy-8- (1-piperazinyl) quinoline in 10 ml 1,2-dichloroethane was added 4- (lH- pyrrolo [2,3- b] 177.9 mg (0.83 mmol) of cyclohexanone, 254 mg (1.2 mmol) of sodium triacetoxyborohydride and 78 mg (1.3 mmol) of glacial acetic acid are added. The reaction is monitored by TLC on silica gel plate using CH 2 Cl 2 / MeOH (10: 1) as eluent. On the 23 ℃ stirred for 64 hours, the reaction was quenched with 10 ml 1N NaOH, and extracted with CH 2 Cl 2 (2 x 25 ml). The aqueous layer is adjusted to pH 10 with AcOH and further extracted with CH 2 Cl 2 (2 x 75 ml). The combined organic layers were washed with brine (2 x 75 ml), dried over MgSO 4 filtered and then evaporated to a yellow solid adaptation. [1578] The crude product is purified by flash chromatography on silica gel using gradient elution of CH 2 Cl 2 / MeOH (40: 1 to 10: 1 to 4: 1). The appropriate fractions were combined and evaporated to give 94.8 mg (0.21 mmol, 27% yield) of the title compound as a tan crystalline solid. [1579] Oxalic acid 19 mg (0.21 mmol) was added to the title compound 92 mg (0.21 mmol) in 1 ml of ethanol at 23 ° C to give the oxalate salt of the title compound. After stirring at 23 [deg.] C for 64 hours, a solid precipitates in the solution. Diethyl ether (5 ml) is added to the suspension and cooled to 0 < 0 > C to further crystallize the product. The precipitated solid was collected and washed with ether to give 79.5 mg (15 mmol, 71% yield) of oxalate salt. mp: 216-220 [deg.] C; MS (ES) m / z: 442.3 (MH) < + & gt ; , 221.6 (M / 2 + H) < + & gt ; . [1580] Elemental analysis: C 29 H 33 N 5 O 5 [1581] Calculated: C 65.48; H 6.25; N 13.17 [1582] Found: C 62.66; H 5.95; N 11.67 [1583] Example 79 [1584] Pyrrolo [2,3-b] pyridin-3-yl) cyclohexyl] -1-piperazinyl} quinoline [1585] Pyrrolo [2,3-b] pyridin-3-yl) - cyclohexanone in place of 4- (lH- pyrrolo [2,3- b] pyridin- The title compound is prepared by the procedure described in example 78 using cyclohexanone (204.7 mg, 0.89 mmol). Yield: 30% (108.5 mg, 0.24 mmol): viscous yellow oil. [1586] Oxalate salt was prepared as described in Example 78 using 108.5 mg (0.25 mmol) of the title compound. Yield: 30% (39.2 mg, 0.072 mmol), mp: 105-110 ℃; MS (ES) m / z: 456.3 (MH) +, 228.8 (M / 2 + H) +. [1587] Elemental analysis: C 30 H 35 N 5 O 5 [1588] Calculated: C 66.00; H 6.46; N 12.83 [1589] Found: C 58.43; H 6.31; N 10.57 [1590] Example 80 [1591] 8- {cis-4- [4- (6-fluoro-lH-indol-3-yl) cyclohexyl] -1- piperazinyl} -6-methoxyquinoline [1592] Fluoro-lH-indol-3-yl) -cyclohexanone (401 mg, 1.87 < RTI ID = 0.0 & mmol), < / RTI > the title compound is prepared. Yield: 28% (243 mg, 0.53 mmol): White crystalline solid. [1593] The oxalate salt was prepared as 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, mp: 239-243 [deg.] C; MS (ES) m / z: 459.3 (MH) < + & gt ; , 230.1 (M / 2 + H). [1594] Elemental analysis: C 30 H 33 FN 4 O 5 [1595] Calculated: C 65.64; H 6.06; N 10.21 [1596] Found: C 65.16; H 6.40; N 9.86 [1597] Example 81 [1598] 8- {cis-4- [4- (6-fluoro-l-methyl-lH-indol-3-yl) cyclohexyl] -1- piperazinyl} -6-methoxyquinoline [1599] Instead of 4- (6-fluoro-l-methyl-lH-indol-3-yl) -cyclohexanone ( 230 mg, 0.94 mmol), the title compound is prepared. Yield: 30% (131.6 mg, 0.28 mmol): white crystalline solid. [1600] Oxalate salt was prepared as described in Example 78 using 127.9 mg (0.27 mmol) of the title compound. Yield: 20% (30.1 mg, 0.054 mmol), mp: 219-223 [deg.] C; MS (ES) m / z: 473.2 (MH) < + & gt ; . [1601] Elemental analysis: C 31 H 35 FN 4 O 5 [1602] Calculated: C 66.14; H 6.27; N 9.95 [1603] Found: C 66.26; H 6.16; N 7.49 [1604] Example 82 [1605] 6-methoxy-8- (4- {cis) -4- [5- (trifluoromethyl) -lH-indol-3- yl] cyclohexyl} -1- piperazinyl) quinoline [1606] (5-trifluoromethyl-lH-indol-3-yl) -cyclohexanone (271.5 mg, , 0.97 mmol), the title compound was prepared. Yield: 12% (57 mg, 0.12 mmol): off-white solid. [1607] The oxalate salt is prepared as described in Example 78 using 25.6 mg (0.050 mmol) of the title compound. Yield: 67% (20 mg, 0.033 mmol), mp 143-147 [deg.] C; MS (ES) m / z: 509.4 (MH) < + & gt ; . [1608] Elemental analysis: C 31 H 33 F 3 N 4 O 5 [1609] Calculated: C 62.17; H 5.55; N 9.35 [1610] Found: C 57.55; H 5.84; N 8.63 [1611] Example 83a [1612] (Trifluoromethyl) -lH-indol-3-yl] cyclohexyl} piperazinyl) quinoline < / RTI > [1613] (L-methyl-5-trifluoromethyl-lH-indol-3-yl) -cyclohexane in place of 4- (lH- pyrrolo [2,3- b] pyridin- The title compound is prepared by the procedure described for example 78 using < RTI ID = 0.0 > (750.3 < / RTI > Flash chromatography is carried out using gradient elution of ethyl acetate / MeOH (40: 1 to 10: 1 to 4: 1): Rf = 0.36. Yield: 12% (162.1 mg, 0.30 mmol): tan solid. [1614] The oxalate salt was prepared as described in Example 78 using 93.5 mg (0.18 mmol) of the title compound. Yield: 29% (31.4 mg, 0.051 mmol), mp: 101-104 [deg.] C; MS (ES) m / z: 523.2 (MH) < + & gt ; . [1615] Elemental analysis: C 32 H 35 F 3 N 4 O 5 [1616] Calculated: C 62.70; H 5.76; N 9.14 [1617] Found: C 55.43; H 6.21; N 7.75 [1618] Example 83b [1619] (Trifluoromethyl) -lH-indol-3-yl] cyclohexyl} piperazinyl) quinoline < / RTI > [1620] The trans compound (R f = 0.26) was isolated as a tan solid simultaneously with the cis isomer in 11% yield (140 mg, 0.27 mmol). Oxalate salt was prepared as described in Example 78 using 100 mg (0.19 mmol) of the title compound. Yield: 86% (101 mg, 0.16 mmol), mp: 111-115 [deg.] C; MS (ES) m / z: 523.3 (MH) < + & gt ; . [1621] Elemental analysis: C 32 H 35 F 3 N 4 O 5 [1622] Calculated: C 62.70; H 5.76; N 9.14 [1623] Found: C 59.47; H 5.80; N 7.93 [1624] Example 84 [1625] 3 - {(cis) -4- [4- (6-methoxy-8-quinolinyl) -1-piperazinyl] cyclohexyl} -1-methyl-1H-carbonitrile [1626] (4-oxo-cyclohexyl) -1H-indole-6-carbonitrile (164 < RTI ID = 0.0 & mg, 0.69 mmol), the title compound is prepared. Flash chromatography is carried out using gradient elution of ethyl acetate / MeOH (40: 1 to 10: 1 to 4: 1) instead of CH 2 Cl 2 / MeOH. Yield: 20% (80.4 mg, 0.17 mmol): yellow solid. [1627] Oxalate salt was prepared as described in Example 78 using 80.4 mg (0.17 mmol) of the title compound and DMF instead of EtOH. Yield: 56% (53.4 mg, 0.094 mmol), mp: 111-114 [deg.] C; MS (ES) m / z: 480.2 (MH) < + & gt ; , 240.7 (M / 2 + H) < + & gt ; . [1628] Elemental analysis: C 32 H 35 N 5 O 5 [1629] Calculated: C 67.43; H 6.19; N 12.29 [1630] Found: C 62.99; H 5.98; N 11.16 [1631] Example 85 [1632] 3- {4- [4- {6-Methoxy-8-quinolinyl) -1-piperazinyl] cyclohexyl} -1H-indole- [1633] (4-oxo-cyclohexyl) -1H-indole-6-carbonitrile (404.8 mg, 1.7 mmol) instead of 4- (lH- pyrrolo [2,3- b] pyridin- ), ≪ / RTI > the title compound is prepared. Flash chromatography is performed using gradient elution of ethyl acetate / MeOH (40: 1 to 10: 1 to 4: 1). Yield: 63% (493.7 mg, 1.06 mmol): tan solid. [1634] Oxalate salt was prepared as described in Example 78 using 183.5 mg (0.39 mmol) of the title compound and DMF instead of EtOH. Yield: 43% (93 mg, 0.20 mmol), mp: 242-244 [deg.] C; MS (ES) m / z: 466.2 (MH) < + & gt ; . [1635] Elemental analysis: C 31 H 33 N 5 O 5 [1636] Calculated: C 66.97; H 5.98; N 12.60 [1637] Found: C 67.56; H 6.09; N 13.15 [1638] Example 86a [1639] Yl} -cyclohexyl] -piperazin-1-yl} -6-methoxy-8- {4 - [(1,4- Lt; / RTI > [1640] 0.245 g of 4- (5-fluoro-1-methyl-1H-3-indolyl) -cyclohexane was added to a solution of 0.270 g of 6-methoxy, 8-piperazino-quinoline in 20 ml of CH 2 Cl 2 , 0.530 g of sodium triacetoxyborohydride and 0.09 ml of acetic acid are added. The reaction is stirred overnight at room temperature. It is quenched with 1N NaOH and the product is extracted with CH 2 Cl 2 . The organic phase is washed with water and dried over magnesium sulphate. 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 yield 0.115 g of the desired product: mp 216-218 [deg.] C; MS (ES) m / z (relative intensity): 473 (M < + & gt ; + H, 100). [1641] Example 86b [1642] Yl} -cyclohexyl] -piperazin-1-yl} -6-methoxy-8- {4 - [(1,4-trans) -4- Lt; / RTI > [1643] The trans isomer is separated off simultaneously with the cis isomer as an off-white solid (0.013020 g). mp: 198-200 [deg.] C. MS (ES) m / z (relative intensity): 473 (M < + & gt ; + H, 100). [1644] Example 87a [1645] - {4- [4 - ((l, 4-cis) -lH-indol-3- yl) -cyclohexyl] -piperazin- 1 -yl} -6-methoxy-quinoline [1646] To a solution of 0.350 g of 6-methoxy, 8-piperazino-quinoline in 10 ml of CH 2 Cl 2 was added 0.335 g of 4- (1H-3-indolyl) -cyclohexane followed by 0.840 g of sodium triacetoxyborohydride 0.2 ml of acetic acid is added. The reaction is stirred overnight at room temperature. It is quenched with 1N NaOH and the product is extracted with CH 2 Cl 2 . The organic phase is washed with water and dried over magnesium sulphate. 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: mp 165-171 [deg.] C; MS (ES) m / z (relative intensity): 441 (M < + & gt ; + H, 100). [1647] Example 87b [1648] -8- {4- [4 - ((1,4-trans) -lH-indol-3-yl) -cyclohexyl] -piperazin- 1- yl} -6-methoxy-quinoline [1649] The trans isomer is separated off simultaneously with the cis isomer as an off-white solid (0.023 g). mp: 118-122 [deg.] C. MS (ES) m / z (relative intensity): 441 (M < + & gt ; + H, 100). [1650] Example 88a [1651] - (l, 4-cis) -4- [4- (6-methoxy-quinolin-8-yl) -piperazin- 1- yl] -cyclohexyl} - Carbonitrile [1652] 0.252 g of 3- (4-oxo-cyclohexyl) -1-methyl-1H-indole-5-carbonitrile was added to a solution of 0.242 g of 6-methoxy, 8-piperazino-quinoline in 10 ml of CH 2 Cl 2 , Then 0.527 g of sodium triacetoxyborohydride and 0.2 ml of acetic acid are added. The reaction is stirred overnight at room temperature. It is quenched with 1N NaOH and the product is extracted with CH 2 Cl 2 . The organic phase is washed with water and dried over magnesium sulphate. 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: mp 239-240 [deg.] C; MS (ES) m / z (relative intensity): 480 (M < + & gt ; + H, 100). [1653] Example 88b [1654] 1 - [(1,4-trans) -4- [4- (6-methoxy-quinolin-8-yl) -piperazin- 1- yl] -cyclohexyl} - Carbonitrile [1655] The trans isomer is separated off simultaneously with the cis isomer as an off-white solid (0.029 g). mp: 225-228 [deg.] C. MS (ES) m / z (relative intensity): 480 (M < + & gt ; + H, 100). [1656] Example 89a [1657] Yl) -cyclohexyl] -piperazin-1-yl} - quinoline (prepared according to the procedure described for the synthesis of 6-methoxy-8- [1658] To a solution of 0.243 g of 6-methoxy, 8-piperazino-quinoline in 10 ml of CH 2 Cl 2 was added 0.250 g of 4- (l-methyl-lH-3-indolyl) -cyclohexanone followed by sodium triacetoxyborane 0.527 g of the Lohaiide and 0.2 ml of acetic acid are added. The reaction is stirred overnight at room temperature. It is quenched with 1N NaOH and the product is extracted with CH 2 Cl 2 . The organic phase is washed with water and dried over magnesium sulphate. 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 yield 0.120 g of the desired product: mp 190-191 [deg.] C; MS (ES) m / z (relative intensity): 455 (M < + & gt ; + H, 100). [1659] Example 89b [1660] - [4- (l- methyl-lH-indol-3-yl) -cyclohexyl] -piperazin- 1-yl} - quinoline [1661] The trans isomer is separated off simultaneously with the cis isomer as an off-white solid (0.027 g). mp: 208-210 [deg.] C. MS (ES) m / z (relative intensity): 455 (M < + & gt ; + H, 100). [1662] Example 90a [1663] - cyclohexyl] -piperazin-l-yl} -6-methyl-lH-pyrrolo [2,3-c] - quinoline [1664] 0.326 g of 4- (5-fluoro-1-methyl-3-indolyl) -cyclohexanone was added to a solution of 0.275 g of 6-methyl, 8-piperazino-quinoline in 10 ml of CH 2 Cl 2 , 0.639 g of cetoxyborohydride and 0.2 ml of acetic acid are added. The reaction is stirred overnight at room temperature. It is quenched with 1N NaOH and the product is extracted with CH 2 Cl 2 . The organic phase is washed with water and dried over magnesium sulphate. 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 yield 0.145 g of the desired product: mp 179-181 DEG C; MS (ES) m / z (relative intensity): 457 (M < + & gt ; + H, 100). [1665] Example 90b [1666] Yl) -cyclohexyl] -piperazin-l-yl} -6-methyl-lH-indol- - quinoline [1667] The trans isomer is separated off simultaneously with the cis isomer as an off-white solid (0.043 g). mp: 98-103 [deg.] C. MS (ES) m / z (relative intensity): 457 (M < + & gt ; + H, 100). [1668] Example 91a [1669] - {(l, 4-cis) -4- [4- (5-cyano-lH-indol-3- yl) -cyclohexyl] -piperazin- [1670] To a solution of 0.300 g of 6-methyl, 8-piperazino-quinoline in 10 ml of CH 2 Cl 2 was added 0.280 g of 4- (1H-3-indolyl) -cyclohexanone followed by 0.280 g of sodium triacetoxyborohydride And 0.2 ml of acetic acid are added. The reaction is stirred overnight at room temperature. It is quenched with 1N NaOH and the product is extracted with CH 2 Cl 2 . The organic phase is washed with water and dried over magnesium sulphate. 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 yield 0.125 g of the desired product: mp 132-135 [deg.] C; MS (ES) m / z (relative intensity): 425 (M < + & gt ; + H, 100). [1671] Example 91b [1672] - {(l, 4-cis) -4- [4- (5-cyano-lH-indol-3- yl) -cyclohexyl] -piperazin- [1673] To a solution of 0.275 g of 6-methyl, 8-piperazino-quinoline in 10 ml of CH 2 Cl 2 was added 0.315 g of 3- (4-oxo-cyclohexyl) -1H-indole-5-carbonitrile followed by sodium triacetoxyborane 0.639 g of the Lohaiide and 0.2 ml of acetic acid are added. The reaction is stirred overnight at room temperature. It is quenched with 1N NaOH and the product is extracted with CH 2 Cl 2 . The organic phase is washed with water and dried over magnesium sulphate. 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 yield 0.175 g of the desired product: mp 142-147 [deg.] C; MS (ES) m / z (relative intensity): 450 (M < + & gt ; + H, 100). [1674] Example 92 [1675] 1-yl} -6-methoxy-8- {(l, 4-cis) -4- [4- Lt; / RTI > [1676] 0.300 g of 4- (5-fluoro-1-ethyl-3-indolyl) -cyclohexanone was added to a solution of 0.400 g of 6-methoxy, 8-piperazino-quinoline in 20 ml of CH 2 Cl 2 , 0.651 g of triacetoxyborohydride and 0.4 ml of acetic acid are added. The reaction is stirred overnight at room temperature. It is quenched with 1N NaOH and the product is extracted with CH 2 Cl 2 . The organic phase is washed with water and dried over magnesium sulphate. 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 yield 0.041 g of the desired product: mp 203-205 [deg.] C; MS (ES) m / z (relative intensity): 487 (M < + & gt ; + H, 100). [1677] Example 93a [1678] 1-yl} -6-me- < / RTI > < RTI ID = 0.0 ≪ / RTI > [1679] 0.565 g of 4- (5-methoxy-1-methyl-3-indolyl) -cyclohexanone was added to a solution of 0.500 g of 6-methoxy, 8-piperazino-quinoline in 20 ml of CH 2 Cl 2 , 1.1 g of triacetoxyborohydride and 0.4 ml of acetic acid are added. The reaction is stirred overnight at room temperature. It is quenched with 1N NaOH and the product is extracted with CH 2 Cl 2 . The organic phase is washed with water and dried over magnesium sulphate. 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: mp 170-172 [deg.] C; MS (ES) m / z (relative intensity): 485 (M < + & gt ; + H, 100). [1680] Example 93b [1681] - {(1,4-trans) -4- [4- (5-methoxy-lH-indol-3- yl) -cyclohexyl] -piperazin- 1 -yl} -6-methoxy-quinoline [1682] The trans isomer is separated off simultaneously with the cis isomer as an off-white solid (0.039 g). mp: 185-186 [deg.] C. MS (ES) m / z (relative intensity): 485 (M < + & gt ; + H, 100). [1683] Example 94a [1684] 1-yl] -cyclohexyl} -l-methyl-lH-indole-lH-indole- 5-Carbonitrile [1685] To a solution of 0.350 g of 6-isopropoxy, 8-piperazino-quinoline in 10 ml of CH 2 Cl 2 was added 0.356 g of 3- (4-oxo-cyclohexyl) -1-methyl-1H-indole- , Followed by 0.405 g of sodium triacetoxyborohydride and 0.08 ml of acetic acid. The reaction is stirred overnight at room temperature. It is quenched with 1N NaOH and the product is extracted with CH 2 Cl 2 . The organic phase is washed with water and dried over magnesium sulphate. 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 yield 0.141 g of the desired product: mp 223-226 [deg.] C; MS (ES) m / z (relative intensity): 508 (M + + H, 100). [1686] Example 94b [1687] 1-yl] -cyclohexyl} -l-methyl-lH-indole-lH-indole- 5-Carbonitrile [1688] The trans isomer is separated off simultaneously with the cis isomer as an off-white solid (0.087 g). mp: 221-223 [deg.] C. MS (ES) m / z (relative intensity): 508 (M + + H, 100). [1689] Example 95a [1690] - (l, 4-cis) -4- [4- (6-fluoro-quinolin-8-yl) -piperazin- 1- yl] -cyclohexyl} - Carbonitrile [1691] 0.411 g of 3- (4-oxo-cyclohexyl) -1-methyl-1H-indole-5-carbonitrile was added to a solution of 6-fluoro, 8-piperazino-quinoline 0.300 g in 10 ml of CH 2 Cl 2 , Then 0.359 g of sodium triacetoxyborohydride and 0.1 ml of acetic acid are added. The reaction is stirred overnight at room temperature. It is quenched with 1N NaOH and the product is extracted with CH 2 Cl 2 . The organic phase is washed with water and dried over magnesium sulphate. 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 yield 0.187 g of the desired product: mp 230 [deg.] C; MS (ES) m / z (relative intensity): 468 (M < + & gt ; + H, 100). [1692] Example 95b [1693] 1 - [(1,4-trans) -4- [4- (6-fluoro-quinolin-8-yl) -piperazin- 1- yl] -cyclohexyl} - Carbonitrile [1694] The trans isomer is separated off simultaneously with the cis isomer as an off-white solid (0.039 g). mp: 214-216 [deg.] C. MS (ES) m / z (relative intensity): 468 (M < + & gt ; + H, 100). [1695] Example 96a [1696] 1 - [(1,4-cis) -4- [4- (6-trifluoromethoxy-quinolin-8-yl) -piperazin- 1-yl] -cyclohexyl} -5-carbonitrile [1697] 0.272 g of 3- (4-oxo-cyclohexyl) -1-methyl-1H-indole-5-carbonitrile was added to a solution of 0.297 g of 6-trifluoromethoxy, 8- 0.316 g of sodium triacetoxyborohydride and 0.1 ml of acetic acid were added. The reaction is stirred overnight at room temperature. It is quenched with 1N NaOH and the product is extracted with CH 2 Cl 2 . The organic phase is washed with water and dried over magnesium sulphate. 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 yield 0.166 g of the desired product: mp 206 [deg.] C; MS (ES) m / z (relative intensity): 534 (M < + & gt ; + H, 100). [1698] Example 96b [1699] 1 - [(1,4-trans) -4- [4- (6-trifluoromethoxy-quinolin-8-yl) -piperazin- 1- yl] -cyclohexyl} -5-carbonitrile [1700] The trans isomer is separated off simultaneously with the cis isomer as an off-white solid (0.064 g). mp: 170 [deg.] C. MS (ES) m / z (relative intensity): 534 (M < + & gt ; + H, 100). [1701] Example 97a [1702] 1-yl] -cyclohexyl} -l-methyl-lH-indole-5 < / RTI > - Carbonitrile [1703] To a solution of 0.500 g of 5-methoxy, 8-piperazino-quinoline in 10 ml of DCE was added 0.544 g of 3- (4-oxo-cyclohexyl) -1-methyl-lH- indole-5-carbonitrile followed by sodium tri 0.633 g of cetoxyborohydride and 0.2 ml of acetic acid were added. The reaction is stirred overnight at room temperature. It is quenched with 1N NaOH and the product is extracted with CH 2 Cl 2 . The organic phase is washed with water and dried over magnesium sulphate. 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: mp 221 [deg.] C; MS (ES) m / z (relative intensity): 480 (M < + & gt ; + H, 100). [1704] Example 97b [1705] 1 - [(1,4-trans) -4- [4- (5-methoxy-quinolin-8-yl) -piperazin- 1-yl] -cyclohexyl} - Carbonitrile [1706] The trans isomer is separated off simultaneously with the cis isomer as an off-white solid (0.118 g). mp: 206 [deg.] C. MS (ES) m / z (relative intensity): 480 (M < + & gt ; + H, 100). [1707] Example 98a [1708] - {(l, 4-cis) -4- [4- (5-Fluoro-lH-indol-3- yl) -cyclohexyl] -piperazin- 1- yl} -6- fluoro-quinoline [1709] To a solution of 0.300 g of 6-fluoro, 8-piperazino-quinoline in 10 ml of DCE was added 0.411 g of 4- (5-fluoro-1-methyl-3-indolyl) - cyclohexanone followed by sodium triacetoxyborane 0.349 g of LOHHIDOR and 0.1 mL of acetic acid are added. The reaction is stirred overnight at room temperature. It is quenched with 1N NaOH and the product is extracted with CH 2 Cl 2 . The organic phase is washed with water and dried over magnesium sulphate. 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 yield 0.190 g of the desired product: mp 194.5 [deg.] C; MS (ES) m / z (relative intensity): 461 (M < + & gt ; + H, 100). [1710] Example 98b [1711] - {(1,4-trans) -4- [4- (5-fluoro-lH-indol-3- yl) -cyclohexyl} -piperazin- 1- yl} -6- [1712] The trans isomer is separated off simultaneously with the cis isomer as an off-white solid (0.062 g). mp: 171 [deg.] C. MS (ES) m / z (relative intensity): 461 (M < + & gt ; + H, 100). [1713] Example 99a [1714] 1-yl] -cyclohexyl} -l-methyl-lH-indole-5 < / RTI > - Carbonitrile [1715] To a solution of 0.300 g of 6-benzyloxy, 8-piperazino-quinoline in 10 ml of DCE was added 0.252 g of 3- (4-oxo-cyclohexyl) -1-methyl-1H- indole- 0.297 g of cetoxyborohydride and 0.1 ml of acetic acid are added. The reaction is stirred overnight at room temperature. It is quenched with 1N NaOH and the product is extracted with CH 2 Cl 2 . The organic phase is washed with water and dried over magnesium sulphate. 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 yield 0.172 g of the desired product: mp 171 [deg.] C; MS (ES) m / z (relative intensity): 556 (M < + & gt ; + H, 100). [1716] Example 99b [1717] 1 - [(1,4-trans) -4- [4- (6-benzyloxy-quinolin-8-yl) -piperazin- 1- yl] -cyclohexyl} - Carbonitrile [1718] The trans isomer is separated off simultaneously with the cis isomer as an off-white solid (0.083 g). mp: 118.5 [deg.] C. MS (ES) m / z (relative intensity): 556 (M < + & gt ; + H, 100). [1719] Example 100 [1720] 1 - [(1,4-cis) -4- [4- (6-hydroxy-quinolin-8-yl) -piperazin- 1- yl] -cyclohexyl} - Carbonitrile [1721] 1-yl] -cyclohexyl} -1-methyl-1H-indole-2-carboxylic acid ethyl ester in THF was added to a solution of 3 - {(1,4- A solution of 5-carbonitrile is added to a suspension of 0.015 g 10% Pd / C in MeOH and hydrogenated for 1/2 hour. Filtration followed by evaporation of the solvent afforded 0.045 g of the desired product. mp 144 [deg.] C. MS (ES) m / z (relative intensity): 466 (M < + & gt ; + H, 100). [1722] Example 101 [1723] - (l, 4-cis) -4- [4- (6-fluoro-8-quinolinyl) -1-piperazinyl] -cyclohexyl} Carboxamide [1724] To a solution of 6-fluoro-8- {4- [4- (5-fluoro-1-methyl-lH-indol-3- yl) cyclohexyl] -1- piperazinyl} quinoline To a solution of 0.100 g is added 1 ml of 5N NaOH followed by 2 ml of 30% H 2 O 2 . The mixture is stirred at room temperature for 24 hours. Water is added and the product is filtered to give 0.035 g of the desired product. mp 289 [deg.] C. MS (ES) m / z (relative intensity): 486 (M < + & gt ; + H, 100). [1725] Example 102a [1726] L-yl] -cyclohexyl} -l-methyl-lH-indole < / RTI > -5-carbonitrile [1727] 0.224 g of 3- (4-oxo-cyclohexyl) -1-methyl-1H-indole-5-carbonitrile was added to a solution of 0.250 g of 5-trifluoromethyl, 8- 0.287 g of sodium triacetoxyborohydride and 0.2 ml of acetic acid are added. The reaction is stirred overnight at room temperature. It is quenched with 1N NaOH and the product is extracted with CH 2 Cl 2 . The organic phase is washed with water and dried over magnesium sulphate. 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 yield 0.057 g of the desired product: mp 231 [deg.] C; MS (ES) m / z (relative intensity): 518 (M < + & gt ; + H, 100). [1728] Example 102b [1729] 1-yl] -cyclohexyl} -1-methyl-1H-indole < RTI ID = 0.0 > -5-carbonitrile [1730] The trans isomer is separated off simultaneously with the cis isomer as an off-white solid (0.044 g). mp: 194-197 [deg.] C. MS (ES) m / z (relative intensity): 518 (M < + & gt ; + H, 100). [1731] Example 103a [1732] L-yl] -cyclohexyl} -l-methyl-lH-indol-5- < / RTI > Carbonitrile [1733] To a solution of 0.300 g of 6-chloro, 8-piperazino-quinoline in 10 ml of DCE was added 0.305 g of 3- (4-oxo-cyclohexyl) -l-methyl-lH- indole-5-carbonitrile followed by sodium triacetoxy 0.274 g of hydrazide and 0.2 ml of acetic acid are added thereto. The reaction is stirred overnight at room temperature. It is quenched with 1N NaOH and the product is extracted with CH 2 Cl 2 . The organic phase is washed with water and dried over magnesium sulphate. 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 yield 0.057 g of the desired product: mp 222 deg. MS (ES) m / z (relative intensity): 485 (M < + & gt ; + H, 100). [1734] Example 103b [1735] L-yl] -cyclohexyl} -l-methyl-lH-indol-5- < / RTI > Carbonitrile [1736] The trans isomer is separated off simultaneously with the cis isomer as an off-white solid (0.044 g). mp: 229 [deg.] C. MS (ES) m / z (relative intensity): 485 (M < + & gt ; + H, 100). [1737] Example 104a [1738] Yl} -cyclohexyl} -piperazin-1-yl} -6-chloro-pyrimidin-4- - quinoline [1739] 0.245 g of 4- (5-fluoro-l-methyl-3-indolyl) -cyclohexanone was added to a solution of 0.247 g of 6-chloro, 8-piperazino-quinoline in 10 ml of DCE, followed by sodium triacetoxyborohydride 0.274 g of hydride and 0.2 ml of acetic acid are added. The reaction is stirred overnight at room temperature. It is quenched with 1N NaOH and the product is extracted with CH 2 Cl 2 . The organic phase is washed with water and dried over magnesium sulphate. 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 yield 0.070 g of the desired product: mp 219 [deg.] C; MS (ES) m / z (relative intensity): 478 (M < + & gt ; + H, 100). [1740] Example 104b [1741] Yl} -cyclohexyl} -piperazin-1-yl} -6-chloro-pyrimidin-4- - quinoline [1742] The trans isomer is separated off simultaneously with the cis isomer as an off-white solid (0.049 g). mp: 193 [deg.] C. MS (ES) m / z (relative intensity): 478 (M < + & gt ; + H, 100). [1743] Example 105a [1744] - (l, 4-cis) -4- [4- (5-chloro-8-quinolinol) -l-piperazinyl] -cyclohexyl} Nitrile [1745] 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-lH- indole-5-carbonitrile followed by sodium triacetoxy 0.274 g of hydrazide and 0.2 ml of acetic acid are added thereto. The reaction is stirred overnight at room temperature. It is quenched with 1N NaOH and the product is extracted with CH 2 Cl 2 . The organic phase is washed with water and dried over magnesium sulphate. 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: mp 243-248 [deg.] C; MS (ES) m / z (relative intensity): 485 (M < + & gt ; + H, 100). [1746] Example 105b [1747] 3 - {(1,4-trans) -4- [4- (5-chloro-8-quinolinyl) -1-piperazinyl] -cyclohexyl} -1-methyl-1H-indole- Nitrile [1748] The trans isomer is separated off simultaneously with the cis isomer as an off-white solid (0.034 g). mp: 192-196 [deg.] C. MS (ES) m / z (relative intensity): 485 (M < + & gt ; + H, 100). [1749] Example 106a [1750] 1-yl} -5-chloro-pyrimidin-4-ylmethyl) -piperazin-1- - quinoline [1751] To a solution of 0.250 g of 5-chloro, 8-piperazino-quinoline in 10 ml of DCE was added 0.224 g of 4- (5-fluoro-l-methyl-3-indolyl) -cyclohexanone followed by sodium triacetoxyborane 0.274 g of hydride and 0.1 ml of acetic acid are added. The reaction is stirred overnight at room temperature. It is quenched with 1N NaOH and the product is extracted with CH 2 Cl 2 . The organic phase is washed with water and dried over magnesium sulphate. 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 yield 0.053 g of the desired product: mp 196 [deg.] C; MS (ES) m / z (relative intensity): 478 (M < + & gt ; + H, 100). [1752] Example 106b [1753] 1-yl} -5-chloro-pyridin-4-ylmethyl) -pyrrolidin-1- - quinoline [1754] The trans isomer is simultaneously separated off with the cis isomer as an off-white solid (0.025 g). mp: 196 [deg.] C. MS (ES) m / z (relative intensity): 478 (M < + & gt ; + H, 100). [1755] Example 107a [1756] 1-yl} -5-chloro-pyrimidin-4-ylmethyl) -piperazin-1- - quinoline [1757] 0.250 g of 4- (6-fluoro-l-methyl-3-indolyl) -cyclohexanone was added to a solution of 0.250 g of 5-chloro, 8-piperazino- quinoline in 10 ml of DCE, followed by sodium triacetoxyborane 0.274 g of hydride and 0.2 ml of acetic acid are added. The reaction is stirred overnight at room temperature. It is quenched with 1N NaOH and the product is extracted with CH 2 Cl 2 . The organic phase is washed with water and dried over magnesium sulphate. 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 yield 0.030 g of the desired product: mp 107-110 [deg.] C; MS (ES) m / z (relative intensity): 478 (M < + & gt ; + H, 100). [1758] Example 107b [1759] 1-yl} -5-chloro-pyrimidin-4-yl) -pyrrolidin-1- - quinoline [1760] The trans isomer is separated off simultaneously with the cis isomer as an off-white solid (0.014 g). mp: 228 [deg.] C. MS (ES) m / z (relative intensity): 478 (M < + & gt ; + H, 100). [1761] Example 108a [1762] 1-yl} -6-methoxy-8- {(l, 4-cis) Lt; / RTI > [1763] 0.959 g of 4- (5-benzyloxy-l-methyl-3-indolyl) -cyclohexanone was added to a solution of 0.650 g of 6-methoxy, 8-piperazino-quinoline in 15 ml of DCE, 0.790 g of Lohyder and 0.5 ml of acetic acid are added. The reaction is stirred overnight at room temperature. It is quenched with 1N NaOH and the product is extracted with CH 2 Cl 2 . The organic phase is washed with water and dried over magnesium sulphate. 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 yield 0.175 g of the desired product: mp 168 [deg.] C; MS (ES) m / z (relative intensity): 561 (M < + & gt ; + H, 100). [1764] Example 108b [1765] 1-yl} -6-methoxy-8- {(l, 4-trans) -4- [4- (5-benzyloxy- l- methyl- lH-indol-3- yl) -cyclohexyl] -piperazin- Lt; / RTI > [1766] The trans isomer is separated as an off-white solid (0.055 g) simultaneously with the cis isomer. mp: 228 [deg.] C. MS (ES) m / z (relative intensity): 561 (M < + & gt ; + H, 100). [1767] Example 109a [1768] Yl} -5-fluoro-5-fluoro-5-fluoro-4- -Quinoline [1769] To a solution of 0.231 g of 5-fluoro, 8-piperazino-quinoline in 10 ml of DCE was added 0.245 g of 4- (6-fluoro-l-methyl-3-indolyl) -cyclohexanone followed by sodium triacetoxyborane 0.274 g of the Lohaiide and 0.1 ml of acetic acid are added. The reaction is stirred overnight at room temperature. It is quenched with 1N NaOH and the product is extracted with CH 2 Cl 2 . The organic phase is washed with water and dried over magnesium sulphate. 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 yield 0.030 g of the desired product: mp 112-115 C; MS (ES) m / z (relative intensity): 461 (M < + & gt ; + H, 100). [1770] Example 109b [1771] 1-yl} -5-fluoro-5-fluoro-4-fluoro-4- -Quinoline [1772] The trans isomer is separated off simultaneously with the cis isomer as an off-white solid (0.010 g). MS (ES) m / z (relative intensity): 461 (M < + & gt ; + H, 100). [1773] Example 110 [1774] 3- {(l, 4-cis) -4- [4- (6-methoxy-8- quinolinyl) -1- piperazinyl] -cyclohexyl} All [1775] 1-yl} -cyclohexyl] -piperazin-1-yl} - < / RTI > -6-methoxy-quinoline in 10 ml of dichloromethane is added to a suspension of 0.110 g of 10% Pd / C in MeOH and hydrogenated for 1 hour. Filtration followed by evaporation of the solvent afforded 0.036 g of the desired product. mp 250 [deg.] C. MS (ES) m / z (relative intensity): 471 (M < + & gt ; + H, 100). [1776] Example 111a [1777] 1-yl} -5-fluoro-5-fluoro-4-methoxy- -Quinoline [1778] 0.245 g of 4- (5-fluoro-l-methyl-3-indolyl) -cyclohexanone was added to a solution of 0.200 g of 5-fluoro, 8-piperazino- quinoline in 10 ml of DCE followed by sodium triacetoxyborohydride 0.274 g of the Lohaiide and 0.1 ml of acetic acid are added. The reaction is stirred overnight at room temperature. It is quenched with 1N NaOH and the product is extracted with CH 2 Cl 2 . The organic phase is washed with water and dried over magnesium sulphate. 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: mp 199-202 [deg.] C; MS (ES) m / z (relative intensity): 461 (M < + & gt ; + H, 100). [1779] Example 111b [1780] Yl} -5-fluoro-5-fluoro-4-fluoro-4- -Quinoline [1781] The trans isomer is separated off simultaneously with the cis isomer as an off-white solid (0.021 g). mp 197 [deg.] C. MS (ES) m / z (relative intensity): 461 (M < + & gt ; + H, 100). [1782] Example 112a [1783] (4-fluoro-1-methyl-1H-indol-3-yl) -cyclohexyl] -1-piperazinyl} quinoline [1784] 0.245 g of 4- (5-fluoro-l-methyl-3-indolyl) -cyclohexanone was added to a solution of 0.247 g of 8-chloro, 8-piperazino-quinoline in 10 ml of DCE, followed by sodium triacetoxyborohydride 0.274 g of hydride and 0.1 ml of acetic acid are added. The reaction is stirred overnight at room temperature. It is quenched with 1N NaOH and the product is extracted with CH 2 Cl 2 . The organic phase is washed with water and dried over magnesium sulphate. 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 yield 0.085 g of the desired product: mp 182-184 [deg.] C; MS (ES) m / z (relative intensity): 478 (M < + & gt ; + H, 100). [1785] Example 112b [1786] (4-fluoro-1-methyl-1H-indol-3-yl) -cyclohexyl] -1-piperazinyl} quinoline [1787] The trans isomer is simultaneously separated off with the cis isomer as an off-white solid (0.025 g). mp 181-182 [deg.] C. MS (ES) m / z (relative intensity): 478 (M < + & gt ; + H, 100). [1788] Example 113a [1789] 3- {(l, 4-cis) -4- [4- (8-chloro-7-quinolinyl) - 1-piperazinyl] -cyclohexyl} -l-methyl-lH-indole- Nitrile [1790] 0.252 g of 4- (5-fluoro-l-methyl-lH-3-indolyl) -cyclohexanone was added to a solution of 0.247 g of 8-chloro, 7-piperazino- quinoline in 10 ml of DCE, 0.274 g of hydrazide and 0.2 ml of acetic acid are added thereto. The reaction is stirred overnight at room temperature. It is quenched with 1N NaOH and the product is extracted with CH 2 Cl 2 . The organic phase is washed with water and dried over magnesium sulphate. 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: mp 240-242 [deg.] C; MS (ES) m / z (relative intensity): 485 (M < + & gt ; + H, 100). [1791] Example 113b [1792] 3 - {(1,4-trans) -4- [4- (8-chloro-7-quinolinyl) -1-piperazinyl] -cyclohexyl} -1-methyl-1H-indole- Nitrile [1793] The trans isomer is separated off simultaneously with the cis isomer as an off-white solid (0.015 g). mp 233-237 [deg.] C. MS (ES) m / z (relative intensity): 485 (M < + & gt ; + H, 100). [1794] Example 114a [1795] 4-fluoro-quinolin-8-yl) -piperazin-1-yl] -cyclohexyl} -lH-indole-5-carbonitrile [1796] To a solution of 0.310 g of 4-fluoro-8-piperazino-quinoline in 50 ml of CH 2 Cl 2 was added 0.319 g (1.34 mmol) 3- (4-oxo-cyclohexyl) 0.402 g (1.5 eq) of sodium triacetoxyborohydride and 0.076 ml of acetic acid are then added. The reaction is stirred overnight at room temperature. It is quenched with 1N NaOH and the product is extracted with ether. The organic phase is 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 product: mp 152-160 [deg.] C; MS (ES) m / z (relative intensity): 454.3 (M < + & gt ; + H, 100). [1797] Example 114b [1798] 4-fluoro-quinolin-8-yl) -piperazin-l-yl] -cyclohexyl} -lH-indole-5-carbonitrile [1799] The trans isomer (0.065 g) was isolated as an off-white solid simultaneously with the cis isomer. mp 144-152 [deg.] C. MS (ES) m / z (relative intensity): 454.4 (M < + & gt ; + H, 100). [1800] The activity of the compounds is demonstrated by the following standard pharmacological test procedures. [1801] PCR cloning of the human 5-HT 1A receptor subtype from the human genomic library has been previously described (Chanda et al., Mol. Pharmacol., 43: 516 (1993)). A stable Chinese hamster ovary cell line (5-HT 1A CHO cell) expressing the human 5-HT 1A receptor subtype is used throughout this study. Cells are maintained in DMEM supplemented with 10% fetal calf serum, non-essential amino acids and penicillin / streptomycin. [1802] Cells are grown to 95-100% fusion into a single layer prior to harvesting the membrane for binding studies. Cells are gently scraped off the culture plate and transferred to a centrifuge tube and washed twice with centrifugation (2000 rpm, 4 ° C for 10 minutes) in buffer (50 mM Tris, pH 7.5). Aliquot the resulting pellets and leave at -80 ° C. On the day of analysis, the cells are thawed on ice and resuspended in buffer. The study is carried out using [ 3 H] 8-OH-DPAT as a radioligand. Binding assays are performed in a 96 well microtiter plate with a final total volume of 250 [mu] l of buffer. Competition experiments are performed using 7 concentrations of non-labeled drug and 1.5 nM of final ligand concentration. Non-specific binding is measured in the presence of 10 [mu] M 5HT. Saturation assays are performed using [ 3 H] 8-OH-DPAT at concentrations ranging from 0.3 to 30 nM. After 30 minutes of incubation at room temperature, the reaction was terminated by the addition of ice-cold buffer, followed by rapid filtration through a GF / B filter pre-immersed in 0.5% polyethyleneimine for 30 min using an M-96 Brandel Cell Harvester (Gaithersburg, MD) do. [1803] The affinity of the compounds for serotonin transporters is determined using a protocol similar to that used by Cheetham et al., Neuropharmacol., 32: 737 (1993). Briefly, an anterior cortical membrane prepared from Sprague-Dole rat male is incubated with 3 H-paroxanthin (0.1 nM) for 60 min at 25 ° C. All tubes also contain vehicle, test compound (1-8 concentrations), or saturating concentrations of fluoxintine (10 [mu] M) to define specific binding. All reactions are terminated by the addition of ice-cold Tris buffer followed by rapid filtration using a Tom Tech filtration apparatus to separate the bound from the free 3 H-paroxantine. Binding radioactivity is quantified using a Wallac 1205 Beta Plate R counter. IC 50 values were determined using non-linear regression analysis and compared to those reported by Cheng and Prusoff, Biochem Pharmacol., 22: 3099 (1973); The Ki value is converted using the method of Ki = IC50 / ((radioligand concentration) / (1 + KD)). [1804] The [ 35 S] -GTPgS binding assay was performed using the Lazareno and Birdsall, Br. J. Pharmacol. 109: 1120 (1983). Briefly, 5-HT 1A cloned receptor membrane fragments (as used for 5-HT 1A receptor binding assays) are stored at -70 ° C until needed. If necessary, the membranes were thawed rapidly and centrifuged at 40,000 xg for 10 min and then resuspended in assay buffer (25 mM HEPES, 3 mM MgCl 2 , 100 mM NaCl, 1 mM EDTA, 10 μM GDP, 500 mM DTT, pH 8.0) Lt; / RTI > These membranes were then incubated with [ 35 S] GTPgS (1 nM) in the presence of vehicle, test compound (1 to 8 concentrations), or excess 8-OH-DPAT for 30 min at 30 ° C to define maximal agonist response do. All reactions by rapid filtration using a Tom Tech filtration device to the next one R terminated by adding ice-cold Tris buffer recall separated ones from the combined glass [35 S] GTPgS. Agonists cause an increase in the amount of [ 35 S] GTPgS bound, whereas antagonists do not cause an increase in binding. The bound radioactivity is counted and analyzed as above. [1805] The following assays are performed by incubating the cells with DMEM containing 25 mM HEPES, 5 mM theophylline and 10 [mu] M pargyline for 20 min at 37 [deg.] C. The functional activity was assessed by treating the cells with the test compound (6 concentrations) immediately after treating the cells with phosholin (1 μM final concentration) for an additional 10 minutes at 37 ° C. In separate experiments, six concentrations of antagonist are pre-incubated for 20 min prior to the addition of 10 nM 8-OH-DPAT and phokolin. The reaction is terminated by removing the medium and adding 0.5 ml of ice-cold assay buffer. Plates are stored at -20 [deg.] C prior to evaluation of cAMP formation by cAMP SPA assay (Amersham). [1806] The compounds tested correspond to those prepared in Examples 1-13 above. The results of the procedure are listed in Table 1. [1807] Table 1 [1808] [1809] [1810] As demonstrated by the foregoing results, the compounds of the present invention are active against 5HT 1A receptors and generally elevate serotonin levels by inhibiting 5-HT transport. Thus, the present compounds are useful in the treatment of diseases associated with a deficiency of serotonin levels. [1811] The compounds of the present invention may be administered orally or parenterally, with or without conventional pharmaceutical carriers. Solid carriers that may be applied may include one or more substances that may also act as flavoring agents, lubricants, solubilizing agents, suspending agents, fillers, lubricants, compression aids, binders or tablet-disintegrating or encapsulating materials. In powders, the carrier is a finely divided solid which is mixed with the finely divided active component. In the case of tablets, the active ingredient is mixed with the carrier having the required compressibility in suitable proportions and compacted to the desired shape and size. The powders and tablets preferably contain up to 99% of the active ingredient. Solid carriers known to those skilled in the art can be used with the compounds of the present invention. Particularly suitable solid carriers are, for example, calcium phosphate, magnesium stearate, talc, sugar, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, sodium, carboxymethylcellulose, polyvinylpyrrolidone, Ion exchange resins. [1812] Liquid carriers may be used in the preparation of solutions, suspensions, emulsions, syrups and elixirs of the compounds of the present invention. The compounds of the present invention may be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of the two, or a pharmaceutically acceptable oil or fat. The liquid carrier may contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colorants, viscosity regulators, stabilizers or osmotic agents. Suitable examples of liquid carriers for oral and parenteral administration include water (especially those containing the aforementioned additives, for example, a cellulose derivative, preferably a sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols such as glycols And derivatives and oils thereof (e. G., Fractionated coconut oil and arachis oil). For parenteral administration, the carrier may also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid compositions for parenteral administration. [1813] Liquid pharmaceutical compositions that are sterile solutions or suspensions may be used, for example, intramuscularly, intraperitoneally or subcutaneously. The sterile solution may also be administered intravenously. Compositions for oral administration may be in the form of a liquid or solid composition. [1814] Preferably, the pharmaceutical compositions containing the compounds of the invention are unit dosage forms, for example tablets or capsules. In this form, the composition may be subdivided into unit doses containing a suitable amount of a compound of the present invention. The unit dosage form may be, for example, packet powder, vials, ampoules, pre-filled syringes, or a new shaker containing liquid. Alternatively, the unit dosage form may be, for example, a capsule or tablet itself, or it may be in the form of a package of a suitable number of such compositions. [1815] The therapeutically effective amount of a compound of the invention and the dosage regimen administered will depend on the subject's body weight, age, sex and medical condition, severity of the disease, the route and frequency of administration, and various factors including the particular compound employed, . However, it is contemplated that the pharmaceutical compositions may contain the compounds of the present invention in the range of about 0.1 to about 2000 mg, preferably in the range of about 0.5 to about 500 mg, more preferably about 1 to about 100 mg. The scheduled daily dose of active compound is from about 0.01 to about 100 mg / kg body weight. The daily dose may conveniently be administered 2 to 4 times per day. [1816] The present invention may be embodied in other specific forms without departing from the spirit and essential attributes thereof, and therefore, reference is made to the appended claims rather than to the foregoing specification as indicating the scope of the invention.
权利要求:
Claims (10) [1" claim-type="Currently amended] A compound of formula (I) or a pharmaceutically acceptable salt thereof. Formula 1 In this formula, R a , R 1 , R 2 and R 3 are each independently selected from the group consisting of hydrogen or halogen, CF 3 , alkyl, alkoxy, MeSO 2 , amino or aminocarbonyl (each optionally substituted with one or two groups selected from alkyl and benzyl) Optionally substituted by hydroxy, carboxy, or alkoxycarbonyl; Two adjacent R a and R 1-4 together may form a 5-7 membered carbocyclic or heterocyclic ring optionally substituted by a substituent as defined above; R 4 is hydrogen, halogen, or alkyl; R < 5 > is hydrogen, alkyl, alkylaryl, or aryl; R 6 is hydrogen, halogen, CF 3, CN, cover imide, alkoxy or benzyloxy, and; X 1 , X 2 and X 3 are each carbon or one of X 1 , X 2 or X 3 may be nitrogen; Y is CH or nitrogen; Z is carbon or nitrogen. [2" claim-type="Currently amended] A compound according to claim 1, wherein R a , R 1 , R 2 and R 3 are each independently hydrogen, halogen, alkyl, alkoxy or together form a 5-7 membered carbocyclic or heterocyclic ring . [3" claim-type="Currently amended] 3. The compound according to claim 1 or 2, wherein R < 4 > is hydrogen or halogen. [4" claim-type="Currently amended] 4. The compounds according to any one of claims 1 to 3, wherein R < 5 > is hydrogen, alkyl or alkylaryl. [5" claim-type="Currently amended] 5. Compounds according to any one of claims 1 to 4, wherein R < 6 > is hydrogen, halogen, CN or alkoxy. [6" claim-type="Currently amended] The compound according to any one of claims 1 to 5, wherein X 1 , X 2 , X 3 , Y and Z are each carbon. [7" claim-type="Currently amended] The method according to claim 1, 3- [cis-4- [4- (1H-Indol-4-yl) -1-piperazinyl] cyclohexyl] -1H-indole; 3- [trans-4- [4- (1H-indol-4-yl) -1-piperazinyl] cyclohexyl] -1H-indole; 4-Fluoro-3- [cis-4- [4- (1H-indol-4-yl) -1-piperazinyl] cyclohexyl] -1H-indole; 4-Fluoro-3- [trans-4- [4- (1H-indol-4-yl) -1-piperazinyl] cyclohexyl] -1H-indole; 5-Fluoro-3- [cis-4- [4- (1H-indol-4-yl) -1-piperazinyl] cyclohexyl] -1H-indole; 5-Fluoro-3- [trans-4- [4- (1H-indol-4-yl) -1-piperazinyl] cyclohexyl] -1H-indole; 6-Fluoro-3- [cis-4- [4- (1H-indol-4-yl) -1-piperazinyl] cyclohexyl] -1H-indole; 6-Fluoro-3- [trans-4- [4- (1H-indol-4-yl) -1-piperazinyl] cyclohexyl] -1H-indole; 5-Bromo-3- [cis-4- [4- (lH-indol-4-yl) -1-piperazinyl] cyclohexyl] -lH-indole; 5-Bromo-3- [trans-4- [4- (1H-indol-4-yl) -1-piperazinyl] cyclohexyl] -1H-indole; 5-Chloro-3- [cis-4- [4- (1H-indol-4-yl) -1-piperazinyl] cyclohexyl] -1H-indole; 5-chloro-3- [trans-4- [4- (1H-indol-4-yl) -1-piperazinyl] cyclohexyl] -1H-indole; 3- {4 - [(l, 4-cis) -4- (lH-Indol-4-yl) -piperazinyl- l-yl] cyclohexyl} -lH-indole-5-carbonitrile; 3- {4 - [(1,4-trans) -4- (1H-indol-4-yl) -piperazin-1 -yl] cyclohexyl} -1H-indole-5-carbonitrile; 5-Methoxy-3- [cis-4- [4- (1H-indol-4-yl) -1-piperazinyl] cyclohexyl] -1H-indole; 5-Methoxy-3- [trans-4- [4- (1H-indol-4-yl) -1-piperazinyl] cyclohexyl] -1H-indole; 3- [cis-4- [4- (1H-Indol-4-yl) -1-piperazinyl] cyclohexyl] -2-methyl-1H-indole; 3- [trans-4- [4- (1H-indol-4-yl) -1-piperazinyl] cyclohexyl] -2-methyl-1H-indole; 3 - {(1,4-cis-4- [4-1H-indol-4-yl) -piperazin- 1-yl] -cyclohexyl} -IH- pyrrolo [2,3-b] pyridine; LH-pyrrolo [2,3-b] pyridine prepared in step 2 of Example 1 was prepared in accordance with the general method of example 1 from 3 - {(l, 4-trans) -4- [4- ; 6-Fluoro-l-methyl-3- {cis-4- [4- (l-methyl-lH-indol-4-yl) -1-piperazinyl] cyclohexyl} -1H-indole; 3 - {(l, 4-cis) -4- [4- (lH-indol-4-yl) -piperazin-l-yl] cyclohexyl} -l-methyl-lH-indole-5-carbonitrile; 3 - {(1,4-trans) -4- [4- (1H-indol-4-yl) -piperazin-1-yl] cyclohexyl} -1-methyl-1H-indole-5-carbonitrile; 1-yl] -cyclohexyl} -lH-indole-5-carbonitrile < / RTI >; 1-yl] -cyclohexyl} -l-propyl-lH-indole-5-carbonitrile < / RTI >; 4-yl] -cyclohexyl} -l-propyl-lH-indole-5-carbonitrile < / RTI >; 4-yl) -piperazin-l-yl] -cyclohexyl} -l-isopropyl-lH-indole-5-carbo Nitrile; 1-yl] cyclohexyl} -l-isopropyl-lH-indole-5-carbonitrile < / RTI >; 1-yl] -cyclohexyl} -lH-indole-5-carbonitrile < / RTI >; 1 -yl] cyclohexyl} -lH-indole-5-carbo < / RTI >Nitrile; 1-yl] -piperazin-1-yl] -cyclohexyl} -1H-indole- 5-carbonitrile; 5-Fluoro-3 - {(cis) -4- [4- (2-methoxy-phenyl) -piperazin-1-yl] -cyclohexyl} -1H-indole; 5-Fluoro-3 - {(l, 4-cis) -4- [4- (2-methoxy-phenyl) -piperidin- l-yl] -cyclohexyl} -lH-indole; 5-Fluoro-3 - {(1,4-trans) -4- [4- (2-methoxy-phenyl) -piperidin- l-yl] -cyclohexyl} -1H-indole; 5-Methoxy-3 - {(l, 4-cis) -4- [4- (2-methoxy-phenyl) -piperazin-l-yl] -cyclohexyl} -lH-indole; 5-Methoxy-3 - {(1,4-trans) -4- [4- (2-methoxy-phenyl) -piperazin-1-yl] -cyclohexyl} -1H-indole; LH-pyrrolo [2,3-b] piperidine-lH-pyrrolo [2,3-b] Dean; 5-Fluoro-3 - {(cis) -4- [4- (5-fluoro-2-methoxy-phenyl) -piperazin-1-yl] -cyclohexyl} -1H-indole; 5-Fluoro-3 - {(trans) -4- [4- (5-fluoro-2-methoxy-phenyl) -piperazin-1-yl] -cyclohexyl} -1H-indole; Yl) -piperazin-1-yl] -cyclohexyl} -piperazin-1-yl) -4-fluoro-lH-indole < / RTI > Yl) -piperazin-1-yl] -cyclohexyl} - (3, 4-dihydro- 4-fluoro-lH-indole; Yl) -piperazin-1-yl] -cyclohexyl} - (2, 3-dihydro-benzo [ 5-fluoro-lH-indole; Yl) -piperazin-1-yl] -cyclohexyl} - (2, 3-dihydro-benzo [ 5-fluoro-lH-indole; Yl) -piperazin-1-yl] -cyclohexyl} - (3, 4-dihydro- 6-fluoro-lH-indole; Yl) -piperazin-1-yl] -cyclohexyl} - (2, 3-dihydro-benzo [ 6-fluoro-lH-indole; Benzo [1,4] dioxin-5-yl) -cyclohexyl} -1H-indole-5-carbo Nitrile; Yl) -piperazin-1-yl] -cyclohexyl} - (3, 4-dihydro- 1H-indole-5-carbonitrile; Yl) -piperazin-1-yl] -cyclohexyl} - (2, 3-dihydro-benzo [ 1H-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; Yl) -cyclohexyl] -piperazin-1-yl} - quinolin-4-yl) ; 3 - [(l, 4-cis) -4- (4-quinolin-8-yl-piperazin-l-yl) -cyclohexyl] -lH-indole-5-carbonitrile; 3 - [(1,4-trans) -4- (4-quinolin-8-yl-piperazin-1-yl) -cyclohexyl] -1H-indole-5-carbonitrile; L-Methyl-3 - [(l, 4-cis) -4- (4-quinolin-8-yl-piperazin-l-yl) -cyclohexyl] -lH-indole-5-carbonitrile; Yl) -piperazin-l-yl] -cyclohexyl} -1H-indole < / RTI >; Yl) -piperazin-l-yl] -cyclohexyl} -lH-indole < / RTI >; Yl) -piperazin-1-yl] - (4-fluoro-benzyl) -piperazin-1- Cyclohexyl} -1H-indole; Yl) -piperazin-1-yl] - (4-fluoro-benzyl) -piperazin- Cyclohexyl} -1H-indole; Yl) -piperazin-l-yl] -cyclohexyl} - lH- (l, 4-dihydro- - indole-5-carbonitrile; Yl) -piperazin-l-yl] -cyclohexyl} - lH-pyrrolo [2,3-d] pyrimidin- - indole-5-carbonitrile; Yl) -piperazin-1-yl] -cyclohexyl} - 1 - ((4-fluoro-benzyloxy) Methyl-lH-indole-5-carbonitrile; 3 - [(l, 4-cis) -4- [4- (benzofuran-7-yl-piperazin-l-yl) -cyclohexyl] -lH-indole-5-carbonitrile; 3 - [(1,4-trans) -4- [4- (benzofuran-7-yl-piperazin-1-yl) -cyclohexyl] -1H-indole-5-carbonitrile; 5-Fluoro-3- {4- [4- (2-methoxy-phenyl) -piperazin-l-yl) -cyclohex-1-enyl} -lH-indole; 3- {4- [4- (1H-Indol-4-yl) -piperazin-1-yl] -cyclohex-1-enyl} -1H-indole-5-carbonitrile; 5-Fluoro-3- {cis-4- [4- (1H-indol-4-yl) piperazinyl] -cyclohexyl} -1-methyl-1H-indole; 1-yl] -cyclohexyl} -lH-indole-5-carbonitrile < / RTI > Or a pharmaceutically acceptable salt thereof. [8" claim-type="Currently amended] A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. [9" claim-type="Currently amended] A method of treating depression in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of a therapeutically effective amount of a compound of formula 1 according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof. [10" claim-type="Currently amended] a) reacting a compound of formula 2 with a compound of formula 4; or b) reducing the compound of formula 5 to yield a compound of formula 1; or c) acidifying the basic compound of formula (I) with a pharmaceutically acceptable acid to obtain a pharmaceutically acceptable salt; or d) isolating a mixture of cis and trans isomers of the compound of formula (I) to isolate one isomer that is substantially free of the other isomer; or e) reacting a compound of formula (I) having a reactive substituent group to yield a compound of formula (I) having a different substituent group; or f) reacting a compound of formula (I) with a reactive moiety (e.g., NH) to obtain a compound of formula (1) having a substituent group at that site, ≪ / RTI > (2) Formula 4 Formula 5 In this formula, R a , R 1-6 , Y, Z and X 1-3 are as defined above.
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同族专利:
公开号 | 公开日 CN1166636C|2004-09-15| CA2355342A1|2000-07-13| EP1147083A1|2001-10-24| IL143979D0|2002-04-21| BR0007424A|2001-10-09| CZ20012444A3|2002-02-13| DK1147083T3|2004-08-16| JP2002534411A|2002-10-15| WO2000040554A1|2000-07-13| HU0200309A2|2002-06-29| NO20013369D0|2001-07-06| PT1147083E|2004-09-30| HU0200309A3|2003-05-28| AU2490900A|2000-07-24| ES2219302T3|2004-12-01| NO20013369L|2001-09-03| ZA200105190B|2002-09-23| AT269303T|2004-07-15| DE60011570T2|2004-11-25| EP1147083B1|2004-06-16| AR028810A1|2003-05-28| DE60011570D1|2004-07-22| CN1336916A|2002-02-20|
引用文献:
公开号 | 申请日 | 公开日 | 申请人 | 专利标题
法律状态:
1999-01-07|Priority to US22658399A 1999-01-07|Priority to US09/226,583 2000-01-06|Application filed by 이곤 이 버그, 아메리칸 홈 푸로닥츠 코포레이션 2000-01-06|Priority to PCT/US2000/000223 2001-09-08|Publication of KR20010086163A
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申请号 | 申请日 | 专利标题 US22658399A| true| 1999-01-07|1999-01-07| US09/226,583|1999-01-07| PCT/US2000/000223|WO2000040554A1|1999-01-07|2000-01-06|Arylpiperazinyl-cyclohexyl indole derivatives for the treatment of depression| 相关专利
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