MXPA00009565A

MXPA00009565A - AMINOALKYL SUBSTITUTED 9H-PYRIDINO[2,3-b]INDOLE AND 9H-PYRIMIDINO[4,5-b]INDOLE DERIVATIVES

Info

Publication number: MXPA00009565A
Application number: MXPA/A/2000/009565A
Authority: MX
Inventors: Raymond F Horvath; James W Darrow; George D Maynard
Original assignee: James W Darrow; Raymond F Horvath; George D Maynard; Neurogen Corporation
Priority date: 1998-04-02
Filing date: 2000-09-29
Publication date: 2001-09-07

Abstract

Disclosed are compounds of formula (I), wherein Ar, R1, W and X are substituents as defined herein, which compounds are (1) antagonists at CRF1 receptors and are, therefore, useful in the diagnosis and treatment of stress related disorders such as post traumatic stress disorder (PTSD) as well as depression, headache and anxiety;and (2) are neuropeptide Y1 receptor antagonists, and are therefore useful in the treatment of a variety of clinical conditions which are characterized by the presence of an excess of neuropeptide Y.

Description

DERIVATIVES OF 9H-PYRIDINE [2, 3-b] INDOL AND 9H-PYRIMIDINO [4,5-bJ INDOL SUBSTITUTED WITH AMINOALKYLL: RECEPTORS OF CRF1 AND NPY1 BACKGROUND OF THE INVENTION Field of the Invention The present invention relates to 9H-pyridino [2, 3-b] indole and 9H-pyrimidino [4, 5-b] indole derivatives substituted with a non-dialkyl that selectively bind to the 'factor' receptors. release of corticotropin (CRFi) and the neuropeptide Y receptors of mammals (NPYi). Additionally, it relates to pharmaceutical compositions containing these compounds and to the use of these compounds in the treatment of physiological disorders induced or facilitated by CRF or those associated with an excess of neuropeptide Y.

Description of the Related Art The corticotropin releasing factor (referred to herein as CRF), a 41 amino acid peptide, is the main physiological regulator of the secretion of the peptide derived from proopiomelanocortin (POMC) from the gland.

REF .: 123625 anterior pituitary [J. Rivier et al., Proc. Na t. Aca d. Sci. (USA) 80: 4851 (1983); W. Vale et al., Sci in ce 213: 1394 (1981)] 4. In addition to its endocrine role in the pituitary gland, the immunohistochemical location of CRF has shown that the hormone has a wide extra-hypothalamic distribution in the central nervous system and produces a broad spectrum of autonomic, electrophysiological and behavioral effects consistent with a role of neurotransmitter or neuromodulator in the brain [. Vale et al., Rec. Prog. Horm. Res. 39: 245 (1983); G.F. Koob, Persp. Behav. Med. 2:39 (1 985); E.B. De Souza et al., J. Neurosci, 5: 3189 (1985)]. There is also evidence that CRF plays a significant role in the integration of the immune system response to physiological, psychological and immunological stressors [J. E. Blalock, Physiological Review 69: 1 (18989); J.E. Morley, Life Sci. 41: 527 (1987)]. Clinical data provide evidence that CRF has a role in psychiatric disorders and neurological diseases including depression, anxiety-related disorders and eating disorders. A role for CRF has also been postulated in the etiology and pathophysiology of Alzheimer's disease, Parkinson's disease, Huntington's disease, progressive supranuclear palsy and amyotrophic lateral sclerosis, since they are related to the dysfunction of CRF neurons in the central nervous system [for review see EB De Souza, Hosp. Practice 23:59 (1988)]. In affective disorder or major depression, the concentration of CRF is significantly increased in the spinal, cerebral fluid (CSF) of drug-free individuals [C.B. Nemeroff et al., Science 226: 1342 (1984); C.M. Banki et al., Am. J. Psychiatry 144: 873 (1987); R.D. Fr et al., Biol. Psychiatry 26:86 (1988); M. Arato et al., Biol. Psyciatry 25: 355 (1989)]. Additionally, the density of CRF receptors decreases significantly in the frontal cortex of suicide victims, consistent with a hypersecretion of CRF [C.B. Nemeroff et al., Arch. Gen. Psychiatry 45: 577 (1988)]. In addition, there is a response of adrenocort icot ropin (ACTH) hindered to CRF (administered i.v.) observed in depressed patients [P.W. Gold et al, Am. J.

Psychiatry 141: 619 (1984); F. Holsboer et al., Psychoneuroendocrinology 9: 147 (1984); P. Gold et al., New Eng. J. Med. 314: 1129 (1986)]. Preclinical studies in rats and non-human primates provide additional support for the hypothesis that hypersecretion of CRF may be comprised in the symptoms seen in human depression [R.M. Sapolsky, Arch. Gen. Psychiatry 46: 1047 (1989)]. There is preliminary evidence that tricyclic antidepressants can alter CRF levels and thus modulate the numbers of CRF receptors in the brain [Grigoriadis et al., Neuropsychopharmacology 2:53 (1989)]. There has also been a postulated role for CRF in the etiology of anxiety-related disorders. CRF produces anxiogenic effects in animals and interactions between benzodiazepine and non-benzodiazepine anxiolytics and CRF has been demonstrated in a variety of behavioral anxiety models [D.F. Britton et al., Life Sci. 31: 363 (1982); C.W. Berridge and A.J. Dunn Regul. Peptides 16:83 (1986)]. Preliminary studies using the putative CRF receptor agonist, ovine-helical CRF (9-41) in a variety of behavioral paradigms demonstrate that the antagonist produces "anxiolytic-like" effects that are qualitatively similar to benzodiazepines [C.V. Berridge and A.J. Dunn Horm. Behav. 21: 393 (1987), Brain Research Reviews 15:71 (1990)]. Receptor binding studies, endocrine neurochemicals have all demonstrated interactions between CRF and benzodiazepine anxiolytics providing additional evidence for the involvement of CRF in these disorders. Chlordiazepoxide attenuates the "anxiogenic" effects of CRF in both the conflict test [K.T. Britton et al., Psychopharmacology 86: 170 (1985); K.T. Britton et al., Psychopharmacology 94: 306 (1988)] and in the acoustic startle test [N.R. Swerdlow et al., Psychopharmacology 88: 147 (1986)] in rats. The benzodiazepine receptor antagonist (Ro 15-1788), which was without behavioral activity alone in the operant conflict test, reversed the effects of CRF in a dose-dependent manner while the inverse benzodiazepine agonist (FG 7142 ) improved the actions of the CRF [KT Britton et al., Psychopharmacology 94: 306 (1988)]. Additionally, it has been postulated that CRF has a role in immunological, cardiovascular or heart-related diseases such as hypertension, tachycardia and congestive heart failure, shock and osteoporosis. CRF has also been implicated in premature birth, psychosocial dwarfism, stress-induced fever, ulcer, diarrhea, post-operative colic, and colonic hypersensitivity associated with disturbance and psychopathological stress. The mechanisms and sites of action through which anxiolytics and normal antidepressants produce their therapeutic effects remain to be made clear. However, hypotheses have been made that are included in the suppression of CRF hypersecretion observed in these disorders. Of particular interest is that preliminary studies examining the effects of a CRF receptor antagonist (CRF 9_? A-helical) in a variety of behavioral paradigms have shown that the CRF antagonist produces "anxiolytic-like" effects qualitatively similar to benzodiazepines [for review see GF Koob and K.T. Britton, In: Corticotropin-Releasing Factor: Basic and Clinical Studies of a Neuropeptide, E. B. De Souza and C.F.

Nemeroff eds., CRF Press p.221 (1990)]. Neuropeptide Y, a peptide first isolated in 1982, is widely distributed in central and peripheral neurons and is responsible for a multitude of biological effects in the brain and periphery. Several animal studies have shown that activation of the NPYX neuropeptide receptors are related to vasoconstriction, Wahlestedt et al., Regul. Peptides, _13_: 307-318 (1986), McCauley and Wetfall, J. Pharmacol. Exp. Ther. 261: 863-868 (1992); and to the stimulation of consummatory behavior, Flood and Morley, Peptides, 1_0: 963-966 (1989), Leibowitz and Alexander, Peptides, Y2.- '1251-1260 (1991), and Stanley et al., Peptides, _13: 581 -587 (1992). Grundemar and Hakanson, TiPs, l _: 153-159 (1994), point out that in animals the neuropeptide Y is a powerful stimulus of food uptake and an inducer of vasoconstriction that leads to hypertension. They also point out that the low levels of neuropeptide Y are associated with loss of appetite. These reports clearly indicate that compounds that inhibit the activity of this protein will reduce hypertension and appetite in animals.

BRIEF DESCRIPTION OF THE INVENTION This invention provides novel compounds of Formula I that interact with CRFi receptors and NPYi receptors. Additionally refers to the use of these compounds, pharmaceutical compositions comprising these compounds and methods useful for the treatment of psychiatric and affective disorders and neurological diseases, including major depression, headaches, anxiety-related disorders, post-traumatic stress disorder, paralysis supranuclear, as well as the treatment of immunological, cardiovascular or cardiac diseases, hypertension, eating disorders, diabetes, dyslipidemia, colonic hypersensitivity associated with psychopathological disturbance, and tension. It further relates to the use of these compounds in the treatment of psychological disorders induced or facilitated by CRF or those associated with an excess of neuropeptide Y. In particular, this invention provides 9H-pyridino [2, 3-b] indole and 9H- derivatives pyrimidino [4, 5-b] indole substituted with aminoalkyl of Formula I which selectively bind to receptors of corticotropin releasing factor (CRFj.) and / or to neuropeptide Y receptors of mammalian (NPYi). Accordingly, a broad embodiment of the invention is directed to a compound of Formula I: wherein Ar is phenyl, 1- or 2-naphthyl, 2-, 3-, or 4-pyridyl, 2-, 4-, or 5-pyrimidinyl, optionally mono-, di-, or tri-substituted with halogen, trifluoromethyl , hydroxy, amino, lower alkylamino, lower dialkylamino, caboxamido, N- (lower alkyl) -carboxamido, N, N- (lower dialkyl) -carboxamido, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms , with the proviso that at least one of the positions ortho or para to the point of attachment of Ar to the tricyclic ring system is substituted; Ri is hydrogen, halogen, trifluoromethyl, alkyl of 1 to 6 carbon atoms, or (Cj.-C6alkyl) -G1-R2, wherein G1 is oxygen or sulfur and R2 is hydrogen or alkyl of 1 to 6 carbon atoms; W is N or C-R3, where R3 is hydrogen or alkyl of 1 to 6 carbon atoms; Y X is , where V1 and V2 are CH2, CO, CS, S02 or CH (C? -Calkyl), with the proviso that both Vi and V2 can not be both CO, CS or S02; Y1 e. Y2 independently represent a bond or alkylene of 1 to 6 carbon atoms; A1 is NR4R5, wherein R4 and R5 are independently hydrogen, a lower alkyl group which optionally forms a heterocycloalkyl group with Y1; arylalkyl of 1 to 6 carbon atoms or heteroarylalkyl of 1 to 6 carbon atoms, where aryl is phenyl and heteroaryl is 2-, 3-, or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2 - or 4-imidazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4-, or 5-thiazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or 4-triazolyl, 2- pyrazinyl, or 1-, 2- or 5-tet razolyl, each of which is optionally mono-, di-, or tri-substituted with halogen, trifluoromethyl, hydroxy, amino, lower alkylamino, lower dialkylamino, lower alkylcarboxamido, alkyl lower, lower alkoxy, with the proviso that 2 adjacent substituents may together form a heterocycloalkyl or cycloalkyl ring fused with 5-7; lower alkanoyl, lower alkylsulfonyl, with the proviso that R4 and R5 can not be both alkanoyl or alkylsulfonyl; or NR4R5 together form a heterocycloalkyl of 3 to 6 carbon atoms or a group of the Formula: where e and f are independently 1, 2 or 3 and the sum of e and f is at least 3; and G2 is NR6, wherein R6 is hydrogen or alkyl of 1 to 6 carbon atoms, or CH (Co-Cealkylene) -G3-R7 wherein G3 is CONH, CONH (C? -C6alkyl), NH, NH (C C6alkyl) and R7 is hydrogen or alkyl of 1 to 6 carbon atoms; or CONH2, CO [N (C? -C6alkyl) R8], wherein R8 is hydrogen or alkyl of 1 to 6 carbon atoms; arylalkyl of 1 to 6 carbon atoms or heteroarylalkyl of 1 to 6 carbon atoms, wherein aryl is phenyl and heteroaryl is 2-, 3-, or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2- or 4-imidazolyl, 2-, 4- or 5-oxazolyl, 2-, 4-, or 5-thiazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or 4-triazolyl, 2- pyrazinyl, or 1-, 2- or 5-tet razolyl, each of which is optionally mono-, di-, or tri-substituted with halogen, trifluoromethyl, hydroxy, amino, lower alkylamino, lower dialkylamino, lower alkylcarboxamido, lower alkyl, lower alkoxy, with the proviso that 2 adjacent substituents may together form a heterocycloalkyl or cycloalkyl ring fused to 5-7; A2 is hydrogen, alkyl of 1 to 6 carbon atoms, (Ci-C-alkylene) -G-R9 wherein G4 is oxygen or sulfur and R9 is hydrogen, trifluoromethyl or alkyl of 1 to 6 carbon atoms; Heteroar il 'Y2 s / VV VN - * (ii) wherein heteroaryl is 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2- or 4-imidazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4- , or 5-thiazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or 4-triazolyl, 2-pyrazinyl, or 1-, 2- or 5-tetrazolyl, each of which is optionally mono- or di-substituted with halogen, trifluoromethyl, amino, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, with the proviso that tetrazolyl can have at most one substituent; Z1 is alkyl of 1 to 6 carbon atoms; Y V2, Y2 and A2 are as defined above; (iii) it is carbon or nitrogen; where when Z is CH, n is 0, 1, 2 or 3 and p is 1, RJ is carboxamido, or (Co-C-alkylene) -G ~ -R 11 wherein G5 is NH, NH (d-C6alkyl) and R11 is hydrogen, alkyl of 1 to 6 carbon atoms, arylalkyl of 1 to 6 carbon atoms or heteroarylalkyl of 1 to 6 carbon atoms, where aryl is phenyl and heteroaryl is 2-, 3-, or 4-pyridyl, 2-, 4-, or 5-pyrimidinyl, 1-, 2-, or 4-imidazolyl, 2-, 4-, or 5-oxalolyl, 2-, 4-, or 5-thiazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3-, or 4-triazolyl, 2-pyrazinyl, or 1- , 2- or 5-tetrazolyl, each of which is optionally mono-, di- or tri-substituted with halogen, trifluoromethyl, hydroxy, amino, lower alkylamino, lower dialkylamino, lower alkylcarboxamido, lower alkyl, lower alkoxy, with the proviso that at least two adjacent substituents can together form a fused heterocycloalkyl or cycloalkyl ring of 5-7; when Z2 is carbon, n is l or 2 and p is l or R, 1J0 is ammo, when z is nitrogen, n is l or 2 and p is l or 2, R, 10 is hydrogen; or (iv) a nitrogen heterocycle of the Formula: wherein the N-ring represents triazolyl, tetrazolyl, imidazolyl, or pyrazolyl, each of which is optionally substituted with amino, trifluoromethyl, carboxamido, or (C? -C6alkylene) -G6-R12? n where G6 is NH, NH (C? -C6alkyl) and R12 is hydrogen, alkyl of 1 to 6 carbon atoms, arylalkyl of 1 to 6 carbon atoms or heteroarylalkyl of 1 to 6 carbon atoms, wherein aryl is phenyl, and heteroaryl is 2-, 3-, or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2- or 4-imidazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4-, or 5-thiazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or 4-triazolyl, 2-pyrazinyl, or 1-, 2-, or 5-tetrazolyl each of which is optionally mono-, di-, or tri -substituted with halogen, trifluoromethyl, hydroxy, amino, lower alkylamino, lower dialkylamino, lower alkylcarboxamido, lower alkyl, lower alkoxy, with the proviso that 2 adjacent substituents may together form a cycloalkyl or heterocycloalkyl ring I merged it from 5-7. The compounds of Formula (I) are antagonists of the CRFi receptor and are useful in the diagnosis and treatment of stress-related disorders such as post-tum ratatic stress disorder (PTSD) as well as depression., headache and anxiety. They are useful in methods for the treatment of psychiatric and affective disorders and neurological diseases, including major depression, headaches, anxiety-related disorders, post-traumatic stress disorder, supranuclear palsy, as well as the treatment of immunological, cardiovascular or other diseases. cardiac, hypertension, eating disorders, diabetes, dislipidemia, colonic hypersensitivity associated with psychopathological disturbance and tension. These methods comprise administering to a mammal an effective amount of a compound of the invention. The compounds of Formula I are also antagonists of the neuropeptide Yi receptor and therefore, are also of value in the treatment of a wide variety of clinical conditions characterized by the presence of an excess of • neuropeptide Y. Formula I have different chemical structures that affect their selectivity towards either CRFi or NPYí receptors.

DETAILED DESCRIPTION OF THE INVENTION The new compounds encompassed by the present invention can be described by the General Formula I: Ar wherein Ar is phenyl, 1- or 2-naphthyl, 2-, 3-, or 4-pyridyl, 2-, 4-, or 5-pyrimidinyl, optionally mono-, di-, or tri-substituted with halogen, trifluoromethyl , hydroxy, amino, lower alkylamino, lower dialkylamino, caboxamido, N- (lower alkyl) -carboxamido, N, N- (lower dialkyl) -carboxamido, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms , with the proviso that at least one of the positions ortho or para to the point of attachment of Ar to the tricyclic ring system is substituted; Ri is hydrogen, halogen, trifluoromethyl, alkyl of 1 to 6 carbon atoms, or (Ci-C-alkyl) -G 1 -R 2, wherein G 1 is oxygen or sulfur and R 2 is hydrogen or alkyl of 1 to 6 carbon atoms; W is N or C-R3, where R3 is hydrogen or alkyl of 1 to 6 carbon atoms; Y X is , where V1 and V2 are CH2, CO, CS, S02 or CH (C? -Cealkyl), with the proviso that both Vi and V2 can not be both CO, CS or S02; Y1 and Y2 independently represent a bond or alkylene of 1 to 6 carbon atoms; A1 is NR4R5, where * R4 and R5 are independently hydrogen, a lower alkyl group which optionally forms a heterocycloalkyl group with Y1; arylalkyl of 1 to 6 carbon atoms or heteroarylalkyl of 1 to 6 carbon atoms, where aryl is phenyl and heteroaryl is 2 -, 3 -, or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, . 2 - or 4-imidazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4-, or 5-thiazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or 4-triazolyl, 2 -pyrazinyl, or 1-, 2- or 5-tet razolyl, each of which is optionally mono-, di-, or tri-substituted with halogen, trifluoromethyl, hydroxy, amino, lower alkylamino, lower dialkylamino, lower alkylcarboxamido, lower alkyl, lower alkoxy, with the proviso that 2 adjacent substituents may together form a heterocycloalkyl or cycloalkyl ring fused to 5-7; lower alkanoyl, lower alkylsulfonyl, with the proviso that R4 and R5 can not be both alkanoyl or alkylsulfonyl; or NR4R5 together form a heterocycloalkyl of 3 to 6 carbon atoms or a group of the Formula: where e and f are independently 1, 2 or 3 and the sum of e and f is at least 3; and G2 is NR6, wherein R6 is hydrogen or alkyl 1 to 6 carbon atoms, or CH (Co-Cealkylene) -G3-R7 wherein G3 is CONH, CONH (Ci-Cealkyl), NH, NH (C? -Cealkyl) and R7 is hydrogen or alkyl of 1 to 6 carbon atoms; or CONH2, CO [N (C? -C6alkyl) R8], wherein R8 is hydrogen or alkyl of 1 to 6 carbon atoms; arylalkyl of 1 to 6 carbon atoms or heteroarylalkyl of 1 to 6 carbon atoms, wherein aryl is phenyl and heteroaryl is 2-, 3-, or 4-pyridyl ,. 2-, 4- or 5-pyrimidinyl, 1-, 2- or 4-imidazolyl, 2-, 4- or 5-oxazolyl, 2-, 4-, or 5-thiazolyl, 1-, 3- or 4-pyrazolyl , 1-, 3- or 4-triazolyl, 2-pyrazinyl, or 1-, 2- or 5-tetrazolyl, each of which is optionally mono-, di-, ot-substituted with halogen, trifluoromethyl, hydroxy , amino, lower alkylamino, lower dialkylamino, lower alkylcarboxamido, lower alkyl, lower alkoxy, with the proviso that 2 adjacent substituents can together form a heterocycloalkyl or cycloalkyl ring fused to 5-7; A2 is hydrogen, alkyl of 1 to 6 carbon atoms, (Ci-C-alkylene) -G-R9 wherein G4 is oxygen or sulfur and R9 is hydrogen, trifluoromethyl or alkyl of 1 to 6 carbon atoms; wherein heteroaryl is 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2- or 4-imidazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4- , or 5-thiazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or 4-triazolyl, 2-pyrazinyl, or 1-, 2- or 5-tet razolyl, each of which is optionally mono - or di-substituted with halogen, trifluoromethyl, amino, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, with the proviso that the tetrazolyl can have at most one substituent; Z1 is alkyl of 1 to 6 carbon atoms; and V2, Y2 and A2 are as defined above; , 10 it is carbon or nitrogen; where when Z is CH, n is 0, 1, 2 3 and p is 1 2 or 3, R10 is carboxamido, or (C0-C6alkylene) -G5-R11 wherein G5 is NH, NH (C? -C6alkyl) and R11 is hydrogen, alkyl of 1 to 6 carbon atoms, arylalkyl of 1 to 6 carbon atoms or heteroarylalkyl of 1 to 6 carbon atoms, where aryl is phenyl and heteroaryl is 2-, 3-, or 4-pyridyl, 2-, 4-, or 5-pyrimidinyl, 1-, 2-, or 4 -imidazolyl, 2-, 4-, or 5-oxalolyl, 2-, 4-, or 5-thiazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3-, or 4-triazolyl, 2-pyrazinyl, or 1-, 2- or 5-tet razolyl, each of which is optionally mono-, di- or tri-substituted with halogen, trifluoromethyl, hydroxy, amino, lower alkylamino, lower dialkylamino, lower alkylcarboxamido, lower alkyl, lower alkoxy, with the proviso that at least two adjacent substituents can together form a fused heterocycloalkyl or cycloalkyl ring of 5-7; when Z2 is carbon, n is l or 2 and p is l or 2, R10 is amino; or when z2 is nitrogen, n is l or 2 and p is l or 2, R10 is hydrogen; or (iv) a nitrogen heterocycle of the Formula: XX \ ?? < wherein the N-ring represents triazolyl, tetrazolyl, imidazolyl, or pyrazolyl, each of which is optionally substituted with ao, trifluoromethyl, carboxamido, (Ci- C6alkylene) -G6-R12 wherein G6 is NH, NH (C -C6alkyl) and R12 is hydrogen, alkyl of 1 to 6 carbon atoms, arylalkyl of 1 to 6 carbon atoms or heteroarylalkyl of 1 to 6 carbon atoms, wherein aryl is phenyl, and heteroaryl is 2-, 3- , or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2- or 4-imidazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4-, or 5-thiazolyl, 1- , 3- or 4-pyrazolyl, 1-, 3- or 4-triazolyl, 2-pyrazinyl, or 1-, 2-, or 5-tetrazolyl each of which is optionally mono-, di-, or tri-substituted with halogen, trifluoromethyl, hydroxy, amino, lower alkylamino, dialkylamino lower, lower alkylcarboxamido, lower alkyl, lower alkoxy, with the proviso that 2 substituents. adjacent ones can jointly form a fused cycloalkyl or heterocycloalkyl ring of 5-7.

- Preferred compounds of Formula I include those of Formula IA: IA wherein each Ra is alkyl of 1 carbon atoms Rb is hydrogen or methyl; Ri is alkyl of 1 to 6 carbon atoms; Rs is alkyl of 1 to 6 carbon atoms, (C3-C5) cycloalkyl (C1-C3) alkyl, (C1-C3) alkoxy (C? ~ C3) alkyl, or (C3-C5) cycloalkyl; t is 1, 2 or 3; and Rx is hydrogen, alkyl of 1 to 6 carbon atoms, phenyl (C6C6) alkyl wherein phenyl is optionally mono- or di-substituted independently with alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms carbon, halogen or hydroxy; and Ry is hydrogen, alkyl of 1 to 6 carbon atoms, (C3-C6) cycloalkyl; or NRxRy represent pyrrolidinyl, N (CX-Ce) alkylpyrrolidin-2-yl, piperidinyl, morpholinyl, or N- (C? -C6) alkylpiperazinyl. Preferred compounds of Formula IA include those where Rs is alkyl of 1 to 6 carbon atoms or cyclopropylmethyl. Other preferred compounds of Formula IA include those wherein Rs is cyclopropyl (C 1 -C 3) alkyl. Still other preferred compounds of Formula IA include those wherein R x and R y independently represent hydrogen or alkyl of 1 to 2 carbon atoms. The most preferred compounds of IA include those where Rs is cyclopropyl (C? -C3) alkyl, Rx and Ry independently represent hydrogen or alkyl of 1 to 2 carbon atoms; and every Ra is methyl. Particularly preferred compounds of IA are those where W is nitrogen. Other preferred compounds of Formula I include those of Formula IB: IB wherein each Ra is alkyl of 1 to 6 carbon atoms Ri is alkyl of 1 to 6 carbon atoms; Rs is alkyl of 1 to 6 carbon atoms, (C3-C5) (C 1 -C 3) alkyl, (C 1 -C 3) alkoxy (C 1 -C 3) alkyl, or (C 3 -C 5) cycloalkyl; t is 1, 2 or 3; and Rx is hydrogen, alkyl of 1 to 6 carbon atoms, phenyl (Ci-Ce) alkyl wherein phenyl is optionally mono- or di-substituted independently with alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms , halogen or hydroxy; and Ry is hydrogen, alkyl of 1 to 6 carbon atoms, (C3-C6) cycloalkyl; or NR x R y represent pyrrolidinyl, N (C 1 -C 6) alkyl pyrrolidin-2-yl, piperidinyl, morpholinyl, or N- (Ci-Cβ) alkylpiperazinyl.

Preferred compounds of Formula IB include those wherein Rs is alkyl of 1 to 6 carbon atoms or cyclopropylmethyl. Other preferred compounds of Formula IB include those wherein Rs is cyclopropyl (C 1 -C 3) alkyl. Still other preferred compounds of Formula IB include those where t is 1 and Rx and Ry independently represent hydrogen or alkyl of 1 to 2 carbon atoms. The most preferred compounds of Formula IB include those where Rs is (C1-C3) alkyl-cyclopropyl, t is 1 and Rx and Ry independently represent hydrogen or alkyl of 1 to 2 carbon atoms. Particularly preferred compounds of IB are those where each Ra is methyl, Rs is cyclopropyl (C1-C3) alkyl, t is 1 and Rx and Ry independently represent hydrogen or alkyl of 1 to 2 carbon atoms. The highly preferred compounds of Formula IB are those where W is nitrogen. Other preferred compounds of Formula I include those of Formula IC IC wherein each Ra is alkyl of 1 to 6 carbon atoms; Ri is alkyl of 1 to 6 carbon atoms; t is .1 or 2; Rx and Ry are different and represent hydrogen; (C3-C7) cycloalkylamino (C1-C3) alkyl, carboxamido, (C3-C7) cycloalkylamino, alkanoyl of 2 to 6 carbon atoms optionally substituted at the? with alkyl of 1 to 6 carbon atoms or phenyl optionally mono- and di-substituted independently with alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halogen or hydroxy, with the proviso that at least one of Rx and Ry is hydrogen. Preferred compounds of Formula IC include those wherein R 1 is alkyl of 1 to 2 carbon atoms and is nitrogen. Other preferred compounds of IC are those wherein each 'Ra is methyl and W is nitrogen. Other preferred compounds of the invention have Formula II: II wherein each R-a independently represents alkyl of 1 to 6 carbon atoms; Ri is hydrogen, halogen, trifluoromethyl, alkyl of 1 to 6 carbon atoms, or (C6C6alkyl) -G1-R2, wherein G1 is oxygen or sulfur and R2 is hydrogen or alkyl of 1 to 6 carbon atoms; W is N or C-R3, where R3 is hydrogen or alkyl of 1 to 6 carbon atoms; Y X is , where V1 and V2 are CH2, CO, CS, S02 or CH (C? -Cdalquilo), with the proviso that both Vi and V2 can not be both CO, CS or S02; Y1 and Y2 independently represent a bond or alkylene of 1 to 6 carbon atoms; A1 is NR4R5, wherein R 'and R- are independently hydrogen, a lower alkyl group which optionally forms a heterocycloalkyl group with Y1; arylalkyl of 1 to 6 carbon atoms or heteroarylalkyl of 1 to 6 carbon atoms, where aryla is phenyl and heteroaryl is 2-, 3-, or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2 - or 4-imidazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4-, or 5-thiazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or 4-triazolyl, 2- pyrazinyl, or 1-, 2- or 5-tetrazolyl, each of which is optionally mono-, di-, or tri-substituted with halogen, trifluoromethyl, hydroxy, amino, lower alkylamino, lower dialkylamino, lower alkylcarboxamido, alkyl lower, lower alkoxy, with the proviso that 2 adjacent substituents can together form a heterocycloalkyl or cycloalkyl ring fused to 5-7; lower alkanoyl, lower alkylsulfonyl, with the proviso that R4 and R5 can not be both alkanoyl or alkylsulfonyl; or NR4R5 together form a heterocycloalkyl of 3 to 6 carbon atoms or a group of the Formula: where e and * f are independently 1, 2 or 3 and the sum of e and f is at least 3; and G2 is NR6, wherein R6 is hydrogen or alkyl 1 to 6 carbon atoms, or CH (Co-Cgalkylene) -G3-R7 wherein G3 is CONH, CONH (d-C6alkyl), NH, NH (C? ~ Cdalkyl) and R7 is hydrogen or alkyl of 1 to 6 carbon atoms; or CONH2, CO [N (C? -C6alkyl) R8], wherein R8 is hydrogen or alkyl of 1 to 6 carbon atoms; arylalkyl of 1 to 6 carbon atoms or heteroarylalkyl of 1 to 6 carbon atomsWT. , wherein aryl is phenyl and heteroaryl is 2-, 3-, or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2- or 4-imidazolyl, 2-, 4- or 5-oxazolyl. , 2-, 4-, or 5-thiazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or 4-triazolyl, 2-pyrazinyl, or 1-, 2- or 5-tetrazolyl, each which is optionally mono-, di-, or tri-substituted with halogen, trifluoromethyl, hydroxy, amino, lower alkylamino, lower dialkylamino, lower alkylcarboxamido, lower alkyl, lower alkoxy, provided that 2 adjacent substituents can together form a ring of heterocycloalkyl or cycloalkyl fused with 5-7; A2 is hydrogen, alkyl of 1 to 6 carbon atoms, (C6-C6alkylene) -G4-R9 wherein G4 is oxygen or sulfur and R9 is hydrogen, trifluoromethyl or alkyl of 1 to 6 carbon atoms; wherein heteroaryl is 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2- or 4-imidazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4- , or 5-thiazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or 4-triazolyl, 2-pyrazinyl, or 1-, 2- or 5-tetrazolyl, each of which is optionally mono- or di-substituted with halogen, trifluoromethyl, amino, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, with the proviso that the tetrazolyl may have at most one substituent; Z1 is alkyl of 1 to 6 carbon atoms; and V2, Y2 and A2 are as defined above; it is carbon q nitrogen; where when Z is CH, n is 0, 1, 2 3 and p is 1, or R, 1J0 is carboxamido, or (Co-C6alkylene) -G ~ -R 11 where G5 is NH, NH (C? -C6alkyl) and R11 is hydrogen, alkyl of 1 to 6 carbon atoms, arylalkyl- of 1 to 6 carbon atoms or heteroarylalkyl of 1 to 6 carbon atoms, where aryl is phenyl and heteroaryl is 2-, 3-, or 4- , pyridyl, 2-, 4-, or 5-pyrimidinyl, 1-, 2-, or 4-imidazipyl, 2-, 4-, or 5-oxalolyl, 2-, 4-, or 5-thiazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3-, or 4-triazolyl, 2-pyrazinyl, or 1-, 2- or 5-tet razolyl, each of which is optionally mono-, di- or tri-substituted with halogen, trifluoromethyl, hydroxy, amino, lower alkylamino, lower dialkylamino, lower alkylcarboxamido, lower alkyl, lower alkoxy, con. the proviso that at least two adjacent substituents can together form a fused heterocycloalkyl or cycloalkyl ring of 5-7; when Z2 is carbon, n is l or 2 and p is l or R, 1J0 is the same, when z is nitrogen, n is l or 2 and p is l RJ is hydrogen; or (iv) a nitrogen heterocycle of the Formula wherein the N-ring represents triazolyl, tetrazolyl, imidazolyl, or pyrazolyl, each of which is optionally substituted with amino, trifluoromethyl, carboxamido, or (Ci- C6alkylene; • Gb-R 112¿ where it is NH, NH (CX-C6alkyl) and R12 is hydrogen, alkyl of 1 to 6 carbon atoms, arylalkyl of 1 to 6 carbon atoms or heteroarylalkyl of 1 to 6 carbon atoms, wherein aryl is phenyl, and heteroaryl is 2 -, 3-, or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2- or 4-imidazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4-, or 5-thiazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or 4-triazolyl, 2-pyrazinyl, or 1-, 2-, or 5-tet razolyl each of which is optionally mono-, di-, or tri-substituted with halogen, trifluoromethyl, hydroxy, amino, lower alkylamino, lower dialkylamino, lower alkylcarboxamido, lower alkyl, lower alkoxy, with the proviso that 2 adjacent substituents may together form a cycloalkyl or heterocyclic ring fused loal of 5-7. Preferred compounds of Formula II are those wherein V1 and V2 represent methylene; Y1 is a bond, A1 represents pyrrolidinyl, morpholinyl, piperazinyl, mono- or di-Ci-Cealkyl, arylalkyl of 1 to 6 carbon atoms or heteroarylalkyl of 1 to 6 carbon atoms, where aryl is phenyl and heteroaryl is 2-, 3-, or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2- or 4-imidazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4-, or 5-thiazolyl , 1-, 3- or 4-pyrazolyl, 1-, 3- or 4-triazolyl, 2-pyrazinyl, or 1-, 2- or 5-tetrazolyl, each of which is optionally mono-, di-, or tri-substituted with halogen, trifluoromethyl, hydroxy, amino, lower alkylamino, lower dialkylamino, lower alkylcarboxamido, lower alkyl, lower alkoxy, with the proviso that 2 adjacent substituents may together form a fused heterocycloalkyl or cycloalkyl ring of 5-7; Y2 represents a bond or methylene; and A2 represents alkyl of 1 to 6 carbon atoms or alkoxymethyl of 1 to 6 carbon atoms. Other preferred compounds of the invention have Formula III III wherein each Ra independently represents alkyl of 1 to 6 carbon atoms; Ri is hydrogen, halogen, trifluoromethyl, alkyl of 1 to 6 carbon atoms, or (C? -C6alkyl) -G1-R2, wherein G1 is oxygen or sulfur and R 'is hydrogen, alkyl of 1 carbon atoms; W is N or C-R3, where R3 is hydrogen or alkyl of 1 to 6 carbon atoms; Y X is , where V1 and V2 are CH2, CO, CS, S02 or CH (C? -Cealkyl), with the proviso that both Vi and V2 can not be both CO, CS or S02; Y1 and Y2 independently represent a bond or alkylene of 1 to 6 carbon atoms; A1 is NR4R5, wherein R4 and R5 are independently hydrogen, a lower alkyl group which optionally forms a heterocycloalkyl group with Y1; arylalkyl of 1 to 6 carbon atoms or heteroarylalkyl of 1 to 6 carbon atoms, where aryl is phenyl and heteroaryl is 2-, 3-, or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2 - or 4-imidazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4-, or 5-thiazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or 4-triazolyl, 2- pyrazinyl, or 1-, 2- or 5-tetrazolyl, each of which is optionally mono-, di-, or tri-substituted with halogen, trifluoromethyl, hydroxy, amino, lower alkylamino, lower dialkylamino, lower alkylcarboxamido, lower alkyl , lower alkoxy, with the proviso that 2 adjacent substituents may together form a heterocycloalkyl or cycloalkyl ring fused to 5-7; lower alkanoyl, lower alkylsulfonyl, with the proviso that R4 and R5 can not be both alkanoyl or alkylsulfonyl; or NR4R5 together form a heterocycloalkyl of 3 to 6 carbon atoms or a group of the Formula: JSt / \ (CH2) e (CH2) f \ / N \ ?? where e and f are independently 1, 2 or 3 and the sum of e and f is at least 3; and G2 is NR6, wherein R6 is hydrogen or alkyl 1 to 6 carbon atoms, or CH (C0-C6alkylene) -G3-R7 wherein G3 is CONH, CONH (C ^ Cealkyl), NH, NH (C? ~ C-alkyl) and R7 is hydrogen or alkyl of 1 to 6 carbon atoms; or CONH2, CO [N (C? -C6alkyl) R8], wherein R8 is hydrogen or alkyl of 1 to 6 carbon atoms; arylalkyl of 1 to 6 carbon atoms or heteroarylalkyl of 1 to 6 carbon atoms, wherein aryl is phenyl and heteroaryl is 2-, 3-, or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2- or 4-imidazolyl, 2-, 4- or 5-oxazolyl, 2-, 4-, or 5-thiazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or 4-triazolyl, 2- pyrazinyl, or 1-, 2- or 5-tet razolyl, each of which is optionally mono-, di-, or tri-substituted with halogen, trifluoromethyl, hydroxy, amino, lower alkylamino, lower dialkylamino, lower alkylcarboxamido, alkyl lower, lower alkoxy, with the proviso that 2 adjacent substituents may together form a heterocycloalkyl or cycloalkyl ring fused to 5-7; A2 is hydrogen, alkyl of 1 to 6 carbon atoms, (Ci-Cdalquilen) -G4-R9 wherein G4 is oxygen or sulfur and R9 is hydrogen, trifluoromethyl or alkyl of 1 to 6 carbon atoms; wherein heteroaryl is 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2- or 4-imidazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4- , or 5-thiazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or 4-triazolyl, 2-pyrazinyl, or 1-, 2- or 5-tet razolyl, each of which is optionally mono - or di-substituted with halogen, trifluoromethyl, amino, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, - with the proviso that the tetrazolyl may have at most one substituent; Z1 is alkyl of 1 to 6 carbon atoms; and V2, Y2 and A2 are as defined above; , 10 (iii) it is carbon or nitrogen; where when Z is CH, n is 0, 1 3 and p is 1 RJ is carboxamido (C0-C6alquilen) -G ° -R 11 where it is NH NH (C? -C6alkyl) and R11 is hydrogen, alkyl of 1 to 6 carbon atoms, arylalkyl of 1 to 6 carbon atoms or heteroarylalkyl of 1 to 6 carbon atoms, where aryl is phenyl and heteroaryl is 2-, 3-, or 4-pyridyl, 2-, 4-, or 5-pyrimidinyl, 1-, 2-, or 4-imidazolyl, 2-, 4-, or 5-oxalolyl, 2-4. -, or 5-thiazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3-, or 4-triazolyl, 2 -pyrazinyl, or 1-, 2- or 5-tet razolyl, each of which is optionally mono-, di- or tri-substituted with halogen, trifluoromethyl, hydroxy, amino, lower alkylamino, lower dialkylamino, lower alkylcarboxamido, lower alkyl, lower alkoxy, with the proviso that at least two adjacent substituents may together form a heterocycloalkyl ring or fused cycloalkyl of 5-7; when Z2 is carbon, n is l or 2 and p is l or 2, R, 10 is arnmo, when z is nitrogen, n is 1 2 and p is 1 2, R is hydrogen; (iv) a nitrogen heterocycle of the Formula wherein the N-ring represents triazolyl, tetrazolyl, imidazolyl, or pyrazolyl, each of which is optionally substituted with amino, trifluoromethyl, carboxamido, or (Ci-C6alkylene) -G6-R12 wherein G6 is NH, NH (CX) -C6alkyl) and R12 is hydrogen, alkyl of 1 to 6 carbon atoms, arylalkyl of 1 to 6 carbon atoms or heteroarylalkyl of 1 to 6 carbon atoms, wherein aryl is phenyl, and heteroaryl is 2-, 3- , or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2- or 4-imidazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4-, or 5-thiazolyl, 1- , 3- or 4-pyrazolyl, 1-, 3- or 4-triazolyl, 2-pyrazinyl, or 1-, 2-, or 5-tet razolyl each of which is optionally mono-, di-, or tri- substituted with -halogen, trifluoromethyl, hydroxy, amino, lower alkylamino, lower dialkylamino, lower alkylcarboxamido, lower alkyl, lower alkoxy, with the proviso that 2 adjacent substituents may together form a cycloalkyl or heterocycloalkyl ring fused uilo of 5-7. Preferred compounds of Formula III are those wherein V1 and V2 represent methylene; Y1 is a bond, A1 represents pyrrolidinyl, morpholinyl, piperazinyl, mono- or di-C? -C6alkyl, arylalkyl of 1 to 6 carbon atoms or heteroarylalkyl of 1 to 6 carbon atoms, where aryl is phenyl and heteroaryl is 2- , 3-, or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2- or 4-imidazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4-, or 5-thiazolyl , 1-, 3- or 4-pyrazolyl, 1-, 3- or 4-triazolyl, 2-pyrazinyl, or 1-, 2- or 5-tet razol ilo, each of which is optionally mono-, di- or tri-substituted with halogen, trifluoromethyl, hydroxy, amino, lower alkylamino, lower dialkylamino, lower alkylcarboxamido, lower alkyl, lower alkoxy, with the proviso that 2 adjacent substituents can together form a fused heterocycloalkyl or cycloalkyl ring of 5-7; Y2 represents a bond or methylene; and A2 represents alkyl of 1 to 6 carbon atoms or alkoxymethyl of 1 to 6 carbon atoms. Preferred compounds of the invention include: 4- (N- (2-N ', N' -Dimethylaminoethyl) -N-ethyl) amino-2-methyl-9- (4-bromo-2,6-dimethyl-phenyl) -9H-pyrimidino [4, 5 b] indole 4- (N- (2-N1, N '-Dimethylaminoethyl) -N-propyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole 4- (N- (2-N ', N' -Dimethylaminoethyl) -N-2-methoxyethyl) amino-2-methi 1-9- (2,, 6-trimethylphenyl-9H-pyridino [2,3-b] indole 4- (N- (2-N ', N' -Dimethylaminoethyl) -N-cyclopropylmethyl) amino-2-met-il- 9- (2,4,6-trimethylphenyl) -9H-pyridino [2, 3-b ] indole 4- (N- (2-Pyrrolidinoethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole 4- (N- (2-N'-Ethylaminoethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole 4- (N- (2-N'-Ethyl-N '-methylaminoethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2, 3-b ] indole 4- (N- (2-N ', N' -Dimethylaminoethyl) -N-cyclopropylmethyl) amino-2-methi 1-9- (4-methoxy-2-methylphenyl) 9H-pyridino [2,3-b] indole 4- (N- (2-N ', N' -Dietylaminoethyl) -N-cyclopropylmethyl) amino-2-met-il- 9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole 4- (N- (2-N * -Methylaminoethyl) -N-cyclopropylmethyl) amino-2-meth i 1-9- (2,4,6-trimethylphenyl) -9H-pyridino [2, 3-b] indole 4- (N- (2-Aminoethyl) -N-cyclopropylmethyl) amino) 2-methyl-9 (2,4, ß-trimethylphenyl) -9H-pyridino [2,3-b] indole 4- (N- (2-Piperidinoethyl) -N-cyclopropylmethyl) 1) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole 4- (N- (2-Pyrrolidinoethyl) -N-propyl) amino-2-met i 1-9- (-2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole 4- (N- (2-Piperidinoethyl) -N-propyl) amino-2-methi 1-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole 4- (2-Morpholinoethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2, 4, 6-trimethylphenyl) -9H-pyridino [2,3-b] indole 4- (N- (2-N'-Ethyl-N'-methylaminbetyl) -N-propyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b ] indole 4- (N- (2-N ', N' -Dimethylaminoethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyrimidine [4,5 -b] indole 4- (N- (2- (1-Imidazolyl) ethyl) -N-cyclopropylmethyl) amino-2-met i 1-9- (2,4,6-trimethylphenyl) -9H-pyridino [2, 3-b ] indole 4- (N- (2-Pyrrolidinoethyl) -N-1-oxopropyl) amino-2-methyl-9- (2,4,6-t rimet-ilphenyl) -9H-pyridino [2,3-b] indole 4- (N- (2-Pyrrolidinoethyl) -N-cyclopropyloxomethyl) amino-2-methyl-9- (2,4,6-trimethyl-phenyl) -9H-pyridino [2,3-b] indole 4- (N-2- (N1-methyl-piperazinyl) ethyl-N-cyclopropylmethyl) -amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole 4- (N- (2-Pyridylmethyl) -N-cyclopro-ilmeti-1) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole 4 -Piperaz ini1-2 -methyl- 9- (2,4,6-t rimet ilphenyl) -9H-pyridino [2,3-b] indole 4- (N- (2-Aminoethyl) -N-propyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole 4- (N- (2-aminoethyl) -N-ethyl) amino-2-methyl-9- (2,4,6-t-rimethylphenyl) -9H-pyridino [2,3-b] indole 4- (N- (2- (4-Triazolyl) ethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole 4- (N- (2-Pyrrol idinoethyl) -N-cyclopropylmethyl) amino-2-methi 1-9- (2,4-dimethyl-phenyl) -9H-pyridino [2,3-b] indole 4- (N- (3-Pyrrolidinopropyl) -N-cyclopropylmethyl) amino-2-met i 1-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole 4- (N- (2- (2-Fenetylamino) ethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2, 3-b] indole 4- (N- (2-pyrrolidinoethyl) -N-cyclopropylmethyl) amino) 2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyrimidino [4,5-b] indole 4- (N- (2-Pyrrolidinoethyl) -N-2-methoxyethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole 4- (N- (2-Pyrrolidinoethyl) -N-ethyl) amino-2-met i 1-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole 4- (N- (2-Pyrrolidinoethyl) -N-butyl) amino-2-met-il- 9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole 4- (N- (2-Pyrrolidinoethyl) -N-2-methyl-propyl) amino-2-methyl-9- (2,4,6-t-rimethyl-phenyl) -9H-pyridino [2,3-b] indole 4- (N- (2-Carboxamidoethyl) -N-cyclopropylmethyl) amino-2-methi 1-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole 4- (N- (2-Pyrrolidinoethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (4-bromo-2,6-dimethylphenyl) -9H-pyrimidino [4,525-b] indole 4- (N - (2-N ', N' -Dimethylaminoethyl) -N-2-methylpropyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole 4- (N- (2-N'-Ethyl-N '-methylaminoethyl) -N-2-methylpropyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridine [2,3 -b] indole 4- (N- (2-N '/ NI -Dimethylaminooethyl) -N-propyl) amino-2-methyl-9- (2, 4, 6-t rimet-ilphenyl) -9H-pyrimidino [4,5-b] indole 4- (N- (2-N ', N' -Dimethylaminooethyl) -N-butyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyrimidino [4,5-b] indole 4- (N- (2-N ', N' -Dimethylaminooethyl) -N-cyclopropyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) 9H-pyrimidino [4,5-b] indole 4- (N- (2- (l-Methyl-2-pyrrolidino) ethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2, 3 b] indole 4- (N- (2-N 1, N '-Dimethylaminoethyl) -N-cyclobutyl) amino-2-methyl-9- (2,4,6-t rimethylphenyl) -9 H -pyrimidino [4,5 -b] indole 4- (N- (2-N ', N' -Dimethylaminoethyl) -N-isopropyl) amino-2-methyl-9- (2,4,6-t-rimethyl-phenyl) -9H-pyrimidino [4,5- b] indole 4- (N- (2-Pyrrolidinoethyl) -N-isopropyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyrimidino [4,5-b] indole 4- (N- {2-N ', N' -Dimethylaminoethyl) -N-isopropyl) amino-2-met i 1-9- (2,4,6-trimethylphenyl) -9H-pyrimidine [4, 5 -b] indole In certain situations, the compounds of Formula I may contain one or more asymmetric carbon atoms, so that the compounds may exist in different stereoisomeric forms. These compounds can be, for example, racemates or optically active forms. In this situations, the individual enantiomers, that is, optically active forms, can be obtained by asymmetric synthesis or by resolution of the racemates. The resolution of the racemates can be achieved, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using for example a chiral HPLC column. Representative compounds of the present invention, which are encompassed by Formula I, include, without limitation, the compounds in Table I and their pharmaceutically acceptable acid addition salts. In addition, if the compound of the invention is obtained as an acid addition salt, the free base can be obtained by gasifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, according to conventional procedures for prepare the acid addition salts from these base compounds. Non-toxic pharmaceutical salts include salts of acids such as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic, toluenesulfonic, methanesulfonic, nitric, benzoic, citric, tartaric, maleic, hydroiodic, alkanoic such as acetic acid, HOOC- (CH2) n -COOH, where n is 0-4, and the like. Those skilled in the art will recognize a wide variety of pharmaceutically acceptable, non-toxic addition salts. The present invention also encompasses the acylated pro-drugs of the compounds of Formula I. Those skilled in the art will recognize various synthetic methodologies that can be employed to prepare pharmaceutically acceptable, non-toxic addition salts, and prodrugs of the compounds covered by Formula I. By "alkyl", "lower alkyl" or alkyl of 1 to 6 carbon atoms in the present invention is meant straight or branched chain alkyl groups having 1-6 carbon atoms which optionally form a carbocycle of 3 to 6 atoms , such as, for example, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethyl, n-butyl, sec-butyl, tert-butyl, cyclobutyl, pentyl, 2-pentyl, isopentyl, neopentyl, cyclopentyl, hexyl, 2-hexyl, 3-hexyl, 3-methylpentyl, cyclohexyl. By alkylene of 0 to 6 carbon atoms is meant a direct bond to an alkylene group of 1 to 6 carbon atoms, which optionally forms a carbocycle of 3 to 6 atoms, such as methylene, ethylidene, propylidene, butylidene, pentylidene, Cyclopentylidene, hexylidene, cyclohexylidene. By "alkoxy", "lower alkoxy" or alkoxy of 1 to 6 carbon atoms in the present invention is meant straight or branched chain alkoxy groups having 1-6 carbon atoms which optionally form a carbocycle of 3 to 6 atom , such as, for example, methoxy, ethoxy, propoxy, isopropoxy, cyclopropylmethoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentoxy, isopentoxy, neopentoxy, cyclopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, 3-met ilpentoxy, cyclohexoxi. By "alkanoyl", "lower alkanoyl", or alkanoyl of 1 to 6 carbon atoms as used herein is meant straight or branched chain alkanoyl groups having 1-6 carbon atoms which optionally form a carboxyl of 3 carbon atoms. to 6 atoms such as, for example, acetyl, propionyl, isopropionyl, cyclopropionyl, butanoyl ', pentanoyl, cyclopentanoyl, hexanoyl, cyclohexanoyl. The "W position" in the alkanoyl groups herein is the terminal carbon atom. CONH represents a functional group of O amide, i.e., Hp The term "heterocycle" or "heterocycloalkyl" means a monocyclic or bicyclic hydrocarbon group in which one or more of the ring carbon atoms has been replaced with a heteroatom, for example, oxygen, sulfur or nitrogen. these groups preferably have from 4 to 10 carbon atoms and from 1 to 4 heteroatoms. By the term "halogen" in the present invention is meant fluorine, bromine, chlorine and iodine. - The derivatives of 9H-pyridino [2, 3-b] indole and Representative aminoalkyl-substituted 9H-pyrimidino [4, 5-b] indole of the present invention, which are encompassed by Formula I, include, without limitation, the compounds in Examples 1-18 and their pharmaceutically acceptable addition salts . The interaction of the aminoalkyl-substituted 9H-pir idino [2, 3-b] indole and 9H-pyrimidino [4, 5-b] indole derivatives of the invention with the CRFi and NPYX receptors are shown in the examples. This interaction results in the pharmacological activities of these compounds as illustrated in the relevant animal models. The compounds of the General Formula I can be administered orally, topically, parenterally, by inhalation or spray or rectally in the dosage unit formulations containing conventional, non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term "parenteral" as used herein includes subcutaneous injections, intravenous, intramuscular, intranasal injections, or infusion techniques. In addition, a pharmaceutical formulation comprising a compound of the General Formula I of a pharmaceutically acceptable carrier is provided. One or more compounds of the General Formula I may be present in association with one or more pharmaceutically acceptable, non-toxic carriers and / or diluents and / or adjuvants and if desired other active ingredients. The pharmaceutical compositions containing the compounds of the General Formula I may be in a form suitable for oral use, for example, as tablets, chips, lozenges, aqueous or oily suspensions, powders or dispersible granules, emulsion, hard or soft capsules or syrups or elixirs. Compositions proposed for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and these compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preservative agents in order to provide pharmaceutically elegant and tasty preparations. The tablets contain the active ingredient in admixture with pharmaceutically acceptable non-toxic excipients which are suitable for the manufacture of tablets. These excipients can be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, sodium phosphate; granulation and disintegration agents, for example, corn starch or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to achieve disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a prolonged period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate. Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid ingredient, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the Active ingredient is mixed with water or an oily medium, for example, peanut oil, liquid paraffin or olive oil. Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. These excipients are dispersing agents, for example sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and acacia gum, dispersing agents or humectants can be a naturally occurring phosphatide, for example, lecithin or condensation products of a alkylene oxide with fatty acids, for example polyoxyethylene stearates, condensation products of ethylene oxide with long-chain aliphatic alcohols, for example, heptadecaethyleneoxycetanol, or condensation products of ethylene acid with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitan monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example, polyethylene glycol monooleate. The aqueous suspensions may also contain one or more preservatives, for example n-propyl or ethyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, one or more sweetening agents, such as sucrose or saccharin. Oily suspensions may be formulated by dispersing the active ingredients in a vegetable oil, for example arachid oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. Oily suspensions may contain a thickening agent, e.g., beeswax, burn or cetyl alcohol. * Sweetening agents such as those discussed above and flavoring agents may be added to provide flavorful oral preparations. These preparations can be preserved by the addition of an antioxidant such as ascorbic acid. Dispersible powders and granules suitable for the preparation of an aqueous suspension by the addition of water provide the active ingredient or mixture with a dispersing or wetting agent, suspending agent of one or more preservatives. Suitable dispersing or wetting agents and suspending agents are simplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents may also be present. The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase can be a vegetable oil, for example olive oil or arachid oil, or a mineral oil, for example liquid paraffin or mixtures thereof. Suitable emulsifying agents can be naturally occurring gums, for example, acacia gum, tragacanth gum, naturally occurring phosphatides for example soy lecithin, and partial esters or esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monooleate and condensation products of the partial esters with ethylene oxide, for example, polyoxyethylene-sorbitol monooleate. The emulsions may also contain sweetening and flavoring agents. The syrups and elixirs can be formulated with sweetening agents, for example, glycerol, propylene glycol, sorbitol or sucrose. These formulations may also contain an emollient, a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of an aqueous or oleaginous suspension, injectable, sterile. This suspension can be formulated according to the known art using those suitable wetting or dispersing agents or suspending agents that have been mentioned above. The sterile injectable preparation can also be an injectable, sterile solution or suspension in a non-toxic, parenterally-acceptable diluent or solvent, for example as a solution in 1,3-but-anodiol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, sterile oils are conventionally employed as a solvent or suspending medium. For this purpose, any soft fixed oil can be employed including synthetic mono- or di-glycerides. In addition, fatty acids such as aleic acid find use in the preparation of injectable products. The compounds of the General Formula I can also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. These materials are cocoa butter and polyethylene glycols. The compounds of the General Formula I can be administered parenterally in a sterile medium. The drug, depending on the vehicle and concentration used, can be either dispersed or dissolved in the vehicle. Advantageously, adjuvants such as local anesthetics, preservatives, and buffering agents can be dissolved in the vehicle. The dose levels of the order of about 0.1 μg to about 140 μg per kilogram of body weight per day are useful in the treatment of the conditions mentioned above (about 0.5 μg to about 7 μg per patient per day). The amount of the active ingredient that can be combined as carrier materials to produce an individual dosage form will vary depending on the host treated and the particular mode of administration. The unit dosage forms will generally contain between about 1 μm to about 500 μm of an active ingredient. However, it will be understood that the specific dose level for a particular patient will depend on a variety of factors including the activity of the specific compound employed, humidity, body weight, general health, sex, diet, time of administration, route of administration and speed of secretion, combination of drugs and the severity of the particular disease that is low or therapeutic.

Preparation of 9H-pyridino [2, 3-b] indole and 9H-pyrimidino [4, 5-b] indole analogues substituted with alkylamino An illustration of the preparation of the compounds of the present invention is given in Scheme I, Scheme II and Scheme III. Those skilled in the art will recognize that the starting materials may be varied and the additional steps employed to produce the compounds encompassed by the present invention.

It burns I Ar wherein Ar, R1 and 3 are as defined above for Formula I; and R14, R15 and R16 are encompassed by the definition of X as defined in Formula I.

Scheme II wherein Ar, RJ and R are as defined above for Formula I; and R15 and R16 are encompassed by the definition of X as defined in Formula I.

It's burning I I I wherein Ar and R1 are as defined above for Formula I; and R15, R16 and R17 are encompassed by definition X as defined in Formula I. Descriptions of all articles and references mentioned in this application, including patents are prepared herein as a reference. The preparation of the compounds of the present invention are further illustrated with the following examples, which is not to be construed as limiting the invention in scope or spirit to the specific methods and compounds described therein. Commercial reagents were used without further purification. THF refers to tetrahydrofuran. LDA refers to lithium diisopropylamide and DDQ refers to 2,3-dichloro-5,6-dicyano-1,4-benzoquinone. Ambient temperature of the room refers to 20 to 25 ° C. the concentration involves the use of a rotary evaporator. TLC refers to thin layer chromatography. The mass spectrum data were obtained either by Cl or APCI methods.

Example 1 A. 2 -Amino-4, 5, 6, 7-tetrahydro-1-phenyl-1H-indole-3-carbonitrile A mixture of 2, 4, 6-t rimet ilaniline (500 g) and adipoin (464 g) in toluene (2.5 L) is heated to reflux. A theoretical amount of water is removed azeotropically for 3 hours. The mixture is cooled to room temperature, then malononitrile (244 g) and ammonium acetate (57 g) are added. The reaction is slowly warmed back to reflux for about 1 hour with azeotropic removal of water. After cooling, the precipitate formed overnight is collected by filtration. The dark solid is washed with ethanol and dried to give 540 g of a white powder: MS 280 (M + H) B. 4-amino- 2 -met i 1-9- (2,4,6-trimethylphenyl) -5,6,7, tetrahydro-9H-pyridino [2,3-b] indole To the product of Example IA (535 g) dissolved in dichloroethane (4 L) are added 2-methoxypropene (550 mL) and p-toluenesulfonic acid monohydrate (3.6 g). The mixture is refluxed for 1 hour then the solvent is removed by distillation. The residue is dissolved in THF (3 L) and cooled to 0 ° C. To this solution, under an atmosphere of nitrogen gas, LDA (2.0 M, 1.2 L) is added at a rate to maintain the internal temperature of the reaction below 10 ° C. After 3 hours, the reaction is neutralized with aqueous HCl. The aqueous layer is extracted with ethyl acetate and combined with the THF layer. The combined organic phase is extracted with 3 M HCl and the latter is made alkaline (pH = 10) with ION NaOH and ice. The aqueous solution is extracted with dichloromethane and dried with sodium sulfate, filtered and concentrated to give a crystalline solid: MS 320 (M + H).

C. 4-amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole The product of Example IB (600 g) is dissolved in decahydronaphthalene (4 L) and heated to distill the low boiling point impurities that are present. The solution is cooled to room temperature and charged with 10% palladium on carbon (250 g) under a blanket of argon gas. The mixture is heated to the reflux temperature of 191-193 ° C for 9 hours to give the flavored product. The cooled mixture is diluted with dichloromethane and filtered through a pad of Ceuta. . The dichloromethane in the filtrate is removed under reduced vacuum. The remaining decahydronaphthalene solution is treated by bubbling in a stream of hydrochloric acid gas with ice cooling for about 5 minutes. The solid is filtered, washed with diethyl ether and dried to yield 580 g of the product as the HCl salt. The salt is recrystallized from an ethyl acetate salt and ethanol mixture to give a white product: MS (free base) 316 (M + H).

D. 4- (N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole A solution of dichloroethane (250 mL) containing the product of Example IC (50 g as the HCl salt) and cyclopropanecarbonyl chloride (14 mL) under reflux is heated with dropwise addition of N, N-diisopropylethylamine (54 mL ). After heating for 0.5 hours, the reaction is cooled to room temperature and poured into aqueous potassium carbonate solution. The product is extracted with dichloromethane, dried over sodium sulfate, filtered and concentrated to give a white solid. This solid is redissolved in THF (600 mL) and the complex of borane-methyl sulfide (10 M, 43 mL) is mixed. The mixture is refluxed for 8 hours and cooled rapidly to room temperature with a severe excess of methanol (approximately 200 mL). The mixture is refluxed for 1 hour, then concentrated under reduced pressure. Further methanol (another 200 mL) is added to the gummy residue and the solution is re-concentrated to yield a white solid: MS 370 (M + H).

E. 4- (N- (2-chloroethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole A solution containing the product of Example ID (52 g) and chloroacetyl chloride (34 mL) in dichloroethane (500 mL) is refluxed for 4 hours. The solvent and excess reagent are removed under reduced pressure. Aqueous potassium carbonate is added to the remaining oily residue and extracted with dichloromethane. The extract is dried with sodium sulfate, filtered and concentrated. The latter chloroacetyl compound (63 g) is dissolved in THF (250 mL). Borane-methyl sulfide complex (10 M, 14 mL) is added and stirred at room temperature for 15 minutes then for 1 hour at reflux temperature. The solution is cooled back to room temperature, cooled rapidly with a large excess of methanol (100 mL) and refluxed for 1 hour. The solution is concentrated to give a viscous oily that crystallizes at rest: MS 432 (M + H) -.

F. 4- (N- (2-pyrrolidinoethyl) -N-cyclopropylmethyl) -amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino- [2-, 3-b] indole (Compound 1) A steel honeycomb containing the product of Example 1E (61 g), pyrrolidine (60 mL) and N-methylpyrrolidinone (250 mL) is sealed and heated at 120 ° C for 5 hours. The mixture is poured into water and extracted with ethyl acetate. The organic layer is washed with water, dried over sodium sulfate, filtered and concentrated. The product is purified by flash chromatography. First, 100% ethyl acetate is used to dilute the impurities followed by 10% methanol in dichloromethane to dilute the desired product. 60 g of the compound that crystallizes at rest is obtained. The sulfate salt of the amine is formed by adding concentrated sulfuric acid (2.4 mL) to the amine (21.4 g) dissolved in ethanol (50 mL). Isopropanol (200 mL) is added to the refluxing ethanol solution. The sulfato crystals that are formed on cooling are collected by filtration and washed with cold isopropanol: MS (free base) 467 (M + H).

G. 4-propylamino-2-methyl-9- (2, 4, 6-trimethylphenyl) 9H-pyridino [2,3-b] indole An excess of sodium borohydride (approximately 1 g) is added in portions to a solution of propionic acid (10 mL) of the product of Example IC (1.4 g). After the gas emission ceases, the reaction is heated to 100 ° C for 0.5 hours. The propionic acid is removed from the mixture under reduced pressure and the crude product is extracted from aqueous potassium carbonate with dichloromethane. The dichloromethane extract is dried over sodium sulfate, filtered and concentrated: MS 358 (M + H).

H. 4-cyclopropylamino-2-methyl-9- (2, 4, 6-trimethylphenyl) -9H-pyridino [2,3-b] indole To a solution of the product of Example IC (10 g) and 2-methoxypropene (50 mL) in dichloroethane (100 mL) is added acetic acid (1.6 mL) and sodium triacetoxyborohydride (25 g). The mixture is stirred at room temperature for 24 hours then concentrated. Dissolve the residue in ethyl acetate and wash with water, followed by IN sodium hydroxide and brine. Dry over sodium sulfate, filter and concentrate: MS 358 (M + H).

Example 2 The following compounds are prepared essentially according to the procedures set forth above in Example 1 a) 4- (N- (2-N ', N' -Dimethylaminoethyl) -N-propyl) amino-2-methi 1-9- (2,4,6-t-rimethylphenyl) -9H-pyridino [2,3 -b] indole: MS 429 (M + H). (Compound 2) b) 4- (N- (2-N ', N' -Dimethylaminoethyl) -N-2-methoxyethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridine [2, 3 -b] indole: MS 445 (M + H). (Compound 3) c) 4- (N- (2-N ', N' -Dimethylaminoethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2, 3- b] indole: MS 441 (M + H). (Compound 4) d) 4- (N- (2-N * -ethylaminoethyl) -N-cyclopropylmethyl) amino-2-methi 1-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole : MS 441 (M + H). (Compound 5) e) 4- (N- (2- (N'-Ethyl-N'-methyl) aminoethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridine [2, 3-b] indole: MS 455 (M + H). (Compound 6) f) 4- (N-2- (2- (S) -methoxymethylpyrrolidino) ethyl- N -cyclopropylmethyl) amino-2-methy1-9- (2,4,6-trimethylphenyl) -9H-pyridine [2, 3-b] indole: MS 511 (M + H). (Compound 7) g) 4- (N- (2-N ', N' -Dimethylaminoethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (4-methoxy-2-methylphenyl) -9H-pyridino [2, 3-b ] indole: MS 443 (M + H) (Compound 8) h) 4- (N- (2-N ', N' -Dietylaminoethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6-tri-ethylphenyl) -9H-pyridino [2, 3 b] indole: MS 469 (M + H). (Compound 9) i) 4- (N- (2'-methylaminoethyl) -N-cyclopropylmethyl) amino-2-meth i 1-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole : MS 427 (M + H). (Compound 10) j) 4- (N- (2-Piperidinoethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole: MS 481 (M + H). (Compound 11) k) 4- (N- (2-Pyrrolidinoethyl) -N-propyl) amino-2-methyl-9 (-2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole : MS 455 20 (M + H). (Compound 12) 1) 4- (N- (2-Piperidinoethyl) -N-propyl) ami o-2-met il-9 (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole: MS 469 (M + H). (Compound 13) m) 4- (N- (2-Morpholinoethyl) -N-cyclopropylmethyl) amino-2-met i 1-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole: MS 483 (M + H). (Compound 14) n) 4- (N- (2-N'-Ethyl-NI-methylaminoethyl) -N-propyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2, 3 -b] indole: MS 443 (M + H). (Compound 15) o) 4- (N- (2- (1-Imidazolyl) ethyl) -N-cyclopropylmethyl) amino-2-met i 1-9- (2,4,6-trimethylphenyl) -9H-pyridino [2, 3- b] indole: MS 464 (M + H). (Compound 16) p) 4- (N-2- (N'-Methylpiperazinyl) ethyl-N-cyclopropylmethyl) amino-2-methi 1-9- (2,4,6-trimethylphenyl) -9H-pyridino [2, 3-b] indole: MS 496 (M + H). (Compound 17) q) 4- (N-2- (N '-Methyl-homopyperazinyl) -ethyl-N-10-cyclopropylmethylamino-2-methyl-9- (2,4,6-tri-ethylphenyl) -9H-pyridino [2, 3 -b] indole: MS 510 (M + H). (Compound 18) r) 4- (N- (2-N '-Isopropylaminoethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole: MS 454 (M + H). (Compound 19) s) 4- (N- (2- (2- (l-Methyl-2-pyrrolidino) ethyl) aminoet yl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2, 3-b] indole: MS 524 (M + H). (Compound 20) t) 4- (N- (2-Piperazinylethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole: MS 482 ( M + H). (Compound 21) u) 4- (N- (2-Pyrrolidinoethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4-dimethylphenyl) -9H-pyridino [2,3-b] indole: MS 453 (M + H). (Compound 22) v) 4- (N- (3-Pyrrolidinoproyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole: MS 481 ( M + H). (Compound 23) ) 4- (N- (2-Methyl-2-pyrrolidinoethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole : MS 481 (M + H). (Compound 24) • x) 4- (N- (4-Pyrrolidinobutyl) -N-cyclopropylmethyl) amino-2-methi 1-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole: MS 495 (M + H). (Compound 25) y) 4- (N- (2- (4-Piperidinopiperidinyl) ethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2, 3-b] indole: MS 564 (M + H). (Compound 26) z) 4- (N- (2- (2-phenethylamino) ethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2, 3-b] indole: MS 517 (M + H). (Compound 27) aa) 4- (N- (2-N '-Methylaminoethyl) -N-methyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole: MS 387 (M + H). (Compound 28) bb) 4- (N- (2-Pyrrolidinoet yl) -N-2-methoxyet i 1) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole: MS 471 (M + H). (Compound 29) ce) 4- (N- (2-pyrrolidinoethyl) -N-ethyl) amino-2-methyl-9 (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole: MS 441 (M + H) (Compound 30) dd) 4- (N- (2-Pyrrolidinoethyl) -N-butyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole: MS 469 (M + H). (Compound 31) ee) 4- (N- (2-Pyrrolidinoethyl) -N-2-methylpropyl) amino-2-met il-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b ] indole: MS 469 (M + H). (Compound 32) ff) 4- (N- (2-N ', N' -Dimethylaminoethyl) -N-2-methylpropyl) amino-2-methyl-9- (2, 4, 6-t rimet ilphenyl) -9H -pyridino [2, 3-b] indole: MS 443 (M + H). (Compound 33) gg) 4- (N- (2- (N '-Ithi-NI-methyl) aminoet yl) -N-2-methyl-ylpropyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) - 9H-pyridino [2, 3-b] indole: MS 457 (M + H). (Compound 34) hh) 4- (N- (2-Pyrrolidinoethyl) -N-isopropyl) amino-2-methyl-9- (2,4,6-t-rimethyl-phenyl) -9H-pyridino [2,3-b] indole: MS 455 (M + H). (Compound 35) ii) 4- (N- (2-N ', N' -Dimethylaminoethyl) -N-isopropyl) amino-2-methi 1-9- (2,4,6-trimethylphenyl) -9H-pyridino [2, 3- b] indole: MS 429 (M + H). (Compound 36) jj) 4- (N- (2-Guanidinoethyl) -N-cyclopropylmethyl) amino-2-methi 1-9- (2,4,6-trimethylphenyl) -9H-pyrimidino [4,5-b] indole: MS 455 (M + H). (Compound 37) kk) 4- (N- (2- (2- (4-methoxy) phenethylamino) ethyl) -N-ethyl) amino-2-methyl-a- (2,4,6-trimethylphenyl) - 9H-pyridino [2, 3-b] indole: MS 521 (M + H). (Compound 38; 11) 4- (N- (2-N'-Cyclopentylamino-yl) -N-ethyl) amino-2-methyl-9- (2,4,6-t-rimethylphenyl) -9H-pyridino [2,3-b] ] indole: MS 455 '(M + H). (Compound 39) mm) 4- (N- (2-N ', N' -Dimethylaminoethyl) -N-ethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] ] indole: MS 415 (M + H). (Compound 40) nn) 4- (N- (2-N ', N' -Dimethylaminoethyl) -N-cyclopropylmethyl) amino-2-met-il- 9- (2,6-dimethylphenyl) -9H-pyridino [2, 3-b] indole: MS 427 (M + H). (Compound 41) Example 3 4- (N- (2-aminoethyl) -N-cyclopropylmethyl) amino) -2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2, 3-b] indole (Compound 42) A solution of the product of Example 1E (900 mg) and sodium azide (410 mg) in N-methylpyrrolidinone (10 mL) is heated at 120 ° C for 2 hours. The mixture is poured into water and extracted with ethyl acetate. The organic layer is washed with water, dried over sodium sulfate, filtered and concentrated. A solution of ethanol (10 mL) of the crude product and 10% palladium in carbon (approximately 300 mg) is hydrogenated for 8 hours at about a pressure of 1 atmosphere. The suspension is filtered over Celite and the concentrated product is purified by flash chromatography, then converted to the hydrochloride salt: MS (free base) 413 (M + H). (Compound 42). The following compounds are prepared essentially according to the procedure set forth in Example 3. a) 4- (N- (3-Aminopropyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole: MS 427 ( M + H). (Compound 43) b) 4- (N- (2-Amino-2-methylethyl) -N-cyclopropylmethyl) -amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2, 3-b ] indole: MS 427 (M + H). (Compound 44) c) 4- (N- (2-aminoethyl) -N-propyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole: MS 401 (M + H). (Compound 45) d) 4- (N- (2-aminoet i 1) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4-dimethyl-phenyl) -9H-pyridino [2,3-b] indole MS 399 ( M + H). (Compound 46) e) 4- (N- (2-Aminoethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,6-dimethylphenyl) -9H-pyridino [2,3-b] indole MS 399 (M + H). (Compound 47) f) 4- (N- (2-aminoethyl) -N-ethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole: MS 387 (M + H) (Compound 48) g) 4- (N- (4-Aminobutyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole: MS 441 ( M + H). (Compound 49) Example 4 4- (N- (2- (4-triazolyl) ethyl) -N-cyclopropylmethyl) -amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino- [2, 3-b ] indole. ' Compound 50) A solution that contains the product of Example 3 (380 mg) in toluene (8 mL) with N, N'-dimethylformamide-azine (195 mg) and p-toluenesulfonic acid monohydrate (6 mg) is heated to reflux. A flowing stream of nitrogen gas is used to displace the enveloping dimethylamine. After 12 hours, the heating is discontinued and the solution is diluted with ethyl acetate and washed with water, brine and dried over sodium sulfate, filtered and concentrated to a tan oil. The product is purified by preparative TLC using 7% methanol and 0.1% ammonium hydroxide in dichloromethane as eluent to give 340 mg of the product: MS 465 (M + H).

Example 5 4- (N- (2-carboxamidoethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3- b] indole (Compound 51) H, N Dissolve the compound of Example 3 (1.0 g) and sodium cyanide (540 mg) in N-methylpyrrolidinone (20 mL) and heat at 95 ° C for 2 hours. The mixture is poured into water and extracted with ethyl acetate. The organic layer is washed with water, dried over sodium sulfate, filtered and concentrated. Purify by flash chromatography using 20% ethyl acetate in hexanes to give a white solid. dissolve nitrile (130 mg) and solid sodium hydroxide (800 mg) in ter-butanol (5 mL). Reflux the mixture for about 1 hour. Then, neutralize with 6N hydrochloric acid, concentrate and purify the residue by preparative TLC using 10% methanol in dichloromethane as eluent: MS 441 (M + H).

Example 6 4- (N- (2-N'-acetyl-N '-methylaminoethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6-trimethyl-phenyl) -9H-pyridine [2, 3 b] indole (Compound 53) To a solution of the compound of Example 2i (170 mg) in dichloromethane (5 mL) is added acetic anhydride (0.1 mL) and diisopropylethylamine (0.2 mL). The solution is stirred for 0.5 hours and then concentrated. The residue is dissolved in ethyl acetate, washed with sodium carbonate and water, dried over sodium sulfate, filtered and concentrated. The product is purified by preparative TLC using 70% ethyl acetate in hexanes as eluent: MS 469 (M + H).

Example 7 The following examples are prepared essentially according to the procedures set forth above in Example 6. a) 4- (N- (2- (N1-Methanesulfonyl-N1-methylamino) ethyl; -N-cyclopropylmethyl) amino-2-methy1-9- (2,4,6-trimethylphenyl) -9H-pyridine [2 , 3-b] indole: MS 505 (M + H). (Compound 54) b) 4- (N- (2- (N '-Methyl-N' -trif luoromethanesulfonyl) -aminoethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6-t rimethephenyl) -9H-pyridino [2,3-b] indole: MS 559 (M + H). (Compound 55) c) 4- (N- (2- (4-Aminophenylsulfonamido) ethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2, 3-b] indole: MS 568 (M + H). (Compound 56) d) 4- (N- (2- (2-Thienyl sulfonamido) ethyl) -N-cyclopropylmethyl) amino-2-met il-9- (2,4,6-trimethylphenyl) -9H-pyridino [2, 3- b] indole: MS 559 (M + H). (Compound 57) e) 4- (N- (2- (2- (2-thienyl) -l-oxoethyl) aminoethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H- pyridino [2, 3-b] indole: MS 537 (M + H). (Compound 58) f) 4- (N- (2- (2-Phenyl-1-oxoethyl) aminoethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2, 3-b] indole: MS 531 (M + H). (Compound 59) Example 8 4- (N- (2-N '-N' -dimet i lamino-1-oxoet yl) -N-cyclopropylmethyl) amino-2-methyl-9- (2, 4, 6-t rimet ilphenyl 9H-pyridino [ 2, 3-b] indole (Compound 60) Chilled dimethylamine (approximately 4 mL) is poured into a solution of the chloroacetyl compound of Example 1E (1.9 g) and acetonitrile (20 mL). The reaction vessel is sealed and the mixture is stirred at room temperature for 2 hours and then concentrated. Water is added to the residue and the aqueous layer is extracted with ethyl acetate. The extract is dried over sodium sulfate, filtered and concentrated. The product is purified in preparative TLC with 100% ethyl acetate as elution solvent: MS 443 (M + H).

Example 9 The following compounds are prepared essentially according to the procedure set forth in Example 8. a) 4- (N- (2-N ', N' -Dimet i lamino-1-oxoethyl) -N-propyl) amino-2-met i 1-9- (2, 4, 6-trimethylphenyl) -9H -pyridino [2, 3-b] indole: MS 443 (M + H). (Compound 61) b) 4- (N- (2-N ', N' -Dimethylamino-1-oxoethyl) -N-2-methoxyethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridine [2, 3-b] indole: MS 459 (M + H). (Compound 62) c) 4- (N- (2-Pyrrolidino-1-oxoethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl; 9H-pyridino [2,3-b] indole: MS 481 (M + H). (Compound 63) d) 4- (N- (2-N'-Ethyl amino-1-oxoethyl) -N-cyclo-propylmethyl) amino-2-met-il- 9- (2,4,6-trimethylphenyl) -9H-pyridino [ 2, 3-b] indole: MS 455 (M + H). (Compound 64) e) 4- (N- (2- (N1-Ethyl-NI-methyl) amino-1-oxoet yl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H -pyridino [2, 3-b] indole: MS 469 (M + H). (Compound 65) f) 4- (N- (2- (2- (S) -methoxymethylpyrrolidino) -1-oxoethyl) -N-cyclopropylmethyl) amino-2-met-il-9- (2,4,6-trimethylphenyl) -9H- pyridino [2, 3-b] indol: MS 525 (M + H). (Compound 66) g) 4- (N- (2- (1-Imidazolyl) -1-oxoethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) • 9H-pyridino [2 , 3-b] indole: MS 478 (M + H). (Compound 67) Example 10 A. 4- (N- (2-Chloro-1-oxoethyl) -N-propyl) amino-2-methyl-9- (274,6-trimethylphenyl) -9H-pyridino [2,3-b] indole A solution of the compound of Example IC (5.7 g), acetyl chloride (3 mL) and diisopropylethylamine "(3 mL) in dichloroethane (90 mL) is refluxed for 0.5 hour After concentrating the mixture, the carbonate aqueous potassium is added and the product is extracted with dichloromethane, the extract is dried over sodium sulfate, filtered and concentrated, the chloride (1.0 g) is dissolved in acetonitrile (20 mL) and mixed with pyrrolidine (2 mL). The solution is stirred for 2 hours at room temperature, then it is concentrated, water is added to the residue and the aqueous layer is extracted with ethyl acetate.The extract is dried over sodium sulfate, filtered and concentrated: MS 392 (M + H) B. 4- (N- (2-pyrrolidinoethyl) -N-1-oxopropyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole (Compound 68) To a solution of the compound of Example 10A (1.0 g) in acetonitrile (25 mL) is added pyrrolidine (1.0 mL). The solution is stirred at room temperature for 2 hours then concentrated. Water is added to the residue and the aqueous layer is extracted with ethyl acetate. The extract is dried over sodium sulfate, filtered and concentrated. The isolated aminoamide (1.1 g) is dissolved in THF (25 mL) ,. it is treated with complete borane-methyl sulfide (1.0 L) and refluxed for 8 hours. The solution is cooled and cooled rapidly with an excess of methanol (25 mL). Then, N, N '-dimet-ilethylenediamine (1.1 mL) is added and the mixture is re-heated to reflux for 4 hours. The solution is concentrated, diluted with ethyl acetate, washed with water, dried over sodium sulfate, filtered and concentrated. A solution containing the latter product (330 mg), diisopropylethylamine (0.2 mL) and dichloroethane (10 mL) is added (0.1 mL). The mixture is refluxed for 0.5 hours, then poured into aqueous potassium carbonate and extracted with ethyl acetate. The extract is dried over sodium sulfate, filtered and concentrated. The product is purified in preparative TLC with 10% methanol in. dichloromethane as the elution solvent: 469 (M + H).

Example 11 The following compounds are prepared essentially according to the procedure set forth in Example 10 a) 4- (N- (2-Pyrrolidinoethyl) -N-cyclopropyloxomethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole: MS 481 (M + H). (Compound 69) b) 4- (N- (2-Dimethylaminoethyl) -N-methoxymethyloxomethyl) -amino-2-meth i 1-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole: MS 459 (M + H). (Compound 70) Example 12 4- (N- (2-pyridylmethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6-t rimethylphenyl) -9H-pyridino [2, 3-b] indole (Compound 71) A solution of Example 1-D (110 mg), picolinyl chloride (98 mg) and N, N-diisopropylethylamine in DMF (5 mL) is stirred at 60 ° C for 12 hours. The mixture is poured into water and extracted with ethyl acetate. The extract is washed with water, dried over sodium sulfate, filtered and concentrated. The product is purified by preparative TLC using 30% ethyl acetate in hexane as eluent: MS 461 (M + H).

Example 13 The following compounds are prepared essentially according to the procedure of Example 12. a) 4- (N- (2- A '-Dimethylamino-2-oxoethyl) -N-2-methoxyethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2 , 3-b] indole: MS 459 (M + H). (Compound 72) b) 4- (N- (2-N ', N' -Dimethylamino-2-oxoet yl) -N-propyl) amino-2-met-il-9- (2,4,6-trimethylphenyl) -9H- pyridino [2, 3-b] indole: MS 443 (M + H). (Compound 73) c) 4- (N- (2-N ', N' -Dimet i lamino-2-oxoethyl) -N-2-methoxy-1-oxoethyl) amino-2-methyl-9- (2, 4, 6 trimethylphenyl) -9H-pyridino [2,3-b] indole: MS 473 (M + H). (Compound 74) d) 4- (N- (2-N ', N' -Dimetylamino-l-oxoethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [ 2, 3-b] indole: MS 455 (M + H). (Compound 75.) Example 14 4- (4-triazolyl) -2-met-il-9- (2,4,6-t rimet-ilphenyl) -9H-pyridino [2, 3-b] ind "o1 (Compound 76) A solution containing the compound of Example 1C (560 mg) in toluene (10 mL) with N, NI-dimet ilformamide-azine (400 mg) and p-toluenesulfonic acid monohydrate (50 mg) is heated to reflux. A fluid stream of nitrogen gas is used to displace the enveloping dimethylamine. After 24 hours the heating is discontinued and the solution is diluted with ethyl acetate and washed with water, brine and dried over sodium sulfate, filtered and concentrated to a tan solid. The product is purified by preparative TLC using 100% ethyl acetate as eluent to give 340 mg of the product: MS 368 (M + H).

Example 15 A. 4-chloro-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole Dissolve tert-but ilnit rite (0.65 g) in acetonitrile (10 L) and add copper chloride (II) (0.68 g). Then, the compound of Example IC (1.33 g) is added in portions to the brown green solution and the mixture is stirred for 12 hours.

The acetonitrile is removed by evaporation and the residue is partitioned between water and dichloromethane. The aqueous layer is extracted with more dichloromethane and the combined extract is washed with water, dried over sodium sulfate, filtered and concentrated. The product is filtered through a plug of silica gel using 20% ethyl acetate hexanes as eluent to give a tan solid: MS 335 (M + H).

B. 4-piperazinyl-2-methyl-2-9 (2,4,6-trimethylphenyl; 9H-pyridino [2,3-b] indole (Compound 77) Combine the compound of Example 15A (200 mg) and piperazine (0.58 g) in N-methylpyrrolidinone. (2 ml) and heat the solution at 120 ° C for 12 hours. Pour the mixture into water and extract with ethyl acetate. Wash the extract with aqueous ammonium chloride then with water. Dry the extract over sodium sulfate, filter and concentrate. Purify by preparative TLC using 10% methanol in dichloromethane as eluent: MS 385 (M + H).

Example 16 The following compounds are prepared essentially according to the procedures set forth above in Example 15. a) 4- (4-Methylpiperazinyl) -2-met il-9-2, 4,6-trimethylphenyl) -9H-pyridino [2, 3-b] indole: MS 399 (M + H). (Compound 78) b) 4-Homopiperazinyl-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole: MS 399 (M + H). (Compound 79) c) 4- (N- (2- (l-Methyl-2-pyrrolidino) ethyl) -N-cyclopropicarbonyl) amino-2-met-il-9- (2,4,6-trimethylphenyl) -9H-pyridino [ 2, 3-b] indole: MS 495. (M + H). (Compound 80) d) 4- (N-2- (S) -Pyrrolidinomethylpyrrolidinyl) -2-methyl-9 (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole: MS 453 ( M + H). (Compound 81) e) 4 - (4-Aminomethylpiperidino) -2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole MS 413 (M + H). (Compound 82) f) 4- (4-Piperidinopiperidinyl) -2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole: MS 467 (M + H). (Compound 83) g) 4- (4-Carboxamidopiperidinyl) -2-met il-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole: MS 427 (M + H). (Compound 84) h) 4- (3-Aminopyrrolidinyl) -2-methyl-9- (2,4,6-t rimethylphenyl) -9H-pyridino [2,3-b] indole: MS 385 (M + H). (Compound 85) i) 4- (N- (2- (1-Methyl-2-pyrrolidino) ethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2, 4,6-trimethylphenyl) -9H-pyridino [2, 3-b] indole: MS 481 (M + H). (Compound 86) j) 4- (N-2- (S) -Cyclope t ilaminomet ilpyrrole idinyl) -2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-bjindol: MS 467 (M + H). (Compound 87) k) 4- (N-2- (R) -Cyclopentylaminomethylpyrrolidinyl) -2-methyl-9- (2,4,6-t rimethylphenyl) -9H-pyridino [2,3-b] indole: MS 467 (M + H) (Compound 88) 1) 4- (N-3-Cyclopentylaminopyrrolidinyl) -2-met il-9 (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole: MS 467 (M + H). (Compound 89) m) 4- (N -3- (2- (3-Methoxy-4-ethoxy) phenethyl) amino-pyrrolidinyl) -2-methi 1-9- (2,4,6-trimethylphenyl) -9H-pyridino [2 , 3-b] indole: MS 563 (M + H). (Compound 90) n) 4- (N-3- (l-oxo-2- (3-methoxy-4-ethoxy) phenethyl) amino pyrrolidinyl) -2-methyl-9- (2,4,6-t rimeti 1 phenyl) - 9H-pyridino [2, 3-b] indole: MS 577 (M + H). (Compound 91) o) 4- (N-2- (2- (R) - (4-Methoxy) phenethyl) aminomet i 1-pyrrolidinyl) -2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [ 2, 3-b] indole: MS 533 (M + H). (Compound 92 p) 4- (N-2- (2- (S) - \ 4-Methoxy) phenethyl) aminometupyrrolidinyl) -2-met il-9- (2,4,6-trimethylphenyl) -9H-pyridine [2, 3-b] indole: MS 533 (M + H). (Compound 93) q) 4- (N-4- (2- (3-Methoxy-4-ethoxy) phenethyl) aminomethyl piperazinyl) -2-met i 1-9- (2,4,6-trimethylphenyl) -9H-pyridino [2 , 3-b] indole: MS 563 (M + H). (Compound 94) Example 17 A. 2-amino-1-phenyl-1H-indole-3-carbonitrile Dissolve the compound of Example IA (20 g) in 1,4-dioxane (300 mL) and add DDQ (34 g) as a portion to the solution. The reaction is stirred for 1 hour then filtered through celite to remove the insoluble by-products.

The filtrate is concentrated and allowed to solidify The product is collected by filtration and washed with ethanol to yield 16 g of a tan solid: MS 276 (M + H).

B. 4-hydroxy-2-met-il-9- (2,4,6-t rimet-ilphenyl) -9H-pyridino [4,5-b] indole A mixture of the compound of Example 12A (30 g) acetic anhydride (15 mL) and acetic acid (30 mL) is refluxed for 1 hour, then concentrated to a solid. Phosphoric acid (40 L, 85%) is added to the amide. The mixture is then refluxed for 0.5 hour if it is cooled to room temperature. The solution is poured onto ice and the precipitate that forms is collected by filtration. The solids are washed with water and some ethanol: MS 318 (M + H) 4-chloro-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [4,5-b] indole The compound of Example 12B (2.2 g) is refluxed in phosphoryl chloride (30 mL) for 3 hours. The phosphoryl chloride is removed under reduced pressure and the residue is partitioned between aqueous potassium carbonate and dichloromethane. The aqueous layer is extracted with more dichloromethane. The combined extracts are dried over sodium sulfate, filtered and concentrated to give a brown solid: MS 336 (M + H).

D. 4-cyclopropylamino-2-met-il-9- (2,4,6-trimethylphenyl) -9H-pyridino [4,5-b] indole A mixture of the compound of Example 12C (750 mg) and cyclopropylamine (1.6 mL) in N-met ilpyrrolidinone (2 mL) is heated at 65 ° C in a sealed tube for 24 hours. Dilute the mixture with ethyl acetate and wash with water, brine, dry over sodium sulfate, filter and concentrate to give a tan solid. Purify by radial chromatography using 40% ethyl acetate in hexanes as eluent to give 730 mg of the product: MS 357 (M + H).

E. 4- (N- (2-N ', N' -Dimet ylaminooet ii) -N-cyclopropyl) amino-2-methi 1-9- (2,4,6-t rimet ilphenyl) 9H-pyridino [4, 5-b] indole To a solution of the compound of Example 12D (200 mg) in dimethylformamide (5 mL) at 0 ° C, under a blanket of nitrogen, sodium hydride (60 5, 100 mg) was added. After stirring the solution for 15 minutes, 2-dimethylaminoetyl chloride hydrochloride (170 mg) is added, the mixture is then heated at 60 ° C for 2 hours, then quenched with ice and water. Dilute with ethyl acetate and wash with water, brine, dry over sodium sulfate, filter and concentrate. Purified by radial chromatography using 7% methanol and 0.5% ammonium hydroxide in dichloromethane as eluent to obtain 190 mg of the product: MS-428 '(M + H).

Example 18 The following examples are prepared essentially in accordance with the procedure of Example 17. a) 4- (N- (2-N ', N' -Dimethylaminoethyl) -N-methyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyrimidino [4, 5-b ] indole: MS 466 (M + H). (Compound 96) b) 4- (N- (2-N ', N' -Dimethylaminoethyl) -N-ethyl) amino-2-methyl-9- (4-bromo-2,6-dimethylphenyl) -9H-pyrimidino [4,5 -b] indole: MS 480 (M + H). (Compound 97) c) 4- (N- (2-N ', N' -Dimethylaminoethyl) -N-ethyl) amino-2-methyl-9- (4-chloro-2-methyl-phenyl) -9H-pyrimidino [4, 5 b] indole: MS 422 (M + H). (Compound 98) d) 4- (N- (2-Morpholinoethyl) -N-propyl) amino-2-met i 1-9- (2-chloro-4-methylphenyl) -9H-pyrimidino [4, 5-b] ] indole: MS 478 (M + H). (Compound 99) e) 4- (N- (2-N ', N' -Dimethylaminoethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyrimidino [4, 5-b ] indole: MS 442 (M + H). (Compound 100) f) 4-Piperazinyl-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyrimidino [4, 5-b] indole: MS 386 (M + H). (Compound 101) g) 4- (N- (2-Pyrrolidinoethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridine [4,5-b] indole: MS 468 (M + H). (Compound 102) h) 4- (3-Aminopyrrolidinyl) -2-methyl-9-trimethylphenyl) -9H-pyrimidino [4, 5-b] indole: MS 386 (M + H). (Compound 103) i) 4- (2- (S) -Aminomet-1-pyrrolidino) -2-methi 1-9- (2,4,6-trimethylphenyl) -9H-pyrimidino [4, 5-b] indole: MS 400 (M + H). (Compound 104) j) 4- (3-Amino-2-triazo-l-u) -2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyrimidino [4, 5-b] indole: MS 384 (M + H). (Compound 105) k) 4- (3-Amino-l-triazolyl) -2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyrimidino [4, 5-b] indole: MS 384 (M + H) ( Compound 106) 1) 4- (3-Amino-4-triazolyl) -2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyrimidino [4, 5-b] indole: MS 384 (M + H) ( Compound 107) m) 4- (N- (2-Pyrrolidinoethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (4-bromo-2,6-dimethylphenyl) -9H-pyrimidino [4,5-b] indole: MS 532 (M + H). (Compound 108) ' n) 4- (N- (2-Pyrrol idinoethyl) -N-propyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyrimidino [4,5-b] indole: MS 456 (M + H). (Compound 109) o) 4- (N- (2-Pyrrolidinoethyl) -N-butyl) amino-2-met-il-9 (2,4,6-trimethylphenyl) -9H-pyrimidino [4,5-b] indole: MS 470 ( M + H). (Compound 110) p) 4- (N- (2-Pyrrolidinoethyl) -N-cyclopropyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyrimidino [4,5-b] indole : MS 454 (M + H). (Compound 111) q) 4- (N- (2-N ', N' -Dimethylaminoethyl) -N-propyl) amino-2-met il-9- (2,4,6-t rimet-ilphenyl) -9H-pyrimidino [4, 5-b] indole: MS 430 (M + H). (Compound 112) r) 4- (N- (2-N ', N' -Dimethylaminoethyl) -N-butyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyrimidino [4, 5-b] ] indole MS 444 (M + H). (Compound 113) s) 4- (N- (2-Piperidinoethyl) -N-propyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyrimidino [4,5-.b] indole MS 470 ( M + H). (Compound 114) t) 4- (N- (2-Piperidinoethyl) -N-butyl) amino-2-methi 1-9- (2,4,6-trimethylphenyl) -9H-pyrimidino [4,5-b] indole: MS 484 (M + H). (Compound 115) u) 4- (N- (2-N ', N' -Dimethylaminoethyl) -N-cyclobutyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyrimidino [5-b] ] indole: MS 442 (M + H). (Compound 116) v) 4- (N- (2-N ', N' -Dimethylaminoethyl) -N-cyclopentyl) amino-2-methyl-9- (2,4,6-t-rimethyl-phenyl) -9H-pyrimidine [4, 5-b] indole: MS 456 (M + H). (Compound 117) w) 4- (N- (2-N ', N' -Dimethylaminoethyl) -N-isopropyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyrimidino [4, 5-b ] indole: MS 430 (M + H). (Compound 118) x) 4- (N- (2-N'-methylaminoethyl) -N-methyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyrimidino [4,5-b] indole: MS 388 (M + H). (Compound 119) y) 4- (4- (N-Methylamino) piperidino) -2-meth i 1-9- (2,4,6-trimethylphenyl) -9H-pyrimidino [4,5-b] indole: MS 414 (M + H) (Compound 120) z) 4- (4- (2-Aminoethyl) piperazinyl) -2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyrimidino [4, 5-b] indole: MS 429 (M + H) . (Compound 121) aa) 4- (N- (2-N'-ethylaminoethyl) -N-ethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyrimidino [4, 5 b] indole: MS 416 (M + H). (Compound 122) bb) (+) - 4- (N- (2-N ', N' -Dimethylaminoethyl) -Nl-methylpropyl) amino-2-met-il-9- (2,4,6-t rimet ilphenyl) - 9H -pyrimidino [4, 5-b] indole: MS 444 (M + H). (Compound 123) ce) 4- (N- (2-N ', N' -Dietylaminoet yl) -N-cyclopropylmethyl) amino) 2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyrimidine [ 4, 5-b] indole: MS 470 (M + H). (Compound 124) dd) 4- (N- (2-N ', N' -Dietylaminoet yl) -N-cyclopropyl) amino-2-met i 1-9- (2,4,6-trimethylphenyl) -9H-pyrimidino [4 , 5-b] indole: MS 456 (M + H). (Compound 125) ee) 4- (N- (2-N ', N' -Dimethylaminoethyl) -N-2-methoxyethyl) ami o-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyrimidino [ 4, 5-b] indole: MS 446 (M + H). (Compound 126) ff) 4- (N- (2-N ', N' -Dimethylaminoethyl) -N-2-ethoxyethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H- pyrimidino [4, 5-b] indole: MS 450 (M + H). (Compound 127) gg) 4- (N- (2-N '-ethylaminoethyl) -N-ethyl) amino-2-methyl-9 (2-methyl-4-chlorophenyl) -9H-pyrimidino [4, 5-b] indole: MS 423 (M + H). (Compound 128) hh) 4- (N- (Cyclopentylaminopiperidin-4-yl) -N-ethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyrimidino [4,5-b] indole: MS 468 (M + H). (Compound 129) ii) 4- (N- (2-N ', N' -Dimethylaminoethyl) -N-isobutyl) amino-2-met il-9- (2,4,6-t rimet-ilphenyl) -9H-pyrimidino [4, 5-b] indole: MS 444 (M + H). (Compound 130) jj) 4- (N- (2- (3-Methoxy-4-ethoxy) phenethyl) aminopiperidin-4-yl) -N-ethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H -pyrimidino [4, 5-b] indole: MS 578 (M + H). (Compound 131) kk) 4- (N- (S) - (1-Oxo-2- (4-methoxy) phenethyl ') amino-pyrrolidin-2-yl) -2-methyl-9- (2, 4, 6-trimethylphenyl) -9H-pyrimidino [4, 5-b] indole: MS 54 (M + H). (Compound 132) 11) 4- (N- (S) - (2- (4-Methoxy) phenethyl) amino pyrrolidin-2-yl) -2-methi 1-9- (2,4,6-trimethylphenyl) -9H-pyrimidino [ 4, 5b] indole: MS 578 (M + H). (Compound 133) Example 19 The pharmaceutical utility of the compounds of this invention is indicated by the following assays for human CRF1 and NPY1 receptor activity.

Assay for CRF receptor binding activity The binding to the CRF receptor is performed using a modified version of the assay described by Grigoriadis and De Souza (Methods in Neurosciences, Vol. 5, 1991). The membrane pellets containing the CRF receptors are re-dispersed in 50 mM Tris buffer, pH 7.7 containing 10 mM MgCl 2 and 2 mM EDTA and centrifuged for 10 minutes at 48,000 g. The membranes are again washed and placed at a final concentration of 1500 mg / ml in binding buffer (anterior Tris buffer with 0.1% BSA, 15 mM bacitracin and 0.01 mg / mL aprotinin). For the binding assay, 100 mL of the membrane preparation is added to 96-well microtube plates containing 100 mL of 125 I-CRF (SA 2200 Ci / mmol, final concentration of 100 pM) and 50 mL of drug. The binding is carried out at room temperature for 2 hours. The plates are collected in a Brandel 96-well cell harvester and the filters are counted for gamma emissions in a Wallac 1205 Betaplate liquid scintillation counter. Non-specific binding is defined by cold CRF i mM. IC 50 values are calculated with the RS / 1 non-linear curve fitting program (BBN Software Products Corp., Cambridge, MA). The binding affinity for the compounds of Formula I expressed as the IC50 value, varies in general from about 0.5 nanomolar to about 10 micromolar. Alternatively, the binding activity of the compounds of Formula I to the human CRFi receptor can be measured as follows: Assay for the activity of binding to the human CRF receptor in IMR32 cells [125I] Sauvagine binding to CRF1 receptors endogenously expressed in IMR-32 cells. Human IMR-32 neuroblastoma cells were cultured at 80% confluence in Earle's balanced salts containing EMEM and 2 mM l-glutamine with 10% FBS, 25 mM HEPES, 1 mM sodium pyruvate, and non-essential amino acids. At this time, cell flasks are treated with 5-bromo-2'-deoxyuridine 2.5 μM (Br-dU) for 10 days. The media was changed every 3-4 days through the 10-day period. Cells were harvested using No-Zyme (JRH Biosciences) and wiped with PBS. For membrane preparation, cells were homogenized in wash buffer (50 mM Tris-HCl, 10 mM MgCl 2, 2 mM EGTA, pH 7.4) and centrifuged at 48,000 x g for 10 minutes at 4 ° C. The sediments were re-dispersed, homogenized and centrifuged two additional times. The receptor binding assay was performed using assay buffer (50 mM Tris-Hcl, 10 mM MgCl 2, 2 mM EGTA, pH 7.4, 0.1% BSA, 0.1 mM bacitracin (22.0 mg / 100 mL)), 150 μg of protein / tube, and [125I) Sauvagine (NEN: 100 pM for competition analysis 6 10 pM-1 nM for saturation analysis) to produce a final volume of 200 μL. The non-specific binding is defined using CRF r / h 2 μM or alpha-helical CRF 9-41. The cells are incubated for 2 hours at room temperature. The test is terminated by rapid vacuum filtration (Tomtec: Deepwell 3) through GFC filters pre-wetted in 1% PEI using ice-cold 50 mM Tris-HCl and completely dried with air. Specific binding: 70-80%, Kd (nM): 0.30 nM; Bmax (fmol / mg of protein): 40-50. The IC 50 values are calculated with the adjustment program to the non-linear line RS / 1 (BBN Sortware Products Corp. Cambridge, MA). The binding affinities for the compounds of Formula I towards the CRFi result are expressed as IC 50 values and are less than 10 micromolar.

Assay for human NPYl receptor binding activity Compounds are titrated for activity using the following method: baculovirus infected f9 cells expressing human, recombinant NPY Yl receptors are harvested at 42-48 hours at which time batches of 500 mL of cell suspension are pelleted with centrifugation. Each pellet is re-dispersed in 30 mL of lysis buffer (10 mM HEPES, 20 mM sucrose, 0.5 μg / mL leupeptin, 2 μg / mL aprotonin, 200 μM PMSF, and 2.5 mM EDTA, pH 7.4) and Gently homogenize by 50 strokes using a dounce homogenizer. The homogenate is centrifuged at 4 ° C for 10 minutes at 356 x g to settle the nuclei. The supernatant is collected in a fresh tube and centrifuged twice therein, buffered at 48,000 x g for 40 minutes. The final pellet is subsequently re-dispersed in 10 mL "of PBS containing 5 mM EDTA by dounce homogenization and stored in aliquots at -80 ° C. The purified membranes are washed by PBS and re-dispersed by soft pipetting into buffer binding (50 mM Tris (HCl), 5 mM KCl, 120 mM NaCl, 2 mM CaCl 2, 1 mM MgCl 2, 0.1% bovine serum albumin (BSA), pH 7.4), membranes (5 μg) are added to Silicone-treated propylene tubes (Sig acotes, Sigma) plus [125I) NPY (porcine) 0.050 nM for competition analysis or [125I) NPY (porcine) 0.010-0.500 nM for saturation analysis. The effects of guanine nucleotides on affinity to the GTP receptor are added to a final concentration of 100 μM, cold displacers are added at concentrations ranging from 10 ~ 12 M to 10 ~ 6 M to produce a final volume of 0.250 mL. Non-specific binding is determined in the presence of NPY (human) 1 μM and the count of less than 10 % of total binding After an incubation of 2 hours at room temperature, the reaction is terminated by rapid filtration in vacuo. The samples are filtered on pre-moistened Whatman GF / C filters (1.05 polyethylene imine for 2 hours) and rinsed 2 times with 5 mL of cold binding buffer lacking BSA. The remaining bound radioactivity is measured by gamma counting. To estimate Bmax, Kd and Ki, the results of the binding experiments are performed using the computer program SigmaPlot (Jandel). The binding affinities for the compounds of Formula I toward the NPYX receptor are expressed as IC50 values and are less than 10 micromolar. The invention and the way of the process to elaborate and use it, are now described in complete, clear, concise and exact terms to allow any person expert in the technique to which it corresponds, make and use it. It will be understood that the foregoing describes preferred embodiments in the present invention and that modifications may be made herein without departing from the spirit or scope of the present invention as set forth in the claims. To particular note and distinctly claim the subject matter or invention, the following claims conclude this specification.

It is noted that with respect to this date, the best method known to the applicant to carry out the present invention is that which is clear from the present description of the invention. Having described the invention as above, the content of the following is claimed as property:

Claims

1. A compound of the formula: or pharmaceutically acceptable salts thereof characterized in that: Ar is phenyl, 1- or 2-naphthyl, 2-, 3-, or 4-pyridyl, 2-, 4-, or 5-pyrimidinyl, optionally mono-, di-, or tri-substituted with halogen, trifluoromethyl, hydroxy, amino, lower alkylamino, dialkylamino lower, caboxamido, N- (lower alkyl) -carboxamido, N, N- (lower dialkyl) -carboxamido, alkyl of 1 to 6 carbon atoms, alkoxy from 1 to 6 carbon atoms, with the proviso that at least one of the positions ortho or para to the point of attachment of Ar to the tricyclic ring system is substituted; Ri is hydrogen, halogen, trifluoromethyl, alkyl of 1 to 6 carbon atoms, or (C 1 -C-alkyl) -G 1 -R 2, wherein G 1 is oxygen or sulfur and R < hydrogen is alkyl of 1 6 carbon atoms; W is N or C-R3, where R3 is hydrogen or alkyl of 1 to 6 carbon atoms; Y X is , where V1 and V2 are CH2, CO, CS, S02 or CH (C? -C6alkyl), with the proviso that both Vi and V2 can not be both CO, CS or S02; Y1 and Y2 independently represent a bond or alkylene of 1 to 6 carbon atoms; A1 is NR R5, wherein R4 and R5 are independently hydrogen, a lower alkyl group which optionally forms a heterocycloalkyl group with Y1; arylalkyl of 1 to 6 carbon atoms or heteroarylalkyl of 1 to 6 carbon atoms, where aryl is phenyl and heteroaryl is 2-, 3-, or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2 - or 4-imidazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4-, or 5-thiazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or 4-triazolyl, 2- pyrazinyl, or 1-, 2- or 5-tet razolyl, each of which is optionally mono-, di- ,. or tri-substituted with halogen, trifluoromethyl, hydroxy, amino, lower alkylamino, lower dialkylamino, lower alkylcarboxamido, lower alkyl, lower alkoxy, with the proviso that 2 adjacent substituents may together form a heterocycloalkyl or cycloalkyl ring fused with 5-7; lower alkanoyl, lower alkylsulfonyl, with the proviso that R4 and R5 can not be both alkanoyl or alkylsulfonyl; or NR4R5 together form a heterocycloalkyl of 3 to 6 carbon atoms or a group of the Formula: where e and f are independently 1, 2 or 3 and the sum of e and f is at least 3; and G2 is NR6, wherein R6 is hydrogen or alkyl of 1 to 6 carbon atoms, or CH (C0-C6alkylene) -G-R wherein G3 is CONH, CONH (C! -C6alkyl), NH, NH ( C6-C6alkyl) and R7 is hydrogen or alkyl of 1 to 6 carbon atoms; or CONH2, CO [N (C? -C6alkyl) R8], wherein R8 is hydrogen or alkyl of 1 to 6 carbon atoms; arylalkyl of 1 to 6 carbon atoms or heteroarylalkyl of 1 to 6 carbon atoms, wherein aryl is phenyl and heteroaryl is 2-, 3-, or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2- or 4-imidazolyl, 2-, 4- or 5-oxazolyl, 2-, 4-, or 5-thiazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or 4-triazolyl, 2-pyrazinyl, or 1-, 2- or 5-tetrazolyl, each of which is optionally mono-, di-, or tri-substituted with halogen, trifluoromethyl, hydroxy, amino, alkylamino, or dialkylamino lower, lower alkylcarboxamido, lower alkyl, lower alkoxy, with the proviso that 2 adjacent substituents may together form a heterocycloalkyl or cycloalkyl ring fused to 5-7; A2 is hydrogen, alkyl of 1 to 6 carbon atoms, (Ci-Cealkylene) -G4-R9 wherein G4 is oxygen or sulfur and R9 is hydrogen, trifluoromethyl or alkyl of 1 to 6 carbon atoms; wherein heteroaryl is 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2- or 4-imidazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4- , or 5-thiazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or 4-triazolyl, 2-pyrazinyl, or 1-, 2- or 5-tetrazolyl, each of which is optionally mono- or di-substituted with halogen, trifluoromethyl, amino, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, with the proviso that tetrazolyl can have at most one substituent; Z1 is alkyl of 1 to 6 carbon atoms; and V2, Y2 and A2 are as defined above; , 10 (iii) is carbon or nitrogen; where when Z is CH, n is 0 3 and p is 1 2 or 3, R is carboxamido, or (C0-C6alquilen) -G -R 11 wherein G ° is NH, NH (C! -C6alkyl) and R 1X1i is hydrogen, alkyl of 1 to 6 carbon atoms, arylalkyl of 1 to 6 carbon atoms or heteroarylalkyl of 1 to 6 carbon atoms, where aryl is phenyl and heteroaryl is 2-, 3-, or 4-pyridyl, 2-, 4-, or 5-pyrimidinyl, 1-, 2-, or 4-imidazolyl, 2-, 4-, or 5-oxalolyl, 2- , 4-, or 5-thiazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3-, or 4-triazolyl, 2-pyrazinyl, or 1-, 2- or 5-tetrazolyl, each of which is optionally mono-, di- or tri-substituted with halogen, trifluoromethyl, hydroxy, amino, lower alkylamino, dialkylamino lower, alkylcarboxamido lower, lower alkyl, lower alkoxy, with the proviso that at least two adjacent substituents can together form a ring of heterocycloalkyl or fused cycloalkyl of 5-7; when Z2 is carbon, n is l or 2 and p is l or 2, R10 is amino; or when z2 is nitrogen, n is l or 2 and p is l 2, R is hydrogen; (iv) a nitrogen heterocycle of the Formula wherein the N-ring represents triazolyl, tetrazolyl, imidazolyl, or pyrazolyl, each of which is optionally substituted with amino, trifluoromethyl, carboxamido, or (C? -C6alkylene) -G6-R12 wherein G6 is NH, NH ( C6-C6alkyl) and R12 is hydrogen, alkyl of 1 to 6 carbon atoms, arylalkyl of 1 to 6 carbon atoms or heteroarylalkyl of 1 to 6 carbon atoms, wherein aryl is phenyl, and heteroaryl is 2-3 -, or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2- or 4-imidazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4-, or 5-thiazolyl, -, 3- or 4-pyrazolyl, 1-, 3- or 4-triazolyl, 2-pyrazinyl, or 1-, 2-, or 5-tetrazolyl each of which is optionally mono-, di-, or tri- substituted with halogen, trifluoromethyl, hydroxy, amino, lower alkylamino, lower dialkylamino, lower alkylcarboxamido, lower alkyl, lower alkoxy, with the proviso that 2 adjacent substituents may together form a cycloalkyl or heterocycloalkyl ring fused uilo of 5-7.

2. A compound according to claim 1, characterized in that W is Ch, Ar is 2, 4, 6-t rimethylphenyl, Ri is methyl and X is N- (2-aminoethyl) -N- (cyclopropylmethyl), N- ( 2-pyrrolidinoethyl) -N- (cyclopropylmethyl), N- (2-N ', N'-dimethylaminoethyl) -N- (propyl), N- (2- (N', N'-dimethyl) aminoethyl) -N- (2-methoxyethyl), N- (2- (N ', N'-dimethyl) aminoethyl) -N- (cyclopropylmethyl), N- (2- (N'-ethyl) aminoethyl) -N- (cyclopropylmethyl), N- (2- (N '-methyl-N' -ethyl) aminoethyl) -N- (cyclopropylmethyl), N- (2- (N ', N' -diethyl) aminoethyl) -N- (cyclopropylmethyl), N- (2- (N '-methyl) aminoethyl) -N- (cyclopropylmethyl), N- (2-piperidinoethyl) -N- (cyclopropylmethyl), N- (2-pyrrolidinoethyl) -N- (propyl), N- (2-piperidinoethyl) -N- (propyl), N- (2-morpholinoethyl) - (cyclopropylmethyl), N- (2- (N '-methyl-N'-ethyl) aminoethyl) -N (propyl), N - (2- (N '-methyl) piperazinyl) -N- (cyclopropylmethyl), N- (2- (N'-methyl) homopiperazinyl) -N- (cyclopropylmethyl), N- (2-N'-isopropyl) aminoethyl ) -N- (cyclopropylmethyl), N- (3-aminopropyl) -N- (cyclopropylmethyl), N- (2-aminoethyl) -N- (propyl), N- (2-aminoethyl) -N- (ethyl), N- (3-pyrrolidinopropyl) -N- (cyclopropylmethyl), N- (4-pyrrolidinobutyl) -N- (cyclopropy 1-methyl), N- (2- (N'-2-phenethyl) aminoethyl) -N- ( cyclopropylmethyl), N- (2-pyrrolidinoethyl) -N- (2-methoxyethyl), N- (2-pyrrolidinoethyl) -N- (ethyl), N- (2-pyrrolidinoethyl) -N- (butyl), N- ( 2-pyrrolidinoet i 1) - N- (isopropyl), N- (2- (N ', N' -dimethyl) aminoethyl-N- isobutyl), N- (2- (N '-methyl-N'-ethyl) to me noethyl-N- isobutyl), N- (2- (N '-methylpyrrolidin-2-yl) ethyl-N-cyclopropylmethyl), N- (2-pyrrolidinoethyl-N- isopropyl), N- (2- (N' , N'-dimethyl) aminoethyl-N- isopropyl), N- (2- (N 1 -cyclopentyl) aminoethyl-N-ethyl), N- (2- (N'-2- (-methoxy) phenethyl) aminoethyl-N ethyl), N - ((1-met il-2-pyrrolidino) ethyl-N-cyclopropyl methyl), N- ((1-met il-2-amino) ethyl-N-cyclopropyl methyl).

3. A compound according to claim 1, characterized in that W is CH, Ar is 2,4,6-trimethylphenyl, Ri is methyl and X is N- (l-oxo-2- (N ', N' N-dimethyl) aminoethyl) -N- (propyl), N- (2-oxo-2- (N1, N 'N-dimethyl) aminoethyl) -N- (propyl), N- (1-oxo-2- (N', N 'N-dimethyl) aminoethyl) -N- (cyclopropylmethyl), N- (2-pyrrolidinoethyl) -N- (1-oxo-propyl), N- (2-pyrrolidinoethyl) -N- (1-oxo-cyclopropyl), N- (2-oxo-2- (N ', N'-dimethyl) aminoethyl) -N- (cyclopropyl).

4. A compound according to claim 1, characterized in that W is CH, Ar is 2,4,6-trimethylphenyl, Rx is methyl and X 2- (S) - (cyclopentylaminomethyl) pyrrolidinyl, 4- (carboxamido) piperidinyl, 3- (cyclopentyllamino) pyrrolidinyl, 3- (l-oxo-2- ((3-methoxy-4-ethoxy) phenyl) aminoethyl) pyrrolidinyl, 2- (2- (-methoxy) phenyl) aminoethyl) pyrrolidinyl, 3- ( 1-oxo-2- ((3-methoxy-4-ethoxy) phenyl) ethyl) pyrrolidinyl, 4- (2- ((3-methoxy-4-ethoxy) phenyl) aminoethyl) piperidinyl.

5. A. compound according to claim 1, characterized in that W is CH, Ar is 2, "4,6-trimethyl phenyl, Rx is methyl and X is N- (2-pyrrolidinoethyl) -N- (cyclopropylmethyl), N- (2 -pyrrolidinoethyl) -N- (propyl), N- (2-pyrrolidinoethyl) -N- (butyl), N- (2-pyrrolidinoethyl) -N- (cyclopropyl), N- (2- (N ', N'N -dimethyl) aminoethyl) -N- (propyl), 2- (N ', N' -dimethylaminoethyl) -N- (butyl), N- (2- (N ', N' -dimethyl) aminoethyl) -N- ( cyclopropylmethyl), N- (2- (N ', N'-dimethyl) aminoethyl) -N- (cyclopropyl), N- (2-piperidinoethyl) -N- (propyl), N- (2-piperidinoethyl) -N- (butyl), N- (2- (', N' -dimethyl) aminoethyl) -N- (cyclobutyl), N- (2- (N ', N' -dimethyl) aminoethyl) -N- (cyclopentyl), N - (2- (N ', N' -dimethyl) aminoethyl) -N-2-methoxyethyl) N- (2- (N ', N' -dimethyl) aminoethyl) -N- (isopropyl) N- (2- ( N'-ethyl) aminoethyl) N- (cyclopropyl), piperazinyl

6. A compound according to claim 1, characterized in that W is CH, Ar is 2,6-dimethyl-4-bromo-phenyl, R is methyl and X is N- (2- (N ', N' -dimethyl) aminoethyl) -N- (ethyl) or N- (2-pirr lidinoethyl) - (cyclopropylmethyl).

7. A compound according to claim 1, characterized in that W is CH, Ar is 2-met il-4-methoxy-phenyl, Ri is methyl and X is N- (2- (N ', N' -dimethyl) aminoethyl) -N- (cyclopropylmethyl).

8. A compound according to claim 1, characterized in that W is CH, Ar is 2,4-dimethylphenyl, Ri is methyl and X is N- (2-pyrrolidinoethyl) -N- (cyclopropylmethyl).

9. A compound according to claim 1, characterized in that W is CH, Ar is 2,6-dimethylphenyl, Ri is methyl and X is N- (2- (N ', N' -dimethyl) aminoethyl) -N- (cyclopropylmethyl) ).

10. A compound according to claim 1, characterized in that W is CH, Ar is 2,4,6-trimethylphenyl, Ri is methyl and X is N- (2- (1-imidazolyl) aminoethyl) -N- (cyclopropylmethyl), N- (2- (1, 2,4-triazol-4-yl) aminoethyl) -N- (cyclopropylmethyl).

11. A compound of the formula characterized in that: each Ra is alkyl of 1 to 6 carbon atoms Rb is hydrogen or methyl; Ri is alkyl of 1 to 6 carbon atoms; Rs is alkyl of 1 to 6 carbon atoms, (C3-C5) cycloalkyl (C1-C3) alkyl, (C1-C3) alkoxy (Ci-C3) alkyl, or (C3-C5) cycloalkyl; t is 1, 2 or 3; and Rx is hydrogen, alkyl of 1 to 6 carbon atoms, phenyl (Ci-Cβ) alkyl wherein phenyl is optionally mono- or di-substituted independently with alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms , halogen or hydroxy; and Ry is hydrogen, alkyl of 1 to 6 carbon atoms, (C3-C6) cycloalkyl; or NRxRy represent pyrrolidinyl, N (C? -C6) alkylpyrrolidin-2-yl, piperidinyl, morpholinyl, or N- (Ci-C?) alkylpiperazinyl.

12. A compound according to claim 11, characterized in that Rs is alkyl of 1 to 6 carbon atoms or cyclopropylmethyl.

13. A compound according to claim 12, characterized in that Rs is cyclopropyl (C 1 -C 3) alkyl.

14. A compound according to claim 13, characterized in that R x and R y independently represent hydrogen or alkyl of 1 to 2 carbon atoms.

15. A compound according to claim 14, characterized in that each Ra is methyl.

16. A compound according to claim 15, characterized in that W is nitrogen.

17 A compue sto of the formula characterized in that: each Ra is alkyl of 1 to 6 carbon atoms Ri is alkyl of 1 to 6 carbon atoms; Rs is alkyl of 1 to 6 carbon atoms, (C3-C5) cycloalkyl (C1-C3) alkyl, (C1-C3) alkoxy (Cx-C3) alkyl, or (C3-C5) cycloalkyl; t is 1, 2 or 3; and Rx is hydrogen, alkyl of 1 to 6 carbon atoms, phenyl (C6C6) alkyl wherein phenyl is optionally mono- or di-substituted independently with alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms carbon, halogen or hydroxy; and Ry is hydrogen, alkyl of 1 to 6 carbon atoms, (C3-C6) cycloalkyl; or NRxRy represent pyrrolidinyl, N (C? -Cg) alkylpyrrolidin-2-yl, piperidinyl, morpholinyl, or N- (C? -C6) alkylpiperazinyl.

18. A compound according to claim 17, characterized in that Rs is alkyl of 1 to 6 carbon atoms or cyclopropylmethyl.

19. A compound according to claim 18, characterized in that Rs is cyclopropyl (C 1 -C 3) alkyl.

20. A compound according to claim 19, characterized in that t is 1 and Rx and Ry independently represent hydrogen or alkyl of 1 to 2 carbon atoms.

21. A compound according to claim 20, characterized in that each Ra is methyl.

22. A compound according to claim 21, characterized in that W is nitrogen.

23. A compound of the formula characterized in that: each Ra is alkyl of 1 to 6 carbon atoms; Ri is alkyl of 1 to 6 carbon atoms; t is 1 or 2; Rx and Ry are different and represent hydrogen; (C3-C7) cycloalkylamino (C1-C3) alkyl, carboxamido, (C3-C7) cycloalkylamino, alkanoyl of 2 to 6 carbon atoms optionally substituted at the? with alkyl of 1 to 6 carbon atoms or phenyl optionally mono- and disubstituted independently with alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halogen or hydroxy, with the proviso that at least one of Rx and Ry is hydrogen.

24. A compound according to claim 23, characterized in that R1 is alkyl of 1 to 2 carbon atoms and W is nitrogen.

25. A compound according to claim 24, characterized in that each Ra is methyl.

26. A compound according to claim 1, characterized in that it is: 4- (N- (2-pyrrolidinoethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6-t rimethephenyl) -9H -pyridino [2,3-b] indole; 4- (N- (2-N ', N' -Dimethylaminoethyl) -N-propyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole; 4- (N- (2-N ', N' -dimethylaminoethyl) -N-2-methoxyethyl) amino-2-methyl-9- (2,4,6-t rimethylphenyl) -9H-pyridino [2, 3 -b] indole; 4- (N- (2-N1, N '-Dimethylaminoethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2, 3-b] indole; 4- (N- (-2-N'-ethylaminoethyl) -N-cyclopropylmethyl) amino-2-met i 1-9- (2,4,6-t rimet ilphenyl) -9H-pyridino [2,3-b ] indole; 4- (N- (2- (N'-Ethyl-N '-methyl) aminoethyl) -N-cyclopropylmethyl) amino-2-methi 1-9- (2,4,6-trimethylphenyl) -9H-pyridino [2 , 3-b] indole; 4- (N-2- (2- (S) -methoxymethylpyrrolidino) ethyl-N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole; 4- (N- [2-N ', N' -Dimethylaminoethyl) -N-cyclopropylmethyl) amino) 2-met il-9- (4-methoxy-2-methylphenyl) -9H-pyridino [2, 3-b ] indole; 4- (N- (2-N 'NI -diethylaminoethyl) -N-cyclopropylmethyl) amino-2-methi 1-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole; or 4- (N- (2-N * -Methylaminoethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6-t-rimethylphenyl) -9H-pyridino [2,3-b] indole .

27. A compound according to claim 1, characterized in that it is: 4- (N- (2-Piperidinoethyl) -N-cyclopropylmethyl) amino) 2-methyl-9- (2,4,6-t rimethylphenyl) -9H-pyridino [2,3-b] indole; 4- (N- (2-Pyrrolidinoethyl) -N-propyl) amino-2-met-il- 9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole; 4- (N- (2-Piperidinoethyl) -N-propyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole; 4- (N- (2-Morpholinoethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3- b] id 1; 4- (N- (2-N'-Ethyl-N '-methylaminoethyl) -N-propyl) amino-2-met-il-9- (2,4,6-trimethylphenyl) -9H-pyridine [2 , 3- b] indole; 4- (N- (2- (1-Imidazolyl) ethyl) -N-cyclopropylmethyl) -amino-2-met-il-9- (2,4,6-trimethylphenyl) -9H-pyridino [2, 3-b] indole; 4- (N-2- (N'-Methylpiperazinyl) ethyl-N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole; 4- (N-2- (N '-Methyl-homopyperazinyl) -ethyl-N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6-trimethyl-phenyl) -9H-pyridino [2,3-b] indole; 4- (N- (2-N '-Isopropylaminoethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole; 4- (N- (2- (2- (1-Methyl-2-pyrrolidino) ethyl) aminoethyl) • N-cyclopropylmethyl) amino-2-met-il- 9- (2,4,6-trimethylphenyl) -9H- pyridino [2, 3-b] indole; or 4- (N- (2-Piperazinylethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-. b] indole.

28. A compound according to claim 1, characterized in that it is: 4- (N- (2-Pyrrolidinoethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4-dimethyl-ilphenyl) -9H-pyridino [2,3-b] indole; 4- (N- (3-Pyrrolidinoproyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6-t rimethylphenyl) -9H-pyridino [2,3-b] indole; 4- (N- (2-Methyl-2-pyrrolidinoethyl) -N-cyclopropylmethyl) amino-2-met-il- 9- (2,4,6-t-rimethylphenyl) -9H-pyridino [2,3-b] indole; Í53 4- (N- (4-Pyrrolidinobutyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6-t rimethylphenyl) -9H-pyridino [2,3-b] indole; 4- (N- (2- (4-Piperidinopiperidinyl) ethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole; 4- (N- (2- (2-Fethylamino) ethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole; 4- (N- (2-N'-methylaminoethyl) -N-methyl) amino-2-met-il- 9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole; 4- (N- (2-Pyrrolidinoethyl) -N-2-methoxyethyl) amino) 2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole; 4- (N- (2-Pyrrolidinoethyl) -N-ethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole; 4- (N- (2-Pyrrolidinoethyl) -N-butyl) amino-2-met-il- 9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole; or 4- (N- (2-Pyrrolidinoethyl) -N-2-methylpropyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole.

29. A compound according to claim 1, characterized in that it is: 4- (N- (2-N ', N' -Dimethylaminoethyl) -N-2-methylpropyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridine [2, 3 b] indole; 4- (N- (2- (N'-Ethyl-NI-methyl) aminoethyl) -N-2-methylpropyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [ 2, 3-b] indole; 4- (N- (2-Pyrrol idinoethyl) -N-isopropyl) araino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole; 4- (N- (2-N1, N '-Dimethylaminoethyl) -N-isopropyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole. 4- (N- (2-Guanidinoethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyrimidino [4, 5-b] indole; 4- (N- (2- (2- (4-Methoxy) phenethylamino) ethyl) -N-ethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2, 3 -b] indole; 4- (N- (2-N'-Cyclopentylaminoethyl) -N-ethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole; 4- (N- (2-N ', N' -Dimethylaminoethyl) -N-ethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole; 4- (N- (2-N '/ N1 -Dimethylaminoethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,6-dimethylphenyl) -9H-pyridino [2,3-b] indole; or 4- (N- (2-aminoethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole.

30. A compound according to claim 1, characterized in that it is: 4- (N- (3-Aminopropyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole; 4- (N- (2-amino-2-methylethyl) -N-cyclopropylmethyl) -amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole; 4- (N- (2-Aminoethyl) -N-propyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole; 4- (N- (2-Aminoet il) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4-dimethyl-ilphenyl) -9H-pyridino [2,3-b] indole; 4 - . 4 - . 4 - (N- (2-aminoet i 1) -N-cyclopropylmethyl) amino-2-methyl-9- (2,6-dimethylphenyl) -9H-pyridino [2,3-b] indole; 4- (N- (2-Aminoethyl) -N-ethyl) amino-2-met-il- 9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole; 4 - (N- (4-aminobutyl) -N-cyclopropylmethyl) amino-2-methyl-9 (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole; 4- (N- (2- (4-Triazolyl) ethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6-t-rimethylphenyl) -9H-pyridino [2, 3-b] indole; 4- (N- (2-Carboxamidoethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6-t rimethylphenyl) -9H-pyridino [2,3-b] indole; or 4- (N- (2-N '-acetyl-N' -methylaminoethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] ] indole

31. A compound according to claim 1, characterized in that it is: 4- (N- (2- (N 1 -Metanesulfonyl-N '-methylamino) ethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridine [2, 3 -b] indole; 4- (N- (2- (N '-Methyl-N' -tri fluorometansul fonyl) -aminoethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H -pyridino [2,3-b] indole; 4- (N- (2- (4-Aminophenylsulfonamido) ethyl) -N- (cyclopropylmethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole; 4- (N- (2- (2-Thienylsulfonamido) ethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole; 4- (N- (2- (2- (2-Thienyl) -1-oxoethyl) aminoethyl) -N-cyclopropylmethyl) amino-2-methi 1-9- (2,4,6-trimethylphenyl) -9H-pyridine [2, 3-b] indole; 4- (N- (2- (2-Phenyl-l-oxoethyl) aminoethyl) -N-5-cyclopropylmethyl) amino-2-met il-9- (2,4,6-trimethylphenyl) -9H-pyridino [2 , 3-b] indole; 4- (N- (2-N ', N' -dimethylamino-1-oxoethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2, 3 -b] indole; 4- (N- (2-N'N '-Dimethylamino-1-oxoethyl) -N-propyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2, 3- b] indole; 4- (N- (2-N ', N' -Dimethyl-amino-1-oxoet i 1) -N-2-methoxyethyl) amino-2-methi 1-9- (2,4,6-trimethylphenyl) 9H- pyridino [2, 3-b] indole; or 4- (N- (2-Pyrrolidino-1-oxoethyl) -N-cyclopropylmethyl) -amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole.

32. A compound according to claim 1, characterized in that it is: 4- (N- (2-N '- Ethylamino-1-oxoethyl) -N-cyclopropyl ethyl) amino-2-r-2-methi 1-9- (2,4,6-trimethylphenyl) -9H-pyridino [ 2, 3-b] indole; 4- (N- (2- (N'-Ethyl-NI-methyl) amino-1-oxoet yl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H- pyridino [2, 3-b] indole; 4- (N- (2- (2- (S) -methoxymethylpyrrolidino) -1-oxoethyl) N-cyclopropylmethyl) amino-2-met-il- 9- (2,4,6-trimethylphenyl) -9H-pyridino [ 2, 3-b] indole; 4- (N- (2- (1-Imidazolyl) -1-oxoethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2, 3 b] indole; 4- (N- (2-pyrrolidinoethyl) -N-1-oxopropyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole;

1. 60 4- (N- (2-Pyrrolidinoethyl) -N-cyclopropyloxomethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole; 4- (N- (2-Dimethylaminoethyl) -N-methoxymethyloxomethyl) -amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole; 4- (N- (2-pyridylmethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6-t rimethylphenyl) -9H-pyridino [2,3-b] indole; 4- (N- (2-N ', N' -Dimethylamino-2-oxoethyl) -N-2-methoxyethyl) mino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2 , 3-b] indole; or 4- (N- (2-N ', N' -Dimet i lamino-2-oxoethyl) -N-propyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2 , 3-b] indole; 4- (N- (2-N ', N' -Dimethyl-amino-2-oxoethyl) -N-2-methoxy-1-oxoethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) - 9H-pyridino [2, 3-b] indole; 4- (N- (2-N ', N' -Dimet i 1 amino-1-oxoethyl) -N-cyclopropylmethyl) amino-2-met-il- 9- (2,4,6-trimethylphenyl) 9H-pyridino [ 2, 3-b] indole; 4- (4-Triazolyl) -2-met il-9- (2,4,6-t rimet-ilphenyl) -9H-pyridino [2,3-b] indole; 4-Piperazinyl-2-methyl-9- (2,4,6-t rimethylphenyl) -9H-pyridino [2,3-b] indole; 4- (4-Methylpiperazinyl) -2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole; 4-Homopiperazinyl-2-met il-9- (2,4,6-t rimet-ilphenyl-9H-pyridino [2,3-b] indole; 4- (N- (2- (l-Methyl-2-pyrrolidino) ethyl) -N-cyclopropicarbonyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2, 3-b] indole; 4- (N-2- (S) -Pyrrolidinomethylpyrrolidinyl) -2-met il-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole; 4- (4-Aminomethylpiperidino) -2-methyl-9- (2, 4, 6-trimethylphenyl) -9H-pyridino [2,3-b] indole; 4- (4-Piperidinopiperidinyl) -2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole; 4- (4-Carboxamidopiperidinyl) -2 -met i 1-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole; 4- (3-Aminopyrrolidinyl) -2-met il-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole;

33. A compound according to claim 1, characterized in that it is: 4- (N- (2- (l-Methyl-2-pyrrolidino) ethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2, 3 b] indole; 4- (N-2- (S) -Cyclopentylaminomethylpyrrolidinyl) -2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole; 4- (N-2- (R) -Ci c 1 opent i laminómet i lpirrol idini 1) -2-methyl-9- (2,4,6-trimethylphenyl) -9 H -pyridino [2,3-b] indole; 4- (N-3-Cyclopentyl-laminopyrrole idini 1) -2-methi 1-9- (2,4,6-t rimet-ilphenyl) -9H-pyridino [2,3-b] indole; 4- (N -3- (2- (3-Methoxy-4-ethoxy) phenethyl) amino-pyrrolidinyl) -2-met il-9- (2,4,6-trimethylphenyl) -9H-pyridine [2,3 -b] indole; 4- (N-3- (l-oxo-2- (3-Methoxy-4-ethoxy) phenethyl) amino-pyrrolidinyl) -2-met-il-9- (2,4,6-t rimet-ilphenyl) -9H -pyridine [2, 3-b] indole; 4- (N-2- (2- (R) - (4-Methoxy) phenethyl) aminomethyl-pyrrolidinyl) -2-methyl-9- (2,4,6-t rimethylphenyl) -9H-pyridino [2, 3-b] indole; 4- (N-2- (2- (S) - (4-Methoxy) phenethyl) aminomethyl-pyrrolidinyl) -2-met i 1-9- (2,4,6-t rimet ilphenyl) -9H-pyridino [ 2, 3-b] indole; 4- (N-4- (2- (3-Methoxy-4-ethoxy) phenethyl) to inomethyl-piperazinyl) -2-met il-9- (2,4,6-trimethylphenyl) -9H-pyridino [2, 3-b] indole; or 4- (N- (2-N ', N' -Dimethylaminooethyl) -N-cyclopropyl) amino-2-methi 1-9- (2,, 6-trimethylphenyl) 9H-pyrimidino [4,5-b] indole .

34. A compound according to claim 1, characterized in that it is: 4- (N- (2-N ', N' -Dimethylaminoethyl) -N-methyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyrimidino [4,5-b] indole; 4- (N- (2-N ', N' -Dimethylaminoethyl) -N-ethyl) amino-2-methyl-9- (4-bromo-2,6-dimethylphenyl) -9H-pyrimidino [4, 5-b ] indole; 4- (N- (2-N ', N' -Dimethylaminoethyl) -N-ethyl) amino-2-methyl-9- (4-chloro-2-methylphenyl) -9H-pyrimidino [4,5-b] indole; 4- (N- (2-Morpholinoethyl) -N-propyl) amino-2-methyl-9- (2-chloro-4-methyl-phenyl) -9H-pyrimidino [4, 5-b] indole; 4- (N- (2-N ', N' -Dimethylaminoethyl) -N-cyclopropylmethyl) 1) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyrimidino [4, 5-b ] indole; 4-Piperazinyl-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyrimidino [4, 5-b] indole; 4- (N- (2-Pyrrolidinoethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyrimidino [4, 5-b] indole; 4- (3-Aminopyrrolidinyl) -2-met-il-9- (2,4,6-trimethylphenyl) -9H-pyrimidino [4,5-b] indole; 4- (2- (S) -Aminomethylpyrrolidino) -2-met il-9- (2,4,6-trimethylphenyl) -9H-pyrimidino [4,5-b] indole; or 4- (3-Amino-2-triazolyl) -2-met i 1-9- (2,4,6-trimethylphenyl) -9H-pyrimidino [4, 5-b] indole.. •

35 A compound according to claim 1, characterized in that it is: 4- (3-amino-1 -tria zolyl) -2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyrimidino [4,5-b] indole; 4- (3-Amino-4-triazolyl) -2-met il-9- (2,4,6-t-rimethylphenyl) -9H-pyrimidino [4, 5-b] indole; 4- (N- (2-Pyrrolidinoethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (4-bromo-2,6-dimethylphenyl) -9H-pyrimidino [4,5-b] indole; 4- (N- (2-Pyrrolidinoethyl) -N-propyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyrimidino [4, 5-b] indole; 4- (N- (2-Pyrrolidinoethyl) -N-butyl) amino-2-met-il- 9- (2,4,6-trimethylphenyl) -9H-pyrimidino [4,5-b] indole; 4- (N- (2-Pyrrolidinoethyl) -N-cyclopropyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyrimidino [4, 5-b] indole; 4- (N- (2-N ', N' -Dimethylaminooethyl) -N-propyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyrimidino [4,5-b] indole; 4- (N- (2-N ', N' -Dimethylaminoethyl) -N-butyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyrimidino [4,5-b] indole; 4- (N- (2-Piperidinoethyl) -N-propyl) amino-2-met-il- 9- (2,4,6-trimethylphenyl) -9H-pyrimidino [4,5-b] indole, or 4- (N- (2-Piperidinoethyl) -N-butyl) amino-2-met-il- 9- (2,4,6-trimethylphenyl) -9H-pyrimidino [4,5-b] indole.

36. A compound according to claim 1, characterized in that it is: 4- (N- (2-N ', N' -Dimethylaminoethyl) -N-cyclobutyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyrimidino [4,5-b] indole; 4- (N- (2-N ', N' -Dimethylaminoethyl) -N-cyclopentyl) amino-2-methyl-9- (2,, 6-trimethylphenyl) -9H-pyrimidino [4, 5-b] indole; 4- (N- (2-N (', N' -Dimethylaminoethyl) -N-isopropyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyrimidino [4,5-b] indole; 4- (N- (2-N * -Methylaminoethyl) -N-methyl) amino-2-met-il- 9- (2,4,6-trimethylphenyl) -9H-pyrimidino [4,5-b] indole; 4- (4- (N-Metilamino) piperidino) -2-methi 1-9- (2,4,6-trimethylphenyl) -9H-pyrimidino [4,5-b] indole; 4- (4- (2-Aminoethyl) piperazinyl) -2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyrimidino [4, 5-b] indole; 4- (N- (2-N '-ethylaminoethyl) -N-ethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyrimidino [4, 5-b] indole; (±) -4- (N- (2-N ', N' -Dimethylaminoethyl) -Nl-methylpropyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyrimidino [4,5] -b] indole; 4- (N- (2-N ', N' -Dietylaminoethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyrimidino [4,5-b] indole; or 4- (N- (2-N ', N' -Dietylaminoethyl) -N-cyclopropyl) amino-2-methyl-9- (2,4,6-t rimet-ilphenyl) -9H-pyrimidino [4, 5-b ] indole

37. A compound according to claim 1, characterized in that it is: 4- (N- (2-N ', N' -Dimethylaminoethyl) -N-2-methoxyethyl) amino-2-met i 1-9- (2,4,6-t rimet-ilphenyl) -9H-pyrimidino [4 , 5-b] indole; 4- (N- (2-N ', N' -Dimethylaminoethyl) -N-2-ethoxyethyl) amino-2-methyl-9- (2,4,6-t rimethylphenyl) -9H-pyrimidino [4,5 -b] indole; 4- (N- (2-N 1 -ethylaminoethyl) -N-ethyl) amino-2-methyl-9- (2-methyl-4-chlorophenyl) -9 H -pyrimidino [4,5-b] indole; 4- (N- (Cyclopentyl aminopiperidin-4-yl) -N-ethyl) amino-2-methyl-9- (2,4,6-t rimethylphenyl) -9H-pyrimidino [4,5-b] indole; 4- (N- (2-N ', N' -Dimethylaminoethyl) -N-isobutyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyrimidino [4,5-b] indole; 4- (N- (2- (3-Methoxy-4-ethoxy) phenethyl) aminopiperidin-4-yl) -N-ethyl) amino-2-met-il-9- (2,4,6-trimethylphenyl) -9H -pyrimidino [4, 5-b] indole; 4- (N- (S) - (l-Oxo-2- (4-methoxy) phenethyl) amino pyrrolidin-2-yl) -2-methi 1-9- (2,4,6-trimethylphenyl) -9H- pyrimidino [4, 5-b] indole; or 4- (N- (S) - (2- (4-Methoxy) phenethyl) aminopyrrolidin-2-yl) -2-met il-9- (2,4,6-t rimethylphenyl) -9H-pyrimidino [4 , 5-b] indole.

A method for the treatment of physiological disorders associated with an excess of CRF, a method comprising administration to a patient in need thereof and a reducing amount of CRF and a compound according to claim 1.

39. A method to treat affective disorder, anxiety, depression, migraineirritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immunosuppression, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa or other eating disorder, addition to drugs, withdrawal symptoms of drugs or alcohol, generally inflammatory, Cardiovascular or heart-related diseases, fertility problems, human immunodeficiency virus infections, hemorrhagic stress, obesity, infertility, spinal column and head trauma, epilepsy, shock, ulcers, amyotrophic lateral sclerosis, hypoglycemia or a disorder, treatment which can be made or facilitated by antagonizing CRF, including but not limited to disorders induced or facilitated by CRF, in mammals, characterized in that it comprises: administering to the mammal a therapeutically effective amount and a compound of claim 1.

40. The use of a compound for the manufacture of the medicament for the treatment of affective disorder, anxiety, depression, migraine, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immunosuppression, Alzheimer's disease, gastrointestinal diseases, anorexia nervous or other eating disorder, addition to drugs, withdrawal symptoms of drugs or alcohol, generally inflammatory, cardiovascular or heart-related diseases, fertility problems, human immunodeficiency virus infections, hemorrhagic stress, obesity, infertility, traumas the spinal column and head, epilepsy, shock, ulcers, amyotrophic lateral sclerosis, hypoglycemia or a disorder, the treatment of which may be effected or facilitated by antagonizing CRF, including but not limited to disorders induced or facilitated by CRF, in mammals, characterized in that it comprises: administering the mam Fero therapeutically effective amount a compound of claim 1.

41. A method of treating or preventing a physiological condition in a mammal characterized by the presence of an excess of neuropeptide Y characterized in that it comprises administering to a mammal in need of this treatment a therapeutically effective amount of a compound according to claim 1, a prodrug, or a pharmaceutically acceptable salt thereof.

42. A pharmaceutical composition according to claim 1, for the treatment of disorders or disease states caused by eating disorders, obesity, bulimia nervosa, diabetes, dyslipidemia, hypertension, memory loss, epileptic seizures, migraine, sleep disorders, pain, cerebral hemorrhage, shock, congestive heart failure, nasal congestion or diarrhea.