JP2002510688A - Aminoalkyl-substituted 9H-pyridino [2,3-b] indole and 9H-pyrimidino [4,5-b] indole derivatives - Google Patents

Abstract

(57) [Summary] Formula (I) Wherein Ar, R ¹ , W and X are substituents as defined herein, wherein the compound is (1) an antagonist at the CRF ₁ receptor, Therefore, useful stress-related disorders such as post-traumatic stress disorder (PTSD), and depression, diagnosis and treatment of headache and anxiety; and (2) are antagonists of neuropeptide Y ₁ receptor, and therefore , Useful in the treatment of various clinical conditions characterized by the presence of excess neuropeptide Y.

Description

DETAILED DESCRIPTION OF THE INVENTION

BACKGROUND OF THE INVENTION 1. Technical Field The present invention relates to aminoalkyl-substituted peptides that selectively bind to the corticotropin releasing factor (CRF ₁ ) receptor and the mammalian neuropeptide Y (NPY ₁ ) receptor. 9H-pyridino [2,3-b] indole and 9H-pyrimidino [4,5-
b] Indole derivatives. The present invention further provides a pharmaceutical composition comprising the compound,
It also relates to the use of the compounds in the treatment of physiological diseases induced or promoted by CRF or physiological diseases associated with excess neuropeptide Y.

2. Description of the Related Art A 41-amino acid peptide, a corticotropin-releasing factor (herein CRF
) Is a major physiological regulator of proopiomelanocortin (POMC) -derived peptide secretion from the anterior pituitary gland [J. Rivier et al., Proc. N
at. Acad. Sci. (USA) 80: 4851 (1983); Va
le et al., Science 213: 1394 (1981)]. In addition to its endocrine role in the pituitary gland, due to the immunohistochemical localization of CRF, this hormone has a broad extrahypothalamic distribution in the central nervous system and a neurotransmitter or neuromodulatory role in the brain Have been demonstrated to produce a wide range of autonomic, electrophysiological and behavioral effects consistent with [W. Vale et al., Rec. Prog. Horm
. Res. 39: 245 (1983); F. Koob, Persp. Beh
av. Med. 2:39 (1985); B. De Souza et al. Ne
urosci. 5: 3189 (1985)]. There is also evidence that CRF plays a significant role in integrating the immune system's response to physiological, psychological, and immunological stressors [J. E. FIG. Blackock, Physiological
al Reviews 69: 1 (1989); E. FIG. Morley, Life
e Sci. 41: 527 (1987)].

[0003] Clinical data provide evidence that CRF plays a role in psychiatric and neurological disorders, including depression, anxiety-related disorders and eating disorders. The role of CRF has also been implicated in Alzheimer's disease, Parkinson's disease, Huntington's disease, progressive supranuclear palsy and amyotrophic lateral sclerosis, as they are associated with impairment of CRF neurons in the central nervous system, and It is postulated to be in pathophysiology [for a review, see E.C. B. De Souza, Hosp. Practice 23: 5
9 (1988)].

[0004] In affective disorders or major depression, the concentration of CRF is significantly increased in cerebrospinal fluid (CSF) in untreated individuals [C. B. Nemeroff
Et al., Science 226: 1342 (1984); M. Banki et al.
Am. J. Psychiatry 144: 873 (1987); D. Fr
ance et al., Biol. Psychiatry 28:86 (1988);
Arato et al., Biol Psychiatry 25: 355 (1989)].
In addition, CRF receptor density was significantly reduced in the suicide frontal cortex,
F is consistent with hypersecretion of F [C. B. Nemeroff et al., Arch. Gen. Ps
ychiatry 45: 577 (1988)]. In addition, CR
A blunt adrenocorticotropic hormone (ACTH) response to F (intravenous administration) is observed [P. W. Gold et al., Am J. et al. Psychiatry 141: 619
(1984); Holsboer et al., Psychoneuroendocr
innovation 9: 147 (1984); W. Gold et al., New En
g. J. Med. 314: 1129 (1986)]. Preclinical studies in rats and non-human primates provide further support for the hypothesis that hypersecretion of CRF may contribute to the symptoms seen in human depression [R. M. Sapolsky, A
rch. Gen. Psychiatry 46: 1047 (1989)]. There is preliminary evidence that tricyclic antidepressants can alter CRF levels and thus modulate brain CRF receptor numbers [Grigoridis et al., Neu.
ropsychopharmacology 2:53 (1989)].

[0005] The role of CRF is also postulated in the pathogenesis of anxiety-related diseases. CRF produces anxiety effects in animals as well as interactions between benzodiazepine / non-benzodiazepine anxiolytics, and CRF has been demonstrated in various behavioral anxiety models [D. R. Britton et al., Life Sci. 31: 363 (1982)
); W. Berridge and A.M. J. Dunn Regul. Pept
ids 16:83 (1986)]. Estimated CRF in various behavioral paradigms
Preliminary studies using the receptor antagonist α-helical sheep CRF (9-41) demonstrate that the antagonists produce an “anxiolytic-like” effect qualitatively similar to benzodiazepines [C. W. Berridge and A.M. J.
Dunn Home. Behav. 21: 393 (1987), Brain R
search Reviews 15:71 (1990)]. Neurochemical, endocrine, and receptor binding studies all demonstrate the interaction of CRF or benzodiazepine anxiolytics, which provides further evidence that CRF is involved in these diseases. Chlordiazepoxide was tested in rats in a conflict test [K. T. Br
Itton et al., Psychopharmacology 86: 170 (198).
5); T. Britton et al., Psychopharmacology 9
4: 306 (1988)] and the sound startle test [N. R. Swedlow et al., P
sychopharmacology 88: 147 (1986)] attenuates the "anxiety-producing" effects of CRF. A benzodiazepine receptor antagonist (Ro15-1788), which has only behavioral activity in the operant conflict test, reverses the effect of CRF in a dose-dependent manner, whereas a benzodiazepine inverse agonist (FG7142) has The effect was enhanced [K. T. Britto
n et al., Psychopharmacology 94: 306 (1988)].

[0006] In addition, CRF can be used for immunological, cardiovascular or heart related diseases such as hypertension,
It is hypothesized to play a role in tachycardia and congestive heart failure, stroke and osteoporosis. CRF also affects premature birth, psychosocial short stature, stress-induced fever, ulcers, diarrhea,
It is also involved in postoperative ileus and colon hypersensitivity associated with psychopathological disorders, and stress.

[0007] The mechanisms and sites of action by which standard anxiolytics and antidepressants exert their therapeutic effects remain to be elucidated. However, they have been postulated to be involved in the suppression of CRF hypersecretion observed in these diseases. Of particular interest are, by a preliminary study to examine the effect of the CRF receptor antagonist in a variety of behavioral paradigms (α- helical CRF 9- _41), CRF antagonists, leads to a qualitatively similar to the benzodiazepines "anxiolytic-like" effect [For a review, see G.S. F. Koob and K.C. T. Britton, corticotropin-releasing factor: basic and clinical studies on neuropeptides, E.C. B. D
e Souza and C.I. B Nemeroff, CRC Press p2
21 (1990)].

[0008] Neuropeptide Y, a peptide first isolated in 1982, is widely distributed in central and peripheral neurons and is involved in many biological effects in the brain and periphery. By various animal studies, activation of neuropeptide NPY ₁ receptors, vasoconstriction (Wahlestedt like, Regul.Peptides,
13: 307-318 (1986), McCauley and Westfall.
J. Pharmacol. Exp. Ther. 261: 863-868 (19
92), and Grundmar et al., Br. J. Pharmacol. 105
: 45-50 (1992)); and stimulation of consumption behavior (Flood and Mor).
ley, Peptides, 10: 963-966 (1989), Leibow.
itz and Alexander, Peptides, 12: 1251-126.
0 (1991), and Stanley et al., Peptides, 13: 581-
587 (1992)). Grundemar and Halanson, TiPS, 15: 153-159 (1994) describe that in animals, neuropeptide Y is a potent food intake stimulator and an inducer of vasoconstriction leading to hypertension. They further point out that low levels of neuropeptide Y are associated with decreased appetite. These reports clearly show that compounds that inhibit the activity of this protein reduce hypertension and appetite in animals.

SUMMARY OF THE INVENTION The present invention provides novel compounds of Formula I that interact with the CRF ₁ and NPY ₁ receptors. The invention further relates to the use of said compounds, pharmaceutical compositions containing these compounds, and psychiatric disorders, including major depression, headache, anxiety related disorders, post-traumatic stress syndrome, supranuclear palsy and Treatment of affective disorders and neurological disorders, as well as the treatment of immunological, cardiovascular or heart related disorders, hypertension, eating disorders, diabetes, dyslipidemia, colon hypersensitivity, and stress associated with psychopathological disorders. Methods useful for treatment. The invention further relates to the use of the compounds in the treatment of physiological disorders induced or promoted by CRF or physiological disorders associated with excess neuropeptide Y. In particular, the present invention relates to corticotropin releasing factor (CR)
Aminoalkyl-substituted 9H-pyridino [2,3-b] indoles and 9H-pyrimidino [4,5-, of formula I, which selectively bind to F ₁ ) and mammalian neuropeptide Y (NPY ₁ ) receptors. b] providing indole derivatives.

Accordingly, a broad embodiment of the present invention is a compound of formula I:

Embedded image Wherein Ar is phenyl, 1- or 2-naphthyl, 2-, 3-, or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, which, if desired, is halogen, trifluoromethyl , Hydroxy, amino, lower alkylamino, lower dialkylamino, carboxamide, N-lower alkylcarboxamide, N, N-
Lower dialkylcarboxamide, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy substituted 1, 2 or 3 with the proviso that Ar or ortho position relative to the point where Ar is attached to the tricyclic system. At least one is substituted; R ¹ is hydrogen, halogen, trifluoromethyl, C ₁ -C ₆ alkyl, or (
C ₁ -C ₆ alkyl) -G ¹ -R ² , wherein G ¹ is oxygen or sulfur, R ² is hydrogen or C ₁ -C ₆ alkyl; W is N or C—R ³ , wherein R ³ is hydrogen or C ₁ -C ₆ alkyl; and X is of the formula (i)

Embedded image Wherein V ¹ and V ² are CH ₂ , CO, CS, SO ₂ or CH (C ₁ -C ₆ alkyl), provided that both V ¹ and V ² are both CO, CS or not obtained represent or SO _2; ^{Y 1} and ^{Y 2} is independently a bond or _C 1 -C ₆ represents an alkylene; ^{a 1} is ^NR 4 ^{R 5,} wherein, ^{R 4} and ^{R 5,} Independently, hydrogen, a lower alkyl group, which optionally forms a heterocycloalkyl group with Y ¹ ; C ₁ -C ₆ arylalkyl or C ₁ -C ₆ heteroarylalkyl, 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-, The other is 5-thiazolyl,
1-, 3-, or 4-pyrazolyl, 1-, 3-, or 4-thiazolyl, 2-
Pyrazinyl, or 1-, 2- or 5-tetrazolyl, each of which is optionally halogen, trifluoromethyl, hydroxy, amino, lower alkylamino, lower dialkylamino, lower alkylcarboxamide, lower alkyl, lower alkoxy With the proviso that two adjacent substituents together can form a 5-7 fused cycloalkyl or heterocycloalkyl ring; lower alkanoyl, lower alkylsulfonyl, provided that R ⁴ and R ⁵ cannot both be alkanoyl or alkylsulfonyl; or NR ⁴ R ⁵ are both C ₃ -C ₆ heterocycloalkyl or a formula:

Embedded imageWherein e and f are independently 1, 2 or 3, and the sum of e and f is at least
Is also 3; G²Is NR⁶Where R⁶Is hydrogen or C₁-C₆Alkyl, also
Is CH (C₀-C₆Alkylene) -G³-R⁷, Where G³Is CONH, C
ONH (C₁-C₆Alkyl), NH, NH (C₁-C₆Alkyl) and R ⁷ Is hydrogen or C₁-C₆Alkyl; or CONH₂, CO [N (C₁-C₆Alkyl) R⁸], Where R⁸Is hydrogen or
Is C₁-C₆Alkyl; C₁-C₆Arylalkyl or C₁-C₆Heteroarylalkyl,
Where aryl is phenyl and heteroaryl is 2-, 3-, or 4
-Pyridyl, 2-, 4-, or 5-pyrimidinyl, 1-, 2-, or 4-a
Midazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4-, or 5-thio
Azolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or 4-thiazolyl
, 2-pyrazinyl, or 1-, 2- or 5-tetrazolyl, each of which is
Is halogen, trifluoromethyl, hydroxy, amino, lower
Alkylamino, lower dialkylamino, lower alkylcarboxamide, lower alcohol
Alkyl, lower alkoxy, 1, 2 or 3 substituted, provided that 2
The two adjacent substituents together are 5-7 fused cycloalkyl or heterocycloalkyl
A, which can form a ring);²Is hydrogen, C₁-C₆Alkyl, (C₁-C₆Alkylene) -G⁴-R⁹,
Where G⁴Is oxygen or sulfur; R⁹Is hydrogen, trifluoromethyl or
Or C₁-C₆Alkyl]]; formula (ii)

Embedded image Wherein heteroaryl is 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2- or 4-imidazolyl, 2-, 4- or 5-oxazolyl, -, 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 substituted by halogen, trifluoromethyl, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, provided that tetrazolyl can have at most one substituent; Z ¹ is C ₁ -C ₆ alkyl; and V ² , Y ² and A ² are as defined above]; formula (iii)

Embedded image Wherein Z ² is carbon or nitrogen; wherein, when Z ² is CH, n is 0, 1, 2, or 3, and p is 1,
2, or 3, wherein R ¹⁰ is carboxamide, or (C ₀ -C ₆ alkylene) -G ⁵ -R ¹¹ , wherein G ⁵ is NH, NH (C ₁ -C ₆ alkyl) R ¹¹ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ arylalkyl or C ₁ -C ₆ heteroarylalkyl, 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, if desired, is 1,2 by halogen, trifluoromethyl, hydroxy, amino, lower alkylamino, lower dialkylamino, lower alkylcarboxamide, lower alkyl, lower alkoxy. Or 3 substituted, provided that the two adjacent substituents are both 5-7
Can form a fused cycloalkyl or heterocycloalkyl ring; when Z ² is carbon, n is 1 or 0, p is 1 or 2, R ¹⁰ is amino; or Z ² is nitrogen Wherein n is 1 or 2, p is 1 or 2, and R ¹⁰ is hydrogen]; or formula (iv)

Embedded image[Wherein the N ring represents triazolyl, tetrazolyl, imidazolyl or pyrazolyl
Each of which is optionally amino, trifluoromethyl, carboxamide,
Or (C₁-C₆Alkylene) -G⁶-R¹²Has been replaced by
G⁶Is NH, NH (C₁-C₆Alkyl) and R¹²Is hydrogen, C₁-C ₆ Alkyl, C₁-C₆Arylalkyl or C₁-C₆Heteroarylal
Where aryl is phenyl and heteroaryl is 2-, 3-
-Or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2- or
Is 4-imidazolyl, 2-, 4- or 5-oxazolyl, 2-, 4-, or
5-thiazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or 4-thia
Zolyl, 2-pyrazinyl, or 1-, 2- or 5-tetrazolyl;
Each is optionally halogen, trifluoromethyl, hydroxy, amino,
Lower alkylamino, lower dialkylamino, lower alkylcarboxamide,
Substituted by lower alkyl, lower alkoxy, 1, 2, or 3;
And two adjacent substituents are both 5-7 fused cycloalkyl or heterocycloalkyl.
Which can form an alkyl ring].

The compounds of formula I are antagonists at the CRF ₁ receptor and are useful in the diagnosis and treatment of stress-related diseases such as post-traumatic stress syndrome (PTSD), as well as depression, headache and anxiety.

[0012] They are used for the treatment of psychiatric and affective disorders and neurological diseases, including major depression, headache, anxiety-related illness, post-traumatic stress syndrome, supranuclear palsy, and immunological Useful for methods for the treatment of cardiovascular or heart related diseases, hypertension, eating disorders, diabetes, dyslipidemia, colon hypersensitivity associated with psychopathological disorders, and stress. The method comprises administering to the mammal an effective amount of a compound of the present invention.

The compounds of formula I are also neuropeptide Y ₁ receptor antagonists and are therefore of value in the treatment of various clinical conditions characterized by the presence of excess neuropeptide Y. The compounds of formula I have different chemical structures that affect their selectivity for CRF ₁ or NPY ₁ receptors.

DETAILED DESCRIPTION OF THE INVENTION The novel compounds encompassed by the present invention have the general formula I:

Embedded image Wherein Ar is phenyl, 1- or 2-naphthyl, 2-, 3- or 4-pyridyl,
2-, 4- or 5-pyrimidinyl, which optionally includes halogen,
Trifluoromethyl, hydroxy, amino, lower alkylamino, lower dialkylamino, carboxamide, N- lower alkyl carboxamides, N, N- lower dialkyl _{carboxamides,} C 1 -C _{6 alkyl,} by C 1 -C ₆ alkoxy 1
R ¹ is hydrogen, halogen, trifluoromethyl, which is substituted at the ortho or para position relative to the point where Ar is attached to the tricyclic system; , C ₁ -C ₆ alkyl, or (
C ₁ -C ₆ alkyl) ^-G 1 -R ^2, wherein ^{wherein G 1} is oxygen or sulfur, and ^{R 2} is hydrogen or _C 1 -C ₆ alkyl]; W is, N or C- R ³ , wherein R ³ is hydrogen or C ₁ -C ₆ alkyl; and X is

Embedded image Wherein V ¹ and V ² are CH ₂ , CO, CS, SO ₂ or CH (C ₁ -C ₆ alkyl), provided that V ¹ and V ² are both CO, CS or SO ₂ And Y ¹ and Y ² independently represent a bond or C ₁ -C ₆ alkylene; A ¹ is NR ⁴ R ⁵ , wherein R ⁴ and R ⁵ are independently A hydrogen, a lower alkyl group, which optionally forms a heterocycloalkyl group with Y ¹ ; a C ₁ -C ₆ arylalkyl or a C ₁ -C ₆ heteroarylalkyl, 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 , Halogen, trifluoromethyl, hydroxy, amino, lower alkylamino, lower dialkylamino, lower alkylcarboxamide, lower alkyl, lower alkoxy, 1, 2 or 3 substituted, provided that two adjacent substituents are , Which can form a 5-7 fused cycloalkyl or heterocycloalkyl ring); lower alkanoyl, lower alkylsulfonyl, provided that both R ⁴ and R ⁵ cannot both be alkanoyl or alkylsulfonyl]; NR ⁴ R ⁵ _may also C 3 -C ₆ heterocycloalkyl Formula:

Embedded image Wherein e and f are independently 1, 2 or 3, and the sum of e and f is
And G ² is NR ⁶ (where R ⁶ is hydrogen or C ₁ -C ₆ alkyl), or CH (C ₀ -C ₆ alkylene) -G ³ -R ⁷ (wherein G ³ is CONH, CON
H (C ₁ -C ₆ alkyl), NH, NH (C ₁ -C ₆ alkyl) and R ⁷ is hydrogen or C ₁ -C ₆ alkyl); or CONH ₂ , CO [N (C _1- C ₆ alkyl) R ⁸ ], wherein R ⁸ is hydrogen or C ₁ -C ₆ alkyl; C ₁ -C ₆ arylalkyl or C ₁ -C ₆ heteroarylalkyl, wherein aryl is , Phenyl, and heteroaryl are 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 halogen, tri Fluoromethyl, hydroxy, amino,
Lower alkylamino, lower dialkylamino, lower alkylcarboxamide, lower alkyl, lower alkoxy, 1, 2 or 3 substituted, provided that two adjacent substituents are both 5-7 fused cycloalkyl or heterocycloalkyl A ² is hydrogen, C ₁ -C ₆ alkyl, (C ₁ -C ₆ alkylene) -G ⁴ -R ⁹ (
Where G ⁴ is oxygen or sulfur, and R ⁹ is hydrogen, trifluoromethyl or C ₁ -C ₆ alkyl);

Embedded image Wherein the 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 substituted one or two by halogen, trifluoromethyl, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, provided that tetrazolyl has at most one substituent Z ¹ is C ₁ -C ₆ alkyl, and V ² , Y ² and A ² are as defined above];

Embedded image Wherein Z ² is carbon or nitrogen; wherein when Z ² is CH, n is 0, 1, 2 or 3 and p is 1, 2 or 3; R ¹⁰ is carboxamide, or (C ₀ -C ₆ alkylene) -G ⁵ -R ¹¹ (where G ⁵ is NH, NH (C ₁ -C ₆ alkyl), and R ¹¹ is hydrogen, C ₁ -C _{6 alkyl,} C 1 -C ₆ arylalkyl or _C 1 -C ₆ heteroarylalkyl (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 substituted by halogen, trifluoromethyl, hydroxy, amino, lower alkylamino, lower dialkylamino, lower alkylcarboxamide, lower alkyl, lower alkoxy, , 2 or 3 is substituted, provided that two adjacent substituents together be a 5-7 fused cycloalkyl or heterocycloalkyl ring can be formed); if Z ² is carbon, n is 1 Or 2 and p is 1 or 2 and R ¹⁰ is amino; or when Z ² is nitrogen, n is 1 or 2 and p is 1 or 2 , R ¹⁰ is hydrogen]; or (iv) a compound of the formula:

Embedded image[Wherein, the N ring represents triazolyl, tetrazolyl, imidazolyl, or pyrazolyl
, Each of which is optionally amino, trifluoromethyl, carboxamide, or
Or (C₁-C₆Alkylene) -G⁶-R¹²(Where G⁶Is NH, NH (C ₁ -C₆Alkyl) and R¹²Is hydrogen, C₁-C₆Alkyl, C₁ -C₆Arylalkyl or C₁-C₆Is a heteroarylalkyl (here
Wherein aryl is phenyl and heteroaryl is 2-, 3-, or
Is 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-tri
Azolyl, 2-pyrazinyl, or 1-, 2- or 5-tetrazolyl,
Each of which is optionally halogen, trifluoromethyl, hydroxy, amino
, Lower alkylamino, lower dialkylamino, lower alkylcarboxamide,
Substituted by lower alkyl, lower alkoxy, 1, 2, or 3;
And two adjacent substituents are both 5-7 fused cycloalkyl or heterocycloalkyl.
Which can form an alkyl ring). Preferred compounds of formula I are represented by the formula IA:

Embedded image[Wherein each R_aIs C₁-C₆R is alkyl;_bIs hydrogen or methyl; R₁Is C₁-C₆R is alkyl;_sIs C₁-C₆Alkyl, (C₃-C₅) Cycloalkyl (C₁-C₃A)
Luquil, (C₁-C₃) Alkoxy (C₁-C₃) Alkyl, or (C₃-C ₅ T is 1, 2 or 3; and R_xIs hydrogen, C₁-C₆Alkyl, phenyl (C₁-C₆) With alkyl
Here, phenyl can be independently C₁-C₆Alkyl, C₁-C₆Arco
R is mono- or di-substituted with xy, halogen, or hydroxy; and R_yIs hydrogen, C₁-C₆Alkyl, (C₃-C₆) Cycloalkyl;
Or NR_xR_yIs pyrrolidinyl, N- (C₁-C₆) Alkylpyrrolidine-2-i
, Piperidinyl, morpholinyl, or N- (C₁-C₆) Alkyl piperazi
Represents nyl].

Preferred compounds of formula IA include R_sBut C₁-C₆Alkyl
Is cyclopropylmethyl. Other preferred compounds of formula IA
As a compound, R_sIs cyclopropyl (C₁-C₃) What is alkyl
Is mentioned. Still other preferred compounds of Formula IA include R_xAnd
And R_yIs independently hydrogen or C₁-C₂And those representing alkyl.
Even more preferred compounds of formula IA include R_sBut cyclopropyl
Le (C₁-C₃) Alkyl;_xAnd R_yIs independently hydrogen or C ₁ -C₂Alkyl, and each R_aIs methyl. I
Particularly preferred compounds represented by A are those wherein W is nitrogen.

Other preferred compounds of formula I include compounds of formula IB:

Embedded image Wherein each R _a is C ₁ -C ₆ alkyl; R ₁ is C ₁ -C ₆ alkyl; R _s is C ₁ -C ₆ alkyl, cyclopropyl (C ₁ -C ₃ ) Alkyl or (
T is 1 or 2; _Rx is hydrogen, C ₁ -C ₆ alkyl, phenyl (C ₁ -C ₆ ) alkyl; C ₁ -C ₃ ) alkoxy (C ₁ -C ₃ ) alkyl; Wherein phenyl is conveniently and independently 1 or 2 substituted with C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, or hydroxy; and R _y is hydrogen, C ₁ -C 6 Or NR _x R _y is pyrrolidinyl, N- (C ₁ -C ₆ ) alkylpyrrolidin-2-yl, piperidinyl, morpholinyl, or N- (C ₁ ) ₆ alkyl, (C ₃ -C ₆ ) cycloalkyl; —C ₆ ) represents alkylpiperazinyl].

Preferred compounds of formula IB include those wherein R _s is C ₁ -C ₆ alkyl or cyclopropylmethyl. Other preferred compounds of formula IB include those wherein R _s is cyclopropyl (C ₁ -C ₃ ) alkyl. Still other preferred compounds of Formula IB include wherein t is 1
And wherein R _x and R _y independently represent hydrogen or C ₁ -C ₂ alkyl. Even more preferred compounds of formula IB are those wherein R _s is cyclopropyl (C ₁ -C ₃ ) alkyl, t is 1 and R _x and R _y are independently hydrogen or Those representing C ₁ -C ₂ alkyl are exemplified. Particularly preferred compounds of the formula IB are those wherein each R _a is methyl;
R _s is cyclopropyl (C ₁ -C ₃ ) alkyl, t is 1 and R _x and R _y independently represent hydrogen or C ₁ -C ₂ alkyl. Highly preferred compounds of formula IB are those wherein W is nitrogen.

Other preferred compounds of formula I include compounds of formula IC:

Embedded image Wherein each R _a is C ₁ -C ₆ alkyl; R ₁ is C ₁ -C ₆ alkyl; t is 1 or 2; R _x and R _y are different And hydrogen; optionally substituted at the ω-position with (C ₃ -C ₇ ) cycloalkylamino (C ₁ -C ₃ ) alkyl, carboxamide, (C ₃ -C ₇ ) cycloalkylamino, C ₁ -C ₆ alkyl. and are _C 2 -C ₆ alkanoyl or _C 1 -C ₆ alkyl by _{convenience,,} C 1 -C ₆ alkoxy,
Halogen or phenyl independently mono- or di-substituted by hydroxy, provided that at least one of R _x and R _y is hydrogen.]

Preferred compounds of formula IC include those wherein R ¹ is C ₁ -C ₂ alkyl and W is nitrogen. Other preferred compounds of formula IC include those wherein each R _a is methyl and W is nitrogen.

Another preferred compound of the present invention is represented by Formula II:

Embedded image[Wherein each R_aIs independently C₁-C₆R represents alkyl;¹Is hydrogen, halogen, trifluoromethyl, C₁-C₆Alkyl or (C ₁ -C₆Alkyl) -G¹-R²(Where G¹Is oxygen or sulfur; R² Is hydrogen or C₁-C₆X is alkyl)); X is

Embedded image Wherein V ¹ and V ² are CH ₂ , CO, CS, SO ₂ or CH (C ₁ -C ₆ alkyl), provided that both V ¹ and V ² are both CO, CS or SO obtained not represent or _2; ^{Y 1} and ^{Y 2} is independently a bond or _C 1 -C ₆ represents an alkylene; ^{a 1} is ^NR 4 ^{R 5,} wherein, ^{R 4} and ^{R 5} are independently And is hydrogen, a lower alkyl group (optionally forming a heterocycloalkyl group with Y ¹ ); C ₁ -C ₆ arylalkyl or C ₁ -C ₆ heteroarylalkyl (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 is optionally 1, 2, or 3 substituted with halogen, trifluoromethyl, hydroxy, amino, lower alkylamino, lower dialkylamino, lower alkylcarboxamide, lower alkyl, lower alkoxy, provided that two Neighboring substituents can together form a 5-7 fused cycloalkyl or heterocycloalkyl ring); lower alkanoyl, lower alkylsulfonyl, provided that R ⁴ and R ⁵ cannot both be alkanoyl or alkylsulfonyl. ; or NR ⁴ R ^5, _together, C 3 -C ₆ heterocycloalkyl al Le or the formula:

Embedded image Wherein e and f are independently 1, 2 or 3, and the sum of e and f is at least 3; and G ² is NR ^6, wherein R ⁶ is hydrogen or C ₁ -C ₆ alkyl), or CH (C ₀ -C ₆ alkylene) -G ³ -R ⁷ (where G ³ is CONH, CON
H (C ₁ -C ₆ alkyl), NH, NH (C ₁ -C ₆ alkyl) and R ⁷ is hydrogen or C ₁ -C ₆ alkyl); or CONH ₂ , CO [N (C _1- C ₆ alkyl) R ⁸ ], wherein R ⁸ is hydrogen or C ₁ -C ₆ alkyl; C ₁ -C ₆ arylalkyl or C ₁ -C ₆ heteroarylalkyl, wherein aryl is , Phenyl, and heteroaryl are 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 halogen, tri Fluoromethyl, hydroxy, amino,
Lower alkylamino, lower dialkylamino, lower alkylcarboxamide, lower alkyl, lower alkoxy, 1, 2 or 3 substituted, provided that two adjacent substituents are both 5-7 fused cycloalkyl or heterocycloalkyl A ² is hydrogen, C ₁ -C ₆ alkyl, (C ₁ -C ₆ alkylene) -G ⁴ -R ⁹ (
Wherein G ⁴ is oxygen or sulfur, and R ⁹ is hydrogen, trifluoromethyl or C ₁ -C ₆ alkyl))];

Embedded image Wherein the 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 disubstituted by halogen, trifluoromethyl, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, provided that tetrazolyl has at most one substituent Z ¹ is C ₁ -C ₆ alkyl, and V ² , Y ² and A ² are as defined above];

Embedded image Wherein Z ² is carbon or nitrogen; wherein when Z ² is CH, n is 0, 1, 2 or 3 and p is 1, 2 or 3; R ¹⁰ is carboxamide, or (C ₀ -C ₆ alkylene) -G ⁵ -R ¹¹ (where G ⁵ is NH, NH (C ₁ -C ₆ alkyl), and R ¹¹ is hydrogen, C ₁ -C _{6 alkyl,} C 1 -C ₆ arylalkyl or _C 1 -C ₆ heteroarylalkyl (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 substituted by halogen, trifluoromethyl, hydroxy, amino, lower alkylamino, lower dialkylamino, lower alkylcarboxamide, lower alkyl, lower alkoxy, , 2 or 3 is substituted, provided that two adjacent substituents together be a 5-7 fused cycloalkyl or heterocycloalkyl ring can be formed); if Z ² is carbon, n is 1 Or 2 and p is 1 or 2 and R ¹⁰ is amino; or when Z ² is nitrogen, n is 1 or 2 and p is 1 or 2 , R ¹⁰ is hydrogen]; or (iv) a compound of the formula:

Embedded image[Wherein, the N ring represents triazolyl, tetrazolyl, imidazolyl, or pyrazolyl
, Each of which is optionally amino, trifluoromethyl, carboxamide, or
Or (C₁-C₆Alkylene) -G⁶-R¹²(Where G⁶Is NH, NH (C ₁ -C₆Alkyl) and R¹²Is hydrogen, C₁-C₆Alkyl, C₁ -C₆Arylalkyl or C₁-C₆Heteroarylalkyl (where a
Reel is phenyl, and heteroaryl is 2-, 3-, or 4-
Pyridyl, 2-, 4-, or 5-pyrimidinyl, 1-, 2-, or 4-imi
Dazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4-, or 5-thia
Zolyl, 1-, 3- or 4-pyrazolyl, 1-, 3-, or 4-triazolyl
, 2-pyrazinyl, or 1-, 2- or 5-tetrazolyl, each of which
Each optionally includes halogen, trifluoromethyl, hydroxy, amino, lower
Alkylamino, lower dialkylamino, lower alkylcarboxamide, lower
Alkyl, lower alkoxy, 1, 2 or 3 substituted, provided that 2
The two adjacent substituents together are 5-7 fused cycloalkyl or heterocycloalkyl
Which is capable of forming a ring).

A preferred compound of formula II is V¹And V²Represents methylene, and Y represents ¹ Is a bond, and A¹Is pyrrolidinyl, morpholinyl, piperazinyl, mono
-Or di-C₁-C₆Alkyl, C₁-C₆Arylalkyl or C₁-C ₆ Denotes heteroarylalkyl, wherein aryl is phenyl and
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-
Lazolyl, 1-, 3-, or 4-triazolyl, 2-pyrazinyl, or 1-
, 2- or 5-tetrazolyl, each of which, if desired, is halogen,
Trifluoromethyl, hydroxy, amino, lower alkylamino, lower dialkyl
Amino, lower alkyl carboxamide, lower alkyl, lower alkoxy,
1, 2 or 3 substituted, provided that two adjacent substituents are both 5-7 condensed
Can form a cycloalkyl or heterocycloalkyl ring: Y²Is
Or methylene, and A²Is C₁-C₆Alkyl or C₁-C₆Al
It indicates koxymethyl.

Another preferred compound of the invention together has the formula

Embedded image Wherein each R _a independently represents C ₁ -C ₆ alkyl; R ₁ is hydrogen, halogen, trifluoromethyl, C ₁ -C ₆ alkyl, or (
C ₁ -C ₆ alkyl) -G ¹ -R ^2, wherein G ¹ is oxygen or sulfur;
And R ² is hydrogen or C ₁ -C ₆ alkyl)] and X is

Embedded image Wherein V ¹ and V ² are CH ₂ , CO, CS, SO ₂ or CH (C ₁ -C ₆ alkyl), provided that both V ¹ and V ² are CO, CS or SO ₂ Impossible: Y ¹ and Y ² independently represent a bond or C ₁ -C ₆ alkylene; A ¹ is NR ⁴ R ⁵ , wherein R ⁴ and R ⁵ are independently A hydrogen, a lower alkyl group, which optionally forms a heterocycloalkyl group with Y ¹ ; a C ₁ -C ₆ arylalkyl or a C ₁ -C ₆ heteroarylalkyl, 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 Halogen, trifluoromethyl, hydroxy, amino, lower alkylamino, lower dialkylamino, lower alkylcarboxamide, lower alkyl, lower alkoxy, 1, 2, or 3 substituted, provided that two adjacent substituents are both 5-7 fused cycloalkyl or heterocycloalkyl ring); lower alkanoyl, lower alkylsulfonyl, provided that R ⁴ and R ⁵ cannot both be alkanoyl or alkylsulfonyl); or NR ⁴ R ^5, _together, C 3 -C ₆ heterocycloalkyl or

Embedded image Wherein e and f are independently 1, 2 or 3, and the sum of e and f is
And G ² is NR ⁶ (where R ⁶ is hydrogen or C ₁ -C ₆ alkyl), or CH (C ₀ -C ₆ alkylene) -G ³ -R ⁷ (wherein G ³ is CONH, CON
H (C ₁ -C ₆ alkyl), NH, NH (C ₁ -C ₆ alkyl) and R ⁷ is hydrogen or C ₁ -C ₆ alkyl); or CONH ₂ , CO [N (C _1- C ₆ alkyl) R ⁸ ], wherein R ⁸ is hydrogen or C ₁ -C ₆ alkyl; C ₁ -C ₆ arylalkyl or C ₁ -C ₆ heteroarylalkyl, 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 halogen, tri Fluoromethyl, hydroxy, amino,
Lower alkylamino, lower dialkylamino, lower alkylcarboxamide, lower alkyl, lower alkoxy, 1, 2, or 3 substituted, provided that two adjacent substituents are both 5-7 fused cycloalkyl or heterocycloalkyl. A ² is hydrogen, C ₁ -C ₆ alkyl, (C ₁ -C ₆ alkylene) -G ⁴ -R ⁹ (
Where G ⁴ is oxygen or sulfur, and R ⁹ is hydrogen, trifluoromethyl or C ₁ -C ₆ alkyl);

Embedded image Wherein the 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 disubstituted by halogen, trifluoromethyl, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, provided that tetrazolyl has at most one substituent Z ¹ is C ₁ -C ₆ alkyl, and V ² , Y ² and A ² are as defined above];

Embedded image Wherein Z ² is carbon or nitrogen; wherein when Z ² is CH, n is 0, 1, 2 or 3 and p is 1, 2 or 3; R ¹⁰ is carboxamide, or (C ₀ -C ₆ alkylene) -G ⁵ -R ¹¹ (where G ⁵ is NH, NH (C ₁ -C ₆ alkyl), and R ¹¹ is hydrogen, C ₁ -C _{6 alkyl,} C 1 -C ₆ arylalkyl or _C 1 -C ₆ heteroarylalkyl (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 substituted by halogen, trifluoromethyl, hydroxy, amino, lower alkylamino, lower dialkylamino, lower alkylcarboxamide, lower alkyl, lower alkoxy, , 2 or 3 is substituted, provided that two adjacent substituents together be a 5-7 fused cycloalkyl or heterocycloalkyl ring can be formed); if Z ² is carbon, n is 1 Or 2 and p is 1 or 2 and R ¹⁰ is amino; or when Z ² is nitrogen, n is 1 or 2 and p is 1 or 2 , R ¹⁰ is hydrogen]; or (iv) a compound of the formula:

Embedded image[Wherein, the N ring represents triazolyl, tetrazolyl, imidazolyl, or pyrazolyl
, Each of which is optionally amino, trifluoromethyl, carboxamide, or
Or (C₁-C₆Alkylene) -G⁶-R¹²(Where G⁶Is NH, NH (C ₁ -C₆Alkyl) and R¹²Is hydrogen, C₁-C₆Alkyl, C₁ -C₆Arylalkyl or C₁-C₆Heteroarylalkyl (where a
Reel is phenyl, and heteroaryl is 2-, 3-, or 4-
Pyridyl, 2-, 4-, or 5-pyrimidinyl, 1-, 2-, or 4-imi
Dazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4-, or 5-thia
Zolyl, 1-, 3- or 4-pyrazolyl, 1-, 3-, or 4-triazolyl
, 2-pyrazinyl, or 1-, 2- or 5-tetrazolyl, each of which
Each optionally includes halogen, trifluoromethyl, hydroxy, amino, lower
Alkylamino, lower dialkylamino, lower alkylcarboxamide, lower
Alkyl, lower alkoxy, 1, 2 or 3 substituted, provided that 2
The two adjacent substituents together are 5-7 fused cycloalkyl or heterocycloalkyl
Which is capable of forming a ring).

A preferred compound of formula III is where V ¹ and V ² represent methylene;
Y ¹ is a bond, and A ¹ is pyrrolidinyl, morpholinyl, piperazinyl, mono- or di-C ₁ -C ₆ alkyl, C ₁ -C ₆ arylalkyl or C _1-
Denotes C ₆ heteroarylalkyl, 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 halogen,
It is 1, 2, or 3 substituted by trifluoromethyl, hydroxy, amino, lower alkylamino, lower dialkylamino, lower alkylcarboxamide, lower alkyl, lower alkoxy, provided that two adjacent substituents are each 5- 7
A fused cycloalkyl or heterocycloalkyl ring can be formed: Y ² represents a bond or methylene, and A ² represents C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxymethyl.

Preferred compounds of the present invention include 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-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-trimethyl Phenyl) -9H-
Pyridino [2,3-b] indole, 4- (N- (2-N ′, N′-dimethylaminoethyl) -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-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-methyl-9- (4-methoxy -2-methylphenyl) -9
H-pyridino [2,3-b] indole, 4- (N- (2-N ′, N′-dimethylaminoethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4, 6-trimethylphenyl) -9H
-Pyridino [2,3-b] indole, 4- (N- (2-N'-methylaminoethyl) -N-cyclopropylmethyl)
Amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole, 4- (N- (2-aminoethyl) -N-cyclopropylmethyl) amino -2-
Methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-
b] Indole, 4- (N- (2-piperidinoethyl) -N-cyclopropylmethyl) amino-
2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2
3-b] indole, 4- (N- (2-pyrrolidinoethyl) -N-propyl) amino-2-methyl-
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] indole, 4- (N- (2-N'-ethyl-N'-methylaminoethyl) -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
-Pyrimidino [4,5-b] indole, 4- (N- (2- (1-imidazolyl) ethyl) -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, 4- (N- (2-pyrrolidinoethyl) -N-cyclopropyloxymethyl) amino-2-methyl-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-pyridylmethyl) -N-cyclopropylmethyl) amino-2
-Methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3
-B] indole, 4-piperazinyl-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-aminoethyl) -N-ethyl) 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-trimethylphenyl) -9H-pyridino [2,3-b] indole, 4- (N- (2-pyrrolidinoethyl) -N-cyclopropylmethyl) amino-
2-methyl-9- (2,4-dimethylphenyl) -9H-pyridino [2,3-b
Indole, 4- (N- (3-pyrrolidinopropyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2
, 3-b] indole, 4- (N- (2- (2-phenethylamino) 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-methyl-9
-(2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole, 4- (N- (2-pyrrolidinoethyl) -N-butyl) amino-2-methyl-9
-(2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole, 4- (N- (2-pyrrolidinoethyl) -N-2-methylpropyl) amino-2
-Methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3
-B] indole, 4- (N- (2-carboxamidoethyl) -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- (4-bromo-2,6-dimethylphenyl) -9H-pyrimidino [4,5-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'-dimethylaminoethyl) -N-2-methylpropyl) amino-2-methyl-9- (2,4 , 6-Trimethylphenyl) -9H-pyridino [2,3-b] indole, 4- (N- (2-N ', N'-dimethylaminoethyl) -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-N ', N'-dimethylaminoethyl) -N-cyclopropyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyrimidino [4,5-b] indole, 4- (N- (2- (1-methyl-2-pyrrolidino) ethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2, 4,6-trimethylphenyl)-
9H-pyridino [2,3-b] indole, 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-isopropyl)
Amino-2-methyl-9- (2,4,6-trimethylphenyl) -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-methyl-9- (2,4,6-trimethylphenyl) -9H-pyrimidino [4,5-b] indole.

In certain situations, the compounds of formula I may contain one or more asymmetric carbon atoms, and thus the compounds may exist in different stereoisomeric forms. These compounds can be, for example, in racemic or optically active form. In these situations, the single enantiomer, ie, the optically active form, can be obtained by asymmetric synthesis or by resolution of the racemate. Racemic resolution can be accomplished by conventional methods, for example, crystallization in the presence of a resolving reagent, or chromatography, for example, using a chiral HPLC column.

Representative compounds of the present invention encompassed by Formula I include, but are not limited to, the compounds of Table I and pharmaceutically acceptable acid addition salts thereof. Further, when the compound of the present invention is obtained as an acid addition salt, the free base can be obtained by making the solution of the acid salt basic. Conversely, when the product is a free base, addition salts, particularly pharmaceutically acceptable addition salts, are prepared by dissolving the free base in a suitable solvent and following conventional methods for producing acid addition salts from basic compounds. It can be produced by treating the solution with an acid.

Non-toxic pharmaceutical salts include hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid, sulfinic acid, formic acid, toluenesulfonic acid, methanesulfonic acid, nitric acid, benzoic acid, citric acid, tartaric acid, maleic acid, hydrogen iodide including acids, alkanoic acids such as _{acetic, HOOC- (CH 2) n -COOH} ( wherein, n represents a is 0-4) a salt of an acid such as an acid. One skilled in the art will recognize a wide variety of non-toxic, pharmaceutically acceptable addition salts.

The present invention also encompasses acylated prodrugs of the compounds of formula I. Those skilled in the art
One recognizes various synthetic methods that can be used to prepare non-toxic pharmaceutically acceptable addition salts and acylated prodrugs of the compounds encompassed by Formula I.

The “alkyl”, “lower alkyl”, or C ₁ -C ₆ alkyl of the present invention may be a linear or straight chain having 1-6 carbon atoms, optionally forming a 3-6 carbon atom ring. Branched alkyl groups such as methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethyl, n-butyl, sec-butyl, te
It means rt-butyl, cyclobutyl, pentyl, 2-pentyl, isopentyl, neopentyl, cyclopentyl, hexyl, 2-hexyl, 3-hexyl, 3-methylpentyl, cyclohexyl.

C ₀ -C ₆ alkylene optionally forming a 3-6 atom carbocycle;
A direct bond or _C 1 -C ₆ alkylene group, for example, methylene, ethylidene, propylidene, butylidene, pentylidene, cyclopentylidene, hexylidene, a cyclohexylidene.

The “alkoxy”, “lower alkoxy”, or C ₁ -C ₆ alkoxy of the present invention is a straight or branched chain having 1-6 carbon atoms, optionally forming a 3-6 carbon atom ring. Chain alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy, cyclopropylmethoxy, n-butoxy, sec-butoxy, t
ert-butoxy, pentoxy, 2-pentoxy, isopentoxy, neopentoxy, cyclopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, 3-methylpentoxy, cyclohexoxy.

As used herein, “alkanoyl”, “lower alkanoyl”, or C _1-
The C ₆ alkanoyl, to form a desired 3-6 atom carbocyclic ring, 1-6
Linear or branched alkanoyl groups having carbon atoms, for example, acetyl, propionyl, isopropionyl, cyclopropionyl, butanoyl, pentanoyl,
It means cyclopentanoyl, hexanoyl and cyclohexanoyl. The “ω position” of the alkanoyl group here is a terminal carbon atom.

CONH is an amide function, ie

Embedded image Is shown.

The term “heterocycle” or “heterocycloalkyl” refers to a monocyclic or bicyclic hydrocarbon in which one or more ring carbon atoms is replaced by a heteroatom such as oxygen, sulfur or nitrogen Means a group. Such groups preferably have 4-10 carbon atoms and 1-4 heteroatoms.

By the term “halogen” in the present invention is meant fluorine, bromine, chlorine and iodine.

Representative aminoalkyl-substituted 9H-pyridino [2,3-b] indole and 9H-pyrimidino [4,5-b] indole derivatives of the present invention encompassed by Formula I are described in Examples 1-18. And pharmaceutically acceptable addition salts thereof.

[0037] shown in the interaction examples of aminoalkyl-substituted 9H- pyridino [2,3-b] indole and 9H- pyrimidino [4,5-b] indole derivatives and CRF ₁ and NPY ₁ receptors of the present invention. This interaction results in the pharmacological activity of these compounds as shown in relevant animal models.

The compounds of general formula I may be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques. Further provided is a pharmaceutical formulation comprising a compound of general formula I and a pharmaceutically acceptable carrier. One or more compounds of general formula I may be present with one or more non-toxic pharmaceutically acceptable carriers and / or diluents and / or adjuvants and, if desired, other active ingredients. Pharmaceutical compositions comprising a compound of general formula I include, for example, tablets, lozenges, sweetened tablets,
It may be in a form suitable for oral use, such as an aqueous or oily suspension, dispersible powder or granules, emulsion, hard or soft capsule, or syrup or elixir.

[0039] Compositions for oral use can be prepared according to any method known in the art for the preparation of pharmaceutical compositions, which can be used to provide pharmaceutically nice and palatable formulations. It may comprise one or more substances selected from the group consisting of sweeteners, flavoring agents, coloring agents and preservatives. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These additives include, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, such as corn starch, or alginic acid; binders, such as starch, Gelatin or acacia, and lubricants,
For example, it may be magnesium stearate, stearic acid, or talc.
The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.

Formulations for oral use may also contain the active ingredient as hard gelatin capsules, mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or the active ingredient as water or peanut oil, liquid paraffin or It can be presented as a soft gelatin capsule mixed with an oil vehicle such as olive oil.

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
The additives include sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone,
Suspending agents, such as tragacanth gum and acacia gum; dispersing or wetting agents can be natural phosphatides, such as lecithin, or the condensation products of fatty acids, such as polyoxyethylene stearate, with alkylene oxides, or heptadecaethylene. A condensation product of ethylene oxide with a long-chain aliphatic alcohol such as oxycetanol, or a condensation product of ethylene oxide with a partial ester obtained from a fatty acid and hexitol, such as polyoxyethylene sorbitol monooleate;
Alternatively, it may be a condensation product of ethylene oxide with a partial ester obtained from a fatty acid and hexitol anhydride, such as polyethylene sorbitan monooleate.
Aqueous suspensions may also contain one or more preservatives, such as ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more, such as sucrose or saccharin. Sweeteners.

Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional additives such as sweetening, flavoring and coloring agents may also be present.

The pharmaceutical composition of the present invention may also be an oil-in-water emulsion. The oil layer may be a vegetable oil, such as olive oil or peanut oil, or a mineral oil, such as liquid paraffin, or a mixture thereof. Suitable emulsifiers include natural gums such as gum acacia or tragacanth, natural phosphatides such as soybean, lecithin, and esters or partial esters obtained from fatty acids and hexitols, anhydrides such as sorbitan monooleate, and poly monooleate. It may be a condensation product of the partial ester such as oxyethylene sorbitan and ethylene oxide. The emulsion may also contain sweetening and flavoring agents.

Syrups and elixirs can be formulated with sweetening agents, such as glycerol, propylene glycol, sorbitol or sucrose. The formulation may also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, such as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, including synthetic mono- or diglycerides,
Any sterile fixed oil may be used. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

The compounds of general formula I may 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 nonirritating excipient which is solid at normal temperatures but liquid at rectal temperatures and thus melts and releases the drug in the rectum. Such materials are cocoa butter and polyethylene glycol.

The compound of general formula I in a sterile medium may be administered parenterally. The drug, depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle. Advantageously, adjuvants such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle.

Drug levels on the order of about 0.1 mg / kg to about 140 mg / kg of body weight per day are useful in treating the conditions indicated above (from about 0.5 mg / patient / day to about 0.5 mg / patient). About 7 g). The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Dosage unit forms will generally contain about 1 mg to about 500 mg of an active ingredient.

However, the specific dosage level in any particular patient will depend on the activity, age, weight, general health, sex, diet, time of administration, route of administration, and excretion rate of the particular compound used, drug Combinations, and the severity of the particular disease being treated
It is understood that it depends on various factors.

Preparation of Aminoalkyl-Substituted 9H-Pyridino [2,3-b] indole and 9H-Pyrimidino [4,5-b] indole Analogues The preparation of compounds of the present invention is described in Scheme I, Scheme II and Scheme I
Illustrated in II. One skilled in the art will recognize that the starting materials can be varied and additional steps can be used to prepare the compounds encompassed by the present invention.

[0051]

Embedded image Wherein Ar, R ¹ and R ³ are as defined above for formula I;
R ¹⁴ , R ¹⁵ and R ¹⁶ are encompassed by the definition of X as defined in formula I.

[0052]

Embedded image Wherein Ar, R ¹ and R ³ are as defined above for formula I;
R ¹⁵ and R ¹⁶ are encompassed by the definition of X as defined in formula I.

[0053]

Embedded image Wherein Ar and R ¹ are as defined above for Formula I; R ¹⁵ , R ¹⁶ and R ¹⁷ are encompassed by the definition of X as defined in Formula I.

The disclosures of all articles and references mentioned in this application, including patents, are incorporated herein by reference.

[0055]

【Example】

The preparation of the compounds of the present invention is further illustrated by the following examples, which are not to be construed as limiting the scope or spirit of the invention to the specific methods and compounds described therein.

Commercial reagents were used without further purification. THF means tetrahydrofuran. LDA means lithium diisopropylamide, DDQ is 2,3
-Dichloro-5,6-dicyano-1,4-benzoquinone. Room or ambient temperature means 20-25 ° C. Concentration means the use of a rotary evaporator. TL
C means thin layer chromatography. Mass spectrometry data is CI or APCI
Obtained by any of the methods.

Example 1 A. 2-amino-4,5,6,7-tetrahydro-1-phenyl-1H-indole-3-carbonitrile

Embedded image A mixture of 2,4,6-trimethylaniline (500 g) and adipoin (464 g) in toluene (2.5 L) is heated to reflux. The theoretical amount of water is removed azeotropically over 3 hours. The mixture is cooled to ambient temperature, after which malononitrile (244 g) and ammonium acetate (57 g) are added. The reaction is slowly reheated back to reflux for about 1 hour to azeotropically remove water. After cooling, the precipitate that forms overnight is collected by filtration. Wash the dark solid with ethanol and dry to give 540 g of a white powder: MS 280 (M + H).

B. 4-amino-2-methyl-9- (2,4,6-trimethylphenyl) -5
6,7,8-tetrahydro-9H-pyridino [2,3-b] indole

Embedded image To the product of Example 1A (535 g) dissolved in dichloroethane (4 L) was added 2-
Methoxypropene (550 mL) and p-toluenesulfonic acid monohydrate (3.
6 g) is added. The mixture is refluxed for 1 hour, after which the solvent is distilled off. Dissolve the residue in THF (3 L) and cool 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 layers are extracted with 3M HCl and the latter is made alkaline (pH = 10) using 10N NaOH and ice. The aqueous solution is extracted with dichloromethane, dried over sodium sulfate, filtered and concentrated to give a crystalline solid: MS320 (M + H).

C. 4-amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H
-Pyridino [2,3-b] indole

Embedded image The product of Example 1B (600 g) is dissolved in decahydronaphthalene (4 L) and heated to distill off any low boiling impurities present. Cool the solution to ambient temperature,
Under a blanket of argon gas, add 10% palladium on carbon (250 g). The mixture is heated at the reflux temperature of 191-193 ° C. for 9 hours to give the aromatized product.
Dilute the cooled mixture with dichloromethane and filter through a pad of celite. The dichloromethane in the filtrate is removed under reduced pressure. The residual decahydronaphthalene solution is treated by bubbling in a stream of hydrochloric acid gas for 5 minutes while cooling with ice. The solid is filtered, washed with diethyl ether and dried to give 580 as the HCl salt.
g of product are obtained. The salt is recrystallized from a mixture of ethyl acetate and ethanol 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

Embedded image A refluxing solution of dichloroethane (250 mL) containing the product of Example 1C (50 g as the HCl salt) and cyclopropanecarbonyl chloride (14 mL) was added to N, N
Work up by dropwise addition of diisopropylethylamine (54 mL). 0.5
After heating for an hour, the reaction is cooled to ambient temperature and poured into aqueous potassium carbonate. 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 mixed with borane-methyl sulfide complex (10 M, 43 mL). The mixture is heated at reflux for 8 hours and quenched at room temperature with a large excess of methanol (about 200 mL). The mixture is again heated at reflux for 1 hour and then concentrated under reduced pressure. More methanol (
Another 200 mL) is added to the gummy residue and the solution is concentrated again to give 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

Embedded image A solution containing the product from Example 1D (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 residual oily residue and extracted with dichloromethane. The extract is dried over sodium sulfate, filtered, and concentrated. Dissolve the latter chloroacetyl compound (63 g) in THF (250 mL). Borane
Add methyl sulfide complex (10 M, 14 mL) and stir at ambient temperature for 15 minutes, then at reflux for 1 hour. The solution is cooled back to room temperature, quenched with a large excess of methanol (100 mL) and heated to reflux again for 1 hour. Concentration of the solution gives a viscous oil which crystallizes on standing: 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)

Embedded image A steel cylinder containing the product from Example 1E (61 g), pyrrolidine (60 mL) and N-methylpyrrolidinone (250 mL) is sealed and heated to 120 ° C. for 5 hours. Pour the mixture into water and extract with ethyl acetate. Wash the organic layer with water, dry over sodium sulfate, filter and concentrate. The product is purified by flash chromatography. The impurities are eluted first using 100% ethyl acetate, followed by 10% methanol in dichloromethane to elute the desired product. 6
0 g of compound are obtained, which crystallizes on standing. Ethanol (50 mL)
Concentrated sulfuric acid (2.44 mL) is added to the amine (21.4 g) dissolved in to form the sulfate of the amine. Isopropanol (200 mL) is added to the refluxing ethanol solution. The sulfate crystals 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

Embedded image Excess sodium borohydride (about 1 g) is added portionwise to a solution of the product from Example 1C (1.4 g) in propionic acid (10 mL). After gas evolution has ceased, the reaction is heated to 100 ° C. for 0.5 hour. The propionic acid is removed from the mixture under reduced pressure and the crude product is extracted from aqueous potassium carbonate with dichloromethane.
Dry the dichloromethane extract over sodium sulfate, filter and concentrate: MS3
58 (M + H).

H. 4-cyclopropylamino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole

Embedded image Product from Example 1C (10 g) and 2-methoxypropene (50 mL)
Acetic acid (1.6 mL) and sodium triacetoxyborohydride (25 g) are added to a solution of the above in dichloroethane (100 mL). The mixture is stirred at room temperature for 24 hours and then concentrated. The residue is dissolved in ethyl acetate and washed with water, then with 1N sodium hydroxide and brine. Dry over sodium sulfate, filter and concentrate: MS 358 (M + H).

Example 2 The following compounds are prepared substantially according to the method set forth above in Example 1.

A) 4- (N- (2-N ′, N′-dimethylaminoethyl) -N-propyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole: MS429 (M + H). (Compound 2) b) 4- (N- (2-N ′, N′-dimethylaminoethyl) -N-2-methoxyethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H
-Pyridino [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)- 9
H-Pyridino [2,3-b] indole: MS 441 (M + H). (Compound 4) d) 4- (N- (2-N′-ethylaminoethyl) -N-cyclopropylmethyl) amino-2-methyl-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-pyridino [2,3-b] indole: MS 455 (M + H). (
Compound 6) f) 4- (N-2- (2- (S) -methoxymethylpyrrolidino) ethyl-N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-Pyridino [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'-dimethylaminoethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9
H-Pyridino [2,3-b] indole: MS469 (M + H). (Compound 9) i) 4- (N- (2-N′-methylaminoethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole: MS427 (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: MS481 (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: MS455 (M + H). (Compound 12) l) 4- (N- (2-piperidinoethyl) -N-propyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] Indole: MS469 (M + H). (Compound 13) m) 4- (N- (2-morpholinoethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2
, 3-b] indole: MS483 (M + H). (Compound 14) n) 4- (N- (2-N'-ethyl-N'-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-methyl-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-methyl-9- (2,4,6-trimethylphenyl) -9H
-Pyridino [2,3-b] indole: MS 496 (M + H). (Compound 17) q) 4- (N-2- (N'-methylhomopiperazinyl) ethyl-N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl)-
9H-pyridino [2,3-b] indole: MS 510 (M + H). (Compound 1
8) 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- (1-methyl-2-pyrrolidino) ethyl) aminoethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4 , 6-
Trimethylphenyl) -9H-pyridino [2,3-b] indole: MS524
(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: MS482 (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: MS481 (M + H). (Compound 23) w) 4- (N- (2-methyl-2-pyrrolidinoethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-
Pyridino [2,3-b] indole: MS481 (M + H). (Compound 24) x) 4- (N- (4-pyrrolidinobutyl) -N-cyclopropylmethyl) amino-2-methyl-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: MS387 (M + H). (Compound 28) bb) 4- (N- (2-pyrrolidinoethyl) -N-2-methoxyethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2
, 3-b] Indole: MS 471 (M + H). (Compound 29) cc) 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: MS469 (M + H). (Compound 31) ee) 4- (N- (2-pyrrolidinoethyl) -N-2-methylpropyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2
, 3-b] indole: MS469 (M + H). (Compound 32) ff) 4- (N- (2-N ', N'-dimethylaminoethyl) -N-2-methylpropyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9
H-Pyridino [2,3-b] indole: MS 443 (M + H). (Compound 33
Gg) 4- (N- (2- (N'-ethyl-N'-methyl) aminoethyl) -N-
2-Methylpropyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole: MS457 (M + H). (
Compound 34) hh) 4- (N- (2-pyrrolidinoethyl) -N-isopropylidyl) amino-2-
Methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-
b] Indole: MS455 (M + H). (Compound 35) ii) 4- (N- (2-N ', N'-dimethylaminoethyl) -N-isopropyl) amino-2-methyl-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-methyl-9- (2,4,6-trimethylphenyl) -9H-pyrimidino [4,5 -B] Indole: MS455 (M + H). (Compound 37) kk) 4- (N- (2- (2- (4-methoxy) phenethylamino) ethyl)-
N-ethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl)-
9H-Pyridino [2,3-b] indole: MS 521 (M + H). (Compound 3
8) 11) 4- (N- (2-N′-cyclopentylaminoethyl) -N-ethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3 -B] Indole: MS455 (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-methyl-9- (2,6-dimethylphenyl) -9H-
Pyridino [2,3-b] indole: MS427 (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)

Embedded image The product from Example 1E (900 mg) and sodium azide (410 mg)
)) In N-methylpyrrolidinone (10 mL) is heated to 120 ° C. for 2 hours.
Pour the mixture into water and extract with ethyl acetate. Wash the organic layer with water, dry over sodium sulfate, filter and concentrate. A solution of the crude product in ethanol (10 mL) and 10% palladium on carbon (about 300 mg) are hydrogenated at about 1 atmosphere for 8 hours. The suspension is filtered through celite and the concentrated product is purified by flash chromatography before being converted to the hydrochloride salt: MS (free base) 413 (M + H). (Compound 42) The following compound is prepared substantially according to the method described 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: MS427 (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: MS401 (M + H). (Compound 45) d) 4- (N- (2-aminoethyl) -N-cyclopropylmethyl) amino-2
-Methyl-9- (2,4-dimethylphenyl) -9H-pyridino [2,3-b]
Indole: MS399 (M + H). (Compound 46) e) 4- (N- (2-aminoethyl) -N-cyclopropylmethyl) amino-2
-Methyl-9- (2,6-dimethylphenyl) -9H-pyridino [2,3-b]
Indole: MS399 (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)

Embedded image A solution containing the product from Example 3 (380 mg) in toluene (8 mL) together with N, N'-dimethylformamidazine (195 mg) and p-toluenesulfonic acid monohydrate (6 mg) is heated to reflux. The generated dimethylamine is replaced using a stream of nitrogen gas. After 12 hours, stop heating and extract the solution with ethyl acetate, wash with water, brine, dry over sodium sulfate, filter and concentrate to give a tan solid. 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)

Embedded image Compound from Example 3 (1.0 g) and sodium cyanide (540 mg)
Is dissolved in N-methylpyrrolidinone (20 mL) and heated to 95 ° C. for 2 hours. Pour the mixture into water and extract with ethyl acetate. Wash the organic layer with water, dry over sodium sulfate, filter and concentrate. Purification by flash chromatography using 20% ethyl acetate in hexane gives a white solid. Nitrile (1
30 mg) and solid sodium hydroxide (800 mg) are dissolved in tert-butanol (5 mL). The mixture is refluxed for about 1 hour. It is then neutralized with 6N hydrochloric acid, concentrated and the residue is purified 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-trimethylphenyl )
-9H-pyridino [2,3-b] indole (compound 53)

Embedded image To a solution of the compound from Example 2i (170 mg) in dichloromethane (5 mL)
Add 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. Preparative TLC of the product using 70% ethyl acetate in hexane as eluent
Purified by: MS 469 (M + H).

Example 7 The following compounds are prepared essentially according to the method set forth above in Example 6.

A) 4- (N- (2- (N′-methanesulfonyl-N′-methylamino) ethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6- Trimethylphenyl) -9H-pyridino [2,3-b] indole: MS505 (M
+ H). (Compound 54) b) 4- (N- (2- (N'-methyl-N'-trifluoromethanesulfonyl)
(Aminoethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,
4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole: M
S559 (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: MS568 (M + H). (
Compound 56) d) 4- (N- (2- (2-thienylsulfonamido) ethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl)
-9H-Pyridino [2,3-b] indole: MS559 (M + H). (Compound 57) e) 4- (N- (2- (2- (2-thienyl) -1-oxoethyl) aminoethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4, 6-trimethylphenyl) -9H-pyridino [2,3-b] indole: MS537 (
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: MS531 (M + H).
. (Compound 59) Example 8 4- (N- (2-N ', N'-dimethylamino-1-oxoethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6- Trimethylphenyl) -9H-pyridino [2,3-b] indole (Compound 60)

Embedded image Frozen dimethylamine (about 4 mL) was added to the chloroacetyl compound from Example 1E (
1.9 g) and acetonitrile (20 mL). The reaction vessel is sealed and the mixture is stirred at ambient temperature for 2 hours before concentrating. 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 by preparative TLC using 100% ethyl acetate as eluent: MS 443 (M + H).

Example 9 The following compounds are prepared essentially according to the method set forth in Example 8.

A) 4- (N- (2-N ′, N′-dimethylamino-1-oxoethyl) -N-
Propyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9
H-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-pyridino [2,3-b] indole: MS459 (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: MS481 (M + H). (Compound 63) d) 4- (N- (2-N′-ethylamino-1-oxoethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl)
-9H-Pyridino [2,3-b] indole: MS455 (M + H). (Compound 64) e) 4- (N- (2- (N′-ethyl-N′-methyl) amino-1-oxoethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4 , 6-Trimethylphenyl) -9H-pyridino [2,3-b] indole: MS469 (
M + H). (Compound 65) f) 4- (N- (2- (2- (S) -methoxymethylpyrrolidino) -1-oxoethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4 , 6
-Trimethylphenyl) -9H-pyridino [2,3-b] indole: MS52
5 (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: MS478 (M + H). (Compound 67) Example 10 4- (N- (2-chloro-1-oxoethyl) -N-propyl) amino-2
-Methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3
-B] Indole

Embedded image A solution of the compound from Example 1C (5.7 g), chloroacetyl chloride (3 mL) and diisopropylethylamine (3 mL) in dichloroethane (90 mL) was prepared.
Reflux for 0.5 hour. After concentrating the mixture, aqueous potassium carbonate is added and the product is extracted with dichloromethane. The extract is dried over sodium sulfate, filtered, and concentrated. Dissolve chloride (1.0 g) in acetonitrile (20 mL) and mix with pyrrolidine (2 mL). The solution is stirred for 2 hours at ambient temperature and then concentrated. Water is added to the residue and the aqueous layer is extracted with ethyl acetate. Dry the extract over sodium sulfate, filter and concentrate: 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)

Embedded image To a solution of the compound from 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 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 isolated aminoamide (1.1 g) was converted to TH
F (25 mL) and borane-methylsulfide complex (10 M, 1.0 mL
) And reflux for 8 hours. Cool the solution and quench with excess methanol (25 mL). Next, N, N'-dimethylethylenediamine (1.1 mL) is added and the mixture is again heated to reflux for 4 hours. The solution is concentrated, diluted with ethyl acetate, washed with water, dried over sodium sulfate, filtered and concentrated. The latter product (33
0 mg), diisopropylethylamine (0.2 mL) and dichloroethane (
(10 mL) is added to the solution containing propionyl chloride (0.1 mL). The mixture is refluxed for 0.5 hour, then poured into aqueous potassium carbonate and extracted with ethyl acetate. The extract is dried over sodium sulfate, filtered, and concentrated. Purify the product by preparative TLC using 10% methanol in dichloromethane as eluent: 469
(M + H).

Example 11 The following compounds are prepared essentially according to the method described in Example 10.

A) 4- (N- (2-pyrrolidinoethyl) -N-cyclopropyloxomethyl)
Amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole: MS481 (M + H). (Compound 69) b) 4- (N- (2-dimethylaminoethyl) -N-methoxymethyloxomethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2 , 3-b] indole: MS459 (M + H). (Compound 70) Example 12 4- (N- (2-pyridylmethyl) -N-cyclopropylmethyl) amino-2-
Methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-
b] Indole (Compound 71)

Embedded image A solution of the compound from Example 1D (110 mg), picolinyl chloride (98 mg) and N, N-diisopropylethylamine in DMF (5 mL) was added at 60 ° C. for 12 minutes.
Stir for hours. Pour the mixture into water and extract 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 method of Example 12.

A) 4- (N- (2-N ′, N′-dimethylamino-2-oxoethyl) -N-
2-Methoxyethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole: MS459 (M + H). (
Compound 72) b) 4- (N- (2-N ', N'-dimethylamino-2-oxoethyl) -N-
Propyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9
H-Pyridino [2,3-b] indole: MS 443 (M + H). (Compound 73
C) 4- (N- (2-N ', N'-dimethylamino-2-oxoethyl) -N-
2-methoxy-1-oxoethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole: MS473 (
M + H). (Compound 74) d) 4- (N- (2-N ′, N′-dimethylamino-1-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-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole (Compound 76)

Embedded image Compound (560 mg) from Example 1C in N, N 'in toluene (10 mL).
A solution containing -dimethylformamide azine (400 mg) and p-toluenesulfonic acid monohydrate (50 mg) is heated to reflux. The generated dimethylamine is replaced using a stream of nitrogen gas. After 24 hours, stop heating and extract the solution with ethyl acetate, wash with water, brine, dry over sodium sulfate, filter and concentrate to give 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

Embedded image Dissolve tert-butyl nitrite (0.65 g) in acetonitrile (10 mL) and add copper (II) chloride (0.68 g). Thereafter, the compound from Example 1C (1.33 g) is added portionwise to the orange 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 extracts are washed with water, dried over sodium sulfate, filtered, and concentrated. The product is filtered through a plug of silica gel using 20% ethyl acetate in hexane as eluent to give a tan solid: MS 335 (M + H).

B. 4-piperazinyl-2-methyl-9- (2,4,6-trimethylphenyl)
-9H-pyridino [2,3-b] indole (Compound 77)

Embedded image Compound (200 mg) from Example 15A and piperazine (0.58 g) were combined with N
-Mix in methylpyrrolidinone (2 mL) and heat the solution to 120 ° C for 12 hours. Pour the mixture into water and extract with ethyl acetate. The extract is washed with aqueous ammonium chloride and then with water. The extract is dried over sodium sulfate, filtered, and concentrated. 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 method set forth above in Example 15.

A) 4- (4-Methylpiperazinyl) -2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole: MS399 (M +
H). (Compound 78) b) 4-Homopiperazinyl-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole: MS399 (M + H). (Compound 79) c) 4- (N- (2- (1-methyl-2-pyrrolidino) ethyl) -N-cyclopropylcarbonyl) amino-2-methyl-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: MS467 (
M + H). (Compound 83) g) 4- (4-Carboxamidopiperidinyl) -2-methyl-9- (2,4,
6-trimethylphenyl) -9H-pyridino [2,3-b] indole: MS4
27 (M + H). (Compound 84) h) 4- (3-Aminopyrrolidinyl) -2-methyl-9- (2,4,6-trimethylphenyl) -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: MS481 (M + H). (Compound 86) j) 4- (N-2- (S) -cyclopentylaminomethylpyrrolidinyl) -2-
Methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-
b] Indole: MS467 (M + H). (Compound 87) k) 4- (N-2- (R) -cyclopentylaminomethylpyrrolidinyl) -2-
Methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-
b] Indole: MS467 (M + H). (Compound 88) l) 4- (N-3-cyclopentylaminopyrrolidinyl) -2-methyl-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) aminopyrrolidinyl) -2-methyl-9- (2,4,6-trimethylphenyl)- 9H
-Pyridino [2,3-b] indole: MS 563 (M + H). (Compound 90) n) 4- (N-3- (1-oxo-2- (3-methoxy-4-ethoxy) phenethyl) aminopyrrolidinyl) -2-methyl-9- (2,4,6- Trimethylphenyl) -9H-pyridino [2,3-b] indole: MS577 (M + H). (
Compound 91) o) 4- (N-2- (2- (R)-(4-methoxy) phenethyl) aminomethylpyrrolidinyl) -2-methyl-9- (2,4,6-trimethylphenyl)- 9H
-Pyridino [2,3-b] indole: MS533 (M + H). (Compound 92) p) 4- (N-2- (2- (S)-(4-methoxy) phenethyl) aminomethylpyrrolidinyl) -2-methyl-9- (2,4,6-trimethylphenyl) -9H
-Pyridino [2,3-b] indole: MS533 (M + H). (Compound 93) q) 4- (N-4- (2- (3-methoxy-4-ethoxy) phenethyl) aminomethylpiperazinyl) -2-methyl-9- (2,4,6-trimethylphenyl)
-9H-Pyridino [2,3-b] indole: MS563 (M + H). (Compound 94) Example 17 2-amino-1-phenyl-1H-indole-3-carbonitrile

Embedded image The compound from Example 1A (20 g) is dissolved in 1,4-dioxane (300 mL) and DDQ (34 g) is added portionwise to the solution. The reaction is stirred for 1 hour and then filtered through celite to remove insoluble by-products. The filtrate is concentrated and solidified. The product is collected by filtration and washed with ethanol to give 16 g of a tan powder: MS 276 (M + H).

B. 4-hydroxy-2-methyl-9- (2,4,6-trimethylphenyl)-
9H-pyrimidino [4,5-b] indole

Embedded image The compound from Example 12A (30 g), acetic anhydride (15 mL) and acetic acid (3
(0 mL) is refluxed for 1 hour and then concentrated to a solid. Phosphoric acid (40
mL, 85%) to the amide. Thereafter, the mixture is refluxed for 0.5 hour and cooled to ambient temperature. The solution is poured on ice and the precipitate formed is collected by filtration. Wash the solid with water and some ethanol. MS 318 (M + H) C.I. 4-chloro-2-methyl-9- (2,4,6-trimethylphenyl) -9H
-Pyrimidino [4,5-b] indole

Embedded image The compound from Example 12B (2.2 g) was treated with phosphoryl chloride (30 mL) in 3
Reflux for hours. Excess phosphoryl chloride is removed under reduced pressure and the residue is partitioned between aqueous potassium carbonate and dichloromethane. Extract the aqueous layer with more dichloromethane. The combined extracts are dried over sodium sulfate, filtered, and concentrated to give a tan solid: MS 336 (M + H).

D. 4-cyclopropylamino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyrimidino [4,5-b] indole

Embedded image Compound from Example 12C (750m) in N-methylpyrrolidinone (2mL)
A mixture of g) and cyclopropylamine (1.6 mL) is heated to 65 ° C. in a sealed tube for 24 hours. The mixture is diluted with ethyl acetate, washed with water, brine, dried over sodium sulfate, filtered, and concentrated to give a tan solid. Purification by radial chromatography using 40% ethyl acetate in hexane as eluent gives 730 mg of product: MS 357 (M + H).

E. 4- (N- (2-N ', N'-dimethylaminoethyl) -N-cyclopropyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyrimidino [4,5 -B] Indole (Compound 95)

Embedded image Dimethylformamide (5 mL) of the compound from Example 12D (200 mg)
The solution was added at 0 ° C. under a blanket of nitrogen under sodium hydride (60%, 100%
mg). After stirring the solution for 15 minutes, 2-dimethylaminoethyl chloride hydrochloride (170 mg) is added. Thereafter, the mixture is heated to 60 ° C. for 2 hours and then quenched with ice and water. Dilute with ethyl acetate, wash with water, brine,
Dry over sodium sulfate, filter and concentrate. Purification by radial chromatography using 7% methanol and 0.5% ammonium hydroxide in dichloromethane as eluent gives 190 mg of the product: MS 428 (M +
H).

Example 18 The following compounds are prepared essentially according to the method 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: MS466 (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: MS480 (M + H). (Compound 97) c) 4- (N- (2-N ', N'-dimethylaminoethyl) -N-ethyl) amino-2-methyl-9- (4-chloro-2-methylphenyl) -9H- Pyrimidino [4,5-b] indole: MS422 (M + H). (Compound 98) d) 4- (N- (2-morpholinoethyl) -N-propyl) amino-2-methyl-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)- 9
H-Pyrimidino [4,5-b] indole: MS442 (M + H). (Compound 1
00) 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-pyrimidino [
4,5-b] indole: MS468 (M + H). (Compound 102) h) 4- (3-Aminopyrrolidinyl) -2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyrimidino [4,5-b] indole: MS 386 (M
+ H). (Compound 103) i) 4- (2- (S) -aminomethylpyrrolidino) -2-methyl-9- (2,4
, 6-Trimethylphenyl) -9H-pyrimidino [4,5-b] indole: M
S400 (M + H). (Compound 104) j) 4- (3-Amino-2-triazolyl) -2-methyl-9- (2,4,6-
Trimethylphenyl) -9H-pyrimidino [4,5-b] indole: MS38
4 (M + H). (Compound 105) k) 4- (3-Amino-1-triazolyl) -2-methyl-9- (2,4,6-
Trimethylphenyl) -9H-pyrimidino [4,5-b] indole: MS38
4 (M + H). (Compound 106) l) 4- (3-Amino-4-triazolyl) -2-methyl-9- (2,4,6-
Trimethylphenyl) -9H-pyrimidino [4,5-b] indole: MS38
4 (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-pyrrolidinoethyl) -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-methyl-
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-methyl-9- (2,4,6-trimethylphenyl) -9H- Pyrimidino [4,5-b] indole: MS430 (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: MS444 (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-methyl-
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 [4,5-b] indole: MS442 (M + H). (Compound 116) v) 4- (N- (2-N ', N'-dimethylaminoethyl) -N-cyclopentyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H- Pyrimidino [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: MS430 (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: MS388 (M + H). (Compound 119) y) 4- (4- (N-methylamino) piperidino) -2-methyl-9- (2,4
, 6-Trimethylphenyl) -9H-pyrimidino [4,5-b] indole: M
S414 (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) -N-1
-Methylpropyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyrimidino [4,5-b] indole: MS444 (M + H). (
Compound 123) cc) 4- (N- (2-N ', N'-diethylaminoethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl)-
9H-Pyrimidino [4,5-b] indole: MS 470 (M + H). (Compound 124) dd) 4- (N- (2-N ', N'-diethylaminoethyl) -N-cyclopropyl) amino-2-methyl-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) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9
H-Pyrimidino [4,5-b] indole: MS 446 (M + H). (Compound 1
26) ff) 4- (N- (2-N ', N'-dimethylaminoethyl) -N-2-ethoxyethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9
H-Pyrimidino [4,5-b] indole: MS460 (M + H). (Compound 1
27) 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: MS468 (M + H). (Compound 129) ii) 4- (N- (2-N ', N'-dimethylaminoethyl) -N-isobutyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H- Pyrimidino [4,5-b] indole: MS444 (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: MS57
8 (M + H). (Compound 131) kk) 4- (N- (S)-(1-oxo-2- (4-methoxy) phenethyl) aminopyrrolidin-2-yl) -2-methyl-9- (2,4,6- Trimethylphenyl) -9H-pyrimidino [4,5-b] indole: MS54 (M + H). (
Compound 132) 11) 4- (N- (S)-(2- (4-methoxy) phenethyl) aminopyrrolidin-2-yl) -2-methyl-9- (2,4,6-trimethylphenyl) -9H
-Pyrimidino [4,5-b] indole: MS578 (M + H). (Compound 13
3).

Example 19 The pharmaceutical utility of the compounds of the present invention is demonstrated by the following assay for human CRF1 and NPY1 receptor activity.

Assay for CRF Receptor Binding Activity CRF receptor binding was determined by Grigoriadis and De Souza (Me
methods in Neurosciences, Vol. 5, 1991) using a modified version of the assay. Membrane pellet containing CRF receptor,
50 mM Tris buffer pH containing 10 mM MgCl ₂ and 2 mM EDTA
Resuspend at 7.7 and centrifuge at 48000 g for 10 minutes. The membrane is washed again to a final concentration of 1500 mg / ml in binding buffer (Tris buffer as above containing 0.1% BSA, 15 mM bacitracin and 0.01 mg / mL aprotinin).
For the binding assay, 100 mL of the membrane preparation was combined with 100 mL of ¹²⁵ I-CR.
Add to a 96-well microtube plate containing F (SA2200 Ci / mmol, final concentration 100 pM) and 50 mL of drug. The coupling is performed for 2 hours at room temperature.
The plates are then collected on a Brandel 96-well cell collector, and the filters are counted for gamma emission on a Wallac 1205 beta plate liquid scintillation counter. Non-specific binding is defined by 1 mM non-radioactive CRF. IC ₅₀ value
Calculated using the non-linear curve fitting program RS / 1 (BBN Software Products, Cambridge, Mass.). The binding affinity of a compound of Formula I, expressed as an IC ₅₀ value, generally ranges from about 0.5 nanomolar to about 10 micromolar.

[0090] Separately, binding activity to human CRF ₁ receptors of the compounds of formula I, the measurement can be as follows: endogenously expressed in IMR32 assay IMR32 cells of human CRF receptor binding activity in a cell [ ¹²⁵ I] sorbazine binding to the CRF1 receptor: IMR-32 human neuroblastoma cells were transformed with Eagles balanced salt and 2
mM 1-glutamine was grown in EMEM containing 10% FBS, 25 mM HEPES, 1 mM sodium pyruvate, and non-essential amino acids for 80 min.
% Confluency. At this time, the cell flask was filled with 2.5 μM 5-bromo-2.
Treat with '-deoxyuridine (Br-dU) for 10 days. The medium is changed every 3-4 days during a 10 day period. Cells are harvested using No-Zyme (JRH Biosciences) and rinsed with PBS. For membrane preparation, cells were washed with wash buffer (5
0 mM Tris HCl, 10 mM MgCl ₂ , 2 mM EGTA, pH 7.4)
And centrifuged at 48,000 xg for 10 minutes at 4 ° C. The pellet is resuspended, homogenized and centrifuged twice more. The receptor binding assay was performed using assay buffer (50 mM Tris HCl, 10 mM MgCl ₂ , 2 mM EGT
A, pH 7.4, 0.1% BSA, 0.1 mM bacitracin (22.0 mg / 1
00 mL)), 150 μg protein / tube, and [ ¹²⁵ I] sorbazine (NEN; 100 pM for competition analysis and 10 pM-1 nM for saturation analysis) to a final volume of 200 μL. Non-specific binding was determined at 2 μM r / h
Determined using CRF or 9-41α-helical CRF. Incubate the cells for 2 hours at room temperature. Assays were performed at 1% P using ice cold 50 mM Tris HCl.
Terminate by rapid vacuum filtration (Tomtec: Deepwell 3) through a GFC filter presoaked in EI and air dry. Specific binding: 70-80%; K
d (nM): 0.30 nM; Bmax (fmole / mg protein): 40-
50. IC ₅₀ values are calculated using the non-linear curve fitting program RS / 1 (BBN Software Products, Cambridge, Mass.).

The binding affinity of a compound of formula I for the CRF ₁ receptor is expressed as an IC ₅₀ value,
10 μmol or less.

Assay for NPY1 Receptor Binding Activity Compound activity is assayed using the following method: Recombinant human NPY Y
Baculovirus-infected Sf9 cells expressing 1 receptor are harvested at 42-48 hours, at which time a batch of 500 mL of cell suspension is pelleted by centrifugation. Dissolve each pellet in 30 mL lysis buffer (10 mM HEPES, 250 mM
Sucrose, 0.5 μg / mL leupeptin, 2 μg / mL aprotonin, 20
Resuspend in 0 μM PMSF and 2.5 mM EDTA, pH 7.4)
Gently homogenize 50 strokes using a dounce homogenizer.
The homogenate is centrifuged at 536 × g at 4 ° C. for 10 minutes to pellet nuclei. The supernatant is collected in a new tube and centrifuged twice at 48,000 × g for 40 minutes in the same buffer. The final pellet is then resuspended by dounce homogenization in 10 ml of PBS containing 5 mM EDTA and stored in aliquots at -80 ° C.

The purified membrane was washed with PBS and the binding buffer (50 mM Tris (HCl), 5 mM
KCl, 120 mM NaCl, 2 mM CaCl ₂ , 1 mM MgCl ₂ ,
Resuspend by gentle pipetting in 0.1% bovine serum albumin (BSA), pH 7.4). Added membranes (5 [mu] g) siliconized (Sigmacote, Sigma) polypropylene tubes, further, the competitive analysis 0.050nM ^[1 25 I] NPY (porcine) or 0.010-0.500nM the saturation analysis [ ¹ Add ²⁵ I] NPY (porcine). To assess the effect of guanine nucleotides on receptor affinity, GTP is added at a final concentration of 100 μM. A concentration of non-radioactive replacement ranging from 10 ⁻¹² M to 10 ⁻⁶ M was added to bring the final volume to 0.25.
Make 0 mL. Non-specific binding is determined in the presence of 1 μM NPY (porcine) and accounts for less than 10% of the total binding. After 2 hours of incubation at room temperature, the reaction is terminated by rapid vacuum filtration. The sample is filtered through a presoaked GF / C Whatman filter (1.0% polyethyleneimine for 2 hours) and rinsed twice with 5 mL of non-radioactive binding buffer without BSA. The residual bound radioactivity is measured by gamma measurement. The results of the binding experiments are analyzed using Sigma plot software (Jandel) to estimate Bmax, Kd, and Ki.

The binding affinity of the compound of formula I for the NPY ₁ receptor is expressed as an IC ₅₀ value,
10 μmol or less.

The present invention and the modes and processes for making and using the same are described herein in complete, clear, concise, and precise terms so that those skilled in the art can make and use the same. The foregoing describes the preferred embodiments of the invention and it is understood that modifications can be made thereto without departing from the spirit or scope of the invention as set forth in the appended claims. In order to particularly point out and distinctly claim the subject matter regarded as the invention, the following claims conclude this specification.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI theme coat ゛ (Reference) A61P 3/04 A61P 3/04 3/06 3/06 3/10 3/10 9/00 9/00 15 / 00 15/00 25/00 25/00 25/06 25/06 25/08 25/08 25/20 25/20 25/22 25/22 25/24 25/24 25/28 25/28 25/30 25/30 25/32 25/32 29/00 29/00 31/18 31/18 37/04 37/04 37/06 37/06 43/00 43/00 111 111 C07D 487/04 140 C07D 487/04 140 (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, UG) ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN , CU, CZ, DE, DK, EE, ES, FI, GB, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ , TM, TR, TT, UA, UG, US, UZ, VN, YU, ZA, ZW (72) Inventors: Darrow, James. United States 06492 Wallingford, Connecticut Dinail Drive 4 (72) Inventors Maynard, George Dee. United States 06413 Clinton Glenwood Road, Connecticut 27 F-term (reference) 4C050 AA01 AA07 BB04 CC07 EE03 FF05 GG02 GG03 GG04 4C065 AA04 AA18 BB04 CC02 CC03 DD02 EE02 JJ07 JJ08 PP09 PP10 4C086 AA01 ZA12 ZA12 Z05A05 ZA70 ZC08 ZC35 ZC39 ZC55

Claims (42)

[Claims] 1. The formula: embedded imageWherein Ar is phenyl, 1- or 2-naphthyl, 2-, 3-, or 4-pyridyl
, 2-, 4- or 5-pyrimidinyl, which are optionally halogen
, Trifluoromethyl, hydroxy, amino, lower alkylamino, lower dial
Killamino, carboxamide, N-lower alkylcarboxamide, N, N-
Lower dialkylcarboxamide, C₁-C₆Alkyl, C₁-C₆Alkoxy
With the proviso that Ar is attached to a tricyclic system
At least one of the ortho or para positions is substituted with respect to¹Is hydrogen, halogen, trifluoromethyl, C₁-C₆Alkyl, or (
C₁-C₆Alkyl) -G¹-R²Where G¹Is oxygen or sulfur
R²Is hydrogen or C₁-C₆W is N or C—R³Where R³Is hydrogen or C₁-C₆Alkyl
And X is of the formula (i)[Where V¹And V²Is CH₂, CO, CS, SO₂Or CH (C₁-C₆Archi
), Where V¹And V²Are both CO, CS or SO₂ Is not possible; Y¹And Y²Is independently a bond or C₁-C₆A represents an alkylene;¹Is NR⁴R⁵Where R⁴And R⁵Is, independently, hydrogen, lower
An alkyl group, which is optionally Y¹Forms a heterocycloalkyl group with
C₁-C₆Arylalkyl or C₁-C₆Heteroarylalkyl, 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-thiazolyl, 2-
Pyrazinyl, or 1-, 2- or 5-tetrazolyl, each of which is
If desired, halogen, trifluoromethyl, hydroxy, amino, lower alkyl
Amino, lower dialkylamino, lower alkylcarboxamide, lower alkyl
, 1, 2, or 3 substituted by lower alkoxy, provided that two adjacent
Both tangential substituents form a 5-7 fused cycloalkyl or heterocycloalkyl ring.
Lower alkanoyl, lower alkylsulfonyl, provided that R⁴And R⁵Is both
Cannot be alkanoyl or alkylsulfonyl; or NR⁴R⁵Are both C₃-C₆Heterocycloalkyl or formula:Wherein e and f are independently 1, 2 or 3, and the sum of e and f is at least
Is also 3; G²Is NR⁶Where R⁶Is hydrogen or C₁-C₆Alkyl, also
Is CH (C₀-C₆Alkylene) -G³-R⁷, Where G³Is CONH, C
ONH (C₁-C₆Alkyl), NH, NH (C₁-C₆Alkyl) and R ⁷ Is hydrogen or C₁-C₆Alkyl; or CONH₂, CO [N (C₁-C₆Alkyl) R⁸], Where R⁸Is hydrogen or
Is C₁-C₆Alkyl; C₁-C₆Arylalkyl or C₁-C₆Heteroarylalkyl,
Where aryl is phenyl and heteroaryl is 2-, 3-, or 4
-Pyridyl, 2-, 4-, or 5-pyrimidinyl, 1-, 2-, or 4-a
Midazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4-, or 5-thio
Azolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or 4-thiazolyl
, 2-pyrazinyl, or 1-, 2- or 5-tetrazolyl, each of which is
Is halogen, trifluoromethyl, hydroxy, amino, lower
Alkylamino, lower dialkylamino, lower alkylcarboxamide, lower alcohol
Alkyl, lower alkoxy, 1, 2 or 3 substituted, provided that 2
The two adjacent substituents together are 5-7 fused cycloalkyl or heterocycloalkyl
A, which can form a ring);²Is hydrogen, C₁-C₆Alkyl, (C₁-C₆Alkylene) -G⁴-R⁹,
Where G⁴Is oxygen or sulfur; R⁹Is hydrogen, trifluoromethyl or
Or C₁-C₆Alkyl); formula (ii):Wherein the heteroaryl is 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyridyl
Midinyl, 1-, 2- or 4-imidazolyl, 2-, 4- or 5-oxa
Zolyl, 2-, 4-, or 5-thiazolyl, 1-, 3- or 4-pyrazolyl
, 1-, 3- or 4-triazolyl, 2-pyrazinyl, or 1-, 2- or
Is 5-tetrazolyl, each of which is optionally halogen, trifluoro
Methyl, amino, C₁-C₆Alkyl, C₁-C₆Depending on the alkoxy, 1 or
Being disubstituted, provided that tetrazolyl can have at most one substituent;¹Is C₁-C₆Alkyl; and V², Y²And A²Is as defined above]; formula (iii):[Where Z²Is carbon or nitrogen; where Z²Is CH, n is 0, 1, 2, or 3, and p is 1,
2, or 3, and R¹⁰Is carboxamide, or (C₀-C₆Archi
Len) -G⁵-R¹¹Where G⁵Is NH, NH (C₁-C₆Archi
R) and R¹¹Is hydrogen, C₁-C₆Alkyl, C₁-C₆Arylalkyl
Or C₁-C₆Heteroarylalkyl 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, if desired, is halogen,
Trifluoromethyl, hydroxy, amino, lower alkylamino, lower dialkyl
By amino, lower alkyl carboxamide, lower alkyl, lower alkoxy
1, 2, or 3 substituted, provided that the two adjacent substituents are both 5-7
Z can form a fused cycloalkyl or heterocycloalkyl ring;²Is carbon, n is 1 or 0, p is 1 or 2, R¹⁰ Is amino; or Z²Is nitrogen, n is 1 or 2, p is 1 or 2, and R is¹⁰ Is hydrogen]; or formula (iv)[Wherein the N ring represents triazolyl, tetrazolyl, imidazolyl or pyrazolyl
Each of which is optionally amino, trifluoromethyl, carboxamide,
Or (C₁-C₆Alkylene) -G⁶-R¹²Has been replaced by
G⁶Is NH, NH (C₁-C₆Alkyl) and R¹²Is hydrogen, C₁-C ₆ Alkyl, C₁-C₆Arylalkyl or C₁-C₆Heteroarylal
Where aryl is phenyl and heteroaryl is 2-, 3-
-Or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2- or
Is 4-imidazolyl, 2-, 4- or 5-oxazolyl, 2-, 4-, or
5-thiazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or 4-thia
Zolyl, 2-pyrazinyl, or 1-, 2- or 5-tetrazolyl;
Each is optionally halogen, trifluoromethyl, hydroxy, amino,
Lower alkylamino, lower dialkylamino, lower alkylcarboxamide,
Substituted by lower alkyl, lower alkoxy, 1, 2, or 3;
And two adjacent substituents are both 5-7 fused cycloalkyl or heterocycloalkyl.
Or a pharmaceutically acceptable salt thereof. 2. W is CH, Ar is 2,4,6-trimethylphenyl, R ₁ is methyl, 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) -N
-(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- (cyclopropyl Methyl), N- (3-aminopropyl) -N-
(Cyclopropylmethyl), N- (2-aminoethyl) -N- (propyl), N
-(2-aminoethyl) -N- (ethyl), N- (3-pyrrolidinopropyl)-
N- (cyclopropylmethyl), N- (4-pyrrolidinobutyl) -N- (cyclopropylmethyl), 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-pyrrolidinoethyl) -N- (isopropyl), N- (2- (N ', N'-dimethyl) aminoethyl) -N- (isobutyl), N- ( 2- (N'-methyl-N'-ethyl) aminoethyl) -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'-cyclopentyl) aminoethyl)
-N- (ethyl), N- (2- (N'-2- (4-methoxy) phenethyl) aminoethyl) -N- (ethyl), N-((1-methyl-2-pyrrolidino) ethyl)
-N- (cyclopropylmethyl), N-((1-methyl-2-amino) ethyl)
The compound according to claim 1, which is -N- (cyclopropylmethyl). 3. W is CH, Ar is 2,4,6-trimethylphenyl, R ₁ is methyl, and X is N- (1-oxo-2- (N ′, N′-). Dimethyl) aminoethyl) -N- (propyl), N- (2-oxo-2- (N ', N
'-Dimethyl) aminoethyl) -N- (propyl), N- (1-oxo-2- (
N ', N'-dimethyl) aminoethyl) -N- (cyclopropylmethyl), N-
(2-pyrrolidinoethyl) -N- (1-oxo-propyl), N- (2-pyrrolidinoethyl) -N- (1-oxo-cyclopropyl), N- (2-oxo-2-
The compound according to claim 1, which is (N ', N'-dimethyl) aminoethyl) -N- (cyclopropyl). 4. W is CH, Ar is 2,4,6-trimethylphenyl, R ₁ is methyl, X is 2- (S)-(cyclopentylaminomethyl) pyrrolidinyl, 4- ( Carboxamido) piperidinyl, 3- (cyclopentylamino) pyrrolidinyl, 3- (1-oxo-2-((3-methoxy-4-ethoxy) phenyl) aminoethyl) pyrrolidinyl, 2- (2- (4-methoxy) phenyl ) Aminoethyl) pyrrolidinyl, 3- (1-oxo-2-((3-methoxy-4-ethoxy) phenyl) ethyl) pyrrolidinyl, 4- (2-((3-methoxy-4-ethoxy) phenyl) aminoethyl 1) is piperidinyl.
The compound according to the above. 5. W is N, Ar is 2,4,6-trimethylphenyl, R ₁ 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'-dimethyl) aminoethyl)-
N- (propyl), N- (2-N ', N'-dimethylaminoethyl) -N- (butyl), N- (2- (N', N'-dimethyl) aminoethyl) -N- (cyclo Propylmethyl), N- (2- (N ′, N′-dimethyl) aminoethyl) -N- (
Cyclopropyl), N- (2-piperidinoethyl) -N- (propyl), N- (
2-piperidinoethyl) -N- (butyl), N- (2- (N ', N'-dimethyl) aminoethyl) -N- (cyclobutyl), N- (2- (N', N'-dimethyl) amino Ethyl) -N- (cyclopentyl), N- (2- (N ', N'-dimethyl) aminoethyl) -N- (2-methoxyethyl), N- (2- (N', N'-
The compound according to claim 1, which is dimethyl) aminoethyl) -N- (isopropyl), N- (2- (N'-ethyl) aminoethyl) -N- (cyclopropyl), piperazinyl. 6. W is N, Ar is 2,6-dimethyl-4-bromophenyl, R ₁ is methyl, and X is N- (2- (N ′, N′-dimethyl) amino. The compound according to claim 1, which is ethyl) -N- (ethyl) or N- (2-pyrrolidinoethyl) -N- (cyclopropylmethyl). 7. W is CH, Ar is 2-methyl-4-methoxyphenyl, R ₁ is methyl, and X is N- (2- (N ′, N′-dimethyl) aminoethyl). -N-cyclopropylmethyl). 8. W is CH, Ar is 2,4-dimethylphenyl,
The compound according to claim 1, wherein R ₁ is methyl and X is N- (2-pyrrolidinoethyl) -N- (cyclopropylmethyl). 9. W is CH, Ar is 2,6-dimethylphenyl,
R ₁ is methyl and X is N- (2- (N ′, N′-dimethyl) aminoethyl)
The compound according to claim 1, which is -N- (cyclopropylmethyl). 10. W is CH, Ar is 2,4,6-trimethylphenyl, R ₁ is methyl, and X is N- (2- (1-imidazolyl) aminoethyl) -N- ( (Cyclopropylmethyl), N- (2- (1,2,4-triazol-4-yl) aminoethyl) -N- (cyclopropylmethyl).
The compound according to the above. 11. The formula: embedded image[Wherein each R_aIs C₁-C₆R is alkyl;_bIs hydrogen or methyl; R₁Is C₁-C₆R is alkyl;_sIs C₁-C₆Alkyl, (C₃-C₅) Cycloalkyl (C₁-C₃A)
Luquil, (C₁-C₃) Alkoxy (C₁-C₃) Alkyl, or (C₃-C ₅ T) is 1, 2, or 3; and R_xIs hydrogen, C₁-C₆Alkyl, phenyl (C₁-C₆Alkyl)
Wherein the phenyl optionally is independently C₁-C₆Alkyl, C₁-C₆ Mono- or di-substituted by alkoxy, halogen or hydroxy;
And R_yIs hydrogen, C₁-C₆Alkyl, (C₃-C₆) Is cycloalkyl;
Or NR_xR_yIs pyrrolidinyl, N- (C₁-C₆) Alkylpyrrolidine-2-i
, Piperidinyl, morpholinyl, or N- (C₁-C₆) Alkyl piperazi
Represents nyl]. 12. The compound according to claim 11, wherein R _s is C ₁ -C ₆ alkyl or cyclopropylmethyl. 13. R _s is cyclopropyl _(C 1 -C ₃₎ alkyl,
A compound according to claim 12. 14. The compound according to claim 13, wherein R _x and R _y independently represent hydrogen or C ₁ -C ₂ alkyl. 15. The compound according to claim 14, wherein each _Ra is methyl. 16. The compound according to claim 15, wherein W is nitrogen. 17. The formula: embedded image Wherein each R _a is C ₁ -C ₆ alkyl; R ₁ is C ₁ -C ₆ alkyl; R _s is C ₁ -C ₆ alkyl, cyclopropyl (C ₁ -C ₃ ) Alkyl or (
T is 1 or 2; R _x is hydrogen, C ₁ -C ₆ alkyl, phenyl (C ₁ -C ₆ alkyl); C ₁ -C ₃ ) alkoxy (C ₁ -C ₃ ) alkyl; ,
Wherein phenyl is optionally and independently substituted 1 or 2 by C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, or hydroxy; and R _y is hydrogen, C ₁ -C ₁ -C ₆ -alkyl. C _{6 alkyl,} or is _(C 3 -C ₆₎ cycloalkyl;
Or NR _x R _y represents pyrrolidinyl, N- (C ₁ -C ₆ ) alkylpyrrolidin-2-yl, piperidinyl, morpholinyl, or N- (C ₁ -C ₆ ) alkylpiperazinyl] . 18. The compound according to claim 17, wherein R _s is C ₁ -C ₆ alkyl or cyclopropylmethyl. 19. R _s is cyclopropyl (C ₁ -C ₃ alkyl),
A compound according to claim 18. 20. The compound according to claim 19, wherein t is 1 and R _x and R _y independently represent hydrogen or C ₁ -C ₂ alkyl. 21. The compound according to claim 20, wherein each _Ra is methyl. 22. The compound according to claim 21, wherein W is nitrogen. 23. The formula: Wherein each R _a is C ₁ -C ₆ alkyl; R ₁ is C ₁ -C ₆ alkyl; t is 1 or 2; R _x and R _y are different and hydrogen; _The ω-position is optionally substituted by _1- C ₆ alkyl, or optionally, independently, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, or phenyl mono- or disubstituted by hydroxy. and _{which, (C} 3 -C ₇₎ cycloalkylamino _(C 1 -C ₃₎ shows an alkyl, _carboxamide, and _(C 3 -C ₇₎ cycloalkyl _amino, C 2 -C ₆ alkanoyl, however, _{R x} and At least one of R _y is hydrogen.] 24. The compound of claim 23, wherein R ₁ is C ₁ -C ₂ alkyl and W is nitrogen. 25. The compound according to claim 24, wherein each _Ra is methyl. 26. 4- (N- (2-pyrrolidinoethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9
H-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-trimethylphenyl ) -9H-pyridino [2,3-b] indole; 4- (N- (2-N ′, 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-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole; 4- (N- (2- (N'-ethyl-N'-methyl) aminoethyl) -N-cyclopropylmethyl) amino-2-methyl-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- Chill-9- (4-methoxy-2-methylphenyl)-9H
-Pyridino [2,3-b] indole; 4- (N- (2-N ', N'-dimethylaminoethyl) -N-cyclopropylmethyl) amino-2-methyl-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-trimethylphenyl 2.) The compound of claim 1, which is) -9H-pyridino [2,3-b] indole. 27. 4- (N- (2-piperidinoethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9
H-pyridino [2,3-b] indole; 4- (N- (2-pyrrolidinoethyl) -N-propyl) amino-2-methyl-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] indole; 4- (N- (2-N'-ethyl-N'-methylaminoethyl) -N-propyl)
Amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole; 4- (N- (2- (1-imidazolyl) ethyl) -N-cyclo Propylmethyl)
Amino-2-methyl-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′-methylhomopiperazini) Ru) ethyl-N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -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- Methyl-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. The compound according to claim 1, which is 3-b] indole. 28. 4- (N- (2-pyrrolidinoethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4-dimethylphenyl) -9H-pyridino [2,3-b Indole; 4- (N- (3-pyrrolidinoproyl) -N-cyclopropylmethyl) amino-
2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2
3-b] indole; 4- (N- (2-methyl-2-pyrrolidinoethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H- Pyridino [2,3-b] indole; 4- (N- (4-pyrrolidinobutyl) -N-cyclopropylmethyl) amino-2
-Methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3
-B] indole; 4- (N- (2- (4-piperidinopiperidinyl) ethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9
H-pyridino [2,3-b] indole; 4- (N- (2- (2-phenethylamino) ethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6- Tri (methylphenyl) -9H-pyridino [2,3-b] indole; 4- (N- (2-N′-methylaminoethyl) -N-methyl) amino-2-methyl-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-methyl-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) The compound according to claim 1, which is indole. 29. 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′-methyl) aminoethyl) -N-2-methylpropyl) amino-2-methyl-9- (2,4,6-trimethylphenyl)
-9H-pyridino [2,3-b] indole; 4- (N- (2-pyrrolidinoethyl) -N-isopropylidyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H -Pyridino [2,3-b] indole; 4- (N- (2-N ', N'-dimethylaminoethyl) -N-isopropyl) amino-2-methyl-9- (2,4,6-trimethyl Phenyl) -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 ', N'-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
] The compound according to claim 1, which is an indole. 30. 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-aminoethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2 , 4-Dimethylphenyl) -9H-pyridino [2,3-b] indole; 4- (N- (2-aminoethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,6- Dimethylphenyl) -9H-pyridino [2,3-b] indole; 4- (N- (2-aminoethyl) -N-ethyl) amino-2-methyl-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-trimethylphenyl) -9H-pyridino [2,3-b] indole; 4- (N- (2-carboxyamidoethyl) -N-cyclopropylmethyl) Amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [
2,3-b] indole; or 4- (N- (2-N′-acetyl-N′-methylaminoethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6 -Trimethylphenyl)
The compound according to claim 1, which is -9H-pyridino [2,3-b] indole. 31. 4- (N- (2- (N′-methanesulfonyl-N′-methylamino) ethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (
2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole; 4- (N- (2- (N′-methyl-N′-trifluoromethanesulfonyl) aminoethyl) -N-cyclo Propylmethyl) 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) -9
H-pyridino [2,3-b] indole; 4- (N- (2- (2- (2-thienyl) -1-oxoethyl) aminoethyl)
-N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole; 4- (N- (2- (2-phenyl) 4- (N-oxoethyl) aminoethyl) -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-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′-dimethylamino-1-oxoethyl) -N-2-
Methoxyethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole; or 4- (N- (2-pyrrolidino-1-oxoethyl)- The compound according to claim 1, which is N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole. 32. 4- (N- (2-N′-ethylamino-1-oxoethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H -Pyridino [2,3-b] indole; 4- (N- (2- (N'-ethyl-N'-methyl) amino-1-oxoethyl)
-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-methyl-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; 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-trimethylphenyl) -9H-pyridino [2,3-
b] Indole; 4- (N- (2-N ', N'-dimethylamino-2-oxoethyl) -N-2-
Methoxyethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole; or 4- (N- (2-N ′, N′-dimethyl) Amino-2-oxoethyl) -N-propyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-
Pyridino [2,3-b] indole; 4- (N- (2-N ′, N′-dimethylamino-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 ′) -(Dimethylamino-1-oxoethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole; 4- (4 -Triazolyl) -2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole; 4-piperazinyl-2-methyl-9- (2,4,6- Trimethylphenyl) -9
H-pyridino [2,3-b] indole; 4- (4-methylpiperazinyl) -2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] Indole; 4-homopiperazinyl-2-methyl-9- (2,4,6-trimethylphenyl)
-9H-pyridino [2,3-b] indole; 4- (N- (2- (1-methyl-2-pyrrolidino) ethyl) -N-cyclopropylcarbonyl) amino-2-methyl-9- (2, 4,6-trimethylphenyl)
-9H-pyridino [2,3-b] indole; 4- (N-2- (S) -pyrrolidinomethylpyrrolidinyl) -2-methyl-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-methyl-9- (2,4,6-
Tri (methylphenyl) -9H-pyridino [2,3-b] indole; 4- (3-aminopyrrolidinyl) -2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2 3. The compound according to claim 1, which is 3-b] indole. 33. 4- (N- (2- (1-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) -cyclopentylaminomethylpyrrolidinyl) -2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b]
Indole; 4- (N-3-cyclopentylaminopyrrolidinyl) -2-methyl-9- (2,
4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole; 4- (N-3- (2- (3-methoxy-4-ethoxy) phenethyl) aminopyrrolidinyl) -2-methyl -9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole; 4- (N-3- (1-oxo-2- (3-methoxy-4-ethoxy) phenethyl) ) Aminopyrrolidinyl) -2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole; 4- (N-2- (2- (R)- (4-methoxy) phenethyl) aminomethylpyrrolidinyl) -2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole; 4- (N-2- (2- (S)-(4-methoxy) phenethyl ) Aminomethylpyrrolidinyl) -2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyridino [2,3-b] indole; 4- (N-4- (2- (3- Methoxy-4-ethoxy) phenethyl) aminomethylpiperazinyl) -2-methyl-9- (2,4,6-trimethylphenyl) -9
H-pyridino [2,3-b] indole; or 4- (N- (2-N ′, N′-dimethylaminoethyl) -N-cyclopropyl)
The compound according to claim 1, which is amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyrimidino [4,5-b] indole. 34. 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-methylphenyl) -9H-pyrimidino [4,5-b] indole; 4- (N- (2-N ', N'-dimethylaminoethyl) -N-cyclopropylmethyl) amino -2-methyl-9- (2,4,6-trimethylphenyl) -9H-
Pyrimidino [4,5-b] indole; 4-piperazinyl-2-methyl-9- (2,4,6-trimethylphenyl) -9
H-pyrimidino [4,5-b] indole; 4- (N- (2-pyrrolidinoethyl) -N-cyclopropylmethyl) amino-2
-Methyl-9- (2,4,6-trimethylphenyl) -9H-pyrimidino [4,
4- (3-aminopyrrolidinyl) -2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyrimidino [4,5-b] indole; 4- (2 -(S) -aminomethylpyrrolidino) -2-methyl-9- (2,4,6
-Trimethylphenyl) -9H-pyrimidino [4,5-b] indole; or 4- (3-amino-2-triazolyl) -2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyrimidino The compound according to claim 1, which is [4,5-b] indole. 35. 4- (3-amino-1-triazolyl) -2-methyl-9
-(2,4,6-trimethylphenyl) -9H-pyrimidino [4,5-b] indole; 4- (3-amino-4-triazolyl) -2-methyl-9- (2,4,6-trimethyl Phenyl) -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-methyl-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'-dimethylaminoethyl) -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-methyl-9
-(2,4,6-trimethylphenyl) -9H-pyrimidino [4,5-b] indole; or 4- (N- (2-piperidinoethyl) -N-butyl) amino-2-methyl-9-
The compound according to claim 1, which is (2,4,6-trimethylphenyl) -9H-pyrimidino [4,5-b] indole. 36. 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'-dimethyl) Aminoethyl) -N-cyclopentyl)
Amino-2-methyl-9- (2,4,6-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-methyl-9- (2,4,6-trimethylphenyl) -9H-pyrimidino [4,5-b
Indole; 4- (4- (N-methylamino) piperidino) -2-methyl-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) -N-1-methylpropyl) amino-2-methyl-9- (2,4,6-trimethylphenyl )-
9H-pyrimidino [4,5-b] indole; 4- (N- (2-N ′, N′-diethylaminoethyl) -N-cyclopropylmethyl) amino-2-methyl-9- (2,4,6 -Trimethylphenyl) -9H-
Pyrimidino [4,5-b] indole; or 4- (N- (2-N ′, N′-diethylaminoethyl) -N-cyclopropyl)
The compound according to claim 1, which is amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyrimidino [4,5-b] indole. 37. 4- (N- (2-N ′, N′-dimethylaminoethyl)-
N-2-methoxyethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyrimidino [4,5-b] indole; 4- (N- (2-N ′, N '-Dimethylaminoethyl) -N-2-ethoxyethyl) amino-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-methyl-4-chlorophenyl) -9H-pyrimidino [4,5-b
Indole; 4- (N- (cyclopentylaminopiperidin-4-yl) -N-ethyl) amino-2-methyl-9- (2,4,6-trimethylphenyl) -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-methyl-9- (2,4 , 6-Trimethylphenyl) -9H-pyrimidino [4,5-b] indole; 4- (N- (S)-(1-oxo-2- (4-methoxy) phenethyl) aminopyrrolidin-2-yl)- 2-methyl-9- 2,4,6-trimethylphenyl)
-9H-pyrimidino [4,5-b] indole; or 4- (N- (S)-(2- (4-methoxy) phenethyl) aminopyrrolidine-2
The compound according to claim 1, which is -yl) -2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyrimidino [4,5-b] indole. 38. A method for treating or preventing a physiological disorder associated with excess CRF, wherein the method comprises providing a patient in need thereof with a CRF-reducing amount. The above method comprising administering a compound of formula (I). 39. A mammal comprising administering to the mammal a therapeutically effective amount of the compound of claim 1, wherein the mammal has affective disorders, anxiety, depression, headache, irritable bowel syndrome, post-traumatic stress syndrome, Supranuclear palsy, immunosuppression, Alzheimer's disease, gastrointestinal illness,
Anorexia nervosa, or other eating disorders, drug addiction, drug or alcohol withdrawal syndrome, inflammatory diseases, cardiovascular or heart-related diseases, fertilization problems, human immunodeficiency virus infection, bleeding stress, obesity, infertility, Successful treatment by antagonizing CRF, including but not limited to head and spinal cord trauma, epilepsy, stroke, ulcers, amyotrophic lateral sclerosis, hypoglycemia, or diseases induced or promoted by CRF Or a method of treating a disease that can be promoted. 40. A mammal comprising administering to the mammal a therapeutically effective amount of the compound of claim 1, wherein the mammal has affective disorders, anxiety, depression, headache, irritable bowel syndrome, post-traumatic stress syndrome, Supranuclear palsy, immunosuppression, Alzheimer's disease, gastrointestinal illness,
Anorexia nervosa, or other eating disorders, drug addiction, drug or alcohol withdrawal syndrome, inflammatory diseases, cardiovascular or heart-related diseases, fertilization problems, human immunodeficiency virus infection, bleeding stress, obesity, infertility, Successful treatment by antagonizing CRF, including but not limited to head and spinal cord trauma, epilepsy, stroke, ulcers, amyotrophic lateral sclerosis, hypoglycemia, or diseases induced or promoted by CRF Or use of a compound in the manufacture of a medicament for the treatment of a disease that may be facilitated. 41. A method of treating or preventing a physiological condition in a mammal characterized by the presence of an excess of neuropeptide Y, comprising administering to the mammal in need of such treatment a therapeutically effective amount of the compound of claim 1, Such a method, comprising administering a prodrug, or a pharmaceutically acceptable salt thereof. 42. Disease or disease state caused by eating disorder, obesity, bulimia nervosa, diabetes, dyslipidemia, hypertension, memory loss, epileptic seizure, migraine, sleep disorder, pain, cerebral hemorrhage, shock The pharmaceutical composition according to claim 1, for the treatment of congestive heart failure, nasal congestion, or diarrhea.