HK1099017A

HK1099017A - Tetraazabenzo[e]azulene derivatives and analogs thereof

Info

Publication number: HK1099017A
Application number: HK07106054.3A
Authority: HK
Inventors: K．O．卡梅伦; R．L．埃利奥特; M.哈蒙德
Original assignee: 辉瑞产品公司
Priority date: 2004-05-25
Filing date: 2005-05-13
Publication date: 2007-08-03

Description

Tetraazabenzo [ e ] azulene derivatives and analogs thereof

Technical Field

The present invention relates to compounds of formula (I), pharmaceutical compositions comprising said compounds, alone or in combination with other agents, methods of using the compounds and combinations, and intermediates and processes for preparing the compounds. The compounds of formula (I) are agonists of the cholecystokinin-A (CCK-A) receptor and are therefore useful, for example, in the control of body weight and in the treatment of obesity and related diseases.

Background

Obesity is a significant public health concern due to its increased prevalence and associated health risks. In addition, obesity can affect a person's quality of life through restricted activities and decreased physical endurance, as well as social, academic, and work discrimination.

Obesity and overweight are generally defined by Body Mass Index (BMI), which is related to total body fat and can be a measure of the risk of certain specific diseases. BMI is calculated by dividing body weight (kilograms) by height (square meters) (kg/m)²)。Overweight is generally defined as 25-29.9kg/m²The BMI of (1), obesity is generally defined as 30kg/m²Or higher BMI. See, for example, National Heart, Lung and Blood Institute, Clinical Guidelines on The identification, Evaluation, and Treatment of upside and Obesistance in additives, The Evaluation Report, Washington, DC: U.S. department of Health and Human Services, NIH publication No.98-4083 (1998).

Recent studies have found that obesity and its associated health risks are not limited to adults, but may also affect children and adolescents to a surprising extent. According to the statistics of the centers for disease control, the percentage of children and adolescents defined as overweight has multiplied more since the early 70 s and now about 15% of children and adolescents are overweight. Risk factors for heart disease, such as high cholesterol and hypertension, occur more frequently in overweight children and adolescents than in normal-weight subjects of similar age. And type 2 diabetes, previously considered a disease of adults, has increased dramatically in children and adolescents. Overweight conditions and obesity are closely associated with type 2 diabetes. It has recently been estimated that overweight teenagers have a 70% chance of becoming overweight or obese adults. This probability increases to about 80% if at least one of the parents is overweight or obese. The most direct consequence of overweight perceived by children themselves is social discrimination.

Overweight or obesity may have adverse health consequences because such individuals are at increased risk of illness (co-morbid) such as hypertension, dyslipidemia, type 2 (non-insulin dependent) diabetes, insulin resistance, glucose intolerance, hyperinsulinemia, coronary heart disease, angina, congestive heart failure, stroke, gallstones, cholecystitis, cholelithiasis, gout, osteoarthritis, obstructive sleep apnea and respiratory problems, gall bladder disease, certain forms of cancer (e.g., endometrium, breast, prostate and colon) and psychological disorders (e.g., depression, eating disorders, crooked body images and reduced self-esteem). The negative health consequences of obesity make it the second leading cause of preventable death in the united states and have significant economic and psychosocial impact on society. See, McGinnis M, Foege WH., "Actual cases of Deathin the United States," JAMA, 270, 2207-12 (1993).

Obesity is now considered a chronic disease that requires treatment to reduce its associated health risks. While weight loss is an important therapeutic outcome, one of the primary goals of obesity control is to improve cardiovascular and metabolic values to reduce morbidity and mortality associated with obesity. It has been shown that a 5-10% reduction in body weight can greatly improve metabolic values such as blood glucose, blood pressure and lipid concentrations. Thus, it is believed that an intentional weight loss of 5-10% reduces morbidity and mortality.

Currently available prescription drugs for the management of obesity generally reduce body weight primarily by inducing satiety or reducing dietary fat absorption. Satiety is achieved by increasing synaptic levels of norepinephrine, 5-hydroxytryptamine, or both. For example, stimulation of the 1B, 1D, and 2C subtypes of 5-hydroxytryptamine receptors and 1-and 2-adrenergic receptors may reduce food intake by modulating satiety. See, Bray GA, "The New Era of Drug Trea. Pharmacological treatment of Obesity: symposium Overview, "bes res, 3(suppl4), 415s-7s (1995). Adrenergic agents (e.g., diethyldiethenone, benzphetamine, phendimetrazine, mazindol, and phentermine) act by promoting catecholamine release, modulating central norepinephrine and dopamine receptors. Older adrenergic weight-loss drugs (e.g., amphetamine, methamphetamine, and phenmetrazine), which are strongly involved in the dopamine pathway, are no longer recommended because of their risk of abuse. Fenfluramine and dexfenfluramine, both 5-hydroxytryptamine-capable agents for regulating appetite, are no longer available.

Cholecystokinin (CCK) is a brain-gut peptide that exerts the effects of gastrointestinal hormones, neurotransmitters and neuromodulators in the central and peripheral nervous systems. Cholecystokinin is a peptide that exists in multiple active forms of varying lengths (e.g., CCK-58; CCK-39; CCK-33; CCK-8; and CCK-4), the different forms predominating in different species. Cholecystokinin-58 is the major molecular form in humans, dogs and cats, but not in the intestine of pigs, cattle or rats. See, for example, G.A. Eberlien, V.E.Eysselein and H.Goebell, 1988, Peptides 9, pp.993-998. The peripheral action of CCK, of which the O-sulfated octapeptide CCK-8S is believed to be the predominant form, is primarily focused on its role as a factor in gastrointestinal satiety.

CCK has been shown to be released from the mucosal I-cells of the duodenum and jejunum in response to eating, particularly fat or protein in the diet. Once released, CCK triggers a number of responses that act synergistically to promote digestion and regulate food intake, including mediating bile emptying in the gall bladder, regulating the release of digestive enzymes from the pancreas, controlling gastric emptying by regulating the pyloric sphincter, and neurons transmitting signals to the CNS (central nervous system) via vagal afferent neurons.

Within the CNS, CCK has been found in numerous anatomical locations, including the cerebral cortex, hippocampus, septum, amygdala, olfactory bulb, hypothalamus, thalamus, parabrachial nucleus, spinal nucleus, substantia nigra, ventral midbrain, nucleus solitarius, ventral medulla, and spinal cord. See, e.g., T.Hokfelt et al, 1988, J.chem.Neuroanat.1, pp.11-52; j.j.vanderhaeghen, j.c.signeu and w.gepts, 1975, Nature 257, pp.604-605; and J-J.Vanderhaegen and S.N.Schiffmann (1992) pp.38-56, eds.C.T.Dourish, S.J.Cooper, S.D.Iversen and L.L.Iversen, Oxford university Press, Oxford. Neuronal CCK is believed to mediate several events within the CNS, including modulation of dopaminergic neurotransmission and analogenic effects, as well as affecting cognition and nociception. See, e.g., j.n.crawley and r.l.corwin, 1994, Peptides, 15: 731-755; n.s.baber, c.t.dourish, and d.r.hill, Pain (1989), 39(3), 307-28; and P.DeTullio, J.Delage and B.Pitotte, ExpertOption on Investigational Drugs (2000), 9(1), 129-.

Cholecystokinin has been shown to pass through two receptor subtypes: the CCK-A (CCK1) and CCK-B (CCK2) subtypes mediate its many different hormonal and neuromodulatory functions (see, e.g., G.N.Woodruff and J.Hughes, Annu.Rev.Pharmacol.Toxicol. (1991), 31: 469-.

Both the CCK-A and CCK-B receptor subtypes belong to the seven transmembrane G-protein-coupled superfamily of receptors. The nucleotide sequences of the peripheral and central CCK-A receptors in humans are identical; similarly, the human CCK-B receptor and gastrin receptor were found to be identical. See, e.g., S.A.Wank et al (1994), NY Acad.Sci.713, pp.49-66.

The CCK-a receptor is located primarily peripherally and includes pancreatic acinar cells, pyloric sphincter, gallbladder, and vagal afferent fibers where it mediates exocrine pancreatic secretion, gastric emptying, and gallbladder contraction, and transmits a postprandial satiety signal to the CNS. In addition, CCK-a receptors are found in discrete regions within the CNS, including the solitary bundle nucleus, the posterior most region, and the dorsal medial hypothalamus. CCK-B receptors are predominantly located in the CNS and are less localized in the periphery.

Many studies have shown that CCK mediates its satiety effects through the CCK-a receptor, which transmits postprandial satiety signals to the CNS via vagal afferent nerves. See, e.g., G.P.Smith et al, Science 213(1981) pp.1036-1037; and j.n.crawley et al, j.pharmacol.exp.ther, 257(1991) pp.1076-1080. For example, CCK and CCK agonists have been reported to reduce food intake in animals, including rats (see, e.g., J.Gibbs, R.C.Young and G.P.Smith, 1973, J.Comp.Physiol.Psychol84: 488-95), dogs and primates (including humans) (see, e.g., Himick and R.E.Peter, 1994, am.J.Physiol.267: R841-R851; Y.Hirosue et al, 1993, am.J.Physiol.265: R481-R486; and K.E.Asin et al, 1992, Pharmacol.biochem.Behav.42: 9-704), and the appetite-reducing effect is mediated via CCK-A receptors located on vagal afferent fibers (see, e.g., C.T.Dourish, 1992. N.42: 9-D, CNS J.D, CNS J.D.D.D, CNS J.D.D.D.D.D.D, CNS J.D.D.D.D.D.D.D.D. D. D, CNS J.D.D.D. D. K. D. K. E.E. E.E.E. E. K. E. D. E. D. E. D. E. D. E. D. E., 1981, Science 213, pp.1036-1037).

Other lines of evidence supporting the involvement of the CCK-A receptor in regulating food intake include the finding that OLETF rats, which lack CCK-A receptors, are not sensitive to the anorexia effects of CCK. Also, CCK-A selective antagonists, but not CCK-B antagonists, have been reported to block the anorexia effect of CCK and CCK analogs and to increase animal feeding (see, e.g., G.Hewson et al, 1988, Br.J.Pharmacol.93: 79-84; R.D.Reidelberger and M.F.O' Rourke, 1989, am.J.Physiol.257: R1512-R1518; T.H.Moran et al, 1993, am.J.Physiol.265: R620-R624; and M.Covasa and R.C.Ritter, Peptides (New York, NY, US) (2001), 22(8), 9-1348), including humans (see, e.g., O.M.Woolkitz et al, 1990, biol.Y. 28: 169).

Finally, infusion of CCK or a selective CCK-A agonist has been reported to reduce food intake and caloric intake in animals, including humans (see, e.g., L.Degen et al, Peptides (New York, NY) (2001), 22(8), 1265-.

The development of non-peptidic CCK-A agonists has been reported in the literature. For example, Sanofi has reported in U.S. Pat. No.5,798,353 that certain 3-amido-5- (polysubstituted phenyl) -1, 4 benzodiazepine * -2-ones act as CCK-A agonists. Certain 1, 5-benzodiazepine * ketones have been reported to be CCK-A agonists with appetite-reducing activity in rodents (see, e.g., E.E. Sugg et al, (1998) Pharmaceutical Biotechnology11(Integration of Pharmaceutical Discovery and Development): 507- & 524). Sherrill et al, in Bioorganic & Medicinal chemistry letters (2001), 11(9), 1145-1148 disclose certain 1, 4-benzodiazepines * as peripheral CCK-A receptor agonists with anorectic activity in a rat feeding model. A series of 3- (1H-indazol-3-ylmethyl) -1, 5-benzodiazepines *, discussed by b.r.henke et al in j.med.chem. (1997), 40(17), 2706-.

While research is in progress, there is still a need for more effective and safe therapeutic treatments for reducing or preventing weight gain.

SUMMARY

The present invention relates to compounds of formula (I) or a pharmaceutically acceptable salt thereof or a prodrug of said compound or said salt

Wherein A, B, X, D, E and G are independently-C (R)⁵) -or-N-,

provided that at most two of A, B, X and D are simultaneously N and at least one of E and G is N;

R¹is selected from (C)₂-C₆) Alkyl, halogen-substituted (C)₁-C₆) Alkyl-, (C)₁-C₆) Alkylamino-, di (C)₁-C₆Alkyl) amino-, (C)₁-C₆) Alkylamino radical (C)₁-C₆) Alkyl-, di (C)₁-C₆) Alkylamino radical (C)₁-C₆) Alkyl-, aryl (C)₁-C₆) Alkyl-, heteroaryl-A (C)₁-C₆) Alkyl-, 4-to 7-membered partially or fully saturated heterocycle-A, 4-to 7-membered partially or fully saturated heterocyclyl-A (C)₁-C₆) Alkyl-and partially or fully saturated (C)₃-C₇) Cycloalkyl (C)₁-C₆) Alkyl-, and when R⁶And R⁷When neither is benzyl-, R¹Selected from the above groups and partially or fully saturated (C)₃-C₇) A cycloalkyl group;

wherein heteroaryl-A is selected from the group consisting of thienyl, thiazolyl, isothiazolyl, indolyl, 2-pyridyl, pyridazinyl, pyrimidinyl, oxazolyl, furanyl, imidazolyl, isoxazolyl, quinolinyl, isoquinolinyl, benzothienyl, benzofuranyl, pyrazinyl, and pyrazolyl,

and the partially or fully saturated heterocycle-A is selected from the group consisting of pyranyl, morpholinyl and tetrahydrofuranyl,

and wherein aryl, heteroaryl-A, partially or fully saturated heterocycle-A or partially or fully saturated cycloalkyl or a portion of a group is optionally substituted with 1-3 substituents independently selected from halogen, (C)₁-C₃) Alkoxy-, halogen-substituted (C)₁-C₃) Alkoxy-, -OH, (C)₁-C₃) Alkyl, -CN and halogen-substituted (C)₁-C₃) Alkyl-substituted;

R²is-CH₂C(O)N(R⁶)(R⁷)；

R³And R⁴One of (A) is H, halogen, (C)₁-C₆) Alkyl radical (C)₁-C₆) Alkoxy-or partially or fully saturated (C)₃-C₇) Cycloalkyl radical and R³And R⁴is-C (R)⁸)(R⁹)(R¹⁰) (ii) a Or

R³And R⁴Together to form ═ CHR¹¹；

Each R⁵Independently selected from H, (C)₁-C₆) Alkoxy-, -OH, halogen, -CN, -NH₂and-NO₂；

R⁶And R⁷Is (C)₃-C₆) Alkyl radicals or radicals partially or whollySaturated (C)₃-C₇) Cycloalkyl radical, and R⁶And R⁷Is phenyl, optionally substituted with 1-3 substituents independently selected from-OH, -CN, halogen-C₁-C₆) Alkyl-, halogen-substituted (C)₁-C₃) Alkoxy-, (C)₁-C₆) Alkyl and (C)₁-C₃) Alkoxy-substituted; benzyl-, wherein the phenyl moiety is optionally substituted with 1-3 substituents independently selected from-OH, -CN, halogen — (C)₁-C₆) Alkyl-, halogen-substituted (C)₁-C₃) Alkoxy-and (C)₁-C₃) Alkoxy-substituted; or heteroaryl-B, optionally substituted with 1-3 substituents independently selected from-OH, -CN, halogen-C₁-C₆) Alkyl-, halogen-substituted (C)₁-C₃) Alkoxy-, (C)₁-C₆) Alkyl and (C)₁-C₃) Alkoxy-substituted; and wherein said heteroaryl-B is selected from thienyl, thiazolyl, isothiazolyl, isoquinolyl, quinolinyl, 3-or 4-pyridyl, pyrimidinyl, oxazolyl, furanyl, imidazolyl, isoxazolyl, pyrazinyl, pyridazinyl, and pyrazolyl;

R⁸，R⁹and R¹⁰Are independently H or (C)₁-C₆) Alkyl and R⁸，R⁹And R¹⁰Another one of (A) is phenyl, partially or fully saturated (C)₃-C₇) Cycloalkyl, heteroaryl-C or a 4-to 7-membered partially or fully saturated heterocycle-B wherein heteroaryl-C is selected from indol-2-yl, indol-3-yl, indazol-3-yl, 7-azaindol-2-yl and 7-azaindol-3-yl; said phenyl, partially or fully saturated cycloalkyl, heteroaryl-C or partially or fully saturated heterocycle-B being optionally substituted on carbon by 1 to 3 substituents independently selected from (C)₁-C₆) Alkoxy-, F, Cl, -CN, -OH, -CO₂H, tetrazole and halogen-substituted (C)₁-C₆) Alkoxy-substituted; and is

R¹¹Is phenyl, partially or fully saturated (C)₃-C₇) Cycloalkyl, heteroaryl-C or a 4-to 7-membered partially or fully saturated heterocycle-B wherein heteroaryl-C is selected from indol-2-yl, indol-3-yl, indazol-3-yl, 7-azaindol-2-yl and 7-azaindol-3-yl; said phenyl, partially or fully saturated cycloalkyl, heteroaryl-C or partially or fully saturated heterocycle-B being optionally substituted on carbon by 1 to 3 substituents independently selected from (C)₁-C₆) Alkoxy-, F, Cl, -CN, -OH, -CO₂H, tetrazole and halogen-substituted (C)₁-C₆) Alkoxy-substituted.

In one aspect of the invention, one of A, B, X and D in formula (I) is-N-and the other of A, B, X and D is-C (R)⁵) -. In another aspect, two of A, B, X and D are-N-and the other of A, B, X and D is-C (R)⁵) -. In a preferred embodiment, in formula (I) A, B, X and D are each independently-C (R)⁵) -, as described in the following formula (II)

Each substituent R of the compound of the formula (II)¹，R²，R³，R⁴And R⁵And the ring atoms E and G are each as defined above and below for the compounds of the formula (I).

In one embodiment of the invention, E is-N-and G is-C (R) in formula (I)⁵) -. In another embodiment, E is-C (R)⁵) -and G is-N-. Preferably, E and G are each-N-. The substituents and other parameters in these embodiments are generally and preferably as defined above and below for the compounds of formula (I).

A preferred embodiment of the present invention relates to compounds of formula (I), as described in formula (III) below, wherein A and D are-CH-, and X and B are-C (R)⁵) -and E and G are-N-. The substituents in formula (III) are generally and preferably as defined above and below for the compounds of formula (I).

R in the formula (I)¹Preferably selected from (C)₂-C₆) Alkyl, -CF₃Phenyl, phenyl (C)₁-C₃) Alkyl-, heteroaryl-A (C)₁-C₃) Alkyl-, 4-to 7-membered partially or fully saturated heterocycle-A, 4-to 7-membered partially or fully saturated heterocyclyl-A (C)₁-C₃) Alkyl-and partially or fully saturated (C)₃-C₇) Cycloalkyl (C)₁-C₃) Alkyl-, and when R⁶And R⁷When neither is benzyl-, R¹Also preferably partially or fully saturated (C)₃-C₇) A cycloalkyl group. More preferably, R¹Is phenyl or 2-pyridyl, or when R is⁶And R⁷When neither is benzyl-, R¹Even more preferably partially or fully saturated (C)₅-C₇) A cycloalkyl group. More preferably, R¹Is phenyl, or when R⁶And R⁷R when both are not benzyl-radicals₁Is cyclohexyl. Most preferably, R¹Is phenyl.

R¹heteroaryl-A is preferably selected from thienyl, 2-pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and pyrazolyl. More preferably, it is 2-pyridyl.

R¹Aryl, heteroaryl-A, partially or fully saturated heterocycle-A or partially or fully saturated cycloalkyl or a part of a group is optionally substituted, preferably by 1 to 3 independently selected substituents, preferably selected from F, Cl, (C)₁-C₃) Alkoxy-, -OH, (C)₁-C₃) Alkyl, -CN and-CF₃(ii) a More preferably from F, Cl, (C)₁-C₃) Alkoxy-, -OH, (C)₁-C₃) Alkyl, and-CF₃(ii) a In particular from F, Cl, (C)₁-C₃) Alkoxy-, -OH and- (C)₁-C₃) An alkyl group. When R is¹Is phenyl, most preferably it is unsubstituted, but if substituted, it is most preferably substituted1-3F atoms or-OH groups.

Each R in the formula (I)⁵Independently preferably selected from H, (C)₁-C₄) Alkoxy-, -OH, F, Cl and-CN; more preferably selected from H, -OH and F; more preferably selected from H and F. Most preferably, each R⁵Is that^H。

When A, B, X, and D in formula (I) are each-C (R)⁵) When R is not more than⁵At least one of which is H, more preferably such R⁵At least two or three of which are^H. Most preferably, each such R⁵Are all H.

When one of E and G in the formula (I) is-C (R)⁵) When R is such that⁵Also most preferred is H.

Preferably, R in the formula (I)⁶And R⁷Is a branched chain (C)₃-C₆) An alkyl group; more preferably branched chain (C)₃-C₅) An alkyl group; more preferably branched chain (C)₃Or C₄) An alkyl group; and isopropyl is most preferred.

R in the formula (I)⁶And R⁷The other of which is preferably phenyl, benzyl-or heteroaryl-B, wherein the phenyl moiety of phenyl, benzyl or the heteroaryl-B group is optionally substituted.

Preferably, R⁶Or R⁷Phenyl optionally substituted with 1-3 substituents independently selected from-OH, -CN, F, Cl, F-or Cl- (C)₁-C₃) Alkyl-, F-or Cl-substituted (C)₁-C₃) Alkoxy-, (C)₁-C₄) Alkyl and (C)₁-C₃) Alkoxy-substituted. More preferably, the phenyl is optionally substituted (C) by 1-3 substituents independently selected from-OH, -CN, F, Cl, F-₁-C₃) Alkyl-, F-substituted (C)₁-C₃) Alkoxy-, (C)₁-C₄) Alkyl and (C)₁-C₃) Alkoxy-substituted. More preferably, the phenyl group is optionally substituted with 1 to 3 substituents independently selected from-OH, F, Cl, -CF₃，-OCF₃，(C₁-C₄) Alkyl and (C)₁-C₃) Alkoxy-substituted. More preferably, the phenyl group is optionally substituted by 1 or 2 groups independently selected from F, Cl, -CF₃，-OCF₃，-CH₂And (C)₁-C₃) Alkoxy-substituted. More preferably, the phenyl group is optionally substituted with 1 or 2F atoms. When R is⁶And R⁷When one of them is optionally substituted phenyl, it is preferably unsubstituted phenyl and 4-F-phenyl.

Preferably, R⁶Or R⁷The phenyl moiety of the benzyl group is optionally substituted with 1 to 3 substituents independently selected from the group consisting of-OH, -CN, and (C)₁-C₃) Alkoxy-substituted. More preferably, the phenyl moiety is optionally substituted with 1 or 2 substituents independently selected from-OH and-OCH₃Is substituted with the substituent(s). Most preferably, the phenyl moiety of the benzyl group is unsubstituted.

Preferably, R⁶Or R⁷heteroaryl-B groups optionally substituted with 1-3 substituents independently selected from-OH, -CN, F, Cl, F-or Cl- (C)₁-C₃) Alkyl-, F-or Cl-substituted (C)₁-C₃) Alkoxy-, (C)₁-C₄) Alkyl and (C)₁-C₃) Alkoxy-substituted. More preferably, the heteroaryl-B group is optionally substituted (C) by 1 to 3 substituents independently selected from-OH, -CN, F, Cl, F-₁-C₃) Alkyl-, F-substituted (C)₁-C₃) Alkoxy-, (C)₁-C₄) Alkyl and (C)₁-C₃) Alkoxy-substituted. More preferably, the heteroaryl-B group is optionally substituted with 1-3 substituents independently selected from-OH, F, Cl, -CF₃，-OCF₃，(C₁-C₄) Alkyl and (C)₁-C₃) Alkoxy-substituted. More preferably, it is optionally substituted by 1 or 2 substituents independently selected from F, Cl, -CF₃，-OCF₃，-CH₃And (C)₁-C₃) Alkoxy-substituted. More preferably, the heteroaryl-B group is optionally substituted by 1 or 2 groups independently selected from F, Cl and (C)₁-C₃) Alkoxy-substituted. More preferably, heteroaryl-B is optionally substituted by 1 or 2 substituents independently selected from Cl, -OCH₃and-OCH₂CH₃Is substituted with the substituent(s). In a particularly preferred embodimentIn one embodiment, heteroaryl-B is generally or preferably substituted by one substituent selected from the groups described above, especially-OCH₃And (4) substitution.

R⁶Or R⁷heteroaryl-B is preferably selected from thienyl, 3-or 4-pyridyl, pyrimidinyl, and pyrazinyl. More preferably, it is 3-or 4-pyridyl, especially 3-pyridyl, which may be unsubstituted or, preferably, substituted as described above. When the 3-pyridyl group is mono-substituted, it is preferably substituted at the C-6 position. In a particularly preferred embodiment, the heteroaryl group is 6-methoxypyridin-3-yl.

In a preferred embodiment, R in formula (I)³And R⁴One of (A) is H, (C)₁-C₃) Alkyl or (C)₁-C₃) Alkoxy-; more preferably H or (C)₁-C₃) Alkyl radicals, e.g., -CH₃(ii) a Most preferably H. R in the formula (I)³And R⁴is-C (R)⁸)(R⁹)(R¹⁰)。

In the compound of formula (I) — C (R)⁸)(R⁹)(R¹⁰) In the sense that R⁸，R⁹And R¹⁰Two of (A) are preferably H, and R is⁸，R⁹And R¹⁰Is heteroaryl-C. Preferably, heteroaryl-C is selected from indol-3-yl, indazol-3-yl and 7-azaindol-3-yl. More preferably, heteroaryl-C is indol-3-yl or indazol-3-yl; most preferably, indol-3-yl. The heteroaryl-C group is optionally substituted on a carbon atom, preferably on the phenyl or pyridyl ring of the heteroaryl-C group, with 1-3 substituents; preferably, 1 or 2 substituents; more preferably, 1 substituent. The substituents are independently selected, preferably from (C)₁-C₃) Alkoxy-, F, Cl, -CN, -OH, -CO₂H, tetrazole and F-substituted (C)₁-C₃) Alkoxy- (e.g. -OCF)₃) (ii) a More preferably selected from F and Cl. More preferably the heteroaryl-C group is optionally substituted with 1 or 2 or 3 (preferably 1) F atoms. Most preferably the heteroaryl group is unsubstituted.

In alternative embodiments, R³And R⁴Together to form ═ CHR¹¹. In this embodiment, wherein R in formula (I)³And R⁴Together, R¹¹R is generally and preferably as defined above and below⁸，R⁹And R¹⁰The "other" of (a) is the same.

Preferred embodiments of the present invention are shown in formula (IV)

Wherein X¹is-CH-and X²is-N-or-C (R)¹²) -, or X¹is-N-and X²is-C (R)¹²) -. Preferably, X¹is-CH-or-N-and X²is-C (R)¹²) -. Each R¹²Independently, preferably selected from H, (C)₁-C₃) Alkoxy-, F, Cl, -CN, -OH, -CO₂H, tetrazole and F-substituted (C)₁-C₃) Alkoxy- (e.g., -OCF)₃) (ii) a More preferably selected from H, F and Cl; more preferably selected from H and F; with the proviso that R¹²Up to three of which are not H. Most preferably, each R¹²Is H. The other substituents and parameters in formula (IV) are generally and preferably as defined above and below.

Formula (V), wherein substituents and other parameters are generally and preferably as defined above, represents a preferred subclass of formula (IV).

Preferred compounds of the invention include:

2- [4- (6-fluoro-1H-indol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-N- (6-methoxy-pyridin-3-yl) -acetamide,

2- [4- (1H-indol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-N- (6-methoxy-pyridin-3-yl) -acetamide,

2- [4- (5-fluoro-1H-indol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-N- (6-methoxy-pyridin-3-yl) -acetamide,

2- [ 1-cyclohexyl-4- (1H-indol-3-ylmethyl) -5-oxo-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-N- (6-methoxy-pyridin-3-yl) -acetamide,

2- [1- (3-hydroxy-phenyl) -4- (1H-indol-3-ylmethyl) -5-oxo-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-N- (6-methoxy-pyridin-3-yl) -acetamide,

n-benzyl-2- [8, 9-difluoro-4- (5-fluoro-1H-indol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-acetamide,

2- [1- (3-hydroxy-phenyl) -4- (1H-indol-3-ylmethyl) -5-oxo-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-N-phenyl-acetamide,

n-benzyl-2- [8, 9-difluoro-4- (1H-indol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-acetamide,

n-benzyl-2- [8, 9-difluoro-4- (6-fluoro-1H-indol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-acetamide,

n-isopropyl-2- [ 5-oxo-1-phenyl-4- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-phenyl-acetamide,

n-benzyl-2- [4- (1H-indol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-acetamide,

n- (6-chloro-pyridin-3-yl) -2- [4- (1H-indol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-acetamide,

n- (6-ethoxy-pyridin-3-yl) -2- [4- (1H-indol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-acetamide,

2- [4- (1H-indazol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-N- (6-methoxy-pyridin-3-yl) -acetamide,

2- [4- (1H-indazol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-N-phenyl-acetamide,

n-benzyl-2- [8, 9-difluoro-4- (1H-indazol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-acetamide,

n-benzyl-2- [4- (1H-indazol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-acetamide,

2- [4- (1H-indol-3-ylmethyl) -4-methyl-5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-N-phenyl-acetamide,

2- [1- (2-fluoro-phenyl) -4- (1H-indazol-3-ylmethyl) -5-oxo-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-N-phenyl-acetamide,

2- [1- (3-fluoro-phenyl) -4- (1H-indazol-3-ylmethyl) -5-oxo-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-N-phenyl-acetamide,

2- [ 1-cyclohexyl-4- (1H-indazol-3-ylmethyl) -5-oxo-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-N-phenyl-acetamide,

2- [1- (4-fluoro-phenyl) -4- (1H-indazol-3-ylmethyl) -5-oxo-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-N-phenyl-acetamide,

n- (4-fluoro-phenyl) -2- [4- (1H-indazol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-acetamide,

2- [4- (1H-indol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-N-phenyl-acetamide,

2- [ 1-cyclohexyl-4- (1H-indol-3-ylmethyl) -5-oxo-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-N-phenyl-acetamide,

2- [1- (2-fluoro-phenyl) -4- (1H-indol-3-ylmethyl) -5-oxo-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-N-phenyl-acetamide, and

2- [4- (1H-indol-3-ylmethylene) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-N-phenyl-acetamide;

or a pharmaceutically acceptable salt thereof.

A subset of such preferred compounds include:

2- [4- (1H-indol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-N-phenyl-acetamide;

n-benzyl-2- [4- (1H-indol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-acetamide;

n-benzyl-2- [4- (1H-indazol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-acetamide; and

2- [4- (1H-indazol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-N-phenyl-acetamide;

2- [4- (1H-indol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-N- (6-methoxy-pyridin-3-yl) -acetamide;

or a pharmaceutically acceptable salt thereof.

Another subgroup of such preferred compounds includes the enantiomers:

(-)2- [4- (1H-indol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-N-phenyl-acetamide;

(-) N-benzyl-2- [4- (1H-indol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-acetamide;

(-) N-benzyl-2- [4- (1H-indazol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-acetamide; and

(-)2- [4- (1H-indazol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-N-phenyl-acetamide;

(-)2- [4- (1H-indol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-N- (6-methoxy-pyridin-3-yl) -acetamide;

or a pharmaceutically acceptable salt thereof.

Another aspect of the present invention relates to intermediates of formula (D) or formula (F-1), or salts thereof, which are useful intermediates for preparing compounds of formula (I).

A，B，X，D，R¹And R²In general and preferably as defined above for the compounds of formula (I).

R is (C)₁-C₆) Alkyl or (C)₃-C₆) A cycloalkyl group; preferably, (C)₁-C₄) An alkyl group; more preferably, it is straight-chain (C)₁-C₄) Alkyl radicals, e.g. -CH₃or-CH₂CH₃。

Formula (D-1), wherein generally and preferably R is as defined above for formula (D) and R⁷Are a preferred subgroup as defined above for the compounds of formula (I) and represents formula (D).

Formula (F-1a), wherein generally and preferably, R⁷Are a preferred subgroup as defined above for the compounds of formula (I) and representing formula (F-1).

Another aspect of the invention relates to a process for the preparation of a compound of formula (C)

Which comprises contacting a compound of formula (a) with a compound of formula (B) in the presence of an acid catalyst, wherein a, B, X and D are generally and preferably as defined above for formula (I). Each R is independently (C)₁-C₆) Alkyl or (C)₃-C₆) A cycloalkyl group; preferably, (C)₁-C₄) An alkyl group; more preferably, it is straight-chain (C)₁-C₄) Alkyl radicals, e.g. -CH₃or-CH₂CH₃。

The acid catalyst may be a mineral acid, for example, hydrochloric acid or sulfuric acid; organic sulfonic acids, for example, benzenesulfonic acid or p-toluenesulfonic acid; or carboxylic acids, for example, acetic acid. Acetic acid is the preferred catalyst.

The process is generally carried out in the presence of a solvent, preferably an aprotic solvent such as DMF, acetone, methyl ethyl ketone, ethyl acetate, dichloromethane, chloroform, dioxane, THF, toluene or xylenes. More preferably, the solvent is a hydrocarbon solvent such as toluene or xylene(s); in particular xylene(s).

The process may be carried out at room temperature, e.g. about 25 ℃, or at elevated temperature, typically in the range of about 50 ℃ to reflux temperature, with preferred ranges up to about 150 ℃ or 200 ℃.

The process may be carried out at atmospheric or positive pressure, for example up to 10, 20,30, 40 or 50 atmospheres.

In a preferred laboratory scale embodiment, a solution of the compound of formula (B) in an aprotic solvent is added to a heated solution of the compound of formula (a) and the acid catalyst in an aprotic solvent in a reaction vessel and the whole is heated at elevated temperature, more particularly as described in preparations (3A) and (3B) in the examples section.

The product (C), under preferred conditions, can be isolated from the reaction mixture simply by filtration.

Also provided is a process for preparing a compound of formula (D), a compound of formula (E), a compound of formula (F-1) or a compound of formula (I-1)

Which comprises converting a compound of formula (C) produced by the process described above into a compound of formula (D), a compound of formula (E), a compound of formula (F-1) or a compound of formula (I-1), wherein A, B, X, D, R¹，R²，R³And R⁴Generally and preferably as defined above.

The invention also relates to salts and solvates, including hydrates, of the compounds of the invention. The basic compounds and intermediates of the present invention are capable of forming a wide variety of salts with various inorganic and organic acids. Acids which can be used to prepare pharmaceutically acceptable acid addition salts of such compounds are those which form non-toxic acid addition salts, i.e. salts containing a pharmaceutically acceptable anion. Certain compounds and intermediates of the invention are acidic and are capable of forming salts with various bases. Sodium and potassium salts are preferred.

The invention also relates to prodrugs of the compounds of the invention. The compounds of formula (I) having a free carboxyl, amino or hydroxyl group may be converted to, for example, an ester or amide, acting as a prodrug.

In another embodiment of the present invention, there is provided a pharmaceutical composition comprising a compound of formula (I). In another embodiment, the composition further comprises at least one additional pharmaceutical agent, which is preferably an anti-obesity agent. The additional agent may also be an agent for treating a co-morbid condition for which the composition is primarily indicated. The composition preferably comprises a therapeutically effective amount of a compound of formula (I) or a therapeutically effective amount of a compound of formula (I) in combination with an additional agent. The composition also preferably comprises a pharmaceutically acceptable excipient, diluent or carrier.

Also provided is a method of treating a disease, condition, or disorder modulated by a CCK-a receptor agonist in an animal, comprising administering to an animal in need of such treatment a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a solvate or hydrate of said compound or said salt. The compounds of formula (I) may be used alone or in combination with at least one additional agent, preferably an anti-obesity agent or agents useful in the treatment of co-morbid conditions of the disease, condition or disorder.

Diseases, conditions or disorders modulated by CCK-A receptor agonists in animals include obesity, overweight, and gallstones. Co-morbidities with such diseases, conditions or disorders may be associated with improvement.

Accordingly, there is provided a method for treating obesity in an animal, comprising administering to an animal in need of such treatment a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a solvate or hydrate of said compound or said salt. The compounds of formula (I) may be used alone or in combination with at least one additional pharmaceutical agent, preferably an anti-obesity agent.

Also provided is a method for controlling body weight in an animal comprising administering to the animal a body weight controlling amount of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a solvate or hydrate of the compound or the salt. The compounds of formula (I) may be used alone or in combination with at least one additional pharmaceutical agent, preferably an anti-obesity agent.

The present invention also provides a method for reducing food intake in an animal comprising administering to the animal a food intake reducing amount of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a solvate or hydrate of the compound or the salt. The compounds of formula (I) may be used alone or in combination with at least one additional pharmaceutical agent, preferably an anti-obesity agent.

Also provided is a method for preventing gallstones in an animal comprising administering to the animal a gallstone preventing amount of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a solvate or hydrate of said compound or said salt. The compounds of formula (I) may be used alone or in combination with at least one additional agent, preferably an agent for the treatment or prevention of gallstones.

Another aspect of the invention relates to a pharmaceutical kit for use by a consumer in the treatment of obesity. The kit includes (a) a suitable dosage form containing a compound of formula (I), and (b) instructions describing a method of using the dosage form for treating or preventing obesity.

The invention also relates to combining the separate pharmaceutical compositions in a kit form. This aspect of the invention provides a pharmaceutical kit comprising: (a) a first pharmaceutical composition comprising a compound of formula (I), (b) a second pharmaceutical composition comprising a second compound useful for treating obesity, preventing gallstones, or treating obesity-comorbidities; and (c) a container holding the first and second compositions. Typically, the kit will also include instructions for administering the individual components. This kit form is particularly advantageous when the individual components are preferably administered in different dosage forms or at different dosing intervals.

One example of a kit according to the invention is a so-called blister pack. Blister packs are widely used in the pharmaceutical industry for packaging unit dosage forms (tablets, capsules, etc.). The blister pack consists of a sheet of relatively stiff material covered with a foil of preferably transparent plastic material. During the packaging process, depressions are formed in the plastic foil. The depression has the size and shape of the tablet or capsule to be packaged. Next, a tablet or capsule is placed in the recess and a sheet of relatively hard material is sealed to the plastic foil on the side of the foil opposite to the direction in which the recess is formed. As a result, the tablet or capsule is sealed in the recess between the plastic foil and the sheet. Preferably, the strength of the sheet is such that the tablet or capsule can be removed from the blister pack by applying pressure by hand to the depression, thereby forming an opening in the sheet at the depression. The tablet or capsule can then be removed through the opening.

It may be desirable to provide a memory aid on the kit, for example in the form of a number marked next to the tablet or capsule, whereby the number corresponds to the number of days in the dosage regimen that the tablet or capsule so specified should be ingested. Another example of such a memory aid is a calendar printed on the kit, e.g., "first week, monday, tuesday,. et al. Other variations of the memory aid may be apparent. The "daily dose" may be a single tablet or capsule or several pellets or capsules to be taken within a specified day. Alternatively, the daily dose of a compound of the invention may consist of one tablet or capsule, while the daily dose of a second compound may consist of several tablets or capsules, or vice versa. The memory aid should reflect this.

Definition of

The following terms used herein have the meanings ascribed to them unless otherwise indicated.

The term "alkyl" refers to the general formula C_nH_2n+1A straight or branched hydrocarbon group of (1). For example, the term "(C)₁-C₆) Alkyl "refers to a monovalent straight or branched chain saturated aliphatic group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, 3, 3-dimethylpropyl, hexyl, 2-methylpentyl, and the like). Likewise, the alkyl part of a group such as alkoxy, acyl, alkylamino or dialkylamino or alkylthio has the same meaning as above. "halo-substituted alkyl" refers to alkyl substituted with one or more halogen atoms (e.g., -CH)₂Cl，-CHF₂，-CF₃，-C₂F₅Etc.). Similarly, terms such as "F-substituted alkyl" or "Cl-substituted alkyl" refer to alkyl groups substituted with one or more fluorine or chlorine atoms, respectively.

The term "acyl" refers to alkyl-, cycloalkyl-, heterocycle-, aryl-, and heteroaryl-substituted carbonyl groups. For example, acyl includes groups such as (C)₁-C₆) Alkanoyl (e.g., formyl, acetyl, propionyl, etc.), (C)₃-C₆) Cycloalkylcarbonyl (e.g., cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, etc.), heterocyclylcarbonyl (e.g., pyrrolidinylcarbonyl, pyrrolidin-2-one-5-carbonyl, piperidinylcarbonyl, piperazinylcarbonyl, tetrahydrofurylcarbonyl, etc.), aroyl (e.g., benzoyl) and heteroaroyl (e.g., thienyl-2-carbonyl, thienyl-3-carbonyl, furyl-2-carbonyl, furyl-3-carbonyl, 1H-pyrrolyl-2-carbonyl, 1H-pyrrolyl-3-carbonyl), benzo [ b]Thienyl-2-carbonyl, and the like.

The term "halogen" refers to F, Cl, Br or I. Preferably, halogen is F, Cl or Br; more preferably F or Cl.

"Ar" refers to an aryl group. The term "aryl" refers to an aromatic moiety having a single (e.g., phenyl) or fused ring system (e.g., naphthalene, anthracene, phenanthrene, etc.). Typical aryl groups are 6-to 10-membered aromatic carbocyclic ring systems. Unless otherwise specified, an aryl group may be attached to a chemical entity or moiety via any one of the carbon atoms in the aromatic ring system. The aryl portion (i.e., aromatic portion) of a group (e.g., aralkyl) has the same meaning as above.

The term "partially or fully saturated carbocycle" (also referred to as "partially or fully saturated cycloalkyl") refers to a non-aromatic ring that is partially or fully hydrogenated and may exist as a monocyclic, bicyclic or spiro ring. Unless otherwise specified, carbocycles are generally 3-to 8-membered (preferably, 3-to 6-membered) rings. For example, partially or fully saturated carbocyclic/cycloalkyl rings include groups such as cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, norbornyl (bicyclo [2.2.1] heptyl), norbornenyl, bicyclo [2.2.2] octyl, and the like. Unless otherwise specified, a carbocyclic group may be attached to a chemical entity or moiety via any one of the carbon atoms within the cycloalkyl ring system. The cycloalkyl portion of a group (e.g., cycloalkylalkyl, cycloalkylamino, etc.) has the same meaning as above.

The term "partially or fully saturated heterocyclic ring" (also referred to as "partially or fully saturated heterocyclic ring" or "partially or fully saturated heterocyclic group") refers to a partially or fully hydrogenated, non-aromatic ring containing at least one ring heteroatom and which may exist in the form of a monocyclic, bicyclic or spiro ring. Unless otherwise specified, heterocycles are generally 4-to 7-membered rings containing 1-4 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen or nitrogen. Heterocycles include groups such as epoxy, aziridinyl, pyranyl, tetrahydrofuranyl, pyrrolidinyl, N-methylpyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, pyrazolidinyl, morpholino, tetrahydrothienyl 1, 1-dioxide, and the like. Unless otherwise indicated, a heterocyclic group may be attached to a chemical entity or moiety via any one of the ring atoms within the heterocyclic ring system. The heterocyclic moiety of a group (e.g., heterocyclylalkyl) has the same meaning as above.

The term "heteroaryl" refers to an aromatic moiety (e.g., pyridyl, pyrazolyl, indolyl, indazolyl, azaindolyl, thienyl, furyl, benzofuranyl, oxazolyl, isoxazolyl, imidazolyl, tetrazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, isothiazolyl, quinolinyl, isoquinolinyl, benzothienyl, and the like) having at least one heteroatom (e.g., oxygen, sulfur, nitrogen, or a combination thereof) within a 5-to 10-membered aromatic ring system. The heteroaromatic moiety may consist of a single or fused ring system. Typical single heteroaromatic rings are 5-to 6-membered ring systems containing 1-3 heteroatoms independently selected from oxygen, sulfur and nitrogen, and typical fused heteroaromatic ring systems are 9-to 10-membered ring systems containing 1-4 heteroatoms independently selected from oxygen, sulfur and nitrogen. Unless otherwise indicated, a heteroaryl group can be attached to a chemical entity or moiety via any one of the atoms in the aromatic ring system (e.g., imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, imidazol-5-yl). The heteroaryl portion of a group (e.g., heteroarylalkyl) has the same meaning as above.

The term "solvate" refers to a molecular complex of a compound with one or more solvent molecules. As regards solvates of the compounds of formula (I), including prodrugs and pharmaceutically acceptable salts thereof, the solvent molecules are those commonly used in the pharmaceutical field, which are known to be harmless to the receptor, e.g. water, ethanol and the like. The term "hydrate" refers to a solvate in which the solvent molecule is water.

The term "protecting group" or "Pg" refers to a substituent that is commonly used to block or protect a particular functional group while reacting other functional groups on a compound. For example, an "amino-protecting group" is a substituent attached to an amino group that blocks or protects the amino functionality in a compound. Suitable amino-protecting groups include acetyl, trifluoroacetyl, tert-Butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and 9-fluorenylmethoxycarbonyl (Fmoc). Likewise, "hydroxy-protecting group" refers to a substituent on a hydroxy group that blocks or protects the hydroxy functionality. Suitable hydroxy-protecting groups include acetyl and silyl groups. "carboxy-protecting group" refers to a substituent that blocks or protects a carboxy functional group, such as an ester group. Common carboxy-protecting groups include-CH₂CH₂SO₂Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrophenylsulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitroethyl and the like. Protective groups and their use are summarized in T.W.Greene, protective groups in Organic Synthesis, John Wiley& Sons，New York，1991。

The expression "prodrug" refers to a drug precursor compound that, after administration, releases the drug in vivo via some chemical or physiological process (e.g., the prodrug reaches physiological pH or is converted to the desired drug form by enzymatic action).

The phrase "pharmaceutically acceptable" means that the substance or composition is chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or the animal to be treated therewith.

The phrase "therapeutically effective" is intended to quantify the amount of an agent used in the treatment of a disease, condition, or disorder, which (i) treats or prevents a particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein.

The term "treatment" includes both prophylactic and palliative treatment.

The term "animal" refers to humans and all other warm-blooded members of the kingdom animalia that have homeostatic mechanisms, including mammals (e.g., pets, zoo and food-borne animals), and birds. Some examples of pets are dogs (e.g., dogs), cats (e.g., cats) and horses; some examples of food-source animals are pigs, cattle, sheep, poultry, etc. Preferably, the animal is a mammal, preferably the mammal is a human, a pet or a food-source animal. Most preferably, the animal is a human.

The terms "compound of the invention" and the like (unless otherwise specified in detail) refer to compounds of formula (I), as generally and preferably defined above (including all embodiments), prodrugs thereof, pharmaceutically acceptable salts of the compounds and/or prodrugs, and hydrates or solvates of the compounds, salts and/or prodrugs, as well as all stereoisomers, atropisomers, tautomers and isotopically labeled derivatives of the compounds of formula (I).

Detailed description of the invention

In general, the compounds of the invention may be prepared by the methods described herein or by other methods within the ability of those of ordinary skill in the art of medicinal chemistry, including methods analogous to those described in the art for producing compounds similar or analogous to the compounds of the invention or having substituents similar or identical to the compounds of the invention. Certain intermediates and processes for preparing the compounds of the invention are provided as additional features of the invention and are illustrated by the following reaction schemes. These methods may be performed in a sequential or convergent synthesis path. Other methods are described in the experimental section. Purification operations include crystallization and normal or reverse phase chromatography.

In the following discussion relating to the reaction schemes, specific common abbreviations and acronyms are used, which include: AcOH (acetic acid), DMF (dimethyl formamide)Amide), DMSO (dimethyl sulfoxide), NH₄OAc (ammonium acetate), NMP (N-methylpyrrolidone), OTS (p-toluenesulfonyloxy), Pg (protecting group) and THF (tetrahydrofuran).

Scheme I below illustrates one way of preparing compounds of formula (I) wherein E and G are both-N-. In the structures in scheme I below, A, B, X, D, R¹，R²，R³And R⁴Generally and preferably as defined above.

Scheme 1

According to scheme I, the compounds of formula (C) are prepared by coupling a diamine of formula A with a suitable bis-alkoxy acrylate of formula (B), such as ethyl 3, 3-diethoxy acrylate, in the presence of an acid catalyst such as acetic acid, for example, by heating both compounds in a suitable solvent such as toluene or xylene(s). Diamines of formula (a) are commercially available and can be prepared according to methods described in the literature or can be prepared from readily available starting materials by methods analogous to those described in the literature for analogous compounds or by methods within the abilities of one of ordinary skill in the medical chemistry arts.

Then, with alkylating agent R²N-alkylating an imino ether of formula (C) with L, wherein L is a leaving group such as Cl, Br, I or OTs, (e.g., Br in 2-bromo-N-isopropyl-N-phenyl-acetamide), using an inert solvent such as NMP or DMF and a base such as lithium hexamethizazide or sodium hydride, at a temperature of about-20C to about 70 ℃ for about 2 to about 48 hours, provides an N-alkylated imino ether of formula (D).

Alternatively, under the above conditions, the alkylating agent L-CH is used₂CO₂Pg (where L is a leaving group and Pg is a protecting group) such as a 2-haloacetate (e.g., benzyl 2-bromoacetate) alkylates the compound of formula (C) and removesDe-esterification of the protecting group to provide the corresponding carboxylic acid, i.e. wherein R²is-CH₂A compound of formula (D) of COOH. The carboxylic acid compound is then coupled with an amine HNR using standard amide coupling methods⁶R⁷Coupling of provided in which R²is-CH₂C(O)N(R⁶)(R⁷) A compound of formula (D). Then, by reacting a compound of formula (D) with a compound of formula R¹CONHNH₂In an organic solvent, such as glacial acetic acid or toluene, at a temperature of about 0 ℃ to reflux temperature, to cause condensation of the acylhydrazide of (A) wherein R²is-CH₂C(O)N(R⁶)(R⁷) The compound of formula (D) is converted into a triazine derivative of formula (F-1).

Alternatively, the compound of formula (C) is converted to a triazine of formula (E) under the conditions described above for the formation of a triazine ring. The compound of formula (E) is then N-alkylated in the manner described above for the alkylation of the compound of formula (C) to form the compound of formula (F-1).

Using a suitable electrophile such as (R)⁸)(R⁹)(R¹⁰) C-halide or-tosylate (e.g. R)³L wherein R³is-C (R)⁸)(R⁹)(R¹⁰) And L is a leaving group such as Cl, Br, I or OTs), a suitable base such as lithium hexamethyisilazide or sodium hydride, and an inert solvent such as DMF, NMP or THF, at a temperature of about-20 deg.C to about 70 deg.C, to alkylate the compound of formula (F-1) on the C-3 carbon to provide the monoalkylated product of formula (I-1), wherein R is³is-C (R)⁸)(R⁹)(R¹⁰) And R is⁴Is H. Using a suitable base and alkylating agent (e.g., R)⁴L, wherein R⁴Is alkyl or cycloalkyl and L is a leaving group such as Cl, Br, I or OTs) to provide a compound of formula (I-1) wherein R³is-C (R)⁸)(R⁹)(R¹⁰) And R is⁴Is an alkyl or cycloalkyl group. Wherein R is³And R⁴A compound in which one is halogen can be prepared by similarly forming an anion on C-3 with a strong base such as lithium hexamethyisiliazide or sodium hydride in an inert solvent such as DMF, NMP or THF at a temperature of about-78 ℃ to room temperature, followed by reaction with a suitable halogenating agent (e.g.,Br₂，Cl₂(diethylamino) sulfur trifluoride (DAST) or 1- (chloromethyl) -4-fluoro-1, 4-diazania bicyclo [2, 2]Octane bis (tetrafluoroborate) (Selectfluor)^TMAvailable from Air Products and Chemicals, inc., 7201 Hamilton Boulevard, Allentown, PA)) capture the anion to yield a C-3 halogenated compound. Likewise, capture of the C-3 anion with a suitable oxidizing agent, such as 2- (benzenesulfonyl) -3-phenyloxaziridine or oxoperoxy molybdenum (pyridine) (hexamethylphosphoric triamide (MoOPh), can provide a C-3 hydroxy compound, which can then be converted to a C-3 alkoxy compound by O-alkylation under standard conditions with an alkyl halide and a suitable base.

Alternatively, the compound of formula (F-1) is reacted with the aldehyde R in an organic solvent such as toluene or xylene, preferably in the presence of a base such as piperidine, at a temperature ranging from room temperature to reflux temperature¹¹CHO, such as indole-3-carbaldehyde, provides the corresponding α - β unsaturated intermediate (i.e., wherein R is³And R⁴Together to form ═ CHR¹¹) Which can be prepared under standard conditions (e.g., Zn-AcOH; h₂Pd-C) to provide a compound of formula (I-1) wherein R is³And R⁴Is H and R³And R⁴is-CH₂R¹⁰(R¹¹And R¹⁰The same).

The following scheme II illustrates the preparation wherein E is-N-and G is-C (R)⁵) -one mode of the compound of formula (I). In the structure of scheme II below, A, B, X, D, R¹，R²，R³，R⁴And R⁵Generally and preferably as defined above.

Scheme II

According to scheme II, amidines of the formula (G) are prepared by reaction with NH₃Or a source of ammonia (e.g. NH)₄OAc) treating the imino ether of formula (C). The amidines are then reacted under standard conditions with, for example, the formula R¹CH(Br)C(O)R⁵To provide the imidazole of formula (H). Alternatively, the imidoamidine of formula (C) may be reacted with a compound of formula H₂NCH(R⁵)C(O)R¹Condensation of the alpha-aminoketones of (a) to give imidazoles of the formula (H) (see, for example, M.Langlois et al, J.heterocyclic. chem. (1982), 19(1), 193-200).

The imidazole of formula (H) is then N1-alkylated (i.e., R is introduced)²Substituents) using procedures similar to those described above for N-alkylation of compounds of formula (C) or (E) in scheme I, to produce N-alkylated imidazoles of formula (F-2). This compound is then alkylated at C3 using conditions similar to those outlined in scheme I for the conversion of the compound of formula (F-1) to the compound of formula (I-1) to provide the compound of formula (I-2) of scheme II.

The following scheme III illustrates the preparation of compounds wherein E is-C (R)⁵) -and G is-N-is one mode of the compound of formula (I). In the structure of scheme III below, A, B, X, D, R¹，R²，R³，R⁴And R⁵Generally and preferably as defined above.

Scheme III

The compounds of formula (I-3) can be synthesized by methods similar to those reported in the chemical and patent literature for similar or analogous compounds (see, e.g., "Diazepinederivatives," Net. appl., NL 7803585 (1978); Armin Walser, "Imidazodiazepine derivatives," Ger. Offen., DE 2813549 (1978); and Armin Walser and Rodney Ian Fryer, "Imidazo [1, 5-a ] [1, 5] benzodiazepines," U.S.4080323 (1978)). Thus, condensation of a compound of formula (D) with the anion of a nitroalkane, which may be produced by treating the nitroalkane with a strong base such as lithium hexamethyidilide, sodium hydride, potassium tert-butoxide or lithium diisopropylamide in an inert organic solvent such as THF, DMSO or DMF, at a temperature of about-30 ℃ to about 100 ℃ provides a compound of formula (J). This compound is then reduced using a metal catalyst, such as palladium, platinum or nickel, in the presence of hydrogen to provide the compound of formula (K).

Introduction of R using a suitable acylating agent¹The compound of formula (K) is acylated with CO-, e.g., an acid halide/base or a carboxylic acid/coupling reagent (e.g., EDCI, N-carbonyldiimidazole) to provide a compound of formula (L), which is then subjected to standard dehydration ring-closure conditions to yield the compound of formula (M). The oxidation of the compound of formula (M) to produce the compound of formula (F-3) is accomplished using an oxidizing agent such as manganese dioxide or potassium permanganate. The compound of formula (F-3) may be converted to the compound of formula (I-3) in a similar manner as described for the conversion of the compound of formula (F-1) to the compound of formula (I-1) in scheme I.

Conventional methods and/or techniques of isolation and purification known to those of ordinary skill in the art can be used to isolate the compounds of the present invention, as well as various intermediates associated therewith. Such techniques are well known to those of ordinary skill in the art and may include, for example, all types of chromatography (high pressure liquid chromatography (HPLC), column chromatography using common adsorbents such as silica gel, and thin layer chromatography), recrystallization, and differential (i.e., liquid-liquid) extraction techniques.

The compounds of the present invention may be isolated and used as such or in the form of their pharmaceutically acceptable salts, solvates and/or hydrates. The term "salt" includes inorganic and organic salts. These salts can be prepared in situ during the final isolation and purification of the compound or by separately reacting the compound with a suitable inorganic or organic acid or base and isolating the salt thus formed. Salts of the intermediates need not be pharmaceutically acceptable.

Representative pharmaceutically acceptable acid addition salts of the compounds of this invention include the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, acid sulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, pamoate, palmitate, malonate, stearate, laurate, malate, borate, hexafluorophosphate, naphthenate, glucoheptonate, lactobionate, and laurylsulfonate salts, among others. A preferred salt of the compound is the hydrochloride salt.

Salts formed with bases include cations based on alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as ammonium, quaternary ammonium, and 1, 2, or 3 amine-derived cations including, but not limited to, ammonium, tetramethylammonium, and tetraethylammonium, as well as cations derived from methylamine, ethylamine, dimethylamine, trimethylamine, triethylamine, and the like. See, e.g., Berge et al, j.pharm.sci., 66, 1-19 (1977).

The invention also includes prodrugs of the compounds of formula (I). The term "prodrug" as used herein refers to a compound that is converted in vivo to yield a compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate of the compound. This conversion can occur by various mechanisms, such as hydrolysis in blood. Discussion of prodrug use is by t.higuchi and w.stella, "Pro-drugs Novel Delivery Systems," vol.14 of the a.c.s.symposium series; bioreversible Carriers in Drug Design, ed. edward b.roche, American Pharmaceutical Association and pergamon press, 1987; advanced Drug Delivery Reviews, 1996, 19, 115; and j.med.chem.1996, 39, 10.

For example, if a compound of the invention contains a carboxylic acid functional group, a prodrug may contain an ester formed by replacing a hydrogen atom in the acid group with a group such as: such as (C)₁-C₈) Alkyl radical (C)₂-C₁₂) Alkanoyloxymethyl, 1- (alkanoyloxy) ethyl having 4 to 9 carbon atoms, 1-methyl-1- (alkanoyloxy) -ethyl having 5 to 10 carbon atoms, having 3-Alkoxycarbonyloxymethyl of 6 carbon atoms, 1- (alkoxycarbonyloxy) ethyl of 4 to 7 carbon atoms, 1-methyl-1- (alkoxycarbonyloxy) ethyl of 5 to 8 carbon atoms, N- (alkoxycarbonyl) aminomethyl of 3 to 9 carbon atoms, 1- (N- (alkoxycarbonyl) amino) ethyl of 4 to 10 carbon atoms, 3-benzo [ c ] c]Furanone, 4-crotonolactone, gamma-butyrolactone-4-yl, di-N, N- (C)₁-C₂) Alkylamino radical (C)₂-C₃) Alkyl (e.g.. beta. -dimethylaminoethyl), carbamoyl- (C)₁-C₂) Alkyl, N, N-di (C)₁-C₂) Alkylcarbamoyl- (C)₁-C₂) Alkyl and piperidino-, pyrrolidinyl-or morpholino (C)₂-C₃) An alkyl group.

Likewise, if a compound of the invention contains an alcohol functional group, a prodrug may be formed by replacing the hydrogen atom of the alcohol group with a group such as: such as (C)₁-C₆) Alkanoyloxymethyl, 1- ((C)₁-C₆) Alkanoyloxy) ethyl, 1-methyl-1- ((C)₁-C₆) Alkanoyloxy) ethyl group, (C)₁-C₆) Alkoxycarbonyloxymethyl, N- (C)₁-C₆) Alkoxycarbonylaminomethyl, succinyl, (C)₁-C₆) Alkanoyl, alpha-amino (C)₁-C₄) Alkanoyl, aroyl and α -aminoacyl, or α -aminoacyl- α -aminoacyl, wherein each α -aminoacyl is independently selected from a naturally occurring L-amino acid; p (O) (OH)₂，P(O)(O(C₁-C₆) Alkyl) 2 or a glycosyl (the radical resulting from the removal of the hydroxyl group from the hemiacetal form of the carbohydrate).

If a compound of the invention contains an amine functional group, a prodrug may be formed by replacing a hydrogen atom in the amine group with a group such as: such as R-carbonyl-; RO-carbonyl-; (R ') (R) N-carbonyl-wherein R and R' are each independently (C)₁-C₁₀) Alkyl radical (C)₃-C₇) Cycloalkyl or benzyl; or R-carbonyl is a natural alpha-aminoacyl or a natural alpha-aminoacyl-natural alpha-aminoacyl; -C (OH) C (O) OY 'wherein Y' is H, (C)₁-C₆) Alkyl or benzyl; -C (OY)⁰)Y¹Wherein Y is⁰Is (C)₁-C₄) Alkyl and Y¹Is (C)₁-C₆) Alkyl, carboxyl (C)₁-C₆) Alkyl, amino (C)₁-C₄) Alkyl or mono-N-or di-N, N- (C)₁-C₆) An alkylaminoalkyl group; or-C (Y)²)Y³Wherein Y is²Is H or methyl and Y³Is mono-N-or di-N, N- (C)₁-C₄) Alkylamino, morpholino, piperidin-1-yl or pyrrolidin-1-yl.

Many of the compounds and certain intermediates of the invention contain one or more asymmetric or chiral centers (e.g., with R in formula (I))³And R⁴C-3 carbon atom) and thus exist in different stereoisomeric forms (e.g., enantiomers and diastereomers). Many of the compounds of the invention also exhibit atropisomerism. All stereoisomeric forms of the compounds and intermediates of the invention and mixtures thereof, including racemic and diastereomeric mixtures, which possess properties useful in the treatment of the conditions discussed herein or intermediates used in the preparation of compounds having such properties, form part of the invention. Typically, one enantiomer will be more biologically active than the other. However, the less active enantiomer can be converted to the racemic mixture by epimerization at the C-3 stereocenter using a strong base, such as sodium methoxide dissolved in methanol. The racemic mixture can then be separated into individual enantiomers using standard conditions, such as resolution or chiral chromatography. In addition, the present invention includes all geometric isomers and atropisomers. For example, if an intermediate or compound of the present invention contains a double bond or fused ring, both cis-and trans-forms, as well as mixtures, are included within the scope of the present invention.

Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physicochemical differences by methods well known to those skilled in the art, such as chromatography and/or fractional crystallization. Enantiomers can be separated by using a chiral HPLC column. They can also be isolated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., a chiral auxiliary, such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) each diastereomer to the corresponding pure enantiomer.

The compounds and intermediates of the present invention may exist in unsolvated as well as solvated forms with solvents such as water, ethanol, isopropanol, and the like, and both solvated and unsolvated forms are intended to be encompassed within the scope of the present invention. Solvates for use in the method aspect of the invention should be formed with pharmaceutically acceptable solvents.

The various compounds of the invention and intermediates thereof exhibit tautomerism and thus may exist in different tautomeric forms under specific conditions. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that may be interconverted via a low energy barrier. For example, proton tautomers (also referred to as prototropic tautomers) include interconversions via proton transfer, such as keto-enol and imine-enamine isomerizations. A specific example of a proton tautomer is the imidazole moiety, where hydrogen can migrate between ring nitrogens. Valence tautomers include interconversions through structural recombination of certain bonded electrons. All such tautomeric forms (e.g., all keto-enol and imine-enamine forms) are within the scope of the invention. The description herein of any particular tautomeric form in any formula is not intended to be limited to that form, but rather is meant to represent the entire tautomeric set.

The invention also includes isotopically-labelled compounds, which are identical to those of formula (I) or an intermediate thereof, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes which can be incorporated into the intermediates or compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine, e.g. each²H，³H，¹¹C，¹³C，¹⁴C，¹³N，¹⁵N，¹⁵O，¹⁷O，¹⁸O，³¹P，³²P，³⁵S，¹⁸F，¹²³I，¹²⁵I and ³⁶And (4) Cl. Compounds of the present invention, prodrugs thereof, and pharmaceutically acceptable salts, hydrates, and solvates of the compounds and the prodrugs that contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention.

Certain isotopically-labeled compounds of the present invention (e.g., with³H and¹⁴c-labeled those) can be used in compound and/or substrate tissue distribution assays. For their ease of preparation and detection, tritiation (i.e.,³H) and carbon-14 (i.e.,¹⁴C) isotopes are particularly preferred. In addition, the heavy isotopes such as deuterium (i.e.,²H) substitution may produce specific therapeutic benefits due to higher metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and is therefore preferred in certain circumstances. Positron emitting isotopes such as¹⁵O，¹³N，¹¹C, and¹⁸f can be used in Positron Emission Tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of the present invention can generally be prepared by following procedures analogous to those disclosed in the schemes and/or examples herein, wherein an isotopically labeled reagent is substituted for a non-isotopically labeled reagent.

The compounds of the present invention are useful, for example, in the treatment of diseases, conditions and disorders modulated by cholecystokinin a receptor (e.g., CCK-a receptor agonist). Such diseases, conditions and disorders include obesity and gallstones, as well as non-obese overweight conditions and normal weight conditions requiring control or management of body weight to prevent the onset of obesity or an overweight condition or to merely maintain an optimally healthy body weight. And the compounds of the invention are useful in the treatment or prevention of diseases, conditions and disorders which are post-clinical manifestations or comorbidities of obesity, such as hypertension, dyslipidemia, type 2 (non-insulin dependent) diabetes mellitus, insulin resistance, glucose intolerance, hyperinsulinemia, coronary heart disease, angina pectoris, congestive heart failure, stroke, gall stones, cholecystitis, cholelithiasis, gout, osteoarthritis, obstructive sleep apnea and respiratory problems, gall bladder disease, certain forms of cancer (e.g., endometrium, breast, prostate and colon) and psychological disorders (e.g., depression, eating disorders, body distortion and low self-esteem). Furthermore, the compounds of the present invention may be used to treat any condition in which weight loss or reduced food intake is desired.

Accordingly, the present invention provides a method of treating or preventing such diseases, conditions and/or disorders modulated by CCK-A receptor agonists in an animal comprising administering to an animal in need of such treatment a compound of formula (I), preferably a therapeutically effective amount thereof.

The compounds of the present invention are typically administered in the form of pharmaceutical compositions. Accordingly, the present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) in combination with a pharmaceutically acceptable excipient, diluent or carrier, and methods of using such a composition for treating a disease, condition and/or disorder modulated by a CCK-a receptor agonist, or a post-clinical morbidity or comorbidity thereof in an animal comprising administering such a pharmaceutical composition to an animal in need of such treatment.

The compounds of formula (I) and compositions containing them are also useful in the manufacture of medicaments for the therapeutic applications mentioned herein.

The compounds of the present invention may be administered to a patient at dosage levels of from about 0.1mg to about 3,000mg per day. Human doses are generally from about 1mg to about 1,000mg per day; more typically, from about 1mg to about 400mg or 500mg per day; preferably, from about 1mg to about 200mg or 250mg per day; more preferably, from about 1mg to about 75mg or 100mg per day; typically from about 1mg to about 50mg or 60mg per day. The particular dosage and dosage range that may be employed will depend upon a variety of factors including the age and weight of the patient, the mode of administration, the severity of the disease, condition and/or disorder being treated, and the pharmacological activity of the compound being administered. The determination of a dosage range and optimal dosage for a particular patient is within the ability of one of ordinary skill in the art.

The compounds of the present invention may be used in combination with other agents (sometimes referred to herein as "combinations") for the treatment of the diseases, conditions and/or disorders mentioned herein or co-morbidities thereof. Accordingly, the invention also provides methods of treatment comprising administering a compound of the invention in combination with other agents.

Suitable agents which may be used in the combination aspects of the invention include anti-obesity agents such as cannabinoid-1 (CB-1) antagonists (e.g. rimonabant), 11 beta-hydroxysteroid dehydrogenase-1 (11 beta-HSD type 1) inhibitors, peptides YY (PYY) and PYY agonists (e.g. PYY)_3-36) MCR-4 agonists, monoamine reuptake inhibitors (e.g. sibutramine), sympathomimetics, beta₃Adrenergic receptor agonists, dopamine receptor agonists (e.g., bromocriptine), melanocyte stimulating hormone receptor analogs (e.g., those discussed in U.S. patent No.6,716,810), 5HT2c receptor agonists, melanin concentrating hormone antagonists, leptin (OB protein), leptin receptor agonists, somatotropin neuropeptide antagonists, lipase inhibitors (e.g., lipstatin, orlistat), bombesin receptor agonists, neuropeptide-Y (NPY) receptor antagonists (e.g., NPY Y5 receptor antagonists), thyromimetic agents, dehydroepiandrosterone, glucocorticoid receptor agonists or antagonists, orexin receptor antagonists, glucagon-like peptide-1 receptor agonists, ciliary neurotrophic factors (e.g., Axokine)^TMFrom Regeneron Pharmaceuticals, Inc., Tarrytown, NY and Procter&Gamble Company, Cincinnati, OH), human agouti-related protein (AGRP) antagonists, ghrlin receptor antagonists, histamine 3 receptor antagonists or inverse agonists, neuregulin U receptor agonists, MTP/ApoB secretion inhibitors, T-type calcium channel blockers (e.g., zonisamide), opioid receptor antagonists (e.g., those discussed in PCT patent application publication nos. WO 03/101963 and WO 2004/026305), and the like.

Preferred NPY receptor antagonists include NPYY5 receptor antagonists, such as those described in US patent nos. 6,566,367; 6,649,624, respectively; 6,638,942, respectively; 6,605,720, respectively; 6,495,559, respectively; 6,462,053, respectively; 6,388,077, respectively; 6,335,345 and 6,326,375; U.S. patent application publication nos. 2002/0151456 and 2003/036652 and PCT patent application publication No. wo 03/010175; spiro compounds as described in WO 03/082190 and WO 02/048152. All references cited above are incorporated herein by reference.

Preferred anti-obesity agents include orlistat (U.S. Pat. No.5,274,143; 5,420,305; 5,540,917; and 5,643,874), sibutramine (U.S. Pat. No.4,929,629), bromocriptine (U.S. Pat. Nos. 3,752,814 and 3,752,888), ephedrine, leptin, pseudoephedrine, zonisamide (U.S. Pat. No.4,172,896), and peptide YY3-36 or an analog or derivative thereof (U.S. Pat. application publication No.2002/0141985 and PCT patent application publication No. WO 03/026591, all references cited above are incorporated herein by reference.

The compounds of the present invention may also be used in combination with other agents (e.g., LDL-cholesterol lowering agents, triglyceride lowering agents) to treat the diseases/conditions mentioned herein. For example, the compounds of the present invention may be used in combination with HMG-CoA reductase inhibitors (e.g., atorvastatin, simvastatin, fluvastatin, pravastatin, cervastatin, rosuvastatin or pitavastatin), HMG-CoA synthase inhibitors, HMG-CoA reductase gene expression inhibitors, squalene synthetase/cyclooxygenase/cyclase inhibitors, cholesterol synthesis inhibitors, cholesterol absorption inhibitors (e.g., ezetimibe), CETP inhibitors (e.g., torcetrapib), PPAR modulators or other cholesterol lowering agents such as fibrates, nicotinic acid, ion-exchange resins, antioxidants, ACAT inhibitors (e.g., avasimibe, CS-505(Sankyo) and eflucimibe) or bile acid sequestrants. Other agents useful in practicing the combination aspects of the invention include bile acid reuptake inhibitors, ileal bile acid transporter inhibitors, ACC inhibitors, antihypertensive agents (e.g., Norvasc ®), antibiotics, antidiabetic agents (e.g., metformin, pfenformin or buformin), PPAR γ activators, insulin secretagogues (e.g., sulfonylureas and glinides), insulin, Aldose Reductase Inhibitors (ARIs) (e.g., zopolrestat, Sorbitol Dehydrogenase Inhibitors (SDI)), and anti-inflammatory agents such as aspirin or anti-inflammatory agents that preferably inhibit cyclooxygenase-2 (Cox-2) to a greater extent than cyclooxygenase-1 (Cox-1), such as celecoxib (U.S. Pat. No.5,466,823), valdecoxib (U.S. Pat. No.5,633,272), parecoxib (U.S. Pat. No.5,932,598), deracoxib (CAS RN 90-41-4), CAS 959590-16990-16901), etoricoxib (CAS RN 202409-33-4) or lumiracoxib (CASRN 220991-20-8).

The compounds of the present invention may also be administered in combination with naturally occurring substances that lower plasma cholesterol levels. These naturally occurring materials are commonly referred to as nutraceuticals and include, for example, garlic extract, Hoodia plant extract, and niacin. Sustained release forms of niacin are commercially available under the trade name Niaspan. Nicotinic acid may also be administered in combination with other therapeutic agents such as lovastatin, which is an HMG-CoA reductase inhibitor. This combination therapy is known as Advicor^®(KosPharmaceuticals Inc.)。

The compounds of formula (I) of the present invention may also be used in combination with an antihypertensive agent. Preferred antihypertensive agents include calcium channel blockers such as Cardizem^®，Adalat^®，Calan^®，Cardene^®，Covera^®，Dilacor^®，DynaCirc^®’Procardia XL^®，Sular^®，Tiazac^®，Vascor^®，Verelan^®，Isoptin^®，Nimotop^®’Norvasc^®And Plendil^®(ii) a Angiotensin Converting Enzyme (ACE) inhibitors, e.g. Accupril^®，Altace^®，Captopril^®，Lotensin^®，Mavik^®，Monopril^®，Prinivil^®，Univasc^®，Vasotec^®And Zestiil^®。

Diabetes (particularly type II), insulin resistance, impaired glucose tolerance, and the like can be treated by administering a therapeutically effective amount of a compound of formula (I), preferably in combination with one or more other agents useful in the treatment of diabetes (e.g., insulin).

Any glycogen phosphorylase inhibitor may be used as the second agent in combination with the compounds of formula (I) according to the present invention. The term glycogen phosphorylase inhibitor refers to a compound that inhibits the biotransformation of glycogen to glucose-1-phosphate, which conversion is catalyzed by the enzyme glycogen phosphorylase. This glycogen phosphorylase inhibitory activity is readily determined by standard assays well known in the art (e.g., J.Med.chem.41(1998) 2934-. Glycogen phosphorylase inhibitors of interest herein include those described in PCT patent application publication nos. WO 96/39384 and WO 96/39385. The references cited above are incorporated herein by reference.

Aldose reductase inhibitors may also be used in the practice of the combination aspects of the invention. These compounds inhibit the bioconversion of glucose to sorbitol, which is catalyzed by the enzyme aldose reductase. Aldose reductase inhibition is readily determined by standard assays (e.g., J.Malone, Diabetes, 29: 861-A864 (1980) 'Red Cell sorbent, an indicator of Diabetes Control', incorporated herein by reference). Various aldose reductase inhibitors are known to those skilled in the art. The references cited above are incorporated herein by reference.

Any sorbitol dehydrogenase inhibitor may be used in combination with the compounds of formula (I) of the present invention. The term sorbitol dehydrogenase inhibitor refers to a compound that inhibits the bioconversion of sorbitol to fructose, catalyzed by the enzyme sorbitol dehydrogenase. Such sorbitol dehydrogenase inhibitor activity is readily determined by using standard assays well known in the art (e.g., Analyt. biochem (2000) 280: 329-331). Sorbitol dehydrogenase inhibitors of interest include those disclosed in U.S. patent nos. 5,728,704 and 5,866,578. The references cited above are incorporated herein by reference.

Any glucosidase inhibitor may be used in the combination aspect of the invention. Such compounds inhibit the enzymatic hydrolysis of complex carbohydrates to bioavailable simple sugars, such as glucose, by a glucoside hydrolase, such as amylase or maltase. The rapid metabolic action of glucosidase, particularly after ingestion of high levels of sugar, results in a dietetic hyperglycemic state, which in obese or diabetic subjects results in enhanced insulin secretion, increased fat synthesis and reduced fat degradation. Following this hyperglycemia, hypoglycemia frequently occurs due to the increased levels of insulin present. In addition, chyme remaining in the stomach is known to promote gastric juice production, which causes or promotes the occurrence of gastritis or duodenal ulcer. Therefore, glucosidase inhibitors are known to have utility in accelerating the passage of sugars through the stomach and inhibiting the absorption of glucose in the intestine. In addition, the conversion of sugars to lipids in adipose tissue and the subsequent incorporation of dietary fat into the adipose tissue deposits is thereby reduced or delayed with the concomitant benefit of reducing or preventing the deleterious abnormalities that result therefrom. Such glucosidase inhibitory activity is readily determined by those skilled in the art according to standard assays (e.g., Biochemistry (1969) 8: 4214), which are incorporated herein by reference.

Generally preferred glucosidase inhibitors include amylase inhibitors. An amylase inhibitor is a glucosidase inhibitor that inhibits the enzymatic degradation of starch or glycogen to maltose. This amylase inhibitory activity can be readily determined using standard assays (e.g., methods enzymol. (1955) 1: 149, incorporated herein by reference). Inhibition of this enzymatic degradation is beneficial in reducing the amount of bioavailable sugars, including glucose and maltose, and mitigating the concomitant harmful conditions that result therefrom.

Preferred glucosidase inhibitors include acarbose, lipolytics, voglibose, miglitol, emiglitate, canaglibose, tendamistat, trestatin, pradimicin-Q and salbostatin. The glucosidase inhibitor acarbose and various aminosugar derivatives related thereto are disclosed in U.S. patent nos. 4,062,950 and 4,174,439, respectively. The glucosidase inhibitor lipolytic enzyme is disclosed in U.S. patent No.4,254,256. The glucosidase inhibitor voglibose (3, 4-dideoxy-4- [ [ 2-hydroxy-1- (hydroxymethyl) ethyl ] amino-2-C- (hydroxymethyl) -D-epi-inositol) and various N-substituted pseudo-aminosugars related thereto are disclosed in U.S. patent No.4,701,559. The glucosidase inhibitor miglitol ((2R, 3R, 4R, 5S) -1- (2-hydroxyethyl) -2- (hydroxymethyl) -3, 4, 5-piperidinetriol) and the various 3, 4, 5-trihydroxypiperidines related thereto are disclosed in U.S. patent No.4,639,436. The glucosidase inhibitor, etoglitate (ethyl p- [2- [ (2R, 3R, 4R, 5S) -3, 4, 5-trihydroxy-2- (hydroxymethyl) piperidino ] ethoxy ] -benzoate), various derivatives related thereto, and pharmaceutically acceptable acid addition salts thereof are disclosed in U.S. patent No.5,192,772. The glucosidase inhibitor MDL-25637(2, 6-dideoxy-7-O- β -D-glucopyranosyl-2, 6-imino-D-glycero-L-glucoheptitol), various homo-disaccharides related thereto and pharmaceutically acceptable acid addition salts thereof are disclosed in U.S. patent No.4,634,765. The glucosidase inhibitor, canglibose (methyl 6-deoxy-6- [ (2R, 3R, 4R, 5S) -3, 4, 5-trihydroxy-2- (hydroxymethyl) piperidino ] -a-D-glucopyranoside sesquihydrate), its related deoxy-nojirimycin derivatives, various pharmaceutically acceptable salts thereof and synthetic methods for their preparation are disclosed in U.S. patent nos. 5,157,116 and 5,504,078. The glycosidase inhibitor salcostatin and various pseudo sugars related thereto are disclosed in U.S. patent No.5,091,524. All documents cited above are incorporated herein by reference.

Amylase inhibitors of interest herein are disclosed in U.S. patent No.4,451,455, U.S. patent No.4,623,714(AI-3688 and the various cyclic polypeptides associated therewith) and U.S. patent No.4,273,765 (trestatins consisting of a mixture of trestatins a, B and C, and the various trehalose-containing aminosugars associated therewith). All documents cited above are incorporated herein by reference.

The dosage of the additional agent will generally depend upon a variety of factors including the health of the subject being treated, the degree of treatment desired, the nature and kind of concomitant therapy, if any, and the frequency of treatment and nature of the effect desired. Generally, the dosage range of the additional agent is from about 0.001mg to about 100mg/Kg of body weight of the subject per day, preferably from about 0.1mg to about 10mg/Kg of body weight of the subject per day. However, depending on the age and weight of the subject being treated, the intended route of administration, the particular anti-obesity agent being administered, etc., some variation from the general dosage range may also be required. Determination of dosage ranges and optimal dosages for a particular patient also falls within the ability of one of ordinary skill in the art having the benefit of the present disclosure.

In accordance with the treatment methods of the present invention, a compound or combination of the present invention is administered to a subject in need of such treatment, preferably in the form of a pharmaceutical composition. In the combined aspects of the invention, the compounds of the invention may be administered separately from the other agents or in the form of a pharmaceutical composition comprising both. It is generally preferred that such administration be oral.

When a combination of a compound of the present invention and at least one other agent is administered together, such administration may be sequential in time or simultaneous. Simultaneous administration of the combination of drugs is generally preferred. For sequential administration, the compound of the invention and the additional agent may be administered in any order. It is generally preferred that such administration be oral. It is particularly preferred that such administration is oral and simultaneous. When the compound of the present invention and the additional agent are administered sequentially, the respective administrations may be carried out by the same or different methods.

Thus, the compounds or combinations of the present invention may be administered to a patient separately or together in any conventional oral, rectal, transdermal, parenteral (e.g., intravenous, intramuscular, or subcutaneous), intracisternal, intravaginal, intraperitoneal, topical (e.g., powders, ointments, creams, sprays, or lotions), buccal, or nasal dosage form (e.g., sprays, drops, or inhalants).

The compounds or combinations of the present invention are generally administered in admixture with one or more suitable pharmaceutical excipients, diluents or carriers which are known in the art and which are selected with regard to the intended route of administration and standard pharmaceutical practice. The compounds or combinations of the present invention may be formulated to provide immediate-, delayed-, modified-, sustained-, pulsed-or controlled-release dosage forms, depending on the desired route of administration and the specificity of the release profile, to match the therapeutic need.

The pharmaceutical compositions contain the compounds or combinations of the present invention in an amount generally from about 1% to about 75%, 80%, 85%, 90% or even 95% by weight of the composition, typically from about 1%, 2% or 3% to about 50%, 60% or 70%, more typically from about 1%, 2% or 3% to less than 50%, such as about 25%, 30% or 35%.

Methods for preparing various pharmaceutical compositions containing a specific amount of an active compound are known to those skilled in the art. See, for example, Remington: ihe Practice of Pharmacy, Lippincott Williams and Wilkins, Baltimore MD, 20th ed.2000.

Compositions suitable for parenteral injection typically include pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous or nonaqueous carriers or diluents (including solvents and excipients) include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, and the like), suitable mixtures thereof, triglycerides including vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Preferably the carrier is Miglyol^®Caprylic/capric acid esters of glycerol or propylene glycol (e.g., Miglyol)^®812，Miglyol^®829，Miglyol^®840) Obtained from Condea Vista co., Cranford, NJ. Maintenance of suitable fluidity can be achieved, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

These compositions for parenteral injection may also contain excipients such as preservatives, wetting agents, emulsifying agents, and dispersing agents. The composition for preventing microbial contamination can be carried out using various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example, sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical composition can be brought about by the use of agents capable of delaying absorption, for example, aluminum monostearate and gelatin.

Solid dosage forms for oral administration include capsules, tablets, chewables, lozenges, pills, powders, and multiparticulate (granular) formulations. In such solid dosage forms, the compound or combination of the present invention is admixed with at least one inert excipient, diluent or carrier. Suitable excipients, diluents or carriers include materials such as sodium citrate or dicalcium phosphate and/or (a) fillers or fillers (e.g.,microcrystalline cellulose (Avicel)^TMAvailable from FMC corp.), starch, lactose, sucrose, mannitol, silicic acid, xylitol, sorbitol, glucose, calcium hydrogen phosphate, dextrin, α -cyclodextrin, β -cyclodextrin, polyethylene glycol, medium-chain fatty acid, titanium dioxide, magnesium oxide, aluminum oxide, etc.); (b) a binder (e.g., carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, gelatin, gum arabic, ethyl cellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, tragacanth, alginate, gelatin, polyvinylpyrrolidone, sucrose, gum arabic, etc.); (c) humectants (e.g., glycerin, etc.); (d) disintegrating agents (e.g., agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, sodium carbonate, sodium lauryl sulfate, sodium starch glycolate (Explotab @^TMAvailable from Edward Mendell Co.), crospovidone, croscarmellose sodium type A (Ac-di-sol)^TM) Polyacrilin potassium (ion exchange resin), etc.); (e) dissolution retarders (e.g., paraffin, etc.); (f) absorption accelerators (e.g., quaternary ammonium compounds, etc.); (g) wetting agents (e.g., cetyl alcohol, glycerol monostearate, and the like); (h) adsorbents (e.g., kaolin, bentonite, etc.); and/or (i) lubricants (e.g., talc, calcium stearate, magnesium stearate, stearic acid, polyoxyl stearate, cetyl alcohol, talc, hydrogenated castor oil, sucrose fatty acid ester, dimethylpolysiloxane, microcrystalline wax, yellow beeswax, white beeswax, solid polyethylene glycol, sodium lauryl sulfate, etc.). In the case of capsules and tablets, the dosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers in soft or hard-filled gelatin capsules using such excipients, diluents or carriers as lactose, and high molecular weight polyethylene glycols and the like.

Solid dosage forms such as tablets, dragees, capsules, and granules can be prepared with coatings and shells such as enteric coatings and others well known in the art. They may also contain opacifying agents and may also have a composition that releases the compound of the invention and/or additional agent(s) in a delayed manner. Examples of embedding compositions which can be used are polymeric substances and waxes. The medicament may also be in microencapsulated form, if appropriate with one or more of the excipients, diluents or carriers described above.

In the case of tablets, the active agent will generally comprise less than 50% by weight of the formulation, for example less than about 10% such as 5% or 2.5% by weight. The main part of the formulation comprises excipients, diluents or carriers such as fillers, disintegrants, lubricants and optionally flavouring agents. The composition of these excipients is well known in the art. Typically, the filler/diluent comprises a mixture of two or more of the following components: microcrystalline cellulose, mannitol, lactose (any/all types), starch, and dicalcium phosphate. The excipient, diluent or carrier mixture typically comprises less than about 98% and preferably less than about 95%, for example about 93.5% of the formulation. Preferred disintegrants include Ac-di-sol^TM，Explotab^TMStarch and sodium lauryl sulfate. When present, disintegrants typically comprise less than about 10% or less than about 5%, for example about 3% of the formulation. When present, lubricants typically comprise less than about 5% or less than about 3%, for example about 1%, of the formulation. A preferred lubricant is magnesium stearate.

Tablets may be manufactured by standard tableting processes, such as direct compression or wet compression, dry or melt granulation, melt congealing processes and extrusion. The core may be single-layered or multi-layered and may be coated with suitable coatings known in the art.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the compounds or combinations of the present invention, the liquid dosage forms may contain inert excipients, diluents or carriers commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, dimethylformamide, oils (e.g., cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, sesame oil and the like), Miglyol^®(obtained from CONDEAVISTA Co., Cranford, NJ.), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and sorbitan fatty acid esters, or mixtures of these substances, and the like.

In addition to such inert excipients, diluents or carriers, the compositions may also include wetting agents, emulsifying and/or suspending agents and sweetening, flavoring and/or perfuming agents.

Oral liquid forms of the compounds or combinations of the invention include solutions wherein the active compound is completely dissolved. Examples of solvents include all pharmaceutically customary solvents suitable for oral administration, in particular those in which the compounds of the invention exhibit good solubility, for example polyethylene glycol, polypropylene glycol, edible oils and systems based on glyceryl-and glyceryl esters-. Glyceryl-and glyceride-based systems may include, for example, the following trademarked products (and corresponding generic products): captex^TM355 EP (tricaprylin/tricaprin from Abitec, ColumbusOH), Crodamol^TMGTC/C (medium chain triglycerides, from Croda, Cowick Hall, UK) or Labrafac^TMCC (Medium chain Triglycerides, from Gattefose), Captex^TM500P (glyceryl triacetate, i.e., triacetin, from Abitec), Capmul^TMMCM (medium chain mono-and diglycerides from Abitec), Migyol^TM812 (caprylic/capric triglyceride from Condea, Cranford NJ), Migyol^TM829 (caprylic/capric/succinic triglycerides, from Condea), Migyol^TM840 (propylene glycol dicaprylate/dicaprate from Condea), Labrafil^TMM1944CS (oleoyl macrogol-6 glycerides, from Gattefose), Peceol^TM(Glycerol monostearate from Gattefose) and Maisine^TM35-1 (glyceryl monooleate, from Gattefose). Of particular interest are medium chains (about C)₈-C₁₀) A triglyceride oil. These solvents often constitute the major part of the composition, i.e. more than about 50%, usually more than about 80%, such as about 95%, 97% or 99%. Other excipients, diluents or carriers may also be included in the solvent, primarily as taste masking agents, palatability and flavoring agents, antioxidants, stabilizers, texture and viscosity modifiers, solubilizers, and the like。

In addition to the compounds or combinations of the present invention, the suspensions may contain excipients, diluents or carriers such as suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, or mixtures of these substances, and the like.

Compositions for rectal or vaginal administration preferably comprise suppositories which can be prepared by mixing the compounds or combinations of the invention with suitable non-irritating excipients, diluents or carriers such as cocoa butter, polyethylene glycol or a suppository wax, which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity, thereby releasing the active ingredient.

Dosage forms for topical administration of the compounds or combinations of the present invention include ointments, creams, lotions, powders and sprays. The medicament is mixed with a pharmaceutically acceptable excipient, diluent or carrier, and any preservatives, buffers, or propellants that may be required or desired.

For any compound of the present invention that is poorly soluble in water, e.g., less than about 1 μ g/mL, a liquid composition dissolved in a solubilizing non-aqueous solvent such as the medium chain triglyceride oils discussed above is a preferred dosage form. Solid amorphous dispersions, including those formed by spray-drying processes, are also preferred dosage forms for the less soluble compounds of the present invention. By "solid amorphous dispersion" is meant a solid substance in which at least a portion of the less soluble compound is in an amorphous form and is dispersed in a water-soluble polymer. By "amorphous" is meant that the less soluble compound is not crystalline. By "crystalline" is meant that the compound exhibits long range order in three dimensions of at least 100 repeat units in each dimension. Thus, the term amorphous is intended to include not only substantially disordered materials, but also materials that may have some lesser degree of order, but which order is less than three-dimensional and/or ordered only over a short distance. Amorphous materials can be characterized by techniques known in the art, such as powder x-ray diffraction (PXRD) crystallography, solid state NMR, or thermal techniques such as Differential Scanning Calorimetry (DSC).

Preferably, at least a major portion (i.e., at least about 60 weight percent) of the less soluble compound in the solid amorphous dispersion is amorphous. The compound may be present in relatively pure amorphous domains or regions within the solid amorphous dispersion, as a solid solution with the compound uniformly distributed throughout the polymer, or any combination of these states or those states lying between them. Preferably, the solid amorphous dispersion is substantially homogeneous, such that the amorphous compound is dispersed as homogeneously as possible in the polymer. As used herein, "substantially homogeneous" means that the portion of the compound present in the relatively pure amorphous domains or regions within the solid amorphous dispersion is relatively small, on the order of less than about 20% by weight, and preferably less than about 10% by weight, of the total amount of drug.

Water-soluble polymers suitable for use in the solid amorphous dispersion should be inert, meaning that they do not chemically react in an adverse manner with poorly soluble compounds, are pharmaceutically acceptable, and have at least some solubility in aqueous solution at physiologically relevant pH (e.g., 1-8). The polymer may be neutral or ionizable and should have a water solubility of at least 0.1mg/mL over at least a portion of the pH range of 1-8.

Water-soluble polymers suitable for use in the present invention may be cellulosic or non-cellulosic. The polymer may be neutral or ionizable in aqueous solution. Among these, ionizable and cellulosic polymers are preferred, and ionizable cellulosic polymers are more preferred.

Exemplary water-soluble polymers include hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose phthalate (HPMCP), carboxymethyl ethylcellulose (CMEC), Cellulose Acetate Phthalate (CAP), Cellulose Acetate Trimellitate (CAT), polyvinylpyrrolidone (PVP), hydroxypropyl cellulose (HPC), Methylcellulose (MC), block copolymers of ethylene oxide and propylene oxide (PEO/PPO, also known as poloxamers), and mixtures thereof. Particularly preferred polymers include HPMCAS, HPMC, HPMCP, CMEC, CAP, CAT, PVP, poloxamer, and mixtures thereof. Most preferred is HPMCAS. See European patent application publication No. 0901786A 2, the contents of which are incorporated herein by reference.

The solid amorphous dispersion may be prepared according to any method that forms a solid amorphous dispersion that results in at least a majority (at least 60%) of the less soluble compound being in an amorphous state. Such methods include mechanical, thermal and solvent methods. Exemplary mechanical methods include milling and extrusion; melting methods include high temperature fusion, solvent-modified fusion and melt-congealing methods; and solvent methods including non-solvent precipitation, spray coating and spray drying. See, for example, the following U.S. patents, the relevant contents of which are incorporated herein by reference: U.S. Pat. Nos. 5,456,923 and 5,939,099, which describe forming dispersions by an extrusion process; nos. 5,340,591 and 4,673,564, which describe the formation of dispersions by a milling process; and nos. 5,707,646 and 4,894,235, which describe the formation of dispersions by the melt-congealing method. In a preferred process, the solid amorphous dispersion is formed by spray drying, as disclosed in european patent application publication No. 0901786 a 2. In this process, the compound and polymer are dissolved in a solvent such as acetone or methanol, and the solvent in the solution is rapidly removed by spray drying, thereby forming a solid amorphous dispersion. The solid amorphous dispersion can be prepared to contain up to about 99 wt% of the compound, e.g., 1 wt%, 5 wt%, 10 wt%, 25 wt%, 50 wt%, 75 wt%, 95 wt%, or 98 wt%, as desired.

The solid dispersion may be used as a dosage form per se, or it may be used as a manufacture-use-product (MUP) in the preparation of other dosage forms such as capsules, tablets, solutions or suspensions. An example of an aqueous suspension is a 1: 1(w/w) compound/HPMCAS-HF spray dried dispersion of 2.5mg/mL compound in 2% polysorbate-80. Solid dispersions for use in tablets or capsules can generally be mixed with other excipients or adjuvants typically found in such dosage forms. For example, an exemplary filler for a capsule contains 21(w/w) Compound/HPMCAS-MF spray-dried Dispersion (60%), lactose (fast flow) (15%), microcrystalline cellulose (e.g. Avicel)^(R0-102) (15.8%), sodium starch (7%), sodium lauryl sulfate (2%) and magnesium stearate (1%).

The available low, medium and high HPMCAS polymers are Aqoat, respectively^(R)-LF，Aqoat^(R)-MF and Aqoat^(R)HF, available from Shin-Etsu Chemical Co., LTD, Tokyo, Japan. Higher MF and HF stages are generally preferred.

The pharmaceutical composition may be packaged for use in a variety of ways depending on the method of administration of the pharmaceutical composition. Generally, articles for dispensing include containers having pharmaceutical preparations in a suitable form contained therein. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), pouches, ampoules, plastic bags, metal cylinders and the like. The container may also include a protective device to prevent inadvertent access to the contents of the package. In addition, the container has a label disposed thereon that describes the contents of the container. The tag may also include appropriate warnings.

Application in veterinary medicine

The following paragraphs describe exemplary formulations, dosages, etc. for animals other than humans. Administration of the compounds of the invention and combinations of the compounds of the invention and anti-obesity agents may be carried out orally or non-orally.

The amount of the compound of the present invention or the combination of the compound of the present invention and the anti-obesity agent administered is an effective dose. Typically, the daily dose orally administered to an animal is from about 0.01 to about 1,000mg/kg body weight, for example from about 0.01 to about 300mg/kg or from about 0.01 to about 100mg/kg or from about 0.01 to about 50mg/kg, or from about 0.01 to about 25mg/kg, or from about 0.01 to about 10mg/kg or from about 0.01 to about 5mg/kg body weight.

For convenience, the compounds (or combinations) of the present invention may be placed in drinking water to take up a therapeutic dose of the compound with the daily supply of water. The compound can be metered directly into the drinking water, preferably in the form of a liquid water-soluble concentrate (e.g., an aqueous solution of a water-soluble salt).

For convenience, the compounds (or combinations) of the invention may also be added directly to the feed, either as such or in the form of an animal feed supplement, the latter also being referred to as a premix or concentrate. Premixes or concentrates of compounds in excipients, diluents or carriers are more commonly used to entrain agents in feed. Suitable excipients, diluents or carriers are, as required, liquids or solids, such as water, various meals, such as alfalfa meal, soybean meal, cottonseed oil meal, linseed oil meal, corncob meal and corn meal, molasses, urea, bone meal, and meal mixtures (as are commonly used in poultry feed). Particularly effective excipients, diluents or carriers are the respective animal feed itself; i.e. a small portion of such feed. The carrier may help to distribute the compound evenly throughout the final feed into which the premix is incorporated. Preferably, the compound is fully incorporated into the premix and subsequently mixed into the feed. In this regard, the compound may be dispersed or dissolved in a suitable oily carrier such as soybean oil, corn oil, cottonseed oil, etc., or a volatile organic solvent, and then mixed with the carrier. It will be appreciated that the proportion of the compound in the concentrate can vary widely, as the amount of compound in the final feed can be adjusted by mixing the premix with the feed in appropriate proportions to achieve the desired level of compound.

The high efficiency concentrate can be mixed with a protein carrier, such as soybean oil meal and other meals, by the feed manufacturer, as described above, to produce a concentrated supplement that is suitable for direct feeding to an animal. In this case, the animals are allowed to ingest the usual diet. Alternatively, such concentrated supplements may be added directly to the feed to produce a nutritionally balanced final feed containing therapeutically effective levels of the compounds of the invention. The mixture is thoroughly mixed by standard procedures, such as in a double shell blender, to ensure homogeneity.

If the supplement is used as a top dressing on the feed, it can also help ensure that the compound is evenly distributed over the top of the fattened feed.

Drinking water and feed effective for increasing lean meat deposition and improving lean meat to fat ratio are generally prepared by mixing the compounds of the present invention with sufficient animal feed to provide about 10 in the feed or water^-3-about 500ppm of compound.

Preferred medicated pig, cattle, sheep and goat feed will generally contain from about 1 to about 400 grams of a compound (or combination) of the invention per ton of feed, with an optimum amount for these animals generally being from about 50 to about 300 grams per ton of feed.

Preferred poultry and domestic pet feeds will generally contain from about 1 to about 400 grams and preferably from about 10 to about 400 grams of a compound (or combination) of the invention per ton of feed.

The compounds of the present invention can be administered to animals parenterally. Pellets or standard injection solutions or suspensions are used for parenteral administration. Generally, parenteral administration comprises injecting a compound (or combination) of the invention in an amount sufficient to provide about 0.01 to about 20mg of drug per kg of body weight per day to the animal. The preferred dosage for poultry, swine, cattle, sheep, goats and domestic pets is from about 0.05 to about 10mg of drug per kg of body weight per day.

The compounds (or combinations) of the present invention may be prepared in pellet form and administered as an implant, typically under the skin of the head or ear of an animal, in order to seek to increase lean meat deposition and improve the lean meat to fat ratio in said animal.

Pellets containing an effective amount of a compound, pharmaceutical composition, or combination of the present invention may be prepared by mixing a compound or combination of the present invention with a diluent such as polyethylene glycol, carnuba wax, or the like, and a lubricant such as magnesium stearate or calcium stearate may be added to improve the granulation process.

Of course, it will be appreciated that more than one pellet may be administered to an animal to achieve a desired dosage level, which may be desirable to increase lean meat deposition and improve the lean meat to fat ratio. In addition, implantation may be performed periodically during treatment of the animal in order to maintain appropriate levels of the drug in the animal.

The compounds of the present invention can also be orally administered to animals other than humans, for example, companion animals such as dogs, cats and horses, and food-source animals, in the same dosage forms as those used by humans, such as tablets, capsules, solutions, suspensions, pastes, powders, and the like.

Pastes can be prepared by dispersing the drug in a pharmaceutically acceptable oil such as peanut oil, sesame oil, corn oil, etc.

The present invention has several beneficial veterinary features. The present invention provides a means to accomplish this for the pet owner or veterinarian who wishes to increase lean and/or reduce excess fat in the pet. For poultry, cattle and pig breeders, more lean animals can be produced using the method of the invention, resulting in higher selling prices from the meat industry.

Embodiments of the present invention are illustrated by the following examples. However, it is to be understood that embodiments of the invention are not limited to the specific details of these examples, and that other modifications are known or will be apparent to those of ordinary skill in the art in view of this disclosure.

Examples

Unless otherwise indicated, starting materials are generally obtained from commercial sources such as Aldrich chemical sCo. (Milwaukee, Wis.), Lancaster Synthesis, Inc. (Windham, NH), Acros Organics (Fairlawn, NJ), Maybridge chemical company, Ltd. (Cornwall, England), Tyger Scientific (Princeton, NJ) and AstraZeneca Pharmaceuticals (London, England) or can be prepared from readily available materials using methods known to those of ordinary skill in the art.

General experimental procedures

NMR spectra at 400 and 500MHz, respectively¹H, at room temperature, at Varian Unity^TM400 (available from Varian inc., Palo Alto, CA). Chemical shift relative to as internal referenceExpressed as per percent (ppm) of residual solvent. The peak shape is represented as follows: s, singlet; d, double peak; t, three peaks; q, four peaks; m, multiplet; brs, broad singlet; vbr s, very broad singlet; brm broad multiplet. In some cases, only representative are given¹H NMR peaks.

Mass spectra were recorded by direct flow analysis using a positive and negative atmospheric pressure chemical ionization (APcI) scan mode. A Waters APcI/MS model ZMD mass spectrometer equipped with a Gilson 215 liquid handling system was used to perform the experiments.

Mass spectrometry can also be obtained by RP-HPLC gradient methods of chromatographic separation. Molecular weight determinations were recorded by positive and negative electrospray ionization (ESI) scan patterns. A Waters/Micromass ESI/MS model ZMD or LCZ mass spectrometer (Waters corp., Milford, MA) equipped with a Gilson 215 liquid treatment system (Gilson, inc., Middleton, WI) and HP 1100 dad (hewlett packard) was used to perform the experiments.

When describing the strength of chlorine or bromine containing ions, the expected strength ratio (to the chlorine or bromine containing ions) is observed³⁵Cl/³⁷About 3: 1 for Cl-ions, for⁷⁹Br/⁸¹About 1: 1 for the ion of Br-), giving only ions of lower mass. Optical rotation was measured using sodium D-line (. lamda. ═ 589nm) at the indicated temperature in Perkinelmer^TM241 polarimeters (available from perkin elmer inc., welllesley, MA) and reported below [ alpha ]]_D ^{Temperature of}Concentration (c ═ g/100mL), and solvent.

Baker is used in column chromatography^TMSilica Gel (40 μm, J.T.Baker, Phillipsburg, NJ) or Silica Gel 50(EM Sciences)^TMGibbstown, NJ) on glass columns, Biotage^TMIn a column (Biotage, inc., Charlottesville, USA) or under low nitrogen pressure using an Isco Combiflash Separation System. Radial chromatography using Chromatotron^TM(Harrison Research). Selection purification was performed using Shimadzu Preparation Liquid Chromatography. Chiral separation was performed using a Chirlapak AD, (S, S) -Whelk-O1 or Chiralcel OD column. Introduction of "enantiomer 1"Or "enantiomer 2" refers only to the order in which the compounds elute from the column.

In the following discussion, certain common abbreviations and acronyms are used, including: AcOH (acetic acid), DMAP (4-dimethylaminopyridine), DMF (dimethylformamide), Et₂O (diethyl ether), EtOAc (ethyl acetate), EtOH (ethanol), Et₃N (triethylamine), KHMDS (potassium hexamethyldisilazane), MeOH (methanol), NaBH (OAc)₃Sodium triacetoxyborohydride, NaHMDS (sodium hexamethyldisilazane), TFA (trifluoroacetic acid), THF (tetrahydrofuran).

Example 1(A)

Preparation of 2- [4- (6-fluoro-1H-indol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-N- (6-methoxy-pyridin-3-yl) -acetamide

Step A: 2- [4- (6-fluoro-1H-indol-3-ylmethylene) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-N- (6-methoxy-pyridin-3-yl) -acetamide

To N-isopropyl-N- (6-methoxy-pyridin-3-yl) -2- (5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ]]Azulen-6-yl) -acetamide (preparation 11) (150mg, 0.311mmol) and 6-fluoro-1H-indole-3-carbaldehyde (61mg, 0.373mmol) in toluene (20mL) was added piperidine (100. mu.L). The reaction vessel was equipped with a Dean-Stark trap containing toluene and 4A molecular sieves and heated at reflux for 24 hours. The solution was cooled to room temperature and diluted with water. The aqueous solution was washed with EtOAc (3X) and dried (MgSO)₄) The combined organic extracts were filtered and concentrated. By medium pressure chromatography using a solvent gradient (10% EtOAc in hexane-100% EtOAc) to give 158mg of 2- [4- (6-fluoro-1H-indol-3-ylmethylene) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ]]Azulen-6-yl]-N-isopropyl-N- (6-methoxy-pyridin-3-yl) -acetamide. MS 628.3(M +1), 626.2(M-1).

And B: (2- [4- (6-fluoro-1H-indol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-N- (6-methoxy-pyridin-3-yl) -acetamide)

To 2- [4- (6-fluoro-1H-indol-3-ylmethylene) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ]]Azulen-6-yl]To a solution of-N-isopropyl-N- (6-methoxy-pyridin-3-yl) -acetamide (158mg, 0.252mmol) in MeOH (20mL) was added ammonium formate (463mg, 7.34mmol) and 10% palladium on charcoal (112 mg). The reaction was heated at reflux for 24 hours. The suspension was filtered hot and dissolved in CH₂Cl₂10% MeOH (3X) and CH in (C)₂Cl₂(3x) washing. The combined organic filtrates were concentrated and chromatographed by medium pressure using a solvent gradient (dissolved in CH)₂Cl₂2% MeOH in CH₂Cl₂8% MeOH) to provide 110mg of 2- [4- (6-fluoro-1H-indol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ]]Azulen-6-yl]-N-isopropyl-N- (6-methoxy-pyridin-3-yl) -acetamide.¹H NMR(CD₃OD)δ8.08(d，1H)，7.39-7.62(m，9H)7.15(m，2H)，6.93(m，3H)，6.68(m，1H)，4.80(m，1H)，4.55(m，1H)，4.20(m，1H)，3.95(s，3H)，3.88(t，1H)，3.77(m，1H)，3.67(m，1H)，1.01(m，6H)；MS 630(M+1)，628.5(M-1).

Example 1(B)

Preparation of (-)2- [4- (1H-indol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-N- (6-methoxy-pyridin-3-yl) -acetamide

Step A: 2- [4- (1H-indol-3-ylmethylene) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-N- (6-methoxy-pyridin-3-yl) -acetamide

Following the procedure described in example 1(a), step a, N-isopropyl-N- (6-methoxy-pyridin-3-yl) -2- (5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e [ -c ] was prepared]Azulen-6-yl) -acetamide (preparation 11) (293mg, 0.608mmol) was condensed with 1H-indole-3-carbaldehyde (106mg, 0.729 mmol). By medium pressure chromatography using a solvent gradient (dissolved in CH)₂Cl₂2% MeOH in CH₂Cl₂MeOH) to provide 286mg2- [4- (1H-indol-3-ylmethylene) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] b]Azulen-6-yl]-N-isopropyl-N- (6-methoxy-pyridin-3-yl) -acetamide.¹H NMR(CD₃OD)δ8.25(s)and 7.90(s，total 1H)，8.16(s，1H)，7.58-7.67(m，4H)，7.37-7.53(m，6H)，7.07-7.17(m，3H)，6.94(m，2H)，4.90(m，1H)，4.55(m，1H)，4.25(m，1H)，3.96(m，4H)，1.10(m，6H)；MS 610.8(M+1)，608.5(M-1)

And B: 2- [4- (1H-indol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dioxo-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-N- (6-methoxy-pyridin-3-yl) -acetamide

Following the procedure described in example 1(A), step B, 2- [4- (1H-indol-3-ylmethylene) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10B-tetraaza-benzo [ e ]]Azulen-6-yl]-N-isopropyl-N- (6-methoxy-pyridin-3-yl) -acetamide (276mg, 0.453mmol) reduction and chromatography by medium pressure using a solvent gradient (CH)₂Cl₂-is soluble in CH₂Cl₂MeOH) to provide 86mg of 2- [4- (1H-indol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ]]Azulen-6-yl]-N-isopropyl group-N- (6-methoxy-pyridin-3-yl) -acetamide racemic mixture.¹H NMR(CD₃OD)δ8.08(d，1H)，7.61(m，3H)，7.39-7.53(m，6H)，7.25(d，1H)，7.12(m，2H)，7.00(m，1H)，6.90(m，3H)，4.78(m，1H)，4.55(m，1H)，4.15(m，1H)，3.95(s，3H)，3.89(m，1H)，3.67-3.80(m，2H)，1.01(m，6H)；MS 612.2(M+1)，610.5(M-1).

And C: (-)2- [4- (1H-indol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-N- (6-methoxy-pyridin-3-yl) -acetamide, enantiomer 1

The racemic product of step B, 2- [4- (1H-indol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10B-tetraaza-benzo [ e ] was purified by high pressure chromatography using a Chiralpak AD column (5 cm. times.50 cm) eluting with heptane in EtOH (75: 12) using a flow rate of 85 mL/min]Azulen-6-yl]-N-isopropyl-N- (6-methoxy-pyridin-3-yl) -acetamide (217mg, 0.355mmol) was separated into its enantiomer giving enantiomer 1 with a retention time of 7.04 min. The enantiomer was dissolved in EtOAc and the organic layer was washed with water (1x) and brine (1 x). Drying (MgSO)₄) The organic extract was filtered and concentrated to provide 85mg of 2- [4- (1H-indol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ]]Azulen-6-yl]-N-isopropyl-N- (6-methoxy-pyridin-3-yl) -acetamide (enantiomer 1).¹H NMR(CD₃OD)δ8.08(d，1H)，7.61(m，3H)，7.39-7.53(m，6H)，7.25(d，1H)，7.14(m，2H)，7.00(t，1H)，6.90(m，3H)，4.78(m，1H)，4.54(m，1H)，4.11(m，1H)，3.95(s，3H)，3.89(t，1H)，3.68-3.82(m，2H)，1.01(m，6H)；MS 612.9(M+1)，610.5(M-1)；[α]_D ²¹79.6(c 0.325, ethanol).

Example 1(C)

Preparation of 2- [4- (5-fluoro-1H-indol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-N- (6-methoxy-pyridin-3-yl) -acetamide

Step A: 2- [4- (5-fluoro-1H-indol-3-ylmethylene) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-N- (6-methoxy-pyridin-3-yl) -acetamide

Following the procedure described in example 1(a), step a, N-isopropyl-N- (6-methoxy-pyridin-3-yl) -2- (5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e [ -c ] was prepared]Azulen-6-yl) -acetamide (preparation 11) (120mg, 0.207mmol) was condensed with 5-fluoro-1H-indole-3-carbaldehyde (48mg, 0.248 mmol). By medium pressure chromatography with a solvent gradient (in CH)₂Cl₂1% MeOH in CH₂Cl₂MeOH) to yield 85mg of 2- [4- (5-fluoro-1H-indol-3-ylmethylene) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ]]Azulen-6-yl]-N-isopropyl-N- (6-methoxy-pyridin-3-yl) -acetamide. MS 628.8(M +1), 626.4(M-1).

And B: 2- [4- (5-fluoro-1H-indol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-N- (6-methoxy-pyridin-3-yl) -acetamide

Following the procedure described in example 1(a), step B, 2- [4- (5-fluoro-1H-indol-3-ylmethylene) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10B-tetraaza-benzo [ e ]]Azulen-6-yl]-N-isopropyl-N- (6-methoxy-pyridin-3-yl) -acetamide (85mg, 0.135mmol) reduction and chromatography by medium pressure using a solvent gradient (dissolved in CH)₂Cl₂2% MeOH in CH₂Cl₂9% MeOH) to yield 42mg of 2- [4- (5-fluoro-1H-indol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ]]Azulen-6-yl]-N-isopropyl-N- (6-methoxy-pyridin-3-yl) -acetamide.¹HNMR(CD₃OD)δ8.08(d，1H)，7.38-7.65(m，8H)，7.19(m，3H)，7.14(t，1H)，6.90(d，2H)，6.76(t，1H)，4.80(m，1H)，4.50(m，1H)，4.12(m，1H)，3.94(s，3H)，3.87(t，1H)，3.74(m，1H)，3.64(m，1H)，1.01(m，6H)；MS 630.4(M+1)，628.5(M-1).

Example 1(D)

Preparation of 2- [ 1-cyclohexyl-4- (1H-indol-3-ylmethyl) -5-oxo-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-N- (6-methoxy-pyridin-3-yl) -acetamide

Step A: 2- [ 1-cyclohexyl-4- (1H-indol-3-ylmethylene) -5-oxo-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-N- (6-methoxy-pyridin-3-yl) -acetamide

Following the procedure described in example 1(A), step A, 2- (1-cyclohexyl-5-oxo-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ]]Azulen-6-yl) -N-isopropyl-N- (6-methoxy-pyridin-3-yl) -acetamide (preparation 8(A)) (90mg, 0.184mmol) was condensed with 1H-indole-3-carbaldehyde (32mg, 0.221 mmol). Purification by medium pressure chromatography, eluting with a solvent gradient (10% EtOAc-10O% EtOAc in hexane) afforded 72.5mg of 2- [ 1-cyclohexyl-4- (1H-indol-3-ylmethylene) -5-oxo-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ]]Azulen-6-yl]-N-isopropyl-N- (6-methoxy-pyridin-3-yl) -acetamide.¹H NMR(CDCl₃)δ8.63(s，1H)，8.16(m，1H)，7.88-7.96(m，1H)，7.45-7.76(m，2H)，7.12-7.44(m，6H)，6.83(m，1H)，5.10(m，1H)，4.11-4.35(m，1H)，3.94(t，2H)，3.84(dd，1H)，2.94(m，1H)，2.25(m，1H)，1.99(m，2H)，1.70(m，6H)，1.35(m，3H)，1.15(m，6H)；MS 616.4(M+1)，614.3(M-1).

And B: 2- [ 1-cyclohexyl-4- (1H-indol-3-ylmethyl) -5-oxo-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-N- (6-methoxy-pyridin-3-yl) -acetamide

Reduction of 2- [ 1-cyclohexyl-4- (1H-indol-3-ylmethylene) -5-oxo-4, 5-dihydro-2, 3, 6, 10B-tetraaza-benzo [ e ] according to the procedure described in example 1(A), step B]Azulen-6-yl]-N-isopropyl-N- (6-methoxy-pyridin-3-yl) -acetamide (72.5mg, 0.118 mmol). Purification by medium pressure chromatography, eluting with a solvent gradient (10% EtOAc in hexane to 100% EtOAc), afforded 19.7mg2- [ 1-cyclohexyl-4- (1H-indol-3-ylmethyl) -5-oxo-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ]]Azulen-6-yl]-N-isopropyl-N- (6-methoxy-pyridin-3-yl) -acetamide.¹H NMR(CDCl₃)δ8.21(t，1H)，7.02-8.09(m，10H)，6.84(dd，1H)，5.02(m，1H)，4.18(t，1H)，3.56-3.96(m，5H)，2.79(m，1H)，2.16(m，1H)，1.92(m，1H)，1.69(m，7H)，1.53(m，1H)，1.31(m，2H)，1.05(m，6H)；MS 618.7(M+1).

Example 1(E)

Preparation of 2- [1- (3-hydroxy-phenyl) -4- (1H-indol-3-ylmethyl) -5-oxo-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-N- (6-methoxy-pyridin-3-yl) -acetamide

Step A: 2- [1- (3-benzyloxy-phenyl) -4- (1H-indol-3-ylmethylene) -5-oxo-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-N- (6-methoxy-pyridin-3-yl) -acetamide

Following the procedure described in example 1(a), step a, 2- [1- (3-benzyloxy-phenyl) -5-oxo-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ]]Azulen-6-yl]-N-isopropyl-N- (6-methoxy-pyridin-3-yl) -acetamide (preparation 6) (129mg,0.219mmol) was condensed with 1H-indole-3-carbaldehyde (70mg, 0.48 mmol). Purification by medium pressure chromatography, eluting with a solvent gradient (10% EtOAc-100% EtOAc in hexane) afforded 60mg of 2- [1- (3-benzyloxy-phenyl) -4- (1H-indol-3-ylmethylene) -5-oxo-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ]]azulen-6-yl-N-isopropyl-N- (6-methoxy-pyridin-3-yl) -acetamide.¹H NMR(CD₃OD)δ8.13(m，1H)，7.64(m，2H)，7.23-7.48(m，13H)，7.13(m，3H)，6.93(m，2H)，4.94(m，2H)，4.85(m，1H)，4.63(m，1H)，4.20-4.40(m，1H)，3.96(m，1H)，3.85(d，1H)，0.90-1.05(m，6H)；MS 716.5(M+1)，714.6(M-1)

And B: 2- [1- (3-hydroxy-phenyl) -4- (1H-indol-3-ylmethyl) -5-oxo-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-N- (6-methoxy-pyridin-3-yl) -acetamide

Following the procedure described in example 1(a), step B, 2- [1- (3-benzyloxy-phenyl) -4- (1H-indol-3-ylmethylene) -5-oxo-4, 5-dihydro-2, 3, 6, 10B-tetraaza-benzo [ e ]]Azulen-6-yl]-N-isopropyl-N- (6-methoxy-pyridin-3-yl) -acetamide (60mg, 0.084mmol) was reduced and deprotected for 48 h. Purification by medium pressure chromatography, eluting with a solvent gradient (10% EtOAc-100% EtOAc in hexane) afforded 39.5mg2- [1- (3-hydroxy-phenyl) -4- (1H-indol-3-ylmethyl) -5-oxo-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ]]Azulen-6-yl]-N-isopropyl-N- (6-methoxy-pyridin-3-yl) -acetamide.¹H NMR(CD₃OD)δ8.15(d，2H)，7.63(s，1H)，6.91-7.44(m，14H)，4.80-5.05(m，2H)，4.10-4.60(m，3H)，3.95(s，3H)，3.40-3.90(m，1H)，1.13(m，6H)；MS 627(M+1)，625(M-1).

Example 1(F)

Preparation of N-benzyl-2- [8, 9-difluoro-4- (5-fluoro-1H-indol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-acetamide

Step A: n-benzyl-2- [8, 9-difluoro-4- (5-fluoro-1H-indol-3-ylmethylene) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-acetamide

Following the procedure described in example 1(a), step a, N-benzyl-2- (8, 9-difluoro-5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] was allowed to stand]Azulen-6-yl) -N-isopropyl-acetamide (preparation 9) (100mg, 0.198mmol) was condensed with 5-fluoro-1H-indole-3-carbaldehyde (38.8mg, 0.238 mmol). By medium pressure chromatography using a solution in CH₂Cl₂Purified with 50% EtOAc affording 91.5mg N-benzyl-2- [8, 9-difluoro-4- (5-fluoro-1H-indol-3-ylmethylene) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ]]Azulen-6-yl]-N-isopropyl-acetamide.¹H NMR(CDCl₃)δ7.92(d，1H)，7.10-7.67(m，13H)，6.84(m，1H)，6.64(m，1H)，4.37-4.97(m，5H)，4.20(m，1H)，1.20(m，6H)；MS 647.4(M+1)，645.3(M-1).

And B: n-benzyl-2- [8, 9-difluoro-4- (5-fluoro-1H-indol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-acetamide

Reduction of N-benzyl-2- [8, 9-difluoro-4- (5-fluoro-1H-indol-3-ylmethylene) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10B-tetraaza-benzo [ e ] is carried out according to the procedure described in example 1(A), step B]Azulen-6-yl]-N-isopropyl-acetamide (91.5mg, 0.140mmol) to give 77.2mg of N-benzyl-2- [8, 9-difluoro-4- (5-fluoro-1H-indol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e [ -E ]]Azulen-6-yl]-N-isopropyl-acetamide.¹H NMR(CDCl₃)δ8.04(d，1H)，7.16-7.60(m，13H)，6.85(m，1H)，6.66(m，1H)，4.34-4.90(m，5H)，3.83(m，2H)，3.64(m，1H)，1.23(m，3H)，1.13(m，3H)；MS 649.5(M+1)，647.5(M-1).

Example 1(G)

Preparation of 2- [1- (3-hydroxy-phenyl) -4- (1H-indol-3-ylmethyl) -5-oxo-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-N-phenyl-acetamide

Step A: 2- [1- (3-hydroxy-phenyl) -4- (1H-indol-3-ylmethylene) -5-oxo-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-N-phenyl-acetamide

Following the procedure described in example 1(a), step a, 2- [1- (3-hydroxy-phenyl) -5-oxo-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ]]Azulen-6-yl]-N-isopropyl-N-phenyl-acetamide (preparation 12) (244mg, 0.522 mmol) was condensed with 1H-indole-3-carbaldehyde (105mg, 0.723mmol) for 48H. Purification by medium pressure chromatography, eluting with a solvent gradient (EtOAc-5% MeOH in EtOAc-10% MeOH in EtOAc) afforded 177.9mg of 2- [1- (3-hydroxy-phenyl) -4- (1H-indol-3-ylmethylene) -5-oxo-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ]]Azulen-6-yl]-N-isopropyl-N-phenyl-acetamide.¹H NMR(CD₃OD)δ8.23(d，1H)，7.90(s，1H)，6.90-7.63(m，16H)，4.95(m，1H)，3.68-4.50(m，3H)，1.11(m，6H)；MS 595.3(M+1)，593.3(M-1).

And B: 2- [1- (3-hydroxy-phenyl) -4- (1H-indol-3-ylmethyl) -5-oxo-4, 5-dioxo-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-N-phenyl-acetamide

Following the procedure described in example 1(a), step B, 2- [1- (3-hydroxy-phenyl) -4- (1H-indol-3-ylmethylene) -5-oxo-4, 5-dihydro-2, 3, 6, 10B-tetraaza-benzo [ e ]]Azulen-6-yl]Reduction of-N-isopropyl-N-phenyl-acetamide (177.9mg, 0.299mmol) to 20For an hour and by reverse phase (C-18) high pressure chromatography using a solvent gradient (15% of 0.1% formic acid/CH in 0.1% formic acid/water)₃CN-100% of 0.1% formic acid/CH₃CN) to give 77mg of 2- [1- (3-hydroxy-phenyl) -4- (1H-indol-3-ylmethyl) -5-oxo-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ]]Azulen-6-yl]-N-isopropyl-N-phenyl-acetamide.¹H NMR(CD₃OD)δ7.53(m，7H)，7.32(m，3H)，7.22(t，3H)，6.90-7.03(m，5H)，4.82(m，2H)，4.45(d，1H)，4.12(d，1H)，3.93(d，1H)，3.76(d，1H)，1.04(m，6H)；MS 597.4(M+1)，595.5(M-1).

Example 1(H)

Preparation of N-benzyl-2- [8, 9-difluoro-4- (1H-indol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dioxo-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-acetamide

Step A: n-benzyl-2- [8, 9-difluoro-4- (1H-indol-3-ylmethylene) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-acetamide

Following the procedure described in example 1(a), step a, N-benzyl-2- (8, 9-difluoro-5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] was allowed to stand]Azulen-6-yl) -N-isopropyl-acetamide (preparation 9) (200mg, 0.399mmol) was condensed with 1H-indole-3-carbaldehyde (70mg, 0.479mmol) for 24 hours. By medium pressure chromatography using a solvent gradient (CH)₂Cl₂-is soluble in CH₂Cl₂20% acetone) to afford 190mg of N-benzyl-2- [8, 9-difluoro-4- (1H-indol-3-ylmethylene) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] (iv)]Azulen-6-yl]-N-isopropyl-acetamide. MS629.3(M +1), 627.3(M-1).

And B: n-benzyl-2- [8, 9-difluoro-4- (1H-indol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-acetamide

N-benzyl-2- [8, 9-difluoro-4- (1H-indol-3-ylmethylene) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10B-tetraaza-benzo [ e ] is reacted according to the procedure described in example 1(A), step B]Azulen-6-yl]Reduction of-N-isopropyl-acetamide (185mg, 0.294mmol) for 24 h. Through Celite^®The reaction was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in EtOAc and washed with NaHCO₃Aqueous wash (1 ×). Drying (Na)₂SO₄) The organic solution was filtered and concentrated in vacuo. By preparative chromatography on CH₂Cl₂Eluted with 5% MeOH to provide 35mg of N-benzyl-2- [8, 9-difluoro-4- (1H-indol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ]]azulen-6-yl-N-isopropyl-acetamide.¹H NMR(CD₂Cl₂)δ8.30(d，1H)，6.98-7.64(m，15H)，6.68(q，1H)，4.06-4.90(m，5H)，3.73-3.89(m，3H)，1.08-1.28(m，6H)；MS 631.3(M+1)，629.3(M-1).

Example 1(I)

Preparation of N-benzyl-2- [8, 9-difluoro-4- (6-fluoro-1H-indol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-acetamide

Step A: n-benzyl-2- [8, 9-difluoro-4- (6-fluoro-1H-indol-3-ylmethylene) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-acetamide

Following the procedure described in example 1(a), step a, N-benzyl-2- (8, 9-difluoro-5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzeneAnd [ e ]]Azulen-6-yl) -N-isopropyl-acetamide (preparation 9) (50mg, 0.099mmol) was condensed with 6-fluoroindole-3-carbaldehyde (19.4mg, 0.119 mmol). By medium pressure chromatography, with the solvent dissolved in CH₂Cl₂Eluted with 50% EtOAc to provide 23.5mg of N-benzyl-2- [8, 9-difluoro-4- (6-fluoro-1H-indol-3-ylmethylene) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ]]Azulen-6-yl]-N-isopropyl-acetamide.¹HNMR(CDCl₃)δ7.94(d，1H)，7.61(m，3H)，7.27-7.49(m，9H)，6.95(m，1H)，6.86(m，1H)，6.63(m，1H)，4.35-5.0(m，5H)，4.20(m，1H)，1.23(m，6H)；MS 647.3(M+1)，645.3(M-1).

And B: n-benzyl-2- [8, 9-difluoro-4- (6-fluoro-1H-indol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-acetamide

N-benzyl-2- [8, 9-difluoro-4- (6-fluoro-1H-indol-3-ylmethylene) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10B-tetraaza-benzo [ e ] is reduced at 80 ℃ following the procedure described in example 1(A), step B]Azulen-6-yl]-N-isopropyl-acetamide (23mg, 0.035mmol) for 24 hours. Through Celite^®The reaction was filtered and concentrated in vacuo. The residue was dissolved in EtOAc and washed with NaHCO₃The organic solution was washed with aqueous solution and dried (MgSO)₄) Filtered and concentrated to give 22.7mg of N-benzyl-2- [8, 9-difluoro-4- (6-fluoro-1H-indol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ]]Azulen-6-yl]-N-isopropyl-acetamide.¹H NMR(CDCl₃)δ8.40(s)and 8.28(s，total 1H)，7.10-7.60(m，12H)，6.94(d，1H)，6.77(t，1H)，6.64(m，1H)，4.31-4.95(m，5H)，3.61-3.93(m，3H)，1.07-1.30(m，6H)；MS 649.5(M+1)，647.5(M-1).

Example 1(J)

Preparation of N-isopropyl-2- [ 5-oxo-1-phenyl-4- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-phenyl-acetamide

Step A: n-isopropyl-2- [ 5-oxo-1-phenyl-4- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethylene) -4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-phenyl-acetamide

Following the procedure described in example 1(a), step a, N-isopropyl-2- (5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ]]Azulen-6-yl) -N-phenyl-acetamide (preparation 7(A)) (500mg, 1.10mmol) with 1H-pyrrolo [2, 3-b ]]Pyridine-3-carbaldehyde (160mg, 1.16mmol) was condensed in pyridine (5 mL). By medium pressure chromatography using a solvent gradient (dissolved in CH)₂Cl₂5% of acetone in CH₂Cl₂50% of acetone in CH₂Cl₂MeOH 10%) to give 300mg of N-isopropyl-2- [ 5-oxo-1-phenyl-4- (1H-pyrrolo [2, 3-b))]Pyridin-3-ylmethylene) -4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e]Azulen-6-yl]-N-phenyl-acetamide.¹H NMR(CDCl₃)δ8.31(d，1H)，8.05(d)and 7.96(d，total 1H)，7.71(m，1H)，7.59(m，2H)，7.33-7.51(m，9H)，7.17(m，2H)，7.01(m，1H)，6.80(t，1H)，5.09(m，1H)，4.50(d)and 4.30(d，total 1H)，4.15(m，1H)，3.92(d，1H)，1.14(m，6H)；MS 580.6(M+1).

And B: n-isopropyl-2- [ 5-oxo-1-phenyl-4- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-phenyl-acetamide

N-isopropyl-2- [ 5-oxo-1-phenyl-4- (1H-pyrrolo [2, 3-B ] according to the procedure described in example 1(A), step B]Pyridin-3-ylmethylene) -4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e]Azulen-6-yl]-N-phenyl-acetamide (300mg, 0.518mmol) was reduced at 60 ℃ for 6.5 h. Through Celite^®The reaction was filtered and concentrated in vacuo. The residue was dissolved in EtOAc and the organic solution was washed with water (1 ×). Drying (Na)₂SO₄) The organic solution was filtered and concentrated in vacuo. Reverse phase (C-18) high pressure chromatography was used with a solvent gradient (35% in 0.1% NH) over 6 minutes₄OH/H₂0.1% NH in O₄OH/CH₃CN to 100% 0.1% NH₄OH/CH₃CN) to give 100mg of N-isopropyl-2- [ 5-oxo-1-phenyl-4- (1H-pyrrolo [2, 3-b))]Pyridin-3-ylmethyl) -4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e]Azulen-6-yl]-N-phenyl-acetamide.¹H NMR(CDCl₃)δ8.22(d，1H)，8.00(d，1H)，7.55(m，3H)，7.32-7.48(m，9H)，7.18(m，1H)，7.05(m，2H)，6.85(d，1H)，4.97(m，1H)，4.27(d，1H)，4.06(m，1H)，3.87(d，2H)，3.70(t，1H)，1.09(m，6H)；MS 582.6(M+1)，580.5(M-1).

Example 1(K)

Preparation of (-) -N-benzyl-2- [4- (1H-indol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-acetamide, enantiomer 1

Step A: n-benzyl-2- [4- (1H-indol-3-ylmethylene) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-acetamide

Following the procedure described in example 1(a), step a, N-benzyl-N-isopropyl-2- (5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] is reacted]Azulen-6-yl) -acetamide (preparation 10) (13.9g, 29.8mmol) was condensed with 1H-indole-3-carbaldehyde (5.2g, 35.8mmol) for 48H. The volatiles were concentrated in vacuo to provide 18.5g N-benzyl-2- [4- (1H-indol-3-ylmethylene) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ]]Azulen-6-yl]-N-isopropyl-acetamide.¹H NMR(CDCl₃)δ8.01(d，1H)，7.67-7.50(m，4H)，7.43-7.11(m，12H)，6.99(m，1H)，6.99(m，1H)，6.80(m，1H)，4.96(m，1H)，4.71-4.49(m，4H)，4.23(m，1H)，1.20(m，6H)；MS 593.3(M+1).

And B: n-benzyl-2- [4- (1H-indol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-acetamide

Following the procedure described in example 1(a), step B, N-benzyl-2- [4- (1H-indol-3-ylmethylene) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10B-tetraaza-benzo [ e ]]Azulen-6-yl]-N-isopropyl-acetamide (18.5g, 31.2mmol) was reduced at 60 ℃ for 24 hours. Through Celite^®The reaction was filtered and concentrated in vacuo. Dissolving the residue in CH₂Cl₂And the organic solution was washed with water. Drying (Na)₂SO₄) The organic layer was filtered and concentrated in vacuo. The residue was dissolved in toluene and stirred at 60 ℃ for 24 hours. The solid was filtered to provide 12.4g N-benzyl-2- [4- (1H-indol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ]]Azulen-6-yl]-racemic mixture of N-isopropyl-acetamide.¹H NMR(CDCl₃) δ 8.02(d, 1H), 7.57(d, 3H), 7.46-7.23(m, 8H), 7.17-7.01(m, 6H), 6.83(dd, 1H), 4.96-4.40(m, 5H), 4.17-3.89(m, 2H), 3.80(m) and 3.72(m, total 1H), 1.20(dd, 3H), 1.13(dd, 3H); MS 595.3(M +1).

And C: (-) -N-benzyl-2- [4- (1H-indol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-acetamide, enantiomer 1

The racemic product of step B, N-benzyl-2- [4- (1H-indol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10B-tetraaza-benzo [ e ] was purified by high pressure chromatography using a (S, S) -Whelk-O1 column (5 cm. times.25 cm) eluting with heptane (60: 40) in EtOH at a flow rate of 140 mL/min]Azulen-6-yl]-N-isopropyl-acetamide (13.56g, 22.8mmol) was separated into its enantiomers to yieldEnantiomer 1 with 17 min retention time. The active enantiomer (enantiomer 1) was dissolved in CH₂Cl₂NaHCO is used for neutralization₃The organic solution was washed with aqueous solution (1x) and brine (1 x). Drying (Na)₂SO₄) The organic solution was filtered and concentrated to give 6.4g (-) -N-benzyl-2- [4- (1H-indol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ]]Azulen-6-yl]-N-isopropyl-acetamide (enantiomer 1). Heating a mixture of the solid (6.4g, 10.77mmol) in EtOH (250mL) at 45 ℃ for 96H, slowly cooling to room temperature over 4H, filtering and washing with a minimum amount of EtOH provides 5g of crystalline (-) -N-benzyl-2- [4- (1H-indol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ]]Azulen-6-yl]-N-isopropyl-acetamide (enantiomer 1), mp244-245 ℃.¹H NMR(DMSO-d₆)δ10.79-10.77(d，1H)，7.76-7.74(d，1H)，7.56-7.24(m，7H)，7.20-7.12(m，5H)，7.02-6.91(m，2H)，6.91-6.83(m，2H)，5.20(m，0.5H)，4.95 to 4.83(m，1H)，4.60-4.51(m，2H)，4.47(m，0.5H)，4.25-4.21(m，1H)，3.84-3.78(m，2H)，3.64-3.58(m，2H)，1.12-1.10(d，1.7H)，1.O0-0.99(d，1.7H)，0.94-0.92(d，2.6H)；[α]_D ²⁰49.3(c 1, ethanol).

Example 2(A)

Preparation of N- (6-chloro-pyridin-3-yl) -2- [4- (1H-indol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-acetamide

To [4- (1H-indol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ]]Azulen-6-yl]-acetic acid (preparation 15) (30mg, 0.06mmol) and (6-chloro-pyridin-3-yl) -isopropyl-amine (preparation 2(A)) (10.1mg, 0.06mmol) in benzene (2mL) was added to a solution of PCl₃(2.0M in waterCH₂Cl₂0.1mL, 0.198mmol) and the reaction heated at reflux for 24 hours. The reaction was cooled to room temperature and quenched with CH₂Cl₂And (6) diluting. With NaHCO₃The organic solution was washed successively with aqueous solution (1x), water (1x), 1N HCl (1x), and water (1 x). Drying (MgSO)₄) Organic solution and concentrate the volatiles in vacuo. By medium pressure chromatography using a solution in CH₂Cl₂Eluting with 10% EtOH to purify the residue, 5mg of N- (6-chloro-pyridin-3-yl) -2- [4- (1H-indol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ]]Azulen-6-yl]-N-isopropyl-acetamide.¹H NMR(CDCl₃)δ8.26(s，1H)，8.17(s，1H)，7.76-7.29(m，11H)，7.06(m，3H)，6.83(d，1H)，5.04-4.87(m，1H)，4.45-4.15(m，1H)，3.94-3.82(m，3H)，3.72(m，1H)，0.06(s，6H)；MS 616.6(M+1)，614.5(M-1).

Example 2(B)

Preparation of N- (6-ethoxy-pyridin-3-yl) -2- [4- (1H-indol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-acetamide

[4- (1H-indol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] is reacted at 100 ℃ according to the procedure described in example 2(A)]Azulen-6-yl]Acetic acid (preparation 15) (300mg, 0.65mmol) with (6-ethoxy-pyridin-3-yl) -isopropyl-amine (preparation 2(B)) (117mg, 0.65mmol) and PCl₃In dichloroethane. By medium pressure chromatography using a solvent gradient (5% in CH)₂Cl₂0.5% NH in₄OH/MeOH-10% in CH₂Cl₂0.5% NH in₄OH/MeOH) to provide 85.1mg of N- (6-ethoxy-pyridin-3-yl) -2- [4- (1H-indol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetrakisAza-benzo [ e)]Azulen-6-yl]-N-isopropyl-acetamide.¹H NMR(CD₃OD)δ8.05(d，1H)，7.62(m，3H)，7.38-7.52(m，6H)，7.24(d，1H)，7.11(m，2H)，6.99(t，1H)，6.89(m，3H)，4.78(m，1H)，4.53(m，1H)，4.35(q，2H)，4.12(m，1H)，3.88(t，1H)，3.78(dd，1H)，3.69(dd，1H)，1.38(t，3H)，0.99(m，6H)；MS 626.7(M+1)，624.6(M-1).

Example 3(A)

Preparation of 2- [4- (1H-indazol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-N- (6-methoxy-pyridin-3-yl) -acetamide

Step A: 3- (6- { [ isopropyl- (6-methoxy-pyridin-3-yl) -carbamoyl ] -methyl } -5-oxo-1-phenyl-5, 6-dihydro-4H-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-4-ylmethyl) -indazole-1-carboxylic acid tert-butyl ester

To N-isopropyl-N- (6-methoxy-pyridin-3-yl) -2- (5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] at 0 deg.C]Azulen-6-yl) -acetamide (preparation 11) (520mg, 1.079mmol) in DMF (10mL) was added NaH (60% in oil, 50mg, 1.27 mmol). The reaction was stirred at 0 ℃ for 45 min and tert-butyl 3-bromomethyl-indazole-1-carboxylate (423mg, 1.36mmol) dissolved in DMF (5mL) was added. The reaction was stirred at room temperature for 24 hours and diluted with brine. The aqueous solution was washed with EtOAc (3 ×). The combined organic solutions were washed with brine (1 ×) and dried (MgSO)₄) Filtered and concentrated in vacuo to provide 3- (6- { [ isopropyl- (6-methoxy-pyridin-3-yl) -carbamoyl]-methyl } -5-oxo-1-phenyl-5, 6-dihydro-4H-2, 3, 6, 10 b-tetraaza-benzo [ e ]]Azulen-4-ylmethyl) -indazole-1-carboxylic acid tert-butyl ester.¹H NMR(CD₃OD)δ8.05(d，1H)，6.80-7.75(m，15H)，4.75(m)and 4.60(t，total 3H)，3.85-4.20(m，6H)，1.65(m，9H)，0.98(m，6H)；MS 713.6(M+1)，711.5(M-1).

And B: 2- [4- (1H-indazol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-N- (6-methoxy-pyridin-3-yl) -acetamide

The product of step A, 3- (6- { [ isopropyl- (6-methoxy-pyridin-3-yl) -carbamoyl]-methyl } -5-oxo-1-phenyl-5, 6-dihydro-4H-2, 3, 6, 10 b-tetraaza-benzo [ e ]]Azulen-4-ylmethyl-indazole-1-carboxylic acid tert-butyl ester in CH₂Cl₂(8mL) and TFA (2mL) was added. The reaction was stirred at room temperature for 24 hours and concentrated in vacuo. Purification by medium pressure chromatography, eluting with a solvent gradient (1% MeOH in EtOAc-5% MeOH in EtOAc) afforded 172mg of 2- [4- (1H-indazol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ]]Azulen-6-yl]-N-isopropyl-N- (6-methoxy-pyridin-3-yl) -acetamide.¹H NMR(CD₃OD)δ8.04(d，1H)，7.88(d，1H)，7.64(m，2H)，7.56(d，2H)，7.49(t，2H)，7.39(q，3H)，7.31(t，1H)，7.19(t，1H)，7.11(t，1H)，6.95(d，1H)，6.86(m，1H)，4.72(m，1H)，4.59(m，1H)，4.41(t，1H)，3.99-4.12(m，2H)，3.90(m，4H)，0.95(m，6H)；MS 613.8(M+1)，611.5(m-1).

Example 3(B)

Preparation of 2- [4- (1H-indazol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl-N-isopropyl-N-phenyl-acetamide

Step A: 3- {6- [ (isopropyl-phenyl-carbamoyl) -methyl ] -5-oxo-1-phenyl-5, 6-dihydro-4H-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-4-ylmethyl } -indazole-1-carboxylic acid tert-butyl ester

Following the procedure described in example 3(a), step a, using tert-butyl 3-bromomethyl-indazole-1-carboxylate (309mg, 0.993mmol) to react N-isopropyl-2- (5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ]]Azulen-6-yl) -N-phenyl-acetamide (preparation 7(A)) (411.7mg, 0.9118mmol) was alkylated. Purification by medium pressure chromatography, eluting with a solvent gradient (EtOAc-5% MeOH in EtOAc) afforded 391.9mg of 3- {6- [ (isopropyl-phenyl-carbamoyl) -methyl]-5-oxo-1-phenyl-5, 6-dihydro-4H-2, 3, 6, 10 b-tetraaza-benzo [ e [ -E ]]Azulen-4-ylmethyl } -indazole-1-carboxylic acid tert-butyl ester.¹H NMR(CD₃OD)δ7.99(m，2H)，7.22-7.66(m，15H)，7.01(dd，1H)，4.53-4.81(m，3H)，3.88-4.21(m，3H)，1.65(m，9H)，0.94(m，6H).

And B: 2- [4- (1H-indazol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-N-phenyl-acetamide

To 3- {6- [ (isopropyl-phenyl-carbamoyl) -methyl]-5-oxo-1-phenyl-5, 6-dihydro-4H-2, 3, 6, 10 b-tetraaza-benzo [ e [ -E ]]To a solution of azulen-4-ylmethyl } -indazole-1-carboxylic acid tert-butyl ester (391.9mg, 0.674mmol) in dioxane (8mL) was added 4M HCl in dioxane (6 mL). The reaction was stirred at rt for 24 h and diluted with EtOAc. With NaHCO₃The organic solution was washed with aqueous solution and brine, dried (MgSO)₄) Filtered and concentrated in vacuo. Purification by medium pressure chromatography, eluting with a solvent gradient (EtOAc-10% MeOH in EtOAc) afforded 260.9mg of 2- [4- (1H-indazol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ]]Azulen-6-yl]-racemic mixture of N-isopropyl-N-phenyl-acetamide.¹H NMR(CD₃OD)δ7.90(d，1H)，7.65(d，2H)，7.34-7.54(m，12H)，7.22(t，1H)，7.13(t，1H)，6.99(d，1H)，4.74(m，1H)，4.65(d，1H)，4.42(t，1H)，3.92-4.12(m，3H)，0.99(m，6H)；MS 582.7(M+1)，580.4(M-1).

The preparation method can be selected as follows:

step A: n-isopropyl-2- (5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl) -N-phenyl-acetamide

To a solution of 1-phenyl-4H, 6H-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-5-one (preparation 4(A)) (2.5g, 9.05 mmol 1) in DMF (40mL) at 0 deg.C was added sodium hydride (60% in oil, 0.36g, 9.0 mmol). The reaction was warmed to room temperature and stirred for 40 minutes. The reaction was cooled to-6 ℃ and a solution of 2-bromo-N-isopropyl-N-phenyl-acetamide (preparation 1(a)) (2.55g, 9.95mmol) in DMF (20mL) was added dropwise to the reaction mixture over 0.5 h, maintaining the internal reaction temperature below-3 ℃. The reaction mixture was stirred for 105 minutes below-3 ℃ and brine (200mL) was added. The aqueous solution was washed with ethyl acetate (200 mL). The organic layer was washed with brine, dried over sodium sulfate, and concentrated to 1/3 volumes. Hexane was added slowly until a solid precipitated. The white solid was collected by filtration and washed with diethyl ether and hexanes to give 2.96g N-isopropyl-2- (5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl) -N-phenyl-acetamide. MS 452(M +1). this intermediate was reacted further according to steps a and B of example 3(B) above to provide a racemic mixture of 2- [4- (1H-indazol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10B-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-N-phenyl-acetamide.

Example 3(C)

Preparation of (-)2- [4- (1H-indazol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-N-phenyl-acetamide, enantiomer 2

Racemic 2- [4- (1H-indazol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] using a Chiralcel OD column (10 cm. times.50 cm) eluting with 0.05% diethylamine in heptane/ethanol (3: 1) at a flow rate of 250 mL/min]Azulen-6-yl]-N-isopropyl-N-phenyl-acetamide (example 3(B)) separated into its enantiomers, providing a peptide with a 9.21 minute retention timeMeta (-)2- [4- (1H-indazol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ]]Azulen-6-yl]-N-isopropyl-N-phenyl-acetamide (enantiomer 2).¹H NMR(CD₂Cl₂)δ7.94(d，1H)，7.62(d，2H)，7.34-7.47(m，10H)，7.10-7.22(m，4H)，6.89(d，1H)，4.84(m，1H)，4.41(br d，1H)，4.35(t，1H)，3.93-4.11(m，3H)，1.00(m，6H)；MS 582.5(M+1)；[α]_D ²⁰-109.6(c 1.1, ethanol)

Example 3(D)

Preparation of N-benzyl-2- [8, 9-difluoro-4- (1H-indazol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dioxo-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-acetamide

Step A: 3- {6- [ (benzyl-isopropyl-carbamoyl) -methyl ] -8, 9-difluoro-5-oxo-1-phenyl-5, 6-dihydro-4H-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-4-ylmethyl } -indazole-1-carboxylic acid tert-butyl ester

Following the procedure described in example 3(a), step a, using tert-butyl 3-bromomethyl-indazole-1-carboxylate (136mg, 0.439mmol) to react N-benzyl-2- (8, 9-difluoro-5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ]]Azulen-6-yl) -N-isopropyl-acetamide (preparation 9) (200mg, 0.399mmol) was alkylated. The reaction was diluted with buffer pH 6.8 and the aqueous solution was extracted with EtOAc. The organic solution was washed with brine (4 ×), dried (Na)₂SO₄) Filtered and concentrated in vacuo. By medium pressure chromatography using a solution gradient (CH)₂Cl₂-is soluble in CH₂Cl₂MeOH) to provide 100mg of 3- {6- [ (benzyl-isopropyl-carbamoyl) -methyl group]-8, 9-difluoro-5-oxo-1-phenyl-5, 6-dihydro-4H-2, 3, 6, 10 b-tetraaza-benzo [ e [ -l-methyl ] phenyl]Azulen-4-ylmethyl } -indazole-1-carboxylic acid tert-butyl esterAnd (3) an ester. MS 732.5(M +1), 730.4(M-1).

And B: n-benzyl-2- [8, 9-difluoro-4- (1H-indazol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-acetamide

To 3- {6- [ (benzyl-isopropyl-carbamoyl) -methyl]-8, 9-difluoro-5-oxo-1-phenyl-5, 6-dihydro-4H-2, 3, 6, 10 b-tetraaza-benzo [ e [ -l-methyl ] phenyl]To a solution of azulen-4-ylmethyl } -indazole-1-carboxylic acid tert-butyl ester (100mg, 0.137mmol) in dioxane (1mL) was added HCl (4.0M in dioxane, 2 mL). The reaction was stirred at room temperature for 24 hours. The volatiles were concentrated in vacuo and the residue was dissolved in CH₂Cl₂. With NaHCO₃(1X) organic solution washed with aqueous solution and dried (Na)₂SO₄) Filtered and concentrated in vacuo. By preparative chromatography using a solution in CH₂Cl₂Eluted with 5% MeOH to provide 45mg of N-benzyl-2- [8, 9-difluoro-4- (1H-indazol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ]]Azulen-6-yl]-N-isopropyl-acetamide.¹H NMR(CD₂Cl₂)δ7.92(m，1H)，7.04-7.66(m，14H)，6.67(s，1H)，4.22-4.96(m，6H)，3.91-4.13(m，2H)，1.01-1.22(m，6H)；MS 632.3(M+1)，630.2(M-1).

Example 3(E)

Preparation of (-) N-benzyl-2- [4- (1H-indazol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-acetamide, enantiomer 2

Step A: 3- {6- [ (benzyl-isopropyl-carbamoyl) -methyl ] -5-oxo-1-phenyl-5, 6-dihydro-4H-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-4-ylmethyl } -indazole-1-carboxylic acid tert-butyl ester

Following the procedure described in example 3(a), step a, using tert-butyl 3-bromomethyl-indazole-1-carboxylate (150mg, 0.473mmol) to react N-benzyl-N-isopropyl-2- (5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ]]Azulen-6-yl) -acetamide (preparation 10) (210mg, 0.451mmol) was alkylated. The reaction was diluted with pH 6.8 buffer and the aqueous solution was washed with EtOAc. The (3X) organic solution was washed with brine and dried (Na)₂SO₄) Filtered and concentrated in vacuo. By preparative chromatography using a solution in CH₂Cl₂Eluted with 5% acetone, followed by medium pressure chromatography using a solvent gradient (dissolved in CH)₂Cl₂2% acetone-in CH₂Cl₂14% acetone) to afford 19.1mg of 3- {6- [ (benzyl-isopropyl-carbamoyl) -methyl]-5-oxo-1-phenyl-5, 6-dihydro-4H-2, 3, 6, 10 b-tetraaza-benzo [ e [ -E ]]Azulen-4-ylmethyl } -indazole-1-carboxylic acid tert-butyl ester.¹H NMR(CD₂Cl₂)δ8.05(m，1H)，7.12-7.71(m，15H)，7.03(m，1H)，6.92(d，1H)，5.21(d)and 4.90(d，total 1H)，4.61-4.72(m，2H)，4.49(s，1H)，4.43(t，1H)，4.25-4.32(m，1H)，3.96-4.15(m，2H)，1.61(d，9H)，1.16(dd，3H)，1.04(dd，3H)；MS 696.4(M+1).

And B: n-benzyl-2- [4- (1H-indazol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-acetamide

3- {6- [ (benzyl-isopropyl-carbamoyl) -methyl ] was reacted with HCl (4.0M in dioxane, 0.8mL) over 24 hours according to the procedure described in example 3(B), step B]-5-oxo-1-phenyl-5, 6-dihydro-4H-2, 3, 6, 10 b-tetraaza-benzo [ e [ -E ]]Azulen-4-ylmethyl } -indazole-1-carboxylic acid tert-butyl ester (19.1mg, 0.274mmol) was deprotected. The reaction was diluted with EtOAc and NaHCO₃The organic solution (1X) was washed with aqueous solution and dried (Na)₂SO₄) Filtered and concentrated. By preparative chromatography using a solution in CH₂Cl₂Purification by elution with 5% MeOH in (K) afforded 8.5mg of N-benzyl-2- [4- (1H-Indazol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ]]Azulen-6-yl]-racemic mixture of N-isopropyl-acetamide.¹H NMR(CD₂Cl₂)δ7.97(t，1H)，7.12-7.64(m，15H)，7.05(m，1H)，6.92(m，1H)，5.08(d)and4.81(d，total 1H)，4.60-4.74(m，2H)，4.49(s，1H)，4.45(t，1H)，4.29-4.39(m，1H)，3.96-4.13(m，2H)，1.16(dd，3H)，1.05(dd，3H)；MS 596.2(M+1)，594.2(M-1).

And C: (-) N-benzyl-2- [4- (1H-indazol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-acetamide, enantiomer 2

The racemic product of step B, N-benzyl-2- [4- (1H-indazol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10B-tetraaza-benzo [ e ] was eluted using a Chiralcel OD column (10 cm. times.25 cm) with 50% EtOH in heptane at a flow rate of 250 mL/min]Azulen-6-yl]-N-isopropyl-acetamide (1.57g, 2.64mmol) was isolated as its enantiomer. The enantiomer with a retention time of 17.396 minutes (enantiomer 2) was dissolved in CH₂Cl₂NaHCO is used for neutralization₃The organic solution was washed with aqueous solution (1x) and brine (1 x). Drying (Na)₂SO₄) The organic solution was filtered and concentrated to provide 660mg (-) N-benzyl-2- [4- (1H-indazol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ]]Azulen-6-yl]-N-isopropyl-acetamide (enantiomer 2).¹H NMR(CD₂Cl₂)δ7.97(t，1H)，7.12-7.65(m，15H)，7.05(m，1H)，6.92(m，1H)，5.10(d)and 4.82(d，total 1H)，4.60-4.73(m，2H)，4.49(s，1H)，4.45(t，1H)，4.29-4.39(m，1H)，3.96-4.13(m，2H)，1.16(dd，3H)，1.05(dd，3H)；MS 596.1(M+1)，594.0(M-1)；[α]_D ²⁰145.3(c 1.01, ethanol).

Example 4

Preparation of 2- [4- (1H-indol-3-ylmethyl) -4-methyl-5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-N-phenyl-acetamide

Step A: 3- {6- [ (isopropyl-phenyl-carbamoyl) -methyl ] -5-oxo-1-phenyl-5, 6-dihydro-4H-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-4-ylmethyl } -indole-1-carboxylic acid tert-butyl ester

To 2- [4- (1H-indol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] at 0 deg.C]Azulen-6-yl]-N-isopropyl-N-phenyl-acetamide (example 6(A)) (250mg, 0.431mmol) in CH₂Cl₂(6mL) was added DMAP (5mg, 0.0431mmol) and di-tert-butyl dicarbonate (103mg, 0.47mmol) dissolved in CH₂Cl₂(3 mL). The reaction was stirred at room temperature for 4.5 hours. The reaction was diluted with water and dried (Na)₂SO₄) The organic layer was filtered and concentrated. By medium pressure chromatography using a solvent gradient (dissolved in CH)₂Cl₂Of 10% acetone-in CH₂Cl₂40% acetone) to afford 290mg of 3- {6- [ (isopropyl-phenyl-carbamoyl) -methyl group]-5-oxo-1-phenyl-5, 6-dihydro-4H-2, 3, 6, 10 b-tetraaza-benzo [ e [ -E ]]Azulen-4-ylmethyl } -indole-1-carboxylic acid tert-butyl ester.¹H NMR(CDCl₃)δ7.33-8.10(m，15H)，6.90-7.20(m，4H)，4.15-4.90(m，2H)，3.65-4.05(m，4H)，1.63(m 9H)，0.97(m，6H)；MS 681.2(M+1).

And B: 3- {6- [ (isopropyl-phenyl-carbamoyl) -methyl ] -4-methyl-5-oxo-1-phenyl-5, 6-dihydro-4H-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-4-ylmethyl } -indole-1-carboxylic acid tert-butyl ester

3- {6- [ (isopropyl-phenyl-carbamoyl) -methyl ] at-5 deg.C]-5-oxo-1-phenyl-5, 6-dihydro-4H-2, 3, 6, 10 b-tetraaza-benzo [ e [ -E ]]Azulen-4-ylmethyl } -indole-1-carboxylic acid tert-butyl ester (100mg, 0.14)7mmol) in DMF (2mL) was added KHMDS (0.5M in THF, 322. mu.L, 0.161 mmol). The solution was stirred at-5 ℃ for 20 min and iodomethane (10. mu.L, 0.161mmol) was added. The reaction was stirred at rt for 24 h, diluted with EtOAc and the organic solution was washed with brine (3 ×). Drying (Na)₂SO₄) The organic solution was filtered and concentrated. The residue was purified by preparative chromatography (2X) eluting with 50% EtOAc in hexane to give 34mg of 3- {6- [ (isopropyl-phenyl-carbamoyl) -methyl]-4-methyl-5-oxo-1-phenyl-5, 6-dihydro-4H-2, 3, 6, 10 b-tetraaza-benzo [ e ]]Azulen-4-ylmethyl } -indole-1-carboxylic acid tert-butyl ester.¹H NMR(CD₂Cl₂)δ8.05(d，1H)，7.67(d，1H)，7.36-7.54(m，10H)，7.08-7.30(m，6H)，6.90(d，1H)，5.02(m，1H)，4.29(d，1H)，4.11(m，1H)，2.78(s，2H)，1.80(s，3H)，1.64(s，9H)，1.10(m，6H)；MS 695.3(M+1).

And C: 2- [4- (1H-indol-3-ylmethyl) -4-methyl-5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-N-phenyl-acetamide

To 3- {6- [ (isopropyl-phenyl-carbamoyl) -methyl]-4-methyl-5-oxo-1-phenyl-5, 6-dihydro-4H-2, 3, 6, 10 b-tetraaza-benzo [ e ]]Azulen-4-ylmethyl } -indole-1-carboxylic acid tert-butyl ester in dioxane (1mL) HCl (4.0M in dioxane, 550. mu.L) was added and the reaction stirred at room temperature for 50 h. The volatiles were concentrated in vacuo and the residue was dissolved in CH₂Cl₂In (1). With NaHCO₃The organic solution was washed with aqueous solution (1 ×) and dried (Na)₂SO₄) Filtered and concentrated. By preparative chromatography using a solution in CH₂Cl₂Eluted with 40% acetone to provide 17mg of 2- [4- (1H-indol-3-ylmethyl) -4-methyl-5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ]]Azulen-6-yl]-N-isopropyl-N-phenyl-acetamide.¹H NMR(CD₂Cl₂)δ8.37(s，1H)，7.78(m，1H)，7.53-7.23(m，13H)，7.11(m，2H)，7.02(t，1H)，6.90(d，1H)，5.03(m，1H)，4.33(d，1H)，3.76-3.58(m，1H)，2.83(m，2H)，1.75(s，3H)，1.11(m，6H)；MS 595.2(M+1).

Example 5(A)

Preparation of 2- [1- (2-fluoro-phenyl) -4- (1H-indazol-3-ylmethyl) -5-oxo-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-N-phenyl-acetamide

Following the procedure described for preparation 4 (C); reacting 2-fluoro-benzoic acid hydrazide with 2- (4-ethoxy-2-oxo-2, 3-hydro-benzo [ b ]][1，4]Diaza * -1-yl) -N-isopropyl-N-phenyl-acetamide (preparation 5 (B)). This intermediate was reacted further according to steps a and B of example 3(B) above to provide 2- [1- (2-fluoro-phenyl) -4- (1H-indazol-3-ylmethyl) -5-oxo-4, 5-dihydro-2, 3, 6, 10B-tetraaza-benzo [ e]Azulen-6-yl]-N-isopropyl-N-phenyl-acetamide.¹H NMR(CD₂Cl₂)δ7.92(d，1H)，7.96(dt，1H)，7.59(d，1H)，7.33-7.50(m，7H)，7.15-7.25(m，4H)，7.02-7.10(m，2H)，6.82(dd，1H)，4.90-4.96(m，1H)，4.38(t，1H)，4.17(d，1H)，3.92-4.03(m，3H)，1.04(m，6H)；MS 600(M+1).

Example 5(B)

Preparation of 2- [ (1- (3-fluoro-phenyl) -4- (1H-indazol-3-ylmethyl) -5-oxo-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-N-phenyl-acetamide

Following the procedure described for preparation 4(C), step a; reacting 3-fluoro-benzoic acid hydrazide with 2- (4-ethoxy-2-oxo-2, 3-dihydro-benzo [ b ]][1，4]Diaza * -1-yl-N-isopropyl-N-phenyl-acetamide (PREPARATIONPreparation 5 (B)). This intermediate was reacted further according to example 3(B) steps a and B to provide 2- [1- (3-fluoro-phenyl) -4- (1H-indazol-3-ylmethyl) -5-oxo-4, 5-dihydro-2, 3, 6, 10B-tetraaza-benzo [ e [ -e ]]Azulen-6-yl]-N-isopropyl-N-phenyl-acetamide.¹H NMR(CD₂Cl₂)δ7.95(d，1H)，7.35-7.50(m，10H)，7.15-7.21(m，5H)，6.91(d，1H)，4.76-4.83(m，1H)，4.52(d，1H)，4.34(t，1H)，3.92-4.08(m，3H)，0.98(dd，6H)；MS 600(M+1).

Example 5(C)

Preparation of 2- [ 1-cyclohexyl-4- (1H-indazol-3-ylmethyl) -5-oxo-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-N-phenyl-acetamide

Following the procedure described for preparation 4(C), step a; reaction of cyclohexanecarboxylic acid hydrazide (preparation 14) with 2- (4-ethoxy-2-oxo-2, 3-dihydro-benzo [ b ]][1，4]Diaza * -1-yl) -N-isopropyl-N-phenyl-acetamide (preparation 5 (B)). This intermediate was reacted further according to example 3(B), steps a and B, to provide 2- [ 1-cyclohexyl-4- (1H-indazol-3-ylmethyl) -5-oxo-4, 5-dihydro-2, 3, 6, 10B-tetraaza-benzo [ e ]]Azulen-6-yl]-N-isopropyl-N-phenyl-acetamide.¹H NMR(CD₂Cl₂)δ7.92(d，1H)，7.51-7.61(m，3H)，7.37-7.50(m，6H)，7.16-7.20(m，3H)，4.85(m，1H)，4.24(m，1H)，4.00(d，1H)，3.93(d，1H)，2.77-2.85(m，1H)，2.17(d，1H)，1.91(d，2H)，1.07-1.66(br.m，3H)，1.01(dd，6H)；MS588(M+1).

Example 5(D)

Preparation of 2- [1- (4-fluoro-phenyl) -4- (1H-indazol-3-ylmethyl) -5-oxo-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-N-phenyl-acetamide

Following the procedure described in example 4(C), step a; reacting 4-fluorobenzoic acid hydrazide with 2- (4-ethoxy-2-oxo-2, 3-dihydro-benzo [ b ]][1，4]Diaza * -1-yl) -N-isopropyl-N-phenyl-acetamide (preparation 5 (B)). This intermediate was reacted further according to example 3(B) steps a and B to provide 2- [1- (4-fluoro-phenyl) -4- (1H-indazol-3-ylmethyl) -5-oxo-4, 5-dihydro-2, 3, 6, 10B-tetraaza-benzo [ e [ -e ]]Azulen-6-yl]-N-isopropyl-N-phenyl-acetamide.¹H NMR(CD₂Cl₂)δ7.92(d，1H)，7.64-7.67(m，2H)，7.32-7.44(m，7H)，7.07-7.20(m，6H)，6.87(d，1H)，4.77-4.84(m，1H)，4.48(d，1H)，4.32-4.36(m，1H)，3.91-4.05(m，3H)，0.98(dd，6H)；MS 600(M+1).

Example 5(E)

Preparation of N- (4-fluoro-phenyl) -2- [4- (1H-indazol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-acetamide

The procedure described in step A can be optionally prepared according to preparation 4 (C); 1-phenyl-4H, 6H-2, 3, 6, 10 b-tetraaza-benzo [ e ] using 2-bromo-N- (4-fluoro-phenyl) -N-isopropyl-acetamide (preparation 1(D)) (1.1g, 3.98mmol)]Azulen-5-one (preparation 4(A)) (1.0g, 3.62mmol) was alkylated. This intermediate was reacted further according to example 3(B) steps a and B to provide N- (4-fluoro-phenyl) -2- [4- (1H-indazol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10B-tetraaza-benzo [ e [ -l]Azulen-6-yl]-N-isopropyl-acetamide.¹H NMR(CD₂Cl₂)δ7.94(d，1H)，7.63(d，2H)，7.38-7.59(br.m，7H)，7.12-7.29(b r.m，6H)，6.90(d，1H)，4.79-4.86(m，1H)，4.36-4.45(br.m，2H)，3.95-4.05(br.m，3H)，0.98(dd，6H)；MS 600(M+1).

Example 6(A)

Preparation of 2- [4- (1H-indol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-N-phenyl-acetamide

Step A: 2- [4- (1H-indol-3-ylmethylene) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-N-phenyl-acetamide

To a solution of N-isopropyl-2- (5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl) -N-phenyl-acetamide (preparation 7(a)) (1.2g, 2.7mmol) in toluene (15mL) was added 1H-indole-3-carbaldehyde (0.46g, 3.2mmol) and piperidine (0.4 mL). The reaction mixture was heated to reflux for 14 hours. Activated 4 Å molecular sieve (2g) was added and the reaction mixture was refluxed for 24 hours. The sieve was removed by filtration and the filtrate was concentrated. The residue was triturated with dichloromethane and the solid collected by filtration and dried in vacuo to give 1.5g 2- [4- (1H-indol-3-ylmethylene) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-N-phenyl-acetamide. The filtrate was concentrated and purified by chromatography (20% acetone/dichloromethane) to provide an additional 320mg of 2- [4- (1H-indol-3-ylmethylene) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-N-phenyl-acetamide. MS 579.2(M +1).

And B: 2- [4- (1H-indol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-N-phenyl-acetamide

To 10% Pd/C and EtOH was added 2- [4- (1H-indol-3-ylmethylene) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ]]Azulen-6-yl]-N-isopropyl-N-phenyl-acetamide (0.71g, 1.2 mmol). Another 25mL EtOH was added, followed byAmmonium formate (0.77g, 12.2mmol) was added. The reaction mixture was heated at 80 ℃ for 6 hours. Through Celite^®The catalyst was removed by filtration and the filtrate was concentrated. The residue was dissolved in ethyl acetate and taken up with saturated NaHCO₃The organic solution is washed. The organic phase was dried over sodium sulfate and concentrated. The crude product was purified by chromatography (0% to 18% acetone/dichloromethane) to give 128mg of 2- [4- (1H-indol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ]]Azulen-6-yl]-racemic mixture of N-isopropyl-N-phenyl-acetamide.¹H NMR(CD₂Cl₂)δ8.18(s，1H)，7.64(dd，2H)，7.55(dd，1H)，7.510-7.41(m，8H)，7.36(dd，1H)，7.25(m，3H)，7.09(m，2H)，7.027(m，1H)，6.85(dd，1H)，4.86(m，1H)，4.40(br d，1H)，4.04(dd，1H)，3.79(m，3H)，1.03(dd，6H)；MS 581.4(M+1).

Example 6(B)

Preparation of (-)2- [4- (1H-indol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-N-phenyl-acetamide, enantiomer 1

Racemic 2- [4- (1H-indol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] using a Chiralpak AD column (10 cm. times.50 cm) eluting with heptane/ethanol (80: 20) at a flow rate of 250 mL/min]Azulen-6-yl]-N-isopropyl-N-phenyl-acetamide (example 6(A)) separated into its enantiomers providing (-)2- [4- (1H-indol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] with a retention time of 8.64 min]Azulen-6-yl]-N-isopropyl-N-phenyl-acetamide (enantiomer 1). MS 581(M + 1); [ alpha ] to]_D ²⁰-91.4(c 1.04, ethanol)

Example 6(C)

Preparation of 2- [ 1-cyclohexyl-4- (1H-indol-3-ylmethyl) -5-oxo-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-N-phenyl-acetamide

Following the procedure described in example 6(a), step a; reacting 2- (1-cyclohexyl-5-oxo-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ]]Azulen-6-yl) -N-isopropyl-N-phenyl-acetamide (preparation 8(B)) is condensed with 1H-indole-3-carbaldehyde. This intermediate was reacted further as in step B of example 6(A) to provide 2- [ 1-cyclohexyl-4- (1H-indol-3-ylmethyl) -5-oxo-4, 5-dihydro-2, 3, 6, 10B-tetraaza-benzo [ e ]]Azulen-6-yl]-N-isopropyl-N-phenyl-acetamide.¹H NMR(CD₂Cl₂)δ8.44(s，1H)，7.42-7.48(m，4H)，7.28-7.42(m，4H)，7.17-7.19(m，2H)，7.07-7.10(m，1H)，6.98-7.02(m，1H)，4.90-4.94(m，1H)，4.07-4.15(m，1H)，3.91(d，1H)，3.67-3.73(m，2H)，2.83(br.m，1H)，2.19(br.m，1H)，1.89-1.92(m，2H)，1.68(br.s，4H)，1.50-1.59(m，1H)，1.32-1.35(m，2H)，1.23(t，1H)，1.06(m，6H)；MS 587(M+1).

Example 6(D)

Preparation of 2- [1- (2-fluoro-phenyl) -4- (1H-indol-3-ylmethyl) -5-oxo-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-N-phenyl-acetamide

Following the procedure described in example 6(a), step a; reacting 2- (1- (2-fluorophenyl) -5-oxo-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ]]Azulen-6-yl) -N-isopropyl-N-phenyl-acetamide (preparation 7(B)) is condensed with 1H-indole-3-carbaldehyde. This intermediate was reacted further as in example 6(a), step B, to provide 2- [ -1 (2-fluoro-phenyl) -4- (1H-indol-3-ylmethyl) -5-oxo-4, 5-dihydro-2, 3, 6, 10B-tetraaza-benzo [ e [ -E ]]Azulen-6-yl]-N-isopropyl group-N-phenyl-acetamide.¹H NMR(CD₂Cl₂)δ8.26(s，1H)，7.71-7.74(m，1H)，7.60-7.67(m，2H)，7.40-7.59(m，6H)，7.34-7.38(m，2H)，7.23-7.32(br.m，2H)，7.14-7.20(m，1H)，7.05-7.12(m，3H)，6.81-6.83(m，1H)，4.98-5.03(m，1H)，4.28(d，1H)，3.93(d，1H)，3.83-3.84(m，3H)，1.12(d，6H)；MS 599(M+1).

Example 7

Preparation of 2- [4- (1H-indol-3-ylmethylene) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-N-phenyl-acetamide

To a solution of N-isopropyl-2- (5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl) -N-phenyl-acetamide (preparation 7(a)) (1.2g, 2.7mmol) and piperidine (0.4mL, 1.33mmol) in toluene was added 1H-indole-3-carbaldehyde (0.46g, 3.2 mmol). The reaction mixture was heated at 110 ℃ for 31 hours. Activated 4 Å molecular sieves (2g) were added. The reaction mixture was heated at 110 ℃ for 24 hours. The reaction was cooled to room temperature and the molecular sieve was filtered with the aid of toluene. The filtrate was concentrated and the residue purified by chromatography (12% -20% acetone/methylene bis helium) to give 1.5g 2- [4- (1H-indol-3-ylmethylene) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-N-phenyl-acetamide as a solid. MS 579.2(M +1).

Example 8

The compounds in the following table can be prepared by procedures similar to those described in the examples above.

Preparation 1(A)

Preparation of 2-bromo-N-isopropyl-N-phenyl-acetamide

To N-isopropylaniline (21.58g, 180mmol) was dissolved in CH₂Cl₂To the solution (350mL) was added triethylamine (26.7mL, 190 mmol). The solution was cooled to 0 ℃ and bromoacetyl bromide (14.0mL, 160mmol) was added slowly over 1 hour. The reaction was warmed to room temperature and stirred for 24 hours. The reaction was diluted with 5% aqueous HCl. Using 5% aqueous HCl (2X), NaHCO₃The organic solution was washed with aqueous solution (1x), and brine (1 x). Filtering the organic solution through a silica gel pad with CH₂Cl₂And (4) eluting. Recrystallization from hexane (60mL) provided 22.47g of 2-bromo-N-isopropyl-N-phenyl-acetamide.¹H NMR(CD₂Cl₂)δ7.45(m，3H)，7.21(m，2H)，4.89(m，1H)，3.52(s，2H)，1.05(d，6H)；MS 256.2(M+1).

Preparation 1(B)

Preparation of 2-bromo-N-isopropyl-N- (6-methoxy-pyridin-3-yl) -acetamide

The method comprises the following steps:

step A: isopropylidene- (6-methoxy-pyridin-3-yl) -amines

To a solution of 5-amino-2-methoxypyridine (18g, 161mmol) in methanol (80mL) was added acetone (20mL, 177 mmol).The reaction was heated to reflux for 24 h, and the volatiles were concentrated in vacuo to afford 21.3g of isopropylidene- (6-methoxy-pyridin-3-yl) -amine.¹H NMR(CDCl₃)δ7.59(d，1H)，7.31(m，1H)，6.70(d，1H)，3.91(s，3H)，2.20(s，3H)，1.85(s，3H).

And B: isopropyl- (6-methoxy-pyridin-3-yl) -amine

To a solution of isopropylidene- (4-methoxy-phenyl) -amine (21.3g, 129mmol) in a mixture of EtOH (100mL) and MeOH (50mL) was added NaBH 3 times at 0 deg.C₄(14.7g, 389 mmol). The reaction was stirred at room temperature for 3 hours and diluted with water. The aqueous layer was washed with EtOAc (3X) and dried (MgSO)₄) The combined organic extracts were filtered and concentrated. By medium pressure chromatography using a solvent gradient (dissolved in CH)₂Cl₂2% MeOH in CH₂Cl₂12% MeOH in) to afford 11.26g of isopropyl- (6-methoxy-pyridin-3-yl) -amine.¹H NMR(CDCl₃)δ7.55(d，1H)，6.96(dd，1H)，6.61(d，1H)，3.86(s，3H)，3.52(m，1H)，1.19(d，6H).

The method 2 comprises the following steps:

step A: isopropyl- (6-methoxy-pyridin-3-yl) -amine

To a solution of 5-amino-2-methoxypyridine (747mg, 6.02mmol) in CH₂Cl₂To a solution (50mL) was added acetone (500. mu.L) and sodium triacetoxyborohydride (1.95g, 9.20 mmol). The reaction was stirred at room temperature for 20 h and NaHCO₃And (5) diluting the aqueous solution. By CH₂Cl₂(3X) Wash the aqueous solution and wash the combined organic solution with brine (1X), dry (MgSO)₄) Filtered and concentrated. The residue was purified by medium pressure chromatography, eluting with a solvent gradient (5% EtOAc in hexanes to 50% EtOAc in hexanes) to provide 810mg of isopropyl- (6-methoxy-pyridin-3-yl) -amine.¹H NMR(CDCl₃)δ7.55(s，1H)，6.96(dd，1H)，6.61(d，1H)，3.86(s，3H)，3.52(m，1H)，1.19(d，6H).

And B: 2-bromo-N-isopropyl-N- (6-methoxy-pyridin-3-yl) -acetamide

To isopropyl- (6-methoxy-pyridin-3-yl) -amine (6.73g, 41.0mmol) was dissolved in CH over 0.5 h at 0 deg.C₂Cl₂To a solution (130mL) was added diisopropylethylamine (7.15mL, 41.0mmol) followed by CH dissolved₂Cl₂Bromoacetyl bromide (8.28g, 41.0mmol) in (60 mL). The reaction was stirred at room temperature for 24 hours and diluted with water. The organic solution was washed with brine (1 ×) and dried (MgSO)₄) Filtered and concentrated. By medium pressure chromatography using a solvent gradient (dissolved in CH)₂Cl₂1% MeOH in CH₂Cl₂MeOH) to provide 2.27g of 2-bromo-N-isopropyl-N- (6-methoxy-pyridin-3-yl) -acetamide.¹H NMR(CD₃OD)δ8.08(d，1H)，7.62(dd，1H)，6.89(d，1H)，4.84(m，1H)，3.9(s，3H)，3.60(s，2H)，1.06(m，6H).

Preparation 1(C)

Preparation of N-benzyl-2-bromo-N-isopropyl-acetamide

To N-isopropylbenzylamine (40mL, 240mmol) was dissolved CHCl₃Et (300mL) was added to the solution₃N (36.8 mL). The reaction was cooled to 0 ℃ and bromoacetyl bromide (21.8mL, 251mmol) was added. The mixture was stirred at room temperature for 24 hours and CH₂Cl₂And (6) diluting. Successively with 5% aqueous HCl (1X) and NaHCO₃The organic solution was washed with aqueous solution (1 ×). Drying (Na)₂SO₄) The organic solution was filtered and concentrated. The residue was dissolved in 40% EtOAc in hexanes and filtered through a pad of silica gel to provide 52.2g N-benzyl-2-bromo-N-isopropyl-acetamide.¹H NMR(CD₂Cl₂)δ7.20-7.40(m，5H)，4.53(d，2H)，4.22(m)and 4.74(m，total1H)，4.01(s，1H)，3.72(s，1H)，1.20(d，3H)，1.12(d，3H).

Preparation 1(D)

Preparation of 2-bromo-N- (4-fluoro-phenyl) -N-isopropyl-acetamide

The process described under 1 (A); alkylation of (4-fluoro-phenyl) -isopropyl-amine (13.70g, 89.54mmol) with bromoacetyl bromide (7.78mL, 89.54mmol) provided 15.02g of 2-bromo-N- (4-fluoro-phenyl) -N-isopropyl-acetamide as an oil.¹H NMR(CD₂Cl₂)δ7.14-7.23(m，4H)，4.90(m，1H)，3.53(s，2H)，1.05(d，6H).

Preparation 2(A)

Preparation of (6-chloro-pyridin-3-yl) -isopropyl-amine

To a solution of 2-chloro-5-aminopyridine (500mg, 3.88mmol) and acetone (250. mu.L, 4.27mmol) in dichloroethane (13mL) was added NaBH (OAc)₃(989mg, 4.66mmol) and AcOH (330. mu.L, 5.82 mmol). The reaction was stirred for 24 hours and diluted with 1N NaOH. By CH₂Cl₂(3x) an aqueous wash solution. Drying (Na)₂SO₄) The combined organic solutions were filtered and concentrated. By medium pressure chromatography using a solvent gradient (dissolved in CH)₂Cl₂2% MeOH in CH₂Cl₂MeOH) to provide 505.2mg (6-chloro-pyridin-3-yl) -isopropyl-amine.¹H NMR(CD₃OD)δ7.64(d，1H)，7.10(d，1H)，6.99(dd，1H)，3.55(m，1H)，1.17(d，6H).

Preparation 2(B)

Preparation of (6-ethoxy-pyridin-3-yl) -isopropyl-amine

Following the procedure described for preparation 2(A), 6-ethoxy-pyridin-3-ylamine (10g, 72.4mmol) was reacted with acetone (4.8mL) to provide 11.18g (6-ethoxy-pyridin-3-yl) -isopropyl-amine.¹H NMR(CD₃OD)δ7.48(d，1H)，7.11(dd，1H)，6.61(d，1H)，4.14(q，2H)，3.48(m，1H)，1.32(t，3H)，1.14(d，6H)；MS 181.3(M+1).

Preparation 3(A)

Preparation of 4-ethoxy-1, 3-dihydro-benzo [ b ] [1, 4] diaza * -2-one

Ethyl 3, 3-diethoxyacrylate (30.0g, 159.2mmol) in xylene (80mL) was added dropwise over 50 minutes at 140 ℃ to a solution of phenylenediamine (17.2g, 159.2mmol) and acetic acid (0.4mL) in xylene (225 mL). The reaction was heated at 140 ℃ for 2 hours, cooled to room temperature and stirred for 24 hours. The resulting white precipitate was filtered, washed with diethyl ether (100mL) and dried under vacuum to provide 18.37g of 4-ethoxy-1, 3-dihydro-benzo [ b ] [1, 4] diazepin * -2-one as a white fluffy solid. MS 205(M +1).

Preparation 3(B)

Preparation of 4-ethoxy-7, 8-difluoro-1, 3-dihydro-benzo [ b ] [1, 4] diaza * -2-one

To a solution of 1, 2-diamino-4, 5-difluorobenzene (4.0g, 27.75mmol) in xylene (50mL) at 140 ℃ over 1 hour was added acetic acid (200 μ L), followed by a solution of ethyl 3, 3-diethoxyacrylate (5.22g, 27.75mmol) in xylene (25 mL). Heating the reactants at 140 deg.CAfter 2 hours, cool to room temperature and concentrate. The residue was triturated in hexane to give 5.38g of 4-ethoxy-7, 8-difluoro-1, 3-dihydro-benzo [ b ]][1，4]Diaza * -2-one.¹H NMR(CDCl₃)δ7.05(q，1H)，6.87(q，1H)，4.29(q，2H)，3.18(s，2H)，1.35(t，3H).

Preparation 4(A)

Preparation of 1-phenyl-4H, 6H-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-5-one

To 4-ethoxy-1, 3-dihydro-benzo [ b ]][1，4]Diaza * -2-one (preparation 3(A) (5g, 24mmol) in glacial AcOH (75mL) benzoic acid hydrazide (3.33g, 24.5mmol) was added to the solution, the reaction mixture was heated to 120 ℃ for 2 hours and cooled to room temperature, the solvent was removed in vacuo by azeotropic distillation with heptane (2X), the residue was dissolved in a minimal amount of dichloromethane and 100mL saturated NaHCO was added with stirring₃To a solution of/100 mL water was slowly poured 50mL of ethyl acetate and the solution. Ether (150mL) was added and the mixture was stirred for 5 min. The precipitate was collected by filtration and washed with water and a minimum of diethyl ether to provide 5.89g of 1-phenyl-4H, 6H-2, 3, 6, 10 b-tetraaza-benzo [ e ]]Azulen-5-one.¹H NMR(CDCl₃)δ9.02(br s，1H)，7.48-7.36(m，6H)，7.10(t，1H)，6.95(d，1H)，4.23(d，1H)，3.60(d，1H)；MS 277(M+1).

Preparation 4(B)

Preparation of 1-cyclohexyl-4H, 6H-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-5-one

To 4-ethoxy-1, 3-dihydro-benzo [ b ]][1，4]To a solution of diaza * -2-one (preparation 3(A) (5g, 24.5mmol) in glacial acetic acid (75mL) was added cyclohexanecarboxylic acid hydrazide (preparation 14) (3.5g, 24.5 mmol). The reaction was heated at 120 ℃ for 2.5 h, cooled to room temperature, and EtOAc (50mL), water (50mL) and NaHCO were added₃Aqueous solution (50 mL). The mixture was stirred for 5 min and Et was added₂O (125 mL). The suspension was stirred for 15 minutes and aided by Et₂O filtration removed the solid to give 5.92g1 of cyclohexyl-4H, 6H-2, 3, 6, 10 b-tetraaza-benzo [ e ]]Azulen-5-one.¹H NMR(CDCl₃)δ8.36(s，NH)，7.50(m，1H)，7.41(m，2H)，7.30(d，1H)，4.13(d，1H)，3.47(d，1H)，2.87(m，1H)，2.24(d，1H)，2.00(m，2H)，1.72-1.51(m，4H)，1.33(m，2H)，1.16(m，1H)；MS 283.4(M+1)，281.3(M-1).

Preparation 4(C)

Preparation of 8, 9-difluoro-1-phenyl-4H, 6H-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-5-one

To 4-ethoxy-7, 8-difluoro-1, 3-dihydro-benzo [ b ]][1，4]Diaza * -2-one (preparation 3(B) (5.38g, 22.4mmol) in acetic acid (100mL) was added benzoic acid hydrazide (3.11g, 22.85 mmol). The reaction was heated to 120 deg.C for 18 h and the volatiles concentrated in vacuo₂Cl₂NaHCO is used for neutralization₃The organic solution (1X) was washed with aqueous solution and dried (Na)₂SO₄) Filtered and concentrated. The solid residue was triturated with a warm mixture of EtOAc and hexanes and filtered. In Et₂The solid was triturated in 50% hexane in O to give 3.97g 8, 9-difluoro-1-phenyl-4H, 6H-2, 3, 6, 10 b-tetraaza-benzo [ e ]]Azulen-5-one.¹H NMR(DMSO-d₆)δ7.52-7.36(m，6H)，7.06(m，1H)，3.91(d，1H)，3.76(d，1H)；MS 313.1(M+1)，311.1(M-1).

Preparation 5(A)

Preparation of 2- (4-ethoxy-2-oxo-2, 3-dihydro-benzo [ b ] [1, 4] diaza * -1-yl) -N-isopropyl-N- (6-methoxy-pyridin-3-yl) -acetamide

4-ethoxy-1, 3-dihydro-benzo [ b ] at 0 DEG C][1，4]Diaza * -2-one (preparation 3(A) (2g, 9.79mmol) in DMF (40mL) was added NaH (60% in oil, 431mg, 10.8 mmol.) the reaction was stirred at 0 deg.C for 0.5 h and 2-bromo-N-isopropyl-N- (6-methoxy-pyridin-3-yl) -acetamide (preparation 1(B) (2.95g, 10.28mmol) in DMF (5mL) was added the reaction stirred at room temperature for 2h and water, brine, and CH₂Cl₂And (6) diluting. By CH₂Cl₂(3X) Wash the aqueous solution and wash the combined organic layers with brine, dry (MgSO₄) Filtered and concentrated in vacuo. Purification by medium pressure chromatography, eluting with a solvent gradient (hexane-70% EtOAc in hexane) afforded 2.87g of 2- (4-ethoxy-2-oxo-2, 3-dihydro-benzo [ b ]][1，4]Diaza * -1-yl) -N-isopropyl-N- (6-methoxy-pyridin-3-yl) -acetamide.¹H NMR(CDCl₃)δ8.14(s)and 7.93(s，total 1H)，7.54(m，1H)，7.31(m，1H)，7.24-7.08(m，3H)，6.80(m，1H)，5.05(m，1H)，4.29(m，2H)，4.09(m，1H)，3.95(m，3H)，3.67(d，1H)，3.31(d，1H)，3.08(d，1H)，1.32(m，3H)，1.09(m，6H).

Preparation 5(B)

Preparation of 2- (4-ethoxy-2-oxo-2, 3-dihydro-benzo [ b ] [1, 4] diaza * -1-yl) -N-isopropyl-N-phenyl-acetamide

To a solution of 4-ethoxy-1, 3-dihydro-benzo [ b ] [1, 4] diaza * -2-one (preparation 3(A) (5.0g, 24.5mmol) in DMF (100mL) was added potassium bistrimethylsilylamide (49mL of a 0.5M solution in toluene, 24.5mmol) at 0 deg.C, the reaction mixture was stirred for 20 minutes and cooled to-17 deg.C, a solution of 2-bromo-N-isopropyl-N-phenyl-acetamide (preparation 1(A) (6.9g, 27mmol) in DMF (50mL) was added dropwise, the reaction mixture was stirred at an internal temperature of less than-15 deg.C-16 deg.C for 1 hour, warmed to room temperature and diluted with ethyl acetate, the organic phase was washed with brine, dried over sodium sulfate and concentrated, the resulting light brown solid was triturated with diethyl ether to obtain 3.2g of a white powder of 2- (4-ethoxy-2-oxo-2-one 3-dihydro-benzo [ b ] [1, 4] diazepine * -1-yl) -N-isopropyl-N-phenyl-acetamide. The filtrate was concentrated and the residue was triturated with ether/hexane. The solid was collected by filtration to give a second crop of harvested 2- (4-ethoxy-2-oxo-2, 3-dihydro-benzo [ b ] [1, 4] diazepin * -1-yl) -N-isopropyl-N-phenyl-acetamide (3.4 g). MS 380.2(M +1).

Preparation 6

Preparation of 2- [1- (3-benzyloxy-phenyl) -5-oxo-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-N- (6-methoxy-pyridin-3-yl) -acetamide

Reacting 2- (4-ethoxy-2-oxo-2, 3-dihydro-benzo [ B ] with the process described in preparation 4(B)][1，4]Diaza * -1-yl) -N-isopropyl-N- (6-methoxy-pyridin-3-yl) -acetamide (preparation 5(A) (150mg, 0.365mmol) was reacted with 3-benzyloxyphenylhydrazide (benzydrazide) (88mg, 0.365mmol) to provide 129mg of 2- [1- (3-benzyloxy-phenyl) -5-oxo-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] (N-phenyl-ethyl-phenyl) -5-oxo-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ]]Azulen-6-yl]-N-isopropyl-N- (6-methoxy-pyridin-3-yl) -acetamide.¹H NMR(CD₃OD)δ8.06(d，1H)，7.59(m，2H)，7.51(t，1H)，7.40-7.28(m，8H)，7.19(t，1H)，7.13(d，1H)，6.97(d，1H)，6.91(d，1H)，5.01(d，1H)，4.91(d，1H)，4.76(m，1H)，4.60(m，1H)，4.12(m，1H)，3.95(s，4H)，3.75(d，1H)，0.91(m，6H)；MS 589.8(M+1)，587.5(M-1).

Preparation 7(A)

Preparation of N-isopropyl-2- (5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl) -N-phenyl-acetamide

To 2- (4-ethoxy-2-oxo-2, 3-dihydro-benzo [ b ]][1，4]Diaza * -1-yl) -N-isopropyl-N-phenyl-acetamide (preparation 5(B) (71.14g, 0.187mol) was dissolved in 1.04L AcOH and benzoic acid hydrazide (27.28g, 0.196mol) was added in one portion. The reaction was heated to 80 ℃ and stirred for 4 hours. The reaction was cooled to room temperature and the AcOH removed in vacuo to afford an off-white solid. The solid was dissolved in 1L of dichloromethane. With 1L saturated NaHCO₃The organic solution was washed with brine and then Na₂SO₄And drying. The dichloromethane solution was diluted with an equal volume of methyl tert-butyl ether and the resulting solution was concentrated in vacuo to a small volume, causing the precipitation of a white solid. The precipitate was collected on a sintered glass funnel and washed with methyl tert-butyl ether. The solid was dried in vacuo to give 81.41g of N-isopropyl-2- (5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] as a white solid]Azulen-6-yl) -N-phenyl-acetamide.¹H NMR(CD₂Cl₂)δ7.57-7.35(m，10H)，7.27(br s，1H)，7.21(br s，1H)，7.10(t，1H)，6.87(d，1H)，4.89(m，1H)，4.19-3.99(m，3H)，3.53(d，1H)，1.03(m，6H)；MS 452.3(M+1)，450.5(M-1).

Preparation 7(B)

Preparation of 2- (1- (2-fluorophenyl) -5-oxo-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl) -N-isopropyl-N-phenyl-acetamide

Reacting 2- (4-ethoxy-2-oxo-2, 3-dihydro-benzo [ b ] according to the procedure described for preparation 7(A)][1，4]Diaza * -1-yl) -N-isopropyl-N-phenyl-acetamide (preparation 5(B) (200mg, 0.527mmol) was reacted with 2-fluorobenzenehydrazide (81mg, 0.527 mmol). By medium pressure chromatography using a solvent gradient (CH)₂Cl₂-is soluble in CH₂Cl₂MeOH) to afford 180.2mg of 2- (1- (2-fluorophenyl) -5-oxo-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ]]Azulen-6-yl) -N-isopropyl-N-phenyl-acetamide.¹H NMR(CD₂Cl₂)δ7.73(m，1)，7.64(d，1)，7.91-7.18(m，8)，7.12-7.00(m，2)，6.83(d，1)，4.96(m，1)，4.23(d，1)，4.06(d，1)，3.80(d，1)，3.58(d，1)，1.09(d，6)；MS 470.3(M+1)

Preparation 8(A)

Preparation of 2- (1-cyclohexyl-5-oxo-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl) -N-isopropyl-N- (6-methoxy-pyridin-3-yl) -acetamide

To 1-cyclohexyl-4H, 6H-2, 3, 6, 10 b-tetraaza-benzo [ e ] at 0 DEG C]Azulen-5-one (preparation 4(B) (100mg, 0.354mmol) in DMF (10mL) was added NaH (60%, dissolved in oil, 15mg, 0.372 mmol). The reaction was stirred at 0 deg.C for 30 min, cooled to-10 deg.C and 2-bromo-N-isopropyl-N- (6-methoxy-pyridin-3-yl) -acetamide (preparation 1(B) (107mg, 0.372mmol) in DMF (1mL) was added and the reaction stirred at room temperature for 24 h and diluted with water. the aqueous solution was washed with EtOAc (3X). The aqueous solution was dried (MgSO (3X). The reaction solution was then diluted with EtOAc), and the reaction solution was cooled and washed with water₄) The combined organic solutions were filtered and concentrated. The residue was purified by medium pressure chromatography, eluting with a solvent gradient (1% EtOAc-100% EtOAc in hexane), to give 861.8mg of 2- (1-cyclohexyl-5-oxo-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ]]Azulen-6-yl) -N-isopropyl-N- (6-methoxy-pyridin-3-yl) -acetamide.¹H NMR(CDCl₃)δ8.11-7.48(m，total 3H)，7.36(m，3H)，6.79(dd，1H)，4.99(m，1H)，4.12(m，2H)，3.92(d，3H)，3.65(d)and 3.82(d，total1H)，3.46(dd，1H)，2.83(m，1H)，2.20(d，1H)，2.03-1.86(m，3H)，1.68(m，2H)，1.54(m，2H)1.31-1.41(m，2H)，1.07(m，6H)；MS 489.4(M+1)，487.4(M-1).

Preparation 8(B)

Preparation of 2- (1-cyclohexyl-5-oxo-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl) -N-isopropyl-N-phenyl-acetamide

1-cyclohexyl-4H, 6H-2, 3, 6, 10 b-tetraaza-benzo [ e ] using 2-bromo-N-isopropyl-N-phenyl-acetamide (preparation 1(A)) (580mg, 0.226mmol) according to the procedure described for preparation 8(A)]Azulen-5-one (preparation 4(B) (640mg, 0.226nmol) was alkylated by medium pressure chromatography using a solvent gradient (CH)₂Cl₂-is soluble in CH₂Cl₂MeOH) to provide 668mg of 2- (1-cyclohexyl-5-oxo-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ]]Azulen-6-yl) -N-isopropyl-N-phenyl-acetamide.¹H NMR(CDCl₃)δ7.62-7.31(m，9)，4.93(m，1)，4.10(d，1)，3.91(d，1)，3.76(d，1)，3.45(d，1)，2.85(m，1)，2.19(br.d.，1)，1.91(m，2)，1.69-1.11(m，7)，1.06(m，6)：MS 458.4(M+1).

Preparation 9

Preparation of N-benzyl-2- (8, 9-difluoro-5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl) -N-isopropyl-acetamide

To a solution of KHMDS (0.5M in THF, 16.6mL, 8.33mmol) at 0 deg.C8, 9-difluoro-1-phenyl-4H, 6H-2, 3, 6, 10 b-tetraaza-benzo [ e ] in DMF (20mL) was added]Azulen-5-one (preparation 4(C) (2.0g, 6.4 mmol.) the reaction was stirred at 0 ℃ for 35 minutes, cooled to-10 ℃ and N-benzyl-2-bromo-N-isopropyl-acetamide (preparation 1(C) (1.9g, 7.0mmol) in DMF (20mL) was added-the reaction was stirred at 10 ℃ for 2 hours and the reaction was stirred at room temperature for 24 hours-the reaction was quenched with pH 6.8 buffer and the aqueous solution was washed with EtOAc (3X). the combined organic solution was washed with brine (4X), dried (Na)₂SO₄) Filtered and concentrated. By medium pressure chromatography using a solvent gradient (CH)₂Cl₂-is soluble in CH₂Cl₂MeOH) to afford 2.01g N-benzyl-2- (8, 9-difluoro-5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ]]Azulen-6-yl) -N-isopropyl-acetamide.¹H NMR(CD₂Cl₂)δ7.60-7.17(m，11H)，6.75(q，1H)，4.85-4.38(m，4H)，4.10(q，1H)，3.60(q，1H)，3.41(s，1H)，1.21(q，3H)，1.13(q，3H)；MS 502.4(M+1)，500.3(M-1).

Preparation 10

Preparation of N-benzyl-N-isopropyl-2- (5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl) -acetamide

To 1-phenyl-4H, 6H-2, 3, 6, 10 b-tetraaza-benzo [ e ] at 0 DEG C]To a solution of azulen-5-one (preparation 4(A) (30.0g, 108mmol) in DMF (200mL) was added NaHMDS (1.0M in THF, 13.6g, 118mmol) and N-benzyl-2-bromo-N-isopropyl-acetamide in DMF (25mL) (preparation 1(C) (35.2g, 130mmol) the reaction was stirred at room temperature for 24 h and diluted with pH 6.8 phosphate buffer, the aqueous solution was washed with EtOAc (3X), the combined organic solution was washed with brine (3X), dried (Na)₂SO₄) Filtered and concentrated. By medium pressure chromatography using a solvent gradient (CH)₂Cl₂-is soluble in CH₂Cl₂12% acetone) to afford 13.9g N-benzyl-N-isopropyl-2- (5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ]]Azulen-6-yl) -acetamide.¹H NMR(CDCl₃)δ7.64-7.55(m，2H)，7.44-7.08(m，11H)，6.89(m，1H)，4.96-4.08(m，6H)，3.57(m，1H)，1.17(m，6H).

Preparation 11

Preparation of N-isopropyl-N- (6-methoxy-pyridin-3-yl) -2- (5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl) -acetamide

To 1-phenyl-4H, 6H-2, 3, 6, 10 b-tetraaza-benzo [ e ] at 0 DEG C]Azulen-5-one (preparation 4(A) (6.05g, 21.9mmol) in DMF (120mL) was added NaH (60%, dissolved in oil, 920mg, 23.0 mmol). The reaction was stirred at 0 deg.C for 30 min and isopropyl- (6-methoxy-pyridin-3-yl) -amine (preparation 1(B) (6.21g, 23.0mmol) was added and the reaction stirred at room temperature for 24 h and diluted with water. the aqueous solution was washed with EtOAc (3X). the combined organic solution was washed with water, dried (MgSO 2)₄) Filtered and concentrated. By medium pressure chromatography using a solvent gradient (dissolved in CH)₂Cl₂2% MeOH in CH₂Cl₂MeOH) to afford 8.16g N-isopropyl-N- (6-methoxy-pyridin-3-yl) -2- (5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ]]Azulen-6-yl) -acetamide.¹H NMR(CD₃OD)δ8.10(m，1H)，7.62(m，4H)，7.52(t，2H)，7.43(t，2H)，7.19(t，1H)，6.94(t，2H)，4.82(m，1H)，4.52(d，1H)，4.16(m，1H)，3.96(m，4H)，3.79(d，1H)，1.02(m，6H)；MS 483.3(M+1)，481.1(M-1).

Preparation 12

Preparation of 2- [1- (3-hydroxy-phenyl) -5-oxo-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-N-phenyl-acetamide

To 2- (4-ethoxy-2-oxo-2, 3-dihydro-benzo [ b ]][1，4]Diaza * -1-yl) -N-isopropyl-N-phenyl-acetamide (preparation 5(B) (177mg, 0.466mmol) in glacial acetic acid (4mL) was added 3-hydroxybenzhydrazide (90mg, 0.591 mmol). The reaction was heated to 120 ℃ for 3 hours, cooled to room temperature and concentrated in vacuo. With 50% Et in hexane₂The residue was triturated and the solid was filtered. Dissolving the solid in CH₂Cl₂NaHCO is used for neutralization₃The organic solution was washed with aqueous solution and dried (MgSO)₄) Concentrated to give 244mg of 2- [1- (3-hydroxy-phenyl) -5-oxo-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ]]Azulen-6-yl]-N-isopropyl-N-phenyl-acetamide.¹H NMR(CD₃OD)δ7.74(s，2H)，7.56-7.18(m，10H)，6.91(m，1H)，4.86(m，1H)，4.30-4.10(m，2H)，3.98(d，1H)，3.71(d，1H)，1.06(m，6H).

Preparation 13

Preparation of (5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl) -acetic acid tert-butyl ester

1-phenyl-4H, 6H-2, 3, 6, 10 b-tetraaza-benzo [ e ] using tert-butyl bromoacetate (2.94mL, 19.9mmol) according to the procedure described for preparation 13(A)]Azulen-5-one (preparation 4(A)) (5.0g, 18.1mmol) was alkylated. With Et₂Trituration of O (100mL), hexanes (30mL) and EtOAc (10mL) provided 3.13g (5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ]]Azulen-6-yl) -acetic acid tert-butyl ester.¹H NMR(CD₃OD)δ7.68(d，1H)，7.60-7.51(m，4H)，7.43(m，2H)，7.23(t，1H)，6.99(d，1H)，4.86(d，1H)，4.44(d，1H)，3.99(d，1H)，3.83(d，1H)，1.36(s，9H)；MS 391.4(M+1)，389.3(M-1).

Preparation 14

Preparation of cyclohexanecarboxylic acid hydrazide

To a solution of methyl cyclohexanecarboxylate (12g, 83.9mmol) in MeOH (50mL) was added hydrazine (5.3mL, 1.67 mol). The reaction mixture was heated at 65 ℃ overnight. The reaction mixture was cooled to room temperature, and the resulting solid was collected by filtration and dried in vacuo to give 4.0g of cyclohexanecarboxylic acid hydrazide.

Preparation 15

Preparation of [4- (1H-indol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -acetic acid

Step A: [4- (1H-indol-3-ylmethylene) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -acetic acid tert-butyl ester

To a solution of (5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10B-tetraaza-benzo [ e ] azulen-6-yl) -acetic acid tert-butyl ester (preparation 13(B)) (3.66g, 9.37mmol) in toluene (94mL) was added 1H-indole-3-carbaldehyde (1.63g, 11.2mmol) and piperidine (2.78mL, 28.1 mmol). The reaction was heated to 110 ℃ in a Soxhlet for 10 hours and stirred at room temperature for 24 hours. The precipitate was filtered and washed with toluene to give 6.47g of [4- (1H-indol-3-ylmethylene) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -acetic acid tert-butyl ester. MS 518.5(M +1).

And B: [4- (1H-indol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dioxo-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -acetic acid tert-butyl ester

[4- (1H-indol-3-ylmethylene) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10B-tetraaza-benzo [ e ] is reacted in EtOH (150mL) at 80 ℃ according to the procedure described in example 1(A), step B]Azulene-6-yl]Reduction of tert-butyl acetate (4.84g, 9.37mmol) for 3 hours. The residue was dissolved in EtOAc and washed with NH₄Aqueous Cl (1x) and brine (1 x). Drying (Na)₂SO₄) The organic solution was filtered and concentrated to give 4.26g of [4- (1H-indol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ]]Azulen-6-yl]-tert-butyl acetate.¹H NMR(DMSO-d₆)δ7.65(d，1H)，7.53-7.38(m，7H)，7.27(m，1H)，7.18(m，2H)，6.98(m，1H)，6.89(m，2H)，4.75(d，1H)，4.43(d，1H)，3.82(t，1H)，3.59(m，2H)，1.22(s，9H).

And C: [4- (1H-indol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -acetic acid

To [4- (1H-indol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ]]Azulen-6-yl]-tert-butyl acetate (4.26g, 8.19mmol) in CH₂Cl₂To a solution (27mL) was added TFA (9.5mL, 0.123 mmol). The reaction was stirred at room temperature for 8 hours and concentrated in vacuo. Dissolving the residue in CH₂Cl₂(50mL) and Et₂O (15mL) and stirred for 24 hours. The precipitate was filtered and Et₂O washes to provide 2.33g [4- (1H-indol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ]]Azulen-6-yl]-acetic acid.¹H NMR(DMSO-d₆)δ10.79(s，1H)，7.70(d，1H)，7.54-7.38(m，7H)，7.26(d，1H)，7.17(m，2H)，6.98(t，1H)，6.88(m，2H)，4.90(d，1H)，4.49(d，1H)，3.82(t，1H)，3.59(m，2H).

Biological assay

The utility of the compounds of the present invention as pharmaceutically active agents in the treatment of metabolic disorders, such as those described above, in animals, particularly mammals (e.g., humans), is demonstrated by the activity of the compounds of the present invention in the conventional assays and in vitro and in vivo assays described below. Such assays also provide a means by which the activity of the compounds of the invention can be compared to that of known compoundsThe activities were compared. The results of these comparisons can be used to determine dosage levels. The compounds of examples 1(A) -7 above were tested in the CCK receptor binding assay described below and the IC of these compounds was found under the conditions of the assay₅₀Values are from about 10nM to about 125 nM. The compounds of examples 1(A) -7 above were also tested in the CCK receptor functional assay described below, and it was found that under the conditions of this assay, the EC of these compounds for functional CCK-A agonism₅₀Values are from about 50nM to about 1000 nM.

Cholecystokinin (CCK) receptor binding assay

To determine binding affinity, membrane assay compounds prepared from CHO cells stably transfected and expressing human or rat CCK-a receptors were used. Cell membranes cells from a T-75 flask were prepared as follows: the cells were pelleted at 1000Xg for 5 minutes at 4 ℃ and resuspended in 1ml homogenization buffer (1mM EDTA, 1mM EGTA, 1mM sodium bicarbonate pH 7.4, 100. mu.g/ml benzamidine, 100. mu.g/ml bacitracin, 5. mu.g/ml leupeptin, 5. mu.g/ml aprotinin). After 10 minutes on ice, the cells were homogenized with a Dounce homogenizer. Nuclei and undissolved cells were removed by centrifugation at 1000Xg for 10 minutes at 4 ℃. The supernatant was transferred to a new tube and then spun at 25,000g for 20 minutes at 4 ℃. The pellet was resuspended in 5ml binding buffer (20mM HEPES, pH 7.4, 5mM MgCl)₂118mM NaCl, 5mM KCl, 1mM EGTA, 100. mu.g/ml benzamidine, 100. mu.g/ml bacitracin, 5. mu.g/ml leupeptin, 5. mu.g/ml aprotinin). Protein concentration was determined using BCA protein assay kit (Pierce).

Binding assays were performed in 96-well plates using either 5. mu.g (rat CCK-A receptor) or 10. mu.g (human CCK-A receptor) membranes, at 200. mu.l binding buffer (as described above) per well. Unlabeled CCK-8(Sigma) or compound was diluted in binding buffer and 25. mu.l each was added to the assay plate to a final concentration of 10. mu.M-0.01 nM. In a binding buffer solution¹²⁵I]CCK8(Amersham) was diluted to 0.75nM and 25. mu.l (75 pM final) was added to each well. The assay plates were incubated at 30 ℃ for 75 minutes with gentle shaking. Using PackardFiltermat Harvester (Packard 96-well Unifilter plate in which GF/C membranes were pre-soaked in 0.3% PEI) to remove non-specific counts and cold wash buffer (20mM HEPES, 5mM MgCl. RTM.) was used₂118mM NaCl, 5mM KCl, 1mM EGTA, pH 7.4). After drying, plates were counted by Trilux 1450 Microbeta from Wallac. Data were analyzed using GraphPad Prism software to determine IC₅₀The value is obtained.

CCK receptor functional assay

To determine the functional agonist activity of the compounds, calcium mobilization was measured by FLIPR (fluorescent imaging plate reader, Molecular Devices Corporation, Sunnyvale, CA) in CHO cells stably expressing human or rat CCK-a receptors. In 384-well black/clear bottom poly-D-lysine culture plate, 50 u l medium 15,000 cells in each well, and at 370 degrees C, 5% CO₂And growing for 24 hours. Following removal of the medium, 30. mu.l per well of Fluo-4 cell loading dye (molecular probes, Eugene OR) was used to filter-sterilize FLIPR buffer (50% cell culture medium, 50% Hank's Balanced salt solution, 20mM Hepes, pH 7.4, 1mM CaCl) containing 0.74mg/ml probenecid (Sigma) following manufacturer's instructions₂) Loading the cells. 37 ℃ and 5% CO₂Cells were cultured for 1 hour. The drug plates were assembled to contain 50. mu.l CCK-8(Sigma) or compound diluted in FLIPR buffer. Then 15. mu.l of each compound was added to the assay plate, so that the final concentration ranged from 10. mu.M to 0.01nM prior to FLIPR analysis. EC was determined using GraphPad Prism software₅₀The value is obtained.

Food intake

Male Sprague-Dawley rats (274-325gm) were acclimatized to the automated food intake and locomotor activity assessment system overnight. Food weight and locomotor activity data were acquired by the computer at 10 minute intervals. Immediately before the dark cycle begins the following day, rats (n-5-7/group) were dosed with PO or IP doses of vehicle (propylene glycol, 1ml/kg + saline, 8ml/kg) or test compound (1-12mg/kg in 1ml/kg propylene glycol +8ml/kg saline). Food intake was monitored until the next day. Statistical significance between groups was determined by comparing data from each treatment group by paired t-test.

Method for measuring gallbladder emptying of mice

Male C57Bl/6J mice, approximately 8 weeks old, were fasted for 18 hours, then given either vehicle (0.5% methylcellulose/0.1% Tween 80) or compound orally. Ethanol/propylene glycol/H in a ratio of 2: 3: 5₂O excipient was used to administer the compound intraperitoneally (i.p.). A dosing volume of 5ul/gm body weight was used for oral administration and 1ml/kg for i.p administration. After 30 minutes, mice were sacrificed by cervical dislocation (n ═ 5/treatment), the gall bladder was removed and weighed. ED with evacuated gallbladder₅₀Values were determined by Graphpad Prism. Procedure for all treatment groupswww.randomization.comAnd (4) randomizing.

Claims

1. A compound of formula (I), a pharmaceutically acceptable salt thereof, a prodrug of said compound or said salt, or a solvate or hydrate of said compound, said salt or said prodrug

Wherein A, B, X, D, E and G are independently-C (R)⁵) -or-N-,

R²is-CH₂C(O)N(R⁶)(R⁷)；

R³And R⁴One of (A) is H, halogen, (C)₁-C₆) Alkyl radical (C)₁-C₆) Alkoxy-or partially or fully saturated (C)₃-C₇) CycloalkanesRadical and R³And R⁴is-C (R)⁸)(R⁹)(R¹⁰) (ii) a Or

R³And R⁴Together to form ═ CHR¹¹；

R⁶And R⁷Is (C)₃-C₆) Alkyl or partially or fully saturated (C)₃-C₇) Cycloalkyl radical, and R⁶And R⁷Is phenyl, optionally substituted with 1-3 substituents independently selected from-OH, -CN, halogen-C₁-C₆) Alkyl-, halogen-substituted (C)₁-C₃) Alkoxy-, (C)₁-C₆) Alkyl and (C)₁-C₃) Alkoxy-substituted; benzyl-, wherein the phenyl moiety is optionally substituted with 1-3 substituents independently selected from-OH, -CN, halogen — (C)₁-C₆) Alkyl-, halogen-substituted (C)₁-C₃) Alkoxy-and (C)₁-C₃) Alkoxy-substituted; or heteroaryl-B, optionally substituted with 1-3 substituents independently selected from-OH, -CN, halogen-C₁-C₆) Alkyl-, halogen-substituted (C)₁-C₃) Alkoxy-, (C)₁-C₆) Alkyl and (C)₁-C₃) Alkoxy-substituted; and wherein said heteroaryl-B is selected from thienyl, thiazolyl, isothiazolyl, isoquinolyl, quinolinyl, 3-or 4-pyridyl, pyrimidinyl, oxazolyl, furanyl, imidazolyl, isoxazolyl, pyrazinyl, pyridazinyl, and pyrazolyl;

R⁸，R⁹and R¹⁰Are independently H or (C)₁-C₆) Alkyl and R⁸，R⁹And R¹⁰Is phenyl, partially or fully saturated (C)₃-C₇) Cycloalkyl, heteroaryl-C or a 4-to 7-membered partially or fully saturated heterocycle-B, wherein heteroaryl C is selected from indol-2-yl, indol-3-yl, indazol-3-yl, 7-azaindol-2-yl and 7-azaindol-3-A group; said phenyl, partially or fully saturated cycloalkyl, heteroaryl-C or partially or fully saturated heterocycle-B being optionally substituted on carbon by 1 to 3 substituents independently selected from (C)₁-C₆) Alkoxy-, F, Cl, -CN, -OH, -CO₂H, tetrazole and halogen-substituted (C)₁-C₆) Alkoxy-substituted; and is

R¹¹Is phenyl, partially or fully saturated (C)₃-C₇) Cycloalkyl, heteroaryl-C or a 4-to 7-membered partially or fully saturated heterocycle-B, wherein heteroaryl C is selected from indol-2-yl, indol-3-yl, indazol-3-yl, 7-azaindol-2-yl and 7-azaindol-3-yl; said phenyl, partially or fully saturated cycloalkyl, heteroaryl-C or partially or fully saturated heterocycle-B being optionally substituted on carbon by 1 to 3 substituents independently selected from (C)₁-C₆) Alkoxy-, F, Cl, -CN, -OH, -CO₂H, tetrazole and halogen-substituted (C)₁-C₆) Alkoxy-substituted.

2. A compound of formula (III) according to claim 1 or a pharmaceutically acceptable salt thereof

Wherein R is¹，R²，R³，R⁴And R⁵Is as defined in claim 1.

3. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein

R³And R⁴One of (A) is H, (C)₁-C₃) Alkyl or (C)₁-C₃) Alkoxy-, and R³And R⁴is-C (R)⁸)(R⁹)(R¹⁰) (ii) a Or

R³And R⁴Together to form ═ CHR¹¹；

R¹Is selected from (C)₂-C₆) Alkyl, -CF₃Phenyl, phenyl (C)₁-C₃) Alkyl-, heteroaryl-A (C)₁-C₃) Alkyl-, 4-to 7-membered partially or fully saturated heterocycle-A, 4-to 7-membered partially or fully saturated heterocyclyl-A (C)₁-C₃) Alkyl-and partially or fully saturated (C)₃-C₇) Cycloalkyl (C)₁-C₃) Alkyl-, and when R⁶And R⁷When neither is benzyl-, R¹Selected from the above groups and partially or fully saturated (C)₃-C₇) A cycloalkyl group,

wherein heteroaryl-a is selected from thienyl, 2-pyridyl, pyrimidinyl, pyrazinyl and pyrazolyl; and is

Wherein phenyl, heteroaryl-A, partially or fully saturated heterocycle-A or partially or fully saturated cycloalkyl or part of a group is optionally substituted by 1^-3 are independently selected from F, Cl, (C)₁-C₃) Alkoxy-, -OH, (C)₁-C₃) Alkyl, -CN and-CF₃Is substituted with the substituent(s).

4. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein

Each R⁵Is H;

R⁶and R⁷Is a branched chain (C)₃-C₆) Alkyl, and R⁶And R⁷Is phenyl optionally substituted with 1 to 3 substituents independently selected from-OH, -CN, F, Cl, F-or Cl- (C)₁-C₃) Alkyl-, F-or Cl-substituted (C)₁-C₃) Alkoxy-, (C)₁-C₄) Alkyl and (C)₁-C₃) Alkoxy-substituted; benzyl-, wherein the phenyl moiety is optionally substituted with 1-3 substituents independently selected from-OH, -CN and (C)₁-C₃) Alkoxy-substituted; or heteroaryl-B optionally substituted with 1-3 substituents independently selected from-OH, -CN, F, Cl, F-or Cl- (C)₁-C₃) Alkyl-, F-or Cl-substituted (C)₁-C₃) Alkoxy-, (C)₁-C₄) Alkyl and (C)₁-C₃) Substitution of alkoxy radicalsSubstituted by radicals; and wherein said heteroaryl-B is selected from thienyl, 3-or 4-pyridyl, pyrimidinyl and pyrazinyl;

R⁸，R⁹and R¹⁰Two of (A) are H and R⁸，R⁹And R¹⁰Is a heteroaryl-C selected from indol-3-yl, indazol-3-yl and 7-azaindol-3-yl, optionally substituted by 1-3 substituents independently selected from (C)₁-C₃) Alkoxy-, F, Cl, -CN, -OH, -CO₂H, tetrazole and F-substituted (C)₁-C₃) Alkoxy-substituted; and is

R¹¹Is a heteroaryl-C selected from indol-3-yl, indazol-3-yl and 7-azaindol-3-yl, optionally substituted by 1-3 substituents independently selected from (C)₁-C₃) Alkoxy-, F, Cl, -CN, -OH, -CO₂H, tetrazole and F-substituted (C)₁-C₃) Alkoxy-substituted.

5. A compound of formula (IV) according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof

Wherein

R³Is H or (C)₁-C₃) An alkyl group;

X¹is-CH-and X²is-N-or-C (R)¹²) -, or X¹is-N-and X²is-C (R)¹²) -; and is

Each R¹²Independently selected from H, F and Cl; provided however that R¹²Up to three of which are not H.

6. A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein

R¹Is phenyl or 2-pyridyl, or when R is⁶And R⁷When neither is benzyl-, R¹Can also be part ofPartially or fully saturated (C)₅-C₇) Cycloalkyl in which phenyl, 2-pyridyl or partially or fully saturated (C)₅-C₇) Cycloalkyl is optionally substituted with 1-3 substituents independently selected from F, Cl, (C)₁-C₃) Alkoxy-, -OH, (C)₁-C₃) Alkyl, and-CF₃Substituted with the substituent(s);

R³is H;

R⁶and R⁷Is a branched chain (C)₃-C₅) Alkyl, and R⁶And R⁷Is phenyl optionally substituted with 1-3 substituents independently selected from-OH, -CN, F, Cl, F-₁-C₃) Alkyl-, F-substituted (C)₁-C₃) Alkoxy-, (C)₁-C₄) Alkyl and (C)₁-C₃) Alkoxy-substituted; benzyl-, which is optionally substituted by 1 or 2 substituents independently selected from-OH and-OCH₃Substituted with the substituent(s); or 3-or 4-pyridyl optionally substituted with 1 to 3 substituents independently selected from-OH, -CN, F, Cl, F-₁-C₃) Alkyl-, F-substituted (C)₁-C₃) Alkoxy-, (C)₁-C₄) Alkyl and (C)₁-C₃) Alkoxy-substituted.

7. A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein

When R is⁶And R⁷When neither is benzyl-, R¹Is phenyl or cyclohexyl, wherein phenyl is optionally substituted with 1 to 3F atoms or-OH groups;

R⁶and R⁷Is a branched chain (C)₃Or C₄) Alkyl, and R⁶And R⁷Is phenyl, optionally substituted by 1 to 3 substituents independently selected from the group consisting of-OH, F, Cl, -CF₃，-OCF₃，(C₁-C₄) Alkyl and (C)₁-C₃) Alkoxy-substituted; benzyl-; or 3-or 4-pyridyl optionally substituted with 1 to 3 substituents independently selected from-OH, F, Cl, -CF₃，-OCF₃，(C₁-C₄) Alkyl and (C)₁-C₃) Alkoxy-substituted.

8. According to claim 1^-7A compound of formula (V) according to any one of the preceding claims or a pharmaceutically acceptable salt thereof

Wherein

X¹is-CH-or-N-; and is

R⁶And R⁷Is isopropyl, and R⁶And R⁷Is phenyl, optionally substituted with 1 or 2F atoms; benzyl-; or 3-or 4-pyridyl optionally substituted by 1 or 2 substituents independently selected from F, Cl, -OCH₃and-OCH₂CH₃Substituted with the substituent(s); and each R¹²Independently is H or F; provided however that R¹²Up to three of which are F.

9. A compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein X¹is-CH-;

R⁶and R⁷Is isopropyl and R⁶And R⁷The other of (a) is phenyl or benzyl-; and each R¹²Is H.

10. A compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein X¹is-CH-;

R⁶and R⁷Is isopropyl, and R⁶And R⁷Is 3-pyridyl, optionally substituted by 1 or 2 substituents independently selected from F, Cl, -OCH₃and-OCH₂CH₃Substituted with the substituent(s); and each R¹²Is H.

11. The compound N-benzyl-2- [4- (1H-indol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-acetamide; or a pharmaceutically acceptable salt thereof.

12. The compound (-) N-benzyl-2- [4- (1H-indol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] azulen-6-yl ] -N-isopropyl-acetamide.

13. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, diluent or carrier.

14. A method for treating obesity in an animal comprising administering to an animal in need of such treatment a therapeutically effective amount of a compound of any one of claims 1-12, or a pharmaceutically acceptable salt thereof.

15. A compound of the formula (D) or the formula (F-1) or a salt thereof

Wherein A, B, X and D are independently-C (R)⁵) -or-N-,

provided that at most two of A, B, X and D are simultaneously N;

r is (C)₁-C₆) Alkyl or (C)₃-C₆) A cycloalkyl group;

R¹is selected from (C)₂-C₆) Alkyl, halogen-substituted (C)₁-C₆) Alkyl-, (C)₁-C₆) Alkylamino-, di (C)₁-C₆Alkyl) amino-, (C)₁-C₆) Alkylamino radical (C)₁-C₆) Alkyl-, di (C)₁-C₆) Alkylamino radical (C)₁-C₆) Alkyl-, aryl (C)₁-C₆) Alkyl-, heteroaryl-A (C)₁-C₆) Alkyl-, a 4-to 7-membered partially or fully saturated heterocycle-A, 4-to 7-membered partially or fullySaturated heterocyclic radical-A (C)₁-C₆) Alkyl-and partially or fully saturated (C)₃-C₇) Cycloalkyl (C)₁-C₆) Alkyl-, and when R⁶And R⁷When neither is benzyl-, R¹Selected from the above groups and partially or fully saturated (C)₃-C₇) A cycloalkyl group;

R²is-CH₂C(O)N(R⁶)(R⁷)；

R⁶And R⁷Is (C)₃-C₆) Alkyl or partially or fully saturated (C)₃-C₇) Cycloalkyl radical, and R⁶And R⁷Is phenyl, optionally substituted with 1-3 substituents independently selected from-OH, -CN, halogen-C₁-C₆) Alkyl-, halogen-substituted (C)₁-C₃) Alkoxy-, (C)₁-C₆) Alkyl and (C)₁-C₃) Alkoxy-substituted; benzyl-, wherein the phenyl moiety is optionally substituted with 1-3 substituents independently selected from-OH, -CN, halogen — (C)₁-C₆) Alkyl-, halogen-substituted (C)₁-C₃) Alkoxy-and (C)₁-C₃) Alkoxy-substituted; or heteroaryl-B, optionally substituted with 1-3 substituents independently selected from-OH, -CN, halogen-C₁-C₆) Alkyl-, halogen-substituted (C)₁-C₃) Alkoxy-, (C)₁-C₆) Alkyl and (C)₁-C₃) Alkoxy-substituted; and wherein heteroaryl-B is selected from thienyl, thiazolyl, isothiazolyl, isoquinolyl, quinolinyl, 3-or 4-pyridyl, pyrimidinyl, oxazolyl, furanyl, imidazolyl, isoxazolyl, pyrazinyl, pyridazinyl and pyrazolyl.