WO2012114252A1 - Nouveaux amides d'indole et de pyrrolopyridine - Google Patents

Nouveaux amides d'indole et de pyrrolopyridine Download PDF

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WO2012114252A1
WO2012114252A1 PCT/IB2012/050759 IB2012050759W WO2012114252A1 WO 2012114252 A1 WO2012114252 A1 WO 2012114252A1 IB 2012050759 W IB2012050759 W IB 2012050759W WO 2012114252 A1 WO2012114252 A1 WO 2012114252A1
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pyridin
dihydro
thieno
indol
methanone
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PCT/IB2012/050759
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English (en)
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Martin Bolli
Christoph Boss
Christine Brotschi
Bibia Heidmann
Thierry Sifferlen
Daniel Trachsel
Jodi T. Williams
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Actelion Pharmaceuticals Ltd
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Publication of WO2012114252A1 publication Critical patent/WO2012114252A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention relates to novel indole and pyrrolopyridine amide derivatives of formula (I) and their use as pharmaceuticals.
  • the invention also concerns related aspects including processes for the preparation of the compounds, pharmaceutical compositions containing one or more compounds of formula (I), and especially their use as orexin receptor antagonists.
  • Orexins are novel neuropeptides found in 1998 by two research groups, orexin A is a 33 amino acid peptide and orexin B is a 28 amino acid peptide (Sakurai T. et al., Cell, 1998, 92, 573-585). Orexins are produced in discrete neurons of the lateral hypothalamus and bind to the G-protein-coupled receptors (OX-i and OX 2 receptors). The orexin-1 receptor (OX-i) is selective for OX-A, and the orexin-2 receptor (OX 2 ) is capable to bind OX-A as well as OX-B.
  • Orexin A is a 33 amino acid peptide
  • orexin B is a 28 amino acid peptide (Sakurai T. et al., Cell, 1998, 92, 573-585). Orexins are produced in discrete neurons of the lateral hypothalamus and bind to the G-protein-coupled receptors (OX-i and O
  • Orexins are found to stimulate food consumption in rats suggesting a physiological role for these peptides as mediators in the central feedback mechanism that regulates feeding behaviour (Sakurai T. et al., Cell, 1998, 92, 573-585).
  • orexins regulate states of sleep and wakefulness opening potentially novel therapeutic approaches to insomnia and other sleep disorders (Chemelli R.M. et al., Cell, 1999, 98, 437-451 ).
  • in vitro and in vivo evidence for a critical role of orexin signaling in the ventral tegmental area in neural plasticity relevant to addiction has been published (S. L. Borgland et al. Neuron, 2006, 49, 589-601 ).
  • Orexin neurons are likely to be involved in the coordinated regulation of behavioral and physiological responses in stressful environments (Kuru, M, Ueta, Y, Serino, R, Nakazato, M, Yamamoto, Y, Shibuya, I, Yamashita, H; Centrally administered orexin/hypocretin activates HPA axis in rats. Neuroreport, 1 1 (9) (2000) 1977-1980).
  • cardiovascular responses to conditioned fear and novelty exposure could be attenuated by a dual orexin receptor antagonist in rats (Furlong, TM, Vianna, DM, Liu, L, Carrive, P; Hypocretin/orexin contributes to the expression of some but not all forms of stress and arousal.
  • the acute stress response may include behavioural, autonomic and endocrinological changes, such as promoting heightened vigilance, decreased libido, increased heart rate and blood pressure, or a redirection of blood flow to fuel the muscles, heart and the brain (Majzoub, JA; Corticotropin-releasing hormone physiology European Journal of Endocrinology, 155 (suppM ) (2006) S71-S76).
  • behavioural, autonomic and endocrinological changes such as promoting heightened vigilance, decreased libido, increased heart rate and blood pressure, or a redirection of blood flow to fuel the muscles, heart and the brain (Majzoub, JA; Corticotropin-releasing hormone physiology European Journal of Endocrinology, 155 (suppM ) (2006) S71-S76).
  • the compound has also been shown to enhance memory function in a rat model (WO2007/105177).
  • the compound furthermore decreased brain levels of amyloid-beta ( ⁇ ) as well as ⁇ plaque deposition after acute sleep restriction in amyloid precursor protein transgenic mice [JE Kang et al., "Amyloid-beta dynamics are regulated by orexin and the sleep-wake cycle.”, Science 2009, 326(5955): 1005-1007].
  • the accumulation of the ⁇ in the brain extracellular space is hypothesized to be a critical event in the pathogenesis of Alzheimer's disease.
  • the so-called and generally known "amyloid cascade hypothesis” links ⁇ to Alzheimer's disease and, thus, to the cognitive dysfunction, expressed as impairment of learning and memory.
  • the compound is also active in an animal model of conditioned fear: the rat fear-potentiated startle paradigm (WO2009/0047723) which relates to emotional states of fear and anxiety diseases such as anxieties including phobias and post traumatic stress disorders (PTSDs).
  • the compound has, in addition, been shown to induce antidepressant-like activity in a mouse model of depression, when administered chronically [Nollet et al., NeuroPharm 2011 , 61 (1- 2):336-46]; and to attenuate the natural activation induced by orexin A in fasted hungry rats exposed to food odors [MJ Prud'Neill et al., "Nutritional status modulates behavioural and olfactory bulb Fos responses to isoamyl acetate or food odour in rats: roles of orexins and leptin.” Neuroscience 2009, 162(4), 1287-1298].
  • the present invention provides novel indole and pyrrolopyridine amide derivatives, which are non-peptide antagonists of human orexin receptors. These compounds are in particular of potential use in the treatment of diseases or disorders related to the orexin system, especially comprising all types of sleep disorders, of stress-related syndromes, of addictions (especially psychoactive substance use, abuse, seeking and reinstatement), of cognitive dysfunctions in the healthy population and in psychiatric and neurologic disorders, of eating or drinking disorders.
  • a first aspect of the invention relates to compounds of the formula (I)
  • Z represents a carbon atom or a nitrogen atom and Y represents a carbon atom; and ring A together with the atoms Z and Y represents a 5- or 6-membered aromatic ring;
  • ring A is a benzene, a pyridine, a thiophene, a pyrazole, or a thiazole ring;
  • ring A is an imidazole or a pyrrole ring
  • rings A independently are unsubstituted or substituted with one or two substituents independently selected from the group consisting of (Ci -4 )alkyl, (Ci -4 )alkoxy, (C 2-4 )alkinyl, halogen, cyano, (Ci -3 )fluoroalkyl, (Ci -3 )fluoroalkoxy; (C 3- 6)cycloalkyl, 5- membered heteroaryl, and amino;
  • R 1 represents aryl or heteroaryl, wherein the aryl or heteroaryl independently is:
  • phenyl or 5- or 6-membered heteroaryl wherein said phenyl or 5- or 6- membered heteroaryl is independently unsubstituted, or mono-, di-, or tri- substituted, wherein the substituents are independently selected from the group consisting of (C 1-4 )alkyl, (C 1-4 )alkoxy, halogen, cyano, (C 1-3 )fluoroalkyl, and (C 1-3 )fluoroalkoxy; and
  • phenyl-(C 1-4 )alkoxy or 5- or 6-membered heteroaryl-(C 1-4 )alkoxy wherein said phenyl-(Ci -4 )alkoxy or 5- or 6-membered heteroaryl-(Ci -4 )alkoxy is independently unsubstituted, or mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of (Ci -4 )alkyl, (Ci -4 )alkoxy, halogen, cyano, (Ci -3 )fluoroalkyl, and (Ci -3 )fluoroalkoxy;
  • aryl or heteroaryl is fused to a non-aromatic 5- or 6-membered ring, wherein said ring optionally contains one or two heteroatoms independently selected from oxygen and nitrogen; wherein said ring is optionally substituted with one or two substituents independently selected from (C 1-3 )alkyl, oxo, and halogen;
  • R 2 represents hydrogen, (C 1-6 )alkyl, (C 3-6 )cycloalkyl, (C 1-4 )alkoxy-(C 2-4 )alkyl, hydroxy- (C 2-4 )alkyl, R 8 R 9 N-(C 2-4 )alkyl, or
  • R 3 represents hydrogen or methyl (especially hydrogen);
  • one of U, V, W, and X represents CR 10 or N, and the remaining represent CH;
  • R 10 represents hydrogen, fluorine, chlorine, methyl, or methoxy
  • R 4 and R 5 independently represent hydrogen or (Ci -4 )alkyl
  • R 6 represents hydroxy or amino
  • R 7 represents hydroxy or (Ci -4 )alkoxy
  • R 8 and R 9 independently represent hydrogen or (Ci -4 )alkyl.
  • the compounds of formula (I) may contain one or more stereogenic or asymmetric centers, such as one or more asymmetric carbon atoms.
  • the compounds of formula (I) may thus be present as mixtures of stereoisomers or preferably as pure stereoisomers. Mixtures of stereoisomers may be separated in a manner known to a person skilled in the art.
  • the present invention also includes isotopically labelled, especially 2 H (deuterium) labelled compounds of formula (I), which compounds are identical to the compounds of formula (I) except that one or more atoms have each been replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature.
  • Isotopically labelled, especially 2 H (deuterium) labelled compounds of formula (I) and salts thereof are within the scope of the present invention. Substitution of hydrogen with the heavier isotope 2 H (deuterium) may lead to greater metabolic stability, resulting e.g. in increased in-vivo half-life or reduced dosage requirements, or may lead to reduced inhibition of cytochrome P450 enzymes, resulting e.g. in an improved safety profile.
  • the compounds of formula (I) are not isotopically labelled, or they are labelled only with one or more deuterium atoms. In a sub-embodiment, the compounds of formula (I) are not isotopically labelled at all. Isotopically labelled compounds of formula (I) may be prepared in analogy to the methods described hereinafter, but using the appropriate isotopic variation of suitable reagents or starting materials.
  • dotted lines show the point(s) of attachment of a radical drawn.
  • pharmaceutically acceptable salts refers to non-toxic, inorganic or organic acid and/or base addition salts. Reference can be made to "Salt selection for basic drugs", Int. J. Pharm. (1986), 33, 201-217.
  • halogen means fluorine, chlorine, or bromine, preferably fluorine or chlorine.
  • alkyl refers to a saturated straight or branched chain alkyl group containing one to six carbon atoms.
  • (C x-y )alkyl refers to an alkyl group as defined before, containing x to y carbon atoms.
  • a (C 1-4 )alkyl group contains from one to four carbon atoms.
  • alkyl groups are methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec. -butyl and tert.-butyl. Preferred are methyl and ethyl. Most preferred is methyl.
  • cycloalkyl refers to a saturated cyclic alkyl group containing three to six carbon atoms.
  • (C x-y )cycloalkyl refers to a cycloalkyi group as defined before containing x to y carbon atoms.
  • a (C 3 - 6 )cycloalkyl group contains from three to six carbon atoms.
  • Examples of cycloalkyi groups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Preferred is cyclopropyl.
  • alkoxy refers to an alkyl-O- group wherein the alkyl group is as defined before.
  • (C x-y )alkoxy (x and y each being an integer) refers to an alkoxy group as defined before containing x to y carbon atoms.
  • a (Ci -4 )alkoxy group means a group of the formula (Ci -4 )alkyl-0- in which the term "(Ci -4 )alkyl” has the previously given significance.
  • alkoxy groups are methoxy, ethoxy, n- propoxy, isopropoxy, n-butoxy, isobutoxy, sec.-butoxy and tert.-butoxy. Preferred are ethoxy and especially methoxy.
  • fluoroalkyl refers to an alkyl group as defined before containing one to three carbon atoms in which one or more (and possibly all) hydrogen atoms have been replaced with fluorine.
  • (C x-y )fluoroalkyl (x and y each being an integer) refers to a fluoroalkyl group as defined before containing x to y carbon atoms.
  • a (C 1-3 )fluoroalkyl group contains from one to three carbon atoms in which one to seven hydrogen atoms have been replaced with fluorine.
  • fluoroalkyl groups include trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl and 2,2,2-trifluoroethyl. Preferred are (C-i)fluoroalkyl groups such as trifluoromethyl.
  • fluoroalkoxy refers to an alkoxy group as defined before containing one to three carbon atoms in which one or more (and possibly all) hydrogen atoms have been replaced with fluorine.
  • (C x-y )fluoroalkoxy (x and y each being an integer) refers to a fluoroalkoxy group as defined before containing x to y carbon atoms.
  • a (Ci -3 )fluoroalkoxy group contains from one to three carbon atoms in which one to seven hydrogen atoms have been replaced with fluorine.
  • fluoroalkoxy groups include trifluoromethoxy, difluoromethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy and 2,2,2-trifluoroethoxy.
  • R 8 R 9 N-(C 2-4 )alkyl groups is dimethylaminoethyl.
  • R 4 R 5 N-(C 2-4 )alkoxy groups is dimethylaminoethoxy.
  • R 6 -CO- groups is carboxy.
  • R 7 -CO-(C 1-4 )alkoxy groups are 2-methoxy-2-oxoethoxy and carboxymethoxy.
  • An example of (C 1-3 )fluoroalkyl-sulfonyloxy groups is trifluoromethyl-sulfonyloxy.
  • An example of (C 3- 6)cycloalkyl-oxy groups is cyclopropyloxy.
  • (Ci -4 )alkoxy-(C2-4)alkoxy groups is 2-methoxyethoxy.
  • hydroxy-(C 2 -4)alkoxy groups is 2-hydroxyethoxy.
  • amino refers to a H 2 N- group.
  • aryl alone or in combination, means a phenyl or a naphthyl group.
  • the aryl group may be unsubstituted or substituted as explicitly defined.
  • aryl groups as used for the group R 1 are phenyl, 2-naphthyl, 1 - naphthyl, 3-methyl-phenyl, 4-methoxy-phenyl, 3-methoxy-phenyl, 3,5-dimethoxy-phenyl, 3,4- dimethoxy-phenyl, 2,5-dimethoxy-phenyl, 2,3-dimethoxy-phenyl, 3,4,5-trimethoxy-phenyl, 4- fluoro-phenyl, 3,4-difluoro-phenyl, 4-chloro-phenyl, 3-chloro-phenyl, 2-chloro-phenyl, 2,4- dichloro-phenyl, 3,4-dichloro-phenyl, 2,6-dichloro-phenyl, 4-cyano-phenyl, 3-cyano-phenyl, 2- cyano-phenyl, 3-carboxy-phenyl, 3-hydroxy-4-methoxy-phenyl, 4-hydroxy-3
  • aryl groups a particular sub-group of aryl as used for the group R 1 are "aryl fused to a non-aromatic 5- or 6-membered ring, wherein said ring optionally contains one or two heteroatoms independently selected from oxygen and nitrogen".
  • the aryl is preferably phenyl.
  • Examples of such groups are indanyl, tetrahydronaphthyl, 2,3-dihydrobenzofuranyl, chromanyl, chromenyl, benzo[1 ,3]dioxolyl, 2,3-dihydro-benzo[1 ,4]dioxinyl, benzo[b][1 ,4]dioxinyl, 1 ,2,3,4-tetrahydro- quinolinyl, and 3,4-dihydro-2H-benzo[b][1 ,4]oxazinyl.
  • aryl groups are optionally substituted said non-aromatic 5- or 6-membered ring with one or two substituents independently selected from (C 1-3 )alkyl, oxo, and halogen.
  • aryl groups which are substituted, in a position other than the ortho-position, with phenyl or 5- or 6-membered heteroaryl, wherein said phenyl or 5- or 6- membered heteroaryl is independently unsubstituted, or mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of (Ci_4)alkyl, (Ci -4 )alkoxy, halogen, cyano, (Ci -3 )fluoroalkyl, and (Ci -3 )fluoroalkoxy.
  • Examples of such groups are 3-pyrrazol-1 -yl-phenyl, 3-[1 ,2,4]oxadiazol-3-yl-phenyl, 4-[1 ,2,3]triazol-1 -yl-phenyl, 3-[1 ,2,3]triazol-1 -yl-phenyl, 3-[1 ,2,4]triazol-1-yl-phenyl, 4-[1 ,2,3]triazol-2-yl-phenyl, 3- [1 ,2,3]triazol-2-yl-phenyl, 3-pyrimidin-2-yl-phenyl.
  • aryl groups which are substituted, in a position other than the ortho-position, with phenyl-(Ci -4 )alkoxy or 5- or 6-membered heteroaryl-(Ci -4 )alkoxy, wherein said phenyl-(Ci -4 )alkoxy or 5- or 6-membered heteroaryl-(Ci -4 )alkoxy is independently unsubstituted, or mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of (Ci -4 )alkyl, (Ci -4 )alkoxy, halogen, cyano, (Ci -3 )fluoroalkyl, and (Ci -3 )fluoroalkoxy.
  • An examples of such groups is 3-methoxy-4- benzyloxy-phenyl.
  • heteroaryl if not explicitly stated otherwise, means a 5- to 10-membered monocyclic or fused bicyclic aromatic ring containing 1 to a maximum of 4 heteroatoms independently selected from oxygen, nitrogen and sulfur.
  • monocyclic heteroaryl groups are 5-membered monocyclic heteroaryl groups such as furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, and tetrazolyl; and 6-membered monocyclic heteroaryl such as pyridyl, pyrimidyl, pyridazinyl, and pyrazinyl.
  • bicyclic heteroaryl groups comprise 8-membered bicyclic heteroaryl groups such as 4H-furo[3,2-b]pyrrolyl, pyrrolo[2, 1-b]thiazolyl and imidazo[2, 1- b]thiazolyl; 9-membered bicyclic heteroaryl groups such as indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, benzoxadiazolyl, benzothiadiazolyl, pyrazolo[1 ,5-a]pyridyl, pyrazolo[1 ,5-a]pyrimidyl, imidazo[1 ,2-a]pyridyl, 1 H-pyrrolo[3,2- b]pyrid
  • heteroaryl groups as used for the group R 1 are 5-membered heteroaryl groups such as oxazolyl, isoxazolyl, thienyl, thiazolyl, and isothiazolyl (notably thiazolyl; especially 2-methyl-thiatzol-4-yl).
  • heteroaryl groups as used for the group R 1 are 6-membered monocyclic heteroaryl such as pyrimidyl, pyridazinyl, pyrazinyl and pyridyl (notably pyridyl; especially pyridin-3-yl, pyridin-2- yl, 2-chloro-pyridin-6-yl, 2-methyl-pyridin-5-yl, 2-ethyl-pyridin-5-yl, 2-methoxy-pyridin-6-yl, 2- methoxy-pyridin-5-yl, 2-cyano-pyridin-6-yl, and 2-cyano-pyridin-5-yl).
  • pyrimidyl pyridazinyl
  • pyrazinyl pyridyl
  • pyridyl notably pyridyl; especially pyridin-3-yl, pyridin-2- yl, 2-chloro-pyridin-6-yl, 2-methyl-
  • heteroaryl groups as used for the group R 1 are 8- to 10-membered bicyclic heteroaryl groups, notably 9- or 10-membered bicyclic heteroaryl groups, such as indolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, indazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, quinolinyl, naphthyridinyl, cinnolinyl, quinazolinyl, and quinoxalinyl (notably indolyl, indazolyl, benzimidazolyl, and quinolinyl; especially indol-3-yl, 1-methyl-indol-3-yl, indazol-3-yl, benzimidazol-2-yl, quinolin-8-yl, quinolin-7-yl, and quinolin-6-yl).
  • examples of the particular sub-group of heteroaryl groups which are substituted in a position other than the ortho-position with phenyl or 5- or 6-membered heteroaryl; wherein said phenyl or 5- or 6-membered heteroaryl is independently unsubstituted, or substituted as explicitly defined; are notably oxazolyl, isoxazolyl, thienyl, thiazolyl, isothiazolyl, pyridyl, pyrimidyl and pyrazinyl.
  • Examples of the particular 5- or 6-membered heteroaryl groups which are substituents of the group R 1 are notably oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidyl, and pyrazinyl (notably oxadiazolyl, pyrazolyl, triazolyl, pyridyl, and pyrimidyl; especially pyrazol-1-yl, [1 ,2,4]oxadiazol-3-yl, [1 ,2,3]triazol-1-yl, [1 ,2,3]triazol-1-yl, [1 ,2,4]triazol-1-yl, [1 ,2,3]triazol-2-yl, [1 ,2,3]triazol-2-yl, and pyrimi
  • Examples of the particular 5-membered heteroaryl groups which are substituents of the ring A are oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, and triazolyl (notably pyrazolyl and triazolyl; especially triazol-2-yl).
  • heteroaryl groups as defined herein may be unsubstituted or substituted as explicitly defined.
  • examples are notably 1 ,2,3,4-tetrahydro-isoquinoline, 5,6,7,8-tetrahydro-[1 ,7]naphthyridine, 4,5,6,7-tetrahydro-thieno[2,3-c]pyridine, 4,5,6,7- tetrahydro-thieno[3,4-c]pyridine, 4,5,6,7-tetrahydro-thieno[3,2-c]pyridine, 4,5,6,7-tetrahydro- 1 H-pyrazolo[3,4-c]pyridine, 4,5,6,7-tetrahydro-1 H-pyrazolo[4,3-c]pyridine, 4,5,6,7-tetrahydro- thiazolo[5,4-c]pyridine and 5,6,7,8-tetrahydro-imidazo[1 ,2-a]pyrazine.
  • These groups may be unsubstituted or substituted as explicitly
  • a second embodiment relates to compounds according to embodiment 1 ), which are also compounds of formula (l E i ):
  • a third embodiment relates to compounds according to embodiment 1 ), which are also compounds of formula (l E 2):
  • Another embodiment relates to compounds according to any one of embodiments 1 ) to 3), wherein ring A together with the atoms Y and Z represents a 5- or 6-membered aromatic ring selected from the group consisting of:
  • (R ) n represents one or two optional substituents (i.e. n is 0, 1 or 2) independently selected from the group consisting of (Ci -4 )alkyl, (Ci -4 )alkoxy, (C 2-4 )alkinyl, halogen, cyano, (Ci -3 )fluoroalkyl, (Ci -3 )fluoroalkoxy; (C 3- 6)cycloalkyl, 5-membered heteroaryl, and amino (notably (Ci -4 )alkyl, (Ci -4 )alkoxy, halogen, cyano, and (Ci -3 )fluoroalkyl); (R 6 ) n represents one or two optional substituents (i.e.
  • n is 0, 1 or 2) independently selected from the group consisting of (Ci -4 )alkyl, (Ci -4 )alkoxy, (C 2-4 )alkinyl, halogen, cyano, (C 1-3 )fluoroalkyl, (C 1-3 )fluoroalkoxy; (C 3-6 )cycloalkyl, 5-membered heteroaryl, and amino (notably (C 1-4 )alkyl, (C 1-4 )alkoxy, halogen, cyano, and (C 1-3 )fluoroalkyl); (R 7 ) n represents one or two optional substituents (i.e.
  • n is 0, 1 or 2) independently selected from the group consisting of (Ci -4 )alkyl, (Ci -4 )alkoxy, (C 2-4 )alkinyl, halogen, cyano, (Ci -3 )fluoroalkyl, (Ci -3 )fluoroalkoxy; (C 3-6 )cycloalkyl, 5-membered heteroaryl, and amino (notably (Ci -4 )alkyl, (Ci -4 )alkoxy, halogen, cyano, and (Ci -3 )fluoroalkyl); R 8 , R 9 , R 10 , R 11 , and R 12 independently represent hydrogen, (Ci -4 )alkyl, (Ci -4 )alkoxy, (C 2-4 )alkinyl, halogen, cyano, (Ci -3 )fluoroalkyl, (Ci -3 )fluoroalkoxy; (C 3-6 )cycloal
  • R 8 , R 9 , R 10 , R 11 , and R 12 independently represent hydrogen, (Ci -4 )alkyl, (Ci -4 )alkoxy, (C 2-4 )alkinyl, halogen, cyano, (Ci -3 )fluoroalkyl, (Ci -3 )fluoroalkoxy; (C 3- 6)cycloalkyl, 5- membered heteroaryl, and amino (notably (Ci -4 )alkyl, (Ci -4 )alkoxy, halogen, cyano, and (Ci -3 )fluoroalkyl);
  • R 8 , R 9 , R 10 , R 11 , and R 12 independently represent hydrogen, (Ci -4 )alkyl, (Ci -4 )alkoxy, (C 2-4 )alkinyl, halogen, cyano, (Ci -3 )fluoroalkyl, (Ci -3 )fluoroalkoxy; (C 3-6 )cycloalkyl, 5- membered heteroaryl, and amino (notably hydrogen, (C 1-4 )alkyl, and amino);
  • n represents one or two optional substituents (i.e. n is 0, 1 or 2) independently selected from the group consisting of (Ci -4 )alkyl, (Ci -4 )alkoxy, (C 2-4 )alkinyl, halogen, cyano, (Ci -3 )fluoroalkyl, (Ci -3 )fluoroalkoxy; (C 3-6 )cycloalkyl, 5-membered heteroaryl, and amino (notably (Ci -4 )alkyl, (Ci -4 )alkoxy, halogen, cyano, and (Ci -3 )fluoroalkyl); and
  • (R 14 ) n represents one or two optional substituents (i.e. n is 0, 1 or 2) independently selected from the group consisting of (Ci -4 )alkyl, (Ci -4 )alkoxy, (C 2-4 )alkinyl, halogen, cyano, (Ci -3 )fluoroalkyl, (Ci -3 )fluoroalkoxy; (C 3-6 )cycloalkyl, 5-membered heteroaryl, and amino (notably (Ci -4 )alkyl, (Ci -4 )alkoxy, halogen, cyano, and (Ci -3 )fluoroalkyl); wherein it is well understood that each R 5 to R 14 , and each n may be independently chosen for each respective ring A; and each of the above-listed rings A forms a particular sub- embodiment.
  • (R 7 ) n represents one or two optional substituents (i.e. n is 0, 1 or 2) independently selected from the group consisting of (Ci -4 )alkyl, (Ci -4 )alkoxy, (C 2-4 )alkinyl, halogen, cyano, (Ci -3 )fluoroalkyl, and 5-membered heteroaryl (notably triazolyl); (especially (Ci -4 )alkyl, (Ci -4 )alkoxy, halogen, cyano, and (Ci -3 )fluoroalkyl);
  • R 8 , and R 9 independently represent (Ci -4 )alkyl
  • R 10 , and R 11 independently represent hydrogen, and (Ci -4 )alkyl
  • R 12 represents hydrogen, (Ci -4 )alkyl, or amino (especially hydrogen or amino);
  • Another embodiment relates to compounds according to embodiments 4) or 5), wherein ring A together with the atoms Y and Z represents a 5- or 6-membered aromatic ring selected from the group consisting of:
  • each of the above-listed rings A forms in addition a particular sub-embodiment.
  • FIG. 7 Another embodiment relates to compounds according to any one of embodiments 1 ) to 6), wherein ring A together with the atoms Z and Y is a benzene, a pyridine, a thiophene ring, or an imidazole ring; wherein said ring A independently is unsubstituted or substituted as explicitly defined.
  • Another embodiment relates to compounds according to any one of embodiments 1 ) to 7), wherein the fragment:
  • Another embodiment relates to compounds according to any one of embodiments 1 ) to 8), wherein Z represents a nitrogen atom.
  • R 1 represents aryl or heteroaryl, wherein the aryl or heteroaryl independently is unsubstituted, or mono-, di-, or tri-substituted;
  • substituents are independently selected from the group consisting of (C 1-4 )alkyl, (C 1-4 )alkoxy, (C 3-6 )cycloalkyl, halogen, cyano, hydroxy, (C 1-3 )fluoroalkyl, (C 1-3 )fluoroalkoxy, (C 1-3 )fluoroalkyl-sulfonyloxy, (C 1-4 )alkyl- sulfonyl, (C 3-6 )cycloalkyl-oxy, (C 1-4 )alkoxy-(C 2-4 )alkoxy, hydroxy-(C 2-4 )alkoxy, R 4 R 5 N-(C 2-4 )alkoxy, R 6 -CO-, R 7 -CO-(C 1-4 )alkoxy;
  • R 1 represents phenyl or 5- or 6-membered heteroaryl, wherein the phenyl or 5- or 6-membered heteroaryl independently is mono-, di-, or tri-substituted;
  • phenyl or 5- or 6-membered heteroaryl wherein said phenyl or 5- or 6- membered heteroaryl is independently unsubstituted, or mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of (Ci -4 )alkyl, (Ci -4 )alkoxy, halogen, cyano, (Ci -3 )fluoroalkyl, and (Ci -3 )fluoroalkoxy; or
  • phenyl-(Ci -4 )alkoxy or 5- or 6-membered heteroaryl-(Ci -4 )alkoxy wherein said phenyl-(Ci -4 )alkoxy or 5- or 6-membered heteroaryl- (C 1-4 )alkoxy is independently unsubstituted, or mono-, di-, or tri- substituted, wherein the substituents are independently selected from the group consisting of (C 1-4 )alkyl, (C 1-4 )alkoxy, halogen, cyano, (C 1-3 )fluoroalkyl, and (C 1-3 )fluoroalkoxy;
  • o and the other of said substituents is/are independently selected from the group consisting of (Ci -4 )alkyl, (Ci -4 )alkoxy, halogen, cyano, (Ci -3 )fluoroalkyl, and (Ci -3 )fluoroalkoxy;
  • R 1 represents phenyl or 5- or 6-membered heteroaryl, wherein said phenyl or 5- or 6-membered heteroaryl is fused to a non-aromatic 5- or 6-membered ring, wherein said ring optionally contains one or two heteroatoms independently selected from oxygen and nitrogen; wherein said ring is optionally substituted with one or two substituents independently selected from (Ci -3 )alkyl, oxo, and halogen.
  • Another embodiment relates to compounds according to any one of embodiments 1 ) to), wherein
  • R 1 represents aryl or heteroaryl, wherein the aryl or heteroaryl independently is unsubstituted, or mono-, di-, or tri-substituted;
  • substituents are independently selected from the group consisting of (Ci -4 )alkyl, (Ci -4 )alkoxy, halogen, cyano, hydroxy, (Ci -3 )fluoroalkyl, (C 1-3 )fluoroalkoxy, (C 1-3 )fluoroalkyl-sulfonyloxy, (C 3-6 )cycloalkyl-oxy, hydroxy- (C 2-4 )alkoxy, R 4 R 5 N-(C 2-4 )alkoxy, R 6 -CO-, R 7 -CO-(C 1-4 )alkoxy;
  • R 1 represents phenyl (preferred) or 5- or 6-membered heteroaryl, wherein the phenyl or 5- or 6-membered heteroaryl independently is mono-, or di-substituted (preferred: mono-substituted); wherein
  • phenyl or 5- or 6-membered heteroaryl wherein said phenyl or 5- or 6-membered heteroaryl is independently unsubstituted (preferred), or mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of (Ci -4 )alkyl, (Ci -4 )alkoxy, halogen, cyano, (Ci -3 )fluoroalkyl, and (Ci -3 )fluoroalkoxy; or
  • phenyl-(Ci -4 )alkoxy or 5- or 6-membered heteroaryl-(Ci -4 )alkoxy is independently unsubstituted (preferred), or mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of (C 1-4 )alkyl, (C 1-4 )alkoxy, halogen, cyano, (C 1-3 )fluoroalkyl, and (C 1-3 )fluoroalkoxy; o and the other of said substituents, if present, is/are independently selected from the group consisting of (Ci -4 )alkyl, (Ci -4 )alkoxy, halogen, cyano, (Ci -3 )fluoroalkyl, and (C
  • R 1 represents phenyl which is fused to a non-aromatic 5- or 6-membered ring, wherein said ring contains one or two oxygen atoms.
  • Another embodiment relates to compounds according to any one of embodiments 1 ) to), wherein
  • R 1 represents aryl or heteroaryl, wherein the aryl or heteroaryl independently is unsubstituted, or mono-, di-, or tri-substituted;
  • substituents are independently selected from the group consisting of (Ci -4 )alkyl, (Ci -4 )alkoxy, halogen, cyano, hydroxy, (Ci -3 )fluoroalkyl, (Ci -3 )fluoroalkoxy, (Ci -3 )fluoroalkyl-sulfonyloxy, (C 3- 6)cycloalkyl-oxy, hydroxy- (C 2-4 )alkoxy, R 4 R 5 N-(C 2-4 )alkoxy, R 6 -CO-, and R 7 -CO-(Ci -4 )alkoxy; (notably selected from (Ci -4 )alkyl, (Ci -4 )alkoxy, halogen, cyano, (Ci -3 )fluoroalkyl, (C 1-3 )fluoroalkoxy, and hydroxy-(C 2-4 )alkoxy; especially selected from (C 1-4 )alkoxy, (C 1-4
  • R 1 represents phenyl (preferred) or 6-membered heteroaryl, wherein the phenyl or 6-membered heteroaryl independently is mono-, or di-substituted (preferred: mono- substituted); wherein
  • phenyl or 5- or 6-membered heteroaryl wherein said phenyl or 5- or 6-membered heteroaryl is independently unsubstituted (preferred), or mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of (Ci -4 )alkyl, (Ci -4 )alkoxy, halogen, cyano, (Ci -3 )fluoroalkyl, and (Ci -3 )fluoroalkoxy (especially (Ci -4 )alkyl or halogen);
  • o and the other of said substituents is independently selected from the group consisting of (Ci -4 )alkyl, (Ci -4 )alkoxy, halogen, cyano, (C 1-3 )fluoroalkyl, and (C 1-3 )fluoroalkoxy (notably (C 1-4 )alkyl or (C 1-4 )alkoxy; especially (C 1-4 )alkoxy);
  • R 1 represents a benzodioxinyl, or a benzodioxolyl group.
  • Another embodiment relates to compounds according to any one of embodiments 1 ) to), wherein
  • R 1 represents a group selected from phenyl, naphthyl, pyridinyl, quinolinyl, thiazolyl, indazoly, indolyl, benzimidazolyl; wherein said group independently is unsubstituted or mono-, di-, or tri-substituted; wherein o the substituents are independently selected from the group consisting of (Ci -4 )alkyl, (Ci -4 )alkoxy, halogen, cyano, hydroxy, (Ci -3 )fluoroalkyl, (Ci -3 )fluoroalkoxy, (Ci -3 )fluoroalkyl-sulfonyloxy, (C 3- 6)cycloalkyl-oxy, hydroxy- (C 2-4 )alkoxy, R 4 R 5 N-(C 2-4 )alkoxy, R 6 -CO-, and R 7 -CO-(Ci -4 )alkoxy; (notably
  • R 1 represents phenyl (preferred) or 6-membered heteroaryl, wherein the phenyl or 6-membered heteroaryl independently is mono-, or di-substituted (preferred: mono- substituted); wherein
  • phenyl or 5- or 6-membered heteroaryl wherein said phenyl or 5- or 6-membered heteroaryl is independently unsubstituted (preferred), or mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of (Ci -4 )alkyl, (Ci -4 )alkoxy, halogen, cyano, (Ci -3 )fluoroalkyl, and (Ci -3 )fluoroalkoxy (especially (Ci -4 )alkyl or halogen);
  • o and the other of said substituents is independently selected from the group consisting of (Ci -4 )alkyl, (Ci -4 )alkoxy, halogen, cyano, (Ci -3 )fluoroalkyl, and (Ci -3 )fluoroalkoxy (notably (Ci -4 )alkyl or (Ci -4 )alkoxy, especially (Ci -4 )alkoxy).
  • Another embodiment relates to compounds according to any one of embodiments 1 ) to), wherein
  • R 1 represents a phenyl, or a pyridinyl group wherein said group independently is unsubstituted or mono-, di-, or tri-substituted;
  • substituents are independently selected from the group consisting of (C 1-4 )alkyl, (C 1-4 )alkoxy, halogen, cyano, (C 1-3 )fluoroalkyl, (C 1-3 )fluoroalkoxy, and hydroxy-(C 2-4 )alkoxy (especially selected from (C 1-4 )alkoxy and cyano);
  • R 1 represents phenyl which is mono-, or di-substituted (preferred: mono- substituted); wherein
  • substituents are attached in a position other than the ortho-position (with regard to the position at which R 1 is attached to the rest of the molecule); wherein said substituent is: ⁇ phenyl or 5- or 6-membered heteroaryl (preferred), wherein said phenyl or 5- or 6-membered heteroaryl is independently unsubstituted (preferred), or mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of (Ci-4)alkyl, (Ci -4 )alkoxy, halogen, cyano, (Ci -3 )fluoroalkyl, and (Ci -3 )fluoroalkoxy (especially (Ci -4 )alkyl or halogen);
  • o and the other of said substituents is independently selected from the group consisting of (Ci -4 )alkyl, (Ci -4 )alkoxy, halogen, cyano, (Ci -3 )fluoroalkyl, and (Ci -3 )fluoroalkoxy (notably (Ci -4 )alkyl or (Ci -4 )alkoxy, especially (Ci -4 )alkoxy).
  • R 2 represents hydrogen, (C 1-6 )alkyl, (C 3-6 )cycloalkyl, hydroxy-(C 2-4 )alkyl, or (C 1-4 )fluoroalkyl.
  • Another embodiment relates to compounds according to any one of embodiments 1 ) to 15), wherein R 2 represents (C 1-3 )alkyl; especially methyl or ethyl.
  • Another embodiment relates to compounds according to any one of embodiments 1 ) to
  • Another embodiment relates to compounds according to any one of embodiments 1 ) to
  • R 10 represents hydrogen, fluorine, chlorine, methyl, or methoxy (especially hydrogen or fluorine).
  • Another embodiment relates to compounds according to any one of embodiments 1 ) to 18), wherein U or X represents N, and the remaining of U, V, W, and X represent CH.
  • Trifluoro-methanesulfonic acid 5-[6-(1-ethyl-1 H-indole-3-carbonyl)-4,5,6J-tetrahydro-thieno[2,3-c]pyridin-7- ylmethyl]-2-methoxy-phenyl ester;
  • the compounds of formula (I) and their pharmaceutically acceptable salts can be used as medicaments, e.g. in the form of pharmaceutical compositions for enteral or parental administration.
  • compositions can be effected in a manner which will be familiar to any person skilled in the art (see for example Remington, The Science and Practice of Pharmacy, 21 st Edition (2005), Part 5, "Pharmaceutical Manufacturing” [published by Lippincott Williams & Wilkins]) by bringing the described compounds of formula (I) or their pharmaceutically acceptable salts, optionally in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants.
  • the present invention also relates to a method for the prevention or treatment of a disease or disorder mentioned herein comprising administering to a subject a pharmaceutically active amount of a compound of formula (I).
  • the compounds according to formula (I) are useful for the prevention or treatment of diseases or disorders related to the orexin system.
  • Such diseases or disorders related to the orexin system may be defined as comprising all types of sleep disorders, stress-related syndromes, addictions (especially psychoactive substance use, abuse, seeking and reinstatement), cognitive dysfunctions in the healthy population and in psychiatric and neurologic disorders, and eating or drinking disorders.
  • diseases or disorders related to the orexin system comprise all types of sleep disorders, stress-related syndromes, and addictions (especially psychoactive substance use, abuse, seeking and reinstatement).
  • such diseases or disorders related to the orexin system may be selected from the group consisting of sleep disorders that comprises all types of insomnias, sleep-related dystonias, restless leg syndrome, sleep apneas, jet-lag syndrome, shift-work syndrome, delayed or advanced sleep phase syndrome or insomnias related to psychiatric disorders (notably all types of insomnias, especially primary insomnia).
  • diseases or disorders related to the orexin system may be selected from the group consisting of cognitive dysfunctions that comprise deficits in all types of attention, learning and memory functions occurring transiently or chronically in the normal, healthy, young, adult or aging population, and also occurring transiently or chronically in psychiatric, neurologic, cardiovascular and immune disorders.
  • such diseases or disorders related to the orexin system may be selected from the group consisting of eating disorders that comprise metabolic dysfunction; dysregulated appetite control; compulsive obesities; bulimia or anorexia nervosa.
  • such diseases or disorders related to the orexin system may be selected from the group consisting of all types of addictions (especially psychoactive substance use, abuse, seeking and reinstatement) that comprise all types of psychological or physical addictions and their related tolerance and dependence components.
  • Eating disorders may be defined as comprising metabolic dysfunction; dysregulated appetite control; compulsive obesities; emeto-bulimia or anorexia nervosa.
  • Pathologically modified food intake may result from disturbed appetite (attraction or aversion for food); altered energy balance (intake vs. expenditure); disturbed perception of food quality (high fat or carbohydrates, high palatability); disturbed food availability (unrestricted diet or deprivation) or disrupted water balance.
  • Drinking disorders include polydipsias in psychiatric disorders and all other types of excessive fluid intake.
  • Sleep disorders include all types of parasomnias, insomnias, sleep-related dystonias; restless leg syndrome; sleep apneas; jet-lag syndrome; shift-work syndrome, delayed or advanced sleep phase syndrome or insomnias related to psychiatric disorders.
  • Insomnias are defined as comprising sleep disorders associated with aging; intermittent treatment of chronic insomnia; situational transient insomnia (new environment, noise) or short-term insomnia due to stress; grief; pain or illness. Insomnia also include stress-related syndromes including post-traumatic stress disorders as well as other types and subtypes of anxiety disorders such as generalized anxiety, obsessive compulsive disorder, panic attacks and all types of phobic anxiety and avoidance.
  • Addictions may be defined as addiction to one or more rewarding stimuli, notably to one rewarding stimulus. Such rewarding stimuli may be of either natural or synthetic origin.
  • Psychoactive substance use, abuse, seeking and reinstatement are defined as all types of psychological or physical addictions and their related tolerance and dependence components.
  • Cognitive dysfunctions include deficits in all types of attention, learning and memory functions occurring transiently or chronically in the normal, healthy, young, adult or aging population, and also occurring transiently or chronically in psychiatric, neurologic, cardiovascular and immune disorders.
  • such diseases or disorders related to the orexin system may be defined as comprising notably mental health diseases or disorders relating to orexinergic dysfunctions; especially sleep disorders, anxiety disorders, addiction disorders, cognitive dysfunctions, mood disorders, or appetite disorders; wherein sleep disorders comprise dyssomnias, parasomnias, sleep disorders associated with a general medical condition and substance-induced sleep disorders (especially sleep disorders comprise insomnias, sleep- related dystonias; restless leg syndrome; sleep apneas; jet-lag syndrome; shift work sleep disorder, delayed or advanced sleep phase syndrome, or insomnias related to psychiatric disorders; and, in addition, sleep disorders associated with aging; intermittent treatment of chronic insomnia; situational transient insomnia (new environment, noise) or short-term insomnia due to stress; grief; pain or illness); wherein anxiety disorders comprise generalized anxiety disorders (GAD), obsessive compulsive disorders (OCDs), acute stress disorders, posttraumatic stress disorders (PTSDs), panic anxiety disorders (PADs) including panic attacks, phobic anxieties (PHOBs), generalized
  • further diseases related to the orexin system are selected from treating, controlling, ameliorating or reducing the risk of epilepsy, including absence epilepsy; treating or controlling pain, including neuropathic pain; treating or controlling Parkinson's disease; treating or controlling psychosis including acute mania and bipolar disorder; treating or controlling stroke, particularly ischemic or haemorrhagic stroke; blocking an emetic response i.e. nausea and vomiting; treating or controlling agitation, in isolation or co-morbid with another medical condition.
  • the present compounds may be particularly useful for the treatment of such environmentally conditioned disorder or disease.
  • any characteristics described in this invention for the compounds of formula (I) (whether for the compounds themselves, salts thereof, compositions containing the compounds or salts thereof, uses of the compounds or salts thereof, etc.) apply mutatis mutandis to compounds of formula (l E i ) or formula (l E 2)- Preparation of compounds of formula (I):
  • the compounds of formula (I) can be prepared by the methods given below, by the methods given in the Examples or by analogous methods. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by a person skilled in the art by routine optimisation procedures. The compounds obtained may also be converted into salts thereof in a manner known per se.
  • Compounds of formula (I) are prepared by reaction of an amine of Structure 1 or a salt thereof, such as a hydrochloride salt, with an acid of Structure 2 in the presence of an amide- coupling reagent such as TBTU, EDC, DCC or PyBOP and a base like DIPEA or TEA in a solvent such as MeCN or DMF.
  • an amide- coupling reagent such as TBTU, EDC, DCC or PyBOP and a base like DIPEA or TEA in a solvent such as MeCN or DMF.
  • Compounds of Structure 1 may be prepared by one of the synthetic pathways described below.
  • Structure 1 represents a 4,5,6,7-tetrahydrothieno[2,3-c]pyridine
  • compounds of Structure 1 may be prepared as outlined in Scheme 3.
  • An amine of Structure 13 is either commercially available or prepared by the borane reduction of the corresponding commercially available nitrile of structure 10 in a solvent like THF.
  • an amine of Structure 13 can be prepared in two steps from the corresponding commercially available aldehyde of Structure 11 via a Henry reaction with nitromethane to give a nitro olefin of Structure 12 that can then be reduced with LAH and sulfuric acid in a solvent like THF to furnish an amine of Structure 13.
  • Structure 1 represents a 4,5,6,7-tetrahydrothieno[3,2-c]pyridine
  • compounds of Structure 1 may be prepared as outlined in Scheme 4.
  • An amine of Structure 18 is either commercially available or prepared by the borane reduction of the corresponding commercially available nitrile of Structure 15 in a solvent like THF.
  • an amine of Structure 18 can be prepared in two steps from the corresponding aldehyde of Structure 16 via a Henry reaction with nitromethane to give a nitro olefin of Structure 17 that can then reduced with LAH and sulfuric acid in a solvent like THF to furnish an amine of Structure 18.
  • Structure 1 represents a 4,5,6,7-tetrahydrothieno[3,4-c]pyridine
  • compounds of Structure 1 may be prepared by one of the synthetic pathways described in Scheme 5.
  • substituent R 8 is already present in the starting material
  • a readily available acid of Structure 20 may be reduced with borane in a solvent like THF to give an alcohol of Structure 21 that can be subsequently re-oxidised with Mn0 2 in a solvent like DCM to give the corresponding aldehyde of Structure 22.
  • an aldehyde of Structure 22 can be transformed via a Henry reaction with nitromethane into a nitro olefin of Structure 23 that can then be reduced with LAH and sulfuric acid in a solvent like THF to furnish an amine of Structure 24a.
  • Reaction of an amine of Structure 24a or a salt thereof, such as a hydrochloride salt with an acid of Structure 4 in the presence of an amide- coupling reagent such as TBTU or PyBOP and a base like DIPEA or TEA in a solvent such as MeCN or DMF gives an amide of Structure 25a.
  • the amide of Structure 25a is then subjected to Bischler-Napieralski conditions such as POCI 3 in MeCN followed by reduction of the resulting imine with sodium borohydride in a solvent like MeOH to give compounds of Structure 1.
  • an amine of Structure 24b is either commercially available or can be prepared by the borane reduction of the corresponding nitrile of Structure 26 in a solvent like THF.
  • R 8 Br
  • R 8 can then be further modified in for example a Negishi coupling with a readily available organozinc reagent to give further compounds of Structure 1.
  • R 8 can be converted to an alkoxy substituent, e.g. EtO, by following the procedure described in US2008/71084.
  • Structure 1 represents a 4,5,6,7-tetrahydropyrazolo[3,4-c]pyridine
  • compounds of Structure 1 may be prepared as outlined in Scheme 6.
  • the amide of Structure 28 is then subjected to Bischler-Napieralski conditions such as POCI 3 in MeCN followed by reduction of the resulting imine with sodium borohydride in a solvent like MeOH to give compounds of Structure 1.
  • Structure 1 represents a 4,5,6,7-tetrahydropyrazolo[4,3-c]pyridine
  • compounds of Structure 1 may be prepared in analogy to the procedure described in WO2009038812 and as illustrated in Scheme 7.
  • An amine of Structure 31 either as a single regioisomer or a mixture of both regioisomers (31 , 33) or a salt thereof, may be coupled with an acid of Structure 4 in the presence of an amide-coupling reagent such as TBTU or PyBOP and a base like DIPEA or TEA in a solvent such as MeCN or DMF to give an amide of Structure 32.
  • the amide of Structure 32 is then subjected to Bischler-Napieralski conditions such as POCI 3 in MeCN followed by reduction of the resulting imine with sodium borohydride in a solvent like MeOH to give compounds of Structure 1.
  • Structure 1 represents a 4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridine
  • compounds of Structure 1 may be prepared either by Bischler-Napieralski conditions in analogy to the procedure described by Zheng et al. in J. Med. Chem. 1999, 42, 2287-2294. or alternatively, via a Pictet-Spengler reaction under basic conditions as depicted in Scheme 8.
  • Structure 1 represents a 5,6,7,8-tetrahydroimidazo[1 ,2-a]pyrazine
  • compounds of Structure 1 may be prepared as outlined in Scheme 9.
  • a Boc-protected amino alcohol of Structure 37 either commercially available, or prepared in 2 steps from the corresponding amino acid may be oxidised using conditions like Swern to give the corresponding amino aldehyde of Structure 38.
  • Condensation of aldehyde 38 with a glyoxal derivative in the presence of ammonium hydroxide in a solvent like MeOH gives an imidazole of Structure 39.
  • Structure 1 represents a 1 ,2,3,4-tetrahydropyrrolo[1 ,2-a]pyrazine
  • compounds of Structure 1 may be prepared in analogy to the procedure described in WO2009090054 and as depicted in Scheme 10.
  • An amine of Structure 42 undergoes ring closure by reaction with an aldehyde of Structure 36 in a solvent such as MeOH in the presence of a base like aq. NaOH. Reaction times can vary between 1 h and 5 days.
  • Acids of Structure 2 are either commercially available or prepared as depicted in Scheme 1 1 .
  • a commercially available or well known indole derivative of Structure 43 may be alkylated on nitrogen by initial deprotonation with a base like sodium hydride in a solvent such as DMF or THF followed by reaction with an alkyl halide like methyl iodide.
  • Formylation at the indole-3- position using Duff conditions (hexamethylenetetramine in TFA under reflux) followed by oxidation of the aldehyde using sodium chlorite under buffered conditions in the presence of a chlorine scavenger like 2-methyl-2-butene in a solvent mixture like THF/ f butanol gives an acid of Structure 2.
  • a commercially available ester of Structure 44 can be N- alkylated in the same way as described above followed by hydrolysis of the ester function with aq. NaOH in MeOH to give an acid of Structure 2.
  • bi-(hetero-)aryl-like structures as present in certain groups R 1 can be synthesised using well established Suzuki chemistry in analogy to scheme 12.
  • the enantiomers can be separated using methods known to the one skilled in the art: e.g. by formation and separation of diastereomeric salts or by HPLC over a chiral stationary phase such a Daicel ChiralCel OD-H (5-10 ⁇ ) column, a Daicel ChiralPak IC (5 ⁇ ) column, or a Daicel ChiralPak IA (5-10 ⁇ ) or AD-H (5 ⁇ ) column.
  • a chiral stationary phase such as a Daicel ChiralCel OD-H (5-10 ⁇ ) column, a Daicel ChiralPak IC (5 ⁇ ) column, or a Daicel ChiralPak IA (5-10 ⁇ ) or AD-H (5 ⁇ ) column.
  • Typical conditions of chiral HPLC are an isocratic mixture of eluent A (heptanes or CH 3 CN) and eluent B (EtOH , MeOH, DCM ot tBME in presence or absence of an amine such as TEA or DEA), at a flow rate of 0.8 to 150 mL/min.
  • eluent A heptanes or CH 3 CN
  • eluent B EtOH , MeOH, DCM ot tBME in presence or absence of an amine such as TEA or DEA
  • Method A Agilent 1 100 series with mass spectrometry detection (MS: Finnigan single quadrupole). Column: Zorbax SB-aq (3.5 ⁇ , 4.6 x 50 mm). Conditions: MeCN [eluent A]; water + 0.04% TFA [eluent B]. Gradient: 95% B ⁇ 5% B over 1 .5 min. (flow: 4.5 mL/min.). Detection: UV/Vis + MS.
  • Method B Agilent 1 100 series with mass spectrometry detection (MS: Finnigan single quadrupole). Column: Waters XBridge C18 (5 ⁇ , 4.6 x 50 mm). Conditions: MeCN [eluent A]; water + 0.04% TFA [eluent B]. Gradient: 95% B ⁇ 5% B over 1 .5 min. (flow: 4.5 mL/min.). Detection: UV/Vis + MS.
  • Method C Agilent 1 100 series with mass spectrometry detection (MS: Finnigan single quadrupole). Column: Zorbax Extend C18 (5 ⁇ , 4.6 x 50 mm). Conditions: MeCN [eluent A]; 13 mmol/L NH 3 in water [eluent B]. Gradient: 95% B ⁇ 5% B over 1.5 min. (flow: 4.5 mL/min.). Detection: UV/Vis + MS.
  • Method D Agilent 1 100 series with mass spectrometry detection (MS: Finnigan single quadrupole).
  • MS Finnigan single quadrupole
  • Column Waters XBridge C18 (5 ⁇ , 4.6 x 50 mm).
  • Conditions MeCN [eluent A]; 13 mmol/L NH 3 in water [eluent B].
  • Gradient 95% B ⁇ 5% B over 1.5 min. (flow: 4.5 mL/min.).
  • Detection UV/Vis + MS.
  • Step 1 /V-Bromosuccinimide (9.89 g, 55.0 mmol, 1 .1 eq.) was added cautiously and portionwise over 20 min at RT to a soln. of 1 ,2,3,4-tetrahydroisoquinoline (6.34 mL, 50.0 mmol, 1.0 eq.) in DCM (130 mL) under argon. After complete addition the reaction mixture was stirred for 2h after which 5M aq. NaOH (30 mL) was added and the mixture was stirred for 2h. The organic layer was separated and washed with water (1x) before being extracted with 2M aq. HCI (2x) and subsequently discarded. The combined acidic aq.
  • Step 2 The appropriately substituted benzylmagnesium chloride as a soln. in THF (1.14 mmol, 1 .5 eq.) was added dropwise to a 5°C soln. of 3,4-dihydroisoquinoline from above (0.76 mmol) in THF (3 mL) under argon and after complete addition the reaction mixture was stirred for 1.5h. The reaction was quenched with sat. aq. NH 4 CI, diluted with H 2 0 and extracted with DCM (3x). The combined organic extracts were dried over Na 2 S0 4 , filtered and evaporated in vacuo to give the crude product that was purified by FC (eluent: 2.5% -> 10% MeOH in DCM).
  • Step 1 Molecular sieves 4A (-10 wt%), butylamine (4.8 mmol, 0.12 eq.) and acetic acid (8 mmol, 0.20 eq.) were added to a soln. of the substituted thiophene-3-carbaldehyde 11 (40.00 mmol, 1 eq.) in nitromethane (23 mL) and the resulting mixture was heated to 95°C for 30 min. The reaction mixture was transferred to a new flask to remove the molecular sieves and the solvent was removed in vacuo. The residue was purified by FC (eluent: Hept/EtOAc) to furnish the desired nitro olefin 12.
  • FC eluent: Hept/EtOAc
  • Step 2 H 2 S0 4 (2.87 mL) was added dropwise to a stirred suspension of LiAIH 4 (4.30 g, 108 mmol, 4.46 eq.) in THF (162 mL) under ice-cooling. After stirring for 20 min a soln. of the nitro olefin 12 (24 mmol, 1.0 eq.) in THF (17 mL) was added dropwise over 20 min. After an additional 10 min the cooling bath was removed and the mixture was heated to a gentle reflux for 5 min. The reaction mixture was then cooled to 0°C and carefully quenched by the dropwise addition of 'PrOH (18 mL), followed by 2M aq. NaOH (13 mL). The resulting suspension was filtered and the residue was rinsed with THF. The filtrate was concentrated in vacuo to give the desired substituted 2-thiophen-3-yl-ethylamine as its free base.
  • Step 1 TBTU (8.63 g, 26.88 mmol) was added to a RT soln. of the required arylacetic acid 4 (24.44 mmol 1.0 eq.) and DIPEA (6.3 mL, 36.67 mmol) in DMF (10 mL). After stirring for 5 min a soln. of the 2-thiophen-3-yl-ethylamine 13 or 2-thiophen-3-yl-ethylamine.HCI (24.44 mmol) and DIPEA (6.3 mL, 36.67 mmol) in DMF (10 mL) was added and the resulting mixture was stirred for 16h.
  • the reaction mixture was diluted with MTBE and washed successively with 1 M aq. NaOH (1 x), 1 M aq. HCI (1 x) and H 2 0 (3x).
  • the organic layer was dried over Na 2 S0 4 , filtered and evapotated in vacuo to give the crude product that was either triturated with Et 2 0 or purified by FC (eluent: Hexane/EtOAc) to give the corresponding amide 14.
  • Step 2 POCI 3 (4.88 mL, 52.39 mmol) was added to a RT soln. of the amide from above (10.48 mmol 1 .0 eq.) in MeCN (180 mL) and the resulting mixture was heated to 80°C and stirred for 2h. The volatiles were removed in vacuo and the residue was dissolved in MeOH and re-evaporated (2x). The residue was re-dissolved in MeOH and cooled to 0°C before NaBH 4 (1.27 g, 33.53 mmol) was added portionwise. After complete addition the reaction mixture was stirred for 10 min before being concentrated in vacuo and the residue was partitioned between H 2 0 and EtOAc. The phases were separated and the aq. phase was re- extracted with EtOAc (2x). The combined organic extracts were washed with brine, dried over Na 2 S0 4 , filtered and evaporated in vacuo to give the cyclic amine product that was used further without purification.
  • Step 1 A soln. of Boc 2 0 (227 mg, 1 .04 mmol) in DCM (5 mL) was added dropwise to a RT soln. of rac-7-(4-iodo-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine (363 mg, 1 .02 mmol) and Et 3 N (0.29 mL, 2.1 mmol) in DCM (15 mL) and the reaction mixture was stirred for 30 min. The reaction was quenched by the addition of 1 M aq. citric acid (10 mL) and the mixture was stirred vigorously for 10 min. The layers were separated and the aq. layer was re- extracted with DCM (2x).
  • Step 2 1 H-1 ,2,3-triazole (140 mg, 2 mmol), Cs 2 C0 3 (658 mg, 2 mmol), Cul (9.6 mg, 0.05 mmol) and rac. frans-/V,/V-diaminomethylcyclohexane (29 mg, 2 mmol) were added to a RT soln. of rac-7-(4-iodo-benzyl)-4,7-dihydro-5H-thieno[2,3-c]pyridine-6-carboxylic acid tert-butyl ester (460 mg, 1 mmol) in DMF (4 mL) under argon and the resulting mixture was heated to 120°C for 17h.
  • Step 3a 4M HCI in dioxane (2 mL, 19 eq.) was added to a RT soln. of rac-7-(4-[1 ,2,3]triazol- 2-yl-benzyl)-4,7-dihydro-5H-thieno[2,3-c]pyridine-6-carboxylic acid tert-butyl ester (167 mg, 0.42 mmol) in dioxane (1 mL) under argon and the resulting mixture was stirred for 1 h after which it appeared as a white suspension. The product was collected by filtration washing with Et 2 0 and dried in vacuo to give the title compound as a white solid (137 mg).
  • Step 3b Boc-deprotection of rac-7-(4-[1 ,2,3]triazol-1 -yl-benzyl)-4,7-dihydro-5H-thieno[2,3- c]pyridine-6-carboxylic acid tert-butyl ester as described above gave the 2 nd title compound as a beige solid (86 mg).
  • Step 1 Boc-protection of rac-2-methoxy-4-(4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-7- ylmethyl)-phenol as described above gave rac-7-(4-hydroxy-3-methoxy-benzyl)-4,7-dihydro- 5H-thieno[2,3-c]pyridine-6-carboxylic acid tert-butyl ester.
  • Step 2 Cu(OAc) 2 (167 mg, 0.92 mmol) was stirred in DCM (6 mL) under an air atmosphere for 10 min before vinylboronic anhydride.
  • pyridine complex 147 mg, 0.61 mmol
  • rac-7-(4- hydroxy-3-methoxy-benzyl)-4,7-dihydro-5H-thieno[2,3-c]pyridine-6-carboxylic acid tert-butyl ester 345 mg, 0.92 mmol
  • pyridine (0.75 mL, 9.19 mmol
  • Step 3 A soln. of TFA (0.1 1 mL, 1 .47 mmol) in DCM (0.75 mL) was added to a 0°C soln. of Et 2 Zn (1 .47 mL, 2 eq.) 1 M soln. in hexanes in DCM (1.5 mL) under argon and the resulting mixture was stirred for 20 min before a soln. of CH2I2 (0.12 mL, 1 .47 mmol) in DCM (0.75 mL) was added. After a further 20 min a soln.
  • Step 4 Boc-deprotection of rac-7-(4-cyclopropoxy-3-methoxy-benzyl)-4,7-dihydro-5H- thieno[2,3-c]pyridine-6-carboxylic acid tert-butyl ester as described above gave the title compound as an orange solid (100 mg).
  • LC-MS C: t R 0.87 min; No ionisation.
  • Step 1 2-Chloroethanol (150 ⁇ _, 2.25 mmol) was added to a mixture of rac-7-(4-hydroxy-3- methoxy-benzyl)-4,7-dihydro-5H-thieno[2,3-c]pyridine-6-carboxylic acid tert-butyl ester (375 mg, 1 .0 mmol), K 2 C0 3 (221 mg, 1 .60 mmol) and Kl (1 mg) in DMSO (5 mL) and the reaction mixture was heated to 85°C and stirred for 3h. The reaction mixture was concentrated in vacuo and the residue was diluted with MTBE (30 mL) and washed with water (4x5 mL).
  • Step 2 Boc-deprotection of rac-7-(4-(2-hydroxyethoxy)-3-methoxybenzyl)-4,5- dihydrothieno[2,3-c]pyridine-6(7H)-carboxylate as described above gave the title compound as a white solid (95 mg).
  • Step 1 Boc-protection of rac-7-(3,4-dimethoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3- c]pyridine as described above gave rac-7-(3,4-dimethoxy-benzyl)-4,7-dihydro-5H-thieno[2,3- c]pyridine-6-carboxylic acid tert-butyl ester.
  • Step 2 A soln. of NBS (653 mg, 3.67 mmol) in MeCN (10 mL) was added over a period of 5 min to a RT soln. of rac-7-(3,4-dimethoxy-benzyl)-4,7-dihydro-5H-thieno[2,3-c]pyridine-6- carboxylic acid tert-butyl ester (1 .3 g, 3.34 mmol) in MeCN (40 mL). The reaction mixture was heated to 75°C after which the volatiles were removed in vacuo and the residue was re- dissloved in MeCN and purified by prep.
  • Step 3 TFA (0.53 mL, 6.9 mmol) was added to a RT soln. of the 1 :1 mixture of regioisomers from above (0.54 g, 1.15 mmol) in DCM (5 mL). After stirring for 2h the volatiles were removed in vacuo and the residue was partitioned between EtOAc and sat. aq. NaHC0 3 soln. The phases were separated and the aq. phase was re-extracted with EtOAC (2x).
  • Step 1 Boc-protection of rac-7-(6-chloro-pyridin-3-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3- c]pyridine as described above gave rac-7-(6-chloro-pyridin-3-ylmethyl)-4,7-dihydro-5H- thieno[2,3-c]pyridine-6-carboxylic acid tert-butyl ester.
  • Step 2 A mixture of Pd(ll) trifluoroacetate (41 mg, 0.12 mmol), zinc powder (34 mg, 0.52 mmol), racemic-2-(di-t-butylphosphino)-1 ,1 '-binaphtyl (96 mg, 0.24 mmol), rac-7-(6-chloro- pyridin-3-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyridine-6-carboxylic acid tert-butyl ester (1 .0 g, 2.74 mmol) and Zn(CN) 2 (180 mg, 1.54 mmol) in DMA (15 ml) was heated to 95°C for 2.5h.
  • Step 3 Boc-deprotection of rac-7-(6-cyano-pyridin-3-ylmethyl)-4,7-dihydro-5H-thieno[2,3- c]pyridine-6-carboxylic acid tert-butyl ester using 4M HCI in dioxane as described above gave the title compound as a white solid (0.61 g).
  • Step 1 Me 2 Zn 1.2M soln. in toluene (4.62 ml, 5.54 mmol) was added dropwise to a RT soln. of rac-7-(6-chloro-pyridin-3-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyridine-6-carboxylic acid tert-butyl ester (1 .0 g, 2.74 mmol), and [1 ,1 '- bis(diphenylphosphino)ferrocene]dichloropalladium(ll) complex with CH 2 CI 2 (224 mg, 0.27 mmol) in dioxane (20 mL) and the resulting mixture was stirred overnight.
  • Step 2 Boc-deprotection of rac-7-(6-methyl-pyridin-3-ylmethyl)-4,7-dihydro-5H-thieno[2,3- c]pyridine-6-carboxylic acid tert-butyl ester using 4M HCI in dioxane as described above gave the title compound as a white solid (0.61 g).
  • Step 2 A mixture of rac-7-[3-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-benzyl]-4,7- dihydro-5H-thieno[2,3-c]pyridine-6-carboxylic acid tert-butyl ester (0.25 g, 0.55 mmol), 2- chloropyrimidine (75 mg, 0.66 mmol), 2M aq. Na 2 C0 3 (3.3 mL) and 2-methyltetrahydrofuran (4.7 mL) was degassed with N 2 for 20s.
  • Step 3 Boc-deprotection of rac-7-(3-pyrimidin-2-yl-benzyl)-4,7-dihydro-5H-thieno[2,3- c]pyridine-6-carboxylic acid tert-butyl ester using 4M HCI in dioxane as described above gave the title compound as a white solid (32 mg).
  • Step 2 Boc-deprotection of rac-7-(3-pyrazol-1 -yl-benzyl)-4,7-dihydro-5H-thieno[2,3- c]pyridine-6-carboxylic acid tert-butyl ester using 4M HCI in dioxane as described above gave the title compound as a white solid (8 mg).
  • Step 1 TBTU (2.17 g, 6.77 mmol) was added to a soln. of 2-thiopheneethylamine (0.78 g, 6.16 mmol), 1-naphthylacetic acid (1 .15 g, 6.16 mmol) and DIPEA (2.64 mL, 15.39 mmol) in DMF (10 mL) and the resulting mixture was stirred for 10 min.
  • the reaction mixture was diluted with MTBE and washed successively with 1 M aq. NaOH (1x), 1 M aq. HCI (1x) and H 2 0 (3x).
  • Step 1 1 M Borane.THF complex (103 mL, 0.1 mol) was added dropwise to a RT soln. of 2- methylthiophene-3-carboxylic acid (5.0 g, 35.4 mmol) in THF (60 mL) under argon and the resulting mixture was stirred for 2h. The reaction mixture was cautiously quenched with MeOH and subsequently concentrated in vacuo. The residue was purified by FC (eluent: 8:1 - >5:1 hexane:EtOAc) to give (2-methyl-thiophen-3-yl)-methanol as a colourless oil (4.17 g).
  • Step 2 Mn0 2 (44.59 g, 0.51 mol) was added portionwise to a RT soln. of (2-methyl- thiophen-3-yl)-methanol (4.17 g, 32.53 mmol) in DCM (350 mL) and the resulting mixture was stirred for 18h. The reaction mixture was filtered through a pad of celite rinsing with additional DCM. The filtrate was evapotated in vacuo to give 2-methyl-thiophene-3- carbaldehyde as a yellow liquid (3.66 g).
  • Step 3 Molecular sieves 4A (-10 wt%), butylamine (0.34 mL, 3.41 mmol) and acetic acid (0.34 mL, 5.91 mmol) were added to a soln. of 2-methyl-thiophene-3-carbaldehyde (3.65 g, 28.9 mmol) in nitromethane (16 mL) and the resulting mixture was heated to 95°C for 30 min. The reaction mixture was transferred to a new flask to remove the molecular sieves and the solvent was removed in vacuo. The residue was purified by FC (eluent: DCM) to furnish 2- methyl-3-(£-2-nitrovinyl)thiophene as an orange solid (4.55 g).
  • FC eluent: DCM
  • Step 5 TBTU (735 mg, 2.29 mmol) was added to a RT soln. of 3,4-dimethoxyphenylacetic acid (409 mg, 2.08 mmol) and DIPEA (0.45 mL, 2.6 mmol) in DMF (3 mL). After stirring for 5 min a soln. of 2-(2-methyl-thiophen-3-yl)-ethylamine hydrochloride (370 mg, 2.08 mmol) and DIPEA (0.45 mL, 2.6 mmol) in DMF (1.5 mL) was added and the resulting mixture was stirred for 30 min. The reaction mixture was diluted with MTBE and washed successively with 1 M aq. NaOH (1x), 1 M aq.
  • Step 6 POCI 3 (0.75 mL, 8.1 mmol) was added to a RT soln. of 2-(3,4-dimethoxy-phenyl)-N- [2-(2-methyl-thiophen-3-yl)-ethyl]-acetamide (517 mg, 1.62 mmol) in MeCN (25 mL) and the resulting mixture was heated to 80°C and stirred for 2h. The volatiles were removed in vacuo and the residue was dissolved in MeOH and re-evaporated (2x). The residue was re- dissolved in MeOH (5 mL) and cooled to 0°C before NaBH 4 (196 mg, 5.18 mmol) was added portionwise.
  • 2-(3,4-dimethoxy-phenyl)-N- [2-(2-methyl-thiophen-3-yl)-ethyl]-acetamide 517 mg, 1.62 mmol
  • MeCN 25 mL
  • the volatiles were removed in vacuo and the residue was
  • Step 1 A soln. of Br 2 (0.93 mL, 18 mmol) in AcOH (5 ml.) was added over 10 min to a 0°C soln. of 2-thiophen-3-yl-ethylamine hydrochloride (2.95 g, 18 mmol) in AcOH (10 mL). The resulting suspension was warmed to RT and stirred for 5 min. The reaction mixture was basified with 5M aq. NaOH soln. under ice-cooling and then extracted with MTBE (3x). The combined organic extracts were washed with water (2x) and then extracted with 1 M aq. HCI (2x). The combined acidic aq.
  • Step 2 TBTU (4.9 g, 15.26 mmol) was added to a RT soln. of 3,4-dimethoxyphenylacetic acid (2.72 g, 13.88 mmol) and DIPEA (3.56 mL, 15.26 mmol) in DMF (20 mL). After stirring for 5 min a soln. of 2-(2-bromo-thiophen-3-yl)-ethylamine (2.86 g, 2.08 mmol) and DIPEA (0.45 mL, 2.6 mmol) in DMF (1.5 mL) was added and the resulting mixture was stirred for 6 h. The reaction mixture was diluted with MTBE and washed successively with 1 M aq.
  • Step 3 A soln. of Tf 2 0 (4.84 mL, 28.75 mmol) in DCM (25 mL) was added dropwise over 60 min to a 0°C soln. of A/-[2-(2-bromo-thiophen-3-yl)-ethyl]-2-(3,4-dimethoxyphenyl)acetamide (2.21 g, 5.75 mmol) and DMAP (2.1 1 g, 17.25 mmol) in DCM (150 mL). The reaction mixture was stirred for 2h before the cooling bath was removed and stirring was continued overnight. The reaction mixture was cooled to 0°C and carefully quenched with sat. aq. Na 2 C0 3 soln.
  • Step 2 POCI 3 (372 uL, 3.99 mmol) was added to a soln. of N-[2-(1-methyl-1 H-pyrazol-4-yl)- ethyl]-2-quinolin-7-yl-acetamide (235 mg, 0.80 mmol) in MeCN (10 mL) and the resulting mixture was heated to 80°C and stirred overnight. The volatiles were removed in vacuo and the residue was dissolved in MeOH and re-evaporated (2x). The residue was re-dissolved in MeOH (10 mL) and cooled to 0°C before NaBH 4 (97 mg, 2.56 mmol) was added portionwise.
  • 4,5,6,7-Tetrahydropyrazolo[4,3-c]pyridines of Structure 1 were prepared in analogy to 4,5,6,7-tetrahydropyrazolo[3,4-c]pyridines of Structure 1 via initial amide coupling of the appropriate aryl acetic acid and the required substituted pyrazoleethanamine followed by Bischler-Napieralski cyclisation and reduction.
  • Step 1 DIBAL 1 .7M in toluene (18 mL, 26.9 mmol) was added dropwise to a -78°C soln. of 1-naphthylacetic acid ethyl ester (3.0 g, 14.0 mmol) in toluene (60 mL) and the resulting mixture was stirred for 1 h. The reaction was quenched by the addition of MeOH and the mixture was warmed to 10°C before a soln. of potassium sodium tartrate (18 g in 30 mL H 2 0) was added slowly. The biphasic mixture was stirred for 2h before the layers were separated.
  • Step 2 A soln. of 1 -naphthaleneacetaldehyde (2.12 g, 8.72 mmol) in MeOH (20 ml.) was added in one portion to a soln. of 4-(2-aminoethyl)thiazol-2-amine in 2M aq. NaOH (20 ml.) and MeOH (30 ml.) and the resulting mixture was heated to 80°C for 2h.
  • Step 1 A soln. of Boc 2 0 (712 mg, 3.26 mmol) in DCM (10 ml.) was added to a RT suspension of rac-4-naphthalen-1 -ylmethyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2- ylamine (900 mg, 3.2 mmol) and Et 3 N (0.47 mL, 3.36 mmol) in DCM (10 ml.) and the resulting mixture was stirred for 6h. The DCM was evaporated in vacuo and the residue was partitioned between EtOAc and H 2 0.
  • Step 2 A soln. of rac-2-amino-4-naphthalen-1-ylmethyl-6,7-dihydro-4H-thiazolo[5,4- c]pyridine-5-carboxylic acid tert-butyl ester (1 .14 g, 2.88 mmol) in DMF (9 mL) was added over 5 min to a rapidly stirred 65°C soln. of 'butyl nitrite (0.51 mL, 4.32 mmol) in DMF (6 mL) and the resulting mixture was stirred for 40 min. The reaction mixture was cooled to RT and acidified with 2M aq. HCI (4.5 mL) and stirred for a further 5 min.
  • the mixture was basified with 2M aq. NaOH (4.6 mL), diluted with H 2 0 (50 mL) and extracted with EtOAc (3x30 mL). The combined organic extracts were washed with H 2 0 (3x20 mL), dried over Na 2 S0 4 , filtered and evaporated in vacuo to give the Boc-protected intermediate that was subsequently dissolved in 4M HCI in dioxane (8 mL) and stirred for 40 min. The reaction mixture was evaporated in vacuo and the residue was partitioned between H 2 0 and EtOAc and filtered through a pad of celite. The layers were separated and the aq. phase was basified with 2M aq. NaOH and extracted with EtOAc (3x).
  • Step 2 A soln. of Boc 2 0 (2.88 g, 13 mmol) in DCM (20 mL) was added dropwise to a 0°C suspension of (S)-2-amino-3-(3,4-dimethoxyphenyl)propan-1 -ol (2.54 g, 12 mmol) and Et 3 N (2.01 mL, 14 mmol) in DCM (30 mL) under argon and after complete addition the resulting cream suspension was warmed to RT and stirred overnight. The reaction mixture was washed successively with 1 M aq.
  • Step 3 DMSO (1 .08 mL, 15.15 mmol) was added dropwise to a -60°C soln. of oxalyl chloride (0.69 mL, 8.26 mmol) in DCM (16 ml) and the resulting mixture was stirred for 15 min before a soln. of [(S)-2-(3,4-dimethoxy-phenyl)-1 -hydroxymethyl-ethyl]carbamic acid tert- butyl ester (2.14 g, 6.89 mmol) in DCM (8 mL) was added. After stirring for 3h DIPEA (5.9 mL, 34.43 mmol) was added and the reaction mixture was warmed to RT.
  • DIPEA 5.9 mL, 34.43 mmol
  • Step 4 A mixture of [(S)-2-(3,4-dimethoxy-phenyl)-1 -formyl-ethyl]-carbamic acid tert-butyl ester (994 mg, 3.21 mmol), 40% aq. glyoxal soln. (0.73 mL, 6.43 mmol) and 25% aq. NH 4 OH soln. (1 .21 mL, 16.07 mmol) were dissolved in MeOH (20 mL) at RT and stirred overnight.
  • Step 5 [rac-2-(3,4-Dimethoxy-phenyl)-1 -(1 H-imidazol-2-yl)-ethyl]-carbamic acid tert-butyl ester (1 .03 g, 2.95 mmol) and K 2 C0 3 (531 mg, 3.84 mmol) were added to a RT soln. of bromoacetic acid methylester (0.54 mL, 5.91 mmol) in DMF (10 mL) and the resulting suspension was stirred overnight. The reaction mixture was poured into H 2 0 and extracted with EtOAc (4x).
  • Step 6 4M HCI in dioxane (2.41 mL, 9.63 mmol) was added dropwise to a 0°C soln. of ⁇ 2- [rac-1 -tert-butoxycarbonylamino-2-(3,4-dimethoxy-phenyl)-ethyl]-imidazol-1 -yl ⁇ -acetic acid methyl ester (202 mg, 0.48 mmol) in DCM (10 mL) and the resulting mixture was warmed to RT and stirred overnight. The reaction mixture was concentrated in vacuo and the residue was re-dissolved in DCM (10 mL) before Et 3 N (270 ⁇ , 1 .93 mmol) was added.
  • Step 7 Borane.THF complex 1 M soln. in THF (1 .31 mL, 1.31 mmol) was added dropwise to a 0°C soln. of rac-8-(3,4-dimethoxy-benzyl)-7,8-dihydro-imidazo[1 ,2-a]pyrazin-6-one (94 mg, 0.33 mmol) in THF (3 mL) and the resulting mixture was warmed to RT and stirred overnight. The reaction mixture was cooled to 0°C and quenched with MeOH (3 mL) before being concentrated in vacuo.
  • Step 1 NaH (0.54 g, 14 mmol) was added portionwise to a 0°C soln. of methyl indole-3- carboxylate (2.0 g, 1 1 mmol) in DMF (20 mL) under argon and the resulting mixture was warmed to RT and stirred for 15 min before being cooled back to 0°C.
  • the alkyl halide (12.6 mmol, 1.15 eq.) was added dropwise and the reaction mixture was stirred for 5 min before being warmed to RT and stirred overnight.
  • the reaction mixture was quenched into ice water and extracted with DCM (3x). The combined organic extracts were washed with brine, dried over Na 2 S0 4 , filtered and evaporated in vacuo to give the crude product that was used directly in Step 2.
  • Step 2 2M aq. NaOH soln. (15 ml.) was added to a RT soln. of the crude ester from above (1 1 mmol) in MeOH (30 ml.) and the resulting mixture was heated to reflux for 2h. The MeOH was evaporated in vacuo and the remaining aq. layer was extracted once with DCM. This organic extract was discarded and the aq. phase was acidified with 2M aq. HCI to precipitate the acid product. The product was collected by filtration washing with H 2 0 and dried in a vacuum oven at 40°C overnight.
  • Step 1 NaH (0.74 mmol) was added in one portion to a 0°C soln. of the appropriately substituted 1 H-indole-3-carbaldehyde (0.61 mmol) in DMF (5 mL) under argon and the resulting mixture was warmed to RT and stirred for 15 min before being cooled back to 0°C.
  • the alkyl halide (0.67 mmol, 1.1 eq.) was added dropwise and the reaction mixture was stirred for 5 min before being warmed to RT and stirred for 30 min.
  • the reaction mixture was quenched into ice water and extracted with DCM (3X). The combined organic extracts were washed with brine, dried over Na 2 S0 4 , filtered and evaporated in vacuo to give the crude product that was used directly in Step 2.
  • Step 2 2-Methyl-2-butene 2M soln. in THF (7.0 mmol) was added in one portion to a RT soln. of the crude aldehyde from above (0.61 mmol) in THF (10 mL) and f butanol (2.8 mL) followed by a soln. of sodium chlorite (1 .83 mmol) and sodium dihydrogen phosphate dihydrate (2.75 mmol) in H 2 0 (2.5 mL). The resulting colourless soln. was stirred at RT for 14h.
  • TBTU 34 mg, 0.1 1 mmol was added to a RT soln. of the required acid 2 (0.1 mmol) and DIPEA (25 ⁇ _, 0.15 mmol) in DMF (0.5 mL) and after stirring for 5 min a soln. of the required amine 1 as its free base or HCI salt (0.1 mmol) and DIPEA (25 ⁇ _, 0.15 mmol) in DMF (0.5 mL) was added. The resulting mixture was stirred for up to 4d before being purified directly by prep. HPLC (column: Waters X-bridge, 30x75 mm, 10 urn, UV/MS, basic conditions) to furnish the desired product.
  • HPLC columnumn: Waters X-bridge, 30x75 mm, 10 urn, UV/MS, basic conditions
  • Table 10 Listed in Table 10 below are example compounds, prepared according to the above- mentioned method M, from the corresponding amine 1 , either readily available or prepared as described above and the corresponding indole carboxylic acid 2, either readily available or prepared as described above.

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  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

L'invention se réfère à des dérivés amides d'indole et de pyrrolopyridine représentés par la formule (I), dans laquelle R1, R2, R3, U, V, W, X, Y, Z et le noyau A sont tels que décrits dans le descriptif, à la préparation de ces dérivés, à des sels pharmaceutiquement acceptables de ceux-ci et à leur utilisation comme produits pharmaceutiques, à des compositions pharmaceutiques contenant un ou plusieurs composés représenté(s) par la formule (I), et spécialement à leur utilisation comme antagonistes des récepteurs de l'orexine.
PCT/IB2012/050759 2011-02-21 2012-02-20 Nouveaux amides d'indole et de pyrrolopyridine WO2012114252A1 (fr)

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US9440982B2 (en) 2012-02-07 2016-09-13 Eolas Therapeutics, Inc. Substituted prolines/piperidines as orexin receptor antagonists
US9499517B2 (en) 2012-02-07 2016-11-22 Eolas Therapeutics, Inc. Substituted prolines / piperidines as orexin receptor antagonists
CN106986859A (zh) * 2016-01-20 2017-07-28 广东东阳光药业有限公司 吲哚衍生物及其用途
US10196383B2 (en) 2015-07-17 2019-02-05 Sunshine Lake Pharma Co., Ltd. Substituted quinazoline compounds and preparation and uses thereof
US10221170B2 (en) 2014-08-13 2019-03-05 Eolas Therapeutics, Inc. Difluoropyrrolidines as orexin receptor modulators
CN111527087A (zh) * 2017-11-02 2020-08-11 艾库里斯有限及两合公司 具有抗乙型肝炎病毒(hbv)活性的新的高活性的吡唑并-哌啶取代的吲哚-2-甲酰胺
US10894789B2 (en) 2016-02-12 2021-01-19 Astrazeneca Ab Halo-substituted piperidines as orexin receptor modulators
CN114478213A (zh) * 2020-10-23 2022-05-13 广州一品红制药有限公司 一种利用微通道器制备依他佐辛中间体的方法

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9440982B2 (en) 2012-02-07 2016-09-13 Eolas Therapeutics, Inc. Substituted prolines/piperidines as orexin receptor antagonists
US9499517B2 (en) 2012-02-07 2016-11-22 Eolas Therapeutics, Inc. Substituted prolines / piperidines as orexin receptor antagonists
US9896452B2 (en) 2012-02-07 2018-02-20 Eolas Therapeutics, Inc. Substituted prolines/piperidines as orexin receptor antagonists
US10221170B2 (en) 2014-08-13 2019-03-05 Eolas Therapeutics, Inc. Difluoropyrrolidines as orexin receptor modulators
US10196383B2 (en) 2015-07-17 2019-02-05 Sunshine Lake Pharma Co., Ltd. Substituted quinazoline compounds and preparation and uses thereof
CN106986859A (zh) * 2016-01-20 2017-07-28 广东东阳光药业有限公司 吲哚衍生物及其用途
CN106986859B (zh) * 2016-01-20 2020-02-11 广东东阳光药业有限公司 吲哚衍生物及其用途
US10894789B2 (en) 2016-02-12 2021-01-19 Astrazeneca Ab Halo-substituted piperidines as orexin receptor modulators
US11434236B2 (en) 2016-02-12 2022-09-06 Astrazeneca Ab Halo-substituted piperidines as orexin receptor modulators
CN111527087A (zh) * 2017-11-02 2020-08-11 艾库里斯有限及两合公司 具有抗乙型肝炎病毒(hbv)活性的新的高活性的吡唑并-哌啶取代的吲哚-2-甲酰胺
CN114478213A (zh) * 2020-10-23 2022-05-13 广州一品红制药有限公司 一种利用微通道器制备依他佐辛中间体的方法
CN114478213B (zh) * 2020-10-23 2023-12-08 广州一品红制药有限公司 一种利用微通道器制备依他佐辛中间体的方法

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