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This application relates to chemical compounds which may act as inhibitors of; or which may otherwise modulate the activity of, a bromodomain-containing protein, including bromodomain-containing protein 4 (BRD4), and to compositions and formulations containing such compounds, and methods of using and making such compounds. Compounds include compounds of Formula (I) wherein R1a, R1b, R2, R2b, R3, R4a, R4b, and R5 are described herein.

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The [1,2,4]triazolo[1,5-a]triazine derivative 3, more commonly known in the field of adenosine research as ZM-241385, has previously been demonstrated to be a potent and selective adenosine A2a receptor antagonist, although with limited oral bioavailability. This [1,2,4]triazolo[1,5-a]triazine core structure has now been improved by incorporating various piperazine derivatives. With some preliminary optimization, the A2a binding affinity of some of the best piperazine derivatives is almost as good as that of compound 3. The selectivity level over the adenosine A1 receptor subtype for some of the more active analogues is also fairly high, >400-fold in some cases. Many compounds within this piperazine series of [1,2,4]triazolo[1,5-a]triazine have now been shown to have good oral bioavailability in the rat, with some as high as 89% (compound 35). More significantly, some piperazines derivatives of [1,2,4]triazolo[1,5-a]triazine also possessed good oral efficacy in rodent models of Parkinson’s disease. For instance, compound 34 was orally active in the rat catalepsy model at 3 mg/kg. In the 6-hydroxydopaminelesioned rat model, this compound was also quite effective, with a minimum effective dose of 3 mg/kg po.

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Several syntheses of special isoxazoles bearing a long alkyl or alkenyl side chain in the alpha position of the nitrogen are presented.A very convenient route in the case of an alkyl side chain is the classical 1,3-dipolar cycloaddition of a nitrile-oxide to a vinyl acetate.Although it is a rather long approach, the reaction of hydroxylamine with enone-epoxides represents a new and unequivocal method compatible with alkenyl side chains.The isomerisation of the easily synthesized isoxazoles bearing such substituents alpha to the oxygen, by the reaction of their isoxazolium salts with hydroxylamine, is a fast and general method.Another very convenient access to “alpha-N substituted” isoxazoles is the coupling of magnesium compounds with 3-bromomethyl 5-methyl isoxazole.

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Compounds, compositions and methods are described for inhibiting the TRPC5 ion channel and disorders related to TRPC5.

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2,4-Diaminoquinazolines of formulae I-IV and VI (I, II, III, IV and VI) are useful for treating spinal muscular atrophy (SMA).

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We have previously described the potent and selective (RS)-2-amino-3-(3- hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptor agonist, (RS)-2- amino-3-(3-carboxy-5-methyl-4-isoxazolyl)propionic acid (ACPA), and the AMPA receptor antagonist (RS)-2-amino-3-[3-(carboxymethoxy)-5-methyl-4- isoxazolyl]propionic acid (AMOA). Using these AMPA receptor ligands as leads, a series of compounds have been developed as tools for further elucidation of the structural requirements for activation and blockade of AMPA receptors. The synthesized compounds have been tested for activity at ionotropic excitatory amino acid (EAA) receptors using receptor binding and electrophysiological techniques, and for activity at metabotropic EAA receptors using second messenger assays. Compounds 1 and 4 were essentially inactive. (RS)-2-Amino-3-[3-(2-carboxyethyl)-5-methyl-4-isoxazolyl]propionic acid (ACMP, 2), on the other hand, was shown to be a selective AMPA receptor antagonist (IC50 = 73 muM), more potent in electrophysiological experiments than AMOA (IC50 = 320 muM). The isomeric analogue of 2, compound 5, did not show AMPA antagonist effects, but was a weak NMDA receptor antagonist (IC50 = 540 muM). Finally, compound 3, which is an isomer of ACPA, turned out to be a very weak NMDA antagonist, and an AMPA receptor agonist approximately 1 000 times weaker than ACPA. None of the compounds showed agonist or antagonist effects at metabotropic EAA receptors. (C) 2000 Editions scientifiques et medicales Elsevier SAS.

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We have previously identified the 7,8,9,10-tetrahydro-7,10-ethano-1,2,4- triazolo[3,4-a]phthalazine (1) as a potent partial agonist for the 0.3 receptor subtype with 5-fold selectivity in binding affinity over alpha1. This paper describes a detailed investigation of the substituents on this core structure at both the 3- and 6-positions. Despite evaluating a wide range of groups, the maximum selectivity that could be achieved in terms of affinity for the alpha3 subtype over the alpha1 subtype was 12-fold (for 57). Although most analogues showed no selectivity in terms of efficacy, some did show partial agonism at alpha1 and antagonism at alpha3 (e.g., 25 and 75). However, two analogues tested (93 and 96), both with triazole substituents in the 6-position, showed significantly higher efficacy for the alpha3 subtype over the alpha1 subtype. This was the first indication that selectivity in efficacy in the required direction could be achieved in this series.

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We have previously identified the 7,8,9,10-tetrahydro-7,10-ethano-1,2,4- triazolo[3,4-a]phthalazine (1) as a potent partial agonist for the 0.3 receptor subtype with 5-fold selectivity in binding affinity over alpha1. This paper describes a detailed investigation of the substituents on this core structure at both the 3- and 6-positions. Despite evaluating a wide range of groups, the maximum selectivity that could be achieved in terms of affinity for the alpha3 subtype over the alpha1 subtype was 12-fold (for 57). Although most analogues showed no selectivity in terms of efficacy, some did show partial agonism at alpha1 and antagonism at alpha3 (e.g., 25 and 75). However, two analogues tested (93 and 96), both with triazole substituents in the 6-position, showed significantly higher efficacy for the alpha3 subtype over the alpha1 subtype. This was the first indication that selectivity in efficacy in the required direction could be achieved in this series.

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A novel and general route for the solid phase synthesis of N-substituted alpha-amino acids has been developed. This synthesis employs Fukuyama’s 2- nitrobenzenesulfonamide protecting group for preparation of secondary amines. The versatility of this methodology is demonstrated by the facile synthesis of a trisubstituted diketopiperazine (DKP) skeleton. (C) 2000 Elsevier Science Ltd.

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The invention is based on the discovery that compounds of formula (I) possess unexpectedly high affinity for the A2a adenosine receptor, and can be useful as antagonists thereof for preventing and/or treating numerous diseases, including Parkinson?s disease. In one embodiment, the invention features a compound of formula: (I).

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