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The present invention relates to isothiazoles of general formula (I) which inhibit the mitotic checkpoint : in which A, R1 and R2 are as defined in the claims, to methods of preparing said compounds, to intermediate compounds useful for preparing said compounds, to pharmaceutical compositions and combinations comprising said compounds and to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, in particular of neoplasms, as a sole agent or in combination with other active ingredients.

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2-Chloro-3-methylquinoxaline reacts with aromatic amines in basic medium forming 2-arylamino-3-methylquinoxalines, also it reacts with mercaptoacetic acid.The 3-methyl-2(1H)-quinoxalinone condenses with aromatic aldehydes forming the corresponding 3-(substituted styryl)-2(1H)-quinoxalinones which add bromine in acetic acid to yield the corresponding dibromo derivatives which react with morpholine, sodium methoxide, and piperidine to give the corresponding compounds. 3-Methyl-2(1H)-quinoxalinone undergoes side-chain bromination to yield 3-bromomethyl-2(1H)-quinoxalinone, which reacts with aromatic amines, sodium salt of saccharine, potassium phthalimide… 3-Methyl-2(1H)-quinoxalinone with P2S5 gave 3-methyl-2(1H)-quinoxalinethione which reacts with 2-aminoethanol, dimethyl sulfate, and halo acids.

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Reduction of 3-methyl-2-(arylidcne hydrazino)quinoxalines 5a-1 with NaBH4 in controlled experimental conditions to give the 2-substituted benzyl hydrazine-3-methyl quinoxalines 6a-l have been described. The structure of compounds 6a-l have been confirmed from elemental analysis, IR, 1H NMR and mass spectral data. All the compounds have been screened for their antimicrobial activity against several microbes.

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The compounds of this invention are designated as quinoxalinyl esters of carbamimidothioic acids and exhibit the pharmacological properties of preventing gastric ulcers, reducing gastric secretions and lowering blood pressure. The compounds have the following structural formula: STR1 in which Q is hydrogen or nitro;

A is hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, carbomethoxy, carbethoxy, carbopropoxy, carbisopropoxy, carbobutoxy, carbisobutoxy, or carbo-t-butoxy; and< P>

R 1, R 2, and R 3 are, independently, hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, allyl, or R. sup.1 and R 3 may be concatenated with a carbon chain having 4 carbon atoms with R 2 then being hydrogen; except that, when A and Q are hydrogen, R 1, R 2, and R. sup.3 may not all be hydrogen; and with the further exception that, where A is methyl and R 1, R 2, and Q are all hydrogen, R 3 may not be ethyl;

or a pharmaceutically acceptable salt thereof.

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We report here the remarkable properties of PAd3, a crystalline air-stable solid accessible through a scalable SN1 reaction. Spectroscopic data reveal that PAd3, benefiting from the polarizability inherent to large hydrocarbyl groups, exhibits unexpected electron releasing character that exceeds other alkylphosphines and falls within a range dominated by N-heterocyclic carbenes. Dramatic effects in catalysis are also enabled by PAd3 during Suzuki-Miyaura cross-coupling of chloro(hetero)arenes (40 examples) at low Pd loading, including the late-stage functionalization of commercial drugs. Exceptional space-time yields are demonstrated for the syntheses of industrial precursors to valsartan and boscalid from chloroarenes with ?2 × 104 turnovers in 10 min.

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Mono- and bis-addition reactions of the beta,gamma-unsaturated Grignard reagents 2 and 6 to the C=N bonds of quinoxalines 1 afford high yields of dihydroquinoxalines 4 and tetrahydroquinoxalines 3.Dehydrogenation of 4g-l and 3a-c with DDQ leads to allylic quinoxalines 1i-m and 1e-g respectively in very good yields.Allylic and propargylic quinoxalines 1m and 1s can conveniently be synthesized by “cross-coupling” of 2-chloro-3-methylquinoxaline with 2c and 6a.

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A series of phthalazinyl- and quinoxalinylguanidines has been synthesized and evaluated for potential antihypertensive activity.Unsubstituted guanidines were prepared by treating the appropriate intermediate chloro compounds with guanidine free base.Substituted guanidines were prepared by treating the cyanamides 9 and 16 with the appropriate amine; with hydrazines, cyanamide 9 gave the triazoles 14 and 15.Moderate falls in blood pressure were observed with compounds 10, 11, 14, and 15.The triazole 15 caused a 25percent fall in heart rate.Some of the compounds (10, 11, 13, and 18) displayed weak alpha-adrenoceptor antagonist properties in vitro, and this activity was confirmed in the pithed rat (in vivo).

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Two series of 3,6,7-trisubstituted-2-(1H-imidazol-2-ylsulfanyl)- quinoxalines 2a-1 and 2-(quinoxalin-2-yl)-isothioureas 3a-1 were prepared. All the test compounds 2a-1 and 3a-1 were screened in vitro, in a RIN5F cell-based assay for glucose-dependent insulinotropic activity. A significant concentration and glucose-dependent insulin secretion effect was seen with compounds 2a-1 and the insulinotropic activity of compound 21 was found to be identical to that of the standard compound (6,7-dichloro-2-trifluromethyl-3-(5-methyl-1,3,4- thiadiazo-2-ylsulfanyl)-quinoxaline (1)).

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The synthesis and characterization of 14 monometallic derivatives of quinoline, quinoxaline, quinazoline and tetraazolo<1,5-A>quinoline and a bimetallic derivative of quinoxaline are reported. These species were prepared in 11 to 88% isolated yields by metathesis reactions between NaFp or NaFp? (where Fp = (eta5 – C5H5)Fe(CO)2 and Fp? = (eta5 – indenyl)Fe(CO)2 ) and the appropriate chlorine substituted polyaromatic azines. These reactions are highly regioselective and generally produce a single organometallic product having the organometallic substituent(s) bonded to the more highly activated azine ring. The structures of three representative examples were confirmed by their X-ray crystal structures, which are reported for the title complexes 4-[(eta5-cyclopentadienyl)irondicarbonyl]-7-chloroquinoline (C16H10ClFeNO2; a = 7.608(1)A, b = 12.006(1)A, c = 15.664(1)A, V = 1431A3; orthorhombic; P212121; Z =4), 2-[(eta5-cyclopentadienyl)irondicarbonyl]-3-chloroquinoxaline (C15H9ClFeN2O2; a = 15.291(3) A, b = 6.561(2) A, c = 14.541(4) A, beta = 106.891(21), V= 1395.9A3; monoclinic; P21/c; Z = 4), and 2-[(eta5-indenyl)irondicarbonyl]-3-chloroquinoxaline (C19H11ClFeN2O2; a = 19.131(2)A, b = 6.688(1)A, c = 13.515(2) A, beta= 101.569(11), V = 1694.1 A3; monoclinic; P21/c; Z = 4). The bimetallic quinoxaline derivative 2,3-[(C5H5)2Fe2(CO)4]-quinoxaline has orrto-substituted organometallic groups and the spectroscopic data suggest that it has an unusual structure in solution, perhaps involving bridging cyclopentadienyl and carbonyl ligands.

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A series of 3-chloroquinoxaline-2-carboxamides were designed and prepared by the condensation of 3-chloro-2-quinoxaloylchloride with appropriate Mannich bases of the p-aminophenol in the microwave environment. The synthesized compounds were evaluated for serotonin3 (5-HT3) receptor antagonistic activities in longitudinal muscle-myenteric plexus (LMMP) preparation from guinea pig ileum against the 5-HT3 agonist, 2-methyl-5-HT. Compound 3g exhibited comparable 5-HT3 antagonistic activity (pA2 6.4) to that of standard antagonist Ondansetron (pA2 6.9), while the other compounds exhibited mild to moderate 5-HT3 antagonistic activities.

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