Heteroaryl-substituted compounds

Isothiazoles have been found to be active also as inhibitors of TrKA, kinases receptors for the neurotrophin family of ligands. Compound 117 (R = 4-Cl - Ph, R = H, R = Me) is a potent inhibitor of this enzyme and its derivatives have been prepared. N-Amino-heteroaryl substituted compounds 118 (R = 4-Cl - Ph, R = H) were shown to be good urea surrogates, whereas thioindanyl substituted at C-3 117 were shown to be very potent inhibitors [35]. 

Numerous l,3,4-oxadiazin-5(6//)-ones can be prepared by this type of cyclization. Examples arc 2-(l-ethyl-l-hydroxypropyl)-4-phenyl-4//-l,3,4-oxadiazin-5(6//)-one (6),40 4-phenyl-2-(4-tolyl)-4//-1,3,4-oxadiazin-5(6//)-one (7) (which is claimed to be useful as a miticide and nerna-tocide),41 4-cyanomethyl-, 4-(2-cyanoethyl)-, 4-(3-cyanopropyl)- and 4-(4-cyanobutyl)-6-methyl-2-phenyl-4//-l,3,4-oxadiazin-5(6//)-onc (8, n = 1, 2, 3 and 4, respectively) (which inhibit monoamine oxidase Type A and Type B),42 various 2,4-diaryl-4//-l,3,4-oxadiazin-5(6//)-ones 9 (which possess acaricidal activity),43 cardiotonic 2-aryl derivatives 10,44 and some heteroaryl-substituted compounds, such as 2-[4-(imida/.ol-l-yl)phenyl]-4f/-l,3,4-oxadiazin-5(6//)-one (11) (which is claimed to be cardiotonic and antihypertensive)45 and 2-(2-methylimidazo[l,2-a]pyridin-3-yl)-4//-l,3,4-oxadiazin-5(6//)-one (12) (which inhibits blood platelet aggrega-... 

Ylidene-substituted furazans, which may be used in some cases without purification, are excellent building blocks for the construction of heteroaryl substituted derivatives. Simple variations in the substituents on the furazan ring, the active methylene compounds, and reagents can lead to a variety of products (99MI7) (Scheme 68). 

A further example of the utility of the cyclobuta[ >]chroman system in synthesis (see 6.4.1.3) is provided by the conversion of the cyclobutenedione derivatives (19) into substituted xanthones. Compounds (19) are obtained in high yield from salicylaldehydes and squarate esters and their reaction with alkenyl, aryl and heteroaryl li compounds is both facile and high yielding <96JA12473>. 

US patent 6,753,426, Polymorph and process for preparing same [111], In this patent are disclosed are processes, a new polymorph, and intermediate compounds for preparing various aryl- and heteroaryl-substituted urea compounds. The product compounds are useful in pharmaceutical compositions for treating diseases... 

Eq. (35), these compounds give selenienylselenazoles (103) upon condensation with a-haloketones (102), a reaction that has proven quite general for the preparation of a number of heteroaryl-substituted azoles (104).129... 

When thioxo (or thiol) derivatives (as part of a thiourea function incorporated into the heterocyclic system) are present, effective. Y-alkylation is observed. Thus, the 3-heteroaryl-substituted [l,2,4]triazolo[3,4-/)][l,3,4]thiadiazole-6(5//)-thiones 37 dissolved in sodium hydroxide solution react with alkyl halides to afford the corresponding 6-alkylthio derivatives 38 (Equation 4) <1992IJB167>. The mesoionic compounds 39, inner salts of anhydro-7-aryl-l-methyl-3-methylthio-6-sulfonyl-[l,2,4]triazolo[4,3-A [l,2,4]triazolium hydroxides, are methylated with methyl iodide to give the corresponding quaternary salts 40 (Equation 5) <1984TL5427, 1986T2121>. 

The patent literature covers many pyridazine derivatives claimed as blood platelet aggregation inhibitors and antithrombotic agents. The interest has been focused mainly on 6-aryl-4,5-dihydro-3(2//)-pyridazinones. In these compounds the aryl substituent has been varied within a wide range. Thus, dihydro-pyridazinones bearing a substituted or heterocycle-fused phenyl group at C-6 (60, R R2,R3 = H, alkyl Ar = substituted Ph) [34, 110-112,205-233] as well as various heteroaryl substituted congeners (61, R1, R2, R3 = H, alkyl Ar = pyridyl, thienyl, pyrrolyl, pyrazolyl) [234-241] have been prepared in search of novel antithrombotics. 

Many aryl- and heteroaryl-substituted derivatives of the ir-deficient heterocyclic compounds have been prepared and some of them are of considerable commercial importance, for example as pesticides (paraquat and diquat) and as pharmaceuticals. 

Oxiranes react with the heteroaryl anions to yield, via the alkali metal salts, the N-(2-hydroxyethyl) derivatives (B-77MI30502) and, with the Grignard compounds, the analogous C-substituted compounds (e.g. 65JCS7165, 78H(9)807). 

A similar reaction performed with allyl bromide and A-a-aza-heteroaryl substituted imines has been reported to give partially (3-lactams. This latter, for instance, underwent isomerization to the more stable a, 3-unsaturated carbonyl compounds, and variously substituted pyrimidinones were also isolated (Scheme 67), [163],... 

The imidoyl chloride moiety of 5-chloro-l-alkyl-1,4-benzodiazepin-2-ones participates in Pd-catalyzed, Suzuki crosscoupling reactions, reacting with a range of functionalized aromatic boronic acids to provide an efficient and versatile approach to 5-aryl and 5-heteroaryl compounds (Scheme 19) <2003JOC2844>. This chemistry readily extends to 3-amino-substituted compounds that are orally bioavailable inhibitors of the aspartyl protease 7-secretase <2003BML4143>. 

In line with previous experiments, a series of heteroaryl-substituted dimethylamino-functionalised titanocene dichlorides have been synthesised and evaluated [23], as shown in Fig. 7. Unfortunately, no uniform pattern compared with benzyl-substituted titanocenes was detected. A decrease in cytotoxicity was observed for the thiophenyl-substituted titanocene (18) from 150 pM (for the unbridged analogous compound 6) to 240 pM. On the other side, a significant increase in cytotoxicity was observed for the furyl-substituted titanocene (19) (160-28 pM) and especially for the /V-methyl pyrrole derivative (20), which exhibits an IC50 value of 5.5 pM. In fact, titanocene 20 is one of the most cytotoxic substituted titanocene dichlorides that have been reported up to now. This represents an impressive 400-fold increase in cytotoxic activity compared with the unsubstituted Cp2TiCl2, which reached Phase II clinical trials. 

The application of general reactions available for the synthesis of aryl-boranes to synthesis of boron-substituted heteroaromatic compounds is somewhat restricted by the presence of a sensitive heteroaromatic ring. The substitution reaction of heteroaryl-metallic compounds (1) with halo-boranes (2) has been used to synthesize five-membered ir-excessive het-eroarylboranes (3) (76CB1075) (Scheme 1). 

While Grignards and enolates added to 3-nitroindole 6 to produce trans-2 substi-tuted-3-nitroindolines, heteroaryl lithium compounds cause the phenylsulfinate to be lost in an Sn2 manner to form 2-substituted-3-nitroindoles 108 in moderate to good yields [44]. Reductive acylation of the 2-heteroaryl-3-nitroindoles 108 (Ar = thiophene) followed by Bischler-Napieralski reaction produces the 5-carbolines 110 in high yields (Table 11). 

The Suzuki reaction is a powerful carbon-carbon bond-forming reaction method for the rapid introduction of diverse substituent onto an aromatic ring. Substituted arylacetic acids represent an important class of cyclooxygenase inhibitors. These inhibitors that are built on the phenylacetic acid core, typically incorporating three elements of variability an a-alkyl group, R alkyl, aryl or heteroaryl substitution on the phenyl ring, R and acid or amide functionality (Scheme 31.5). To synthesize this variety of molecules requires successful construction of a combinatorial library of a class of compounds and that depends... 

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