WO1992004350A1

WO1992004350A1 - Oxygenated quinoxalines

Info

Publication number: WO1992004350A1
Application number: PCT/US1991/005555
Authority: WO
Inventors: Eric Jon Jacobsen
Original assignee: The Upjohn Company
Priority date: 1990-09-04
Filing date: 1991-08-09
Publication date: 1992-03-19
Also published as: JPH06500545A; AU8396491A

Abstract

The present invention are 6-, 7-, 8- and 9-oxygenated derivatives of 3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-5-(1-methylethyl)-imidazol[155-a]quinoxalin-4(5H)-one of formula (XIV), where two of R6, R7, R8 and R9 are -H and the other of R6, R7, R8 and R9 is an oxygenated function. These oxygenated quinoxalines (XIV) are useful anxiolytics, hypnotics, anticonvulsants and nootropics.

Description

OXYGENATED OUINOXALINES

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention are 6-, 7-, 8- and 9-oxygenated quinoxalines which are the 6-, 1-, 8- and 9-oxygenated analogs of 3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-5-(1-methylethyl)- imidazol[1,5-a]quinoxalin-4(5H)-one. These compounds are useful as anxiolytics, hypnotics, anticonvulsants and nootropics.

2. Description of the Related Art

3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-5-(l-methylethyl)-imidazol[1,5-a]quinoxaIin-4(5H)- one is known, see US Patent 4,774,245 and EP-320,136 (Example 5, compound 3).

US Patent 4,873,244 discloses quinozalines in which the aromatic ring is substituted (at any place) with a number of substituents including oxygen. The oxygen functions are (substituted) aryloxy, aralkoxy and (substituted) C₃-C₇ cycloalkyloxy.

SUMMARY OF INVENTION

Disclosed is an oxygenated quinoxaline of formula (XIV)

where R₃ is a 1,2,4-oxadiazol-3-yl of formula

or a 1,2,4-oxadiazol-5-yl of formula

where R_3-1 is C₁-C₆ alkyl or C₃-C₇ cycloalkyl;

R₅ is C₁-C₆ alkyl or C₃-C₇ cycloalkyl;

at least two of R₆, R₇, R₈ and R₉ are -H and the others of R₆, R₇, R₈ and R₉ are

-OH,

-O-R₁ where R₁ is C₁-C₄ alkyl,

-O-CO-R₂ where R₂ is C₁-C₃ alkyl or pharmaceutically acceptable salts thereof.

DETAILED DESCRIPTION OF THE INVENTION

The 6-oxygenated, 7-oxygenated and 8-oxygenated quinoxalines (XIV) are prepared from known compounds by methods known to those skilled in the art, see for example, US Patent 4,774,245.

The starting material in virtually all cases is a disubstituted nitrobenzene. Whether it is a dihalo (I), haloalkoxy (II) or haloamino (HI) compound it is converted by known methods to the corresponding oxygenated isopropylammonitrobenzene (IV) as set forth in CHART A. It is necessary that the amino group, -NHR₅ be present. Further, the position of the oxygenated substituted on the nitrobenzene will ultimately determine the position of the oxygenated function in the final product, the oxygenated quinoxaline (XIV).

For the remainder of the synthesis to produce the oxygenated quinoxaline (XIV) the oxygen must be appropriately protected. Alkyl groups (ethers) are acceptable. Should it be desired to protect the oxygen function in a manner different than in the oxygenated aminonitrobenzene (TV), the group on the oxygen is removed producing the hydroxynitroamino compound by means known to those skilled in the art (V) followed by addition of an appropriate protecting group also by means known to those skilled in the art to produce the protected aminonitrobenzene (VI), see CHART B. Suitable protecting groups include alkyl ethers, t-butyldimethylsilyl ethers, methoxymethyl ethers and t-butyl ethers. The oxygenated aminonitrobenzenes (TV) or protected aminonitrobenzenes (VI) are then reduced to the corresponding amino compounds (VII) by hydrogenation using palladium on carbon. The amino (VII) compounds are then converted to the bicyclic diketo compounds (VIII) by reaction with ethyl oxalyl chloride in base. The diketo compounds (VIII) are then reacted with an isocyanide, a 3-isocyanomethyl-5-substituted-1,2,4- oxadiazole (IX-A) to produce the protected quinoxalinones (X) as disclosed in CHART C. In the case where the protecting group is an ether the oxygenated quinoxaline (XIV) are produced directly.

CHART D discloses the transformation of the protected quinoxalinones (X) to the corresponding hydroxy quinoxalinones (XI) and the subsequent conversion of the hydroxy quinoxalinones (XI) to the corresponding ethers (XII) by O-alkylation, or esters (XIII).

The protected quinoxalinones (X) where R₃ is 1,2,4-oxadiazol-5-yl (B) are produced by the process set forth in CHART E. The diketo (VIII) is transformed to the tricyclic ester (XV) by reaction with ethyl isocycanoacetate. The tricyclic ester (XV) is then contacted with an appropriate substituted carboxamide oxime (XVI) to form the protected quinoxalinones (X) where R₃ is (B).

The hydroxy quinoxalinones (XI), ether quinoxalinones (XII) and ester quinoxalinones

(Xπi) are all useful pharmaceutical agents and are useful regardless if the oxygenated function is in the 6-, 7-, 8- or 9- position. All of these compounds are encompassed by the formula of the oxygenated quinoxaline (XIV).

It is preferred that R₃ is 1,2,4-oxadiazol-3-yl (A). It is preferred that R_3-1 is C₁-C₃ alkyl or cyclopropyl, it is more preferred that R_3-1 is cyclopropyl. It is preferred that R₅ is C₁-C₃ alkyl, it is more preferred that R₅ is isopropyl. It is preferred that R₆ or R₇ be the position which is oxygenated. It is preferred that R₁ and R₂ are C₁ alkyl.

The oxygenatged quinoxalines (XIV) of the present invention are useful pharmaceuticals as anxiolytics, hypnotics, anticonvulsants and nootropics. They are administered and used in the same manner and same way as non-oxygenated 3-(5-substituted-1,2,4-oxadiazol-3-yl)-5- (substituted)-imidazol[1,5-a]quinoxalin-4(5H)-ones as set forth in US Patent 4,775,245.

The exact dosage and frequency of administration depends on the particular oxygenated quinoxaline (XTV) used, the particular condition being treated, the severity of the condition being treated, the age, weight, general physical condition of the particular patient, other medication the individual may be taking as is well known to those skilled in the art and can be more accurately determined by measuring the blood level or concentration of the oxygenated quinoxaline (XlV) in the patient's blood and/or the patient's response to the particular condition being treated.

DEFINITIONS AND CONVENTIONS

The definitions and explanations below are for the terms as used throughout this entire document including both the specification and the claims.

T. CONVENTIONS FOR FORMULAS AND DEFINITIONS OF VARIABLES

The chemical formulas representing various compounds or molecular fragments in the specification and claims may contain variable substituents in addition to expressly defined structural features. These variable substituents are identified by a letter or a letter followed by a numerical subscript, for example, "Z_l" or "R_i" where "i" is an integer. These variable substituents are either monovalent or bivalent, that is, they represent a group attached to the formula by one or two chemical bonds. For example, a group Z₁ would represent a bivalent variable if attached to the formula CH₃-C(=Z₁)H. Groups R_i and R_j would represent monovalent variable substituents if attached to die formula CH₃-CH₂-C(R_i)(R_j)H₂. When chemical formulas are drawn in a linear fashion, such as those above, variable substituents contained in parentheses are bonded to the atom immediately to the left of the variable substituent enclosed in parenthesis. When two or more consecutive variable substituents are enclosed in parentheses, each of the consecutive variable substituents is bonded to the immediately preceding atom to the left which is not enclosed in parentheses. Thus, in the formula above, both R_i and R_j are bonded to the preceding carbon atom. Also, for any molecule with an established system of carbon atom numbering, such as steroids, these carbon atoms are designated as C_i, where "i" is the integer corresponding to the carbon atom number. For example, C₆ represents the 6 position or carbon atom number in the steroid nucleus as traditionally designated by those skilled in the art of steroid chemistry. Likewise the term "R₆" represents a variable substituent (either monovalent or bivalent) at the C₆ position.

Chemical formulas or portions thereof drawn in a linear fashion represent atoms in a linear chain. The symbol "-" in general represents a bond between two atoms in the chain. Thus CH₃-O- CH₂-CH(R_i)-CH₃ represents a 2-substituted-1-methoxypropane compound. In a similar fashion, the symbol, "=" represents a double bond, e.g., CH₂=C(R_i)-O-CH₃, and the symbol " =" represents a triple bond, e.g., HC=-C-CH(R _i)-CH₂-CH₃. Carbonyl groups are represented in either one of two ways: -CO- or -C(=O)-, with the former being preferred for simplicity.

Chemical formulas of cyclic (ring) compounds or molecular fragments can be represented in a linear fashion. Thus, the compound 4-chloro-2-methylpyridine can be represented in linear fashion by N*=C(CH₃)-CH=CCl-CH=C*H with the convention that the atoms marked with an asterisk (*) are bonded to each other resulting in the formation of a ring. Likewise, the cyclic molecular fragment, 4-(ethyl)-1-piperazinyl can be represented by -N*-(CH₂)₂-N(C₂H₅)-CH₂ -C*H₂.

A rigid cyclic (ring) structure for any compounds herein defines an orientation with respect to the plane of the ring for substituents attached to each carbon atom of the rigid cyclic compound. For saturated compounds which have two substituents attached to a carbon atom which is part of a cyclic system, -C(X₁)(X₂)- the two substituents may be in either an axial or equatorial position relative to the ring and may change between axial/equatorial. However, the position of the two substituents relative to the ring and each other remains fixed. While either substituent at times may lie in the plane of the ring (equatorial) rather than above or below the plane (axial), one substituent is always above the other. In chemical structural formulas depicting such compounds, a substituent (X₁) which is "below" another substituent (X₂) will be identified as being in the alpha (α) configuration and is identified by a broken, dashed or dotted line attachment to the carbon atom, i.e., by the symbol " - - -" or "...". The corresponding substituent attached "above" (X₂) the other (X₁) is identified as being in the beta (β) configuration and is indicated by an unbroken line attachment to the carbon atom.

When a variable substituent is bivalent, the valences may be taken together or separately or both in the definition of the variable. For example, a variable R_i attached to a carbon atom as -C(=R_i)- might be bivalent and be defined as oxo or keto (thus forming a carbonyl group (-CO-) or as two separately attached monovalent variable substituents α-R_i-j and β-R_i-k. When a bivalent variable, R_i, is defined to consist of two monovalent variable substituents, the convention used to define the bivalent variable is of the form "α-R_i-j:β-R_i-k" or some variant thereof. In such a case both α-R_i-j and β-R_i-k are attached to the carbon atom to give -C(α-R_i-j)(β-R_i-k)-. For example, when the bivalent variable R₆, -C(=R₆)- is defined to consist of two monovalent variable substituents, the two monovalent variable substituents are α-R_6-1:β-R_6-2, .... α-R_6-9:β-R_6-10, etc, giving -C(α-R_6-1)(β-R_6-2)-, .... -C(α-R_6-9)(β-R_6-10)-, etc. Likewise, for the bivalent variable R₁₁, -C(=R₁₁)-, two monovalent variable substituents are α-R_11-1:β-R_11-2. For a ring substituent for which separate a and β orientations do not exist (e.g. due to the presence of a carbon carbon double bond in the ring), and for a substituent bonded to a carbon atom which is not part of a ring the above convention is still used, but the a and β designations are omitted.

Just as a bivalent variable may be defined as two separate monovalent variable substituents, two separate monovalent variable substituents may be defined to be taken together to form a bivalent variable. For example, in the formula -C₁(R_i)H-C₂(R_j)H- (C₁ and C₂ define arbitrarily a first and second carbon atom, respectively) R_i and R_j may be defined to be taken together to form (1) a second bond between C₁ and C₂ or (2) a bivalent group such as oxa (-O-) and the formula thereby describes an epoxide. When R_i and R_j are taken together to form a more complex entity, such as the group -X-Y-, then the orientation of the entity is such that C₁ in the above formula is bonded to X and C₂ is bonded to Y. Thus, by convention the designation "... R_i and R_j are taken together to form -CH₂-CH₂-O-CO- ..." means a lactone in which the carbonyl is bonded to C₂. However, when designated "... R_j and R_i are taken together to form -CO-O-CH₂ -CH₂-the convention means a lactone in which the carbonyl is bonded to C₁.

The carbon atom content of variable substituents is indicated in one of two ways. The first method uses a prefix to the entire name of the variable such as "C₁-C₄", where both "1" and "4" are integers representing the minimum and maximum number of carbon atoms in the variable. The prefix is separated from the variable by a space. For example, "C₁-C₄ alkyl" represents alkyl of 1 through 4 carbon atoms, (including isomeric forms thereof unless an express indication to the contrary is given). Whenever this single prefix is given, the prefix indicates the entire carbon atom content of the variable being defined. Thus C₂-C₄ alkoxycarbonyl describes a group CH₃-(CH₂)_n -0-CO- where n is zero, one or two. By the second method the carbon atom content of only each portion of the definition is indicated separately by enclosing the "C_i-C_j" designation in parentheses and placing it immediately (no intervening space) before the portion of the definition being defined. By this optional convention (C₁-C₃)alkoxycarbonyl has the same meaning as C₂-C₄ alkoxycarbonyl because the "C₁-C₃" refers only to the carbon atom content of the alkoxy group. Similarly while both C₂-C₆ alkoxyalkyl and (C₁-C₃)alkoxy(C₁-C₃)alkyl define alkoxyalkyl groups containing from 2 to 6 carbon atoms, the two definitions differ since the former definition allows either the alkoxy or alkyl portion alone to contain 4 or 5 carbon atoms while the latter definition limits either of these groups to 3 carbon atoms.

ll. DEFINITIONS

All temperatures are in degrees Centigrade.

TLC refers to thin-layer chromatography.

Saline refers to an aqueous saturated sodium chloride solution.

IR refers to infrared spectroscopy.

NMR refers to nuclear (proton) magnetic resonance spectroscopy, chemical shifts are reported in ppm (δ) downfield from tetramethylsilane.

-Φ refers to phenyl (C₆H₅).

MS refers to mass spectrometry expressed as m/e or mass/charge unit. [M + H]⁺ refers to the positive ion of a parent plus a hydrogen atom. El refers to electron impact. CI refers to chemical ionization. FAB refers to fast atom bombardment.

Ether refers to diethyl ether.

Alcohol refers to ethyl alcohol.

Pharmaceutically acceptable refers to those properties and/or substances which are acceptable to the patient from a pharmacological/toxicological point of view and to the manufacturing pharmaceutical chemist from a physical/chemical point of view regarding composition, formulation, stability, patient acceptance and bioavailability.

When solvent pairs are used, the ratios of solvents used are volume/volume (v/v).

Aqueous workup (organic solvent, drying agent) refers to the procedure of quenching the reaction mixture with water, diluting with the indicated organic solvent, separate the organic layer, extracting the aqueous layer several times with the organic solvent, drying the combined organic layers with the indicated drying agent, and removing the solvent using a rotary evaporator at reduced pressure.

Basic workup (organic solvent, aqueous basic solvent,drying agent) refers to a procedure similar to aqueous workup, except the indicated aqueous base was used instead of water.

Acidic workup (organic solvent, organic solvent, drying agent) refers to the procedure of diluting the reaction mixture with the first indicated organic solvent, extracting the organic solution several times with 10% hydrochloric acid, basifying the combined acidic layers with solid potassium hydroxide or ammonium hydroxide, extracting the basic solution with the second indicated organic solvent several times, drying the organic layers with the indicated drying agent, and removing the solvent using a rotary evaporator under reduced pressure.

Tetrahydrofuran (THF) and ether are distilled from sodium and benzophenone. Dimethylformamide (DMF) and pyridine are distilled from calcium hydride at 20 mm and atmospheric pressure, respectively.

All reactions are run under nitrogen or argon.

EXAMPLES

Without further elaboration, it is believed that one skilled in the art can, using the preceding description, practice the present invention to its fullest extent. The following detailed examples describe how to prepare the various compounds and/or perform the various processes of the invention and are to be construed as merely illustrative, and not limitations of the preceding disclosure in any way whatsoever. Those skilled in the art will promptly recognize appropriate variations from the procedures both as to reactants and as to reaction conditions and techniques. EXAMPLE 1 4-Fluoro-2-(isopropyl)aminonitrobenzene (lll )

A solution of isopropylamine (3.1 ml) and acetonitrile (10.0 ml) is added dropwise over

10 min to a mixture of 2,4-difluoronitrobenzene (I, 5.58 g), acetonitrile (30.0 ml) and potassium carbonate (7.50 g) at 0°. The mixture is stirred for 2 h at 0° and 42 hr at 20-25°. Aqueous workup (methylene chloride/magnesium sulfate) and purification by flash chromatography eluting with hexane/ethyl acetate (15/1), pooling and concentration of the appropriate fractions give the title compound, mp 69-70°; IR (mineral oil) 3357, 2980, 2955, 2927, 1638, 1574, 1514, 1460, 1413, 1310, 1263, 1229, 1149 and 1069 cm^-1; NMR (300 MHz, CDCl₃) 8.21, 8.0-8.3, 6.48, 6.25-6.4, 3.6-3:8, and 1.33 δ; MS (El, m/e) 198, 183, 137 and 110.

EXAMPLE 2 4-Methoxy-2-(isopropyl)aminonitrobenzene (IV)

Sodium (290 mg) is dissolved into methanol (15.0 ml). A solution of 4-fluoro-2- (isopropyl)aminonitrobenzene (llI, EXAMPLE 1, 2.00 g) and methanol (15.0 ml) is added. The solution is stirred for 16 hr at 20-25° and 2 hr at reflux. After cooling to 20-25°, acetic acid (0.50 ml) is added and the solution is concentrated. Basic workup (chloroform, sodium bicarbonate and magnesium sulfate) gives the title compound; IR (neat) 3332, 2974, 1620, 1582, 1500, 1458, 1425, 1412, 1315, 1268, 1232, 1206, 1166, 1083, 998 and 828 cm^-1; NMR (300 MHz, CDCl₃) 8.2-8.4, 8.15, 6.21, 6.16, 3.87, 3.6-3.9, 1.34 δ; MS (El, m/e) 210, 195, 177 and 149.

EXAMPLE 3 4-Methoxy-2-(isopropyl)aminoaniline (VII)

A mixture of the 4-methoxy-2-(isopropyl)aminonitrobenzene (lV, EXAMPLE 2, 6.72 g), 10% palladium on carbon (1.68 g) and ethanol (150 ml) is hydrogenated (45 psi) in a Parr flask for 16 hr. Filtration, ethanol wash, and concentration gives the title compound; NMR (300 MHz, CDCl₃) 6.65, 6.26, 6.16, 3.76, 3.4-3.7, 2.98 and 1.24 δ.

EXAMPLE 4 7-Meth oxy-1,2,3,4-tetrahydro-1-(1-methyledιyl)-2,3-dioxoquinoxaIine (VIII) Ethyl oxalyl chloride (0.33 ml) is added dropwise over 5 min to a solution of the diamine 4-methoxy-2-(isopropyl)aminoaniline (IV, EXAMPLE 3, 0.51 g), triethylamine (0.51 ml) and toluene (18 ml) at -78°. The solution is stirred for 1 hr at -78° and is allowed to warm to 20-25°. After 1 hr the mixture is heated at reflux for 20 hr. The mixture is cooled to 0°, diluted with ether, filtered, the solids washed with water (4 x 20 ml) and then ether to give the title compound, mp 228-230°; IR (mineral oil) 3075, 2969, 2954, 2924, 1721, 1683, 1661, 1601, 1521, 1374, 1297, 1251 and 1052 cm^-1; NMR (300 MHz, dimethylsulfoxide-dg) 11.86, 7.10, 7.02, 6.80, 4.95, 3.79 and 1.50 δ; MS (El, m/e) 234, 192, 164 and 149.

EXAMPLE 5 3-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)-7-hydroxy-5-(1-methylethyl)- imidazol[1,5-a]quinoxalin-4(5H)-one 7-methyl ether (X)

Potassium tert-butoxide (4.80 ml) is added to a mixture of the dione, 7-methoxy-1,2,3,4- tetrahydro-1-(1-methylethyI)-2,3-dioxoquinoxaline (VIII, EXAMPLE 4, 1.03 g), tetrahydroruran (3.30 ml) and dimethylformamide (0.90 ml) at 0°. The mixture is allowed to warm to 20-25°. After 30 min the mixture is cooled to -20° and diethyl chlorophosphate (0.830 ml) is added. The mixture is allowed to warm to 20-25°. After 45 min the solution is cooled to -78°. A solution of the isocyanide 3-isocyanomethyl-5-cyclopropyl-1,2,4-oxadiazole (K, 717 mg) and tetrahydroruran (1.5 ml) is added followed by potassium terf-butoxide (4.80 ml). The solution is stirred at -78° for 2 hr and is allowed to warm to 20-25 over 2 hr. After stirring the mixture for 1.5 hr at 20-25°, aqueous workup (ethyl acetate, magnesium sulfate) and purification by flash chromatogra- phy eluting with methylene chloride/acetone (9/1), the appropriate fractions are pooled and concentrated to give the title compound. Recrystallization of the product from ethyl acetate gives the title compound, mp 191-192°; IR (mineral oil) 3092, 2953, 2925, 2855, 1668, 1625, 1580, 1526, 1462, 1374, 1281, 1234 and 1066 cm^-1; NMR (300 MHz, CDCl₃) 8.42, 7.75, 7.06, 6.83, 3.90, 2.2-2.4, 1.65 and 1.15-1.45 δ; HRMS (El, m/e) 365.1481, 323, 282 and 255.

EXAMPLE 6 4-Hydroxy-2-(isopropyl)aminonitrobenzene (V)

A solution of the nitro compound 4-methoxy-2-(isopropyl)aminonitrobenzene (lV, EXAMPLE 2, 4.10 g) and hydrobromous acid (48%, 50.0 ml) is heated at 120° for 16 hr. After cooling to 20-25°, dilution with water (200 ml), basification (ammonium hydroxide), and aqueous workup (chloroform and then ethyl acetate, magnesium sulfate) gave the crude product. Purification by flash chromatography eluting with hexane/ethyl acetate (4/1) the appropriate fractions are pooled and concentrated to give the title compound, mp 138-139°; IR (mineral oil) 3184, 2953, 2925, 1635, 1577, 1527, 1465, 1458, 1256, 1223, 1176 and 1156 cm^-1; NMR (300 MHz, CDCl3) 8.15-8.3, 8.13, 6.20, 6.12, 5.4-5.6, 3.6-3.8 and 1.32 δ; MS (El, m/e) 196, 181 and 163.

EXAMPLE 7 4-Hydroxy-2-(isopropyl)aminonitrobenzene (V)

Ethanethiol (7.50 ml) is added to a mixture of sodium hydride (4.18 g, 60% dispersion in mineral oil) and dimethylformamide (150 ml) at 0°. The mixture is stirred for 30 min at 0° and 45 min at 20-25°. This solution is added over 5 min to a solution of the 4-methoxy-2- (isopropyl)aminonitrobenzene (IV, EXAMPLE 2, 9.99 g) and dimethylformamide (125 ml) at 20-25°. The solution is heated at 100° for 45 min. After cooling to 20-25°, aqueous workup (methylene chloride, aqueous layer acidified to pH 3, magnesium sulfate), purification by flash chromatography eluting with hexane/ethyl acetate (2/1) and 1 % methylene chloride, the appropriate fractions are pooled and concentrated to give the title compound.

EXAMPLE 8 4-tert-Butyldimethylsilyloxy-2-(isopropyl)aminonitrobenzene (VI)

Ter t-butyldimethylsilyl chloride (932 mg) is added to a solution of 4-hydroxy-2- (isopropyl)aminonitrobenzene (V, EXAMPLE 6 or 7, 1.01 g), triethylamine (1.5 ml), Dimethylaminopyridine (32.0 mg) and methylene chloride (16.0 ml). The mixture is stirred for 16 hr at 20-25°. Basic workup (chloroform, sodium bacarbonate, magnesium sulfate) and purification by flash chromatography eluting with hexane/ethyl acetate (15/1), the appropriate fractions are pooled and concentrated to give the title compound; IR (mineral oil) 3358, 2957, 2929, 1617, 1573, 1518, 1487, 1463, 1261, 1241, 1169, 1082, 872 and 835 cm^-1; NMR (300 MHz, CDCl₃) 8.0-8.2, 8.09, 6.16, 6.11, 3.6-3.8, 1.31, 0.98 and 0.25 δ; MS (El, m/e) 310, 295, 277 and 253.

EXAMPLE 9 4-tert-Butyldimetiιylsilyloxy-2-(isopropylaminoaniline (VII)

A mixture of the nitro compound, 4-tm-butyldimethylsilyloxy-2-(isopropyl)- aminonitrobenzene (VI, EXAMPLE 8, 1.37 g), 10% Palladium on carbon (0.250 g) and ethanol (40 ml) is hydrogenated (42 psi) in a Parr flask for 16 hr. Filtration, edianol wash, and concentration gives the title compound; NMR (300 MHz, CDCl₃) 6.58, 6.19, 6.12, 3.4-3.7, 1.24, 0.98 and 0.18 δ.

EXAMPLE 10 7-tert-Butyldimethylsilyloxy-1,2,3,4-tetrahydro-1-(1-methylethyl)-2,3- dioxoquinoxaline (Vlll)

Ethyl oxalyl chloride (0.54 ml) is added to a solution of the diamine, 4-tert- butyldimethylsilyloxy-2-(isopropylaminoaniline (VII, EXAMPLE 9, 1.16 g), triethylamine (0.85 ml) and toluene (30 ml) at -78°. The solution is stirred for 2 hr at -78° and is allowed to warm to 20-25°. After stirring for 2 hr at 20-25, basic workup (chloroform, sodium bacarbonate, magnesium sulfate) provided the uncyclized intermediate.

The residue is taken up in ethanol (25.0 ml) which is heated at reflux for 24 hr. After cooling to 20-25°, concentration and trituration of the residue with ether gives a solid. The filtrate is concentrated and purified by flash chromatography eluting with ethyl acetate/methanol (25/1) to provide additional product, mp 161-162°; IR (mineral oil) 2956, 2926, 2857, 1691, 1505, 1290, 1242 and 890 cm^-1; NMR (300 MHz, CDCl₃) 11.7-11.9, 7.23, 6.87, 6.67, 4.9-5.2, 1.64, 1.00 and 0.22 δ; MS (El, m/e) 334, 277 and 235. EXAMPLE 11 3-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)-7-tert-butyldimethylsilyloxy-5-(1- methyIethyl)imiadiazole[l,5a]quinoxalin-4(5H)-one (X)

Potassium tert-butoxide (19.7 ml, 1.0 M in tetrahydrofuran) is added dropwise over 10 min to a solution of the dione, 7-ter t-butyldimethyIsilyloxy-1,2,3,4-tetrahydro-1-(1-methylethyl)-2,3- dioxoquinoxaline (Vlll, EXAMPLE 10, 5.98 g), tetrahydrofuran (14.1 ml) and dimethylformamide (3.70 ml) at 0°. The solution is allowed to warm to 20-25°. After 30 min the solution is cooled to -20° and diethyl chlorophosphate (2.9 ml) is added dropwise over 5 min. The solution is allowed to warm to 20-25° and is stirred for 45 min. After cooling to -78°, a solution of the isocyanide, 3-isocyanomethyl-5-cyclopropyl-1,2,4-oxadiazole(IX) (2.93 g) and tetrahydrofuran (7.0 ml) is added. Potassium tert-butoxide (19.7 ml) is added dropwise over 10 min and the solution stirred at -78° for 2 hr and is allowed to gradually warm to 0° over 2 hr. The mixture is stirred for an additional hour at 0°. Aqueous workup (chloroform and then ethyl acetate, magnesium sulfate) and purification by flash chromatography eluting with methylene chloride/acetone (10/1) the appropriate fractions are pooled and concentrated to give the title compound mp 176.5-177.5°; IR (mineral oil) 3104, 2955, 2921, 2868, 2856, 1688, 1576, 1525, 1457, 1408, 1360, 1340, 1290, 1234, 1027, 875 and 835 cm^-1; NMR (300 MHz, CDCl₃) 8.42, 7.69, 7.01, 6.76 , 2.2-2.4, 1.64, 1.2-1.4, 1.01 and 0.26 δ; HRMS (El, m/e) 465.2210, 366 and 298.

EXAMPLE 12 3-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)-7-hydroxy-5-(1-methylethyl)- imidazol[1,5-a]quinoxalin-4(5H)-one (XI)

Tetrabutylammonium fluoride (14.5 ml, 1.0 M in tetrahydrofuran) is added to solution of the ether, 3-(5-cycIopropyl-1,2,4-oxadiazol-3-yl)-7-t-butyldimethylsilyloxy-5-(1- methylethyl)imiadiazole[1,5a]quinoxalin-4(5H)-one(X, EXAMPLE 11, 6.65 g) and tetrahydrofuran (33.0 ml) at 0°. After 45 min, aqueous workup (ethyl acetate, magnesium sulfate) and filtration of the resultant precipitate provides the title compound. The filtrate is concentrated and triturated with ethyl acetate several times to provide additional title compound. Purification of the filtrate by flash chromatography eluting with methylene chloride/acetone (3/1) the appropriate fractions are pooled and concentrated to give the title compound mp 260-262°; IR (mineral oil) 3114, 2953, 2924, 2855, 1671, 1613, 1495, 1455, 1331, 1288, 1236, 1223 and 1207 cm^-1; NMR (300 MHz, CD₃OD-d₄) 8.88, 8.00, 7.11, 6.80, 5.0-5.3, 2.3-2.5, 2.15, 1.64 and 1.2-1.4 δ; HRMS (El, m/e) 351.1330, 309, 241.

EXAMPLE 13 3-(5-CycIopropyl-1,2,4-oxadiazol-3-yl)-7-hydroxy-5-(1-methylethyl)- imidazol[1,5-a]quinoxalin-4(5H)-one 7-acetate (Xlll )

Acetic anhydride (0.185 ml) is added to a solution of the 3-(5-cyclopropyl-1,2,4-oxadiazol- 3-yl)-7-hydroxy-5-(1-methylethyl)-imidazol[1,5-a]quinoxalin-4(5H)-one (XI, EXAMPLE 12, 573 mg), methylene chloride (10.0 ml) and pyridine (5.0 ml) at 0°. The solution is stirred for 1 hr at 0° and 1 hr at 20-25°. Basic workup (methylene chloride, sodium bicarbonate, magnesium sulfate) provided 601 mg (94%) of the acetate which is homogeneous by tlc analysis. An analytical sample is prepared by recrystallization from ethyl acetate/hexane to give the title compound mp 199-201°; IR (mineral oil) 3091, 2955, 2924, 1763, 1685, 1570, 1451, 1359, 1220, 1203 and 1024 cm^-1; NMR (300 MHz, CDCl₃) 8.48, 7.83, 7.37, 7.07, 2.37, 2.25-2.4, 1.65 and 1.15-1.45 δ; MS (El, m/e) 393, 351, 309, 241 and 69.

EXAMPLE 14 3-Hydroxy-2-(isopropyl)aminonitrobenzene (V)

A mixture of 2-amino-3-nitrophenol (10.0 g), acetone (250 ml) and magnesium sulfate (15.6 g) is stirred for 16 hr at 20-25°. An additional 10.0 g of magnesium sulfate is added after 6 hr. The mixture is filtered and concentrated. The crude material is combined with methanol (225 ml), and sodium cyanoborohydride (14.0 g) is added. At 1 hr intervals hydrochloric acid (3N, 0.3 ml) is added throughout the experiment. After 30 hr, additional sodium cyanoborohydride (5.00 g) is added. The mixture is stirred for 4 days and is concentrated. Aqueous workup (methylene chloride, magnesium sulfate) and purification by flash chromatography eluting with hexane/ethyl acetate (4/1) the appropriate fractions are pooled and concentrated to give the title compound mp 89-90°; IR (mineral oil) 3456, 2960, 1613, 1518, 1424, 1365, 1343, 1276, 1156, 1116 and 735 cm^-1; NMR (300 MHz, CDCI₃) 7.60, 7.13, 7.01, 3.3-3.5 and 1.15 δ; MS (El, m/e) 196, 181, 163 and 108.

EXAMPLE 15 3-tert-Butyldimeth ylsilyloxy-2-(isopropyl)aminonitrobenzene (VI)

Tert-butyldimethylsilyl chloride (3.65 g) is added to a solution of the 3-hydroxy-2- (isopropyl)aminonitrobenzene (V, EXAMPLE 14, 3.95 g), methylene chloride (100 ml), triethylamine (5.9 ml) and DMAP (129 mg) at 0°. The solution is stirred for 30 min at 0° and 16 hr at 20-25°. Basic workup (methylene chloride, sodium bicarbonate, magnesium sulfate) and purification by flash chromatography eluting with hexane/ethyl acetate (7/1) the appropriate fractions are pooled and concentrated to give the title compound: IR (neat) 3356, 2958, 2932, 1602, 1536, 1495, 1334, 1257, 1191, 865 and 843 cm^-1; NMR (300 MHz, CDCl₃) 7.68, 6.91, 6.64, 4.1-4.3, 1.14, 1.01 and 0.25 δ; MS (El, m/e) 310, 295, 211, 193, 73 and 43.

EXAMPLE 16 3-tert-Butyldimethylsilyloxy-2-(isopropyl)aminoaniline (VII)

A mixture of 3-tert-butyldimethylsilyloxy-2-(isopropyl)aminonitrobenzene(VI, EXAMPLE

15, 6.72 g), ethanol (200 ml), and 10% palladium on carbon (1.23 g) is hydrogenated at 30 psi for 16 hr at 20-25°. The mixture is filtered and is washed with ethanol, methylene chloride, and methanol. Concentration of the combined filtrates provides the title compound; NMR (300 MHz,

CDCl₃) 6.70, 6.35, 6.28, 3.5-4.0, 3.3-3.5, 1.10, 1.02 and 0.24 δ.

EXAMPLE 17 8-tert-Butyldimethylsilyloxy-1,2,3,4-tetrahydro-1-(1-methylethyl)-2,3- dioxoquinoxaline (Vlll)

Ethyl oxalyl chloride (2.4 ml) is added dropwise over 10 min to a solution of the diamine,

3-tert-butyldimethylsilyloxy-2-(isopropyl)aminoaniline(VII, EXAMPLE 16, 5.67 g), triethylamine (3.7 ml) and toluene (135 ml) at -78°. The solution is allowed to stir for 2 hr at -78° and 14 hr at 20-25. Basic workup (chloroform, sodium bicarbonate, magnesium sulfate) provides the uncyclized intermediate as an oil. This material is combined with ethanol (110 ml) and the solution is heated at reflux for 16 hr. Concentration and trituration with hexane provided a solid. Purification of this solid by flash chromatography eluting with hexane/ethyl acetate (1/1→0/1), the appropriate fractions are pooled and concentrated to give the title compound mp 189.5-190.5°; IR (mineral oil) 2951, 2927, 1693, 1676, 1451, 1258, 1238, 886 and 837 cm^-1; NMR (300 MHz, CDCl₃) 11.12, 6.99, 6.88, 6.72, 5.15-5.35, 1.62, 0.98 and 0.37 δ; MS (El, m/e) 334 and 235. EXAMPLE 18 3-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)-6-t-butyldimethylsilyloxy-5-(1- methylethyl)-imidazol[1,5a]quinoxalin-4(5H)-one (X)

Potassium tert-butoxide in tetrahydrofuran (7.80 ml, 1.0 M) is added dropwise over 5 min to a solution of the dione, 8-t-butyldimethylsilyloxy-1,2,3,4-tetrahydro-1-(1-methylethyl)-2,3- dioxoquinoxaline (Vlll, EXAMPLE 17, 2.40 g), tetrahydrofuran (5.6 ml) and dimethylformamide (1.5 ml) at 0°. The solution is allowed to warm to 20-25° and is stirred for 30 min. After cooling to -20°, diethyl chlorophosphate (1.2 ml) is added. The solution is allowed to warm to 20-25° and is stirred for 45 min before being cooled to -78°. A solution of the isocyanide 3-isocyanomethyl-5- cyclopropyl-1,2,4-oxadiazole (lX, 1.17 g) and tetrahydrofuran (2.8 ml) is added. Potassium tert- butoxide (7.8 ml) in tetrahydrofuran is added dropwise over 5 min. The solution is allowed to stir for 2 hr at -78° and is then allowed to warm to 0° over 2 hr. After stirring for 45 min at 0°, aqueous workup (chloroform and then ethyl acetate, magnesium sulfate) and purification by flash chromatography ethyl acetate/hexane (3/1), the appropriate fractions are pooled and concentrated to give the title compound; IR (mineral oil) 2954, 2927, 1653, 1581, 1497, 1469, 1367, 1261, 921 and 827 cm^-1; NMR (300 MHz, CDCl₃) 8.44, 7.37 , 7.14, 6.94, 4.85-5.05, 2.2-2.4, 1.64, 1.2- 1.45, 0.97 and 0.39 δ; MS (El, m/e) 465, 366, 298 and 69.

EXAMPLE 19 3-(5-Cyclopropyl-1,2,4-oxadiazoI-3-yl)-6-hydroxy-5-(1-methylethyl)- imidazol[1,5-a]quinoxalin-4(5H)-one (XI)

Tetrabutylammonium fluoride (6.0 ml, 1.0 M in tetrahydrofuran) is added to a solution of the silyl ether, 3-(5-cyclopropyl-1,2,4-oxadiazol-3-yI)-6-t-butyldimethylsilyloxy-5-(1-methylethyl)- imidazol[1,5a]quinoxalin-4(5H)-one (X, EXAMPLE 18, 2.73 g) and tetrahydrofuran (13.5 ml) at 0°. The solution is stirred for 40 min and then water (40 ml) is added. The mixture is extracted with ethyl acetate several times, and the organic layers dried (magnesium sulfate) and concentrated. Purification by flash chromatography eluting with methylene chloride/acetone (10/1→3/1) gives the title compound mp 263-265°; IR (mineral oil) 2953, 2925, 1678, 1581, 1478, 1463, 1449, 1376, 1302, 1268, 1244, 1205 and 1146 cm^-1; NMR (300 MHz, CDCl₃) 8.39, 7.14, 6.93, 6.75, 4.85-5.0, 2.15-2.30, 1.55 and 1.1-1.35 δ; MS (El, m/e) 351, 309, 241, 69.

EXAMPLE 20 3-(5-CycIopropyl-1,2,4-oxadiazol-3-yl)-6-hydroxy-5-(1-methylethyl)- imidazol[1,5-a]quinoxalin-4(5H)-one 6-methyl ether (Xlll)

Sodium hydride (68.9 mg, 60% dispersion in mineral oil) is added to a solution of 3-(5- cyclopropyl-1,2,4-oxadiazol-3-yl)-6- hydroxy-5-(1-medιylemyl)-imidazol[1,5-a]quinoxalin-4-( 5H)-one (XI, EXAMPLE 19, 505 mg), tetrahydrofuran (14.2 ml) and dimethylformamide (3.9 ml) at 0°. The mixture is stirred for 40 min at 0° and then iodomethane (98.4μl) is added. The mixture is stirred for 20 min at 0° and for 4 hr at 20-25°. Aqueous workup (chloroform, ethyl acetate, magnesium sulfate) and trituration with ether gives the title compound mp 180-181.5°; IR (mineral oil) 3100, 2953, 2925, 1676, 1573, 1498, 1461, 1404, 1355, 1253, 1146 and 956 cm^-1; NMR (300 MHz, CDCl₃) 8.43 , 7.37, 7.25, 6.98, 4.65-4.8, 3.97, 2.2-2.4, 1.64 and 1.15-1.4 δ; MS (El, m/e) 365, 322, 255 and 69.

EXAMPLE 21 5-Methoxy-2-(isopropyl)aminonitrobenzene (IV)

4-Chloro-2-nitroanisole (l l, 10.0 g) and isopropylamine (70.0 ml) are heated in a bomb at 125° for 19 hr, followed by heating at 150° for 48 hr. Basic workup (methylene chloride, sodium bicarbonate) and flash chromatography eluting with ethyl acetate/hexane (15/85), the appropriate fractions are pooled and concentrated to give the title compound, mp 79-80°; IR (mineral oil) 3363, 2969, 2956, 1572, 1517, 1404, 1286 and 1165 cm^-1; NMR (300 MHz, CDCl₃) 8.01, 7.60, 7.14, 6.84, 3.75-3.9, 3.79 and 1.32 δ; MS (El, m/e), 210, 195, 177, 149 and 134.

EXAMPLE 22 5-Methoxy-2-(isopropyl)aminoaniline (VII)

A mixture of 5-methoxy-2-(isopropyl)aminonitrobenzene (lV, EXAMPLE 21, 1.00 g), ethanol (40 ml) and 10% Palladium on carbon (280 mg) is hydrogenated (40 psi) at 20-25° for 20 hr. The mixture is filtered and concentrated to give the title compound; NMR (300 MHz, CDCl₃)

6.95-7.05 , 6.25-6.35, 3.74, 3.55-3.7 and 1.30 δ.

EXAMPLE 23 6-Methoxy-1,2,3,4-tetrahydro-1-(1-methylethyl)-2,3-dioxoquinoxaline

(vlll)

Ethyl oxalyl chloride (2.07 ml) is added dropwise to a solution of 5-methoxy-2-

(isopropyl)aminoaniline (VII, EXAMPLE 22, 3.51 g) and triethylamine (3.5 ml) in 135 ml of toluene at -78°. The mixture is stirred at -78° for 1 hr and is allowed to warm to 20-25° for 19 hr. The mixture is heated at reflux for 24 hr and is cooled. Water (200 ml) and ether (40 ml) are added, and the mixture containing precipitates is stirred in an ice bath for 1 hr and filtered. The solids are washed with water and dried to give the title compound mp 192-194°; IR (mineral oil) 3186, 2925, 2855, 1711, 1666, 1526, 1282 and 1040 cm^-1; NMR (300 MHz, CDCl₃) 11.81, 7.33, 6.88, 6.79, 5.13, 3.86 and 1.65 δ; MS (El, m/e), 234, 192, 164 and 149.

EXAMPLE 24 3-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)-8-hydroxy-5-(1-methylethyl)- imidazol[1,5-a]quinoxalin-4(5H)-one 8-methyl ether (X)

Potassium tert-butoxide solution (1.0 M in tetrahydrofuran, 2.1 ml) is added dropwise to aslurryof6-memoxy-1,2,3,4-tetrahydro-1-(1-methylethyl)-2,3-dioxoquinoxaline(Vlll, EXAMPLE 23, 450 mg) in 0.4 ml of dimethylformamide and 1.5 ml of tetrahydrofuran at 0°. The mixture is stirred for 10 min at 0°, allowed to warm to 20-25° for 20 min, and is cooled to -25°. Diethyl chlorophosphate (0.36 ml) is added dropwise and the mixture is stirred at -25° for 15 min, allowed to warm to 20-25° for 15 min and is cooled to -25°. The oxadiazole isocyanide (315 mg) is added and the mixture is stirred for 5 min. Potassium tert-butoxide (2.1 ml) is added dropwise, and the mixture is stirred for 2 hr at -25° and is allowed to warm to 20-25° over an additional hour. Water (15 ml) and ethyl acetate (2 ml) are added with stirring in an ice bath and the resulting solids are filtered, washed and triturated with water and ethyl acetate/hexane (5/95). Drying gives the title compound mp 219-220°; IR (mineral oil) 3092, 2925, 2868, 1664, 1580 and 1469 cm^-1; NMR (300 MHz, CDCl₃) 8.47, 7.52, 7.31, 7.02, 5.45, 3.93, 2.3-2.4, 1.65, 1.35-1.45 and 1.2-1.3 δ; MS (El, m/e), 365, 323, 282 and 255.

EXAMPLE 25 2-Chloro-5-methoxymethyloxynitrobenzene (ll)

A solution of 3-chloro-2-nitrophenol (4.15 g) in 5 ml of tetrahydrofuran is added dropwise to a stirred slurry of sodium hydride (1.15 g) in 50 ml of tetrahydrofuran at 0°. The mixture is stirred at Oo for 15 min, allowed to warm to 20-25° over 20 min, and is cooled to 0°. Chloromethyl methyl ether (2.2 ml) is added dropwise and the mixture is allowed to warm to 20- 25° and is stirred for 16 hr. Basic workup (ethyl acetate, sodium bicarbonate) gives the title compound; IR (mineral oil) 2961, 2908, 1537, 1483, 1357, 1156 and 995 cm^-1; NMR (300 MHz, CDCl₃) 7.57, 7.44, 7.20, 5.21 and 3.48 δ; MS (El, m/e), 217, 126, 110, 75, 63 and 45.

EXAMPLE 26 2-(Isopropyl)amino-5-methoxymethyloxynitrobenzene (IV)

The 2-chloro-5-methoxymethyloxynitrobenzene (ll, EXAMPLE 25, 4.98 g) and isopropyl- amine (10.0 ml) are heated in a bomb with stirring at 120° for 48 hr. Basic workup (methylene chloride, sodium bicarbonate) and flash chromatography on silica gel (250 g) eluting with ethyl acetate/hexane (7/93), the appropriate fractions are pooled and concentrated to give the title compound; IR (Neat) 3370, 2970, 1572, 1520, 1280, 1235, 1168 and 1006 cm^-1; NMR (300 MHz, CDCl₃) 7.8-8.0, 7.85, 7.23, 6.83, 5.12, 3.75-3.9, 3.49 and 1.32 δ; MS (El, m/e), 240, 225, 195, 179, 153 and 45.

EXAMPLE 27 2-(Isopropyl)amino-5-methoxymethyloxynitrobenzene (VII)

Amkmreofthenitroarylamine,2-(/sopropyl)ami no-5-methoxymethyloxynitrobenzene(IV, EXAMPLE 26, 1.62 g), ethanol (75 ml) and 10% palladium on carbon (400 mg) is hydrogenated (50 psi) at 20-25° for 7 hr. The mixture is filtered and concentrated to give the title compound; NMR (300 MHz, CDCl₃) 6.71, 6.4-6.5, 5.08, 3.71, 3.4-3.6, 3.47 and 1.22 δ.

EXAMPLE 28 6-Methoxymethyloxy-1,2,3,4-tetrahydro-1-(1-methylethyl)-2,3- dioxoquinoxaline (VIII)

Ethyl oxalyl chloride (0.70 ml) is added dropwise to a solution of the diamine, 2-

(isopropyl)amino-5-methoxymethyloxynitrobenzene(Vll, EXAMPLE 27, 1.31 g) and triethylamine (1.1 ml) in 43 ml of toluene at -78°. The mixture is stirred at -78° for an additional hour, allowed to warm to 20-25°, and is stirred for 67 hr. The mixture is heated at reflux for 1 hr, and allowed to cool to 20-25°. Ether (40 ml) is added, and the mixture containing solids is stored overnight at -10°. The solids are filtered, washed with water and dried to give the title compound. A second crop of is obtained from the filtrate to give the title compound mp 165-167°; IR (mineral oil) 2924, 2855, 1695, 1532, 1284, 1154 and 1013 cm^-1; NMR (300 MHz, CDCl₃) 11.50, 7.33, 7.03, 6.93, 5.19, 5.0-5.2, 3.48 and 1.65 δ; MS (El, m/e), 264, 222, 192, 149, 121 and 45.

EXAMPLE 29 3-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)-8-hydroxy-5-(1-methylethyl)- imidazol[1,5-a]quinoxaIin-4(5H)-one 8-methoxymethyl ether (X) Potassium tert-butoxide solution (1.0 M in tetrahydrofuran, 2.93 ml) is added dropwise to a slurry of the quinoxalinedione, 6-methoxymethyloxy-1,2,3,4-tetrahydro-1-(1-methylethyl)-2,3- dioxoquinoxaline (Vlll, EXAMPLE 28, 711 mg) in 0.6 ml of dimethylformamide and 2.2 ml of tetrahydrofuran at 0°. The mixture is stirred 10 min, allowed to warm to 20-25° for 15 min, and is cooled to -30°. Diethyl chlorophosphate (0.50 ml) is added dropwise and the mixture is stirred 15 min at -30°, allowed to warm to 20-25° for 25 min, and is cooled to -50°. The oxadiazole isocyanide, 3-isocyanomethyl-5-cyclopropyl-1,2,4-oxadiazole (437 mg) is added and the mixture is stirred 5 min. Potassium tert-butoxide (2.93 ml) is added dropwise and the mixture is allowed to warm from -50° to -30° over 1.5 hr. Glacial acetic acid (1 ml) is added, causing precipitation of the product. Water (2 ml) is added and the mixture stored at -10° for 12 days. The solids are filtered, washed and triturated with water, 5% ethyl acetate/hexane, and dried to give the title compound mp 179-181°; IR (mineral oil) 3101, 2925, 2855, 1677, 1578, 1447 and 1372 cm^-1; NMR (300 MHz, CDCl₃) 8.48, 7.45-7.55, 7.15 , 5.3-5.6, 5.27, 3.54, 2.3-2.4, 1.65, 1.35-1.45 and 1.2-1.3 δ; MS (El, m/e) 395, 353, 308, 69 and 45.

EXAMPLE 30 3-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)-8-hydroxy-5-(l-methylethyl)- imidazol[1,5-a]quinoxalin-4(5H)-one (XI)

Bromotrimethylsilane (0.40 ml) is added dropwise to a solution of 3-(5-cyclopropyl-1,2,4- oxadiazol-3-yl)-8-hydroxy-5-(1-memylethyl)-imidazol[1,5-a]quinoxalin-4(5H)-one 8-methoxy- methyl ether (X, EXAMPLE 29, 300 mg) at 0°. An additional portion of bromotrimethylsilane (0.15 ml) is added after one hour of stirring at 0°, and the reaction is stored overnight at -10°. Basic workup (chloroform, sodium bicarbonate) and trituration with 5% ethyl acetate/hexane provides the desired product as a solid. An analytical sample is prepared by two recrystallizations from methylene chloride and hexane mp 215-217°; IR (mineral oil) 2923, 2855, 1673, 1569, 1466, 1455 and 1351 cm^-1; NMR (300 MHz, CDCl₃) 8.49, 7.39, 7.2-7.4, 6.92, 5.2-5.5, 2.25- 2.4, 1.63 and 1.2-1.45 δ; MS (El, m/e) 351, 309, 268, 241, 69 and 40.

Claims

1. An oxygenated quinoxaline of formula (XlV)

where R₃ is a 1,2,4-oxadiazol-3-yl of formula

or a 1,2,4-oxadiazol-5-yl of formula

where R₃-₁ is C₁-C₆ alkyl or C₃-C₇ cycloalkyl;

R₅ is C₁-C₆ alkyl or C₃-C₇ cycloalkyl;

-OH,

-O-R₁ where R₁ is C₁-C₄ alkyl,

2. An oxygenated quinoxaline of formula (XTV) according to claim 1 where R₇, R₈ and R₉ are -H.

3. An oxygenated quinoxaline of formula (XIV) according to claim 1 where R₆, R₈ and R₉ are -H.

4. An oxygenated quinoxaline of formula (XIV) according to claim 1 where R₆, R₇ and R₉ are -H.

5. An oxygenated quinoxaline of formula (XlV) according to claim 1 where R₆, R₇ and R₈ are -H.

6. An oxygenated quinoxaline of formula (XlV) according to claim 1 where one of R₆, R₇, R₈ or R₉ is -OH.

7. An oxygenated quinoxaline of formula (XlV) according to claim 1 where one of R₆, R₇, R₈ or R₉ is -O-R₁.

8. An oxygenated quinoxaline of formula (XIV) according to claim 7 where R₁ is C₁ alkyl.

9. An oxygenated quinoxaline of formula (XlV) according to claim 1 where one of R₆, R₇, R₈ or R₉ is -O-CO-R₂.

10. An oxygenated quinoxaline of formula (XlV) according to claim 9 where R₂ is C₁ alkyl.

11. An oxygenated quinoxaline of formula (XlV) according to claim 1 where R₃ is 1,2, 4-oxadizaol-3-yl (A).

12. An oxygenated quinoxaline of formula (XIV) according to claim 11 where R_3-1 is C₁-C₃ alkyl or cycloalkyl.

13. An oxygenated quinoxaline of formula (XTV) according to claim 11 where R_3-1 is cyclopropyl.

14. An oxygenated quinoxaline of formula (XIV) according to claim 1 where R₃ is 1,2,

4-oxadizaol-5-yl (B).

15. An oxygenated quinoxaline of formula (XTV) according to claim 14 where R_3-1 is C₁-C₃ alkyl or cycloalkyl.

16. An oxygenated quinoxaline of formula (XIV) according to claim 14 where R_3-1 is cyclopropyl.

17. An oxygenated quinoxaline of formula (XIV) according to claim 1 where R₅ is C₁-C₃ alkyl.

18. An oxygenated quinoxaline of formula (XTV) according to claim 17 where R₅ is isopropyl.

19. An oxygenated quinoxaline of formula (XTV) according to claim 1 where the oxygenated quinoxaline is selected from the group consisting of

3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-7-hydroxy-5-(1-methylethyl)-imidazol

[1,5-a]quinoxalin-4(5H)-one 7-methyl ether,

3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-7-hydroxy-5-(l-methylethyl)-imidazol

[1,5-a]quinoxalin-4(5H)-one,

3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-7-hydroxy-5-(l-methylethyl)-imidazol

[1 ,5-a]quinoxalin-4(5H)-one 7-acetate,

3-(5-cyclopropyi-1,2,4-oxadiazoI-3-yl)-6-hydroxy-5-(l-methylethyl)-imidazol

[1,5-a]quinoxalin-4(5H)-one,

3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-6-hydroxy-5-(l-memylethyl)-imidazol

[1,5-a]quinoxalin-4(5H)-one 6-methyl ether,

3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-8-hydroxy-5-(1-methylethyl)-imidazol

[1,5-a]quinoxalin-4(5H)-one 8-methyl ether,

3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-8-hydroxy-5-(1-methyIethyl)-imidazol

[1,5-a]quinoxalin-4(5H)-one.