COMPOUNDS AND METHODS

Abstract: This invention relates to 3,4-dinitrobenzamide compounds which are ligands, in particular, antagonists, of the Calcitonin Gene-Related Peptide ("CGRP") receptor. In addition, this invention relates to the treatment and prevention of disease states mediated by CGRP, including, but not limited to, headaches, especially migraines; non-insulin dependent diabetes mellitus; neurogenic inflammation; cardiovascular disorders; chronic inflammation; pain; endotoxic shock; arthritis; allergic rhinitis; allergic contact dermatitis; inflammatory skin conditions; and asthma, all in mammals, by the use of 3,4-dinitrobenzamide CGRP receptor antagonists.

Description: COMPOUNDS AND METHODS Fffit-P OF THE INVENTION This invention relates to 3,4-dinitrobenzamide compounds which are ligands, in particular, antagonists, of the Calcitonin Gene-Related Peptide (hereinafter "CGRP") receptor. In addition, this invention relates to the treatment and prevention of disease states mediated by CGRP, including, but not limited to, headaches, especially migrώnes; non-insulin dependent diabetes mellitus ("NIDDM"); neurogenic inflammation; cardiov.ascular disorders; chronic infl.ammation; p.ain; endotoxic shock; .arthritis; .allergic rhinitis; .allergic contact dermatitis; inflammatory skin conditions; .and asthma, all in mammals, preferably humans, by the use of CGRP receptor ligωds, in particular, 3,4-dinitrobenzamide antagonists, thereof. BACKGROUND OF THE INVENTION CGRP is a 37 amino acid polypeptide that is stored and released from nerve terminals in both the central nervous system .and the peripher∑d nervous system. (Goodman et al., Life Sci., Vol. 38, pp. 2169-2172 (1986)). CGRP has been detected in nerves innervating the he.art, peripheral and cerebral blood vessels, and kidneys by immunohistochemic and radioimmunoassay methods. (Y∑unamoto et al., Prog. Neurobiol. , Vol. 33, pp. 335-386 (1989)). CGRP has been shown to mediate its biological response by binding to specific cell surface receptors that have been identified in a variety of tissues. Evidence from biochemical studies suggest that CGRP receptors belong to the family of G-protein coupled receptors. The widespread distribution of CGRP receptors on muscle, glandular, epitheli∑ϋ and neuronal cells is consistent with its wide range of biological actions, including pain transmission (Collin et ϊd., Pain, Vol. 54, p. 20 (1993); .and J. Neurosci., Vol. 16, No. 7, pp.2342-2351 (1996)); peripheral and cerebral vasodilation (Brain et al., Nature, Vol. 313, pp. 54-56 (1985)); car.di.ac acceleration (Sigrist et al., Endocrinology, Vol. 119, pp. 381-389 (1986)); regulation of calcium metabolism (Grunditz et al., Endocrinology, Vol. 119, pp. 2313-2324 (1986)); reduction of intestinal motility (Fargeas et al, Peptides, Vol. 6, pp. 1167-1171 (1985)); regulation of glucose metabolism, e.g., reduction of insulin secretion and insulin sensitivity, (Hermansen et al., Peptides, Vol. 27, pp. 149-157 (1990); .and Molina et al., Diabetes, Vol. 39, pp. 260-265 (1990)); reduction of appetite and reduction of growth hormone increase (Tannenbaum et al., Endocrinology, Vol. 116, pp. 2685-2687 (1985)); reduction of inflammation of the s-kin, for example in allergic contact dermatitis (Gutwald et al., J. Invest. Derm., Vol. 96, pp. 695-698 (1991)) .and other inflammatory skin conditions (Buckley et al., Neuroscience, Vol. 48, pp. 963-968 (1992); and Escott et al., Br. J. Pharmacol, Vol. 110, pp. 112-116 (1993)). Since CGRP h.as a number of effects on the cardiovascular, central nervous, gastrointestin , respiratory, and endocrine systems, it has now been discovered that limited and selective inhibition of CGRP receptor mechanisms represents a novel preventative and therapeutic approach to the treatment of a broad variety of disease states that are mediated by CGRP. In particular, the development of an active CGRP receptor antagonist would be expected to be useful in the treatment of a variety of disease states that are mediated by CGRP including, but not limited to, headaches, especially migraines; NIDDM; neurogenic inflammation; cardiovascular disorders; chronic inflammation; pain; endotoxic shock; arthritis; allergic rhinitis; allergic contact dermatitis; infljunmatory skin conditions; .and asthma, all in mainmals, preferably humans ("CGRP-mediated diseases"). Surprisingly, it has now been discovered that a class of noπ-peptide compounds, in particular 3,4-dinitrobenzamides of formula (I) function as CGRP receptor antagonists, and therefore, have utility in the treatment of disease states wherein inhibition of CGRP receptor mechanisms is indicated for prevention or therapeutic treatment thereof. SUMMARY OF THE INVENTION In one aspect, the present invention is to a genus of novel compounds of formula (I), or pharmaceutically active salts thereof, said compounds which are also useful in treating the above-mentioned CGRP-mediated dise.ase states: Formula (I) wherein: R 1 is hydrogen, methyl, -(CH2) n . branched (3-6 carbon) al yl, -(CH2)nphenyl, -(CH 2 ) n -N X < CH Λ. , wherein X is CH , oxygen or N-alkyl, or R 1 is -(CH 2 ) n NR 3 R 4 , or -(CH2) n Z. wherein Z is -CO2H, -CO 2 -alkyl, -CONR 3 R 4 , -N(R 3 )CO 2 R 3 , -N(R 3 )C(O)NR 3 R 4 , -OC(O)NR 3 R 4 , or -COR5, and wherein R 3 and R 4 are independently hydrogen, -Cι_4a. lkyl or -C \ _4alkylphenyl, or together with the nitrogen to which they are attached, form a 5-, 6-, or 7-membered heteroring, wherein the heteroring is optionally fused to an optionally substituted phenyl ring, and R5 is methyl, trifluoromethyl, C 2 _ ,alkyl, phenyl or heteroaryl; R2 is optionally substituted .aryl or heteroaryl, or R 2 is A-Ar, wherein A is lower alkyl (C^) or branched alkyl, wherein a branch may cont.ain a substituted phenyl ring, and Ar is substituted phenyl or a substituted 5- or 6-membered hetero.aryl ring which option ly contains one or more heteroatoms selected from N, O or S, or R 2 wherein W is -OH, -NR 3 R 4 , -O-alkyl, an amide derived from an amino acid, NR^R 7 , where R > is H, alkyl, and R? is aryl or substituted aryl, -(CH2) n -aryl, -(CH 2 ) n -subsututed aryl, -(CH2) n -heteroaryl, or -(CH 2 ) n -Z; or Rl and R 2 together with the nitrogen to which they are attached form a 5- or 6- membered heteroring fused to an option ly substituted phenyl ring; m is 1 to 3; and n is 1 to 6, provided that the compound is not N-3-(2,3,4,5-tetrahydro-7,8- dimethoxy- 1 -H-3-benzazepine-3-yl)propyl]-N-(3 ,4-dimethoxyphenyl)-3 ,4- dinitrobenz.amide or N-phenyl-3,4-dinitrobenzarnide. In another aspect, the present invention is to a method of treating CGRP mediated diseases, all in mammals, preferably humans, comprising administering to such mammal in need thereof, an effective amount of a 3,4-dinitrobenz.amide compound of formula (I), or a pharmaceutically active salt thereof. In yet .another aspect, the present invention is to ph.armaceutic.al compositions comprising a compound of formula (I), or a pharmaceutically active salt thereof, and a pharmaceutically acceptable carrier therefor. In particular, the pharmaceutical compositions of the present invention are used for treating CGRP- mediated disease states, including, but not limited to headaches, especially migraines; NIDDM; neurogenic inflammation; cardiovascular disorders; chronic inflammation; pain; endotoxic shock; .arthritis; allergic rhinitis; allergic contact dermatitis; inflammatory skin conditions; and asthma, all in mammals, preferably humans. DETAILED DESCRIPTION OF THE INVENTION It has now been discovered that 3,4-dinitrobenzϊimide compounds of formula (I) are CGRP receptor ligands, in particular, antagonists thereof. It has also now been discovered that selective inhibition of CGRP receptor mechanisms by treatment with the receptor ligands of formula (I), or a pharmaceutically acceptable salt thereof, represents a novel therapeutic and preventative approach to the treatment of a variety of CGRP-mediated disease states. The term "alkyl" is used herein at all occurrences to mean a straight or branched chain radical of 1 to 6 carbon atoms, unless the chain length is limited thereto, including, but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and the like. The terms "halo" or "halogen" are used interchangeably herein at all occurrences to mean radicals derived from the elements chlorine, fluorine, iodine .and bromine. The term "heteroring" is used herein at all occurrences to mean a saturated or wholly or partially unsaturated 5-, 6-, or 7-membered ring system which contains one or more heteroatoms selected from the group consisting of N, O, or S; such as, but not limited to, pyrrolidine, piperidine, piperazine, morpholine, imidazolidine, pyrazolidine, thiazole, immidazole, thiadiazole or triazole. The terms "aryl" or "hetero-aryl" are used herein at all occurrences to mean substituted and unsubstituted .aromatic ring(s) or ring systems which may include bi- or tri-cyclic systems and heteroaryl moieties, which may include, but are not limited to, heteroatoms selected from O, N, or S. Representative examples include, but are not limited to, phenyl, benzyl, naphthyl, pyridyl, quinolinyl, thiazinyl, and furanyl. The term "optionϊdly substituted" is used herein at all occurrences to mean that the moieties may or may not be substituted with one to three various functional groups including methoxy, hydroxy, phenoxy, trifluoromethyl, C^alkyl, halo, nitro, CN, C(O)OH, C(O)NR'R", wherein R' .and R" are independently hydrogen or Cι_4alkyl. It will be understood that the optional substituent(s) may be at a position ortho, meta or para relative to the nitrogen of the amide functionality of formula (I). Preferably, the optional substituent(s) .are positioned ortho relative to the nitrogen of the amide functionality of formula (I). The term "CGRP mediated disease state" is used herein at all occurrences to mean any disease state which is mediated (or modulated) by Calcitonin Gene- Related Peptide. Suitably, pharmaceutically acceptable salts of formula (I) include, but .are not limited to, salts with inorganic acids such as hydrochloric, sulfate, phosphate, diphosphate, hydrobromide .and nitrate or salts with an organic acid such as malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, methanesulfonate, p- toluenesulfonate, palmitate, salicylate and stearate. In addition, pharmaceutically acceptable salts of compounds of formula (I) may also be formed with a pharmaceutically acceptable cation, for instance, if a substituent group comprises a carboxy moiety. Suitable pharmaceutically acceptable cations are well known to those skilled in the art and include alkaline, alkaline earth, ammonium and quaternary ammonium cations. The compounds of the invention can exist in unsolvated as well as solvated forms, including hydrated forms. In general, the solvated forms, with pharmaceutically acceptable solvents such as water, ethanol, and the like, are equivalent to the unsolvated forms for purposes of this invention. The compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic and optically active forms. The stereocenters may be of any combination of R and S configuration, for example, (R,R), (R,S), (S,S) or (S,R). All of these compounds are within the scope of the present invention. For the compounds of formula (I) various embodiments are as follows. Rl is suitably hydrogen, methyl, -(CH2) n > branched (3-6 carbon) alkyl, -(CH 2 ) n -N X -(CH2)nPhenyl, (CH » » , wherein X is CH2, oxygen or N-alkyl, or R 1 is -(CH 2 ) n NR 3 R 4 , or-(CH 2 ) n Z, wherein Z is -CO 2 H, -CO 2 -alkyl, -CONR R 4 , -N(R 3 )CO 2 R 3 , -N(R 3 )C(O)NR 3 R 4 , -OC(O)NR 3 R 4 , or -COR 5 wherein R 3 and R 4 are independently hydrogen, C \ ^al y 1 or C 1 _4alkylphenyl, or together with the nitrogen to which they are attached, form a 5-, 6-, or 7-membered heteroring, wherein the heteroring is optionally fused to an optionally substituted phenyl ring .and R 5 is methyl, trifluoromethyl, C2-6 alkyl, phenyl or heteroaryl. Rl is preferably -(CH2) n Z, wherein Z is -CO2H, -CO2- alkyl, wherein alkyl is tert-butoxy, or -CONR 3 R 4 , wherein R 3 .and R 4 are independently hydrogen, or Cj^alkylphenyl, Cι_4alkyl, -(CH2) n NR 3 R 4 , wherein n is 2 or 3, and R 3 and R 4 are both C1.3al.kyl or R 3 and R 4 form a 5-, 6- or 7- membered heteroring, preferably morpholino, piperidinyl, or piperazine, or wherein the heteroring is option ly fused to an optionally substituted phenyl ring, such as a benzazepine. R 2 is suitably optionally substituted aryl or heteroaryl, or R 2 is A-Ar, wherein A is lower alkyl (Cι_4) or branched alkyl, wherein a branch may contain a substituted phenyl ring, and Ar is substitued phenyl or a substituted 5- or 6- membered hetero.aryl ring which optionally contains one or more heteroatoms selected from N, O or S. R 2 is preferably aryl, more preferably phenyl. Suitable substituents for Ar are C^al yl, halo, cyano, trifluoromethyl, trifluoromethoxy, alkoxy, nitro, and aryl. Preferably, Ar is substituted by Cj^alkyl, most preferably ethyl. Rl .and R 2 together with the nitrogen to which they are attached suitably form a 5- or 6-membered heteroring fused to an optionally substituted phenyl ring. Among the preferred compounds of the invention are the following compounds: N-(2-ethylphenyl)-N-[2-(tert-butoxycarbonyl)ethyl]-3, 4-dinitrobenz.amide; N-[2-(mo holinocarbonyl)ethyl]-N-(2-ethylphenyl)-3, 4-dinitrobenzamide; N-[2-(ethylaminocarbonyl)ethyl]-N-(2-ethylphenyl)-3, 4-dinitrobenz∑unide; N-[2-(diethylaminocarbonyl)ethyl]-N-(2-ethylphenyl)-3, 4-dinitrobenzamide; N-[2-[( 1 -piperidinyl)carbonyl]ethyl]-N-(2-ethylphenyl)-3, 4-dinitrobenz.amide; N-[3-[(diethylaπύno)c.arbonyl]propyl]-N-(2-ethylphenyl)-3, 4-dinitrobenzamide; N-(3-oxo-3-phenylpropyl)-N-(2-ethylphenyl)-3, 4-dinitrobenzamide; N-Methyl-N-(2-methylphenyl)-3, 4-dinitrobenz.amide; N-(2-ethylphenyl)-N-methyl-3, 4-dinitrobenzamide; N-(2, 6-diethyl)phenyl-N-methyl-3, 4-dinitrobenz.amide; N-[3-(2, 3, 4, 5-terahydro-lH-3-benz.azepin-3-yl)propyl]-N-phenyl-3, 4- dinitrobenzamide ; N-[3-(7, 8-dimethoxy-2, 3, 4, 5-terahydro-lH-3-benzazepin-3-yl)propyl]-N- phenyl-3, 4-dinitrobenzamide; N-[3-(N'-methyl-2-phenylethylamino)propyl]-N-phenyl-3, 4-dinitrobenzaLmide; N-[3-(morpholin-4-yl)propyl]-N-(3, 4-dimethoxyphenyl)-3, 4-dinitrobenzamide; N-[3-(piperidin- l-yl)propylj-N-(3, 4-dimethoxyphenyl)-3, 4-dinitrobenzamide; N-[2-(N', N'-dimethylamino)ethyl]-N-phenyl-3, 4-dinitrobenzamide; N-(3-methylbutyl)-N-(3, 4-dimethoxyphenyl)-3, 4-dinitrobenzamide; .and N-methyl-N-phenyl-3, 4-dinitrobenz«unide. Formulation of Pharmaceutical Compositions The pharmaceutically effective compounds of this invention (.and the pharmaceutically acceptable salts thereof) are administered in conventional dosage forms prepared by combining a compound of formula (I) ("active ingredient") in an amount sufficient to treat headaches, especially migraines; NIDDM; neurogenic inflammation; cardiovascular disorders; chronic inflammation; pain; endotoxic shock; arthritis; allergic rhinitis; allergic contact dermatitis; inflammatory slϋn conditions; and asthma, with standard pharmaceutical carriers or diluents according to conventional procedures well known in the .art. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation. The pharmaceutical carrier employed may be, for example, either a solid or liquid. Exemplary of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. Exemplary of liquid carriers are syrup, peanut oil, olive oil, water and the like. Similarly, the carrier or diluent may include time delay material well known to the art, such as glyceryl monoste.arate or glyceryl distearate .alone or with a wax. A wide variety of pharmaceutical forms can be employed. Thus, if a solid carrier is used, the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form or in the form of a troche or lozenge. The .amount of solid carrier will vary widely but preferably will be from about 25 mg to about 1000 mg. When a liquid carrier is used, the preparation will be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampule or nonaqueous liquid suspension. The active ingredient may also be administered topically to a mammal in need of treatment or prophylaxis of CGRP mediated disease states. The amount of active ingredient required for therapeutic effect on topical administration will, of course, vary with the compound chosen, the nature and .severity of the disease state being treated and the mammal undergoing treatment, and is ultimately at the discretion of the physiciω. A suitable dose of an active ingredient is 1.5 mg to 500 mg for topical administration, the most preferred dosage being 1 mg to 100 mg, for example 5 to 25 mg administered two or three times daily. By topical administration is meant non-systemic administration and includes the application of the .active ingredient exteπudly to the epidermis, to the buccal cavity .and instillation of such a compound into the e.ar, eye and nose, and where the compound does not significantly enter the blood stream. By systemic administration is meant oral, intravenous, intraperitoneal and intramuscular administration. While it is possible for .an active ingredient to be administered alone as the raw chemical, it is preferable to present it as a pharmaceutical formulation. The active ingredient may comprise, for topical administration, from 0.001% to 10% w/w, e.g. from 1% to 2% by weight of the formulation although it may comprise as much as 10% w/w but preferably not in excess of 5% w/w and more preferably from 0.1 % to 1% w/w of the formulation. The topical formulations of the present invention, both for veterinary and for human medical use, comprise an active ingredient together with one or more acceptable carrier(s) therefor and optionally any other therapeutic ingredient(s). The carrier(s) must be 'acceptable' in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of infl-a mation such as liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose. Drops according to the present invention may comprise sterile aqueous or oily solutions or suspensions and may be prepared by dissolving the active ingredient in a suitable aqueous or alcoholic solution of a bactericidal and/or fungicidal agent and/or any other suitable preservative, and preferably including a surface active agent. The resulting solution may then be clarified by filtration, transferred to a suitable container which is then sealed and sterilized by autoclaving or maintaining at 98- 100°C for half an hour. Alternatively, the solution may be sterilized by filtration .and transferred to the container by an aseptic technique. Examples of bactericid.al and fungicidal agents suitable for inclusion in the drops .are phenylmercuric nitrate or acetate (0.002%), benzalkonium chloride (0.01%) .and chlorhexidine .acetate (0.01%). Suitable solvents for the preparation of an oily solution include glycerol, diluted alcohol and propylene glycol. Lotions .according to the present invention include those suitable for application to the skin or eye. An eye lotion may comprise a sterile aqueous solution option-ally containing a bactericide and may be prepared by methods similar to those for the preparation of drops. Lotions or liniments for application to the slcin may also include an agent to hasten drying and to cool the skin, such as an .alcohol or acetone, and/or a moisturizer such as glycerol or an oil such as castor oil or arachis oil. Creams, ointments or pastes according to the present invention a . re semi-solid formulations of the active ingredient for extem∑ϋ application. They may be made by mixing the active ingredient in finely-divided or powdered form, alone or in solution or suspension in an aqueous or non-aqueous fluid, with the aid of suitable machinery, with a greasy or non-greasy basis. The basis may comprise hydrocarbons such as hard, soft or liquid paraffin, glycerol, beeswax, a metallic soap; a mucilage; an oil of natural origin such as almond, com, arachis, castor or olive oil; wool fat or its derivatives, or a fatty acid such as steric or oleic acid together with an alcohol such as propylene glycol. The formulation may incorporate any suitable surface active agent such as an anionic, cationic or non-ionic surfactant such as sorbitan esters or polyoxyethylene derivatives thereof. Suspending agents such as natural gums, cellulose derivatives or inorganic materials such as silicaceous silicas, and other ingredients such as lanolin, may also be included. The active ingredient may also be administered by inhalation. By "inhalation" is meant intranasal and oral inhalation administration. Appropriate dosage forms for such administration, such as an aerosol formulation or a metered dose inhaler, may be prepared by conventional techniques. The d ly dosage amount of the active ingredient administered by inhalation is from about 0.1 mg to about 100 mg per day, preferably about 1 mg to about 10 mg per day. In one aspect, this invention relates to a method of treating CGRP-mediated diseases with an .antagonist as depicted in formula (I). By the teπn "treating" is meant either prophylactic or therapeutic therapy. Such foπnula (I) compound can be administered to such mammal in a conventional dosage form prepared by combining the formula (I) compound with a conventional pharmaceutically acceptable carrier or diluent .according to known techniques. It will be recognized by one of skill in the art that the form and character of the ph.armaceutic.ally acceptable carrier or diluent is dictated by the amount of active ingredient with which it is to be combined, the route of .administration and other well-known variables. The formula (I) compound is administered to a mammal in need of treatment for a CGRP-mediated disease state, in an amount sufficient to decrease symptoms associated with these dise.ase st es. The route of administration may be oral or parenteral. The term p.arenteral as used herein includes intravenous, intramuscular, subcutaneous, intra-rectal, intravaginal or intraperitoneal administration. The subcutaneous and intramuscular forms of parenteral administration are generally preferred. The daily parenteral dosage regimen will preferably be from about 30 mg to about 300 mg per day of active ingredient. The daily oral dosage regimen will preferably be from about 100 mg to about 2000 mg per day of active ingredient. It will be recognized by one of skill in the .art that the optimal quantity and spacing of individual dosages of a formula (I) compound will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the particular mammal being treated, and that such optimums can be determined by conventional techniques. It will also be appreciated by one of skill in the art that the optimal course of treatment, i.e., the number of doses of the formula (I) compound given per day for a defined number of days, can be ascertained by those skilled in the art using conventional course of treatment determination tests. Methods of Preparation Generally, the compounds of the invention may be prepared by the following reaction sequence: CH I 2 jCWIIj. triβthylaminβ Formula I The reaction sequence involves the reaction of a compound of Formula π, wherein R* and R 2 are defined above, and a suitable acid chloride derived from 3, 4-dinitrobenzoic acid. This reaction may be accomplished in any of a variety of reaction inert solvents by mixing approximately equimolar .amounts of a compound of Formula π and the acid chloride in the presence of an amine base at or below room temperature. The proper choice of reaction variables is within the skill of the art. Methylene chloride is the preferred solvent. Suitable amine bases are triethylamine, N-methylmorpholine, pyridine, and the like. In general, the reaction is allowed to proceed for about 1 hour to about 24 hours at which time the reaction is substantially complete. The completeness of a particul.ar reaction may be me.asured by known techniques such as thin layer chromatography. The products of the reaction are isolated and purified by standard procedures. For example, the reaction mixture may be concentrated by evaporating the solvent and the residue may be partitioned between water and a convenient nonwater-miscible organic solvent such as ether, ethyl acetate, and the like. The solvent may then be evaporated and the residue chromatographed, for example, on silica gel. Choice of the proper chromatography solvent is within the skill of the art. After, or instead of, chromatography, the product may be recryst-allized. Acid addition salts may be prepared using standard procedures. For example, a hydrochloride salt may be prep-ared by dissolving the free base in a convenient solvent and treating this solution with a solution of hydrogen chloride dissolved in the solvent of choice. The acid addition salts may be reconverted to the respective free base by treatment with a dilute solution of sodium hydroxide or potassium carbonate, for example. The compounds of formula (I) are prepared by art-recognized procedures from known or commercially available starting materials. If the starting materials are unavailable from a commercial source, their synthesis is described herein, or they can be prepared by procedures known in the art. Specifically, compounds of formula I can be prepared according to Scheme 1 (Example 8). Formation of the desired amide (3-Scheme 1) is achieved by the reaction of an amine, such as N-methyl.aniline (1 -Scheme 1), with an acid chloride derived from 3, 4-dinitrobenzoic acid (2-Scheme 1). This is performed in an inert solvent such as methylene chloride in the presence of an amine base such as triethyl-amine at or below room temperature. If the amine (1 -Scheme 1) cont.ains a basic amino group elsewhere in the molecule, such as in Example 6, the triethylamine may be omitted. Scheme 1 In the event that the desired .amine (1 -Scheme 1) is not commercially available it may be prepared according to Schemes 2 or 3. The present invention includes such novel amine intermediates useful in the preparation of a variety of the final compounds of this invention. Scheme 2 illustrates the case where the .amine (1 -Scheme 1) contains a second amine containing group such as in Example 1. Scheme 2 Reagents: a) aniline, CH2CI2, pyri ine; b) 2, 3, 4, 5-tetr.ahydro-lH-3-benz.azepine hydrochloride, triethylamine, acetonitrile, cat. nBu4Nl; c) UAIH4, THF, reflux. In this exjimple, 3-chloropropionyl chloride (1 -Scheme 2) is reacted with aniline in an inert solvent in the presence of an amine base such as pyridine. This provides the 3-chloroamide (2-Scheme 2) which is then reacted with the 3- benz.azepine compound in acetonitrile to provide amide (3-Scheme 2). Tliis amide (3-Scheme 2) is next converted to the desired di-amine (4-Scheme 2) via reduction using a reagent such as lithium .aluminum hydride at reflux in tetrahydrofuran. The synthesis is then completed using (4-Scheme 2) according to Scheme 1. In the case where the desired amine is not commercially available and does not contain an additional amino group, as in Example 7, the amine may be prepared according to Scheme 3. In this example isovaleryl chloride (1 -Scheme 3) is reacted with 3, 4-dimethoxy .aniline in the presence of an amine base such as triethyl-amine in an inert solvent such as methylene choride. This provides amide (2-Scheme 3) which is then converted into the required amine (3-Scheme 3) by reducing the amide functionality by methods previously described. The synthesis is then completed using (3-Scheme 3) .according to Scheme 1. Scheme 3 1 2 a Reagents: a) 3, 4-dimethoxyaniline, CH2CI2, triethylamine; b) L1AIH4, THF, reflux. For the cases where the desired N-methyl .anilines are not commercially available, they are readily prepared from the anilines via a number of methods well known in the art. One such method is that reported by Barluenga et al. (J. Chem. Soc. Chem. Commun., pp. 1334-1335 (1984)). Alternatively, the desired N-methyl amides are obt.ained directly from the second.ary amides via alkylation of the amide anion as illustrated in Scheme 4. Scheme 4 Reagents: a) KN(SiMe 3 ) 2 , THF; b) Methyl iodide. In this example, the secondary amide (1 -Scheme 4) is treated with a non- nucleophilic base such as potassium bis(trimethylsilyl)amide [KN(SiMβ3)2] at or below room temperature in a solvent such as tetrahydrofuran. The reaction solution is then treated with a suitable methylating agent such as methyl iodide. The resulting N-methyl amides (2-Scheme 4) are then recovered using standard isolation and purification methods. Preparation of the compounds in which the ortho position of the phenyl ring contains an amide functionality (e.g., 2-Scheme 5) begins with the ortho carboxylic .acid 1 -Scheme 5 (Example 32). Conversion of this acid to the acid chloride using a chlorinating agent such as thionyl chloride or oxalyl chloride followed by treatment with the desired primary or secondary amine (G1G2NH) produces the corresponding secondary or tertiary amide analogs (2-Scheme 5). Scheme 5 1 Reagents: a) thionyl chloride, CHCI 3 ; b) G1G2NH, triethylamine, CH 2 Cl2. Compounds containing the N-propionate side chain (e.g., Examples 103- 106, 108, 110, 111, 116) were prepared as outlined in Scheme 6. Michael addition of 2-ethylaniline to tert-butyl aery late 1 -Scheme 6 provides the alk lated aniline 2- Scheme 6. This intermediate is next acylated with 3, 4-dinitrobenzoyl chloride as previously described to provide benzamide 3-Scheme 6 (Ex.ample 103). The tert- butyl ester is removed using an anhydrous acid such as trifluoroacetic .acid (TFA) to give the carboxylic acid 4-Scheme 6 (Example 104). Conversion of this acid to the acid chloride using a chlorinating agent such as thionyl chloride or oxalyl chloride followed by treatment with the desired primary or secondary amine (G1G2NH) produces the corresponding secondary or tertiary amide analogs (5- Scheme 6). Alternatively, the acid chloride can also be treated with .an alcohol in place of the amine to produce esters. Reagents: a) 2-Ethylaniline, .acetic acid, reflux; b) 3, 4-dinitrobenzoyl chloride, triethy unine, CH 2 Cl2; c) trifluoroacetic acid, CH2CI2; d) oxalyl chloride, CH 2 Cl2; e) G1G2NH, triethylamine, CH2CI2. An alternative method for the preparation of compounds where R 1 is (CH2)n z » is °y alkylation of the desired aniline with an appropriate alkyl halide such as is illustrated in Scheme 7 for the preparation of Example 117. This procedure is quite general and may be used to prepare a wide range of anilines of which compound 3-Scheme 7 is just one example. In this particular example, 4- chlorobutyryl chloride (1-Scheme 7) is reacted with diethylamine to provide the diethylamide 2-Scheme 7. Alkylation of 2-ethylaniline using 2-Scheme 7 as the alkylating agent then provides 3-Scheme 7. Aniline 3-Scheme 7 is then acylated using 3, 4-dinitrobenzoyl chloride as previously described. In the compound of Example 118, the commercially available 3-chloropropiophenone is used in place of the amide 2-Scheme 7 in Scheme 7. Scheme 7 Reagents: a) diethylamine, triethylamine, CH2CI2, 0 °C; b) 2-e-th~yloaniline, triethylamine, DMF, 100 °C. EXAMPLES Example 1. Preparation of N-f3-(2. 3. .5-terahvdro-lH-3-benzazepin-3- yl propyll-N-phenyl-3. 4-dinitrobenzamide. hvdrochloride a 3-Chloro-N-phenvlpropanamide Aniline (1.86 g, 20 mmol) in dry methylene chloride (50 mL) was treated with anhydrous pyridine (1.58g, 20 mmol), cooled to 0 °C, and treated with 3- chloropropionyl chloride (2.54 g, 20 mmol) in dry methylene chloride (5 mL). The mixture was stirred for 18h, allowing the ice bath to rise to room temperature. The reaction solution was washed with 10% HC1, water, and saturated sodium bicarbonate and dried (Na2SO4). Evaporation gave the title compound as a chalky white solid (3.8 g, 100%.). MS(ES) m/e 184 [M+H]+. b) 3-(2. 3. 4. 5-Tetrahvdro-lH-3-benzazepin-3-vl)-N-phenvlpropanamide 2, 3, 4, 5-Tetrahydro-lH-3-benzazepine hydrochloride (100 mg, 0.54 mmol) and 3-chloro-N-phenylpropanamide (110 mg, 0.60 mmol) were suspended in dry acetonitrile (2.5 mL) and treated with triethylamine (0.23 mL, 1.63 mmol) and tetra-n-butylammonium iodide (20 mg, 0.05 mmol). The reaction was refluxed for 12h. The solvent was removed in vacuo and the residue was dissolved in methylene chloride and washed with water, 5% Na2CO3, and brine and dried (Na2SO4). The product was purified by flash column chromatography (silica, 50, 75, 90% ethyl acetate in hexane) to give 75 mg (50%) of a colorless amorphous solid. MS (ES) m/e 295.4 [M+H]+. c) 3-(2. 3.4. 5-Tetrahvdro-lH-3-benzazepin-3-vl)-N-phenvlpropanamine Amide from Exjimple lb (70 mg, 0.24 mmol) was dissolved in dry tetrahydrofuran (2.5 mL) and treated with lithium aluminum hydride (14 mg, 0.36 mmol). The reaction was refluxed for 3h. The reaction mixture was cooled to 0 °C and quenched with water (0.5 mL), 10% NaOH (0.5 mL), and water (0.5 mL). The solution was then stirred vigorously at room temperature for 15 min. The solution was diluted with ethyl acetate and dried over Na2SO4, filtered, and evaporated to give a dark colored oil. This material was dried under vacuum for 18h and then used directly for the following step. MS (ES) m/e 281.4 [M+H]+. d) N-f3-(2. 3.4. 5-Tetrahvdro-lH-3-benzazepin-3-vttpropyll-N-phenyl-3. 4- dinitrobenza ide hydrog Joride Diamine from Example lc was dissolved in methylene chloride (1.5 mL), cooled in an ice water bath, .and treated with 3, 4-dinitrobenzoyl chloride (41 mg, 0.18 mmol). After 30 min the cooling bath was removed and a thick solid beg.an to form. An additional 1.5 mL of methylene chloride was added and the reaction was stirred at room temperature for .an additional 2h. Dry diethylether was added and the solid was collected by filtration. Obtained 82 mg (67%, for two steps) of the title compound as an off-white powder. MS (ES) m/e 475.4 [M+H]+, free b.ase. Example 2: Preparation of N-f3-(7.8-dimethoxy-2.3.4. S-tetrahvdro-lH-3- benzazepin-3-vI)propyn-N-phenvN3.4-dinitrobenzamide hydrochloride This compound was prepared according to the procedure described for Example 1 substituting 7, 8-dimethoxy-2, 3, 4, 5-tetrahydro-lH-3-benzazepine hydrochloride for 2, 3, 4, 5-tetrahydro-lH-3-benz.azepine hydrochloride. Ruby glass. MS (ES) m e 535.4 [M+H]+. Example 3: Preparation of N-r3-(N , -methyl-2-phenylethylamino)propyll-N- phenyl-3.4-dinitrobenzamide This compound w.as prepared according to the procedure described for Example 1 substituting N-methylphenethylamine for 2, 3, 4, 5-tetrahydro-lH-3- benz.azepine hydrochloride. The title compound was purified by flash column chromatography (silica, 1, 2, 3% methanol in methylene chloride) to give a dark amber oil. MS (ES) m/e 463.4 [M+H]+. Example 4: Preparation of N-r3-(morpholin-4-yl)propyn-N-(3.4- dimethoχyphenyl)-3.4-dinitrobenzamide This compound was prepared according to the procedure described for Ex.ample 1 substituting morpholine for 2, 3, 4, 5-tetrahydro-lH-3-benz.azepine hydrochloride and 3-chloro-N-(3, 4-dimethoxyphenyl)propanamide for 3-chloro-N- phenylprop∑mamide. Amber gl.ass. MS (ES) m/e 475.4 [M+H] + . Example 5: Preparation of N-r3-(piperidin-l-yl)propyll-N-(3.4- dimethoxyphenyl)-3.4-dinitrobenzamide This compound was prepared according to the procedure described for Example 1 substituting piperidine for 2, 3, 4, 5-tetrahydro-lH-3-benzazepine hydrochloride and 3-chloro-N-(3, 4-dimetiιoxyphenyl)prop.an.amide for 3-chloro-N- phenylpropanamide. Amber glass. MS (ES) m/e 473.4 [M+H] + . Example 6; Preparation of N-f2-(N'. N'-dirnethylamino)ethyl1-N-phenyl-3.4- dinitrobenzamide hydrochloride N, N-Dimethyl-N'-phenylethylenedi.amine (165 mg, 1.00 mmol) was dissolved in dry methylene chloride, cooled to 0 °C, and treated with 3, 4- dinitrobenzoyl chloride (230 mg, 1.0 mmol). After 10 min the cooling bath was removed and the reaction was stirred for 16h at room temperature. A solid beg.an to form after lh. The reaction mixture was treated with diethyl ether (2 mL) and the pale yellow solid was filtered off, washed with diethyl ether and dried. Obtained the title compound (363 mg, 92%) .as a hydrochloride salt. MS (ES) m/e 359.3 [M+H]+, free base; 314.3 [M-NMe 2 ] + . Example 7; Preparation of N-(3-methylbutγl)-N-(3.4-dimethoχyphenyl)-3.4- dinitrobenzamide 3, 4-Dimethoxyaniline (1.0 g, 6.5 mmol) WJIS dissolved in methylene chloride and treated with triethylamine (1.5 mL, 10.7 mmol), 4-(N, N- dimethyl.amino)pyridine (80 mg, 0.65 mmol), .and cooled in an ice water bath. The reaction solution was treated dropwise with isovaleryl chloride (0.88 mL, 7.2 mmol). After the addition the cooling bath was removed and the reaction was allowed to stir at room temperature for 16h. The reaction was diluted with ethyl acetate and washed with water, 5% HC1, 5% Na2CO3, and brine. The organic layer was dried over Na2SO4, filtered, and evaporated to give a pinkish amorphous solid. The amide obtained above (475 mg, 2.0 mmol) was dissolved in dry tetrahydrofuran (10 mL) and treated with lithium aluminum hydride (115 mg, 3.0 mmol). The reaction was refluxed for 3.5h. The reaction mixture was cooled to 0 °C and quenched with water (1 mL), 10% NaOH (1 mL), .and water (1 mL). The solution w.as then stirred vigorously at room temperature for 15 min. The solution was diluted with ethyl .acetate and dried over Na2SO4, filtered, and evaporated to give a dark colored oil. The amine obtained above was dissolved in dry methylene chloride (5 mL), cooled in an ice water bath, and treated sequentially with triethylamine (0.61 mL, 4.37 mmol), 4-(N, N-dimethyl.amino)pyridine (25 mg, 0.2 mmol), and 3, 4- dinitrobenzoyl chloride (500 mg, 2.17 mmol). The cooling bath was removed and the reaction was stirred at room temperature for 4h. The reaction was diluted with ethyl acetate and washed with 5% HCl, 5% Na2CO3, and brine. The organic layer was dried over Na2SO4, filtered, and evaporated. The product was purified by flash column chromatography (silica, 25, 30, 35, 40% ethyl acetate in hexane) to give a yellow oil. Crystallization from ethyl acetate and hexane gave the title compound as a yellow crystalline solid. MP 92 -94 °C. Total yield was 626 mg (75% for two steps). Example 8; Preparation of N-methyl-N-phenyl-3.4-dinitrobenzamide N-Methyl.aniline (96.3 mg, 0.9 mmol) in dry methylene chloride (6 mL) was treated with triethylamine (101 mg, 140 uL, 1.0 mmol) followed by a solution of 3, 4-dinitrobenzoyl chloride (230 mg, 1.0 mmol) in methylene chloride ( 1.0 mL). The reaction solution was placed on a shaker overnight at room temperature. The solution was stripped to dryness; the solid WJIS triturated with ether (15 mL) and collected by filtration; the solids were rinsed with water and dried in vacuo to give the title compound as dusty shrimp colored cryst s (128 mg, 47%). *H NMR (400 MHz, CDC1 3 ) δ 7.86 (s,lH), 7.65 (dd, 2H), 7.26-7.36(m, 3H), 7.07 (d, 2H), 3.54 (s, 3H). Example 9; Preparation of N-(3. 4-dimethoxyphenyl)-3. -dinitrobenzamide This compound was prepared according to the procedure described for Example 8 substituting 3, 4-dimethoxy aniline for N-methylaniline. Orange amorphous solid. MS (ES) m/e 346.3 [M-H]". Example 10: Preparation of N-benzyl-N-phenyl-3.4-dinitrobenzamide This compound was prepared according to the procedure described for Example 8 substituting N-benzylaniline for N-methylaniline. *H NMR (250 MHz, CDC1 3 ) δ 7.87 (s, IH), 7.61-7.70 (m, 2H), 7.24-7.30 (m, 8H), 6.92 (s, 2H), 5.12 (s, 2H). Example 11: Preparation of N-isoproPyl-N-phenyl-3.4-dinitrobenzamide This compound was prepared according to the procedure described for Example 8 substituting N-isopropylaniline for N-methylaniline. *H NMR (250 MHz, CDCl 3 +MeOH-d ) δ 7.72 (s, IH), 7.58 (dd, 2H), 7.25-7.27 (m, 3H), 6.98- 7.00 (m, 2H), 4.93-5.03 (m, IH), 3.05-3.60 (m, 6H). Example 12: Preparation of N-(4-Pyridyl)-N-phenyl-3- 4-dinitrobenzamide This compound was prepared according to the procedure described for Ex,ample 8 substituting 4-aminopyridine for N-methylaniline. 1H NMR (400 MHz, CDCI3+ MeOH-d4) δ 8.46 (d, IH), 8.29-8.31 (m, 2H), 8.22-8.24 (dd, IH), 7.92 (d, IH), 7.61 (dd, 2H). Example 13: Preparation of N-(4-nitrophenyl)-3.4-Φ'nitrobenzamide This compound was prepared according to the procedure described for Example 8 substituting 4-nitroaniline for N-methylaniline. ^H NMR (400 MHz, CDCI3+ MeOH-d4) δ 8.44 (d, IH), 8.20-8.23 (m, IH), 8.04-8.07 (m, 2H), 7.90 (d, IH), 7.76-7.79 (m, 2H). Example 14: Preparation of N-(3-fluoro-2-methyl)phenyl-3.4- dinitrobenzamide This compound was prepared according to the procedure described for Ex.ample 8 substituting 3-fluoro-2-methylaniline for N-methylaniline. MS (ES) m/e 318.3 [M-H]-. Example 15: Preparation of N-(3.4-dichloro)phenyl-3.4-dinitrobenzamide This compound was prepared according to the procedure described for Example 8 substituting 3, 4-dichloroaniline for N-methylaniline. MS (ES) m/e 354.2, 356.2 [M-H]-. Example 16: Preparation of N-(4-phenoxy)phenyl-3.4-dinitrobenzamide This compound was prepared according to the procedure described for Example 8 substituting 4-phenoxyaniline for N-methylaniline. MS (ES) m/e 378.3 [M-H]". Example 17: Preparation of N-(2. . 6-trichloro)phenyl-3. 4-dinitrobenzamide This compound was prepared according to the procedure described for Example 8 substituting 2, 4, 6-trichloro.aniline for N-methyl.aniline. *H NMR (250 MHz, DMSO-d^) δ 8.60 (s, IH), 8.25-8.50 (m, 3H), 7.99 (s, IH). Example 18: Preparation of N-(4-bromo-2-methyl)phenyl-3.4- dinitrobenzamide This compound was prepared according to the procedure described for Example 8 substituting 4-bromo-2-methyl.aniline for N-methy ..aniline. MS (ES) m/e 378.1 [M-H]". Example 19: Preparation of N-(2. 2-diphenvI)ethyl-3, 4-dinitrobenzamide This compound was prepared according to the procedure described for Example 8 substituting 2, 2-diphenylethylamine for N-methylaniline. MS (ES) m/e 390.4 [M-H]". Example 20: Preparation of N-(3-methvHsoxazol-5-yl)-3.4-dinitrobenzam.de This compound was prepared according to the procedure described for Example 8 substituting 5-amino-3-methylisoxazole for N-methylaniline. MS (ES) m/e 291.2 [M-H]". Example 21: Preparation of N-(2.6-diethyl)phenyl-3.4-dinitrobenzamide This compound was prepared according to the procedure described for Example 8 substituting 2, 6-diethylaniline for N-methylaniline. ^H NMR (400 MHz, CDC1 3 ) δ 8.44 (d, IH), 8.23-8.25 (m, IH), 7.98 (d, IH), 7.69 (s.lH), 7.30- 7.34 (m, IH), 7.19 (d, IH), 2.60 (q, 4H), 1.20 (t, 6H). Example 22. Preparation of N-(5.6.7.8-tetrahvdronaphth-l-yl)-3.4- dinitrobenzamide This compound was prepared according to the procedure described for Example 8 substituting l-amino-5, 6, 7, 8-tetrahydronaphthalene for N- methylaniline. H NMR (250 MHz, DMSO-d 6 ) δ 8.73 (s, IH), 8.37-8.50 (m, 2H), 7.01-7.65 (m, 3H) 3.33 (s, 2H), 2.55-2.85 ( , 6H). Example 23: Preparation of N-(4-chloro-2-nitro)phenyl-3. 4- dinitrobenzamide This compound was propped .according to the procedure described for Example 8 substituting 4-chloro-2-nitroaniline for N-methylaniline. ^H NMR (250 MHz, DMSO-d 6 ) δ 8.72 (d, IH), 8.42-8.46 (m, 2H), 8.17 (d, IH), 7.91 (dd, IH), 7.71 (d, IH). Example 24: Preparation of N«(l-indolinyl)-3. 4-dinitrobenzamide This compound was prepared according to the procedure described for Example 8 substituting indoline for N-methylaniline. *H NMR (400 MHz, CDCl 3 +MeOH-d4) δ 8.06 (s, IH), 7.86-7.98 (dd, 2H), 7.17-7.19 (d, IH), 6.80-7.16 (m, 2H), 3.85-4.30 (m, 2H), 3.10 (t, 2H). Example 25: Preparation of N-(6-methyl-l. 2. 3. 4-tetrahvdroouinolin-l-vn-3. 4-dinitrobenzam.de This compound was prepared according to the procedure described for Example 8 substituting 6-methyl-l, 2, 3, 4-tetr.ahydroquinoline for N- methylaniline. *H NMR (400 MHz, CDCl 3 +MeOH-d 4 ) δ 7.93 (s, IH), 7.49-7.72 (dd, 2H), 7.27 (s, IH), 6.93 (s, IH), 6.63 (d, IH), 3.78-3.83 (m, 2H), 2.69-2.73 (m, 2H), 2.16 (s, IH), 1.95-1.98 (m, 2H). Example 26: Preparation of N-r2- ( 4-methyl p i p erazin-l-yl ) 1ethyl-N-phenyl-3. 4-dinitrobenzamide This compound was prepared according to the procedure described for Example 1 using chloroacetyl chloride, and N-methylpiperazine. MS (ES) m/e 414.5 [M+H]+. Example 27: Preparation of N-r2-(moroholin-4-vDlethyl-N-(2-methylphenyl)- 3. 4-dinitrobenzamide This compound was prepared according to the procedure described for Ex-ample 1 using chloroacetyl chloride ortho toluidine, and morpholine. MS (ES) m/e 415.4 [M+H] + . Example 28: N. N-Diphenyl-3.4-diπitrobenzamide A solution of diphenylamine (0.1 g, 0.59 mmol) in dry tetrahydrofuran ( 1.5 mL) was cooled to 0 °C and treated with sodium hydride (35 mg, 0.89 mmol). The resulting mixture w.as stirred at room temperature for 5 minutes, cooled to 0 °C, and treated with 3, 4-dinitrobenzoyl chloride (142 mg, 0.62 mmol). The resulting dirty red solution was gradually warmed to room temperature and stirred for 20 h. TLC revealed the presence of a small amount of the unreacted diphenylamine. A catalytic amount of 4-dimethyIaminopyridine (7.2 mg, 0.06 mmol) was added to the reaction mixture and the reaction was stirred for an additional 3 h. The reaction was diluted with methylene chloride and washed with 10% HCl, H2O, saturated NaHCO3, H2O, and brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vαcuo to give a reddish brown oil. Trituration of the crude oil with methanol afforded the title compound as a tan solid (66 mg, 31%). MS (ES) m/e 364.1 [M+H]+. The following compounds were prepared according to Example 8 using the appropriate amines and 3, 4-dinitrobenzoyl chloride unless otherwise noted. Example 29: N-f2-Methylphenyl)-3. 4-dinitrobenzamide *H NMR(400 MHz, CDCl 3 +MeOH-d 4 ) δ 8.50 (d, IH), 8.25 (dd, IH), 7.95 (d,. IH), 7.10 (m, 4H), 2.15 (s, 3H). Example 30: N-Methyl-N-(2-methylphenyl)-3.4-dinitrobenzamide MS (ES) m/e 316.3 [M+H]+, 339.3 [M+Na]+. Example 31: N--f2-Carboχyphenyl)-3.4-dinitrobenzamide MS (ES) m/e 330.2 [M-H]". Example 32: N-Methyl-N-(2-carboxyphenyl)-3.4-dinitrobenzamide MS (ES) m/e 344.3 [M-H]". Example 33: N-(Phenylmethyl)-3.4-dinitrobenzamide MS (ES) m/e 300.2 [M-H] * . Example 34: N-Methyl-N-(phenylmethyl)-3.4-dinitrobenzamide Mp 112-113 °C. Example 35: N-[2-(Aminocarbonyl)phenvπ-3.4-diπitrobenzamide 1H NMR (400 MHz, DMSO-d 6 ) δ 8.6 (m, 2H), 8.5 (m, 5H), 8.0 (m, IH), 7.6 (m, lH), 7.25 (m, IH). Example 36; N-r2-(Aminocarbonyl)phenvn-N-methyl-3. 4-dinitrobenzamide MS (ES) m/e 343.3 [M-H] " . Example 37: N-f2-(Trifluoromethyl )p henvπ-3. 4-dinitrobenzamide MS (ES) m/e 254.2 [M-H]-. Example 38: N-Methyl-N-r2-(trifluoromethvnphenvn-3. 4-dinitrobenzamide *H NMR (400 MHz, CDC1 3 ) δ 7.85 (s, IH), 7.65 (m, 5H), 7.35 (d, IH), 3.51 (s, 3H). Example 39: N-(2-Fluorophenyl)-3. 4-dinitrobenzamide MS (ES) m/e 304.3 [M-H]". Example 40: N-(2-Fluorophenyl)-N-methyl-3. 4-dinitrobenzamide MS (ES) m/e 320.1 [M+H]+ Example 41: N-f3-(Aminocarbonyl)phenvn-3. 4-dinitrobenzamide MS (ES) m/e 331.2 [M+H] + . Example 42: N-r3-(AminocarbonvDphenyl1-N-methyl-3. 4-dinitrobenzamide IH NMR (400 MHz, CDCl 3 +MeOH-d4) δ 7.72 (s, IH), 7.55 (m, 3H), 7.4 (m, IH), 7.15 (t, IH), 7.0 (d, IH), 3.3 (s, 3H). Example 43: N-Pyrazinyl-3. 4-dinitrobenzamide IH NMR (400 MHz, DMSO-d$) δ 9.4 (s, IH), 8.75 (s, IH), 8.52 (m, 2H), 8.45 (d, IH), 8.35 (d, IH). Example 44; N-Methyl-N-pyrazinyl-3. 4-dinitrobenzamide MS (ES) m/e 304.2 [M+HJ+. Example 45: N-(3-Methylpyridin-2-vD-3. 4-dinitrobenzamide MS (ES) m/e 303.3 [M+H]+. Example 46: N-Methyl-N-(3-methylpyridin-2-yl)-3. 4-dinitrobenzamide MS (ES) m/e 317.2 [M+H]+. Example 47: N-(2-Cvanophenyl)-3.4-dinitrobenzamide MS (ES) m/e 311.3 [M-H]". Example 48: N-(2-Cvanophenyl)-N-methyl-3., 4-dinitrobenzamide l NMR (400 MHz, CDCI3) δ 7.8 (s, IH), 7.75 (m, 2H), 7.65 (m, 2H), 7.45 (m, IH), 7.35 (m, IH), 3.5 (s, 3H). Example 49: N-(2-Methoxyphenyl)-3.4-dinitrobenzamide MS (ES) m/e 316.3 [M-H]". Example 50: N-(2-Methoxyphenyl)-N-methyI-3.4-dinitrobenzamide MS (ES) m/e 332.2 [M+HJ+. Example 51: N-(2-Biphenyl)-3.4-dinitrobenzamide MS (ES) m/e 362.3 [M-H]". Example 52: N-(2-Biphenyl)-N-methyl-3.4-dinitrobenzamide MS (ES) m e 378.1 [M+H]+. Example 53: N-(4-Methoxyphenyl)-N-methyl-3. 4-dinitrobenzamide *H NMR (400 MHz, CDCl3+MeOH-d4) δ 7.7 (s, IH), 7.6 (d, IH), 7.42 (dd, IH), 6.8 (d, 2H), 6.65 (d, 2H), 4.15 (s, 3H), 3.55 (s, 3H). Example 54: N-Methyl-N-f(2-trifluoromethoxy)phenyll-3.4- dinitrobenzamide !H NMR (400 MHz, CDCI3) δ 7.65 (s, IH), 7.55 (d, IH), 7.45 (d, IH), 7.2 (m, 3H), 7.05 (m, IH), 3.3 (s, 3H). Example 55: N-(2-Chlorophenyl)-N-methyl-3.4-dinitrobenzamide IH NMR (400 MHz, CDCI3) δ 7.92 (s, IH), 7.72 (m, 2H), 7.48 (m, IH), 7.35 (m, 3H), 3.46 (s, 3H). Example 56: N-r2-[(2-Furanylmethyl)aminocarbonvnphenvn-N-methyl-3.4- dinitrobenzamide MS (ES) m/e 425.3 [M+H]+. Example 57: N-Methyl-N-(l-naphthylmethyl)-3.4-dinitrobenzamide Mp 119.5-120.5 °C. Example 58: N-r2-(Methoxycarbonvπphenvn-N-methyl-3 t 4- dinitrobenzamide MS (ES) m/e 360.2 [M+H]+. Example 59: N-f2-f(2-(3.4-Dimethoxy p henyl ) ethyl)aminocarbonyl1phenyll-N- methyl-3 t 4-dinitrobenzamide MS (ES) m/e 509.2 [M+H]+. Example 60: N-Methyl-N-r2-[(2-phenylethyl)aminocarbonvnphenyll-3.4- dinitrobenzamide MS (ES) m/e 449.3 [M+H]+. Example 61: N-Pentafluorophenyl-3. 4-dinitrobenzamide Mp 161-164 °C. Example 62: N-(2.6-Dimethviphenyl)-3.4-dinitrobenzamide MS (ES) m/e 316.3 [M+H]+. Example 63; N-(3-Fluorophenyl)-3.4-dinitrobenzamide MS (ES) m/e 304.3 [M-H]". Example 64; N-(4-Fluorophenyl)-3.4-dinitrobenzamide MS (ES) m/e 304.3 [M-H]". Example 65: N-(2-Fluoro-5-methylphenvD-3. -dinitrobenzamide MS (ES) m/e 318.3 [M-H]". Example 66: N-(4-Methoxy-2-methylphenyl)-3.4-dinitrobenzamide MS (ES) m e 330.3 [M-H]'. Example 67: N-(2-IodophenvD-3., 4-dinitrobenzamide MS (ES) m/e 412.2 [M-H]". Example 68: N-(2-Chloro-3-methylphenyl)-3.4-dinitrobenzamide MS (ES) m/e 334.2 [M-H]". Example 69: N-(2. 4-Dimethylphenyl ) -3. 4-dinitrobenzamide MS (ES) m/e 314.4 [M-H] " . Example 70: N-r(2-Chlorophenyl)methvπ-3.4-dinitrobenzamide MS (ES) m/e 334.3 [M-H]-. Example 71; N-r(2-Methylphenyl)methvπ-3. 4-dinitrobenzamide MS (ES) m/e 314.4 [M-H]". Example 72: N-(3-Carboxyphenyl)-3., 4-dinitrobenzamide MS (ES) m/e 330.2 [M-H]-. Example 73: N-( -Carboxyphenyl)-3.4-dinitrobenzamide MS (ES) m/e 330.3 [M-H]". Example 74: N-(2. 6-Dichlorophenyl)-3. 4-dinitrobenzamide MS (ES) m/e 354.3 [M-H]'. Example 75: N-(l. 3.4-Thiadiazol-2-yl)-3. 4-dinitrobenzamide MS (ES) m/e 294.3 [M-H]'. Example 76: N-(l.2.4-Triazol-3-yl)-3.4-dinitrobenzamide MS (ES) m/e 296.2 [M+H]+; 294.3 [M-H]-. Example 77: N-(2-NaphthvD-3. 4-dinitrobenzamide *H NMR(400 MHz, DMSO-dό) δ 8.75 (d, IH), 8.51 (dd, IH), 8.42 (m, 2H), 7.82 (m, 4H), 7.48 (m, 2H). Example 78: N-(5-Ouinolinyl)-3. 4-dinitrobenzamide Mp 216-218 °C (dec). Example 79: N-(3-Pyridtnvn-3. 4-dinitrobenzamide MS (ES) m/e 289.2 [M+H]+. Example 80: N-(2-Pyridinyl)-3.4-dinitrobenzamide MS (ES) m/e 289.2 [M+H]+ Example 81: N-(6-Fluorobenzothιazol-2-γl)-3. 4-dinitrobenzamide MS (ES) m/e 363.3 [M+H]+ Example 82: N-(2-Hvdroχyphenyl)-3. 4-dinitrobenzamide MS (ES) m/e 302.3 [M-H]". Example 83: N-(l-Naphthyl)-3.4-dinitrobenzamide MS (ES) m/e 336.3 [M-H]-. Example 84: N-(Diphenylmethyl)-3. 4-dinitrobenzamide MS (ES) m/e 376.2 [M-H]". Example 85: N-[4-(N*. N , -Dimethylamino)phenvn-3. 4-dinitrobenzamide MS (ES) m/e 331.2 [M+H] + . Example 86: N-r2-(N'. N'-Dimethylamino)phenvn-3.4-dinitrobenzamide MS (ES) m/e 331.2 [M+H]+. Example 87: N-(2-Ethylphenyl)-3.4-dinitrobenzamide MS (ES) m/e 314.2 [M-H]". Example 88: N-(l-Indazolyl)-3.4-dinitrobenzamide !H NMR (400 MHz, CDC1 3 ) d 8.75 (s, IH), 8.56 (m, 2H), 8.27 (s, IH), 8.04 (d, IH), 7.84 (d, IH), 7.67 (t, IH), 7.49 (t, IH). Example 89: N»( -Benzimidazolyl)-3.4-dinitrobenzamide *H NMR (400 MHz, CDCI3) d 8.47 (s, IH), 8.24 (m, 4H), 7.86 (dd, IH), 7.53 (m, 2H). Example 90: N-f2-(2-Pyridyl)benzimidazol-l-vn-3.4-dinitrobenzamide J H NMR (400 MHz, CDCI3) d 8.34 (d, IH), 8.18 (s, IH), 7.95 (m, IH), 7.91 (m, IH), 7.87 (d, IH), 7.83 (m, 2H), 7.70 (m, 2H), 7.47 (m, IH). Example 91: N-r6-Methoxy-2-(methoxycarbonvnindol-l-vn-3.4- dinitrobenzamide This compound was prepared according to the procedure described for Example 28 substituting methyl 6-methoxy-2-indolecarboxylate for diphenylaniline. Orange yellow solid. *H NMR (400 MHz, CDCI3) d 8.19 (s, IH), 7.97-7.98 ( , 2H), 7.61 (d, IH), 7.53 (s, IH), 7.44 (s, IH), 7.03 (dd, IH), 3.90 (s, 3H), 3.63 (s, 3H). Example 92: N-(2. 3-Dimethoxyphenyl)-N-methyl-3. 4-dinitrobenzamide Mp 1 13-114 °C. Example 93: N-(2. 3.4.5-Tetrahvdro-lH-3-benzazepin-3-yl .-3. 4- dinitrobenzamide MS (ES) m/e 342.4 [M+H]+. Example 94: Pre p aration of N- ( 2. 3.4. 5-tetrahvdro-lH-l-benzazepin-l-vή-3. 4-dinitrobenzamide This compound was prepared according to the procedure described for Example 8 substituting 2, 3, 4, 5-tetrahydro-lH-l-benz.azepine for N- methyl-aniline. The 2, 3, 4, 5-tetr.ahydro-lH-l-benzazepine was prepared by the metiiod report by Yamamoto et al. in Tetrahedron Lett., 1983, 24, 471 1-4712. MS (ES) m/e 342.4 [M+H]+. Example 95: Preparation of N-(2-ethylphenyl)-N-methyl-3. 4- dinitrobenzamide A solution of the compound of Example 87 (109 mg, 0.35 mmol) in dry tetrahydrofurω (1 mL) under argon was cooled to 0 °C and added (dropwise!) potassium bis(trimethylsilyl)amide (1 mL, 0.53 mmol, 0.5 M solution in toluene). After stirring at 0 °C for 5 minutes, iodome±.ane was added to the reaction mixture and die re.action w.as graduidly warmed to room temperature and stirred for 20 hours. The reaction was diluted with methylene chloride and washed with H2O, 5% Na2CO3, and brine. The orga. nic layer was dried over Na2SO4, filtered, and concentrated in vacuo to give a reddish brown solid. The crude solid w.as purified by flash column chromatography (silica, 20, 30, and 40% ethyl acetate in hexane) to afford 37 mg (32%) of the title compound as a light yellow solid. MS (ES) m/e 330.2 [M+H]+. Example 96: Preparation of N-methyl-N-[2-f(4-methylpiperazin-l- yl)carbonvnphenyll-3. 4-dinitrobenzamide hydrochloride The carboxylic acid prepared in Example 32 (2.0 g, 5.8 mmol) in chloroform (25 mL) was treated with thionyl chloride (5 mL) and gently refluxed for 2 h. After cooling to room temperature the solvent and excess reagent were evaporated to give the acid chloride that was used without further purification. Acid chloride (200 mg, 0.55 mmol) was dissolved in dry methylene chloride (10 mL) and treated with N-methyl pipeline (55.5 uL, 0.5 mmol). The reaction was stirred overnight at RT. The solvent w.as evaporated and the resulting residue was triturated widi diediyl ether to give 99 mg of the desired product. MS (ES) m/e 428.3 [M+H]+. Example 97: Preparation of N-fr2-K3- methoχycarbonyl)phenyllaminocarbonyl1phenyll-N-methyl-3.4- dinitrobenzamide Prepared according to die procedure described for Ex∑unple 96 substituting methyl 3-.aminobenzoate for N-methylpiperazine. MS (ES) m/e 477.2 [M-H]-. Example 98: Preparation of N-methyl-N-rr2-r2-fN'. N » - dimethylamino phenyl1aminocarbonvnphenvn-3.4-dinitrobenzamide Prepared according to die procedure described for Example 96 substituting 2-(N, N-dimeti ylamino)aniline for N-methylpiperazine. MS (ES) m/e 464.3 [M+H]+. Example 99: Preparation of (Sl-N-methyl-N-rr2-ri-(tert-buto. vcarbonvn-2- phenylethvπaminocarbonvPphenyll-3.4-dinitrooenzam.de Prep-ared according to the procedure described for Example 96 substituting L-phenylalanine tert-butyl ester for N-methylpiperazine. MS (ES) m/e 547.1 [MH]" Example lOO: Preparation of N-fr2-f2- (ethoxycarbonyl)ethvnaminocarbonyllphenvn-N-methyl-3.4- dinitrobenzamide Prepared according to die procedure described for Example 96 substituting beta alanine ethyl ester for N-methylpiperazine. MS (ES) m/e 445.1 [M+H] + . Example 101: Preparation of (S)-N-r[2-fl -(aminocarbon yl)-2- phenylethyllaminocarbonyllphenyll-N-methyl-3. 4-dinitrobenzamide Prep.ared according to the procedure described for Example 96 substituting L-phenylalaninamide for N-methylpiperazine. MS (ES) m/e 492.1 [M+H]+. Example 102: Preparation of (S)-N-rf2-f l-carboxy-2- phenylethynaminocarbonyllphenvn-N-methyl-3.4-dinitrobenzamide Tert-butyl ester prepared in Example 99 (50 mg, 0.091 mmol) was treated with cold (0 °C) TFA (3 mL) and stirred at 0 °C for 0.5 h and then at RT for 2 h. Evaporation and trituration of the resulting residue with water gave 29 mg of the desired compound. Mp 96-106 °C. Example 103: Preparation of N-(2-ethylphenyl)-N-r2-(tert- butoxycarbonvPethyll-3.4-dinitrobenzamide a) Tert-butyl 3-(N-2-ethvlphenvnamino proprionate A solution of 2-ethylaniline (12.1g, 100 mmol), tert-butyl acrylate (12.8 g, 100 mmol), and glacial acetic acid (2.5 mL) was gently refluxed for 24 h. The solvents were evaporated under reduced pressure; die viscous residue was taken up in diediyl ether (200 mL) .and the resulting solution was washed in turn with dilute .aqueous sodium bicarbonate solution and water and dried ( Na2SO4). Evaporation of the solvent gave a viscous syrup which was purified by flash column chromatography (silica, 10, 15% ediyl acetate in hexane) to give 4.15 g ( 17%) of a viscous yellow oil. MS(ES) m/e 250.3 [M+H] + . b N- t / 2-Ethylphenvn-N-f2-ι / tert-butvloxvcarbonvl)ethvn-3. 4-dinitrobenzamide A solution of tert-butyl ester from Example 103a (498 mg, 2.0 mmol), 3, 4- dinitrobenzoyl chloride (483 mg, 2.0 mmol), and triethylamine ( 280 uL, 2.0 mmol) in methylene chloride (10 mL) was stirred overnight at room temperature. The reaction mixture was washed in turn witfi water, dilute aqueous sodium bicarbonate solution, dilute aqueous hydrochloric acid, and water and dried (Na2SO4). Evaporation provided 890 mg (100%) of the desired product as a viscous amber syrup. MS(ES) m/e 466.2 [M+Na] + . Example 104: Preparation of N-(2-carboxyethyl)-N-(2-ethylphenyl)-3.4- dinitrobenzamide N-(2-Emylphenyl)-N-[2-(tert-butyloxycarbonyl)ethyl]-3, 4- dinitrobenzamide (800mg, 1.80 mmol) from Example 103 was treated at room temperature with a solution of trifluoroacetic acid (20 mL) and methylene chloride (20 mL). The reaction solution was stirred at room temperature for 2 h. Evaporation provided a syrup that was crystallized from diethyl ether .and hexane to give 550 mg (79%) of the desired product. MS (ES) m/e 386.2 [M-H]". Example 105: Preparation of N-[2-(ethylaminocarbonyl)ethvn-N-(2- ethvIphenvO-3.4-dinitrobenzam.de A solution of the compound of Example 104 (150 mg, 0.387 mmol) in dry methylene chloride (15 mL) was cooled to 0 °C .and treated with oxalyl chloride (3.87 mL) and a ca ytic amount of N, N-dime ylformamide (5 uL). The resulting mixture was gradually warmed to room temperature and stirred for 20 hours. The methylene chloride and excess oxalyl chloride were removed at reduced pressure, and the resulting golden yellow oil (acid chloride) was pump- dried for 30 minutes and used directly in the following step. A solution of the crude .acid chloride (0.129 mmol) in methylene chloride (5 mL) was introduced into a cooled (0 °C) reaction mixture of ethylamine (77 uL, 0.155 mmol, 2M solution in tetrahydrofur∑in), triethylamine (27 uL, 0.19 mmol) and 4-dimethylaminopyridine (1 mg, 0.0065 mmol). After stirring for 1 hour, the reaction was diluted with methylene chloride .and w.ashed with 10% HCl, H2O, and brine. The organic layer was dried over Na2SO,4, filtered, and concentrated in vacuo to give a crude oil. The crude product was purified by flash column chromatography (silica, 1 and 5% metfranol in methylene chloride) to afford 46 mg (86%) of the title compound as a viscous golden yellow oil. MS (ES) m/e 415.3 [M+H]+. Example 106: Preparation of N-r2-(diethylaminocarbonyl)ethyll-N-(2- ethylphenyl)-3.4-dinitrobenzamide This compound was prepared according to the procedure described for Example 105 substituting dietiiylamine for ethylamine. Light yellow solid. MS (ES) m/e 443.2 [M+H]+. Example 107: Preparation of N-(2. 6-diisopropyl)phenyl-3.4- dinitrobenzamide This compound was prepared according to die procedure described for Example 8 substituting 2, 6-diisopropylaniline for N-methylaniline. White, amorphous solid. MS (ES) m/e 370.3 [M-H] " . Example 108: Preparation of N-[2-(aminocarbonyl)ethyll-N-(2-ethylphenyl)- 3. 4-dinitrobenzamide This compound was prepared according to die procedure described for Example 105 substituting ammonium hydroxide for ethyl-amine. Bright yellow solid. MS (ES) m/e 387.2 [M+H]+. Example 109: Preparation of N-(2.6-diethyl)phenyl-N-methyl-3.4- dinitrobenzamide This compound was prepared according to die procedure described for Example 95 substituting the compound of Example 21 for the compound of Example 87. Yellow solid. l H NMR (400 MHz, CDCI3) d 7.75 (s, IH). 7.60-7.67 (m, 2H), 7.26-7.30 (m, IH), 7.13 (d, 2H), 3.38 (t, 3H), 2.58-2.66 (m, 2H), 2.42- 2.52 (m, 2H), 1.24 (t, 6H). Example 110: Preparation of N-r2-[(l-piperidinyl arbonvnethyll-N-f2. ethylphenyl)-3. 4-dinitrobenzamide This compound was prepared according to die procedure described for Example 105 substituting piperidine for ethyl.amine. Pale yellow solid. MS (ES) m/e 455.3 [M+HJ+. Example 111: Preparation of N■^2-^(N , -benzγ|.N , - methylamino)carbonyllethvn-N-(2-ethylphenyl)-3.4-dinitrobenzamide This compound was prepared according to the procedure described for Example 105 substituting N-benzyl-N-methylamine for ethyl-amine. Golden yellow oil. MS (ES) m/e 491.2 [M+H]+. Example 112: Preparation of N-(2.6-diisopropyl)phenyl-N-methyl-3.4- dinitrobenzamide This compound was prepared according to die procedure described for Example 95 substituting die compound of Ex-ample 107 for the compound of Example 87. Light yellow solid. MS (ES) m/e 386.4 [M+HJ+. Example 113: Preparation of N-(2-n-butylphenyl)-3. -dinitrobenzamide This compound was prepa- red .according to the procedure described for Example 8 substituting 2-n-butylaniline for N-methylaniline. Off-white solid. MS (ES) m/e 342.3 [M-H]". Example 114: Preparation of N-(2-isopropylphenyl)-3., 4-dinitrobenzamide This compound was prepared according to the procedure described for Example 8 substituting 2-isopropylamiline for N-methyl.aniline. Off-white solid. MS (ES) m/e 328.1 [M-H] ' . Example 115: Preparation of N-(2-butvIphenyl)-N-methyl-3. 4- dinitrobenzamide This compound was prepared according to the procedure described for Ex.ample 95 substituting the compound of Example 113 for the compound of Example 87. Golden brown oil. *H NMR (400 MHz, CDC1 3 ) d 7.80 (s, IH), 7.61-7.68 (m, 2H), 7.16-7.29 (m, 3H), 7.08 (d, IH), 3.44 (t, 3H), 2.49-2.60 (m, IH), 2.35-2.45 (m, IH), 1.48-1.67 (m, 2H), 1.36-1.45 (m, 2H), 0.95 (t, 3H). Example 116: Preparation of N-r2-(morpholinocarbonyl ethyl1-N-(2- ethy|phenyl)-3. 4-dinitrobenzamide This compound was prepared according to the procedure described for Ex.ample 105 substituting morpholine for ethyl.amine. Pale amber glass. MS (ES) m/e 457.3 [M+H]+. Example 117. Preparation of N-f3-r ( diethylamino)carbonvπpropyπ-N-f2- ethylphenyl)-3.4-dinitrobenzamide a) N-r3-rfDiethvlamino carbonvllpropvn-2-ethvlaniline A solution of diethyl-amine (1.4 mL, 13.7 mmol) in methylene chloride (20mL) was cooled to 0 °C and treated witii triethylamine (2.1 mL, 15 mmol) and 4-chlorobutyryl chloride (1.7 mL, 15 mmol). The resulting mixture was gradually warmed to room temperature and stirred for 20 h. The reaction was diluted with methylene chloride and washed with 10% HCl, water, and brine. The organic layer was dried over Na2SO filtered, and concentrated in vacuo. The resulting crude oil was pump-dried overnight and used directly in the following step. A solution of 2-etiιylaniline (250 mg, 2.06 mmol) in N, N- dimediylformamide (6 mL) was treated with the crude chloride prepared above (550 mg, 3.1 mmol), triethylamine (0.48 mL, 3.4 mmol), and tetra-π- butylammonium iodide (74 mg, 0.2 mmol). The resulting mixture was stirred at 90 °C for 20 hours. The reaction was diluted with etiiyl acetate and washed with water, 10% HCl, water, and brine. The organic layer was dried over Na2SO filtered, .and concentrated in vacuo. The resulting crude oil was purified by flash column chromatography (silica, 20: 10:70 and 30: 10:60 etiiyl acetate-methylene chloride-hex.ane) to afford the title compound (215 mg, 40%) as a viscous light brown oil. 1H NMR (400 MHz, CDCI3) d lΛ l ( l > 1H )« 7 -06 (d, IH), 6.69 (t, IH), 6.61 (d, IH), 4.10 (bs, IH), 3.40 (m. 2H), 3.30 (m, 2H), 3.21 (t, 2H), 2.62-2.40 (m, 4H), 2.13-2.02 (m, 2H), 1.25 (t, 3H), 1.08-1.24 (m, 6H). b) N-r3-rfDiethvl a mino)carbonvllpropvn-N-r2-ethvIphenvn-3 4- dinitrobenzamidg A solution of the compound of Example 117(a) (211 mg, 0.807 mmol) in methylene chloride (2.2 mL) was cooled to 0 °C and treated with triethylamine (0.12 mL, 0.85 mmol) and 3, 4-dinitrobenzoyl chloride (195 mg, 0.85 mmol). The resulting mixture was gradually warmed to room temperature and stirred for 20 h. The reaction was diluted with methylene chloride and washed witii 10% HCl, water, and brine. The organic layer was dried over Na2SO filtered, and concentrated in vacuo. The resulting crude oil was purified by flash column chromatography (silica, 30:10:60, 40:10:50, and 50:10:40 ediyl .acetate-methylene chloride-hexωe) to afford die tide compound (242 mg, 66%) as a golden yellow oil. MS (ES) m/e 457.1 [M+H]+. Example 118. Preparation of N-(3-oxo-3-phenylpropyl)-N-(2-ethylphenyl)-3. 4-dinitrobenzamide This compound was prepared according to die procedure described for Example 117 substituting 3-chloropropiophenone as the a . lkylating agent. MS (ES) m/e 917.1 [2M+Na]+ 1364 [3M+Na] + . BIOLOGICAL DATA Effect of Compounds on the CGRP Receptor The test compounds were assayed for die inhibition of [ 125 I ] CGRP (obt∑tined from Amersham, Chicago, TL) binding and CGRP-activated adenylate cycl.ase activity. SK-N-MC cells were obtained from American Type Culture Collection (Rockville, MD) .and grown in Minimum Essential Media ("MEM") medium containing fetal calf serum (10%). Cells were grown in T- 150 flasks or Costar multiwell plates (24 well) and maintained at 37 °C in a 90% humidified incubator with .an atmosphere of 5% CO2 and 95% air. rl25n CGRP Binding assav: SK-N-MC cells were homogenized in 5 mM Tris-HCl pH 7.4, 10 mM Na- EDTA and the homogenate was centrifuged at 48,000 g for 20 min at 4 °C. The pellet was resuspended in 20 mM Na-HEPES pH 7.4, 10 mM MgCl2 and recentrifuged as above. The membrane pellets were resuspended in the same buffer .and stored frozen at -70 °C. The protein concentration was measured by the Pierce BCA method using bovine serum .albumin as the standard. The [ 125 I] CGRP receptor binding assay was performed using a buffer containing 20 mM Na-HEPES pH 7.4, 10 mM MgCh, 0.05% BSA and 0.1 mg/mL bacitracin. The membranes (50 ug protein/mL) were incubated with various concentrations (1, 10, 30, 60 and 100 uM) of die test compounds and 40 pM [ 125 I] CGRP in a total volume of 500 uL. for 60 min at 25 °C. The reaction was terminated by addition of 2 mL ice-cold 0.9% NaCl, followed by rapid filtration through Skatron Filtermates presoaked in 0.5% polyethylenimine PEI). The filters were rinsed twice with 2 mL of cold 0.9% NaCl and the radioactivity counted in a gamma counter. All binding data was analyzed by computer assisted LIGAND 2 program. Adenylate cvclase activity: Adenylate cyclase activity was measured in triplicate as die rate of conversion of α[ 32 P]ATP to [ 32 P]c.AMP as previously described (Aiyer et al., Endocrinology, Vol. 129, pp 965-969 (1991)). Human neuroblastoma cell ( SK-N- MC ) membranes [40-60 μg] were incubated in triplicate in buffer cont ning 50 mM Tris-HCl (pH 7.4), 10 nM MgCl 2 , 1.2 mM ATP, 1.0 μCi α[ 32 P] ATP, 0.1 mM cAMP, 2.8 nM phosphoenolpyruvate .and 5.2 μg/ml myokinase in a final volume of 100 μl for 20 min at 30°C. The reactions were stopped witii 1 ml solution containing cAMP, ATP and 22000 cpm of [ 3 H] cAMP. [ 32 P]cAMP was separated using sequential chromatography (Dowex and alumina columns) (Salmon et al., Anα..Biochem. Vol. 58, pp. 541-548 (1974)). Adenylate cyclase activities were determined in the absence (basal) or presence of 2.5 nM of hCGRPα with various concentrations (0.1 μM to 30 μM ) of compound. The compounds of this invention show CGRP receptor antagonist activity having IC50 values in die range of 0.001 to 100 μM. The full structure/activity relationship has not yet been established for die compounds of this invention. However, given die disclosure herein, one of ordinary skill in the an can utilize d e present assays in order to determine which compounds of formula (I) are ligands of the CGRP receptor and which bind thereto with an IC50 value m me range of 0.001 to 100 μM. All publications, including, but not limited to, patents and patent applications cited in this specification, are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth. The above description fully discloses the invention including preferred embodiments thereof. Modifications and improvements of the embodiments specifically disclosed herein are widiin the scope of the following claims. Without further elaboration it is believed tiiat one skilled in the art can, given the preceding description, utilize the present invention to its fullest extent. Therefore any examples are to be construed as merely illustrative and not a limitation on the scope of the present invention in any way. The embodiments of die invention in which .an exclusive property or privilege is claimed are defined as follows.

Claims: What is claimed is: 1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: Formula (I) wherein: R 1 is hydrogen, methyl, -(CH2) n . branched (3-6 carbon) alkyl, -(CH2)nphenyl, -{CH 2 ) n -N X V( » , wherein X is CH2, oxygen or N-alkyl, or R 1 is (CH ) n f^R 3 R 4 , or (CH 2 ) n Z. wherein Z is CO H, CO 2 -alkyl, CONR 3 R 4 , -N(R 3 )CO 2 R 3 . -N(R 3 )C(O)NR 3 R 4 , -OC(O)NR 3 R 4 , or COR 5 , and wherein R 3 and R 4 are independendy hydrogen, Ci^alkyl or Cj^alkylphenyl, or together with the nitrogen to which they are attached, form a 5-, 6-, or 7-membered heteroring, wherein the heteroring is optionally fused to an optionally substituted phenyl ring, .and R 5 is metiiyl, trifluoromethyl, C2-6alkyl, phenyl or heteroaryl; R2 is optionally substituted aryl or heteroaryl, or R^ is A-Ar, wherein A is lower alkyl (C1.4) or br.anched alkyl, wherein a branch may contain a substituted phenyl ring, and Ar is substituted phenyl or a substituted 5- or 6-membered hetercaryl ring which optionally contains one or more heteroatoms selected from N, O or S, or R^ wherein W is OH, NR 3 R 4 , O-alkyl, an amide derived from an amino acid, NR^R 7 , where R<> is H, alkyl, and R 7 is aryl or substituted aryl, (CH2) n -aryl, (CH2) n -substituted aiyl, (CH2) n -heteroaryl, or (CH2) n -Z; or Rl and R^ together witii the nitrogen to which they are attached form a 5- or 6- membered heteroring fused to an optionally substituted phenyl ring; m is 1 to 3; and n is 1 to 6, provided that the compound is not N-3-(2,3,4,5-tetr.ahydro-7,8- dimethoxy-l-H-3-benzazepine-3-yl)propyl]-N-(3,4-dimethoxyphenyl)-3,4- dinitrobenz.amide or N-phenyl-3,4-dinitrobenzamide. 2. The compound as claimed in claim 1 selected from: N-(2-edιylphenyl)-N-[2-(tert-butoxycarbonyl)ethyl]-3, 4-dinitrobenz.amide; N-[2-(morpholinocarbonyl)ethyl]-N-(2-ethylphenyl)-3, 4-dinitrobenz.amide; N-[2-(ethylaminocarbonyl)ethyl]-N-(2-ethylphenyl)-3, 4-dinitrobenzjunide; N-[2-(diethylaminocarbonyl)ethyl]-N-(2-ethylphenyl)-3, 4-dinitrobenzamide; N-[2-[(l-piperidinyl)c j ιrbonyl]ethyl]-N-(2-ethylphenyl)-3, 4-dinitrobenz.amide; N-[3-[(dieώyi.amino)c.arbonyl]propyl]-N-(2-ethylphenyl)-3, 4-dinitrobenzamide; N-(3-oxo-3-phenylpropyl)-N-(2-ethylphenyl)-3, 4-dinitrobenz∑ιmide; N-Methyl-N-(2-methylphenyl)-3, 4-dinitrobenzjιmide; N-(2-ethylphenyl)-N-methyl-3, 4-dinitrobenz.amide; N-(2, 6-diedιyl)phenyl-N-methyl-3, 4-dinitrobenz.amide; N-[3-(2, 3, 4, 5-terώydro-lH-3-benzazepin-3-yl)propyl]-N-phenyi-3, 4- dinitrobenz.amide ; N-[3-(7, 8-dimedιoxy-2, 3, 4, 5-terahydro-lH-3-benzazepin-3-yl)propyl]-N- phenyl-3, 4-dinitrobenz.amide; N-[3-(N'-methyl-2-phenyledιylamino)propyl]-N-phenyI-3, 4-dinitrobenzamide; N-[3-(moφholin-4-yl)propyl]-N-(3, 4-dimedιoxyphenyl)-3, 4-dinitrobenzamide; N-[3-(piperidin- 1 -yl)propyl]-N-(3, 4-dimedιoxyphenyl)-3, 4-dinitrobenzamide; N-[2-(N', N'-dimedιylamino)ethyl]-N-phenyl-3, 4-dinitrobenz.amide; N-(3-methylbutyl)-N-(3, 4-dimedιoxyphenyl)-3, 4-dinitrobenz∑unide; and N-methyl-N-phenyl-3, 4-dinitrobenzamide. 3. A pharmaceutical composition comprising a compound of formula (I) according to claim 1 and a pharmaceutically acceptable carrier. 4. A metiiod of treating a CGRP-mediated disease state in mammals which comprises administering to a mammal in need of such treatment, an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof: Formula (I) wherein: R 1 is hydrogen, methyl, -(CH2) n . branched (3-6 carbon) alkyl, -(CH2)nphenyl, -(CH-) n -N X (CH m W herein X is CH2, oxygen or N-alkyl, or R 1 is (CH2) n .NR 3 R 4 , or (CH 2 ) n Z, wherein Z is CO 2 H, CO 2 -alkyl, CONR 3 R 4 , -N(R 3 )CO 2 R 3 , -N(R 3 )C(O)NR R 4 , -OC(O)NR 3 R 4 ,or COR 5 , and wherein R 3 and R 4 are independently hydrogen, Cj^alkyl or Chalky lphenyl, or together with the nitrogen to which they are attached, form a 5-, 6-, or 7-membered heteroring, wherein the heteroring is optionally fused to an optionally substituted phenyl ring, and R 5 is methyl, trifluoromethyl, C2-6 lkyl, phenyl or heteroaryl; R2 is optionally substituted aryl or heteroaryl, or R^ is A-Ar, wherein A is lower alkyl (C^) or branched alkyl, wherein a branch may contain a substituted phenyl ring, and Ar is substituted phenyl or a substituted 5- or 6-membered heteroaryl ring which optionally contains one or more heteroatoms selected from N, O or S, or R^ wherein W is OH, NR 3 R 4 , 0-alkyl, .an .amide derived from an amino acid, NR6R7, where R > is H, alkyl, and R 7 is aryl or substituted aryl, (CH2) n -aryl, (CH2) n -substituted aryl, (CH2) n -heteroaryl, or (CH2) n -Z; or Rl and R^ togedier witii die nitrogen to which tiiey are attached form a 5- or 6- membered heteroring fused to an optionally substituted phenyl ring; m is 1 to 3; and n is 1 to 6, provided diat die compound is not N-3-(2,3,4,5-tetr.ahydro-7,8- dimethoxy- 1 -H-3-benzazepine-3-yl)propyl]-N-(3,4-dimethoxyphenyl)-3,4- dinitrobenzamide or N-phenyl-3,4-dinitrobenzamide. 5. The method as claimed in claim 4 wherein the compound of formula (I) is a compound selected from: N-(2-ethylphenyl)-N-[2-(tert-butoxycarbonyl)ethyl]-3, 4-dinitrobenz.amide; N-[2-(morpholinocarbonyl)ethyl]-N-(2-ethylphenyl)-3, 4-dinitrobenzamide; N-[2-(ethylaminocarbonyl)ethyl]-N-(2-ethylphenyl)-3, 4-dinitrobenzamide; N-[2-(diethyl.aminocarbonyl)ethyl]-N-(2-ethylphenyl)-3, 4-dinitrobenzamide; N-[2-[(l-piperidmyl)carbonyl]ethyl]-N-(2-ethylphenyl)-3, 4-dinitrobenz.arnide; N-[3-[(diethylamino)carbonyl]propyl]-N-(2-ethylphenyl)-3, 4-dinitrobenzamide; N-(3-oxo-3-phenylpropyl)-N-(2-ethylphenyl)-3, 4-dinitrobenz.amide; N-Methyl-N-(2-methylphenyl)-3, 4-dinitrobenz.aπιide; N-(2-ethylphenyl)-N-methyl-3 , 4-dinitrobenzamide; N-(2, 6-diethyl)phenyl-N-methyl-3, 4-dinitrobenzamide; N-[3-(2, 3, 4, 5-terahydro-lH-3-benzazepin-3-yl)propyl]-N-phenyl-3, 4- dinitrobenz.amide; N-[3-(7, 8-dimethoxy-2, 3, 4, 5-terahydτo-lH-3-benz.azepin-3-yl)propyl]-N- phenyl-3, 4-dinitrobenzamide; N-[3-(N , -methyl-2-phenylethyl.amino)propyl]-N-phenyl-3, 4-dinitrobenz.amide; N-[3-(morpholin-4-yl)propyl]-N-(3, 4-dimethoxyphenyl)-3, 4-dinitrobenzamide; N-[3-(piperidin- 1 -yl)propyl]-N-(3, 4-dimetiιoxyphenyl)-3, 4-dinitrobenz.amide; N-[2-(N', N'-dimedιyl.amino)ethyl]-N-phenyl-3, 4-dinitrobenz.amide; N-(3-medιylbutyl)-N-(3, 4-dimedαoxyphenyl)-3, 4-dinitrobenz.amide; .and N-methyl-N-phenyl-3, 4-dinitrobenzamide. 6. A process for preparing a compound defined in claim 1 having die structure of formula (I) Formula (I) which comprises reacting a suitable acid chloride compound derived from 3, 4- dinitrobenzoic acid, with a compound of formula (H) M Formula (II) wherein Rl and R^ are defined in cl-aim 1, in the presence of an .amine base.

Inventors: DAINES ROBERT A, DAINES, ROBERT, A.
Applicants: DAINES ROBERT A, SMITHKLINE BEECHAM CORP, DAINES, ROBERT, A., SMITHKLINE BEECHAM CORPORATION
Application year: 1997
Main classification: A61K31
IPC codes: A61K31, A61P3, A61P9, A61P11, A61P17, A61P19, A61P25, A61P29, A61P37, A61P43, C07C233, C07C237, C07C255, C07D209, C07D213, C07D215, C07D223, C07D231, C07D235, C07D241, C07D249, C07D251, C07D261, C07D277, C07D285, C07D295, C07D307, C07D401