This invention relates to novel trisubstituted aromatic amines, pharmaceutical compositions containing them, and methods of using them in mammals to treat cognitive deficiencies, neurological dysfunction, and mood disturbances .

BACKGROUND OF THF. TNVENTTON

Nervous system disorders cause cognitive and neurological deficiencies and are becoming more prevalent in today's society. These disorders are the direct result of degenerative changes in the nervous system. Specific neurological systems are directly affected in the early stages of some diseases. Multiple neurotransmitter system deficiencies are generally found at later stages of diseases such as senile dementia, multi-infarct dementia, Huntington's disease, etc. This may explain the generally observed symptomology including cognitive, neurological and effective/psychotic components (see Gottfries, Psyrhopharmacol . ££, 245, 1985) . Deficits in the synthesis and release of acetylcholine in the brain are generally thought to be related to cognitive impairment (see Francis et al, New England J. M .. 211, 1, 1985) .

Recent treatment strategies include vasoactive drugs like vincamine and pentoxif lline; "metabolic enhancers" like ergoloid mesylates, piracetam and naftidrofuryl; neurotransmitter precursors like 1-DOPA, choline and 5- hydroxytryptamine; metabolizing enzyme inhibitors like physostigmine; and neuropeptides like ACTH and vasopressin- related peptides. Another strategy is to enhance the residual function of the affected systems by enhancing the stimulus-induced release of neurotransmitters . Such an enhancement might improve the signal-to-noise ratio during chemical transmission of information, thereby reducing deficits in processes related to cognition, neurological function and mood regulation.

SUBSTITUTE SHEET

Cook, L. , et al . , Drug Development Research 19:301-314 (1990), Nickolson, V.J., et al. , Drug Development Research 19:285-300 (1990), and DeNoble, V. J., et al., Pharmacology Biochemistry & Behavior, Vol. 36, pp. 957-961 (1990), all have shown by invi tro testing that the drug DuP 996, 3.3- bis (4-pyridinylmethyl) -l-phenylindolin-2-one, is useful in the treatment of cognition dysfunction.

Saletu, B., et al . , Br. J. Clin. Pharmac. (1989), 28, 1-16, suggested that DuP 996 may exhibit indirect action or may have an active metabolite, and that three metabolites have been identified, a mono-N-oxide, a bis-oxide and a C- dealkylated alcohol. Chem. Abstracts 111 (13) :108875p suggests that the following structure is one of the above named metabolites of Dup 996:

Neither reference presented chemical data to support their hypothesis . European Patent Application 311,010, published April 12, 1989, discloses that α,α-disubstituted aromatics or heteroaromatics of the formula:

or a salt thereof which are useful as cognition enhancers. U.S. Patent no. 4,7 ^' 60,083, issued to Myers et al. on July 26, 1988, discloses that indolines .of formula:

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are useful for treatment of Cognitive deficiencies. These references teach the necessity of heteroaryl groups for activity.

Patent WO 91/01/306, Feb. 7, 1991 discloses oxindole derivatives of formula:

useful for treating senile dementia, i.e. improving brain functions and activating and protecting brain metabolism. This reference only discloses imides and does not suggest alkyl or aryl substituted amides .

EP415-102-A discloses a series of 1, 3-dihydro-l- (pyridinylamino) -2H-indol-2-ones of formula:

which possess analgesic, anticonvulsant, and/or memory enhancing activity and which are useful in the treatment of Alzheimer's disease.

SUMMARY OF THE TNVENTTON

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In the present inevn ion, it has been discovered that certain trisubstituted aromatic amines having a broad ring core structure and pendant hetrocyclic groups enhance the stimulus-induced release of neurotransmitters, specifically acetylcholine, dopamine and serotonin in nervous tissue and improve processes involved in learning and memorization of an active avoidance test.

Accordingly, the present invention provides compounds of formula:

wherein:

A is (CH2) _m wherein m is 0 or 1, C=S, 0, S, SO, SO ₂ , NR ₃ , C=0, or C=N0H;

J, K, L and M independently are selected at each occurrence from the group including N, CR ₃ , CR ₄ or CR ₅ ;

R _l may be phenyl, 2-, 3-, or 4-pyridyl, 2- or 3- thienyl, 2- or 3-furyl, 2-, 4-, or 5-pyrimidyl, 2-pyrazinyl, 3- or 4-pyridazinyl, 3- or 4- pyrazolyl, 2- or 3-tetrahydrofuranyl, or 3- indolyl;

R ₂ may be phenyl, 2, 3, or 4-pyridyl, 2 or 3-thienyl, 2 or 3-furyl, 2, 4, or 5-pyrimidyl, 2 or 3- tetrahydrofuranyl, 2-pyrazinyl, 3 or 4- pyridazinyl, 3 or 4-pyrazolyl, or 3-indolyl when n = 1,

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-C0 ₂ R ₆ , -OR , -N(R ₈ ) ₂ , -NHCORg, when n = 1-4

-CN when n = 1-6, and

-CH ₃ when n = 1-12;

R ₃ , R ₄ and R ₅ independently are selected at each occurrence from the group consisting of H, halo, C ₁ -C ₃ alkyl, C ₁ -C ₃ acyl, OR ₁₀ , NO ₂ , CN, NR10 11 or fluoroalkyl of 1-3 carbon atoms, alternatively, R ₅ may be taken together with R ₃ to form a 2, 3- or a 3, 4-fused benzo ring;

R ₆ , R ₇ , R8» and R ₉ independently are selected at each occurrence from the group consisting of C ₁ -C ₃ alkyl, phenyl, and benzyl;

Ri _O and Rn independently are selected at each occurrence from the group consisting of H, C ₁ -C ₃ alkyl and C ₁ -C ₃ acyl;

n is 1-14;

Y is 0 or 2 hydrogen atoms; and

the Z ring may be a five or six membered ring;

PREFERRED EMBODIMENTS Preferred compounds of the present invention are those wherein:

A is (CH2) _m ^{anc m} is 0;

J, K, L and M independently are selected at each occurrence from the group including N and CR ₃ wherein R ₃ is H;

R _l is 2-, 3-, or 4-pyridyl or 2-, 4-, or 5-pyrimidyl;

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R ₂ is 2-, 3-, or 4-pyridyl, or 2-, 4-, or 5-pyrimidyl when Ri = R ₂ and n = 1, and -C0 ₂ R ₆ when n = 2-3 and Rζ is C ₁ -C3 alkyl, and -CN when n = 2-4; and

R3, R ₄ and R ₅ are H.

Specifically preferred compounds of the present invention are:

N,N-bis- (2-pyridylmethyl)-9-aminofluorene;

N,N-bis- (4-pyridylmethyl) -9-aminofluorene;

N,N-(4-pyridylmethyl) amino-1, 5'- (5H)-Cyclopenta(2, 1- B:3, 4-B' ) dipyridine;

N,N- (2-pyridylmethyl)amino-l, 5'- (5H)-Cyclopenta (2, 1- B:3, 4-B' ) dipyridine;

N,N- (4-pyrimidylmethyl)amino-1, 5 '- (5H) -Cyclopenta(2,1- B:3, 4-B') dipyridine; and

N,N- (4-pyrazinylmethyl)amino-1, 5 '- (5H) -Cyclopenta (2, 1- B:3, 4-B' ) dipyridine.

DETAILED DESCRIPTION OF THE INVENTION The compounds of the present invention may be prepared by a variety of different methods using techniques well known to those skilled in the art of organic synthesis.

The starting materials needed to prepare the compounds of the present invention are commercially available or may be prepared by known methods .

For example, Scheme 1 shows a generally applicable method for the synthesis of compounds of formula (I) wherein Y is 2 hydrogen atoms. This method is a one step procedure that entails a displacement reaction between an aromatic halide or sulfonate of formula (II) and a

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disubstituted amine of formula (III), which has Y = 2 hydrogen atoms, to give the corresponding compound of formula (I) . Aromatic halides and sulfonates of formula (II) are generally commercially available or can be prepared using standard methods known to those skilled in the art. The disubstituted amines of formula (III) are commercially available or can be prepared using standard methods known to those skilled in the art.

In a typical reaction, the aromatic halide or sulfonate of formula (II) and the disubstituted amine of formula (III) are combined in an inert solvent, in the presence of a suitable base, and stirred. The reaction is monitored by thin layer chromatography until complete, and then worked-up. Work-up involves cooling the reaction and filtering the resultant precipitate. Then the solvent is evaporated and the residue is purified either by chromatography or recrystallization.

Suitable bases are those bases which are capable of deprotonating the tertiary amine reaction product, but which will not react with the aromatic halide or sulfonate. Particularly preferred are alkali metal carbonates such as potassium carbonate.

The inert solvent is selected from the group including lower alkyl alcohols of 1 to 6 carbons, dialkylketones, dialkylsulfoxides, alkanenitriles, halocarbons of 1 to 6 carbons, dialkylformamides of 2 to 6 carbons, dialkylacetamides of 3 to 7 carbons, or aromatic or non- aromatic hydrocarbons of 6 to 10 carbons. Preferred solvents are acetone and dimethylsulfoxide. The reaction may be carried out at a temperature between 0° and 200°C. It is preferrable to carry out the reaction between 25°C and 150°C.

Scheme 1

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(ID (I)

The method of Scheme 1 is further illustrated in Equation 1 which shows the reaction of the commercially available 9-bromofluorene and disubstituted amine of formula (III) . The resultant product is a compound of formula (I) wherein J, K, L, and M are CH and A is CH2.. and Ri and R ₂ are as defined for formula (I) above.

Scheme 2 shows a process which affords, sequentially, compounds of formula (I) wherein Y = O and compounds of formula (I) wherein Y is 2 hydrogen atoms. In the first step of this method an aromatic amine of formula (IV) is reacted with an acid derivative, R ₂ (CH ₂ ) _n COX, to give an amide which is a compound of formula (I) wherein Y = 0. The amide of formula (I) is then reacted with a reducing agent to give the compound of formula (I) wherein Y = 2 hydrogen

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atoms. The starting aromatic amines of formula (IV) may be prepared as discussed below. Acid derivatives represented by formula, R ₂ (CH ₂ )nCOX, wherein X is halogen, alkoxy, aryloxy, -ON-hydrosuccina ide, or R ₂ (CH ₂ ) _n C (=0) 0-, are generally commercially available or can be prepared using standard methods known to those skilled in the art.

Step one of Scheme 2 is the reaction of an aromatic amine of formula (IV) with an acid derivative, R ₂ (CH ₂ ) _n COX, to give an amide of formula 1. This reaction can be carried out utilizing any of a great many methods known to those skilled in the art of organic synthesis. For example, Greene, Protective Groups in Organic Synthesis. page 249 (John Wiley & Sons 1981), which is hereby incorporated by reference, teaches many methods for the preparation of amides . The following procedure is offered to further illustrate the preparation of amide intermediates: First, the aromatic amine of formula (IV) is dissolved in an solvent such as methylene chloride and then a suitable base such as triethyl amine is added in excess. Next, the acid derivative, R ₂ (CH ₂ ) _n OX, is added to the reaction at 0-25 °C and the resulting reaction is monitored by thin layer chromatography. Work-up involves pouring the reaction into water, extracting with chloroform, drying of the separated organic layer and removal of solvent. Chromatography or direct recrystallization gives the purified amide of formula (I) .

Step 2 of Scheme 2 is reaction of the amide of formula (I) prepared in Step 1, with a reducing agent to give the corresponding compound of formula (I) wherein Y is 2 hydrogen atoms. The reduction of amides to afford amines is a reaction well known to those skilled in the art of organic synthesis. The general procedure entails dissolving the amide of Step 1 in an inert solvent, mixing with a suitable reducing agent, and stirring the resultant mixture until the reduction is complete. Suitable reducing agents include alkali metal aluminum hydrides such as lithium aluminum hydride, alkali metal borohydrides such as lithium borohydride, alkali metal trialkoxyaluminum

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hydrides such as lithium tri-t-butoxyaluminum hydride, dialkylaluminum hydrides such as di-isobutylaluminum hydride, borane, dialkylboranes such as di-isoamyl borane, alkali metal trialkylboron hydrides such as lithium triethylboron hydride. The preferred reducing agent is lithium aluminum hydride. Inert solvents may be selected from the group including lower alkyl alcohols of 1 to 6 carbons, ethereal solvents such as diethyl ether or tetrahydrofuran, aromatic or non-aromatic hydrocarbons of 6 to 10 carbons. Preferred solvents are ether and tetrahydrofuran. The temperature and duration of the reaction is determined by the substrate. The reduction may be carried out at a temperature between -78° to 200°C. The preferred reaction temperature is the reflux temperature of the reaction mixture. The reaction is monitored by thin layer chromatography and when complete the excess reducing reagent is quenched with water. Work-up of the reaction depends on the substrate and reducing agent used, howerver, when lithium aluminum hydride is used as the reducing agent, work-up involves adding 3 M sodium hydroxide solution, dilution with ethyl acetate, addition of a drying reagent to absorb excess water, and finally filtering through celite and removal of the solvent . Chromatography or direct recrystallization gives the purified compound of formula (I) .

Scheme 2

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SUBSTITUTE SHEET

2. Reducing agent

(I), Y = 2 hydrogen atoms

An alternative method for the preparation of compounds of formula (I) is shown in Scheme 3. This method involves alkylation of an aromatic amine of formula (IV) with an alkylating agent, R ₂ (CH ₂ ) _n X wherein X is Cl, Br, I, OS(0) ₂ CH ₃ , OS(0) ₂ C ₆ H ₄ -CH ₃ , or OS(0) ₂ CF ₃ . The alkylating agents of formula R2(CH2) _n ^χ are commercially available or can be prepared using standard methods known to those skilled in the art. Alkylation of an amine with a suitable electrophile is a widely used procedure for preparing secondary amines. The procedure is similar to the alkylation reaction described in Scheme 1 for preparation of compounds of formula (I) and the methods described for that procedure are applicable here.

Scheme 3 -11-

SUBSTITUTE SHEET

(I), Y is 2 hydrogen atoms

Compounds of formula (IV) may be conveniently prepared by the method shown in Scheme 4. The method entails reductive amination of an aromatic amine of formula (V) and an aldehyde of formula RiCHO. Aromatic amines of formula (V) are commercially available or can be prepared using standard methods known to those skilled in the art . Aldehydes of formula RiCHO are commercially available or can be prepared using standard methods known to those skilled in the art. Reductive amination is a widely used method for preparing secondary amines and many procedures exist for carrying out this reaction which are well known to those skilled in the art of organic sunthesis. ***reference: I think there is an Org. Reactions ref.*** In carrying out the reductive amination, the aromatic amine of formula (V) is dissolved in an inert solvent and the aldehyde of formula RiCHO is added and the resulting mixture is stirred. Then, a mild reducing reagent such as sodium cyanoborohydride, sodium borohydride, or lithium aluminum hydride is added in several portions and the reaction is stirred. The reaction is monitored by thin layer chromatography until complete and then worked-up. The preferred reducing agent is sodium cyanborohydride. Inert solvents which may be used include lower alkyl alcohols of 1 to 6 carbons, ethereal solvents such as diethyl ether or tetrahydrofuran, and aqueous mixtures of these solvents. The preferred solvent is methanol. Where the reducing agent utilized is sodium cyanoborohydride, work-up entails evaporating the solvent and partitioning the residue

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between ethyl acetate and saturated sodium bicarbonate. The organic layer is separated, dried, and concentrated. Chromatography or direct recrystallization gives the desired product .

Scheme 4

R _j CHO reducing agent, solvent

(V) (IV)

An alternative method for the preparation of compounds of formula (IV) is shown in Scheme 5. The method entails monoalkylation of an aromatic amine of formula (V) with and alkylating agent, R ₁ CH ₂ X, wherein X is Cl, Br, I, OS(0) ₂ CH3, OS (O ₂ C ₆ H ₄ -CH3, or OS(0) ₂ CF ₃ to an aromatic amine of formula (IV) . The alkylating agents of formula R ₁ CH ₂ X are commercially available or can be prepared using standard methods known to those skilled in the art . Alkylation of an amine with a suitable electrophile is a widely used procedure for preparing primary amines. The procedure is similar to the alkylation reaction described in Scheme 1 for preparation of compounds of formula (I), and the methods described for that procedure are applicable here.

Scheme 5

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EXAMPLES The invention can be further understood by the following examples in which parts and percentages are by weight unless otherwise indicated; all temperatures are in degrees centigrade.

Example 1 N,N-di- (2-pyridyl) -9-aminofluorene

To a stirred solution of 9-bromofluorene (300 mg) in 100 ml acetone at 25 °C was added neat bis (2-pyridyl)amine (240 mg) dropwise over 1 min. Then K ₂ CO ₃ (250 mg) was added and the reaction stirred at reflux for 70 h. The reaction is cooled and filtered thru celite. The solvent was removed at reduced pressure and the residue chromatographed (silica, 10% methanol in methylene chloride) to give the desired product (200 mg, 45%) as a white solid, m.p. 132- 133 °C. TLC Rf=0.68 (silica, 10% methanol in methylene chloride) .

Example 2 N,N-di- (3-pyridyl)-9-aminofluorene Using the procedure of Example 1 the title compound was prepared from bis (3-pyridyl) amine in a yield of 46%. m.p. 146-148 °C. TLC Rf=0.52 (silica, 10% methanol in methylene chloride) .

Example 3 N, -dibenzyl-9-aminof luorene

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Using the procedure of Example 1 the title compound was prepared from dibenzylamine in a yield of 74%. m.p. 127-128 °C. TLC Rf=0.92 (silica, 10% methanol in methylene chloride) .

Example 4 N- (4-pyridyl)-9-aminofluorene To a suspension of 9-aminofluorene hydrochloride (90 mg) in 3 ml tetrahydrofuran at 25 °C was added NaH (30 mg) in three portions. After 15 min. a solution of 4- picolylchloride (70 mg) in tetrahydrofuran (2 ml) was added dropwise over 2 min. After 18 h, the reaction is quenched with methanol (2 drops), diluted with chloroform (40 ml), washed with water (20 ml) , separated, dried (Na ₂ S0 ₄ ) and the solvent removed. The residue was subjected to flash chromatography (silica, 2-5% methanol in methylene chloride) to give the desired secondary amine as a white solid (80 mg, 70%) . m.p. 152-153 °C. TLC R _f = 0.39 (silica, 10% methanol in methylene chloride) .

Example 5 N-(4-pyridyl)-N- (4-pyridoyl)-9-aminofluorene To a solution of N- (4-pyridyl)-9-aminofluorene (50 mg) in pyridine (3 ml) at 25 °C was added neat 4- picolylchloride (35 mg) in one portion. The reaction was heated to 80 °C for 1 h. The reaction was then cooled and poured into water (20 ml) , extracted with chloroform (2 X 30 ml), the organic layer separated, dried (MgS0 ₄ ) , and the solvent removed. The residue was subjected to flash chromatography (silica, 5-10% methanol in methylene chloride) to give the desired amide as a white solid (60 mg, 80%) . m.p. 195-197 °C. TLC R _f = 0.58 (silica, 10% methanol in methylene chloride) .

Exa ple 6

N-(4-pyridyl) -N- (benzoyl) -9-aminofluorene

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Using the procedure of Example 5 the title compound was prepared from benzoyl chloride in a yield of 70%. m.p. 214-215 °C. TLC Rf=0.58 (silica, 10% methanol in methylene chloride) .

Example 7 N- (4-pyridyl) -N- (butanoyl) -9-aminofluorene Using the procedure of Example 5 the title compound was prepared from butanoyl chloride in a yield of 80%. m.p. 184-188 °C. TLC Rf=0.46 (silica, 10% methanol in methylene chloride) .

The compounds of examples 1-7, and other compounds which may be prepared by the above methods, are illustrated by the structures represented in Table 1. The table is intended to illustrate the invention, but not to limit its breadth.

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-II

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Table 1 continued

Ex. n, m.p. °C

41 N N H, H

N=/

43 I' -G H, H

45 N H, H

N=

47 - H, H

51 N H, H

~~ \ /)

53 ,CN ~Q ^> H, H

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Biochemical Test Procedure

The effect of compounds of formula (I) on acetylcholine release (ACh) from rat cerebral cortex slices was tested using a slice superfusion technique described by Miller et al, Brain Res .. 70 _f 372 (1974), as modified according to Nickolson et al, Naunyn Schmied. Arch. Pharmacol . _f 319. 48, (1982) . Male Wistar rats (Charles River) weighing 175-200 grams were used. The rats were housed for seven days before the experiment under a 12-12 hour light/dark cycle. They had ad lib access to standard rat chow (Purina) and deionized water. Rats were decapitated and brains were dissected immediately. Slices, 0.3 mm thick, from parietal cortex were prepared manually using a recessed Lucite guide and subsequently cut into squares (0.25 x 0.25 mm, average weight 100 mg) . Slices were incubated in 10 ml Krebs-Ringer medium containing (mM) : NaCl (116), KC1 (3), CaCl ₂ (1.3), MgCl ₂ (1.2), KH P0 ₄ (1.2), Na ₂ S0 ₄ (1.2), NaHC03 (25), glucose (11), to which 10 μCi ³ H-Choline (spec. act. approx. 35 Ci/mmol; NEN) and 10 mmoles unlabeled choline had been added to give a final concentration of 10" ⁶ M. Incubation was carried out for 30 minutes at 37 °C under a steady flow of 95% 0 ₂ 5% CO ₂ .

Under these conditions part of the radioactive choline taken up is converted to radioactive acetylcholine by cholinergic nerve endings, stored in synaptic vesicles and released upon depolarization by high K ⁺ -containing media. After ACh stores labelling, the slices were washed 3 times with non-radioactive KR-medium and transferred to a superfusion apparatus to measure the drug effects on ACh release. The superfusion apparatus consisted of 10 thermostated glass columns of 5 mm diameter provided with GF/F glass fiber filters to support the slices (approximately 10 mg tissue/column) . Superfusion was carried out with KR-medium (0.3 ml/min) containing 10 ^~5 M hemicholinium-3 (HC-3) . This prevents choline uptake, formed during the superfusion from phospholipids and released ACh, which would be converted into unlabeled ACh

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and released in preference to the preformed, labelled ACh. The medium was delivered by a 25-channel peristaltic pump and warmed to 37 °C in a thermostated, stainless steel coil before entering the superfusion column. Each column had a 4-way slider valve allowing rapid change of low to high K ⁺ - KR-medium and with two 10-channel, 3-way valves used to change from drug-free to drug-containing low and high K ⁺ - KR-medium.

After a 15 minute washout of non-specifically bound radioactivity, 4 minute fraction collection began. After three 4-minute collections, the KR medium was changed for KR-medium of which the KC1 concentration was increased to 25mM (high K ⁺ -KR-medium) (SI) . Depolarization-induced stimulation of release by high K ⁺ -KR-medium lasted 4 minutes . Drug free low and high K ⁺ -KR-medium were then substituted by drug or vehicle containing low and high K ⁺ - KR-medium and superfusion continued for three 4-min. collections with low K ⁺ -KR-medium, one 4-min. collection with high K ⁺ -KR-medium (S2) and two 4-min. collections with low K ⁺ -KR-medium.

Drug was added to the medium by 100-fold dilution of appropriate concentrations (in 0.9% NaCl/H ₂ θ) with either low or high K ⁺ -KR-medium. All superfusion fractions were collected in liquid sintillation vials. After superfusion, slices were removed from the columns and extracted in 1 ml of 0.1 N HC1. To these fractions and extracts was added 12 ml Liquiscint counting fluid (NEN) and samples counted in a Packard Tricarb Liquid Scintillation Counter. No corrections made for quenching. The S2/S1 ratio (compared to controls were no drug was present during S2) was a measure of the drug to enhance or depress stimulus-induced ACh release. The in vitro ACh release data are summarized in Table 2.

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SUBSTITUTE SHEET

TλV).lft 2

% INCREASE OF STIMULUS-INDUCED ACh RELEASE IN RAT CEREBRAL CORTEX TN VTTRO

EXAMPLE ur ⁵ i .

1 149 2 97 3 117 5 145 6 127 7 166

WE CLAIM:

1. A compound of formula

wherein:

A is (CH2) _m wherein m is 0 or 1, C=S, 0, S, SO, SO ₂ , NR ₃ , C=0, or C=NOH;

J, K, L and M independently are selected at each occurrence from the group including N, CR3, CR ₄ or CR ₅ ;

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