Method for the regioselective preparation of substituted benzo[g]quinoline-3-carbonitriles and benzo[g]quinazolines

Abstract

This invention relates to a method for the regioselective synthesis of 4,6,7,8-substituted benzo[g]quinoline-3-carbonitriles and 4,6,7,8-substituted benzo[g]quinazolines as well as intermediates thereof. The compounds derived from this invention are useful for the treatment of a variety of diseases that are a result of deregulation of these PTK's, and more specifically, are anti-cancer agents and are useful for the treatment of cancer in mammals. In addition, the compounds derived from this invention are useful for the treatment of polycystic kidney disease in mammals.

1 - 7 . (canceled) 
     
     
         8 . A process for the preparation of a benzo[g]quinoline-3-carbonitrile compound of formula B 
       
         
           
           
               
               
           
         
       
       wherein:
 Ar is cycloalkyl of 3 to 7 carbon atoms, which may be optionally substituted with one or more alkyl of 1 to 6 carbon atoms; or 
 Ar is a pyridinyl, pyrimidinyl, or phenyl ring; wherein the pyridinyl, pyrimidinyl, or phenyl ring may be optionally mono-, di-, or tri-substituted with substituent(s) independently selected from the group consisting of halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, alkoxycarbonyl of 2-7 carbon atoms, alkanoyl of 2-7 carbon atoms, benzoyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, alkynoylamino of 3-8 carbon atoms, alkanoyloxy of 1-6 carbon atoms, alkenoyloxy of 3-8 carbon atoms, alkynoyloxy of 3-8 carbon atoms, carbamoyl, N-alkylcarbamoyl of 2-7 carbon atoms, N,N-dialkylcarbamoyl of 3-13 carbon atoms, carboxyalkyl of 2-7 carbon atoms, carboalkoxyalkyl of 3-8 carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of 2-9 carbon atoms, N,N-dialkylaminoalkyl of 3-10 carbon atoms, N-alkylaminoalkoxy of 3-9 carbon atoms, N,N-dialkylaminoalkoxy of 4-10 carbon atoms, mercapto, methylmercapto and benzoylamino; or 
 Ar is a bicyclic aryl or bicyclic heteroaryl ring system of 8 to 12 atoms where the bicyclic heteroaryl ring may contain 1 to 4 heteroatoms selected from N, O, and S wherein the bicyclic aryl or bicyclic heteroaryl ring may be optionally mono- di-, tri, or tetra-substituted with substituent(s) independently selected from the group consisting of halogen, oxo, thiocarbonyl, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, alkoxycarbonyl of 2-7 carbon atoms, alkanoyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, alkynoylamino of 3-8 carbon atoms, carboxyalkyl of 2-7 carbon atoms, carboalkoxyalkyl of 3-8 carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of 2-9 carbon atoms, N,N-dialkylaminoalkyl of 3-10 carbon atoms, N-alkylaminoalkoxy of 3-9 carbon atoms, N,N-dialkylaminoalkoxy of 4-10 carbon atoms, mercapto, methylmercapto, alkanoyloxy of 1-6 carbon atoms, alkenoyloxy of 3-8 carbon atoms, alkynoyloxy of 3-8 carbon atoms, carbamoyl, N-alkylcarbamoyl of 2-7 carbon atoms, N,N-dialkylcarbamoyl of 3-13 carbon atoms, and benzoylamino; or 
 Ar is the radical: 
 
       
         
           
           
               
               
           
         
         A′ is a pyridinyl, pyrimidinyl, or phenyl ring; wherein the pyridinyl, pyrimidinyl, or phenyl ring may be optionally mono- or di-substituted with substituent(s) independently selected from the group consisting of alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halogen, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, alkoxycarbonyl of 2-7 carbon atoms, alkanoyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, alkynoylamino of 3-8 carbon atoms, carboxyalkyl of 2-7 carbon atoms, carboalkoxyalkyl of 3-8 carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of 2-9 carbon atoms, N,N-dialkylaminoalkyl of 3-10 carbon atoms, N-alkylaminoalkoxy of 3-9 carbon atoms, N,N-dialkylaminoalkoxy of 4-10 carbon atoms, mercapto, methylmercapto, alkanoyloxy of 1-6 carbon atoms, alkenoyloxy of 3-8 carbon atoms, alkynoyloxy of 3-8 carbon atoms, carbamoyl, N-alkylcarbamoyl of 2-7 carbon atoms, N,N-dialkylcarbamoyl of 3-13 carbon atoms, and benzoylamino; 
         T is substituted on A′ at carbon and is —NH(CH 2 ) m —, —O(CH 2 ) m —, —S(CH 2 ) m —, —NR(CH 2 ) m —, —(CH 2 ) m —, —(CH 2 ) m NH—, —(CH 2 ) m O—, —(CH 2 ) m S—, —SO(CH 2 ) m —, —SO 2 (CH 2 ) m —, —CO(CH 2 ) m —, —(CH 2 ) m CO—, —(CH 2 ) m SO—, —(CH 2 ) m SO 2 — or —(CH 2 ) m NR—; 
         L is a phenyl ring that is optionally substituted with one, two, or three substituent(s) independently selected from the group consisting of alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halogen, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, alkoxycarbonyl of 2-7 carbon atoms, alkanoyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, alkynoylamino of 3-8 carbon atoms, carboxyalkyl of 2-7 carbon atoms, carboalkoxyalkyl of 3-8 carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of 2-9 carbon atoms, N,N-dialkylaminoalkyl of 3-10 carbon atoms, N-alkylaminoalkoxy of 3-9 carbon atoms, N,N-dialkylaminoalkoxy of 4-10 carbon atoms, mercapto, methylmercapto, alkanoyloxy of 1-6 carbon atoms, alkenoyloxy of 3-8 carbon atoms, alkynoyloxy of 3-8 carbon atoms, carbamoyl, N-alkylcarbamoyl of 2-7 carbon atoms, N,N-dialkylcarbamoyl of 3-13 carbon atoms, and benzoylamino; or 
         L is a 5- or 6-membered heteroaryl ring where the heteroaryl ring contains 1 to 3 heteroatom(s) independently selected from N, O, and S and where the heteroaryl ring may be optionally mono- or di-substituted with substituent(s) independently selected from the group consisting of halogen, oxo, thiocarbonyl, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, alkoxycarbonyl of 2-7 carbon atoms, alkanoyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, alkynoylamino of 3-8 carbon atoms, carboxyalkyl of 2-7 carbon atoms, carboalkoxyalkyl of 3-8 carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of 2-9 carbon atoms, N,N-dialkylaminoalkyl of 3-10 carbon atoms, N-alkylaminoalkoxy of 3-9 carbon atoms, N,N-dialkylaminoalkoxy of 4-10 carbon atoms, mercapto, methylmercapto, alkanoyloxy of 1-6 carbon atoms, alkenoyloxy of 3-8 carbon atoms, alkynoyloxy of 3-8 carbon atoms, carbamoyl, N-alkylcarbamoyl of 2-7 carbon atoms, N,N-dialkylcarbamoyl of 3-13 carbon atoms, and benzoylamino; 
         m is 0-3; 
         n is 0-1; 
         X is NH, O, S, or NR; 
         R is alkyl of 1-6 carbon atoms; 
         R 1 , R 2  and R 3  are each, independently, hydrogen, halogen, hydroxy, amino, arylamino, arylalkylamino, hydroxyamino, trifluoromethyl, trifluoromethoxy, mercapto, alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, alkenyloxy of 2-6 carbon atoms, alkynyloxy of 2-6 carbon atoms, hydroxyalkyl of 1-6 carbon atoms, mercaptoalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, cycloalkoxy of 3-8 carbon atoms, alkylthio of 1-6 carbon atoms, cycloalkylthio of 3-8 carbon atoms, alkylsulphinyl of 1-6 carbon atoms, alkylsulfonyl of 1-6 carbon atoms, alkylsulfonamido of 1-6 carbon atoms, alkenylsulfonamido of 2-6 carbon atoms, alkynylsulfonamido of 2-6 carbon atoms, cyano, nitro, carboxy, alkoxycarbonyl of 2-7 carbon atoms, alkanoyl of 2-7 carbon atoms, alkenoyl of 3-7 carbon atoms, N-alkyl-N-alkenylamino of 4 to 12 carbon atoms, N,N-dialkenylamino of 6-12 carbon atoms, phenylamino, benzylamino, phenoxy, phenyl, thiophenoxy, benzyl, alkylamino of 1-6 carbon atoms, alkanoyloxy of 2-7 carbon atoms, alkenoyloxy of 3-8 carbon atoms, alkynoyloxy of 3-8 carbon atoms, carbamoyl, N-alkylcarbamoyl of 2-7 carbon atoms, N,N-dialkylcarbamoyl of 3-13 carbon atoms, dialkylamino of 2 to 12 carbon atoms, alkanoyloxymethyl group of 2-7 carbon atoms, alkenoyloxymethyl group of 2-7 carbon atoms, alkynoyloxymethyl group of 2-7 carbon atoms, azido, benzoyl, carboxyalkyl of 2-7 carbons, carboalkoxyalkyl of 3-8 carbon atoms, 
       
       
         
           
           
               
               
           
         
         R 5  is independently hydrogen, alkyl of 1-6 carbon atoms, aminoalkyl of 1-6 carbon atoms, N-alkylaminoalkyl of 2-9 carbon atoms, N,N-dialkylaminoalkyl of 3-12 carbon atoms, N-cycloalkylaminoalkyl of 4-12 carbon atoms, N-cycloalkyl-N-alkylaminoalkyl of 5-18 carbon atoms, N,N-dicycloalkylaminoalkyl of 7-18 carbon atoms, morpholino-N-alkyl wherein the alkyl group is 1-6 carbon atoms, piperidino-N-alkyl wherein the alkyl group is 1-6 carbon atoms, N-alkyl-piperazino-N-alkyl wherein either alkyl group is 1-6 carbon atoms, azacycloalkyl-N-alkyl of 3-11 carbon atoms, hydroxyalkyl of 1-6 carbon atoms, alkoxyalkyl of 2-8 carbon atoms, phenyl; 
         V is (CH 2 ) m , O, S, or NR 6 ; 
         R 7  is NR 6 R 6 , OR 6 , J, N(R 6 ) 3   + , or NR 6 (OR 6 ); 
         M is NR 6 , O, S, N—[(C(R 6 ) 2 ) p NR 6 R 6 ], or N—[(C(R 6 ) 2 ) p —OR 6 ]; 
         W is NR 6 , O, S, or is a bond; 
         Het is a heterocycle selected from the group consisting of morpholine, thiomorpholine, thiomorpholine S-oxide, thiomorpholine S,S-dioxide, piperidine, pyrrolidine, aziridine, pyridine, imidazole, 1,2,3-triazole, 1,2,4-triazole, thiazole, thiazolidine, tetrazole, piperazine, furan, thiophene, tetrahydrothiophene, tetrahydrofuran, dioxane, 1,3-dioxolane pyrrole, and tetrahydropyran; wherein the heterocycle is optionally mono- or di-substituted on carbon or nitrogen with R 6 ; optionally mono- or di-substituted on carbon with hydroxy, —N(R 6 ) 2 , or —OR 6 ; optionally mono or di-substituted on carbon with the mono-valent radicals —(C(R 6 ) 2 ) s OR 6  or —[(C(R 6 ) 2 ) s N(R 6 ) 2 ]; or optionally mono or di-substituted on a saturated carbon with divalent radicals ═O or —O(C(R 6 ) 2 ) s O—; 
         Ph is a phenyl ring optionally mono-, di- or tri-substituted with halogen, alkyl of 1-6 carbon atoms, trifluoromethyl, nitro, cyano, azido, halomethyl, carboxyl, alkoxycarbonyl, alkylthio, mercapto, mercaptomethyl, —N(R 6 ) 2 , —OR 6 , —(C(R 6 ) 2 ) s OR 6 , —[(C(R 6 ) 2 ) s N(R 6 ) 2 ], or —(C(R 6 ) 2 ) k Het; 
         R 6  is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 1-6 carbon atoms, alkanoyl of 2-7 carbon atoms, carbamoylalkyl of 2-7 carbon atoms, hydroxyalkyl of 1-6 carbon atoms, hydroxycycloalkyl of 3-6 carbon atoms, or carboxyalkyl of 2-7 carbon atoms; or 
         R 6  is phenyl optionally mono-, di-, or tri-substituted with halogen, alkoxy of 1-6 carbon atoms, trifluoromethyl, amino, alkylamino of 1-3 carbon atoms, dialkylamino of 2-6 carbon atoms, nitro, cyano, azido, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, carboxyl, alkoxycarbonyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, phenylamino, benzylamino; alkanoylamino of 1-6 carbon atoms or alkyl of 1-6 carbon atoms; 
         R 8  and R 9  are each, independently, —[(C(R 6 ) 2 ) r NR 6 R 6 ], or —[(C(R 6 ) 2 ) r OR 6 ]; 
         J is independently hydrogen, chlorine, fluorine, or bromine; 
         g=1-6; 
         k=0-4; 
         p=2-4; 
         q=0-4; 
         r=1-4; 
         s=1-6; 
       
       or a pharmaceutically acceptable salt thereof;
 provided that when R 5  is bound to a nitrogen atom, the resulting structures do not include —N—C—N— or —O—C—N— radicals; and when R 5  is bound to an oxygen atom, the resulting structures do not include an —N—C—O— radical; 
 provided that when R 6  is alkenyl of 2-7 carbon atoms or alkynyl of 2-7 carbon atoms, the alkenyl or alkynyl moieties are bound to a nitrogen or oxygen atom through a saturated carbon atom in the alkenyl or alkynyl chain; 
 provided that when V is NR 6  and R 7  is NR 6 R 6 , N(R 6 ) 3   + , or NR 6 (OR 6 ), then g=2-6; 
 provided that when M is O or S and R 7  is OR 6 , then p=1-4; 
 provided that when V is NR 6 , O, S, then k=2-4; 
 provided that when V is O or S and M or W is O or S, then k=1-4 
 provided that when W is not a bond with Het bonded through a nitrogen atom then q=2-4; and 
 finally provided when W is a bond with Het bonded through a nitrogen atom and V is O or NR 6  or S, then k=2-4 
 
       which process comprises:
 (a) reacting a substituted bicyclo[4.2.0]octa-1(6),2,4-triene-7-carbonitrile of formula 1 
 
       
         
           
           
               
               
           
         
         
           wherein R 1 , R 2 , and R 3  are defined as above; 
           with a base to form a first intermediate having the corresponding anion alpha to the cyano group; 
         
         (b) reacting said first intermediate with a suitable electrophilic sulfur species to yield an alpha-sulfenylated 1-cyanobenzocyclobutene of formula 2 
       
       
         
           
           
               
               
           
         
       
       wherein R 10  is defined as an alkyl of 1-10 carbons, cycloalkyl of 3-10 carbons, alkenyl of 3-10 carbons, cycloalkenyl of 4-10 carbons, alkynyl of 3-10 carbons, Ph or L (where Ph and L are as hereinabove defined) and R 1 , R 2 , and R 3  are defined as above;
 (c) reacting said cyanobenzocyclobutenes of formula 2 with an anionic salt of 
 
       
         
           
           
               
               
           
         
       
       wherein E 1  is alkyl, phenyl, L, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, any of which may be substituted with one or more R 6  groups; wherein L and R 6  are defined as above;
 to provide an amino ester intermediate of formula 3 
 
       
         
           
           
               
               
           
         
       
       wherein E is an alkoxycarbonyl of 2-12 carbons, —CO 2 -Ph, —CO 2 -L, cycloalkoxycarbonyl of 4-12 carbons, alkenyloxycarbonyl of 3-12 carbons, cycloalkenyloxycarbonyl of 5-12 carbons, alkynyloxycarbonyl of 4-12 carbons, any of which may be substituted on a carbon atom with one or more R 6  groups and wherein R 1 , R 2 , R 3 , R 10 , L, R 6 , and Ph, are defined as above; and
 (d) refluxing the formula 3 adducts in a solvent to provide the substituted ester of formula A; 
 
       
         
           
           
               
               
           
         
       
       wherein R 1 , R 2 , R 3 , and E are defined as above;
 (e) reacting the substituted ester of formula A with dimethylformamide dialkyl acetal, optionally in the presence of a solvent, to yield a corresponding amidine intermediate; 
 (f) reacting the amidine intermediate of step (e) with a lithium anion of acetonitrile to yield 3-cyano-4-oxo-1,4-dihydrobenzo[g]quinoline of formula 4; 
 
       
         
           
           
               
               
           
         
       
       wherein R 1 , R 2 , and R 3  are defined as above;
 (g) reacting the compound of formula 4, optionally in the presence of a solvent, with a halogenating agent to yield the corresponding 4-halo-3-cyano-benzo[g]quinoline of formula 5; 
 
       
         
           
           
               
               
           
         
       
       wherein R 1 , R 2 , and R 3  are defined as above;
 (h) condensing the compound of formula 5 with a nucleophilic reagent of formula 6
   HX—(CH 2 ) n —Ar  6 
 
 
       wherein X, n, and Ar are defined as above; 
       to form the 4-anilino-benzo[g]cyanoquinoline compound of formula B. 
     
     
         9 . The process according to  claim 8  wherein the dimethylformamide dialkyl acetal is dimethylformamide dimethyl acetal. 
     
     
         10 . The process according to  claim 8  wherein the halogenating agent is a chlorinating agent. 
     
     
         11 . The process according to  claim 8  wherein R 10  is Ph. 
     
     
         12 . The process according to  claim 8  wherein the condensation step (h) is accelerated by heating the reaction mixture together with pyridine hydrochloride or by using at least one base in an inert solvent, or by using a transition metal catalyst in an inert solvent. 
     
     
         13 . The process according to  claim 12  wherein the reaction mixture is heated in step (h) to a temperature range of 80° to 140° C. 
     
     
         14 . The process according to  claim 12  wherein the transition metal catalyst is tris(dibenzylideneacetone)dipalladium(0). 
     
     
         15 . The process according to  claim 14  wherein the transition metal catalyst is used in conjunction with a ligand selected from the group consisting of 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl, and potassium phosphate. 
     
     
         16 . A process for the preparation of a compound of formula C 
       
         
           
           
               
               
           
         
       
       wherein
 Ar is cycloalkyl of 3 to 7 carbon atoms, which may be optionally substituted with one or more alkyl of 1 to 6 carbon atoms; or 
 Ar is a pyridinyl, pyrimidinyl, or phenyl ring; wherein the pyridinyl, pyrimidinyl, or phenyl ring may be optionally mono-, di-, or tri-substituted with substituent(s) independently selected from the group consisting of halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, alkoxycarbonyl of 2-7 carbon atoms, alkanoyl of 2-7 carbon atoms, benzoyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, alkynoylamino of 3-8 carbon atoms, alkanoyloxy of 1-6 carbon atoms, alkenoyloxy of 3-8 carbon atoms, alkynoyloxy of 3-8 carbon atoms, carbamoyl, N-alkylcarbamoyl of 2-7 carbon atoms, N,N-dialkylcarbamoyl of 3-13 carbon atoms, carboxyalkyl of 2-7 carbon atoms, carboalkoxyalkyl of 3-8 carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of 2-9 carbon atoms, N,N-dialkylaminoalkyl of 3-10 carbon atoms, N-alkylaminoalkoxy of 3-9 carbon atoms, N,N-dialkylaminoalkoxy of 4-10 carbon atoms, mercapto, methylmercapto and benzoylamino; or 
 Ar is a bicyclic aryl or bicyclic heteroaryl ring system of 8 to 12 atoms where the bicyclic heteroaryl ring may contain 1 to 4 heteroatoms selected from N, O, and S wherein the bicyclic aryl or bicyclic heteroaryl ring may be optionally mono- di-, tri, or tetra-substituted with substituent(s) independently selected from the group consisting of halogen, oxo, thiocarbonyl, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, alkoxycarbonyl of 2-7 carbon atoms, alkanoyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, alkynoylamino of 3-8 carbon atoms, carboxyalkyl of 2-7 carbon atoms, carboalkoxyalkyl of 3-8 carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of 2-9 carbon atoms, N,N-dialkylaminoalkyl of 3-10 carbon atoms, N-alkylaminoalkoxy of 3-9 carbon atoms, N,N-dialkylaminoalkoxy of 4-10 carbon atoms, mercapto, methylmercapto, alkanoyloxy of 1-6 carbon atoms, alkenoyloxy of 3-8 carbon atoms, alkynoyloxy of 3-8 carbon atoms, carbamoyl, N-alkylcarbamoyl of 2-7 carbon atoms, N,N-dialkylcarbamoyl of 3-13 carbon atoms, and benzoylamino; or 
 Ar is the radical: 
 
       
         
           
           
               
               
           
         
         A′ is a pyridinyl, pyrimidinyl, or phenyl ring; wherein the pyridinyl, pyrimidinyl, or phenyl ring may be optionally mono- or di-substituted with substituent(s) independently selected from the group consisting of alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halogen, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, alkoxycarbonyl of 2-7 carbon atoms, alkanoyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, alkynoylamino of 3-8 carbon atoms, carboxyalkyl of 2-7 carbon atoms, carboalkoxyalkyl of 3-8 carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of 2-9 carbon atoms, N,N-dialkylaminoalkyl of 3-10 carbon atoms, N-alkylaminoalkoxy of 3-9 carbon atoms, N,N-dialkylaminoalkoxy of 4-10 carbon atoms, mercapto, methylmercapto, alkanoyloxy of 1-6 carbon atoms, alkenoyloxy of 3-8 carbon atoms, alkynoyloxy of 3-8 carbon atoms, carbamoyl, N-alkylcarbamoyl of 2-7 carbon atoms, N,N-dialkylcarbamoyl of 3-13 carbon atoms, and benzoylamino; 
         T is substituted on A′ at carbon and is —NH(CH 2 ) m —, —O(CH 2 ) m —, —S(CH 2 ) m —, —NR(CH 2 ) m —, —(CH 2 ) m —, —(CH 2 ) m NH—, —(CH 2 ) m O—, —(CH 2 ) m S—, —SO(CH 2 ) m —, —SO 2 (CH 2 ) m —, —CO(CH 2 ) m —, —(CH 2 ) m CO—, —(CH 2 ) m SO—, —(CH 2 ) m SO 2 — or —(CH 2 ) m NR—; 
         L is a phenyl ring that is optionally substituted with one, two, or three substituent(s) independently selected from the group consisting of alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halogen, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, alkoxycarbonyl of 2-7 carbon atoms, alkanoyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, alkynoylamino of 3-8 carbon atoms, carboxyalkyl of 2-7 carbon atoms, carboalkoxyalkyl of 3-8 carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of 2-9 carbon atoms, N,N-dialkylaminoalkyl of 3-10 carbon atoms, N-alkylaminoalkoxy of 3-9 carbon atoms, N,N-dialkylaminoalkoxy of 4-10 carbon atoms, mercapto, methylmercapto, alkanoyloxy of 1-6 carbon atoms, alkenoyloxy of 3-8 carbon atoms, alkynoyloxy of 3-8 carbon atoms, carbamoyl, N-alkylcarbamoyl of 2-7 carbon atoms, N,N-dialkylcarbamoyl of 3-13 carbon atoms, and benzoylamino; or 
         L is a 5- or 6-membered heteroaryl ring where the heteroaryl ring contains 1 to 3 heteroatom(s) independently selected from N, O, and S and where the heteroaryl ring may be optionally mono- or di-substituted with substituent(s) independently selected from the group consisting of halogen, oxo, thiocarbonyl, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, alkoxycarbonyl of 2-7 carbon atoms, alkanoyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, alkynoylamino of 3-8 carbon atoms, carboxyalkyl of 2-7 carbon atoms, carboalkoxyalkyl of 3-8 carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of 2-9 carbon atoms, N,N-dialkylaminoalkyl of 3-10 carbon atoms, N-alkylaminoalkoxy of 3-9 carbon atoms, N,N-dialkylaminoalkoxy of 4-10 carbon atoms, mercapto, methylmercapto, alkanoyloxy of 1-6 carbon atoms, alkenoyloxy of 3-8 carbon atoms, alkynoyloxy of 3-8 carbon atoms, carbamoyl, N-alkylcarbamoyl of 2-7 carbon atoms, N,N-dialkylcarbamoyl of 3-13 carbon atoms, and benzoylamino; 
         m is 0-3; 
         n is 0-1; 
         X is NH, O, S, or NR; 
         R is alkyl of 1-6 carbon atoms; 
         R 1 , R 2  and R 3  are each, independently, hydrogen, halogen, hydroxy, amino, arylamino, arylalkylamino, hydroxyamino, trifluoromethyl, trifluoromethoxy, mercapto, alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, alkenyloxy of 2-6 carbon atoms, alkynyloxy of 2-6 carbon atoms, hydroxyalkyl of 1-6 carbon atoms, mercaptoalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, cycloalkoxy of 3-8 carbon atoms, alkylthio of 1-6 carbon atoms, cycloalkylthio of 3-8 carbon atoms, alkylsulphinyl of 1-6 carbon atoms, alkylsulfonyl of 1-6 carbon atoms, alkylsulfonamido of 1-6 carbon atoms, alkenylsulfonamido of 2-6 carbon atoms, alkynylsulfonamido of 2-6 carbon atoms, cyano, nitro, carboxy, alkoxycarbonyl of 2-7 carbon atoms, alkanoyl of 2-7 carbon atoms, alkenoyl of 3-7 carbon atoms, N-alkyl-N-alkenylamino of 4 to 12 carbon atoms, N,N-dialkenylamino of 6-12 carbon atoms, phenylamino, benzylamino, phenoxy, phenyl, thiophenoxy, benzyl, alkylamino of 1-6 carbon atoms, alkanoyloxy of 2-7 carbon atoms, alkenoyloxy of 3-8 carbon atoms, alkynoyloxy of 3-8 carbon atoms, carbamoyl, N-alkylcarbamoyl of 2-7 carbon atoms, N,N-dialkylcarbamoyl of 3-13 carbon atoms, dialkylamino of 2 to 12 carbon atoms, alkanoyloxymethyl group of 2-7 carbon atoms, alkenoyloxymethyl group of 2-7 carbon atoms, alkynoyloxymethyl group of 2-7 carbon atoms, azido, benzoyl, carboxyalkyl of 2-7 carbons, carboalkoxyalkyl of 3-8 carbon atoms, 
       
       
         
           
           
               
               
           
         
         R 5  is independently hydrogen, alkyl of 1-6 carbon atoms, aminoalkyl of 1-6 carbon atoms, N-alkylaminoalkyl of 2-9 carbon atoms, N,N-dialkylaminoalkyl of 3-12 carbon atoms, N-cycloalkylaminoalkyl of 4-12 carbon atoms, N-cycloalkyl-N-alkylaminoalkyl of 5-18 carbon atoms, N,N-dicycloalkylaminoalkyl of 7-18 carbon atoms, morpholino-N-alkyl wherein the alkyl group is 1-6 carbon atoms, piperidino-N-alkyl wherein the alkyl group is 1-6 carbon atoms, N-alkyl-piperazino-N-alkyl wherein either alkyl group is 1-6 carbon atoms, azacycloalkyl-N-alkyl of 3-11 carbon atoms, hydroxyalkyl of 1-6 carbon atoms, alkoxyalkyl of 2-8 carbon atoms, phenyl; 
         V is (CH 2 ) m , O, S, or NR 6 ; 
         R 7  is NR 6 R 6 , OR 6 , J, N(R 6 ) 3   + , or NR 6 (OR 6 ); 
         M is NR 6 , O, S, N—[(C(R 6 ) 2 ) p NR 6 R 6 ], or N—[(C(R 6 ) 2 ) p —OR 6 ]; 
         W is NR 6 , O, S, or is a bond; 
         Het is a heterocycle selected from the group consisting of morpholine, thiomorpholine, thiomorpholine S-oxide, thiomorpholine S,S-dioxide, piperidine, pyrrolidine, aziridine, pyridine, imidazole, 1,2,3-triazole, 1,2,4-triazole, thiazole, thiazolidine, tetrazole, piperazine, furan, thiophene, tetrahydrothiophene, tetrahydrofuran, dioxane, 1,3-dioxolane pyrrole, and tetrahydropyran; wherein the heterocycle is optionally mono- or di-substituted on carbon or nitrogen with R 6 ; optionally mono- or di-substituted on carbon with hydroxy, —N(R 6 ) 2 , or —OR 6 ; optionally mono or di-substituted on carbon with the mono-valent radicals —(C(R 6 ) 2 ) s OR 6  or —[(C(R 6 ) 2 ) s N(R 6 ) 2 ]; or optionally mono or di-substituted on a saturated carbon with divalent radicals ═O or —O(C(R 6 ) 2 ) s O—; 
         Ph is a phenyl ring optionally mono-, di- or tri-substituted with halogen, alkyl of 1-6 carbon atoms, trifluoromethyl, nitro, cyano, azido, halomethyl, carboxyl, alkoxycarbonyl, alkylthio, mercapto, mercaptomethyl, —N(R 6 ) 2 , —OR 6 , —(C(R 6 ) 2 ) s OR 6 , —[(C(R 6 ) 2 ) s N(R 6 ) 2 ], or —(C(R 6 ) 2 ) k Het; 
         R 6  is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 1-6 carbon atoms, alkanoyl of 2-7 carbon atoms, carbamoylalkyl of 2-7 carbon atoms, hydroxyalkyl of 1-6 carbon atoms, hydroxycycloalkyl of 3-6 carbon atoms, or carboxyalkyl of 2-7 carbon atoms; or 
         R 6  is phenyl optionally mono-, di-, or tri-substituted with halogen, alkoxy of 1-6 carbon atoms, trifluoromethyl, amino, alkylamino of 1-3 carbon atoms, dialkylamino of 2-6 carbon atoms, nitro, cyano, azido, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, carboxyl, alkoxycarbonyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, phenylamino, benzylamino; 
         alkanoylamino of 1-6 carbon atoms or alkyl of 1-6 carbon atoms; 
         R 8  and R 9  are each, independently, —[(C(R 6 ) 2 ) r NR 6 R 6 ], or —[(C(R 6 ) 2 ) r OR 6 ]; 
         J is independently hydrogen, chlorine, fluorine, or bromine; 
         g=1-6; 
         k=0-4; 
         p=2-4; 
         q=0-4; 
         r=1-4; 
         s=1-6; 
       
       or a pharmaceutically acceptable salt thereof;
 provided that when R 5  is bound to a nitrogen atom, the resulting structures do not include —N—C—N— or —O—C—N— radicals; and when R 5  is bound to an oxygen atom, the resulting structures do not include an —N—C—O— radical; 
 provided that when R 6  is alkenyl of 2-7 carbon atoms or alkynyl of 2-7 carbon atoms, the alkenyl or alkynyl moieties are bound to a nitrogen or oxygen atom through a saturated carbon atom in the alkenyl or alkynyl chain; 
 provided that when V is NR 6  and R 7  is NR 6 R 6 , N(R 6 ) 3   + , or NR 6 (OR 6 ), then g=2-6; 
 provided that when M is O or S and R 7  is OR 6 , then p=1-4; 
 provided that when V is NR 6 , O, S, then k=2-4; 
 provided that when V is O or S and M or W is O or S, then k=1-4 
 provided that when W is not a bond with Het bonded through a nitrogen atom then q=2-4; and 
 finally provided when W is a bond with Het bonded through a nitrogen atom and V is O or NR 6  or 
 S, then k=2-4 
 
       which process comprises:
 (a) reacting a substituted bicyclo[4.2.0]octa-1(6),2,4-triene-7-carbonitrile of formula 1 
 
       
         
           
           
               
               
           
         
         
           wherein R 1 , R 2 , and R 3  are defined as above; 
           with a base to form a first intermediate having the corresponding anion alpha to the cyano group; 
         
         (b) reacting said first intermediate with a suitable electrophilic sulfur species to yield an alpha-sulfenylated 1-cyanobenzocyclobutene of formula 2 
       
       
         
           
           
               
               
           
         
       
       wherein R 10  is defined as an alkyl of 1-10 carbons, cycloalkyl of 3-10 carbons, alkenyl of 3-10 carbons, cycloalkenyl of 4-10 carbons, alkynyl of 3-10 carbons, Ph or L (where Ph and L are as hereinabove defined) and R 1 , R 2 , and R 3  are defined as above;
 (c) reacting said cyanobenzocyclobutenes of formula 2 with an anionic salt of 
 
       
         
           
           
               
               
           
         
       
       wherein E 1  is alkyl, phenyl, L, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, any of which may be substituted with one or more R 6  groups; wherein L and R 6  are defined as above;
 to provide an amino ester intermediate of formula 3 
 
       
         
           
           
               
               
           
         
       
       wherein E is an alkoxycarbonyl of 2-12 carbons, —CO 2 -Ph, —CO 2 -L, cycloalkoxycarbonyl of 4-12 carbons, alkenyloxycarbonyl of 3-12 carbons, cycloalkenyloxycarbonyl of 5-12 carbons, alkynyloxycarbonyl of 4-12 carbons, any of which may be substituted on a carbon atom with one or more R 6  groups and wherein R 1 , R 2 , R 3 , R 10 , Ph, L and R 6  are defined as above; and
 (d) refluxing the formula 3 adducts in a solvent to provide the substituted ester of formula A; 
 
       
         
           
           
               
               
           
         
       
       wherein R 1 , R 2 , R 3 , and E are defined as above;
 (e) refluxing the substituted ester of formula A in formamide to yield a compound of formula 7 
 
       
         
           
           
               
               
           
         
       
       wherein R 1 , R 2 , and R 3  are defined as above;
 (f) heating the compound of formula 7, optionally in a solvent, with a halogenating agent, optionally with a base, to provide the corresponding 4-chlorobenzo[g]quinazolines of formula 8 
 
       
         
           
           
               
               
           
         
         
           wherein R 1 , R 2 , and R 3  are defined as above; 
         
         (g) condensing the 4-chlorobenzo[g]quinazolines of formula 8 with a nucleophilic reagent of Formula 6
   HX—(CH 2 ) n —Ar  6 
 
       
       wherein X, n, and Ar are defined as above;
 to yield the benzo[g]quinazolines of Formula C. 
 
     
     
         17 . The process according to  claim 16  wherein the halogenating agent is a chlorinating agent. 
     
     
         18 . The process according to  claim 16  wherein R 10  is Ph. 
     
     
         19 . The process according to  claim 16  wherein the condensation step (g) is accelerated by heating the reaction mixture together with pyridine hydrochloride or by using at least one base in an inert solvent, or by using a transition metal catalyst in an inert solvent. 
     
     
         20 . The process according to  claim 19  wherein the reaction mixture is heated in step (g) to a temperature range of 80° to 140° C. 
     
     
         21 . The process according to  claim 19  wherein the transition metal catalyst is tris(dibenzylideneacetone)dipalladium(0). 
     
     
         22 . The process according to  claim 14  wherein the transition metal catalyst is used in conjunction with a ligand selected from the group consisting of 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl, and potassium phosphate. 
     
     
         23 . A process for the preparation of benzo[g]quinolines of formula C 
       
         
           
           
               
               
           
         
       
       wherein
 Ar is cycloalkyl of 3 to 7 carbon atoms, which may be optionally substituted with one or more alkyl of 1 to 6 carbon atoms; or 
 Ar is a pyridinyl, pyrimidinyl, or phenyl ring; wherein the pyridinyl, pyrimidinyl, or phenyl ring may be optionally mono-, di-, or tri-substituted with substituent(s) independently selected from the group consisting of halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, alkoxycarbonyl of 2-7 carbon atoms, alkanoyl of 2-7 carbon atoms, benzoyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, alkynoylamino of 3-8 carbon atoms, alkanoyloxy of 1-6 carbon atoms, alkenoyloxy of 3-8 carbon atoms, alkynoyloxy of 3-8 carbon atoms, carbamoyl, N-alkylcarbamoyl of 2-7 carbon atoms, N,N-dialkylcarbamoyl of 3-13 carbon atoms, carboxyalkyl of 2-7 carbon atoms, carboalkoxyalkyl of 3-8 carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of 2-9 carbon atoms, N,N-dialkylaminoalkyl of 3-10 carbon atoms, N-alkylaminoalkoxy of 3-9 carbon atoms, N,N-dialkylaminoalkoxy of 4-10 carbon atoms, mercapto, methylmercapto and benzoylamino; or 
 Ar is a bicyclic aryl or bicyclic heteroaryl ring system of 8 to 12 atoms where the bicyclic heteroaryl ring may contain 1 to 4 heteroatoms selected from N, O, and S wherein the bicyclic aryl or bicyclic heteroaryl ring may be optionally mono- di-, tri, or tetra-substituted with substituent(s) independently selected from the group consisting of halogen, oxo, thiocarbonyl, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, alkoxycarbonyl of 2-7 carbon atoms, alkanoyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, alkynoylamino of 3-8 carbon atoms, carboxyalkyl of 2-7 carbon atoms, carboalkoxyalkyl of 3-8 carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of 2-9 carbon atoms, N,N-dialkylaminoalkyl of 3-10 carbon atoms, N-alkylaminoalkoxy of 3-9 carbon atoms, N,N-dialkylaminoalkoxy of 4-10 carbon atoms, mercapto, methylmercapto, alkanoyloxy of 1-6 carbon atoms, alkenoyloxy of 3-8 carbon atoms, alkynoyloxy of 3-8 carbon atoms, carbamoyl, N-alkylcarbamoyl of 2-7 carbon atoms, N,N-dialkylcarbamoyl of 3-13 carbon atoms, and benzoylamino; or 
 Ar is the radical: 
 
       
         
           
           
               
               
           
         
         A′ is a pyridinyl, pyrimidinyl, or phenyl ring; wherein the pyridinyl, pyrimidinyl, or phenyl ring may be optionally mono- or di-substituted with substituent(s) independently selected from the group consisting of alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halogen, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, alkoxycarbonyl of 2-7 carbon atoms, alkanoyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, alkynoylamino of 3-8 carbon atoms, carboxyalkyl of 2-7 carbon atoms, carboalkoxyalkyl of 3-8 carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of 2-9 carbon atoms, N,N-dialkylaminoalkyl of 3-10 carbon atoms, N-alkylaminoalkoxy of 3-9 carbon atoms, N,N-dialkylaminoalkoxy of 4-10 carbon atoms, mercapto, methylmercapto, alkanoyloxy of 1-6 carbon atoms, alkenoyloxy of 3-8 carbon atoms, alkynoyloxy of 3-8 carbon atoms, carbamoyl, N-alkylcarbamoyl of 2-7 carbon atoms, N,N-dialkylcarbamoyl of 3-13 carbon atoms, and benzoylamino; 
         T is substituted on A′ at carbon and is —NH(CH 2 ) m —, —O(CH 2 ) m —, —S(CH 2 ) m —, —NR(CH 2 ) m —, —(CH 2 ) m —, —(CH 2 ) m NH—, —(CH 2 ) m O—, —(CH 2 ) m S—, —SO(CH 2 ) m —, —SO 2 (CH 2 ) m —, —CO(CH 2 ) m —, —(CH 2 ) m CO—, —(CH 2 ) m SO—, —(CH 2 ) m SO 2 — or —(CH 2 ) m NR—; 
         L is a phenyl ring that is optionally substituted with one, two, or three substituent(s) independently selected from the group consisting of alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halogen, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, alkoxycarbonyl of 2-7 carbon atoms, alkanoyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, alkynoylamino of 3-8 carbon atoms, carboxyalkyl of 2-7 carbon atoms, carboalkoxyalkyl of 3-8 carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of 2-9 carbon atoms, N,N-dialkylaminoalkyl of 3-10 carbon atoms, N-alkylaminoalkoxy of 3-9 carbon atoms, N,N-dialkylaminoalkoxy of 4-10 carbon atoms, mercapto, methylmercapto, alkanoyloxy of 1-6 carbon atoms, alkenoyloxy of 3-8 carbon atoms, alkynoyloxy of 3-8 carbon atoms, carbamoyl, N-alkylcarbamoyl of 2-7 carbon atoms, N,N-dialkylcarbamoyl of 3-13 carbon atoms, and benzoylamino; or 
         L is a 5- or 6-membered heteroaryl ring where the heteroaryl ring contains 1 to 3 heteroatom(s) independently selected from N, O, and S and where the heteroaryl ring may be optionally mono- or di-substituted with substituent(s) independently selected from the group consisting of halogen, oxo, thiocarbonyl, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, alkoxycarbonyl of 2-7 carbon atoms, alkanoyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, alkynoylamino of 3-8 carbon atoms, carboxyalkyl of 2-7 carbon atoms, carboalkoxyalkyl of 3-8 carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of 2-9 carbon atoms, N,N-dialkylaminoalkyl of 3-10 carbon atoms, N-alkylaminoalkoxy of 3-9 carbon atoms, N,N-dialkylaminoalkoxy of 4-10 carbon atoms, mercapto, methylmercapto, alkanoyloxy of 1-6 carbon atoms, alkenoyloxy of 3-8 carbon atoms, alkynoyloxy of 3-8 carbon atoms, carbamoyl, N-alkylcarbamoyl of 2-7 carbon atoms, N,N-dialkylcarbamoyl of 3-13 carbon atoms, and benzoylamino; 
         m is 0-3; 
         n is 0-1; 
         R is alkyl of 1-6 carbon atoms; 
         R 1 , R 2  and R 3  are each, independently, hydrogen, halogen, hydroxy, amino, arylamino, arylalkylamino, hydroxyamino, trifluoromethyl, trifluoromethoxy, mercapto, alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, alkenyloxy of 2-6 carbon atoms, alkynyloxy of 2-6 carbon atoms, hydroxyalkyl of 1-6 carbon atoms, mercaptoalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, cycloalkoxy of 3-8 carbon atoms, alkylthio of 1-6 carbon atoms, cycloalkylthio of 3-8 carbon atoms, alkylsulphinyl of 1-6 carbon atoms, alkylsulfonyl of 1-6 carbon atoms, alkylsulfonamido of 1-6 carbon atoms, alkenylsulfonamido of 2-6 carbon atoms, alkynylsulfonamido of 2-6 carbon atoms, cyano, nitro, carboxy, alkoxycarbonyl of 2-7 carbon atoms, alkanoyl of 2-7 carbon atoms, alkenoyl of 3-7 carbon atoms, N-alkyl-N-alkenylamino of 4 to 12 carbon atoms, N,N-dialkenylamino of 6-12 carbon atoms, phenylamino, benzylamino, phenoxy, phenyl, thiophenoxy, benzyl, alkylamino of 1-6 carbon atoms, alkanoyloxy of 2-7 carbon atoms, alkenoyloxy of 3-8 carbon atoms, alkynoyloxy of 3-8 carbon atoms, carbamoyl, N-alkylcarbamoyl of 2-7 carbon atoms, N,N-dialkylcarbamoyl of 3-13 carbon atoms, dialkylamino of 2 to 12 carbon atoms, alkanoyloxymethyl group of 2-7 carbon atoms, alkenoyloxymethyl group of 2-7 carbon atoms, alkynoyloxymethyl group of 2-7 carbon atoms, azido, benzoyl, carboxyalkyl of 2-7 carbons, carboalkoxyalkyl of 3-8 carbon atoms, 
       
       
         
           
           
               
               
           
         
         R 5  is independently hydrogen, alkyl of 1-6 carbon atoms, aminoalkyl of 1-6 carbon atoms, N-alkylaminoalkyl of 2-9 carbon atoms, N,N-dialkylaminoalkyl of 3-12 carbon atoms, N-cycloalkylaminoalkyl of 4-12 carbon atoms, N-cycloalkyl-N-alkylaminoalkyl of 5-18 carbon atoms, N,N-dicycloalkylaminoalkyl of 7-18 carbon atoms, morpholino-N-alkyl wherein the alkyl group is 1-6 carbon atoms, piperidino-N-alkyl wherein the alkyl group is 1-6 carbon atoms, N-alkyl-piperazino-N-alkyl wherein either alkyl group is 1-6 carbon atoms, azacycloalkyl-N-alkyl of 3-11 carbon atoms, hydroxyalkyl of 1-6 carbon atoms, alkoxyalkyl of 2-8 carbon atoms, phenyl; 
         V is (CH 2 ) m , O, S, or NR 6 ; 
         R 7  is NR 6 R 6 , OR 6 , J, N(R 6 ) 3   + , or NR 6 (OR 6 ); 
         M is NR 6 , O, S, N—[(C(R 6 ) 2 ) p NR 6 R 6 ], or N—[(C(R 6 ) 2 ) p —OR 6 ]; 
         W is NR 6 , O, S, or is a bond; 
         Het is a heterocycle selected from the group consisting of morpholine, thiomorpholine, thiomorpholine S-oxide, thiomorpholine S,S-dioxide, piperidine, pyrrolidine, aziridine, pyridine, imidazole, 1,2,3-triazole, 1,2,4-triazole, thiazole, thiazolidine, tetrazole, piperazine, furan, thiophene, tetrahydrothiophene, tetrahydrofuran, dioxane, 1,3-dioxolane pyrrole, and tetrahydropyran; wherein the heterocycle is optionally mono- or di-substituted on carbon or nitrogen with R 6 ; optionally mono- or di-substituted on carbon with hydroxy, —N(R 6 ) 2 , or —OR 6 ; optionally mono or di-substituted on carbon with the mono-valent radicals —(C(R 6 ) 2 ) s OR 6  or —[(C(R 6 ) 2 ) s N(R 6 ) 2 ]; or optionally mono or di-substituted on a saturated carbon with divalent radicals ═O or —O(C(R 6 ) 2 ) s O—; 
         Ph is a phenyl ring optionally mono-, di- or tri-substituted with halogen, alkyl of 1-6 carbon atoms, trifluoromethyl, nitro, cyano, azido, halomethyl, carboxyl, alkoxycarbonyl, alkylthio, mercapto, mercaptomethyl, —N(R 6 ) 2 , —OR 6 , —(C(R 6 ) 2 ) s OR 6 , —[(C(R 6 ) 2 ) s N(R 6 ) 2 ], or —(C(R 6 ) 2 ) k Het; 
         R 6  is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 1-6 carbon atoms, alkanoyl of 2-7 carbon atoms, carbamoylalkyl of 2-7 carbon atoms, hydroxyalkyl of 1-6 carbon atoms, hydroxycycloalkyl of 3-6 carbon atoms, or carboxyalkyl of 2-7 carbon atoms; or 
         R 6  is phenyl optionally mono-, di-, or tri-substituted with halogen, alkoxy of 1-6 carbon atoms, trifluoromethyl, amino, alkylamino of 1-3 carbon atoms, dialkylamino of 2-6 carbon atoms, nitro, cyano, azido, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, carboxyl, alkoxycarbonyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, phenylamino, benzylamino; 
         alkanoylamino of 1-6 carbon atoms or alkyl of 1-6 carbon atoms; 
         R 8  and R 9  are each, independently, —[(C(R 6 ) 2 ) r NR 6 R 6 ], or —[(C(R 6 ) 2 ) r OR 6 ]; 
         J is independently hydrogen, chlorine, fluorine, or bromine; 
         g=1-6; 
         k=0-4; 
         p=2-4; 
         q=0-4; 
         r=1-4; 
         s=1-6; 
       
       or a pharmaceutically acceptable salt thereof;
 provided that when R 5  is bound to a nitrogen atom, the resulting structures do not include —N—C—N— or —O—C—N— radicals; and when R 5  is bound to an oxygen atom, the resulting structures do not include an —N—C—O— radical; 
 provided that when R 6  is alkenyl of 2-7 carbon atoms or alkynyl of 2-7 carbon atoms, the alkenyl or alkynyl moieties are bound to a nitrogen or oxygen atom through a saturated carbon atom in the alkenyl or alkynyl chain; 
 provided that when V is NR 6  and R 7  is NR 6 R 6 , N(R 6 ) 3   + , or NR 6 (OR 6 ), then g=2-6; 
 provided that when M is O or S and R 7  is OR 6 , then p=1-4; 
 provided that when V is NR 6 , O, S, then k=2-4; 
 provided that when V is O or S and M or W is O or S, then k=1-4 provided that when W is not a bond with Het bonded through a nitrogen atom then q=2-4; and 
 finally provided when W is a bond with Het bonded through a nitrogen atom and V is O or NR 6  or S, then k=2-4; 
 which process comprises: 
 (a) reacting a substituted bicyclo[4.2.0]octa-1(6),2,4-triene-7-carbonitrile of formula 1 
 
       
         
           
           
               
               
           
         
       
       wherein R 1 , R 2 , and R 3  are defined as above;
 with a base to form a first intermediate having the corresponding anion alpha to the cyano group; 
 (b) reacting said first intermediate with a suitable disulfide electrophile to yield an alpha-sulfenylated 1-cyanobenzocyclobutene of formula 2 
 
       
         
           
           
               
               
           
         
       
       wherein R 10  is defined as an alkyl of 1-10 carbons, cycloalkyl of 3-10 carbons, alkenyl of 3-10 carbons, cycloalkenyl of 4-10 carbons, alkynyl of 3-10 carbons, Ph or L (where Ph and L are as hereinabove defined) and R 1 , R 2 , and R 3  are defined as above;
 (c) reacting an anionic salt of acetonitrile with said cyanobenzocyclobutenes of formula 2 to provide an amino nitrile intermediate of formula 3 
 
       
         
           
           
               
               
           
         
       
       wherein E is cyano and R 1 , R 2 , R 3 , and R 10  are defined as above; and
 (d) refluxing the formula 3 adducts in a solvent to provide the nitrile of formula A; 
 
       
         
           
           
               
               
           
         
       
       wherein R 1 , R 2 , R 3  and E are defined as above;
 (e) reacting the formula A compound with dimethylformamide dimethyl acetal, optionally in the presence of a solvent to form the corresponding amidine intermediate 9 
 
       
         
           
           
               
               
           
         
       
       wherein R 1 , R 2 , and R 3  are as defined above;
 (f) heating the amidine intermediates of formula 9 with an appropriately substituted amine 6 
 
       
         
           
           
               
               
           
         
       
       wherein Ar and n are defined as above;
 in acetic acid to form the compound of formula C. 
 
     
     
         24 . A compound of the formula 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is hydrogen, halogen, hydroxy, amino, arylamino, arylalkylamino, hydroxyamino, trifluoromethyl, trifluoromethoxy, mercapto, alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, alkenyloxy of 2-6 carbon atoms, alkynyloxy of 2-6 carbon atoms, hydroxyalkyl of 1-6 carbon atoms, mercaptoalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, cycloalkoxy of 3-8 carbon atoms, alkylthio of 1-6 carbon atoms, cycloalkylthio of 3-8 carbon atoms, alkylsulphinyl of 1-6 carbon atoms, alkylsulfonyl of 1-6 carbon atoms, alkylsulfonamido of 1-6 carbon atoms, alkenylsulfonamido of 2-6 carbon atoms, alkynylsulfonamido of 2-6 carbon atoms, cyano, nitro, carboxy, alkoxycarbonyl of 2-7 carbon atoms, alkanoyl of 2-7 carbon atoms, alkenoyl of 3-7 carbon atoms, N-alkyl-N-alkenylamino of 4 to 12 carbon atoms, N,N-dialkenylamino of 6-12 carbon atoms, phenylamino, benzylamino, phenoxy, phenyl, thiophenoxy, benzyl, alkylamino of 1-6 carbon atoms, alkanoyloxy of 2-7 carbon atoms, alkenoyloxy of 3-8 carbon atoms, alkynoyloxy of 3-8 carbon atoms, carbamoyl, N-alkylcarbamoyl of 2-7 carbon atoms, N,N-dialkylcarbamoyl of 3-13 carbon atoms, dialkylamino of 2 to 12 carbon atoms, alkanoyloxymethyl group of 2-7 carbon atoms, alkenoyloxymethyl group of 2-7 carbon atoms, alkynoyloxymethyl group of 2-7 carbon atoms, azido, benzoyl, carboxyalkyl of 2-7 carbons, carboalkoxyalkyl of 3-8 carbon atoms, 
 
       
         
           
           
               
               
           
         
         R 2  and R 3  are each, independently, halogen, hydroxy, amino, arylamino, arylalkylamino, hydroxyamino, trifluoromethoxy, alkenyloxy of 2-6 carbon atoms, alkynyloxy of 2-6 carbon atoms, alkoxy of 1-6 carbon atoms, cycloalkoxy of 3-8 carbon atoms, N-alkyl-N-alkenylamino of 4 to 12 carbon atoms, N,N-dialkenylamino of 6-12 carbon atoms, phenylamino, benzylamino, alkylamino of 1-6 carbon atoms, alkanoyloxy of 2-7 carbon atoms, alkenoyloxy of 3-8 carbon atoms, alkynoyloxy of 3-8 carbon atoms, dialkylamino of 2 to 12 carbon atoms, 
       
       
         
           
           
               
               
           
         
         R 5  is independently hydrogen, alkyl of 1-6 carbon atoms, aminoalkyl of 1-6 carbon atoms, N-alkylaminoalkyl of 2-9 carbon atoms, N,N-dialkylaminoalkyl of 3-12 carbon atoms, N-cycloalkylaminoalkyl of 4-12 carbon atoms, N-cycloalkyl-N-alkylaminoalkyl of 5-18 carbon atoms, N,N-dicycloalkylaminoalkyl of 7-18 carbon atoms, morpholino-N-alkyl wherein the alkyl group is 1-6 carbon atoms, piperidino-N-alkyl wherein the alkyl group is 1-6 carbon atoms, N-alkyl-piperazino-N-alkyl wherein either alkyl group is 1-6 carbon atoms, azacycloalkyl-N-alkyl of 3-11 carbon atoms, hydroxyalkyl of 1-6 carbon atoms, alkoxyalkyl of 2-8 carbon atoms, phenyl; 
         V is (CH 2 ) m , O, S, or NR 6 ; 
         R 7  is NR 6 R 6 , OR 6 , J, N(R 6 ) 3   + , or NR 6 (OR 6 ); 
         M is NR 6 , O, S, N—[(C(R 6 ) 2 ) p NR 6 R 6 ], or N—[(C(R 6 ) 2 ) p —OR 6 ]; 
         W is NR 6 , O, S, or is a bond; 
         Het is a heterocycle selected from the group consisting of morpholine, thiomorpholine, thiomorpholine S-oxide, thiomorpholine S,S-dioxide, piperidine, pyrrolidine, aziridine, pyridine, imidazole, 1,2,3-triazole, 1,2,4-triazole, thiazole, thiazolidine, tetrazole, piperazine, furan, thiophene, tetrahydrothiophene, tetrahydrofuran, dioxane, 1,3-dioxolane pyrrole, and tetrahydropyran; wherein the heterocycle is optionally mono- or di-substituted on carbon or nitrogen with R 6 ; optionally mono- or di-substituted on carbon with hydroxy, —N(R 6 ) 2 , or —OR 6 ; optionally mono or di-substituted on carbon with the mono-valent radicals —(C(R 6 ) 2 ) s OR 6  or —[(C(R 6 ) 2 ) s N(R 6 ) 2 ]; or optionally mono or di-substituted on a saturated carbon with divalent radicals ═O or —O(C(R 6 ) 2 ) s O—; 
         Ph is a phenyl ring optionally mono-, di- or tri-substituted with halogen, alkyl of 1-6 carbon atoms, trifluoromethyl, nitro, cyano, azido, halomethyl, carboxyl, alkoxycarbonyl, alkylthio, mercapto, mercaptomethyl, —N(R 6 ) 2 , —OR 6 , —(C(R 6 ) 2 ) s OR 6 , —[(C(R 6 ) 2 ) s N(R 6 ) 2 ], or —(C(R 6 ) 2 ) k Het; 
         R 6  is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 1-6 carbon atoms, alkanoyl of 2-7 carbon atoms, carbamoylalkyl of 2-7 carbon atoms, hydroxyalkyl of 1-6 carbon atoms, hydroxycycloalkyl of 3-6 carbon atoms, or carboxyalkyl of 2-7 carbon atoms; or 
         R 6  is phenyl optionally mono-, di-, or tri-substituted with halogen, alkoxy of 1-6 carbon atoms, trifluoromethyl, amino, alkylamino of 1-3 carbon atoms, dialkylamino of 2-6 carbon atoms, nitro, cyano, azido, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, carboxyl, alkoxycarbonyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, phenylamino, benzylamino; 
         alkanoylamino of 1-6 carbon atoms or alkyl of 1-6 carbon atoms; 
         R 8  and R 9  are each, independently, —[(C(R 6 ) 2 ) r NR 6 R 6 ], or —[(C(R 6 ) 2 ) r OR 6 ]; 
         J is independently hydrogen, chlorine, fluorine, or bromine; 
         g=1-6; 
         k=0-4; 
         p=2-4; 
         q=0-4; 
         r=1-4; 
         s=1-6; and 
         m is 0-3. 
       
     
     
         25 . A compound of the formula 
       
         
           
           
               
               
           
         
       
       wherein
 X′ is Cl or Br; 
 R 1 , R 2  and R 3  are each, independently, not present, hydrogen, halogen, hydroxy, amino, arylamino, arylalkylamino, hydroxyamino, trifluoromethyl, trifluoromethoxy, mercapto, alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, alkenyloxy of 2-6 carbon atoms, alkynyloxy of 2-6 carbon atoms, hydroxyalkyl of 1-6 carbon atoms, mercaptoalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, cycloalkoxy of 3-8 carbon atoms, alkylthio of 1-6 carbon atoms, cycloalkylthio of 3-8 carbon atoms, alkylsulphinyl of 1-6 carbon atoms, alkylsulfonyl of 1-6 carbon atoms, alkylsulfonamido of 1-6 carbon atoms, alkenylsulfonamido of 2-6 carbon atoms, alkynylsulfonamido of 2-6 carbon atoms, cyano, nitro, carboxy, alkoxycarbonyl of 2-7 carbon atoms, alkanoyl of 2-7 carbon atoms, alkenoyl of 3-7 carbon atoms, N-alkyl-N-alkenylamino of 4 to 12 carbon atoms, N,N-dialkenylamino of 6-12 carbon atoms, phenylamino, benzylamino, phenoxy, phenyl, thiophenoxy, benzyl, alkylamino of 1-6 carbon atoms, alkanoyloxy of 2-7 carbon atoms, alkenoyloxy of 3-8 carbon atoms, alkynoyloxy of 3-8 carbon atoms, carbamoyl, N-alkylcarbamoyl of 2-7 carbon atoms, N,N-dialkylcarbamoyl of 3-13 carbon atoms, dialkylamino of 2 to 12 carbon atoms, alkanoyloxymethyl group of 2-7 carbon atoms, alkenoyloxymethyl group of 2-7 carbon atoms, alkynoyloxymethyl group of 2-7 carbon atoms, azido, benzoyl, carboxyalkyl of 2-7 carbons, carboalkoxyalkyl of 3-8 carbon atoms, 
 
       
         
           
           
               
               
           
         
         R 5  is independently hydrogen, alkyl of 1-6 carbon atoms, aminoalkyl of 1-6 carbon atoms, N-alkylaminoalkyl of 2-9 carbon atoms, N,N-dialkylaminoalkyl of 3-12 carbon atoms, N-cycloalkylaminoalkyl of 4-12 carbon atoms, N-cycloalkyl-N-alkylaminoalkyl of 5-18 carbon atoms, N,N-dicycloalkylaminoalkyl of 7-18 carbon atoms, morpholino-N-alkyl wherein the alkyl group is 1-6 carbon atoms, piperidino-N-alkyl wherein the alkyl group is 1-6 carbon atoms, N-alkyl-piperazino-N-alkyl wherein either alkyl group is 1-6 carbon atoms, azacycloalkyl-N-alkyl of 3-11 carbon atoms, hydroxyalkyl of 1-6 carbon atoms, alkoxyalkyl of 2-8 carbon atoms, phenyl; 
         V is (CH 2 ) m , O, S, or NR 6 ; 
         R 7  is NR 6 R 6 , OR 6 , J, N(R 6 ) 3   + , or NR 6 (OR 6 ); 
         M is NR 6 , O, S, N—[(C(R 6 ) 2 ) p NR 6 R 6 ], or N—[(C(R 6 ) 2 ) p —OR 6 ]; 
         W is NR 6 , O, S, or is a bond; 
         Het is a heterocycle selected from the group consisting of morpholine, thiomorpholine, thiomorpholine S-oxide, thiomorpholine S,S-dioxide, piperidine, pyrrolidine, aziridine, pyridine, imidazole, 1,2,3-triazole, 1,2,4-triazole, thiazole, thiazolidine, tetrazole, piperazine, furan, thiophene, tetrahydrothiophene, tetrahydrofuran, dioxane, 1,3-dioxolane pyrrole, and tetrahydropyran; wherein the heterocycle is optionally mono- or di-substituted on carbon or nitrogen with R 6 ; optionally mono- or di-substituted on carbon with hydroxy, —N(R 6 ) 2 , or —OR 6 ; optionally mono or di-substituted on carbon with the mono-valent radicals —(C(R 6 ) 2 ) s OR 6  or —[(C(R 6 ) 2 ) s N(R 6 ) 2 ]; or optionally mono or di-substituted on a saturated carbon with divalent radicals ═O or —O(C(R 6 ) 2 ) s O—; 
         Ph is a phenyl ring optionally mono-, di- or tri-substituted with halogen, alkyl of 1-6 carbon atoms, trifluoromethyl, nitro, cyano, azido, halomethyl, carboxyl, alkoxycarbonyl, alkylthio, mercapto, mercaptomethyl, —N(R 6 ) 2 , —OR 6 , —(C(R 6 ) 2 ) s OR 6 , —[(C(R 6 ) 2 ) s N(R 6 ) 2 ], or —(C(R 6 ) 2 ) k Het; 
         R 6  is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 1-6 carbon atoms, alkanoyl of 2-7 carbon atoms, carbamoylalkyl of 2-7 carbon atoms, hydroxyalkyl of 1-6 carbon atoms, hydroxycycloalkyl of 3-6 carbon atoms, or carboxyalkyl of 2-7 carbon atoms; or 
         R 6  is phenyl optionally mono-, di-, or tri-substituted with halogen, alkoxy of 1-6 carbon atoms, trifluoromethyl, amino, alkylamino of 1-3 carbon atoms, dialkylamino of 2-6 carbon atoms, nitro, cyano, azido, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, carboxyl, alkoxycarbonyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, phenylamino, benzylamino; 
         alkanoylamino of 1-6 carbon atoms or alkyl of 1-6 carbon atoms; 
         R 8  and R 9  are each, independently, —[(C(R 6 ) 2 ) r NR 6 R 6 ], or —[(C(R 6 ) 2 ) r OR 6 ]; 
         J is independently hydrogen, chlorine, fluorine, or bromine; 
         g=1-6; 
         k=0-4; 
         p=2-4; 
         q=0-4; 
         r=1-4; 
         s=1-6; and 
         m is 0-3; 
         with the proviso that when one of R 1 , R 2 , and R 3  is a haloalkoxy of 2-6 carbon atoms, then at least one of the other two is a substituent other than hydrogen, and with the further proviso that at least one of R 1 , R 2 , and R 3  is a substituent other than hydrogen. 
       
     
     
         26 . The compound according to  claim 25  wherein R 1  is hydrogen and R 2  and R 3  are each, independently, halogen, hydroxy, amino, arylamino, arylalkylamino, hydroxyamino, trifluoromethoxy, alkenyloxy of 2-6 carbon atoms, alkynyloxy of 2-6 carbon atoms, alkoxy of 1-6 carbon atoms, cycloalkoxy of 3-8 carbon atoms, N-alkyl-N-alkenylamino of 4 to 12 carbon atoms, N,N-dialkenylamino of 6-12 carbon atoms, phenylamino, benzylamino, alkylamino of 1-6 carbon atoms, alkanoyloxy of 2-7 carbon atoms, alkenoyloxy of 3-8 carbon atoms, alkynoyloxy of 3-8 carbon atoms, dialkylamino of 2 to 12 carbon atoms,