TRICYCLIC COMPOUNDS CAPABLE OF INHIBITING TYROSINE KINASES OF THE EPIDERMAL GROWTH FACTOR RECEPTOR FAMILY

Abstract: Epidermal growth-factor inhibitors of formula (I), wherein: 1) Y and Z are both C (carbon), both N or one N and the other C, in which case the ring structure is a linearly fused 6,6 (5 or 6) tricycle, or 2) one of Y and Z is C=C, C=N, whereupon the other one of Y or Z is simply a bond between the two aromatic rings, then the ring structure is a nonlinear 6,6 (5 or 6) tricycle, or 3) one of Y and Z is N, O or S, whereupon the other one of Y or Z is simply a bond between the two aromatic rings, then the ring structure is a fused 6,5 (5 or 6) tricycle; A, B, D and E can all be carbon, or up to two of them can be nitrogen, whereupon the remaining atoms must be carbon, or any two contiguous positions in A-E can be a single heteroatom, N, O or S, forming a five membered fused ring, in which case one of the two remaining atoms must be carbon, and the other can be either carbon or nitrogen. X = O, S, NH or NR<9>, such that R<9> = lower alkyl, OH, NH2, lower alkoxy or lower monoalkylamino m = 0-3, and Ar is phenyl, thienyl, furanyl, pyrrolyl, pyridyl, pyrimidyl, imidazolyl, pyrazinyl, oxazolyl, thiazolyl, naphthyl, benzothienyl, benzofuranyl, indolyl, quinolinyl, isoquinolinyl and quinazolinyl.

Description: TRICYCLIC COMPOUNDS CAPABLE OF INHIBITING TYROSINE KINASES OF THE EPIDERMAL GROWTH FACTOR RECEPTOR FAMILY Technical Field The present invention relates to tricyclic heteroaromatic compounds which inhibit the epidermal growth factor receptor and related receptors and, in particular, their tyrosine inase enzymic activity. Background Art Cancer is generally a disease of the intra- cellular signalling system, or signal transduction mechanism. Cells receive instructions from many ex¬ tracellular sources, instructing them to either pro¬ liferate or not to proliferate. The purpose of the signal transduction system is to receive these and other signals at the cell surface, get them into the cell, and then pass the signals on to the nucleus, the cytoskeleton, and transport and protein synthesis machinery. The most common cause of cancer is a se- ries of defects, either in these proteins, when they are mutated, or in the regulation of the quantity of the protein in the cell such that it is over or under produced. Most often, there are key lesions in the cell which lead to a constitutive state whereby the cell nucleus receives a signal to proliferate, when this signal is not actually present. This can occur through a variety of mechanisms. Sometimes the cell may start to produce an authentic growth factor for its own receptors when it should not, the so-called autocrine loop mechanism. Mutations to the cell sur- face receptors, which usually signal into the cell by means of tyrosine kinases, can lead to activation of the kinase in the absence of ligand, and passing of a signal which is not really there. Alternatively, many surface kinases can be overexpressed on the cell sur- face leading to an inappropriately strong response to a weak signal. There are many levels inside the cell at which mutation or overexpression can lead to the same spurious signal arising in the cell, and there are many other kinds of signalling defect involved in cancer. This invention touches upon cancers which are driven by the three mechanisms just described, and which involve cell surface receptors of the epidermal growth factor receptor tyrosine kinase family (EGFR) . This family consists of the EGF receptor (also known as Erb-Bl) , the Erb-B2 receptor, and its constitui- tively active oncoprotein mutant Neu, the Erb-B3 re¬ ceptor and the Erb-B4 receptor. Additionally, other biological processes driven through members of the EGF family of receptors can also be treated by compounds of the invention described below. The EGFR has as its two most important ligands Epidermal Growth Factor (EGF) and Transforming Growth Factor alpha (TGFalpha) . The receptors appear to have only minor functions in adult humans, but are apparently implicated in the disease process of a large portion of all cancers, especially colon and breast cancer. The closely related Erb-B2 Erb-B3 and Erb-B4 receptors have a family of Heregulins as their major ligands, and receptor overexpression and muta¬ tion have been unequivocally demonstrated as the major risk factor in poor prognosis breast cancer. Addi¬ tionally, it has been demonstrated that all four of the members of this family of receptors can form heterodimeric signalling complexes with other members of the family, and that this can lead to synergistic transforming capacity if more than one member of the family is overexpressed in a malignancy. Overexpres- sion of more than one family member has been shown to be relatively common in human malignancies. The proliferative skin disease psoriasis has no good cure at present. It is often treated by anti- cancer agents such as methotrexate, which have very serious side effects, and which are not very effective at the toxicity-limited doses which have to be used. It is believed that TGFalpha is the major growth fac¬ tor overproduced in psoriasis, since 50% of transgenic mice which overexpress TGF alpha develop psoriasis. This suggests that a good inhibitor of EGFR signalling could be used as an antipsoriatic agent, preferably, but not necessarily, by topical dosing. EGF is a potent mitogen for renal tubule cells. Fourfold increases in both EGF urinary secre- tion and EGF RNA have been noted in mice with early stage streptozoicin-induced diabetes. In addition increased expression of the EGFR has been noted in patients with proliferative glomerulonephritis (Roychaudhury et al. Pathology 1993, 25, 327) . The compounds of the current invention should be useful in treating both proliferative glomerulonephritis and diabetes-induced renal disease. Chronic pancreatitis in patients has been reported to correlate with large increases in expres¬ sion for both EGFR and TGF alpha. (Korc et al. Gut 1994, 35, 1468) . In patients showing a more severe form of the disease, typified by an enlargement of the head of the pancreas, there was also shown to be over- expression of the erb-B2 receptor (Friess et al. Ann. Surg. 1994, 220, 183) . The compounds of the current invention should prove useful in the treatment of pancreatitis. In the processes of blastocyte maturation, blastocyte implantation into the uterine endometrium, and other periimplantation events, uterine tissues produce EGF and TGF alpha (Taga Nippon Sanka Fujinka Gakkai Zasshi 1992, 44 , 939), have elevated levels of EGFR (Brown et al. Endocrinology, 1989, 124 , 2882), and may well be induced to produce heparin-binding EGF by the proximity of the developing, but not arrested, blastocyte (Das et al. Development 1994, 120, 1071) . In turn the blastocyte has quite a high level of TGF alpha and EGFR expression (Adamson Mol . Reprod. Dev. 1990, 27, 16) . Surgical removal of the submandibular glands, the major site of EGF secretion in the body, and treatment with anti-EGFR monoclonal antibodies both greatly reduce fertility in mice (Tsutsumi et al . J. Endocrinology 1993, 138, 437), by reducing success- ful blastocyte implantation. Therefore, compounds of the current invention should prove to have useful contraceptive properties. PCT patent application Nos. O92/07844 pub- lished May 14, 1992 and 092/14716 published September 3, 1992 describe 2,4-diaminoquinazoline as potentia- tors of chemotherapeutic agents in the treatment of cancer. PCT published application No. O92/20642 published November 26, 1992 discloses bismono- and bicyclic aryl and heteroaryl compounds which inhibit EGF and/or PDGF receptor tyrosine kinase. It is an object of the present invention to inhibit the mitogenic effects of epidermal growth factor utilizing an effective amount of tricyclic pyrimidine derivatives, in particular fused heterocy- clic pyrimidine derivatives. It is another object of the present inven¬ tion to describe tricyclic pyrimidine derivatives, in particular fused heterocyclic pyrimidine derivatives, as inhibitors of the EGF, Erb-B2 and Erb-B4 receptor tyrosine kinases. It is yet another object of the present invention to describe tricyclic pyrimidine deriva- tives, in particular fused heterocyclic pyrimidine derivatives, that are useful at low dosages as inhibi¬ tors of EGF-induced mitogenesis. This therefore leads to a further object of compounds having extremely low cytotoxicity. It is a further object of the present inven¬ tion to describe tricyclic pyrimidine derivatives, in particular fused heterocyclic pyrimidine derivatives, that are useful in suppressing tumors, especially breast cancers, where mitogenesis is heavily driven by EGFR family members. It is another object of the present inven¬ tion to describe tricyclic pyrimidine derivatives, in particular fused heterocyclic pyrimidine derivatives, that have utility as chronic therapy as inhibitors of EGF-induced responses. It is another object of the current inven¬ tion to describe tricyclic pyrimidine derivatives, in particular fused heterocyclic pyrimidine derivatives, that have utility as therapeutic agents against pro¬ liferative overgrowth diseases, including but not limited to, synovial pannus invasion in arthritis, vascular restenosis and angiogenesis. Additional utility of these materials is for pancreatitis and kidney disease as well as contraception. Summary of the Invention Described is a method to inhibit epidermal growth factor by treating, with an effective inhibit¬ ing amount, a mammal, in need thereof, a compound of the following formula: wherein: 1) Y and Z are both C (carbon) , both N or one N and the other C, in which case the ring structure is a linearly fused 6,6 (5 or 6) tricy¬ cle, or 2) one of Y and Z is C=C, C=N whereupon the other one of Y or Z is simply a bond between the two aromatic rings, then the ring structure is a nonlinear 6,6 (5 or 6) tricycle, or 3) one of Y and Z is N, 0 or S, whereupon the other one of Y or Z is simply a bond between the two aromatic rings, then the ring struc- ture is a fused 6,5 (5 or 6) tricycle; A, B, D and E can all be carbon, or up to two of them can be nitrogen, whereupon the remaining atoms must be carbon, or any two contiguous positions in A-E can be a single heteroatom, N, 0 or S, forming a five membered fused ring, in which case one of the two remaining atoms must be carbon, and the other can be either carbon or nitrogen, except that the case where A and B taken together, and D and E taken sepa¬ rately are all three nitrogen atoms; X = 0, S, NH or NR 9 , such that R 9 = lower alkyl (1-4 carbon atoms) , OH, NH 2/ lower alkoxy (1-4 carbon atoms) or lower monoalkylamino (1-4 carbon atoms) ; R- -= H or lower alkyl; n = 0, 1 or 2; if n = 2, R 1 can be independently H or lower alkyl on either linking carbon atom, and both R and S stereocentres on either linker are included; R 2 is lower alkyl (1-4 carbon atoms) , cyclo- alkyl (3-8 carbon atoms) , lower alkoxy (1-4 carbon atoms) , cycloalkoxy (3-8 carbon atoms) , nitro, halo, lower perfluoroalkyl (1-4 carbon atoms) , hydroxy, lower acyloxy (1-4 carbon atoms; -O-C(O)-R), amino, lower mono or dialkylamino (1-4 carbon atoms) , lower mono or dicycloalkylamino (3-8 carbon atoms) , hydroxy- methyl, lower acyl (1-4 carbon atoms; -C(O)R), cyano, lower thioalkyl (1-4 carbon atoms) , lower sulfinyl- alkyl (1-4 carbon atoms) , lower sulfonylalkyl (1-4 carbon atoms) , thiocycloalkyl (3-8 carbon atoms) , sulfinylcycloalkyl (3-8 carbon atoms) , sulfonylcyclo- alkyl (3-8 carbon atoms) , mercapto, lower alkoxy- carbonyl (1-4 carbon atoms) , cycloalkoxycarbonyl (3-8 carbon atoms) , lower alkenyl (2-4 carbon atoms) , cycloalkenyl (4-8 carbon atoms) , lower alkynyl (2-4 carbon atoms) , or two R 2 taken together can form a carbocyclic ring of 5-7 members; and m = 0-3, wherein Ar is phenyl, thienyl, furanyl, pyrrolyl, pyridyl, pyrimidyl, imidazoyl, pyrazinyl, oxazolyl, thiazolyl, naphthyl, benzo- thienyl, benzofuranyl, indolyl, quinolinyl, isoquino¬ linyl and quinazolinyl; R 3 , R 4 , R 5 and R 6 are independently, not pres¬ ent, H, lower alkyl (1-4 carbon atoms) , cycloalkyl (3- 8 carbon atoms) , lower alkoxy (1-4 carbon atoms) , cycloalkoxy (3-8 carbon atoms) , hydroxy, lower acyloxy (1-4 carbon atoms) , amino, lower mono or dialkylamino (1-4 carbon atoms) , lower mono or dicycloalkylamino (3-8 carbon atoms) , lower alkyl (1-4 carbon atoms) or cycloalkyl (3-8 carbon atoms), carbonato (-OC(O)OR) where R is alkyl of from 1-4 carbon atoms or cyclo¬ alkyl of from 3-8 carbon atoms; or ureido or thioureido or N- or 0- linked urethane any one of which is optionally substituted by mono or di-lower alkyl (1-4 carbon atoms) or cyclo¬ alkyl (3-8 carbon atoms) ; lower thioalkyl (1-4 carbon atoms) , thio- cycloalkyl (3-8 carbon atoms) , mercapto, lower alkenyl (2-4 carbon atoms), hydrazino, N- and/or N' - mono- or di lower alkylhydrazino (1-4 carbon atoms) , lower acylamino (1-4 carbon atoms) , hydroxylamino, N- and/or 0- mono- or di lower alkylhydroxylamino (1-4 carbon atoms), or taken together can be methylene-, ethylene- or propylenedioxy, or taken together form a fused pyrrolidine, tetrahydrofuranyl, piperidinyl, piper- azinyl, morpholino or thiomorpholino ring; R 7 and R β can be independently as appropriate, lone pairs of electrons, H, or lower alkyl; any lower alkyl group substituent on any of the substituents in R 3 -R 8 which contain such a moiety can be optionally substituted with one or more of hydroxy, amino, lower monoalkylamino, lower dialkyl¬ amino, N-pyrrolidyl, N-piperidinyl, N-pyridinium, N- morpholino, N-thiomorpholino or N-piperazino groups; if one or two of A through E are N, then if any of R 3 -R 6 is on a neighboring C atom to one of the N atoms, that substituent cannot be either OH or SH; and R 10 is H or lower alkyl (1-4 carbon atoms) , amino or lower mono- or dialkylamino (1-4 carbon atoms) ; if any of the substitutents R 1 , R 2 , R 3 or R 4 contain chiral centers, or in the case of R 1 create chiral centers on the linking atoms, then all stereo- isomers thereof both separately and as racemic and/or diastereoisomeric mixtures are included; or a pharmaceutical salt or hydrate thereof. The invention pertains to the compounds, per se: with the proviso that the ring containing A- E is aromatic; and with the proviso that if A and B taken together and E are nitrogen, and if neither Y nor Z is a heteroatom, and if X = NH, and n = 1, and R 1 = H and Ar = Ph, then one of the imidazole nitrogen atoms must have a substituent from the R 3 -R 6 group other than lone pair or hydrogen; and with the proviso that if A-E are carbon, and Y is a bond, and Z is sulfur, and X = NH, and n = 0, then Ar cannot be unsubstituted phenyl, unsubsti- tuted or substituted pyridyl or unsubstituted or substituted pyrimidyl. Preferably, the compounds are subject to additional provisos: with the proviso that if A-E are carbon, Y and Z cannot be both carbon * or one ethylidene and the other a bond, unless at least one of R 3 -R 6 is not hy- drogen; with the proviso that if A-E are carbon one of Y and Z cannot be nitrogen, substituted with hydro¬ gen, and the other a bond. Brief Description Of The Drawings FIGURE 1 is an effect of Example 1 on EGF receptor autophosphorylation in A431 human epidermoid carcinoma; FIGURE 2 is an effect of Examples 6 and 17 on EGF receptor autophosphorylation in A431 human epidermoid carcinoma; FIGURE 3 is an effect of Example 8 on EGF receptor autophosphorylation in A431 human epidermoid carcinoma; FIGURE 4 is an effect of Example 10 on EGF receptor autophosphorylation in.A431 human epidermoid carcinoma; FIGURE 5 is an effect of Example 15 on EGF receptor autophosphorylation in A431 human epidermoid carcinoma; FIGURE 6 is an effect of Example 25 on EGF receptor autophosphorylation in A431 human epidermoid carcinoma; FIGURE 7 is an effect of Example 28 on EGF receptor autophosphorylation in A431 human epidermoid carcinoma; FIGURE 8 is an effect of Example 29 on EGF receptor autophosphorylation in A431 human epidermoid carcinoma; and FIGURE 9 is an effect of Examples 6 and 17 on soft agar clone formation of MDA-MB-468 human breast carcinoma. Description of Preferred Embodiments Nomenclature and Numbering as used Herein Trihβtβroarornatic Systems Nomenclature. All tricycles containing a benzene ring fused directly to the pyrimidine ring have been named as quinazoline derivatives. All other tricycles are named as pyrimidine derivatives, either fused to a bicyclic nucleus such as indole or benzo- thiophene, or to two separate monocyclic heterocycles such as pyridothiophene. In such cases the first ring given is always the one distal to the pyrimidine ring. Ring fusion numbers. For quinazoline deriv- atives the quinazoline nucleus is lettered counter¬ clockwise with the N1-C2 bond being a, and the three possible ring fusion positions being f, g and h. The C-ring is numbered 1-5/6 from its highest atomic weight heteroatom, with the ring fusion numbering being decided by the numbered bridgehead atom which first meets the counterclockwise flow of the quina¬ zoline lettering. For systems with three fused heteroaromatic rings, the pyrimidine ring (A) is always chosen as the root system and is d-fused to the B-ring lettering in a clockwise direction. The central B-ring is numbered 1-5/6, starting at the heteroatom, and going first via the B/C ring junction and then the B/A ring junction. It can be numbered either clockwise, when the hetero¬ atom is at the bottom, or counterclockwise, when the heteroatom is at the top, (as is illustrated above) , and the ring fusion numbering is decided by the num¬ bered bridgehead atom which first meets the clockwise flow of the pyrimidine lettering. The C-ring is num¬ bered l'-5'/6' from the highest priority heteroatom, towards lower priority heteroatoms if present, and if there are no other heteroatoms, in the direction which gives the lowest numbering to the ring junction. The first C-ring fusion number is that of the bridgehead atom which has the lowest numbering in the B-ring numbering system. In the first set of parentheses the C-ring numbers of the B/C bridgehead atoms are given, followed after the colon by the B-ring numbers for the same atoms. The second set of parentheses contain the B-ring numbers for the A/B-bridgehead atoms, followed after the dash by the shared bond in the A-ring let- tering system. Thus, the example above illustrates a [5' ,4' :2,3] [5,6-d] tricyclic system. Substituent Numbering. In all of the exam¬ ples, the numbering is taken from the bottom nitrogen of the pyrimidine A ring as 1, and then all nonbridge- head atoms are counted consecutively in a counter¬ clockwise direction from that point, as illustrated above for a 6,6,6-system by the bolded numbers. 1. A preferred form of the invention has n = 0, A-E, Y & Z being carbon, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R 8 hydrogen. A suitable ring structure is: 2. Another preferred form of the invention has, n = 0 or 1, with one of A & B or D & E taken together as oxygen, the remaining pair both being carbon, along with Y and Z, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R β hydrogen or a lone pair of electrons where appropriate. A suitable ring structure is: 3. Another preferred form of the invention has, n - 0 or 1, with one of A & B or D _< E taken together as sulfur, the remaining pair both being carbon, along with Y and Z, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R β hydrogen or a lone pair of electrons where appropriate. 4. Another preferred form of the invention has, n = 0 or 1, with one of A __ B or D £. E taken together as nitrogen, the remaining pair both being carbon, along with Y and Z, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R β hydrogen or optional¬ ly lower alkyl if on nitrogen. A suitable ring struc¬ ture is: 5. Another preferred form of the invention has n = 0 or l, A & B taken together as oxygen, and E as nitrogen, or D _ E taken together as oxygen and A as nitrogen, Y and Z both carbon, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R 8 hydrogen or a lone pair of electrons where appropriate. 6. Another preferred form of the invention has n = 0 or l, A & B taken together as sulfur, and E as nitrogen, or D & E taken- together as sulfur and A as nitrogen, Y and Z both carbon, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R 8 hydrogen or a lone pair of electrons where appropriate. A suitable ring structure is: 7. Another preferred form of the invention has n = 0 or l, A & B taken together, and E as nitro¬ gen, Y and Z both carbon, X = NH, Ar a benzene ring, optionally substituted, and R s -R 8 hydrogen or optional- ly lower alkyl if on nitrogen, or a lone pair of elec¬ trons where appropriate. 8. Another preferred form of the invention has n = 0 or 1, A & B taken together as oxygen, and D as nitrogen, or D & E taken together as oxygen and B as nitrogen, Y and Z both carbon, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R 8 hydrogen, lower alkyl, or a lone pair of electrons where appropriate. 9. Another preferred form of the invention has n = 0 or l, A & B taken together as sulfur, and D as nitrogen, or D & E taken together as sulfur and B as nitrogen, Y and Z both carbon, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R 8 hydrogen, lower alkyl, or a lone pair of electrons where appropriate. 10. Another preferred form of the invention has n = 0 or l, A & B taken together, and D as nitro¬ gen, or D & E taken together, and B as nitrogen, Y and Z both carbon, X = NH, Ar a.benzene ring, optionally substituted, and R 5 -R 8 hydrogen, lower alkyl, or a lone pair of electrons where appropriate. A suitable ring structure is: 11. Another preferred form of the invention has n = 0, A & B taken together, with D & E taken separately as nitrogen, Y and Z both carbon, X - NH, Ar a benzene ring, optionally substituted, and R 5 -R 8 hydrogen or optionally lower alkyl if on nitrogen, or a lone pair of electrons where appropriate. 12. Another preferred form of the invention has n = 0 or 1, with one of A, B, D or E as nitrogen, the remaining three being carbon, along with Y and Z, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R 8 hydrogen or a lone pair of electrons where appro¬ priate. 13. Another preferred form of the invention has n = 0, with any two of A, B, D or E as nitrogen, the remaining two being carbon, along with Y and Z, X - NH, Ar a benzene ring, optionally substituted, and R 5 -R 8 hydrogen or a lone pair of electrons where appro¬ priate. 14. Another preferred form of the invention has n = 0, A-E, and one of Y and Z being carbon, the other nitrogen, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R 8 hydrogen or a lone pair of elec- trons where appropriate. A suitable ring structure is: 15. Another preferred form of the invention has, n = 0 or 1, with one of A & B or D & E taken together as oxygen, the remaining pair both being carbon, along with one of Y and Z, the other being nitrogen, X = NH, Ar a benzene ring, optionally sub¬ stituted, and R 5 -R 8 hydrogen or a lone pair of elec¬ trons where appropriate. A suitable structure is: 16. Another preferred form of the invention has, n -= 0 or 1, with one of A & B or D &.E taken together as sulfur, the remaining pair both being . carbon, along with one of Y and Z, the other being nitrogen, X = NH, Ar a benzene ring, optionally sub¬ stituted, and R 5 -R 8 hydrogen or a lone pair of elec¬ trons where appropriate. 17. Another preferred form of the invention has, n = 0 or 1, with one of A & B or D & E taken together as nitrogen, the remaining pair both being carbon, along with one of Y and Z, the other being nitrogen, X = NH, Ar a benzene ring, optionally sub¬ stituted, and R 5 -R 8 hydrogen, or optionally lower alkyl if on nitrogen in the pyrrole ring, or a lone pair of electrons where appropriate. 18. Another preferred form of the invention has n = 0 or l, A & B taken together as oxygen, and E as nitrogen, or D & E taken together as oxygen and A as nitrogen, one of Y and Z being carbon the other nitrogen, X =- NH, Ar a benzene ring, optionally sub¬ stituted, and R 5 -R 8 hydrogen or a lone pair of elec¬ trons where appropriate. A suitable ring structure is: 19. Another preferred form of the invention has n = 0 or 1, A & B taken together as sulfur, and E as nitrogen, or D & E taken- together as sulfur and A as nitrogen, one of Y and Z being carbon the other nitrogen, X -= NH, Ar a benzene ring, optionally sub- stituted, and R 5 -R 8 hydrogen or a lone pair of elec¬ trons where appropriate. 20. Another preferred form of the invention has n = 0 or 1, A & B taken together, and E as nitro¬ gen, one of Y and Z being carbon the other nitrogen, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R 8 hydrogen or optionally lower alkyl if on nitrogen or a lone pair of electrons where appropriate. 21. Another preferred form of the invention has n = 0 or l, A & B taken together as oxygen, and D as nitrogen, or D & E taken together as oxygen and B as nitrogen, one of Y and Z being carbon the other nitrogen, X = NH, Ar a benzene ring, optionally sub¬ stituted, and R 5 -R 8 hydrogen, lower alkyl, or a lone pair of electrons where appropriate. 22. Another preferred form of the invention has n = 0 or 1, A & B taken together as sulfur, and D as nitrogen, or D & E taken together as sulfur and B as nitrogen, one of Y and Z being carbon the other nitrogen, X = NH, Ar a benzene ring, optionally sub- stituted, and R 5 -R 8 hydrogen, lower alkyl, or a lone pair of electrons where appropriate. 23. Another preferred form of the invention has n = 0 or l, A & B taken together, and D as nitro¬ gen, or D & E taken together, and B as nitrogen, one of Y and Z being carbon the other nitrogen, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R 8 hy¬ drogen, lower alkyl, or a lone pair of electrons where appropriate. 24. Another preferred form of the invention has n = 0 or 1, with one of A, B, D or E as nitrogen, the remaining three being carbon, along with one of Y and Z, the other being nitrogen, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R 8 hydrogen or a lone pair of electrons where appropriate. A suitable ring structure is: 25. Another preferred form of the invention has n = 0, with any two of A, B, D or E as nitrogen, the remaining two being carbon, along with one of Y and Z, the other being nitrogen, X -= NH, Ar a benzene ring, optionally substituted, and R s -R 8 hydrogen or a lone pair of electrons where appropriate. 26. A preferred form of the invention has n = 0, A-E carbon, Y and Z nitrogen, X = NH, Ar a ben¬ zene ring, optionally substituted, and R 5 -R 8 hydrogen or a lone pair of electrons where appropriate. A suitable ring structure is: 27. Another preferred form of the invention has n = 0 or 1, A-E being carbon, one of Y & Z being ethylidene, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R 8 hydrogen. A suitable ring structure is: 28. Another preferred form of the invention has, n = 0 or 1, with one of A & B or D & E taken together as oxygen, the remaining pair both being carbon, one of Y & Z being ethylidene, X - NH, Ar a benzene ring, op¬ tionally substituted, and R 5 -R 8 hydrogen or a lone pair of electrons where appropriate. 29. Another preferred form of the invention has, n = 0 or 1, with one of A & B or D & E taken together as sulfur, the remaining pair both being carbon, one of Y & Z being ethylidene, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R 8 hydro¬ gen or a lone pair of electrons where appropriate. 30. Another preferred form of the invention has, n = 0 or 1, with one of A & B or D & E taken together as nitrogen, the remaining pair both being carbon, one of Y & Z being ethylidene, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R 8 hydro¬ gen or optionally lower alkyl if on nitrogen. 31. Another preferred form of the invention . has n = O or l, A & B taken together as oxygen, and E as nitrogen, or D & E taken together as oxygen and A as nitrogen, one of Y & Z being ethylidene, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R 8 hy¬ drogen or a lone pair of electrons where appropriate. 32. Another preferred form of the invention has n = 0 or 1, A & B taken together as sulfur, and E as nitrogen, or D & E taken together as sulfur and A as nitrogen, one of Y & Z being ethylidene, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R 8 hy¬ drogen or a lone pair of electrons where appropriate. 33. Another preferred form of the invention has n = 0, A & B taken together, and E as nitrogen, one of Y & Z being ethylidene, X = NH, Ar a benzene • ring, optionally substituted, and R 5 -R 8 hydrogen or optionally lower alkyl if on nitrogen or a lone pair of electrons where appropriate. A suitable ring structure is: 34. Another preferred form of the invention has n = 0 or l, A & B taken together as oxygen, and D as nitrogen, or D & E taken together as oxygen and B as nitrogen, one of Y & Z being ethylidene, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R B hy¬ drogen, lower alkyl, or a lone pair of electrons where appropriate. 35. Another preferred form of the invention has n = 0 or 1, A & B taken together as sulfur, and D as nitrogen, or D & E taken together as sulfur and B as nitrogen, one of Y & Z being ethylidene, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R 8 hy¬ drogen, lower alkyl, or a lone pair of electrons where appropriate. A suitable ring structure is: 36. Another preferred form of the invention has n = 0 or 1, A & B taken together, and D as ni- trogen, or D & E taken together, and B as nitrogen, one of Y & Z being ethylidene, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R 8 hydrogen, lower alkyl, or a lone pair of electrons where appropriate. 37. Another preferred form of the invention has n = 0 or 1, with one of A, B, D or E as nitrogen, the remaining three being carbon, one of Y & Z being ethylidene, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R 8 hydrogen or a lone pair of elec¬ trons where appropriate. 38. Another preferred form of the invention has n = 0, with any two of A, B, D or E as nitrogen, the remaining two being carbon, one of Y & Z being ethylidene, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R 8 hydrogen or a lone pair of elec¬ trons where appropriate. 39. Another preferred form of the invention has n = 0 or 1, A-E being carbon, one of Y & Z being sulfur, X = NH, Ar a benzene ring, optionally substi¬ tuted, and R 5 -R 8 hydrogen or a lone pair of electrons where appropriate. A suitable ring structure is: 40. Another preferred form of the invention has, n = 0 or 1, with one of A & B or D & E taken together as oxygen, the remaining pair both being carbon, one of Y & Z being sulfur, X = NH, Ar a ben¬ zene ring, optionally substituted, and R 5 -R 8 hydrogen or a lone pair of electrons where appropriate. 41. Another preferred form of the invention has, n = 0 or 1, with one of A & B or D & E- taken together as sulfur, the remaining pair both being carbon, one of Y & Z being sulfur, X = NH, Ar a ben¬ zene ring, optionally substituted, and R 5 -R 8 hydrogen or a lone pair of electrons where appropriate. 42. Another preferred form of the invention has, n = 0 or 1, with one of A & B or D & E taken together as nitrogen, the remaining pair both being carbon, one of Y & Z being sulfur, X = NH, Ar a ben¬ zene ring, optionally substituted, and R 5 -R 8 hydrogen or a lone pair of electrons where appropriate or op¬ tionally lower alkyl if on nitrogen. 43. Another preferred form of the invention has n = 0 or 1, A & B taken together as oxygen, and E as nitrogen, or D & E taken together as oxygen and A as nitrogen, one of Y & Z being sulfur, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R 8 hydro- gen or a lone pair of electrons where appropriate. 44. Another preferred form of the invention has n = 0 or l, A & B taken together as sulfur, and E as nitrogen, or D & E taken together as sulfur and A as nitrogen, one of Y & Z being sulfur, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R 8 hydro¬ gen or a lone pair of electrons where appropriate. A suitable ring structure is: 45. Another preferred form of the invention has n = 0, A & B taken together, and E as nitrogen, one of Y & Z being sulfur, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R 8 hydrogen or optional¬ ly lower alkyl if on nitrogen, or a lone pair of elec¬ trons where appropriate. 46. Another preferred form of the invention has n = 0 or l, A & B taken together as oxygen, and D as nitrogen, or D & E taken togetner as oxygen and B as nitrogen, one of Y & Z being sulfur, X = NH, Ar a benzene ring, optionally substituted, and R s -R 8 hydro¬ gen, lower alkyl, or a lone pair of electrons where appropriate. 47. Another preferred form of the invention has n = 0 or 1, A & B taken together as sulfur, and D as nitrogen, or D & E taken together as sulfur and B as nitrogen, one of Y & Z being sulfur, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R 8 hydro¬ gen, lower alkyl, or a lone pair of electrons where appropriate. 48. Another preferred form of the invention has n = O or l, A & B taken together, and D as nitro¬ gen, or D & E taken together, and B as nitrogen, one of Y & Z being sulfur, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R 8 hydrogen, lower al- kyl, or a lone pair of electrons where appropriate. 49. Another preferred form of the invention has n = 0 or 1, with one of.A, B, D or E as nitrogen, the remaining three being carbon, one of Y & Z being sulfur, X = NH, Ar a benzene ring, optionally substi- tuted, and R 5 -R 8 hydrogen or a lone pair of electrons where appropriate. 50. Another preferred form of the invention has n = 0 or 1, A-E being carbon, one of Y & Z being nitrogen, X = NH, Ar a benzene ring, optionally sub- stituted, and R 5 -R 8 hydrogen, or optionally lower alkyl if on nitrogen. 51. Another preferred form of the invention has, n = 0 or 1, with one of A & B or D & E taken together as oxygen, the remaining pair both being carbon, one of Y & Z being nitrogen, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R 8 hydro¬ gen or a lone pair of electrons where appropriate, or optionally lower alkyl if on nitrogen. 52. Another preferred form of the invention has, n = 0 or 1, with one of A & B or D & E taken together as sulfur, the remaining pair both being carbon, one of Y & Z being nitrogen, Ar a benzene ring, optionally substituted, and R 5 -R B hydrogen or a lone pair of electrons where appropriate, or optional¬ ly lower alkyl if on.nitrogen. 53. Another preferred form of the invention has, n = 0 or 1, with one of A & B or D & E taken together as nitrogen, the remaining pair both being carbon, one of Y & Z being nitrogen, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R 8 hydro¬ gen or optionally lower alkyl if on nitrogen. 54. Another preferred form of the invention has n = 0 or .1, A & B taken together as oxygen, and E as nitrogen, or D & E taken together as oxygen and A as nitrogen, one of Y & Z being nitrogen, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R 8 hydro¬ gen or a lone pair of electrons where appropriate, or optionally lower alkyl if on nitrogen. A suitable ring structure is: 55. Another preferred form of the invention has n = 0 or 1, A & B taken together as sulfur, and E as nitrogen, or D & E taken together as sulfur and A as nitrogen, one of Y & Z being nitrogen, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R 8 hydro¬ gen or a lone pair of electrons where appropriate, or optionally lower alkyl if on nitrogen. 56. Another preferred form of the invention has n = 0, A & B taken together, and E as nitrogen, one of Y & Z being nitrogen, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R 8 hydrogen or optionally lower alkyl if on nitrogen or a lone pair of electrons where appropriate. 57. Another preferred form of the invention has n = 0 or 1, A & B taken together as oxygen, and D as nitrogen, or D & E taken together as oxygen and B as nitrogen, one of Y & Z being nitrogen, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R 8 hydro¬ gen, lower alkyl, or a lone pair of electrons where appropriate. 58. Another preferred form of the invention has n -s- O or l, A & B taken together as sulfur, and D as nitrogen, or D & E taken together as sulfur and B as nitrogen, one of Y & Z being nitrogen, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R 8 hydro¬ gen, lower alkyl, or a lone pair of electrons where appropriate. 59. Another preferred form of the invention has n = 0 or 1, A & B taken together, and D as nitro¬ gen, or D & E taken together, and B as nitrogen, one of Y & Z being nitrogen, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R 8 hydrogen, lower al- kyl, or a lone pair of electrons where appropriate. 60. Another preferred form of the invention has n = 0 or 1, with one of A, B, D or E as nitrogen, the remaining three being carbon, one of Y & Z being nitrogen, X = NH, Ar a benzene ring, optionally sub- stituted, and R 5 -R 8 hydrogen or a lone pair of elec¬ trons where appropriate. 61. Another preferred form of the invention has n = 0 or 1, A-E being carbon, one of Y & Z being oxygen, X = NH, Ar a benzene ring, optionally substi- tuted, and R 5 -R 8 hydrogen or a lone pair of electrons where appropriate. A suitable ring structure is: 62. Another preferred form of the invention has, n = 0 or 1, with one of A & B or D & E taken together as oxygen, the remaining pair both being carbon, one of Y & Z being oxygen, X = NH, Ar a ben¬ zene ring, optionally substituted, and R 5 -R 8 hydrogen or a lone pair of electrons where appropriate. 63. Another preferred form of the invention has, n = 0 or 1, with one of A & B or D & E taken together as sulfur, the remaining pair both being carbon, one of Y & Z being oxygen, X = NH, Ar a ben¬ zene ring, optionally substituted, and R 5 -R 8 hydrogen or a lone pair of electrons where appropriate. 6 . Another preferred form of the invention has, n = 0 or 1, with one of A & B or D & E taken together as nitrogen, the remaining pair both being carbon, one of Y & Z being oxygen, X == NH, Ar a ben- zene ring, optionally substituted, and R 5 -R 8 hydrogen or a lone pair of electrons where appropriate or op¬ tionally lower alkyl if on nitrogen. 65. Another preferred form of the invention has n * = 0 or l, A & B taken together as oxygen, and E as nitrogen, or D & E taken together as oxygen and A as nitrogen, one of Y & Z being oxygen, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R 8 hydro¬ gen or a lone pair of electrons where appropriate. 66. Another preferred form of the invention has n = 0 or l, A & B taken together as sulfur, and E as nitrogen, or D & E taken together as sulfur and A as nitrogen, one of Y & Z being oxygen, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R 8 hydro¬ gen or a lone pair of electrons where appropriate. A suitable ring structure is: 67. Another preferred form of the invention has n = 0, A & B taken together, and E as nitrogen, one of Y & Z being oxygen, X * ■*■ NH, Ar a benzene ring, optionally substituted, and R s -R 8 hydrogen or optional- ly lower alkyl if on nitrogen or a lone pair where appropriate. 68. Another preferred form of the invention has n = 0 or l, A & B taken together as oxygen, and D as nitrogen, or D & E taken together as oxygen and B as nitrogen, one of Y & Z being oxygen, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R 8 hydro¬ gen, lower alkyl, or a lone pair of electrons where appropriate. 69. Another preferred form of the invention has n = 0 or l, A & B taken together as sulfur, and D as nitrogen, or D & E taken together as sulfur and B as nitrogen, one of Y & Z being oxygen, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R 8 hydro¬ gen, lower alkyl, or a lone pair of electrons where appropriate. 70. Another preferred form of the invention has n = 0 or l, A & B taken together, and D as nitro- gen, or D & E taken together, and B as nitrogen, one of Y & Z being oxygen, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R 8 hydrogen, lower al¬ kyl, or a lone pair of electrons where appropriate. 71. Another preferred form of the invention has n = 0 or 1, with one of A, B, D or E as nitrogen, the remaining three being carbon, one of Y & Z being oxygen, X = NH, Ar a benzene ring, optionally substi¬ tuted, and R 5 -R 8 hydrogen or a lone pair of electrons where appropriate. Most Preferred Forms of the Invention 1. A most preferred form of the invention is one where A-E, Y and Z are all carbon, n = 0, X = NH, Ar is phenyl, R 2 is irieta-bromo, m = 1, and R 3 -R 8 are all hydrogen. 2. A most preferred form of the invention is one where A-E, Y and Z are all carbon, n = 1, X = NH, Ar is phenyl, R 1 is [R] -CH 3 and R 2 -R 8 are all hydrogen. 3. A most preferred form of the invention is one where A and B are carbon, D and E taken together are nitrogen, Y and Z are carbon, n = 0, X = NH, Ar is phenyl, R 2 is meta-bromo, m = 1, and R 4 -R 8 are all hydrogen. 4. A most preferred form of the invention is one where A and B taken together are sulfur, E is nitrogen, D, Y and Z are carbon, n = 0, X = NH, Ar is phenyl, R 2 is meta-bromo, = 1, and R 4 and R 6 -R 8 are all hydrogen. 5. A most preferred form of the invention is one where A and B taken together are oxygen, E is nitrogen, D, Y and Z are carbon, n = 0, X = NH, Ar is phenyl, R 2 is meta-bromo, m = 1, and R 4 and R 6 -R 8 are all hydrogen. 6. A most preferred form of the invention is one where A and B taken together are nitrogen, E is nitrogen, D, Y and Z are carbon, n = 0, X = NH, Ar is phenyl, R 2 is meta-bromo, m = 1, and R 4 and R 6 -R 8 are • all hydrogen. 7. A most preferred form of the invention is one where A and B taken together are nitrogen, D and E taken separately are nitrogen, Y and Z are carbon, n = 0, X = NH, Ar is phenyl, R 2 is meta-bromo, m = 1, and R 6 -R 8 are all hydrogen. 8. A most preferred form of the invention is one where A and B taken together are nitrogen, E is v. nitrogen, Y and Z are carbon, n = 0, X = NH, Ar is phenyl, R 2 is meta-bromo, m = 1, and R 4 ,R 7 and R 8 are hydrogen and R 6 is methyl. 9. A most preferred form of the invention is one where A and B taken together are nitrogen, E is nitrogen, Y and Z are carbon, n = 0, X = NH, Ar is phenyl, R 2 is meta-bromo, m = 1, and R 4 ,R 7 and R 8 are hydrogen and R 5 is methyl. 10. A most preferred form of the invention is one where A and E are nitrogen, B, D, Y and Z are all carbon, n = 0, X = NH, Ar is phenyl, R 2 is meta- bromo, m = 1, and R 3 -R 8 are all hydrogen. 11. A most preferred form of the invention is one where A and B taken together are nitrogen, E is nitrogen, Z is ethylidene, and Y a C-C bond, n = 0, X = NH, Ar is phenyl, R 2 is meta-bromo, m = 1, and R 4 and R 6 -R 8 are all hydrogen. 12. A most preferred form of the invention is one where A-E, are all carbon, Z is sulfur, and Y a C-C bond, n = 0, X = NH, Ar is phenyl, R 2 is meta- bromo, m = 1, and R 3 -R 6 are all hydrogen. 13. A most preferred form of the invention is one where A-E, are all carbon, Z is sulfur, and Y a C-C bond, n = 0, X = NH, Ar is phenyl, R 2 is meta- bromo, m = 1, R 5 is nitro R 3 , R 4 and R 6 are all hydrogen. 14. A most preferred form of the invention is one where A-E, are all carbon, Z is sulfur, and Y a C-C bond, n = 0, X = NH, Ar is phenyl, R 2 is meta- bromo, m = 1, R 5 is amino R 3 , R 4 and R 6 are all hydrogen. 15. A most preferred form of the invention is one where A-E, are all carbon, Z is sulfur, and Y a C-C bond, n = 0, X = NH, Ar is phenyl, R 2 is meta- bromo, m = 1, R 6 is methoxy and R 3 -R s are all hydrogen. 16. A most preferred form of the invention is one where A is nitrogen, D and E taken together, and Z are sulfur and Y a C-C bond,n = 0, X = NH, Ar is phenyl, R 2 is meta-bromo, m = 1, and R 3 is hydrogen. 17. A most preferred form of the invention is one where A-E, are all carbon, Z is nitrogen, and Y a C-C bond, n = 0, X - NH, Ar is phenyl, R 2 is meta- bromo, m = 1, and R 3 -R 6 and R 8 are all hydrogen. 18. A most preferred form of the invention is one where A-E, are all carbon, Y is nitrogen, and Z a C-C bond, n = 0, X = NH, Ar is phenyl, R 2 is meta- bromo, m = 1, and R 3 -R 6 and R 8 are all hydrogen. The compounds of the present invention are prepared according to a number of alternative reaction sequences. It is to be appreciated that in the tricyclic structure of Formula I, the ring having A-E is aromatic. By "aromatic" is meant that all members of the ring share electrons and there is a resonance among the members of the ring. Preparative Routes to Compounds of the Invention Scheme 1 for Preferred Group 1 Condensation of commercially available 3- amino-2-naphthoic acid with formamide gives the benzo- quinazoline nucleus. (DMF is dimethyl formamide). Conversion of the carbonyl to halide is followed by displacement with the appropriate amine side chain. Representative examples of compounds that can be made by this route are given in the table below. .<■■>- • _»τn_» 2 for Preferred Group 4 _3.2-σ. Isomer Nitration of methyl 5-methyl-2- nitrobenzoate, and isomer separation gives the 2,4- dinitrobenzoate ester. This is converted to the corresponding benzamide with methanolic ammonia, and both the amide nitrogen and the benzylic methyl are condensed with DMF di-t-butoxy acetal. On Raney Nickel reduction of both nitro groups to amines both the pyrrole and pyrimidone rings spontaneously cyclize to give the desired pyrrolo[3,2-g]quinazolone. Conversion on to the chloride with POCl 3 is followed by displacement of the chlorine with the desired amine. Scheme 3 - Route for Preferred Group 5 .4,5 -σl Isomer For the [4,5-g] isomer 7-chloroquinazol-4- one is nitrated at the 6-position by methods familiar to one skilled in the art. The activated 7-halide is then displaced by methoxide, the methyl ether is cleaved, the nitro group is reduced to amino, and the oxazole ring is cyclized on with formic acid. Phos¬ phorus pentasulfide followed by methyl iodide acti¬ vates the -position, and the synthesis is completed by displacement of the -methylthio group by an appro- priate amine. Scheme 4 - Route for Preferred Group 5 15.4 -σl Isomer For the [5,4-g] isomer the chlorine atom of the known 5-chloro-2,4-dinitrobenzamide is displaced with KOH, and the two nitro groups are then catalytically reduced to the diaminohydroxybenzamide. Treatment of this with excess orthoformate cyclizes both the oxazole and pyrimidone rings simultaneously, to give the desired tricyclic nucleus. Activation of the 4-oxo group with POCl 3 or other suitable chlorinating agent followed by displacement with the appropriate amine gives the desired compounds. Scheme 5 - Route for Preferred Group 6 .4,5 -σl Isomer For the [4,5-g] isomer 7-chloroquinazol-4- one is nitrated at the 6-position by methods familiar to one skilled in the art. The activated 7-halide is then displaced by methiolate ion, and the resultant thiomethyl ether is cleaved under the reaction conditions to give the corresponding thiol. The nitro group is reduced by a noncatalytic method, such as treatment with hydrosulfide ion or Zn/AcOH, and the thiazole ring is cyclized on with orthoformate. Phosphorus pentasulfide followed by methyl iodide actvates the 4-position, and the synthesis is completed by displacement of the 4-methylthio group by an appropriate amine. Scheme 6 - Route for Preferred Group 6 .5,4 -σl Isomer For the [5,4-g] isomer the chlorine atom of the known 5-chloro-2,4-dinitrobenzamide is displaced with NaSH, and the 4-nitro group is concomitantly reduced to give an aminonitrobenzamide disulfide. Treatment of this with borohydride, and then formic acid cyclizes the thiazole ring, to give the benzothiazole derivative. Reduction of the second nitro group followed by orthoformate cyclization gives the desired tricyclic pyrimidone. Activation of the 4-oxo group with P0C1 3 or other suitable chlorinating agent followed by displacement with the appropriate amine gives the desired compounds. Scheme 7 - Route for Group 7 Nitration of 7-chloroquinazol-4-one at the 6-position by methods familiar to one skilled in the art is followed by displacement of the 7-chloro compound with ammonia. If a 3,N-alkyl substituent is required, an appropriate primary amine can be used instead of ammonia. Reduction with Pearlman's catalyst gives 6,7-diaminoquinazolone which on treatment with formic acid cyclizes to the imidazoloquinazolone. Phosphorus pentasulfide followed by methyl iodide activates the 4-position, and the synthesis is completed by displacement of the 4-methylthio group by an appropriate amine. Scheme 8 - Route to Preferred Group 10 [4.3-σ. Iso ers 2,4-Dimethylaniline is diazotized, and cyclized to a benzopyrazole. Nitration of this, followed by chromic acid oxidation and RaNi reduction of the nitro group gives the desired anthranilic acid derivative. This is cyclized to the pyrimidone with formamidine, and activated and displaced at the 4- position in the usual fashion. Sche e 9 - Route to Preferred Group 10 _3.4-cr. Isomers 2,5-Dimethylacetanilide is nitrated, and the acetate group is saponified off. Diazotization leads to the desired benzopyrazole, which in turn is oxidized to the corresponding benzoic acid derivative. Catalytic reduction of the nitro group with Pd/C is followed by formamidine acetate ring cyclization. The pyrimidone is activated to displacement in one of the usual fashions, and a suitable amine is then introduced at the 4-position to give the desired compound. Scheme 10 - Route to Preferred Group 11 [4.5-q. Isomers 6,7-Diaminoquinazoline is prepared as described above in Scheme 7. This compound can be cyclized to the triazoloquinazolone via a diazotization, and then the carbonyl is activated via phosphorus pentasulfide and methyl iodide, as described previously and displaced with an appropriate amine to give the desired product. Scheme 11 - Route to Preferred Group 13 A & E Nitrogen 6,7-Diaminoquinazo ' line is prepared as described above. This compound can be cyclized to a pyrazinoquinazolone by treatment with 2,5-dihydroxy- 1,4-dioxane, and then the carbonyl is activated via phosphorus pentasulfide and methyl iodide, as described previously and displaced with an appropriate amine to give the desired product. Scheme 12 - Route to Preferred Group 13 B & E Nitrogen Reaction of 1,3-diaminobenzene with chloral and hydroxylamine, followed by cyclization with cone, sulfuric acid gives the bis-isatin type tricycle. Oxidation with hydrogen peroxide gives the symmetric diaminodiacid. This is doubly cyclized with formamidine, and converted to the corresponding dichloride with P0Cl 3 or equivalent. Monodisplacement with the desired amine, can be followed by displacement of the remaining chloride hydrogenolytically or by a suitable nucleophile to put in R 5 . Scheme 13 - Route to Preferred Group 33 .4.5-f. Isomer Nitration of 6-acetamidoquinazol-4-one gives the 5-nitro derivative. Hydrolysis of the amide with dilute HC1, followed by reduction with Pearlman's catalyst gives the 5,6-diaminoquinazolone. Fusion of the imidazole ring by a formic acid gives the parent ring skeleton, and then the carbonyl is activated via phosphorus pentasulfide and methyl iodide, as described previously and displaced with an appropriate amine to give the desired product. Scheme 14 - Route to Preferred Group 33 _4.5-h_ Isomer Nitration of 7-chloroquinazol-4-one by means obvious to one skilled in the art gives the 8-nitro derivative as a minor product. This is purified and the chlorine is displaced by ammonia under high temperature and pressure to give the 5-amino compound which is then reduced by Pearlman's catalyst (Pd hydroxide on carbon) to the 7,8-diaminoquinazolone. Fusion of the imidazole ring by a formic acid derivative gives the parent ring skeleton, and then the carbonyl is activated via phosphorus pentasulfide and methyl iodide, as described previously and displaced with an appropriate amine to give the desired product. Scheme 15 - Route to Preferred Group 39 13.2-dl Isomer 2-Fluorobenzonitrile or a suitably substituted derivative of it is treated with ethyl thioglycollate and a base in a dipolar aprotic solvent to give an ethyl 3-aminobenzothiophene-2-carboxylate derivative. This is cyclized to the desired benzothienopyrimidone with formamide, and the carbonyl is replaced by chlorine using standard techniques, and the chloride is displaced by an appropriate amine to give the desired compounds, or precursors that can readily be converted into them. Scheme 16 - Route to Preferred Group 39 .3.2-dl Isomer In a variant of the route described in Scheme 15, lithiation of a suitably substituted fluorobenzene ortho to the fluorine atom is followed by carbonylation. The aldehyde is converted onto a suitable 2-fluorobenzonitrile derivative by oxime formation and dehydration. Alternatively the initial anion can be carboxylated and the resulting acid can be converted via the amide to the desired nitrile. This is then put through the sequence described in Scheme 15, to prepare derivatives which could not be obtained by substitution on 2-fluorobenzonitrile. Scheme 17 - Route to Preferred Group 39 [2,3-d] Isomer Commercially available 4,6- dichloropyrimidine can be monodisplaced with 2- bromobenzenethiolate to give a diarylsulfide. This compound can be metalated at the 5-position of the pyrimidine ring with LDA, and quenched with Me 3 SnCl, to form a halostannane. This halostannane is intramolecularly Stille coupled to give the desired 4- chlorobenzothieno[2,3-d]pyrimidine, from which chlorine can be displaced to give the desired product. Scheme 18 - Route to Preferred Group 41 13' ,2' :2.3114.5-dl Isomer Halogen-metal exchange on 3-bromothiophene in ether at low temperature, followed by treatment with sulfur and then methyl bromoacetate gives methyl (thien-3-ylthio)acetate. Vilsmeier formylation using N-methylformanilide introduces a 2-formyl group on the thienyl ring, without inducing aldol cyclization. Reaction of the aldehyde to the oxime, followed by mesyl chloride/NEt 3 dehydration gives the corresponding nitrile, which cyclizes to methyl 3-aminothieno[3,2- b]thiophene-2-carboxylate on heating to 100 * C in DMSO with NEt 3 . Pyrimidone fusion " is carried out with formamide or an equivalent thereof, and the 4-keto substituent is activated and displaced in the usual manner to give the desired products. Scheme 19 - Route to Preferred Group 41 12'.3': 2,31 [5,4-dl Isomer Metalation of 3-bromothiophene with LDA occurs at the 2-position. Quenching of this anion with 1 equivalent of sulfur, followed by one equivalent of 4,6-dichloropyrimidine gives the thienopyrimidosulfide. Selective metalation with LDA at the 5-position of the pyrimidine ring, followed by stannylation gives a precursor for Stille coupling. After the coupling the 4-chlorine is displace with the appropriate amine to give the desired product. Scheme 20 - Route to Preferred Group 44 [4' .5'; 2.31 _4.5-d. Isomer Reaction of thiazolidin-2,4-dione with P0C1 3 and DMF gives 2,4-dichlorothiazole-5-carbaldehyde. Protection of the aldehyde as an acetal is followed by selective removal of the 2-chlorine by halogen-metal exchange and hydrolysis. The aldehyde is oxidized up to the corresponding nitrile by oxime formation and dehydration, and 4-chloro-5-cyanothiazole on treatment with fresh 2-mercaptoacetamide in basic conditions gives 6-aminothieno[2,3-d]thiazole-5-carboxamide. This can be cyclized to the tricycle with ethyl orthoformate, and the carbonyl replaced by P0C1 3 in the usual manner, and the chloride is then displaced by a suitable amine to give the desired product. Scheme 21 - Route to Preferred Group 45 14 ' . 5 ' : 2.31 _4.5-d_ Isomer l,N-Benzyl-4,5-dibromoimidazole is lithiated with butyl lithium and formylated with DMF. Reaction of the bromoaldehyde with ethyl thioglycollate and base in DMSO leads to the desired aminothienoimida- zole. This in turn is annulated again with formamide or an equivalent thereof, and the tricyclic pyrimidone is chlorinated at the 4-position and displaced with a suitable amine to give the desired product. Scheme 22 - Route to Preferred Group 49 12 ' .3 ' ;2_3_ [4.5-d. Isomer Reaction of 2-chloronicotinonitrile with methyl thioglycollate gives methyl 3-aminopyrido[2,3- d]thiophene-2-carboxylate. Fusion of the pyrimidone ring with formamide gives the corresponding pyrrido thienopyrimidone, which can then be chlorinated on the carbonyl and displaced with appropriate amines in the usual fashion to yield the desired compounds. Scheme 23 - Route to Preferred Group 50 _3_2-d. Isomer A suitably substituted anthranilonitrile derivative is N-alkylated with ethyl bromoacetate, and the pyrrole ring is closed by treating the product of that reaction with KOBu', to give ethyl 3-aminoindole- 2-carboxylate. The pyrimidone ring is fused onto this with formamide, and the carbonyl converted to chloride with P0C1 3 . Displacement of the chlorine with a suitable amine gives the desired compound. Scheme 24 - Route to Preferred Group 50 [2.3-d] Isomer The fluoride of 2-fluoronitrobenzene is displaced by the anion derived from methyl cyanoacetate and K0Bu c . Mild reduction of the nitro group to amino is accompanied by spontaneous closure of the pyrrole ring to give ethyl 2-aminoindole-3- carboxylate. The pyrimidone ring is fused onto this with formamide, and the carbonyl converted to chloride with P0C1 3 . Displacement of the chlorine with a suitable amine gives the desired compound. Scheme 25 - Route to Preferred Group 61 .3.2-d. Isomer O-Alkylation of 2-cyanophenol with methylbromoacetate, followed by treatment with a strong base gives ethyl 3-aminobenzofuran-2- carboxylate. The pyrimidone ring is fused onto this with formamide, and the carbonyl converted to chloride with Vilsmeier reagent. Displacement of the chlorine with a suitable amine gives the desired compound. Biology These compounds are potent and selective inhibitors of the human EGF receptor tyrosine kinase, and other members of the EGF receptor family, including the ERB-B2, ERB-B3 and ERB-B4 receptor kinases, and are useful for the treatment of proliferative diseases in mammals. These inhibitors prevent mitogenesis in cells where mitogenesis is driven by one or more of this family of receptor kinases. This can include normal cells, where it is desired to prevent mitogenesis, as exemplified by the cells transformed by overexpression or mutation of this kinase family as exemplified by poor prognosis breast cancer where overexpression of EGFR, ERB-B2 and ERB-B3 or mutation of ERB-B2 to the oncoprotein NEU is a major factor in cellular transformation. As the preferred compounds are not highly cytotoxic and do not show potent growth inhibitory properties, because of their high specificity toward inhibition of the EGFR kinase family, they should have a much cleaner toxicity profile than most anti-cancer and anti- proliferative drugs. Their very different mode of action to current anti-cancer drugs should allow for their use in multiple drug therapies, where synergism with available agents is anticipated. Compounds of the invention have been shown to be very potent, reversible inhibitors of the EGF receptor tyrosine kinase, by binding with high affinity at the adenosine triphosphate (ATP) binding site of the kinase. These compounds exhibit potent IC 50 s, varying from 10 micromolar to 50 picomolar, for the tyrosine kinase activity of the enzyme, based on an assay examining phosphorylation of a peptide derived from the phosphorylation site of the protein PLCgammal, a known EGFR phosphorylation substrate. This data is shown in Table 1. Biological Data Materials and Methods Purifi ca tion of Epidermal Growth Factor Receptor Tyrosine Kinase - Human EGF receptor tyrosine kinase was isolated from A431 human epidermoid carcinoma cells which overexpress EGF receptor by the following methods. Cells were grown in roller bottles in 50% Delbuco's Modified Eagle and 50% HAM F-12 nutrient media (Gibco) containing 10% fetal calf serum. Approximately 10 9 cells were lysed in two volumes of buffer containing 20 mM 2-(4N-[2- hydroxyethyl]piperazin-l-yl)ethanesulfonic acid (hepes), pH 7.4, 5 mM ethylene glycol bis(2-aminoethyl ether) N,N,N' ,N' -tetraacetic acid, 1% Triton X-100, 10% glycerol, 0.1 mM sodium orthovanadate, 5 mM sodium fluoride, 4 mM pyrophosphate, 4 mM benzamide, 1 mM dithiothreitol, 80 μg/mL aprotinin, 40 μg/mL leupeptin and 1 mM phenylmethylsulfonyl fluoride. After centrifugation at 25,000 x g for 10 minutes, the supernatant was equilibrated for 2 h at 4"C with 10 mL of wheat germ agglutinin sepharose that was previously equilibrated with 50 mM Hepes, 10% glycerol, 0.1% Triton X-100 and 150 mM NaCl, pH 7.5, (equilibration buffer) . Contaminating proteins were washed from the resin with 1 M NaCl in equilibration buffer, and the enzyme was eluted with 0.5 M N-acetyl-1-D-glucosamine in equilibration buffer, followed by 1 mM urea. The enzyme was eluted with 0.1 mg/ml EGF. The receptor appeared to be homogeneous as assessed by Coomassie blue stained polyacrylamide electrophoretic gels. Determination of IC S0 values - enzyme assays for IC 50 determinations were performed in a total volume of 0.1 mL, containing 25 mM Hepes, pH 7.4, 5 mM MgCl 2 , 2 mM MnCl 2 , 50 μM sodium vanadate, 5-10 ng of EGF receptor tyrosine kinase, 200 μM of a substrate peptide, (Ac-Lys-His-Lys-Lys-Leu-Ala-Glu-Gly-Ser-Ala- Tyr 47 -Glu-Glu-Val-NH 2 , derived from the amino acid (Tyr 472 has been shown to be one of four tyrosines in PLC (phospholipaseC) -gamma 1 that are phosphorylated by the EGF receptor tyrosine kinase [Wahl, M. I.; Nishibe, S.; Kim, J. W. ; Kim, H. ; Rhee, S. G. ; Carpenter, G., J. Biol. Chem. , (1990), 265, 3944- 3948.], and peptides derived from the enzyme sequence surrounding this site are excellent substrates for the enzyme.),10 μM ATP containing 1 μCi of [ 32 P]ATP and incubated for ten minutes at room temperature. The reaction was terminated by the addition of 2 mL of 75 mM phosphoric acid and passed through a 2.5 cm phosphocellulose filter disc to bind the peptide. The filter was washed five times with 75 mM phosphoric acid and placed in a vial along with 5 mL of scintillation fluid (Ready gel Beckman) . Table 1 EGF Receptor Tyrosine Kinase Inhibition ■ S O - Cells Swiss 3T3 mouse fibroblasts, A431 human epidermoid carcinoma cells, and MCF-7 (Michigan Cancer Foundation human mammary carcinoma cells) , SK-BR-3 (human mammary carcinoma cells) , MDA-MB-231 and MDA- MB-468 (human mammary carcinoma cells) breast carcinomas were obtained from the American Type Culture Collection, Rockville, Maryland and maintained as monolayers in dMEM (Dulbecco's modified eagle medium) /F12, 50:50 (Gibco/BRL) containing 10% fetal bovine serum. To obtain conditioned medium, MDA-MB-231 cells were grown to confluency in an 850 cm 2 roller bottle and the medium replaced with 50 ml of serum- free medium. After 3 days the conditioned medium was removed, frozen down in aliquots and used as a heregulin source to stimulate erbB-2, 3, 4. Antibodies Monoclonal antibodies raised to phosphotyrosine were obtained from Upstate Biotechnology, Inc., Lake Placid, NY. Anti-EGF receptor antibodies were obtained from Oncogene Science, Uniondale, NY. Immunoprecipitation and Western Blot Cells were grown to 100% confluency in 100 mm Petrie dishes (Corning) . After the cells were treated for 5 minutes with either EGF (epidermal growth factor) , PDGF, or bFGF (basic fibroblast growth factor) (20 ng/ml) or 1 ml of conditioned media from MDA-MB-231 cells, the media was removed and the monolayer scraped into 1 ml of ice cold lysis buffer (50 mM Hepes, pH 7.5, 150 mM NaCl, 10% -glycerol, 1% triton X-100, 1 mM EDTA, 1 mM EGTA, 10 mM sodium pyrophosphate, 30 mM p-nitrophenyl phosphate, 1 mM orthovanadate, 50 mM sodium fluoride, 1 mM phenylmethylsulfonylfluoride, 10 μg/ml of aprotinin, and 10 μg/ml of leupeptin) . The lysate was transferred to a microfuge tube (small centrifuge that holds 1-2 ml plastic centrifuge tubes) , allowed to sit on ice 15 minutes and centrifuged 5 minutes at 10,000 x g. The supernatant was transferred to a clean microfuge tube and 5 μg of antibody was added to designated samples. The tubes were rotated for 2 hours at 4° C after which 25 μl of protein A sepharose was added and then rotation continued for at least 2 more hours. The protein A separose was washed 5 times with 50 mM Hepes, pH 7.5, 150 mM NaCl, 10% glycerol and 0.02% sodium azide. The precipitates were resuspended with 30 μl of Laemlli buffer (Laemmli, NATURE, Vol. 727, pp. 680-685, 1970), heated to 100 * C for 5 minutes and centrifuged to obtain the supernatant. Whole cell extracts were made by scraping cells grown in the wells of 6 well plates into 0.2 ml of boiling Laemmli buffer. The extract were transferred to a microfuge tube and heated to 100° C for 5 minutes. The entire supernatant from the immunoprecipitation or 35 μl of the whole cell extract was loaded onto a polyacrylamide gel (4-20%) and electrophoresis carried out by the method of Laemlli (Laemmli, 1970) . Proteins in the gel were electrophoretically transferred to nitrocellulose and the membrane was washed once in 10 mM Tris buffer, pH 7.2, 150 mM NaCl, 0.01% Azide (TNA) and blocked overnight in TNA containing 5% bovine serum albumin and 1% ovalbumin (blocking buffer) . The membrane was blotted for 2 hours with the primary antibody (lμg/ml in blocking , buffer) and then washed 2 times sequentially in TNA, TNA containing 0.05% Tween- 20 and 0.05% Nonidet P-40 (commercially available detergent) and TNA. The membranes were then incubated for 2 hours in blocking buffer containing 0.1 μCi/ml of [ 125 I] protein A and then washed again as above. After the blots were dry they were loaded into a film cassette and exposed to X-AR X-ray film for 1-7 days. Protein A is a bacterial protein that specifically bonds certain IgG subtypes and is useful in binding to and isolating antibody-antigen complexes. Growth TnhSh-i.tion Assay Cells (2 x 10 4 ) were seeded in 24-well plates (1.7 x 1.6 cm, flat bottom) in two mis of medium with or without various concentrations of drug. Plates were incubated for 3 days at 37o in a humidified atmosphere containing 5% C0 2 in air. Cell growth was determined by cell count with a Coulter Model AM electronic cell counter (Coulter Electronics, Inc., Hialeah, FL) . INHIBITION OF EGF-INDUCED AUTOPHOSPHORYLATION IN A431 EPIDERMOID CARCINOMA CELLS AND CONDITIONED MEDIA- NDUCED AUTOPHOSPHORYLATION IN SK-BR-3 BREAST TUMOR CELLS BY COMPOUNDS OF THE CURRENT INVENTION The gels shown in the drawings, developed as detailed in the experimental section, demonstrate the efficacy of compounds of the current invention at blocking certain EGF-stimulated mitogenic signalling events in whole cells. The numbers to the left of gels indicate the positions of molecular weight standards in kiloDaltons. The lane labelled control shows the degree of expression of the growth-related signal in the absence of EGF stimulation, whereas the lane labelled EGF (or PDGF or b-FGF) shows the magnitude of the growth factor-stimulated signal. The other lanes show the effect of the stated quantities of the named drug on the growth factor-stimulated activity being measured, demonstrating that the compounds of the present invention have potent effects in whole cells, consistent with their ability to inhibit the tyrosine kinase activity of the EGF receptor. See also the results as shown in Figures 1- ANTIPROLIFERATIVE PROPERTIES OF TYROSINE KINASE INHIBITORS IC 50 (nM) B104-1-1 - NIH-3T3 mouse fibroblasts transfected by the neu oncogene: Stern et al. , SCIENCE, 234, pp. 321* 324 (1987) ; SK-BR-3 - Human breast carcinoma overexpressing erbB-2 and erbB-3; MDA-468 " - Human breast carcinoma overexpressing the EGF receptor. Soft Agar Clonogenic Assays Cell monolayers were exposed to the appropriate compound for 1-3 days and were then washed free of drug with warmed serum-free media. The cells were trypsinised and 10,000/mL were seeded into DMEM/F12 media containing 10% fetal calf serum and 0.4% agarose, but no drug. One ml of this solution was placed over a bottom layer of the same medium containing 0.8% agarose in a 35 mm Petri dish, and was incubated at 37 * C in a humidified atmosphere containing 5% carbon dioxide in air. After 3 weeks colonies were counted using an image analyzer for quantification. See Figure 9. It is to be appreciated that the compounds described herein can be used in combination with other components to enhance their activity. Such additional components are anti-neoplastic materials as, doxorubicin, taxol, cis platin, and the like. It has been found that the compounds described herein may inhibit both the erb-B2 and erb- B4 receptors and therefore have significantly increased clinical activity advantageously in combination with the aforementioned anti-neoplastic agents. See J. Basalga et al. , Antitumor Effects of Doxorubicin in Combination With Anti-Epidermal Growth Factor Receptor Monoclonal Antibodies. JNCI, 1993, 85 1327, and Z. Fan et al., Antitumor Effect of Anti- Epidermal Growth Factor Receptor Monoclonal Antibodies Plus Cis Diamminedichloroplatinum on Well Established A431 Cell Xenografts. Cancer Res . 1993, 53, 4637. r->ι-»τn-ir!-.i Experimental Listed below are preferred embodiments wherein all temperatures are in degrees Centigrade and all parts are parts by weight unless otherwise indicated. Example 1 4- (3-bromoanilino)benzofσlquinazoline hvdrochloride 3H-Benzofσlσuinazol-4-one. 3-Amino-2- naphthoic acid (3.74 g, 20 mmol) in stirred formamide is heated under N2 to 135°C for 30 min, and to 175°C for 2 h. The reaction mixture is poured onto vigorously stirred dilute NaOH solution (0.2 M, 50 mL) , containing ice, and the solid is collected by vacuum filtration, rinsed with water (2 x 25 mL) , and dried in a vacuum oven at 60°C to give benzo[g] -3H- quinazol-4-one (3.49 g, 89%) as a pale khaki solid. *H NMR (DMSO) δ 12.08 (IH, brs) , 8.84 (IH, s) , 8.24 (IH, S) , 8.21 (IH, d, J = 7 Hz) , 8.10 (IH, d, J *= 7 Hz), 8.09 (IH, s) , 7.62 ( 2R, apparent d of pentets, J d = 1.3 Hz, J p = 6.7 Hz) . 4-Chlorobenzofσlquinazoline. A suspension of benzo[g] -3H-quinazol-4-one (3.49 g, 18 mmol) in P0C1 3 (40 mL) was refluxed under N 2 for 3 h. The volatiles were removed under reduced pressure, and the residue was partitioned between chloroform (200 mL) and dilute aqueous Na 2 HP0 4 solution (1 M, 50 mL) . The organic phase was filtered through a silica gel plug (50 g) , and the plug was then eluted with 20% EtOAc in CHC1 3 (500 mL) . The combined eluents were concentrated under reduced pressure to give 4-chlorobenzo[g]quin¬ azoline (1.20 g, 31%) as an orange-yellow solid. H NMR (DMSO) δ 9.04 (IH, s) , 8.91 (IH, s) , 8.65 (IH, s) , 8.20-8.09 (2H, m) , 7.75-7.60 (2H, m) . 4- (3-Bromoanilino)benzofσlquinazoline hydrochloride. 4-Chlorobenzo[g]quinazoline (214 mg, 1.0 mmol), 3-bromoaniline (213 mg, 1.25 mmol) and NEt 3 (202 mg, 2.0 mmol) in stirred methoxyethanol (5 mL) were heated under N 2 at 95°C for 6 h. The volatiles were removed under reduced pressure and the residual solid was triturated with MeOH. The solid was recrystallized at 0°C from an EtOH/ dilute hydrochloric acid mixture (1:4, 0.05 M acid, 50 mL) after celite filtration to give 4- (3-bromoanilino) - benzo[g]quinazoline hydrochloride (71 mg, 18%) as a yellow-green solid. X H NMR (DMSO) δ 14.0 (IH brs) , 9.65 (IH, s) , 9.01 (IH, s) , 8.47 (IH, s) , 8.29 (IH, d, J = 8.4 Hz), 8.24 (IH, d, J = 8.4 Hz) , 8.18 (IH, slbrs) , 7.9-7.82 (2H, ) , 7.78 (IH, t, J = 7.5 Hz), 7.58 (IH, d, J = 8 Hz) , 7.51 (IH, t, J = 8 Hz) . Examole 2 4- ( fRI -l-Phenylethylamino)benzofσlquinazoline hydrochloride -Chlorobenzo[g]quinazoline (107 mg, 0.5 mmol), [R] -1-phenylethylamine (72 mg, 0.6 mmol) and NEt 3 (202 mg, 2.0 mmol) in stirred methoxyethanol (2 mL) are heated under N 2 at 100°C for 90 min. On cool¬ ing the reaction mixture is diluted with CHC1 3 (10 mL) , and is shaken with dilute hydrochloric acid (0.2 M, 15 mL) . The heavy yellow precipitate is collected by Buchner filtration, rinsed with water (5 mL) , and dried in vacuo at 60°C to give 4- ( [R] -1-phenylethyl- amino)benzo[g]quinazoline hydrochloride hydrate (122 mg, 64%) as a yellow solid. X H NMR (DMSO) δ 14.75 (IH brs) , 10.85 (IH, d, J «= 8.0 Hz), 9.61 (IH, s) , 8.90 (IH, s) , 8.36 (IH, s) , 8.18 (IH, d, J = 8.2 Hz) , 7.82 (IH, t, J = 7.6 Hz), 7.74 (IH, t, J = 7.4 Hz) , 7.56 (2H, d, J = 7.5 KHz), 7.39 (2H, t, J = 7.6 Hz), 7.30 (IH, t, J = 7.4 Hz), 5.92 (IH, pentet, J = 7.2 Hz), 1.76 (3H, d, J = 7.2 Hz) . Example 3 4- (3-Bromoanilino)pyrrolof3.2-σlquinazoline N- (5- (E.2-dimethylaminoethtenyl) -2.4-dinitr- obenzoyl) -N'N' -dimethylformamidine. To a solution of 5-methyl-2,4-dinitrobenzamide (Blatt, A. H. J. Org. Che 1960, 25, 2030.) (2.25 g, 10 mmol) in DMF (10 mL) is added t-butoxy-bis(dimethylamino)methane (6.2 mL, 30 mL) . The reaction mixture is stirred at 55 °C for 2 h. The solvent is evaporated under reduced pressure and the residue is suspended in water. The precipi- tate is filtered and washed with water and ethyl ether to give N- (5- (E,2-dimethylaminoethtenyl) -2,4-dinitro- benzoyl) -N'N' -dimethylformamidine, 2.76 g (84%). -U NMR (DMSO) δ 8.55 (IH, s) , 8.47 (IH, s),8.04 (IH, d, J ■= 13.0 Hz), 7.76 (IH, s) , 5.95 (IH, d, J = 13.0 Hz), 3.21 (3H, s) , 3.00 (9H, m) . 4-Oxo-3H-pyrroloquinazoline. A mixture of N- (5- (E,2-dimethylaminoethtenyl) -2,4-dinitrobenzoyl) - N'N' -dimethylformamidine (600 mg, 1.79 mmol) and Raney nickel (200 mg) in THF-MeOH (25 :25 mL) is hydrogenat- ed in a rocking autoclave at 1500 psi at room tempera- ture for 22 h. The catalyst is filtered off and the filtrate is concentrated in vacuo. The crude product is triturated in isopropanol and filtered. The solid is then washed with isopropanol and ethyl ether and dried in a vacuum oven at 40 β C to give 4-oxo-3H- pyrroloquinazoline (190 mg, 58%) as a bright red solid . -Η NMR (DMSO) δ 11.8 (IH, brs) , 11.6 (IH, brs,) 8.43 (IH, s) , 7.95 (IH, s, J = 3.1 Hz), 7.73 (IH, d, J = 3.4 Hz) , 7.55 (IH, s) , 6.58 (IH, d, J = 3.4 Hz) . 4- (3-Bromoanilino)pyrrolof3,2-σlquinazoline. 4-Oxo-3H-pyrroloquinazoline (100 mg, 0.54 mmol) in P0C1 3 (5 mL) is refluxed under N 2 for 20 h. The re¬ sulting dark red solution is cooled to room tempera¬ ture and extracted with ethyl acetate (2 x 20 mL) . The organic layer is dried (Na 2 S0 4 ) and concentrated to give a red solid (30 mg) . Without further purifi¬ cation, this is suspended in 2-propanol (2 mL) con¬ taining m-bromoaniline ( 0.1 mL, 0.8 mmol). The reac¬ tion mixture is then refluxed for 1 h. The resulting bright yellow precipitate is filtered and washed with water and ether to yield 4- (3-bromoanilino)pyrrolo- [3,2-g]quinazoline(15 mg, 8 %) . Η NMR (DMSO) δ 11.7 (IH, brs), 10.5 (IH, brs), 8.89 (IH, s) , 8.73 (IH, brs ) , 8 . 16 ( IH, s ) , 7 . 80 ( 3H , m) , 7 . 35 ( 2H, s ) , 6 . 77 ( IH , s ) . Example 4 4- (3-Bromoanilino)thiazolof5.4-σlquinazoline 5.5' -Dithiobis(4-amino-2-nitrobenzamide) . A solution of NaSH in aqueous MeOH (prepared according to Vogel, in "Elementary Practical Organic Chemistry, Part 1") is added dropwise with stirring to a solution of 5-chloro-2,4-dinitrobenzamide (5.00 g, 0.020 mmol) in a mixture of THF/MeOH (1:1, 200 mL) until no further reaction is observed (TLC analysis) . The solution is then diluted with water and washed with CH 2 C1 2 . The aqueous portion is acidified with concentrated HCl, extracted with EtOAc, and the extract is worked up to give an oily solid which is stirred vigorously with MeOH for 3 h. The resultant precipitate is removed by filtration to give 5,5'- dithiobis (4-amino-2-nitrobenzamide) (3.11g, 64%) as a tan powder. *H NMR (DMSO) δ 8.88 (IH, brs), 8.33 (IH, brs), 7.99 (IH, s) , 7.94 (IH, s) , 3.6-3.3 (2H, brs). 5-Nitrobenzothiazole-6-carboxamide. NaBH 4 (0.50 g, 0.013 mmol) is added to a vigorously stirred suspension of 5,5' -dithiobis(4-amino-2-nitrobenzamide) (3.00 g, 7.13 mmol) in MeOH (60 mL) . After 10 min the solution is acidified with concentrated HCl, extracted with EtOAc, and worked up rapidly to give 4-amino-5- mercapto-2-nitrobenzamide as an unstable solid which is used directly. The crude material is dissolved in formic acid (50 mL) heated under gentle reflux for 2 h, and then concentrated to dryness. The residue is triturated with MeOH/EtOAc (1:19), and unreacted disulfide (1.41 g) is recovered by filtration. The filtrate is concentrated and chromatographed on silica. Elution with EtoAc/petroleum ether (4:1) gives foreruns, while EtOAc gives 5-nitrobenzothiazole-6- carboxamide (1.31g, 41%) as a yellow powder. X H NMR (DMSO) δ 9.70 (IH, s) , 8.71 (IH, s) , 8.52 (IH, s) , 8.25 (IH, brs), 7.78 (IH, brs). Thiazolof5,4-σ.cruinazol-4 (3H) -one. A solution of 5-nitrobenzothiazole-6-carboxamide (0.30 g, 1.34 mmol) in MeOH/EtOAc (1:1, 25 mL) is hydrogenated over 5% Pd/C at 60 psi for 1 h to give 5- aminobenzothiazole-6-carboxamide. This is immediately dissolved in triethyl orthoformate (30 mL) and the mixture is heated under gentle reflux for 18 h. An equal volume of petroleum ether is added to the cooled solution, precipitating thiazolo[5,4-g]quinazol-4 (3H) - one (0.17 g, 57%) as a tan powder. H NMR (DMSO) δ 12.30 (IH, brs) , 9.67 (IH, s) . 9.00 (IH, s) , 8.31 (IH, s) , 8.14 (IH, s) . 4- (3-Bromoanilino)thiazolof5.4- σlquinazoline. A suspension of the thiazolo[5,4- g]quinazol- (3H) -one (0.25 g, 1.23 mmol) in P0C1 3 (20 mL) is heated under reflux for 3 h, then concentrated to dryness. The residue is partitioned between saturated aqueous NaHC0 3 and EtOAc, and the organic portion is worked up to give 4-chlorothiazolo[4,5- g]guinazoline (0.21 g, 0.95 mmol) as a yellow solid which is used directly. The crude product and 3- bromoaniline (0.21 L, 1.90 mmol) are heated under reflux for 45 min in THF/propan-2-ol (1:1, 20 mL) containing a trace of concentrated HCl, and then concentrated to dryness. After ' trituration with EtOAc, the residue is partitioned between saturated aqueous NaHC0 3 and EtOAc and the organic portion is worked up to give 4- (3-bromoanilino)thiazolo[5,4-g]quinazoline (0.19 g, 49%), . X H NMR (DMSO) δ 10.05 (IH, brs) , 9.74 (IH, s) , 9.38 (IH, s) , 8.71 (IH, s) , 8.48 (IH, s) , 8.31 (IH, brs), 7.96 (IH, d, J = 7.7 Hz), 7.39 (IH, t, J = 7.7 Hz,) , 7.33 (lH,d, J = 7.7 Hz) . Example 5 4- (3-Bromoanilino)oxazolof5.4-q1quinazoline 2.4-Dinitro-5-hvdroxybenzamide. A solution of 5-chloro-2,4-dinitrobenzamide (5.50 g, 0.022 mmol) in p-dioxane/methanol (1:1, 120 mL) and 6N aqueous KOH (20 mL) is stirred at room temperature for 2 h. After acidification with concentrated HCl, the mixture is diluted with water and extracted into EtOAc. Workup gives 2,4-dinitro-5-hydroxybenzamide (4.91g, 98%) as yellow cubes. X H NMR (DMSO) δ 8.64 (IH, s) , 8.16 (IH, brs), 7.81 (IH, brs), 7.13 (IH, s) , 5.80 (IH, brs). 4-Oxo-3H-oxazolof5,4-σlquinazoline. A solution of 2,4-dinitro-5-hydroxybenzamide (4.00 g, 0.018 mmol) in MeOH/EtOAc (1:1, 50 mL) is hydrogenated over 5% Pd/C at 60 psi for 3 h to give 2,4-diamino-5- hydroxybenzamide, which is used directly. Formic acid (50 mL) is added and the solution is heated under reflux for 48 h. then the volatiles are removed under reduced pressure. The residue is triturated with EtOAc to give crude 4-oxo-3H-oxazolo[5,4-g]quinazoline(3.27 g, 97%) as a tan powder which is used directly. 4-Chlorooxazolof5,4-q.quinazoline. A suspension of 4-oxo-3H-oxazolo[5,4-g]quinazoline (0.98 g, 5.24 mmol) in P0C1 3 (30 mL) is heated under reflux with vigorous stirring for 18 h, and then concentrated to dryness. The residue is partitioned between EtOAc and saturated aqueous NaHC0 3 and the organic portion is worked up to give 4-chlorooxazolo[5,4-g]quinazoline (0.24g, 22%) as a yellow solid which is used directly. 4- (3-Bromoanilino)oxazolof5.4-σ1quinazoline. A mixture of 4-chlorooxazolo[5,4-g]quinazoline (0.24 g, 1.16 mmol) and 3-bromoaniline (0.25 mL, 2.33 mmol) in a THF/propan-2-ol mixture (1:1, 40 mL) containing a trace of concentrated HCl is heated under reflux for 15 min, then concentration to dryness under reduced pressure. The residue is triturated with EtOAc, and then partitioned between saturated aqueous NaHC0 3 and EtOAc. Workup of the organic portion gives 4- (3- bromoanilino)oxazolo[5,4-g]quinazoline (0.18 g, 33%) as a yellow powder, mp (MeOH) 232 °C (dec.) . Example 6 4- (3-Bromoanilino) imidazolof4.5-σlquinazoline A mixture of 4-methylthio-6H-imidazo[4,5- g]quinazoline (0.5 g, 1.6 mmol) [Leonard, N.J.; Morrice, A.G.; Sprecker, M.A-; J. Org. Chem. , 1975, 40, 356-363], 3-bromoaniline (0.35 g, 2.0 mmol), and 3-bromoaniline hydrochloride (0.4 g, 1.9 mmol) in isopropanol (200 mL) is heated under reflux for 1 h to give a precipitate of 4- (3-bromoanilino) -βH- imidazo[4,5-g]quinazoline hydrochloride (0.63 g, 72 %) ' . l E NMR (DMSO) δ 9.93 (IH, brs), 9.01 (IH, s) , 8.66 (2H, s) , 8.39 (IH, s) , 8.04 (2H, m) , 7.39 (IH, t, J = 7.9 Hz), 7.31 (IH, brd, J = 8.0 Hz). Example 7 4- (3-Bromoanilino) triazolo f4.5-σl quinazoline hydrochloride 4-OXO-3H-triazolof4.5-σlquinazoline. A solution of 6,7-diamino-4-oxo-3H-quinazoline (91 g, 5.7 mmol) [Leonard, N.J.; Morrice, A.G.; Sprecker, M.A.; J. Org. Chem. , 1975, 40, 356-363] in 0.1 M HCl (250 mL) is cooled to below 10 °C, and a solution of NaN0 2 (0.41 g, 6 mmol) in water (10 mL) is added over 2 min. After 15 min the solution is neutralized with 0.1 M KOH solution to give a precipitate of 4-oxo-3H- triazolo [4,5-g] quinazoline (1.01 g, 94 %) . X H NMR (DMSO) δ 12.22 (2H, m) , 8.76 (IH, s) , 8.12 (IH, s) , 8.07 (IH, s) . 4-Thiono-3H-triazolof4.5-σl quinazoline. A mixture of 4-oxo-3H-triazolo [4, 5-g] quinazoline (0.56 g, 3 mmol) and P 2 S 5 (1.3 g, 6 mmol) in pyridine (20 mL) is heated under reflux for 2 h, and the solvent is removed under reduced pressure. The residue is treated with boiling water (30 mL) to give a yellow solid which is collected by filtration and dissolved in 0. l M KOH solution. After filtration to remove insolubles, the clear yellow solution is neutralized with dilute HCl to give 4-thiono-3H-triazolo [4, 5-g] quinazoline (0.26 g, 43 %) . IH NMR (DMSO) δ 9.20 (IH, s) , 8.15 (IH, s) , 8.14 (IH, s) . 4-Methylthiotriazolof4.5-σlquinazoline. A solution of 4-thiono-3if-triazolo [4, 5-g] quinazoline (0.203 g, 1 mmol) and-KOH (0.15 g, 2.7 mmol) in 50 % MeOH-H 2 0 (15 mL) is treated with Mel (65 μL, 1.0 mmol) and the mixture is stirred at room temperature overnight. The MeOH is removed under vacuum and the solution neutralized with dilute HCl to give crude 4- methylthiotriazolo [4,5-g] quinazoline (0.12 g, 55 %) . X H NMR (DMSO) δ 8.96 (IH, s) , 8.79, (IH, s) , 8.40 (IH, S) , 2.74 (3H, s) . 4- (3-Bromoanilino) -triazolof4.5- σl quinazoline hydrochloride. A mixture of 4- methylthiotriazolo [4, 5-g] quinazoline (0.30 ' g, 1.38 mmol), 3-bromoaniline (2.1 mmol) and 3-bromoaniline hydrochloride (2.1 mmol) in isopropanol (400 mL) is heated under reflux for 6 h, and the solution is concentrated to give 4- (3-bromoanilino) -triazolo[4, 5- g] quinazoline hydrochloride (0.33 g, 63 %) . 1 H NMR (DMSO) δ 12.01 (IH, brs) , 9.86 (IH, s) , 9.02 (IH, s) , 8.63 (IH, s) , 8.39 (IH, s), " 8.13 (IH, dd, J - 1.9, 1.5 Hz), 7.85 (IH, ddd, J = 7.7, 1.9, 1.5 Hz) , 7.56 (IH, ddd, J = 8.0, 1.7, 1.5 Hz), 7.41 (IH t, J = 7.8 Hz) . Example 8 4- (3-Bromoanilino) -8.N-methylimidazolof4.5- σl quinazoline 8,N-Methyl-3H-imidazof4.5-σlσuinazolin-4- thione. A mixture of of 8,N-methyl-3H-imidazo [4, 5- g]quinazolin-4-one (2.32 g, 11.1 mmol) [Lee, C.-H.; Gilchrist, J.H.; Skibo, E.B.; J. Org. Chem. , 1986, 51 , 4784-4792] and P 2 S 5 (3.96 g, 17.8 mmol) in pyridine (25 mL) is heated under reflux for 16 h. The pyridine is removed under vacuum, and the residue is treated with boiling water (50 mL) ..The precipitate is collected, washed with water, and dissolved in 0.1 M KOH. After filtration to remove insolubles, the clear yellow solution is acidified with AcOH to give 8,N-methyl-3H- imidazo[4,5-g]quinazoline-4-thione (2.12 g, 88 %) . -Η NMR (DMSO) δ 8.91 (IH, s) , 8.53 (IH, s) , 8.12 (IH, s) , 7.91 (IH, s) , 3.93 (3H,s) . 8.N-Methyl-4-methylthioimidazof4.5- σlquinazoline. Mel (0.61 ml, 9.5 mmol) is added to a solution of 8,N-methyl-3H-imidazo[4,5-g]quinazoline-4- thione(1.87 g, 8.65 mmol) and KOH (0.58 g, 10 mmol) in 100 ml 50 % MeOH-H 2 0, and the resulting mixture is stirred at room temperature for 30 min. The precipitated product is filtered off, and dried, to give 8,N-methyl-4-methylthioimidazo[4,5-g]quinazoline (1.89 g, 82 %) . l H NMR (DMSO) δ 8.96 (IH, s) , 8.64 (IH, s) , 8.39 (IH, s) , 8.16 (IH, s) , 3.98 (3H, s) , 2.74 (3H, s) . 4- (3-Bromoanilino) -8,N-methylimidazolof4.5- σlquinazoline. A mixture of 8,N-methyl-4- methylthioi idazo[4,5-g]quinazoline (1.50 g, 6.5 mmol), 3-bromoaniline (1.7 g, 10 mmol), and 3- bromoaniline hydrochloride (2.1 g, 10 mmol) in isopropanol (400 mL) is heated under reflux for 4 h to give a precipitate of the product hydrochloride, which is treated with aqueous NH 3 to give 4- (3-bromoanilino) - 8,N-methylimidazo[4,5-g]quinazoline (1.22 g, 52 %) . : H NMR (DMSO) δ 9.86 (IH, s) , 9.02 (IH, s) , 8.63 (IH, s) , 8.54 (IH, s) , 8.37 (IH, s) , 8.01 (2H, m) , 7.36 (IH, t, J - 8.0 Hz) , 7.28 (IH, brd) , 3.96 (3H, s) . Example 9 4- (3-Bromoanilino) -6.N-methylimidazolof4.5- σlquinazoline 2.4-Dinitro-5-methylaminobenzamide. A solution of 5-chloro-2,4-dinitrobenzamide (6.14 g, 25 mmol) [Goldstein, H. ; Stamm, R. ; Helv. Chim. Acta, 1952, 35, 1330-1333] and 40% aqueous methylamine (20 mL) in ethanol (80 mL) is heated in a sealed pressure vessel at 100 °C for 2 h. After cooling, dilution with water gives 2,4-dinitro-5-methylaminobenzamide (5.89 g, 98 %) . - NMR (DMSO) δ 8.88 (IH, q, J = 4.9 Hz) , 8.76 (IH, s) , 8.07 (IH, brs-), 7.77 (IH, brs), 6.98 (1H,S ) , 3.07 (3H, d, J = 5.0 Hz) 6.N-methyl-3H-imidazof4.5-σlquinazolin-4- one. A suspension of 2,4-dinitro-5- methylaminobenzamide (4.80 g, 20 mmol) in ethanol and formic acid (2.5 mL, 66 mmol) is hydrogenated over 5% Pd/C, and the solvent is removed under reduced pressure. The resulting crude salt is dissolved in formic acid (100 mL) and the mixture is heated under reflux for 2 h. The formic acid is removed under reduced pressure, and the residue is dissolved in the minimum volume of 0.1 M HCl. After clarification with charcoal and filtration through celite, the aqueous solution is neutralized with dilute aqueous NH 3 , and allowed to stand overnight, to give 6,N-methyl-3H- imidazo[4,5-g]quinazolin-4-one (2.99 g, 75 %) . 4_ NMR (DMSO) ό 11.91 (12H, brs) , 8.50 (IH, s) , 8.33 (IH, s) , 8.00 (IH, s) , 7.89 (IH, s) , 3.95 (3H, s) . 6,N-Methyl-3H-imidazof4.5-σlquinazolin-4- thione. A mixture of 6,N-methyl-3-ϊ-imidazo[4,5- g]quinazolin-4-one (2.50 g, 12.5 mmol) and P 2 S 5 (5.55 g, 25 mmol) in pyridine (30 mL) is heated under reflux for 16 h, and the pyridine is removed under reduced pressure. The residue is treated with boiling water (50 mL) , and the resulting yellow precipitate is collected by filtration and dissolved in 0.1 M KOH solution. After filtration to remove insolubles, the solution is neutralized with NH 4 C1 to give 6,N-methyl- 3H-imidazo[4,5-g]quinazolin-4-thione (1.58 g, 59 %) . ~ H NMR (DMSO) δ 13.65 (IH, brs), 8.76 (IH, s) , 8.61 (IH, S) , 8.11 (IH, S) , 7.98 (IH, s) , 3.99 (3H, s) . 6.N-Methyl-4-methylthioimidazof4.5- σlquinazoline. A solution of 6,N-methyl-3H- imidazo[4,5-g]quinazolin-4-thione (1.08 g, 5 mmol) and KOH (0.40 g, 7 mmol) in 50 % aqueous MeOH (100 mL) is treated with Mel (0.33 mL, 5.3 mmol) and the resulting mixture is stirred at room temperature for 1 h. The methanol is then removed under reduced pressure, and the residual aqueous solution is kept at 5 °C overnight to give crystals of 6,N-methyl-4- methylthioimidazo[4,5-g]quinazoline (0.62 g, 54 %) . l H NMR (DMSO) δ 8 . 93 ( IH , s ) , 8 . 67 ( IH , s ) , 8 . 22 ( IH , s ) , 8 . 21 ( IH , s ) , 4 . 01 ( 3H , s ) , 2 . 74 ( 3H, s ) . 4- (3-Bromoanilino) -6.N-methylimidazo[4.5- σlquinazoline hydrochloride. A mixture of 6,N-methyl- 4-methylthioimidazo[4,5-g]quinazoline (0.3 g, 1.3 mmol), 3-bromoaniline (0.34 g, 1.95 mmol), and 3- bromoaniline hydrochloride (0.41 g, 1.95 mmol) in isopropanol (400 mL) is heated under reflux for 6 h. After cooling the precipitated solid is collected by filtration and recrystallized from EtOH to give 4- (3- bromoanilino) -6,N-methylimidazo[4,5-g]quinazoline hydrochloride (0.43 g, 85 %) . - ~ i NMR (DMSO) δ 11.66 IH, brs), 9.43 (IH, s) , 8.96 (IH, s) , 8.80 (IH, s) , 8.19 (IH, s) , 8.16 (IH, brs), 7.89 (IH, brd, J = 7.1 Hz), 7.54-7.43 (2H, m) , 4.05 (3H, s) . Example 10 4- (3-Bromoanilino)pyrazinof2,3-σlquinazoline 7-Acetamido-6-nitro-3H-quinazolin-4-one. A solution of 7-amino-6-nitro-3H-quinazolin-4-one (5.90 g, 28.6 mmol) [Leonard, N.J.; Morrice, A.G.; Sprecker, M.A.; J. Org. Chem. , 1975, 40, 356-363] in a mixture of glacial acetic acid (300 mL) and acetic anhydride (100 mL) is heated under reflux for 6 h, and water (100 mL) is added. The solution is then concentrated to a small volume to give 7-acetamido-6-nitro-3H- quinazolin-4-one (5.37 g, 76 %) . X H NMR (DMSO) δ 10.51 (IH, brs), 8.57 (IH, s) , 8.24 (IH, s) , 7.97 (IH, s) , 2.15 (3H, s) . 7-Acetamido-4- (3-bromoanilino) -6- nitroquinazoline. A solution of 7-acetamido-6-nitro- 3H-quinazolin-4-one (5.00 g, 20 mmol) in POCl 3 (250 mL) is heated under reflux for 2 h, the excess of P0C1 3 is removed under vacuum, and the residue is dissolved in CH 2 C1 2 and washed with aqueous Na 2 C0 3 solution. Workup gives the crude 4-chloro derivative, which is coupled directly with 3-bromoaniline in isopropanol as above, and the resulting hydrochloride is converted directly to the free base, by treatment with aqueous NH 3 , to give 7-acetamido-4- (3-bromoanilino) -6-nitroquinazoline (3.60 g, 45 %) . -Η. NMR (DMSO) δ 10.56 (IH, s) , 10.29 (IH, s) , 9.34 (IH, s) , 8.70 (IH, s) , 8.19 (IH, brs), 7.97 (IH, s) , 7.88 (IH, d, J = 6.0 Hz), 7.43-7.35 (2H, m) , 2.13 (3H, s) . 7-Amino-4- (3-bromoanilino) -6- nitroquinazoline. A solution of 7-acetamido-4- (3- bromoanilino) -6-nitroquinazoline (1.50 g, 3.73 mmol) and KOH (2 g) in MeOH (190 mL) and H 2 0 (10 mL) is heated under reflux for 30 min, and the solvent volume is reduced to give 7-amino-4- (3-bromoanilino) -6- nitroquinazoline (1.17 g, 87 %) . X H NMR (DMSO) δ 10.17 (IH, brs), 9.43 (IH, s) , 8.43 (IH, s) , 8.15 (lH,m brs), 7.86 (IH, d, J = 7.1 Hz), 7.42 (2H, brs), 7.40- 7.31 (2H, m) , 7.12 (IH, s) . 4- (3-Bromoanilino) -6.7-diaminoquinazoline. Iron dust reduction of 7-amino-4- (3-bromoanilino) -6- nitroquinazoline (0.5 g, 1.4 mmol) in 65 % aqueous EtOH containing sufficient aqueous HCl to ensure solubility gives 4- (3-bromoanilino) -6,7- diaminoquinazoline (0.30 g, 65 %) . X H NMR (DMSO) δ 9.14 (IH, s) , 8.27 (IH, s) , 8.23 (IH, brs), 7.85 (IH, d, J = 8.0 Hz), 7.31-7.14 (2H, m) , 7.29 (IH, s) , 6.79 (IH, s) , 5.73 (2H, brs), 5.13 (2H, brs). 4- (3-Bromoanilino)pyrazinof2.3- σlquinazoline. A mixture of 4- (3-bromoanilino) -6,7- diaminoquinazoline (90 mg, 0.27 mmol) and 1,4-dioxane- 2,3-diol (0.2 g, 1.6 mmol) [Venuti, M.C.; Synthesis, 1982, 61-63] in MeOH (20 mL) is stirred at room temperature overnight to give a precipitate of 4- (3- bromoanilino)pyrazino[2,3 -g]quinazoline (80 mg, 83 %) -K NMR (DMSO) δ 10.45 (IH, brs) , 9.52 (IH, s) , 9.09 (IH, d, J = 1.6 Hz), 9.06 (IH, d, J = 1.6 Hz), 8.71 (IH, s) , 8.44 (IH, s) , 8.32 (IH, brs), 7.99 (IH, m) , 7.45-7.34 (2H, m) . Example 11 4- (3-Bromoanilino)imidazolof4.5-hiquinazoline hydrochloride 6-Methylthioimidazof4,5-hiquinazoline. A solution of 3H-imidazo[4,5-h]quinazoline-4-thione (0.41 g, 2 mmol) [Morrice, A.G.; Sprecker, M.A. ; Leonard, N.J.; J. Org. Chem. , 1975, 40, 363-366] and KOH (0.15 g, 27 mmol) in 50 % MeOH-H 2 0 (50 mL) is treated with Mel (0.13 mL) and the mixture is stirred at room temperature for 3 h to give a precipitate of 4-methylthioimidazo[4,5-h]quinazoline (0.35 g, 80 %). X H NMR (DMSO) δ 13.80 (IH, brs), 9.09 (IH, s) , 8.49 (IH, s) , 7.98 (IH, d, J = 8.8 HzH) , 7.85 (IH, d, J = 8.8 Hz) , 2.72 (3H, s) . 4- (3-Bromoanilino) i idazolo [4 , 5- h1 quinazoline. A mixture of 4-methylthioimidazo [4, 5- h] quinazoline (0.216 g, 1 mmol) , 3-bromoaniline (0.25 g, 1.5 mmol) , and 3-bromoaniline hydrochloride (0.31 g, 1.5 mmol) in N-methylpyrrolidone (50 mL) is heated 120 °C for 2 h. The solvent is removed under vacuum and the residue is triturated with EtOH to give a solid which is recrystallized from MeOH to give 4- (3- bromoanilino) imidazo[4,5-h] quinazoline hydrochloride (0.23 g, 61 %) .. X H NMR (DMSO) δ 11.11 (IH, brs) , 8.93 (2H, s) , 8.66 (IH, d, J = 9.0 Hz), 8.11 (IH, brs), 8.07 (IH, d, J = 9.0 Hz) , 7.83 (IH, brd, J = 6.8 Hz) , 7.50-7.40 (2H,m) . Example 12 4- (3-Bromoanilino) imidazolo f4 , 5-f] quinazoline 4-Methylthioimidazof4.5-_f1 quinazoline. A solution of 3H-imidazo [4, 5-f] quinazoline-4-thione (1.01 g, 5 mmol) [Morrice, A.G. ; Sprecker, M.A. ; Leonard, N.J.; J. Org. Chem. , 1975, 40, 363-366] and KOH (0.36 g, 6.5 mmol) in 50 % MeOH-H 2 0 (50 mL) is treated with Mel (0.34 mL) and the mixture is stirred overnight at room temperature. The MeOH is removed under vacuum to give a precipitate of 4- methylthioimidazo[4, 5-f]quinazoline (0.61 g, 57 %) . X H NMR (DMSO) δ 13.23 (IH, m) , 9.05 (IH, s) , 8.60 (IH, S) , 8.24 (IH, d, J = 8.7 Hz), 7.81 (IH, d, J = 8.9 Hz) , 2.71 (3H, S) . 4- (3-bromoanilino) imidazo f4 , 5-f1 quinazoline. A solution of 4-methylthioimidazo [4,5-f] quinazoline (0.43 g, 2 mmol), 3-bromoaniline (0.5 g, 3 mmol) , and 3-bromoaniline hydrochloride (0.63 g, 3 mmol) is heated under reflux for 16 h. The precipitate of hydrochloride salt is converted directly to the free base with aqueous NH 3 , and recrystallized from EtOH to give 4- (3-bromoanilino) imidazo [4, 5-f] quinazoline (0.52 g, 77%) . -E NMR (DMSO) δ 11.53 (IH, brs) , 8.79 (IH, s) , 8.68 (IH, s) , 8.53 (IH, dd, J = 1.8, 1.9 Hz), 8.15 (IH, d, J = 8.8 Hz) , 7.81 (IH, brd, J = 8.6 Hz) , 7.71 (IH, d, J = 8.9 Hz, 1 H) , 7.41 (IH, t, J = 8.0 Hz), 7.32 (IH, brd, J = 7.8 Hz) . Example 13 4-Benzylaminobenzothieno 13.2-dlpyrimidine 4-Chlorobenzothieno [3, 2-d]pyrimidine (111 mg, 0.5 mmol), (see following experimental) and benzylamine (114 mg, 1.0 mmol) (111 mg, 1.1 mmol) in stirred 2-propanol (2 mL) are heated at reflux under N 2 for 26 h. The mixture is allowed to cool, and the precipitate is collected by Buchner filtration, rinsed with 2-propanol and water and dried in an oven to give 4-benzylaminobenzothieno [3,2-d]pyrimidine (100 mg, 68%) as a white powder. X H NMR (DMSO) δ 8.60 (IH, s) , 8.51 (IH, t, J = 5.9 Hz), 8.31 (IH, ddd, J = 0.7, 1.4, 8.0 Hz) , 8.17 (IH, ddd, J = 0.7, 1.8, 8.1 Hz) , 7.68 (IH, ddd, J = 1.2, 7.0, 8.1 Hz) , 7.59 (IH, ddd, J = 1., 7.0, 8.1 Hz) , 7.36 (2H, d, J = 7.4 Hz), 7.33 (2H, t, J = 7.3 Hz), 7.24 (IH, t, J = 7.2 Hz) , 4.79 (2H, d, J = 6.0 Hz) . Example 14 4 - ( fRI -l-Phenylethylamino) benzothieno f 3 . 2 -d] pyrimidine Ethyl 3 -aminobenzothiophene-2 -carboxylate . 2 -Fluorobenzonitrile (0 . 61 g, 5 mmol) , ethyl thioglycollate (0.60 g, 5 mmol) and NEt 3 (1.52 g, 15 mmol) are stirred in DMSO (5 mL) at 100°C under N 2 for 3 h. The reaction mixture is poured onto ice-water (50 mL) , and the solid is collected by suction filtration, rinsed with water, and air dried to give ethyl 3-aminobenzothiophene-2-carboxylate (0.78 g, 70%) as a grey-brown solid. X H NMR (DMSO) δ 8.14 (IH, d, J = 7.7 Hz), 7.88 (IH, d, J = 8.1 Hz), 7.50 (IH, dt, J d = 1.2 Hz, J t = 7.5 Hz), 7.39 (IH, dt, J d = 1.2 Hz, J t = 7.6 Hz), 7.17 (2H, brs), 4.26 (2H, q, J = 7.1 Hz), 1.29 (3H, t, J = 7.1 Hz). Benzothienof3,2-dl -3H-pyrimid-4-one: Ethyl 3-aminobenzothiophene-2-carboxylate (764 mg, 3.45 mmol) is heated in formamide (2 mL) under N 2 at 140°C for 2 h, and at 180°C for 20 h. The solution is allowed to cool to 25°C, and the slurry is diluted with EtOH (5 mL) . The solid is collected by suction filtration, rinsed with EtOH (2x5 mL) , and air dried to give benzothieno[3,2-d] -3H-pyrimid-4-one (0.55 g, 79%) as a highly crystalline dark brown solid. X H NMR (DMSO) δ 12.85 (IH, brs), 8.35 (lH,s), 8.16 (IH, d J = 7.3 Hz), 7.67 (IH, dt, J d = 1.6 Hz, J t = 7.5 Hz), 7.59 (IH, dt, J d = 1.2 Hz, J t = 7.5 Hz,). 4-Chlorobenzothienof3,2-dlpyrimidine. DMF (0.27 g, 3.5 mmol) is added dropwise to a solution of oxalyl chloride (0.44 g, 3.5 mmol) in 1,2- dichloroethane (10 mL) , stirred under N 2 at 25°C. When the vigorous gas evolution ceases, benzothieno[3,2-d] - 3H-pyrimid-4-one (337 mg, 1.53 mmol) is added and the reaction mixture is heated to reflux. After 20 min, the reaction mixture is allowed to cool, and is then quenched with saturated aqueous NaHC0 3 solution (20 L) . The phases are separated, and the aqueous phase is extracted with CHC1 3 (3 x 10 mL) . The combined organic phases are washed with water (2 xlO mL) , saturated brine (10 mL) , and dried (Na 2 S0 4 ) . The solvent is removed under reduced pressure to give 4- chlorobenzothieno[3,2-d]pyrimidine (249 mg, 74%) as a light brown solid. X H NMR (CDC1 3 ) δ 9.09 (IH, s) , 8.53 (IH, dd, J = 1.8, 7.6 Hz), 7.95 (IH, d, J = 7.8 Hz), 7.73 (IH, dt, J d = 1.4 Hz, J t = 7.7 Hz), 7.62 (IH, dt, J d = 1.2 Hz, J t = 7.5 Hz) . 4- ( fRI -1-Phenylethylamino)benzothienof3,2- dlpyrimidine 4-Chlorobenzothieno[3,2-d]pyrimidine (110.1 mg, 0.5 mmol), [R] -1-phenylethylamine (74 mg, 0.6 mmol) and NEt 3 (111 mg, 1.1 mmol) in stirred propanol (2 mL) are heated at reflux under N 2 for 9 h. The mixture is allowed to cool, and is then purified by preparative tic on silica, eluting once with 2% MeOH in CHC1 3 . The yellow solid is recrystallized from EtOH at 0 * C to give 4- ( [R] -l-phenylethylamino)benzo- thienot3,2-d]pyrimidine, (75 mg, 49%) as pale yellow cubic crystals. X H NMR (DMSO) δ 8.53 (IH, s) , 8.30(1H, d, J = 7.2 Hz), 8.15 (IH, d, J = 8.2 Hz), 7.68 (IH, dt, J d =1.2 Hz, J t = 7.5Hz), 7.58 (IH, dt, J d =1 Hz, J t = 7.5Hz), 7.44 (IH, dd, J = 1, 8 Hz) , 7.31 (2H, t, J = 7.7 Hz), 7.21 (1 H, tt, J = 1, 7.7 Hz), 5.58( IH, q, J = 7 Hz) , 1.58 (3H, d, J = 7 Hz) . Example 15 4- (3-Bromoanilino)benzothieno[3.2-dlpyrimidine 4-Chlorobenzothieno[3,2-d]pyrimidine (110.1 mg, 0.5 mmol), (see preceding example) 3- bromoaniline (107.2 mg, 0.62 mmol) and NEt 3 (102.8 mg, 1.0 mmol) in stirred ethoxyethanol (2 L) are heated at 110°C under N 2 for 18 h. The solvent is removed under reduced pressure, and the dark oily residue is purified by preparative layer chromatography, eluting once with 2% MeOH in CHCL 3 . The major band R f 0.40 is extracted to give a yellowish solid (147 mg) which is recrystallized from EtOH (20 mL) to give 4- (3- bromoanilino)benzothieno[3,2-d]pyrimidine (70 mg, 39%) as pale beige glistening plates. H NMR (CDC1 3 ) δ 8.88(1H, s) , 8.49(1H, dd, J = 1.7, 7.1 Hz), 7.96 (IH, t, J = 1.9 Hz), 7.89 (IH, dd, J = 1.6, 7.0 Hz), (IH, d, J = 7.8 Hz), 7.65 (IH, dt, J d = 1.5 Hz, J t = 7 Hz), 7.60 (IH, dd, J = 1.5, 7.5 Hz), 7.57 (IH, dt, J d = 1.5 Hz, J t = 7 Hz), 7.40 (IH, dt, J d = 1.7 Hz, J t = 8 Hz),7.28 (IH, t, J = 7.8 Hz), 6.90 (IH, brs). Example 16 4- (3-Bromoanilino) -8-nitrobenzofb]thieno13.2* d] yrimidine 2-Fluoro-5-nitrobenzonitrile. A mixture of 70% nitric acid and concentrated sulfuric acid (1:1, 30 mL) is added dropwise over 30 min to a solution of 2-fluorobenzonitrile (12.11 g, 0.10 mol) in concentrated sulfuric acid (50 mL) , stirred under N 2 at 0°C. After a further 3h at 0°C the yellow solution is poured onto ice (400 g) , and the solid is collected by Buchner filtration, rinsed with water (4 x 50 mL) , and dried in vacuo to give 2-fluoro-5-nitrobenzonitrile (15.43 g, 93%) as a pale yellow crystalline solid. ~ NMR (CDC1 3 ) δ 8.56 (IH, dd, J = 2.8, 5.5 Hz) , 8.51 (IH, ddd, J = 2.8, 4.4, 9.1 Hz), 7.44 (IH, dd, J = 7.8, 9.0 Hz) . Ethyl 3-amino-5-nitrobenzothiophene-2- carboxylate. 2-Fluoro-5-nitrobenzonitrile (1.664 g, 10 mmol), ethyl thioglycollate (1.21 g, 10 mmol) and NEt 3 (3.06 g, 30 mmol) are stirred in DMSO (5 mL) at 100°C under N 2 for h h. The deep orange-red reaction mixture is poured onto ice-water (50 mL) , and the solid is collected by suction filtration, rinsed with water, and dried in a vacuum oven at 60°C to give ethyl 3-amino-5-nitrobenzothiophene-2-carboxylate (2.675 g, 100%) as a bright orange solid. X H NMR (DMSO) δ 9.23 (IH, d, J = 2.1 Hz), 8.28 (IH, dd, J * ** • 2.3, 8.9 Hz), 8.10 (IH, d, J = 9.0 Hz), 7.45 (2H, brs) , 4.29 (2H, q, J = 7.1 Hz), 1.30 (3H, t, J = 7.1 Hz). 8-Nitrobenzofb]thienof3,2-d] -3H-pyrimid-4- one. Ethyl 3-amino-5-benzothiophene-2-carboxylate (2.66 g, 10 mmol) is heated in formamide (10 mL) under N 2 at 190°C for 4 h, and precipitates after 2 h. The solution is allowed to cool to 25°C, and the solid is collected by suction filtration, rinsed with EtOH (2x5 mL) , and dried in a vacuum oven at 60°C to give 8- nitrobenzo[b]thieno[3,2-d] -3H-pyrimid-4-one (1.91 g, 77%) as a highly crystalline orange-brown solid. ~ E NMR (DMSO) δ 13.00 (IH, brs), 8.85 (lH,s), 8.45 (3H, s) . 4-Chloro-8-nitrobenzo fbl thieno f3 ,2- dlpyrimidine. DMF (0.75 g, 10.3 mmol) is added dropwise to a solution of oxalyl chloride (1.27 g, 10 mmol) in 1, 2-dichloroethane (25 mL) , stirred under N 2 at 25°C. When the vigorous gas evolution ceases, 8- nitrobenzo[b] thieno[3,2-d] -3H-pyrimid-4-one (1.236 g, 5 mmol) is added and the reaction mixture is heated to reflux. After 40 min, the hot reaction mixture is celite filtered, and then recrystallized at 0°C to give 4-chloro-8-nitrobenzothieno [3,2-d]pyrimidine (759 mg, 57%) as a light brown solid. X H NMR (DMSO) δ 9.24 (IH, s) , 8.99 (IH, d, J = 2.0 Hz), 8.57, 8.53 (IH, IH, ABq of d, J M = 9.0 Hz, J d = 2, 0 Hz) . 4- (3-Bromoanilino) -8-nitrobenzo fbl thieno- f3 ,2-dlpyrimidine. 4-Chloro-8-nitrobenzo [b] thieno- [3,2-d]pyrimidine (266 mg, 1.0 mmol), 3- bromoaniline (187.4 mg, 1.1 mmol) and NEt 3 (200 mg, 2.0 mmol) in stirred 1-propanol (4 mL) are heated at 110°C under N 2 for 48 h, becoming a thick yellow paste. The mixture is cooled to 0°C, and the solid is collected by Buchner filtration, and air dried to give 4-(3-bromo- anilino) -8-nitrobenzo[b] thieno [3,2-d]pyrimidine (275 mg, 69%) as a bright yellow solid. ~ E NMR (DMSO) δ 10.12 (IH, brs), 9.03 (IH, s) , 8.88(1H, d, J = 1.8 Hz), 8.54, 8.52 (IH, IH, ABq of d, J M = 7.5 Hz, J d = 0, 1.8 Hz) , 8.18 (IH, d, J = 1.7 Hz), 7.83 (IH, dd, J = 1.5, 7.7 Hz), 7.37, 7.34 (IH, IH, ABq of d, J M = 7.7 Hz, J d -= 7.7, 1.5 Hz) . Example 17 8-Amino-4- (3-bromoanilino)benzo fbl thieno f3 , 2-dlpyrimi¬ dine 4- (3-Bromoanilino) -8-nitrobenzo [b] thieno- [3, 2-d]pyrimidine (97 mg, 0.24 mmol) (see previous experimental) in THF (75 mL) is hydrogenated at 52 psi for 3 h, in the presence of Raney nickel (5 mg) . The reaction mixture is filtered, and the filtrate is concentrated to small volume under reduced pressure, and the residue is purified by preparative thin layer chromatography on silica, eluting with 5% MeOH in CHC1 3 . The band Rf 0.28 is extracted to give 8-amino- 4- (3-bromoanilino)benzo [b] thieno [3,2-d]pyrimidine (47.2 mg, 53%) as a yellow solid. X H NMR (DMSO) δ 9.66 (IH, brs), 8.72 (IH, s) , 8.18 (IH, t, J = 1.9 Hz) , 7.84 (IH, ddd, J = 1.2, 2.0, 8.1 Hz) , 7.78 (IH, d, J = 8.5 Hz), 7.50 (IH, d, J = 2.2 Hz), 7.33 (IH, t, J = 8.1 Hz) , 7.27 (IH, ddd, J = 1.2, 1.8, 8.0 Hz) , 7.02 (IH, dd, J = 2.3, 8.5 Hz) , 5.47 (2H, brs) . Example 18 4- (3-Bromoanilino) -9-methoxybenzo fbl thieno f3.2-dlpyri¬ midine hydrochloride. 2-Fluoro-6-methoxybenzaldoxime. NH 2 OHHCl (334 mg, 4.76 mmol) is added in portions to a solution of NaHC0 3 (395 mg, 4.7 mmol) in water (lOmL) at r.t. To this solution was added dropwise a mixture of 2- fluoro-6-methoxybenzaldehyde (made from 3-fluoroani- sole as described in Tetrahedron Lett . 1992, 33 , 7499) (725 mg, 4.7 mmol) and EtOH (10 mL) . The resulting mixture is stirred at r.t for 2hr. The precipitate is collected by filtration and dried in a vacuum oven at ~50C overnight to give 2-fluoro-6-methoxybenzaldoxime (720 mg, 89%). NMR (DMSO) δ 11.44, ( H, s) , 8.16 (IH, s) , 7.40, (IH, m) 6.85-6.95 (2H, m) ,3.84 (3H, s) . 2-Fluoro-6-methoxybenzonitrile. A solution of 2-fluoro-6-methoxybenzaldoxime (714 mg, 4.2 mmol) in Ac 2 0 (3.6 mL) is heated at reflux for 4 hr. The reaction is cooled to r.t. and the volatiles are stripped off to give a beige solid, which is dried at 50 °C in a vacuum oven to give 2-fluoro-6-methoxy- benzonitrile (635 mg, 84%). E NMR (DMSO) δ 7.8-7.7 (IH, m) , 7.14-7.07 (2H, m),3.95 (3H, s) . Methyl 3-amino-4-methoxybenzothiophene-2- carboxylate. Methyl thioglycollate (0.18 mL, 1.9 mmol) is added dropwise to a suspension of NaH (60% oil suspension, 176 mg, 4.4 mmol) in DMSO (5 mL) , stirred under N 2 at 25 °C. When gas evolution ceases, 2-fluoro-6-methoxybenzonitrile (266 mg, 1.76 mmol) inDMSO 5 mL is added in one portion. After 3 h, the reaction mixture is poured onto ice-water, and the beige precipitate is collected by suction filtration, rinsed and air dried to give methyl 3-amino-4- methoxybenzothiophene-2-carboxylate (345 mg, 83%) . X H NMR (DMSO) δ 7.44-7.37 (2H, m) , 7.00, (2H brs) , 6.90 (IH, d, J = 7.7Hz), 3.95 (3H, s) , 3.76 (3H, s) . 9-Methoxy-4-oxo-3H-benzothienof3,2- dlpyrimidine. A mixture of methyl 3-amino-4- methoxybenzothiophene-2-carboxylate (202mg, 0.85mmol) and formamide (2mL) is heated at 135C for lhr and the temperature is raised to 190C. After 8hr the reaction is cooled to r.t. Upon cooling, black solid forms and is collected by filtration. The precipitate is air dried to give 9-methoxy-4-oxo-3H-benzothieno[3,2- d]pyrimidine (45 mg, 22.5%). -E NMR (DMSO) δ 12.0 (IH, brs), 8.31 (IH, s)7.70-7.55 (2H, m) , 7.10 (IH, d, J = 7.7 Hz) , 3.97 (3H, s) . 4-Chloro-9-methoxybenzothienof3.2 - d] yrimidine. DMF (0.125 mL, 1.7 mmol) is added dropwise to a solution of (C0C1) 2 (0.15 mL, 1.68 mmol) in 1,2-dichloroethane (4.5 mL) at r.t. After gas evolution ceases, 9-methoxy-4-oxo-3H-benzothieno[3,2- d]pyrimidine (73.2 mg, 0.32 mmol) is added. The resulting mixture is heated at reflux for 4hr. After the reaction is cooled to r.t., the black tar is filtered off. The filtrate is stripped to dryness and then mixed with water. A yellow solid forms and is collected via filtration. The solid is washed with water and air dried to give 4-chloro-9- methoxybenzothieno[3,2-d]pyrimidine (53 mg, 66%). X H NMR (DMSO) δ 9.17 (IH, s) , 7.82-7.78 (2H, " m), 7.3-7.2 (IH, m) , 4.06 (3H, s) . 4- (3-bromoanilino) -9-methoxybenzofb] thieno- f3.2-dipyrimidine hydrochloride. A mixture of 4- chloro-9-methoxybenzothieno[3,2-d]pyrimidine (53 mg, 0.21 mmol), 2-methoxyethanol (3 mL) and m-bromoaniline (0.03 mL, 0.28 mmol) is heated at 80C for 1 h. The reaction is cooled to r.t. and yellow solid precipitates. The solid is collected by filtration and dried in a vacuum oven at -50C overnight to give 4- (3- bromoanilino) -9-methoxybenzo[b]thieno[3,2-d]pyrimidine hydrochloride (60 mg, 68%). X H NMR (DMSO) δ 11.14 (IH, brs), 8.95 (IH, s) , 8.07 (IH, d, J = 1.7Hz), 7.87 (IH, d, J = 8.2 Hz), 7.80 (IH, d, J = 8.2 Hz), 7.76 (IH, d, J = 7.5 Hz), 7.49 (IH, d, J = 8.2 Hz), 7.44 (IH, t, J = 8.0 Hz), 7.25 (IH, d, J = 8.0 Hz), 4.10 (3H, s) . Example 19 4- (3-Bromoanilino)thiazolof4' ,5' ; 4,51thienof3.2- dlpyrimidine A mixture of 5-chlorothiazolo[4' ,5' ;4,5] - thieno[3,2-d]pyrimidine (prepared as described by Athmani and Iddon, Tetrahedron , 48, 7689, 1992) (66 mg, 0.29 mmol), 3-bromoaniline (0.033 mL, 0.3 mmol) and 2-methoxyethanol (3 mL) is heated at 95C for 2.5 h and then cooled to room temperature. The reaction is added to water, and the precipitate is collected by Buchner filtration and purified by preparative tic on silica (2% MeOH/CHCl 3 ) . The major band is extracted with 20% MeOH/CHCl 3 . After removal of the solvent under reduced pressure 4- (3-bromoanilino)thiazolo[4' ,5' ; 4,5]thieno[3,2-d]pyrimidine (25 mg, 23%) is obtained. - ~ Η. NMR (DMSO) (J 9.98 (IH, s) , 9.67 (IH, s) , 8.75 (lH,s), 8.17 (IH, s) , 7.82 (IH, d, J = 7.8 Hz), 7.38- 7.31 (2H, m) . Example 20 4- (3-Chloroanilino)pyrido f3' .2' :4.51 thieno f3.2- dlpyrimidine Ethyl 3-aminopyrido f3.2-bl thiophene-2- carboxylate. A solution of 2-chloro-3-cyanopyridine ( 0.14 g, 1.0 mmol) in DMSO (2 mL) is added dropwise to a mixture of ethyl thioglycolate (0.12 mL, 1.1 mmol) , NaH (0.06 g, 1.5 mmol) and DMSO ( 1 mL) stirred under N 2 at 25°C. After 3 h the reaction is worked up by pouring the reaction mixture onto stirred ice water. The light yellow precipitate is collected by Buchner filtration and dried in a vacuum oven to give ethyl 3- aminopyrido[3,2-b] thiophene-2-carboxylate (197 mg, 89%) . H NMR (DMSO) δ 8.68 (IH, dd, J ■ 4.6, 1.6 Hz) , 8.54 (IH, dd. J = 8.2, 1.6 Hz), 7.46 (IH, dd, J = 8.2, 4.5 Hz), 7.31 (2H, brs), 4..3 (2H, q, J = 7.1 Hz), 1.29 (3H, t, J = 7.1 Hz) . 3H-Pyridof3' . 2 ' : 4.51 thienof3.2-dlPyrimid-4* one. A mixture of ethyl 3-aminopyrido[3,2- b]thiophene-2-carboxylate (0.92 g, 4.14 mmol) and formamide (10 mL) is heated at 135C for 1 h and then at 190C for 4 h. The reaction mixture is cooled to 25°C producing a precipitate. The solid is collected by vacuum filtration and is washed with water and dried in a vacuum oven at 60°C to give 3H- pyrido[3' ,2' ; 4,5]thieno[3,2-d]pyrimid-4-one (0.61 g, 72.6%) as yellow-brown needles. X H NMR (DMSO) δ 13.0 (IH, brs), 8.86 (IH, dd, J = 4.6, 1.6 Hz), 8.63 (IH, dd, J - 8.0, 1.6 Hz), 8.4 (IH, s) , 7.68 (IH, dd, J = 8.1, 4.6 Hz) . 4-Chloropyridof3' .2' ; 4.51thienof3,2- dlpyrimidine. To a solution of (C0C1) 2 (1.3 mL,15 mmol) in 1,2-dichloroethane (75 mL) DMF (1.1 mL, 15 mmol) is added dropwise and stirred under N 2 at 25°C. After gas evolution ceases, 3H-pyrido[3' ,2' ; 4,5]thieno[3,2-d]pyrimid-4-one (0.61 g, 3.0 mmol) is added to the mixture and the temperature is raised to 85C. After 2 h, the reaction mixture is cooled to 25°C and extracted with CHC1 3 . The combined extracts are washed with water, saturated brine and dried (MgS0 4 ) . The solvent is removed in vacuo to give 4- chloropyrido[3' ,2' ,- 4,5]thieno[3,2-d]pyrimidine (0.64g, 96%) as a yellow solid. ~ E NMR (DMSO) (J 9.3 (IH, brs), 9.0 (IH, d, J = 1.7 Hz), 8.9 (IH, dd, J = 7.3, 0.8 Hz), 7.8 (IH, dd, J - 4.7, 0.8 Hz). 4- (3-Chloroanilino)pyridof3' ,2' :4,51thienof3,2- dlpyrimidine. A mixture of.4-chloropyrido[3' ,2' ; 4,5]thieno[3,2-d]pyrimidine (0.12 g, 0.54 mmol), 3- chloroaniline (0.06 mL, 0.5 mmol) and 2-ethoxyethanol (5 mL) is heated under N 2 with stirring at 135C for 3 h. Upon cooling a solid precipitates. The solid is collected by filtration, washed with acetone and dried in a vacuum oven at -80C to give 4- (3- chloroanilino)pyrido[3' ,2' ;4,5]thieno[3,2-d]pyrimidine (46 mg, 27%). : H NMR (DMSO) δ 9.97 (IH, s) , 8.88 (IH, dd, J = 4.6, 1.7 Hz), 8.85 (IH, s) , 8.72 (IH, dd, J = 8.0, 1.7 Hz), 8.08 (2H, t, J = 2.0 Hz), 7.79 (IH, ddd, J = 8.3, 2.0, 0.8 Hz), 7.69 (IH, dd, J = 8.0, 4.6 Hz), 7.43 (IH, t, J = 8.0 Hz), 7.19 (IH, ddd, J = 8.0, 2.0, 0.8 Hz) . Example 21 4- (3-bromoanilino)pyridof3' ,2' : 4.51thienof3,2- dlpyrimidine A mixture of 4-chloropyrido[3' ,2' ,- 4,5]thieno[3,2-d]pyrimidine (72 mg, 0.32 mmol) (see previous experimental), 3-bromoaniline (0.04 mL, 0.37 mmol) and 2-ethoxyethanol (5 mL) is heated under N 2 with stirring at 135C for 3 h. Upon cooling a solid precipitates. The solid is collected by filtration, washed with acetone and dried in a vacuum oven at -80C to give 4- (3-bromoanilino)pyrido[3' ,2' ; 4,5]thieno[3,2-d]pyrimidine (45 mg, 39.4%). X H NMR (DMSO) δ 9.96 (IH, s) , 8.88 (IH, dd, J = 4.6, 1.7 Hz), 8.85 (IH, s) , 8.72 (IH, dd, J = 8.0, 1.7 Hz) , 8.20 (IH, t, J = 2.0 Hz), 7.84 (IH, ddd, J = 8.0, 2.0, 1.3 Hz), 7.69 (IH, dd, J = 8.0, 4.7 Hz) , 7.39- 7.31 (2H, m) . Example 22 4-Anilinoindolof3.2-dlpyrimidine A solution of 4-chloroindolo[3,2- d]pyrimidinehydrochloride (240 mg, 1.0 mmol) [ Monge, A.; Palop, J. A.; Goni, T.; Martinez-Crespo, F.; Recalde, I.. J. Het . Chem. , 1986, 23 , 647-9. ], and aniline (0.273 L, 3 mmol) in ethanol (1 mL) is heated at reflux for 3 h, during which time the reaction becomes a thick suspension. After cooling to 25C and diluting with ethanol (4 ml) the mixture is filtered, and the crude product washed with water (15 mL) , and ethanol (15 mL) , giving 274 mg tan solid, which is recrystallized from DMF / water affording pure 4-anilinoindolo[3,2-d]pyrimidine hydrochloride (82 mg, 27%). 'H NMR (DMSO) : δ 12.79 (IH, brs), 11.04 (IH, brs), 8.94 (IH, s) , 8.27 (IH, d, J = 8.2 Hz), 7.96 (2H, d, J = 7.5 Hz), 7.85 (IH, d, J = 8.4 Hz), 7.71 (IH, t, J = 7.7 Hz), 7.49 (2H, t, J = 8.0 Hz), 7.41 (IH, t, J = 7.6 Hz), 7.24 (IH, t, J = 7.4 Hz) . Example 23 4-Benzylaminoindolo[3,2-dlpyrimidine 4-Chloroindolo[3,2-d]pyrimidine hydrochloride (240 mg, 1 mmol, and benzylamine (1 mL) are stirred under a dry nitrogen atmosphere at 150 C for 6 hours, and then concentrated under reduced pressure to give an oily soft solid which is dissolved in EtOAc (20 mL) , and washed with saturated sodium bicarbonate solution (20 mL) , water (3 X 15 mL) , and brine (20 mL) . The solution is dried (MgS0 4 ) and the solvent is removed under reduced pressure. Trituration of the residue with dichloromethane, gives 4-benzylaminoindolo[3,2-d]pyrimidine (190 mg, 69%). X H NMR (CDC1 3 ) : £10.58 (IH, brs), 8.60 (IH, s) , 8.08 (IH, d, J=8.0 Hz), 7.47-7.14 (8H, m) , 4.82 (2H, d, J=5.6 Hz), 2.41 (IH, brs). Example 24 4- ( fRl -1-Phenylethylamino) indolo f3, 2-dlpyrimidine hydrochloride 4-Chloroindolo [3,2-d]pyrimidine hydrochloride 240 mg, 1 mmol) and (R) - (+) -- methylbenzylamine (1 ml) are stirred under a dry nitrogen atmosphere at 150 for 5 hours, and then concentrated under reduced pressure to an oil. This oil is dissolved in EtOAc (20 ml) , and stirred for 16 h. The precipitate which forms is collected by filtration, washed with EtOAc, and dried at 90 in vacuo to give 4- ( [R] -1-phenylethylamino) indolo [3, 2- d]pyrimidine hydrochloride (37 mg, 11%) . X H NMR (DMSO) : -510 (IH, s) , 9.14 (IH, brs), 8.64 (IH, s) , 8.16 (IH, d, J = 8.0 Hz), 7.74 (IH, d, J = 8.5 Hz) , 7.63-7.59 (IH, m) , 7.50 (2H, d, J = 7.2 Hz), 7.38-7.24 (4H, m) , 5.59 (IH, p, J = 7.0 Hz); 1.64 (3H, d, J = 7.0 Hz) . Example 25 4- (3-Bromoanilino) indolo f3.2-dlpyrimidine hydrochloride 4-Chloroindolo [3,2-d]pyrimidine hydrochloride (240 mg, 1 mmol) and 3-bromoaniline (0.33 mL, 3 mmol) in ethanol (3 mL) are heated at reflux under a nitrogen atmosphere for 2h. Filtration and washing of the collected solids with ethanol, followed by recrystallization from DMF gives 4- (3- bromoanilino) indolo [3,2-d]pyrimidine hydrochloride (288 mg, 77%) . X H NMR (DMSO) δ 12.73 (IH, s) , 11.42 (IH, s) , 9.02 (IH, s) , 8.41 (IH, s) , 8.28 (IH, d, J = 7.9 Hz) , 7.95-7.92 (IH, m) , 7.84-7.82 (IH, d, J = 8.6 Hz), 7.74-7.69 (IH, m) , 7.40-7.47 (3H, m) . Example 26 4- (3-Bromoanilino) -5,N-methylindolof3.2-dlpyrimidine hydrochloride A solution of 4-chloro-5,N-methylindolo[3,2- d]pyrimidine (Kadushkin, A.V. ; Nesterova, I.N.; Golovko, T.V. ; Nikolaeva, I.S.; Pushkina, T.V.; Fomina, A.N. ,- Sokolova, A.S.; Chernov, V.A. ; Granik, V.G. Khim. -Farm. Zh . 1990 , 24 , 18-22) (218 mg, 1 mmol) and 3-bromoaniline (0.33 mL, 3 mmol) in 2- propanol (7 mL) containing 0.5% HCl gas is heated at reflux for 3 hr, cooled to 25C, and the solids are filtered and washed with 2-propanol and dried affording 4- (3-bromoanilino) -5,N-methylindolo[3,2- d]pyrimidine hydrochloride (379 mg, 97%), as a bright yellow solid. *H NMR (DMSO) δ 9.80 (IH, s) , 8.83 (IH, s) , 8.34 (IH, d, J = 8.0 Hz.), 7.95-7.90 (2H, m) , 7.79- 7.68 (3H, m) , 7.45-7.41 (3H, m) , 4.27 (3H, s) . Example 27 4-Anilinoindolo12.3-dipyrimidine 4-Chloroindolo[2,3-d]pyrimidine hydrochloride (R. G. Glushkov et. al. , Khim.-Farm. Zh., 1967, 1(9), 25-32) (240 mg, 1 mmol) and aniline (0.27 mL, 3 mmol) in ethanol (1 mL) are heated under reflux for 6 h. The solvent is evaporated under reduced pressure, and the residue triturated with EtOAc to afford a tan powder which is filtered, and washed with cold ethanol. Recrystallization from acetone / pet. ether gives 4-anilinoindolo [2,3- d]pyrimidine (49 mg, 19 %) . X H NMR (DMSO) δ IH, s) , 8.84 (IH, s) , 8.43 (IH, s) , 8.37 (IH, d, J = 8.0 Hz) , 7.74 (2H, d, J = 7.7 Hz) , 7.52-7.08 (6H, m) . Example 28 4- (3-Bromoanilino) indolo f2.3-dlpyrimidine hydrochloride 4-Chloroindolo [2, 3-d]pyrimidine hydrochloride (240 mg, 1 mmol) and 3-bromoaniline (0.33 mL, 3 mmol) in ethanol (3 mL) are heated under reflux for 2h. The solids are collected by suction filtration, washed with ethanol and dried to give 4- (3-bromoanilino) indolo [2,3-d]pyrimidine hydrochloride (248 mg, 73%) . X H NMR (DMSO) J IH, s) , 9.02 (IH, s),8.51 (IH, s) , 8.42 (IH, d, J=7.7 Hz), 8.08 (IH, t, J = 1.9 Hz), 7.82 (IH, d, J = 8.0 Hz), 7.53 (IH, d, J=7.9 Hz), 7.46 (IH, dt, J d = 1.0 Hz, J t = 7.6 Hz) , 7.36-7.27 (3H, m) . Example 29 4- (3-Bromoanilino) -9 ,N-methylindolo f2 , 3-dlpyrimidine . 4-Chloro-9,N-methylindolo [2, 3-d] pyrimidine (Portnov, Yu. N. ; Bulaga, S.N.; Zabrodnyaya, V.G.; Smirnov, L. D. JChi-Ti. Geterotsikl . Soedin . , 1991 . 3, 400-2 ) (220 mg, 1 mmol) and 3-bromoaniline (0.33 mL, 3 mmol) in 2-propanol, containing 0.5% (w : w) HCl gas, (7 mL) is heated under reflux for 6h. After removal of solvent under reduced pressure, the residue is suspended in CHC1 3 (50 mL) , and washed with 1% aqueous NaOH solution (25 mL) , and H 2 0 (2 X 20 mL) , dried (MgS0 4 ) , and concentrated under reduced pressure. Column chromatography (Si0 2 ) with CHC1 3 gives the product as a light tan foam, which slowly crystallizes upon standing at 25 C. Recrystallization from diisopropyl ether (-30 ml ) affords 4- (3- bromoanilino) -9,N-methylindolo [2,3-d]pyrimidine (220 mg, 65%) as a fluffy white solid. X H NMR (CDC1 3 ) δ s, s,m, 3.96 (3H, s) . Example 30 4- (3-Bromoanilino) -9N- (2-N,N-diethylaminoethyl)pyri- mido f2.3-di indole bis hydrochloride 4-Chloro-9N- (2- (N,N-diethylamino) ethyl) - indolo f2.3-dl yrimidine. A suspension of 4-chloroin- dolo [2, 3-d]pyrimidine hydrochloride (407 mg, 2 mmol) , 2-N,N-diethylaminoethyl chloride hydrochloride (413 mg, 2.4 mmol) , anhydrous cesium carbonate (1.95 g, 6 mmol) and 4 molecular sieves (1.5 g) in acetone (6 mL) are heated at reflux under a nitrogen atmosphere for 1.5 h. The mixture is filtered through celite, washing the filter cake with acetone (4X10 ml) , followed by concentration of the filtrate under reduced pressure affording a viscous amber oil, which is dissolved in CH 2 C1 2/ (20 ml) , and washed with water (2 X 25 mL) , dried (MgS0 4 ) , and the solvent is removed in vacuo . The crude product is chromatographed on silica, eluting with 4% methanol/chloroform to give 4- chloro-9N- (2- (N,N-diethylamino) ethyl) indolo [2,3- d]pyrimidine (495 mg, 82%), as a pale yellow oil. X H NMR (DMSO) δ 8.79 (IH, s) , 8.41 (IH, d, J = 8.0 Hz) , 7.66-7.58 (2H, m) , 7.46-7.42 (IH, m) , 4.57 (2H, t, J = 6.8 Hz) , 2.90 (2H, t, J = 7.1 Hz), 2.63 (4H, d, J = 7.0 Hz) , 0.99 (6H, t, J = 7.0 Hz) . 4- (3-Bromoanilino) -9N- (2-N,N-diethylamino- ethyl)pyrimido f2,3-dl indole bis hydrochloride. A suspension of 4-chloro-9N- (2- (N,N-diethylamino) ethyl) - indolo [2,3-d]pyrimidine (240 mg, 1 mmol) and 3-bromo- aniline (0.33 mL, 3 mmol) in 2-propanol (7 mL) , which contains 0.5% HCl gas, is heated under reflux for 6 hr, and then concentrated to a viscous brown oil which is dissolved in chloroform (75 mL) and washed with 1 % aqueous NaOH solution (50 mL) , water (50 mL) , and dried (MgS0 4 ) . The solvent is removed under reduced pressure, and the residue is chromatographed on Si0 2 eluting with 2 % MeOH in CHCL 3 to obtain the free base of the product as a pale yellow oil (411 mg, 93%) . The free base is dissolved in warm ethanol (5 mL) , and is treated with ethanol (2 mL) which had been saturated with HCl gas, affording 4- (3-bromoanilino) - 9N- (2-N,N-diethylaminoethyl) indolo [2, 3-d]pyrimidine bis hydrochloride. IH NMR (DMSO) δ 10.64 (IH, brs) , 9.17 (IH, s) , 8.60 (IH, s) , 8.52 (IH, d, J = 8.0 Hz), 8.07 (IH, S) , 7.93 (IH, d) , 7.80 (IH, d, J = 7.7 Hz) , 7.58 (IH, t, J = 7.7 Hz), 7.41 (IH, t, J = 7.2 Hz), 7.37 -7.39 (2H, m) , 4.90 (2H, t, J = 7.0 Hz) , 3.51 (2H, dd, J = 12.8, 6.5 Hz) 3.31-3.28 (4H, m) , 1.25 (6H, t, J = 7.2 Hz) . Example 31 4- (3-Bromoanilino) 6-methoxyindolo f2,3-dlpyrimidine Cyano- (5-methoxy-2-nitrophenyl) acetic acid ethyl ester. To an ice-cold solution of ethyl cyanoacetate (10.9 mL, 102.4 mmol) in anhydrous THF (170 mL) under N 2 is added of potassium tert-butoxide (12.07 g, 107.5 mmol) . The formed white suspension is stirred for 15 min then treated with 3-fluoro-4- nitroanisole [Halfpenny, P. R.; Horwell, D. C; Hughes, J. ; Hunter, J. C; Rees, D. C. J. Med. Chem. (1990), 33, 286-91] (8.86 g, 51.2 mmol) . The suspension is heated at reflux for 1.5 h. The solution is poured into H 2 0, and the aqueous mixture is acidified to pH 2 with concentrated HCl. The mixture is extracted three times with ether then the combined organic phases are dried (MgS0 4 ) and concentrated to an oil that is pumped at 0.3 mm for 2 days. The oil is dissolved in dichloromethane and purified by flash silica gel chromatography eluting with dichloromethane. The product fractions are combined and concentrated to leave cyano- (5-methoxy-2- nitrophenyl) acetic acid ethyl ester (14.5 g) as a SUBSTITUTESHEET(RULE25) light yellow oil that is about 93-95% pure. λ E NMR (CDC1 3 ) : δ 8.29 (IH, d, J = 9.2 Hz), 7.22 (IH, d, J = 2.7 Hz), 7.04 (IH, dd, J = 9.2, 2.7 Hz), 5.69 (IH, s) , 4.31 (2H, q, J = 7.0 Hz) , 1.34 (3H, t, J = 7.2 Hz) . 2-Amino-5-methoxy-lH-indole-3-carboxylic acid ethyl ester. A solution of cyano- (5-methoxy-2- nitrophenyl)acetic acid ethyl ester (13.2 g, 46.3 mmol, 93-95% pure) in glacial acetic acid (185 mL) is treated with a single charge of zinc dust (12.1 g, 185 mmol) . The mixture is heated at 55 °C for 45 min, then treated with more zinc (4 g) . After heating for another 105 min, the brown mixture is filtered through a pad of flash silica gel. The pad is washed well with acetic acid and the filtrate is concentrated to a residue that is distributed between dichloromethane and H 2 0. The organic phase is washed with 5% aqueous sodium bicarbonate and concentrated to a residue that shows about a 1:1 mixture of products by silica gel thin layer chromatography (dichoromethane:EtOAc, 3:1). The residue is purified by flash silica gel chromatography eluting sequentially with 100:0, 95:5, and 90:10 dichloromethane:EtOAc. The fractions containing the pure higher R f product are combined and concentrated to a solid that, is sonicated in tert- butyl methyl ether. The solids are collected by filtration to give pure 2-amino-5-methoxy-lH-indole-3- carboxylic acid ethyl ester (2.07 g) as an off-white solid. Further chromatography of the combined mother liquor and impure fractions affords 120 mg of additional product. Total yield = 2.19 g (20%). ~ E NMR (DMSO) : δ 10.44 (IH, br s, exchanges with D 2 0) , 7.11 (IH, d, J = 2.2 Hz) , 6.98 (IH, d, J = 8.4 Hz) , 6.61 (2H, br ε, exchanges with D 2 0) , 6.48 (IH, dd, J = 8 . 4 , 2 . 7 Hz ) , 4 . 20 ( 2H , q , J = 7 . 0 Hz ) , 3 . 71 ( 3H , s ) , 1 . 32 (3H, t , J = 7 . 2 Hz ) . 6-Methoxy-3H-indolo f2.3-dlpyrimidine-4-one. A solution of 2-amino-5-methoxy-lH-indole-3-carboxy- lie acid ethyl ester (2.15 g (9.2 mmol), sodium meth- oxide (0.5 g (9.3 mmol), and formamide (200 mL) , is heated under N 2 at 220"C for 1.5 h. The solution is cooled to room temperature, stored for 2.5 days, and filtered. The solvent is evaporated by Kugelrohr distillation at 95 °C/0.8 mm. The residual solids are washed with H 2 0, then heated in 35 mL of boiling N,N- dimethylformamide. The hot suspension is filtered hot over a pad of flash silica gel. The cooled filtrate is concentrated in vacuo to a solid that is sonicated in about 30 mL of MeOH. The solids are filtered, washed with MeOH, and dried to leave 6-methoxy-3H- indolo [2, 3-d]pyrιmidine-4-one (1.71 g,72%) that is about 83 % pure. λ E NMR (DMSO) : δ 12.16 (IH, br s, exchanges with D 2 0) , 12.04 (IH, br ε, exchanges with D 2 0) , 8.08 (IH, d, J = 3.4 Hz, exchanges to s with D 2 0) , 7.46 (IH, d, J = 1.9 Hz), 7.37 (IH, d, J = 8.7 Hz) , 6.95 (IH, dd, J = 8.8, 2.5 Hz) , 3.81 (3 H, ε) . 4-Chloro-6-methoxyindolo f2 , 3.-d1pyrimidine. A εuεpen- εion of 6-methoxy-3H-indolo [2, 3-d]pyrimidine-4-one (800 mg, 3.08 mmol, -83% pure) and POCl 3 (7 mL) iε heated at 90 °C for 6 h. The suspenεion iε concen¬ trated to a solid that is evacuated at 1 mm for 1 h. The solids are cooled in a -78 °C bath then treated dropwiεe with cold H 2 0. The bath iε removed and the frozen εolids are allowed to gradually melt. The εolidε are filtered, washed well with cold H 2 0, and dried to leave -chloro-6-methoxyindolo [2, 3-d]pyrimi- dine (733 mg, 81%) that is about 80% pure. H NMR (DMSO) : δ 12.64 (IH, br s, exchanges with D 2 0) , 8.74 (IH, s) , 7.74 (IH, d, _7 = 2.4 Hz), 7.57 (IH, d, J = 8.9 Hz), 7.28 (IH, dd, J = 8.9, 2.4 Hz), 3.88 (3H, s) . 4- (3-Bromoanilino) -6-methoxyindolo f2.3-d1 - pyrimidine. A mixture of 4-chloro-6-methoxyindolo- [2, 3-d]pyrimidine (107 mg, 0.37 mmol, 80% pure) , 3- bromoaniline (0.15 mL, 1.4 mmol), N,N-dimethylaceta- mide (1 mL) , and 1 drop of a solution of 2-propanol that is 8.5 molar in HCl is heated under N 2 at 120 °C for 5 h. The solution iε concentrated in vacuo to an oily solid that is triturated in 5% aqueous sodium bicarbonate. The solids are collected by filtration, then washed succeεsively with H 2 0 and EtOAc. The solids are warmed in a small volume of N,N- dimethylformamide and filtered. The filtrate is purified by thick layer silica gel chromatography eluting with 3:2 dichloromethane:EtOAc. The product band is collected and sonicated in EtOAc. The mixture iε filtered and the filtrate iε concentrated to a solid that is sonicated in MeOH. The εolidε are collected, waεhed with MeOH, and dried to give pure 4- (3-bromoanilino) -6-methoxyindolo[2,3-d]pyrimidine (39 mg, 28%) hydrated with 0.7 equivalent of H 2 0. X H NMR (DMSO) : δ 11.99 (IH, br ε, exchangeε with D 2 0) , . 8.97 (IH, br ε, exchangeε with D 2 0) , 8.44 (IH, ε) , 8.02 (IH, s) , 7.91 (IH, d, J=2.4 Hz), 7.76 (IH, d, _7= 8.0 Hz) , 7.42 (IH, d, J=8.7 Hz) , 7.36 - 7.24 (2H, m) , 7.08 (lH,dd, J = 8.7, 2.2 Hz) , 3.87 (3H, s) . Example 32 2-Amino-4- (3-bromoanilino)pyrimidof2,3-d] indole 2-Guanidinoindole-3-carboxylic acid ethyl ester hydrochloride. A suspension of 2 aminoindole-3- carboxylic acid ethyl ester ( 2.04 g, 10.0 mmol), cyanamide (534 mg, 12.7 mmol), and concentrated hydrochloric acid (1 mL) in dioxane ( 91 mL) , are heated under reflux for 48 hr. After the reaction mixture has cooled to 25 C it is filtered and the solids washed well with dry diethyl ether, and then air dried to give 2-guanidinoindole-3- carboxylic acid ethyl ester hydrochloride (1.08g, 38 %) 2- guanidinoindole-3-carboxylic acid ethyl ester hydrochloride as an off-white solid, mp >250 C. 2-Amino-4-oxo-3H-indolof2.3-dlpyrimidine. A mixture of 2-guanidinoindole-3-carboxylic acid ethyl ester hydrochloride (1.00 g, 3.5 mmol) and sodium hydroxide (1.5 g) in water (50 mL) is heated to gentle reflux for 6 hr followed by the addition of sufficient 5 % HCl to adjust the solution to pH 1, and filtration of the resulting mixture through celite, washing the pad with water. The filtrate is extracted with ethyl acetate (3 X 25 mL) , and then basified with solid sodium carbonate. The tan precipitate which slowly forms is collected by filtration, washed with water, and dried in vacuoaffording2-amino-4-oxo-3H-indolo[2,3-d]pyrimidine (561 mg, 78%) as light tan cryεtalε, mp> 275 C. 2-Amino-4 -chloroindolo f2.3-dl pyrimidine hydrochloride. A εuεpension of 2-amino-4-oxo-3H- indolo[2,3-d]pyrimidine (490 mg, 2.5 mmol) and phoεphoryl chloride (7 ml, 75 mmol) in dioxane (13 ml) iε heated under reflux for 4 hr, then concentrated in vacuo. The residue is triturated with ethanol, filtered, and the solids washed with 10 : 1 Ethanol : Ethyl Acetate to give 170 mg (27 %) 2-amino-4- chloroindolo[2,3-d]pyrimidine hydrochloride as a grey solid, p >250 C. 2-Amino-4 - (3-bromoa ilino) indolo [2.3- dlpyrimidine. A mixture of 2-amino-4-chloroindolo[2,3- d]pyrimidine hydrochloride (123 mg, 0.6 mmol) and 3- bromoaniline (0.3 mL, 2.8 mmol) in 2-propanol (6 mL) is heated at reflux for 4 hr, filtered through a celite pad, and concentrated in vacuo . The residue iε partitioned between ethyl acetate (25 mL) and water (25 mL) . The aqueouε phase is extracted with further ethyl acetate (2 x 20 mL) , followed by washing the combined extracts with 1% aqueous sodium hydroxide (25 mL) , water (2 x 40 mL) , saturated brine (40 mL) , and drying (Na 2 S0 4 ) . The solution is evaporated to drynesε under reduced pressure to afford 105 mg crude product as a tan powder. The solid iε diεsolved in a minimum amount of methanol, filtered, and further purified by preparative plate chromatography (Si0 2 ; 1 : 1, EtOAc : CH 2 C1 2 ; R f = .40 ) . After extraction of the product from the silica gel with ethyl acetate, the volume of the warm solution is reduced to minimum, and it is filtered through celite, and the solvent is removed under reduced presεure. The oily εolid thuε obtained iε diεsolved in a minimum amount of 2-propanol and allowed to crystallize at 3 C over an 18 h period. The crystalε are collected by εuction filtration, waεhed with a εmall amount of cold 2-propanol, and dried in vacuo to give 2- amino-4- (3-bromoanilino) indolo[2,3-d]pyrimidine (34 mg, 17%). X HNMR, (DMSO): 5brs) , 8.57 (IH, s) , 8.11 (IH, d, J = 8.0 Hz) , 8.01 (IH, s) , 7.94 (IH, d, J = 8.2 Hz) , 7.34- 7.12 (5H, m) , 6.41 (2H, brs) . Example 33 4- (3-Bromoanilino) -9N- (2-N.N-diethylaminoethyl) -6- methoxyindolo f2 , 3-dlpyrimidine bishvdrochloride 4 - Ch l oro - 6 - me t hoxy - 9H - ( 2 - N . N - diethylaminoethyl) indolo f2 , 3-dlpyrimidine. A suspenεion of 4-chloro-6-methoxyindolo [2, 3-d]pyrimidine (773 mg, 2.5 mmol, -80% pure) , 2-diethylaminoethyl chloride hydrochloride (582 mg, 3.4 mmol) , anhydrouε cesium carbonate (2.3 g, 7.1 mmol) , 4 molecular sieves (2.1 g) , and acetone:N,N-dimethylformamide (12 mL, 2:1) is heated at reflux under N 2 for 16.5 h The mixture is filtered over Celite ® and the filter pad is waεhed well with acetone. The filtrate is concentrated in vacuo to a viscous oil that is distributed between dichloromethane and H 2 0. The organic phase is dried (MgS0 4 ) and concentrated to an oil that is purified by flash εilica gel chromatography eluting first with dichloromethane, then with dichloromethane:MeOH (98:2) . The product fractions are combined and concentrated in vacuo to leave 4-chloro-6-methoxy-9H- (2-N,N- diethylaminoethyl) indolo [2, 3.-d]pyrimidine (667 mg, 80 %)as a yellow oil. : H NMR (CDC1 3 ) : δ 8.75 (IH, ε) , 7.87 (IH, d, J=2.4 Hz) , 7.47 (IH, d, J = 8.9 Hz) , 7.25 (IH, dd, J = 8.9, 2.4 Hz) , 4.50 (2H, t, J=7.2 Hz) , 3.96 (3H, ε) , 2.86 (2H, t, J=7.1 Hz) , 2.59 (4H, q, J=7.1 Hz) , 0.96 (6H, t, J=7.1 Hz) . 4- ( 3 -Bromoani 1ino) -6-methoxy- 9H- (2-N.N- diethylaminoethyl) indolo 12,3-dlpyrimidine bishvdrochlor¬ ide. A solution of 4-chloro-6-methoxy-9H- (2-N,N- diethylaminoethyl) indolo[2,3-d]pyrimidine (660 mg, 1.98 mmol) , 3-bromoaniline (0.52 mL, 4.8 mmol, 0.25 mL of a solution of 2-propanol that iε 8.5 molar in HCl, and N,N-dimethylacetamide (4 mL) is heated at 120 °C under N 2 for 2 h. The solution is concentrated in vacuo and the residue is distributed between dichloromethane and 1% aqueous sodium hydroxide. The dichloromethane phase is washed with H 2 0, dried (MgSO , and concentrated to an oil that is purified by flash silica gel chromatography eluting first with EtOAc, then EtOAc:MeOH:triethylamine (95:5:1) . The product fractions are combined and concentrated to leave an oil that is stored at room temperature overnight. The semisolid is treated with an excess of a solution of 2-propanol that is 8.5 molar in HCl. After storage for several hours at room tempera¬ ture, the solidε are collected by filtration, washed with 2-propanol, and dried to leave 4- (3-bromoanilino) - 6-methoxy-9H- {2-N,N-diethylaminoethyl)indolo[2,3-d]pyri¬ midine (727 mg, 65%) as a salt with 2.1 equivalents of HCl and solvated with 0.9 equivalent of H 2 0. H NMR (DMSO) : δ 10.55 (IH, br s, exchangeε with D 2 0) , 9.28 (IH, br ε, exchangeε with D 2 0) , 8.55 (IH, s) , 8.02 (IH, d, J=2.2 Hz), 7.99 (IH, s) , 7.84 (IH, d, J- 8.7 Hz), 7.74 (IH, d, J=7.2 Hz), 7.39 - 7.32 (2H, m) , 7.21 (lH,dd, J = 8.9, 2.2 Hz) , . 5.30 (3H, br s, exchanges with D 2 0 ) , 4.85 (2H, t, J = 7.2 Hz) , 3.90 (3H, s) , 3.48 (2H, dd, J = 12.2, 6.4 Hz); 3.35-3.21 (4H, m) ; 1.23 (6H, t, J = 7.2 Hz) . Example 34 4- (3-Bromoanilino) benzofurano[3.2-dlpyrimidine Methyl 2- (2-cvanophenoxy)ethanoate. Methyl bromoacetate (1.95 mL, 20 mmol) is added dropwise to a solution of 2-cyanophenol (2.38 g, 20 mmol), and K 2 C0 3 (2.78 g, 20.1 mmol) in acetone (100 mL) stirred under N 2 at 25°C. After 24 h, the solid is filtered off and the filtrate is concentrated in vacuo and the residue is dried in a vacuum oven to give methyl 2- (2- cyanophenoxy)ethanoate (3.82 g, 100%) as a beige solid. ~E NMR (DMSO) δ 7.76 (IH, dd, J - 7.6, 1.7 Hz) , 7.64 (IH, dt, J d = 1.6 Hz, J t = 8.0 Hz), 7.20-7.10 (2H, m) , 5.04 (2H, brs) , 3.70 (3H, S) . Methyl 3-aminobenzofbl furan-2-carboxylate. A solution of methyl 2- (2-cyanophenoxy)ethanoate (3.82 g, 20 mmol) in DMSO (40 mL) is added dropwise to a suεpension of NaH (0.84 g, 21 mmol) and DMSO (10 mL) stirred under N 2 at 25°C. After 10 min the mixture is poured onto ice water and extracted with ether. The combined extracts are washed with water, saturated brine and dried (MgS0 4 ) . After removal of the solvent under reduced presεure, methyl 3-aminobenzo[b] furan-2- carboxylate (2.15 g, 56%) iε obtained as a yellow solid. l H NMR (DMSO) 67.95 (IH, d, J = 7.7 Hz) , 7.48 (2H, d, J = 3.4 Hz), 7.29-7.22 (IH, m) , 6.40 (2H, brs), 3.80 (3H, s) . 3H-Benzo uranof3.2-dlpyrimid-4-one. A solution of methyl 3-aminobenzo[b] furan-2-carboxylate (0.28 g, 1.36 mmol) in formamide (5 mL) is heated at 135C for 4 h, then the temperature is raised to 170C. After 4 h the reaction iε cooled to 25°C and a dark purple solid precipitates. The εolid iε collected by vacuum filtration and air dried to give 3H- benzofurano[3,2-djpyrimid-4-one (118 mg, 46.6%) . -E NMR (DMSO) δ 13.0 (IH, brs), 8.25 (IH, β) , 8.05 (IH, d, J = 8.1 Hz) , 7.84 (IH, d, J = 8.3 Hz) , 7.68 (IH, t, J = 7.7 Hz) , 7.51 (IH, t, J = 7.7 Hz) . 4-Chlorobenzofurano[3,2-dlpyrimidine. DMF (0.23 mL, 3.1 mmol) iε added dropwise to a solution of (C0C1) 2 (0.28 mL, 3.1 mmol) in 1,2-dichloroethane (15 mL) at 25 * C. After gas evolution ceases, 3H-benzofurano[3,2- d]pyrimid-4-one (113 mg, 0.61 mmol) is added. The resulting mixture is heated at reflux for 1 h. After the reaction has cooled to 25°C, water iε added and the reεulting mixture iε extracted with CHC1 3 . The combined extractε are waεhed with water, saturated brine and dried (MgS0 4 ) . The solvent is removed under reduced pressure to give 4-chlorobenzofurano[3,2-d]pyrimidine (116mg, 93%) as a yellow solid. X H NMR (DMSO) δ 9.08 (IH, s) , 8.30 (IH, d. J = 8.1 Hz) , 8.02 (IH, d, J = 8.5 Hz), 7.90, (IH, dt, J d = 1.3 Hz, J t = 7.1 Hz), 7.64 (IH, dt, J d = 1.0 Hz, J. = 7.8 Hz). 4- (3-Bromoanilino) benzofurano f 3.2 - dl pyrimidine. A mixture of 4- chlorobenzof urano [3 , 2- d]pyrimidine (116mg, 0.57 mmol) and 3 -bromoaniline (0.07 mL, 0.6 mmol) iε heated at 135 °C under N 2 in εtirred 2- ethoxyethanol for 3 h. The mixture precipitateε upon cooling, and the εolid iε cpllected and recryεtallized from EtOH to give 4- (3-bromoanilino)benzofurano [3, 2- dlpyrimidine (15.7 mg, 8%) . -H NMR (DMSO) δ 10.35 (IH, s) , 8.73 (IH, s) , 8.34 (IH, t, J = 1.9 Hz) , 8.17 (IH, ddd, J = 7.2, 1.2, 0.7 Hz) , 7.93 (IH, ddd, J = 8.2, 2.2, 1.0 Hz) , 7.88 (IH, d, J = 8.4 Hz), 7.77 (IH, dt, J d = 1.4 Hz, J. = 7.2 Hz) , 7.56 (IH, d , J d = 0.8 Hz, J t = 8.0 Hz) , 7.34 (IH, t, J = 8.0 Hz), 7.27 (IH, ddd, J = 8.0, 2.0, 1.0 Hz) . The pharmaceutical compoεitionε of the invention can take any of a wide variety of oral and parenteral dosage forms. The dosage forms comprise as the active components an inhibitor as defined previously. For preparing pharmaceutical compositions, one uses inert, pharmaceutically acceptable carriers that can be either εolid or liquid. Solid form preparations include powderε, tabletε, dispersible granules, capsuleε, cachets, and suppositories. A solid carrier can be one or more substances which may also act as dilutents, flavoring agentε, solubilizers, lubricants, suspending agents, binders, or tablet disintegrating agents; it can also be an encapsulating material. In powders, the carrier is a finely divided solid which is in admixture with the finely divided active compounds. In the tablet, the active compounds are mixed with carrier having the necessary binding properties in suitable proportionε and compacted in the εhape and εize deεired. The powderε and tablets preferably contain from 5% or 10% to about 70% of active ingredients. Suitable solid carriers are magnesium carbonate, magnesium εtearate, talc, εugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low melting wax, cocoa butter, and the like. The term "preparation" iε intended to include the formulation of the active compounds with encapsulating materials aε carrier, providing a capsule in which the active componentε (with or without other carriers) are εurrounded by carrier, which are thus in aεsociation with it. Similarly, cachetε are included. Tabletε, powderε, cachets, and capsules can be used as solid doεage formε suitable for oral administration. Liquid form preparations include solutions, suspensions, and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection. Liquid preparations can also be formulated in solution in aqueous polyethylene glycol solution. Aqueouε solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing, and thickening agents as desired. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active components in water with viscous material, i.e., natural or synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and other well-known suspending agents. Preferably, the pharmaceutical preparation iε in unit doεage form. In such form, the preparation may be subdivided into unit doses containing appropriate quantities of inhibitor and other anti-cancer materials individually or as a combination, i.e., in a mixture. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, for example, packeted tablets, capsuleε, and powderε in vialε or ampoules. The unit doεage form can also be a capsule, cachet, or tablet itself or it can be the appropriate number of any of these in packaged form. Additionally, the unit dosage form may be a dividable form having an inhibitor in one part and other anti- cancer materials in the other part, such as, a dividable capsule, a dividable package, or a two-part ampoule, vial or the like. The quantity of an inhibitor in unit doεageε of preparation may be varied or adjusted from about 0.01 mg/kg to 100.0 mg/kg, preferably 0.03 mg/kg to less than 1.0 mg/kg of inhibitor. The pharmaceutical compositionε preferably are constituted so that they can be administered parenterally or orally. Solutions of the active compounds as free baseε and free acidε or pharmaceutically acceptable salts can be prepared in water suitable mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganismε. The pharmaceutical formε εuitable for injectable use include sterile aqueous solutionε or diεperεions and sterile powderε for the extemporaneous preparation of εterile injectable solutions or dispersions. In all caseε, the form must be sterile and must be fluid to the extent that easy syringability exiεtε. It muεt be stable under the conditions of manufacture and storage and. must be preserved against the contaminating action of the microorganisms such as bacteria and fungi. The carrier can be a εolvent or diεperεion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like) , εuitable mixtures thereof, and vegetable oilε. The proper fluidity can be maintained, for example, by the uεe of a coating εuch as lecithin, by the maintenance of the required particle εize in the caεe of dispersion, and by the use of surfactants. The prevention of the action of microorganismε can be brought about by various antibacterial and antifungal agents, for example, paragens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferred to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions of agents delaying absorption, for example, gelatin. Sterile injectable solutions are prepared by incorporating the active compounds in the required amount in the appropriate solvent with various other ingredientε enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various εterilized active ingredientε, into a sterile vehicle which contains the basic diεperεion medium and the required other ingredientε from those enumerated above. In the case of the sterile powders for the preparation of εterile injectable solutionε, the preferred methodε of preparation are vacuum drying and the freeze-drying technique which yieldε a powder of active ingredientε pluε an additional deεired ingredient from a previously εterile-filtered εolution thereof. Aε used herein, "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances iε well known in the art. Except insofar aε any conventional media or agent is incompatible with the active ingredient, itε use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions. It is especially advantageous to formulate parenteral compositionε in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to phyεically discrete units suitable as unitary dosages for the mammalian subjectε to be treated; each unit containing a predetermined quantity of active materials calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the novel dosage unit formε of the invention are dictated by and directly dependent on (a) the unique characteriεtics of the active materials and the particular therapeutic effect to be achieved, and (b) the limitation inherent in the art of compounding such active materials for the treatment of disease in living subjectε having a diseaεed condition in which bodily health iε impaired aε herein disclosed in detail. The principal active ingredients are compounded for convenient and effective adminiεtration in effective amountε with a. εuitable pharmaceutically acceptable carrier in dosage unit form as hereinbefore diεcloεed. A unit parenteral doεage form can, for example, contain the principal active compound, i.e. an inhibitor, in amountε ranging from about 0.5 to about 100 mg, with from about 0.1 to 50 mg being preferred. The daily parenteral doεeε for mammalian subjects to be treated ranges from 0.01 mg/kg to 10 mg/kg of the inhibitor. The preferred daily dosage range iε 0.1 mg/kg to 1.0 mg/kg. For oral dosageε, the daily amount may range from 0.01 mg of active compound/kg of mammalian εubject to 100 mg/kg, preferably 0.1 to 10 mg/kg of subject. The inhibitor described above may form commonly known, pharmaceutically acceptable salts such as alkali metal and other common basic salts or acid addition salts, etc. References to the base substanceε are therefore intended to include those common saltε known to be εubstantially equivalent to the parent compound and hydrates thereof. The active compounds described herein are capable of further forming both pharmaceutically acceptable acid addition and/or base salts. All of these forms are within the scope of the present invention. Pharmaceutically acceptable acid addition salts of the active compounds include salts derived from nontoxic inorganic acids εuch aε hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic, hydrofluoric, phosphorous, and the like, as well as the salts derived from nontoxic organic acids, such aε aliphatic mono- and dicarboxylic .acidε, phenyl- substituted alkanoic acidε, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Such εalts thuε include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phoεphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, εebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like. Also contemplated are salts of amino acids such as arginate and the like and gluconate, galacturonate (see, for example, Berge, S.M. et al, "Pharmaceutical Salts", JOURNAL OF PHARMACEUTICAL SCIENCE, 66, pp. 1-19 (1977)). The acid addition salts of said basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt in the conventional manner. Preferably, an active compound can be converted to an acidic salt by treating with an aqueous solution of the desired acid, such that the resulting pH is less than 4. The solution can be paεεed through a C18 cartridge to absorb the compound, washed with copiouε amountε of water, the compound eluted with a polar organic εolvent such as, for example, methanol, acetonitrile, and the like, and isolated by concentrating under reduced pressure followed by lyophiliza ion. The free base form may be regenerated by contacting the salt form with a base and isolating the free base in the conventional manner. The free base forms differ from their respective εalt formε somewhat in certain physical properties such as solubility in polar solvents, but otherwise the saltε are equivalent to their reεpective free base for purposeε of the present invention. Pharmaceutically acceptable baεe addition εalts are formed with metals or amineε, such as alkali and alkaline earth metals or organic amineε. Exampleε of metalε uεed as cationε are sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines are N,N' -dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine (see, for example, Berge, S.M. et al, "Pharmaceutical Salts", JOURNAL OF PHARMACEUTICAL SCIENCE, 66, pp. 1-19 (1977)). The base addition salts of said acidic compounds are prepared by contacting the free acid form with a εufficient amount of the desired base to produce the salt in the conventional manner. Preferably, an active compound can be converted to a base salt by treating with an aqueous solution of the desired base, such that the resulting pH is greater than 9. The solution can be passed through a C18 cartridge to absorb the compound, washed with copious amounts of water, the compound eluted with a polar organic solvent such as, for example, methanol, acetonitrile and the like, and isolated by concentrating under reduced presεure followed by lyophilization. The free acid form may be regenerated by contacting the εalt form with an acid and isolating the free acid in the conventional manner. The free acid forms differ from their respective salt forms somewhat in certain physical properties εuch aε εolubility in polar εolventε, but otherwiεe the εaltε are equivalent to their respective free acids for purposes of the present invention. Certain of the compounds of the present invention can exist in unεolvated forms as well as εolvated forms, including hydrated formε. In general, the εolvated formε, including hydrated formε are equivalent to unεolvated forms and are intended to be encompassed within the scope of the present invention. Certain of the compounds of the present invention posεess one or more chiral centers and εuch center may exist in the R(D) or S(L) configuration. The present invention includes all enantiomeric and epimeric forms as well as the appropriate mixtures thereof. While the forms of the invention herein constitute presently preferred embodiments, many others are poεεible. It iε not intended herein to mention all of the poεεible equivalent forms or ramifications of the invention. It is understood that the terms used herein are merely descriptive rather than limiting and that various changes may be made without departing from the spirit or scope of the invention. Scheme 1. Synthesis of Preferred Group 1. Scheme 2. Synthesis of Preferred Group 4: .3.2-gl ring fusion. Scheme 3. Synthesis of Preferred Group 5: f4.5-gl ring fusion. Scheme 4. Synthesis of Preferred Group 5: f5.4-g1 ring fusion. 1. HCONH2 1. NaSH 2. H 2 SO 4 /HNO 3 2. HC(OEt) 3 3. MeSNa (3 equ) Scheme 5. Synthesis of Preferred Group 6: .4.5-gl ring fusion. Scheme 6. Synthesis of Preferred Group 6: 5.4-gl ring fusion. l. RaNi H 2 2. HCOOH Scheme 7. Synthesis of Preferred Group 7. Scheme 8. Synthesis of Preferred Group 10: .4.3-gl ring fusion. Scheme 9. Synthesis of Preferred Group 10: f3.4-gl ring fusion. Scheme 10. Synthesis of Preferred Group 11. Scheme 11. Synthesis of Preferred Group 13: A & E are Nitrogen. Scheme 12. Synthesis of Preferred Group 13: B & E are Nitrogen. 4. Ar(CH 2 ) n NH 2 Scheme 13. Synthesis of Preferred Group 33: (4.5-fl ring fusion Scheme 14. Synthesis of Preferred Group 33: f4.5-h1 ring fusion 1. HSCH,COOEt NEt 3 DMSO 100°C 2. HCONH 2 Scheme 15. Synthesis of Preferred Group 39: r3.2-dl ring fusion 1. HSCH*,COOEt NEt 3 DMSO 100°C 2. HCONH 2 Scheme 16. Synthesis of Preferred Group 39: 13.2-dl ring fusion Scheme 17. Synthesis of Preferred Group 39: .2.3-dl ring fusion 3. MsCl/ NEt 3 Scheme 18. Synthesis of Preferred Group 41: 13'.2':2.31.4.5-d1 ring fusion Scheme 19. Synthesis of Preferred Group 41: f2'.3':2.3115.4-dl ring fusion 4. MsCl/ NEt 3 Scheme 20. Synthesis of Preferred Group 44: 14'.5':2.31.4.5-dl ring fusion C ° 2Et HCONH 2 tHi 2 NaH DMSO 4. Ar(CH : ) n NH : Scheme 21. Synthesis of Preferred Group 45: .4'.5':2.3.f4.5-dl ring fusion 1* HSCH ? COOEt NEt 3 DMSO 100°C 2. HCONH 2 Scheme 22. Synthesis of Preferred Group 49: 12'.3': 2.31.4.5-dl ring fusion Scheme 23. Synthesis of Preferred Group 50: f3.2-d1 ring fusion Scheme 24. Synthesis of Preferred Group 50: T2.3-d1 ring fusion r Scheme 25. Synthesis of Preferred Group 61: f3.2-dl ring fusion

Claims: What Is Claimed Is: 1. A method of inhibiting epidermal growth factor receptor tyrosine kinase by treating, with an effective inhibiting amount, a mammal, in need thereof, a compound of the formula: wherein: 1) Y and Z are both C (carbon) , both N or one N and the other C, in which case the ring structure is a linearly fused 6,6 (5 or 6) tricycle, or 2) one of Y and Z iε C=C, C=N, whereupon the other one of Y or Z is simply a bond between the two aromatic rings, then the ring structure is a nonlinear 6,6 (5 or 6) tricycle, or 3) one of Y and Z is N, 0 or S, whereupon the other one of Y or Z is simply a bond between the two aromatic rings, then the ring structure is a fused 6,5 (5 or 6) tricycle; A, B, D and E can all be carbon t or up to two of them can be nitrogen, whereupon the remaining atoms must be carbon, or any two contiguous positions in A-E can be a single heteroatom, N, 0 or S, forming a five membered fused ring, in which case one of the two remaining atoms must be carbon, and the other can be either carbon or nitrogen, except that the case where A and B taken together, and D and E taken separately are all three nitrogen atoms; X = 0, S, NH or NR 9 , such that R 9 = lower alkyl (1-4 carbon atoms) , OH, NH 2/ lower alkoxy (1-4 carbon atoms) or lower monoalkylamino (1-4 carbon atoms) ; R 1 = H or lower alkyl; n = 0, 1 or 2; if n = 2, R 1 can be independently H or lower alkyl (1-4 carbon atoms) on either linking carbon atom, and both R and S stereocentres on either linker are included; R 2 is lower alkyl (1-4 carbon atoms) , cycloalkyl (3-8 carbon atoms) , lower alkoxy (1-4 carbon atoms) , cycloalkoxy (3-8 carbon atoms) , nitro, halo, lower perfluoroalkyl (1-4 carbon atoms) , hydroxy, lower acyloxy (1-4 carbon atoms; -O-C(O)-R), amino, lower mono or dialkylamino (1-4 carbon atoms) , lower mono or dicycloalkylamino (3-8 carbon atoms) , hydroxymethyl, lower acyl (1-4 carbon atoms; -C(O)R), cyano, lower thioalkyl (1-4 carbon atoms) , lower sulfinylalkyl (1-4 carbon atoms) , lower sulfonylalkyl (1-4 carbon atoms) , thiocycloalkyl (3-8 carbon atoms) , sulfinylcycloalkyl (3-8 carbon atoms) , sulfonylcycloalkyl (3-8 carbon atoms) , mercapto, lower alkoxycarbonyl (1-4 carbon atoms) , cycloalkoxycarbonyl (3-8 carbon atoms) , lower alkenyl (2-4 carbon atoms) , cycloalkenyl (4-8 carbon atoms) , lower alkynyl (2-4 carbon atoms) , or two R 2 taken together can form a carbocyclic ring of 5-7 members; and m = 0-3, wherein Ar is phenyl, thienyl, furanyl, pyrrolyl, pyridyl, pyrimidyl, imidazoyl, pyrazinyl, oxazolyl, thiazolyl, naphthyl, benzothienyl, benzofuranyl, indolyl, quinolinyl, isoquinolinyl and quinazolinyl; R 3 , R", R 5 and R € are independently not present, H, lower alkyl (1-4 carbon atoms) , cycloalkyl (3-8 carbon atoms) , lower alkoxy (1-4 carbon atoms) , cycloalkoxy (3-8 carbon atoms) , hydroxy, lower acyloxy (1-4 carbon atoms) , amino, lower mono or dialkylamino (1-4 carbon atoms) , lower mono or dicycloalkylamino (3-8 carbon atoms) , lower alkyl (1-4 carbon atoms) or cycloalkyl (3-8 carbon atoms), carbonato (-OC(O)OR) where R is alkyl of from 1-4 carbon atoms or cycloalkyl of from 3-8 carbon atoms; or ureido or thioureido or N- or 0- linked urethane any one of which is optionally substituted by mono or di-lower alkyl (1-4 carbon atoms) or cycloalkyl (3-8 carbon atoms) ; lower thioalkyl (1-4 carbon atoms) , thiocyclo- alkyl (3-8 carbon .atoms) , mercapto, lower alkenyl (2-4 carbon atoms), hydrazino, N- and/or N'- mono- or di lower alkylhydrazino (1-4 carbon atoms) , lower acylamino (1-4 carbon atoms) , hydroxylamino, N- and/or 0- mono- or di lower alkylhydroxylamino (1-4 carbon atoms) , or any two substituents on contiguous carbon atoms taken together can be methylene-, ethylene- or propylenedioxy, or taken together form a fused pyrrolidine, tetra- hydrofuranyl, piperidinyl, piperazinyl, morpholino or thiomorpholino ring; R 7 and R β can be independently as appropriate, not present, lone pairs of electrons, H, or lower alkyl (1-4 carbon atoms) ; any lower alkyl group substituent on any of the substituents in R 3 -R 8 which contain such a moiety can be optionally substituted with one or more of hydroxy, amino, lower monoalkylamino, lower dialkylamino, N- pyrrolidyl, N-piperidinyl, N-pyridinium, N-morpholino, N-thiomorpholino or N-piperazino groups; if one or two of A through E are N, then if any of R 3 -R 6 iε on a neighboring C atom to one of the N atomε, that substituent cannot be either OH or SH; and R 10 is H or lower alkyl (1-4 carbon atoms) , amino or lower mono- or dialkylamino (1-4 carbon atoms) ; if any of the substitutents R 1 , R 2 , R 3 or R 4 contain chiral centers, or in the case of R 1 create chiral centers on the linking atoms, then all stereoisomers thereof both separately and as racemic and/or diastereoisomeric mixtures are included; or a pharmaceutical salt or hydrate thereof. 2. The method of claim 1 wherein n = 0, A-E, Y & Z being carbon, X = NH, Ar a benzene ring, op¬ tionally substituted, and R 5 -R 8 hydrogen. The method of claim 2 having the ring structure: 4. The method of claim 1 wherein n = 0 or 1, with one of A & B or D & E taken together as oxygen, the remaining pair both being carbon, along with Y and Z, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R e hydrogen or a lone pair of electrons. 5. The method of claim 4 having the ring structure: 6. The method of claim 1 wherein n = 0 or 1, with one of A & B or D & E taken together as sulfur, the remaining pair both being carbon, along with Y and Z, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R 8 hydrogen. 7. The method of claim 1 wherein n = 0 or 1, with one of A & B or D & E taken together as nitrogen, the remaining pair both being carbon, along with Y and Z, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R B hydrogen or lower alkyl if on nitrogen. The method of claim 7 having the ring structure: 9. The method of claim 1 wherein n = 0 or 1, A Sc B taken together as oxygen, and E as nitrogen, or D St. E taken together as oxygen and A as nitrogen, Y and Z both carbon, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R e hydrogen or a lone pair of electrons. 10. The method of claim 1 wherein n = 0 or 1, A & B taken together as sulfur, and E as nitrogen, or D & E taken together as sulfur and A as nitrogen, Y and Z both carbon, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R 8 hydrogen or a lone pair of electrons. 11. The method of claim 10 having the ring structure: 12. The method of claim 1 wherein n = 0 or 1, A & B taken together, and E aε nitrogen, Y and Z both carbon, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R 6 hydrogen or lower alkyl if on nitrogen, or a lone pair of electrons. 13. The method of claim 1 wherein n = 0 or 1, A & B taken together as oxygen, and D as nitrogen, or D & E taken together as oxygen and B aε nitrogen, Y and Z both carbon, X = NH, Ar a benzene ring, optionally substituted, and R'-R E hydrogen, lower alkyl, or a lone pair of electrons. 1 . The method of claim 1 wherein n = 0 or 1, A & B taken together aε sulfur, and D as nitrogen, or D & E taken together as sulfur and B as nitrogen, Y and Z both carbon, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R B hydrogen, lower alkyl, or a lone pair of electrons. 15. The method of claim 1 wherein n = 0 or 1, A & B taken together, and D as nitrogen, or D & E taken together, and B as nitrogen, Y and Z both carbon, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R 8 hydrogen, lower alkyl, or a lone pair of electrons. 16. The method of claim 15 having the ring structure: 17. The method of claim 1 wherein n = 0, A & B taken together, with D & E taken separately, all as nitrogen, Y and Z both carbon, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R e hydrogen or lower alkyl if on nitrogen, or a lone pair of electrons. 18. The method of claim 1 wherein n = 0 or 1, with one of A, B, D or E aε nitrogen, the remaining three being carbon, along with Y and Z, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R B hydrogen or a lone pair of electrons. 19. The method of claim 1 wherein n = 0, with any two of A, B, D or E as nitrogen, the remaining two being carbon, along with Y and Z, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R 8 hydrogen or a lone pair of electrons. 20. The method of claim 1 wherein n = 0, A-E, and one of Y and Z being carbon, the other nitrogen, X = NH, Ar a benzene ring, optionally substituted, and R 5 - R 8 hydrogen or a lone pair of electrons 21. The method of claim 20 having the ring structure: 22. The method of claim 1 wherein n = 0 or l, with one of A & B or D & E taken together as oxygen, the remaining pair both being carbon, along with one of Y and Z, the other being nitrogen, X = NH, Ar a benzene ring, Optionally substituted, and R 5 -R 8 hydrogen or a lone pair of electrons. 23. The method of claim 22 having the ring structure: 24. The method of claim 1 wherein n = 0 or 1, with one of A & B or D & E taken together as sulfur, the remaining pair both being carbon, along with one of Y and Z, the other being nitrogen, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R 8 hydrogen or a lone pair of electrons. 25. The method of claim 1 wherein n = 0 or 1, with one of A & B or D & E taken together as nitrogen, the remaining pair both being carbon, along with one of Y and Z, the other being nitrogen, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R 8 hydrogen, or optionally lower alkyl if on nitrogen in the pyrrole ring, or a lone pair of electrons. 26. The method of claim 1 wherein n = 0 or 1, A & B taken together aε oxygen, and E as nitrogen, or D & E taken together aε oxygen and A as nitrogen, one of Y and Z being carbon the other nitrogen, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R 8 hydrogen or a lone pair of electrons. 27. The method of claim 26 having the ring structure 28. The method of claim 1 wherein n = 0 or 1, A & B taken together as sulfur, and E as nitrogen, or D & E taken together as sulfur and A as nitrogen, one of Y and Z being carbon the other nitrogen, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R 8 hydrogen or a lone pair of electrons. 29. The method of claim 1 wherein n = 0 or 1, A & B taken together, and E as nitrogen, one of Y and Z being carbon the other nitrogen, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R 8 hydrogen or optionally lower alkyl if on nitrogen or a lone pair of electrons. 30. The method of claim 1 wherein n = 0 or 1, A & B taken together as oxygen, and D as nitrogen, or D & E taken together as oxygen and B as nitrogen, one of Y and Z being carbon the other nitrogen, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R 8 hydrogen, lower alkyl, or a lone pair of electrons. 31. The method of claim 1 wherein n = 0 or 1, A & B taken together aε sulfur, and D as nitrogen, or D & E taken together as εulfur and B as nitrogen, one of Y and Z being carbon the other nitrogen, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R 8 hydrogen, lower alkyl, or a lone pair of electrons. 32. The method of claim 1 wherein n = 0 or 1, A & B taken together, and D as nitrogen, or D & E taken together, and B as nitrogen, one of Y and Z being carbon the other nitrogen, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R 8 hydrogen, lower alkyl, or a lone pair of electrons. 33. The method of claim 1 wherein n = 0 or 1, with one of A, B, D or E as nitrogen, the remaining three being carbon, along with one of Y and Z, the other being nitrogen, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R B hydrogen or a lone pair of electrons. 34. The method of claim 33 having the ring structure: 35. The method of claim 1 wherein n = 0, with any two of A, B, D or E as nitrogen, the remaining two being carbon, along with one of Y and Z, the other being nitrogen, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R β hydrogen or a lone pair of electrons. 36. The method of claim 1 wherein n = 0, A-E carbon, Y and Z nitrogen, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R B hydrogen or a lone pair of electrons. 37. The method of claim 36 having the ring structure: 38. The method of claim 1 wherein n = 0 or 1, A-E being carbon, one of Y & Z being ethylidene, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R 8 hydrogen. 39. The method of claim 38 having the ring structure 40. The method of claim 1 wherein n = 0 or 1, with one of A & B or D & E taken together as oxygen, the remaining pair both being carbon, one of Y & Z being ethylidene, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R 8 hydrogen or a lone pair of electrons. 41. The method of claim 1 wherein n - 0 or 1, with one of A & B or D & E taken together as sulfur, the remaining pair both being carbon, one of Y & Z being ethylidene, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R B hydrogen or a lone pair of electrons. 42. The method of claim 1 wherein n - 0 or 1, with one of A & B or D & E taken together as nitrogen, the remaining pair both being carbon, one of Y & Z being ethylidene, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R 8 hydrogen or lower alkyl if on nitrogen. 43. The method of claim 1 wherein n = 0 or 1, A & B taken together aε oxygen, and E as nitrogen, or D & E taken together as oxygen and A as nitrogen, one of Y & Z being ethylidene, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R 8 hydrogen or a lone pair of electrons. 44. The method of claim 1 wherein n = 0 or 1, A & B taken together aε εulfur, and E aε nitrogen, or D & E taken together aε εulfur and A aε nitrogen, one of Y & Z being ethylidene, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R B hydrogen or a lone pair of electrons. 45. The method of claim 1 wherein n = 0, A & B taken together, and E as nitrogen, one of Y & Z being ethylidene, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R 8 hydrogen or lower alkyl if on nitrogen or a lone pair of electrons. 46. The method of claim 44 having the ring structure: 47. The method of claim 1 wherein n = 0 or 1, A & B taken together as oxygen, and D aε nitrogen, or D & E taken together as oxygen and B as nitrogen, one of Y & Z being ethylidene, X = NH, Ar a benzene ring, optionally subεtituted, and R 5 -R 8 hydrogen, lower alkyl, or a lone pair of electrons. 48. The method of claim 1 wherein n -= 0 or 1, A & B taken together as sulfur, and D aε nitrogen, or D & E taken together aε εulfur and B aε nitrogen, one of Y & Z being ethylidene, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R 8 hydrogen, lower alkyl, or a lone pair of electrons. 49. The method of claim 48 having the ring structure: 50. The method of claim 1 wherein n = 0 or 1, A & B taken together, and D as nitrogen, or D & E taken together, and B as nitrogen, one of Y & Z being ethylidene, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R β hydrogen, lower alkyl, or a lone pair of electrons. 51. The method of claim 1 wherein n = 0 or 1, with one of A, B, D or E as nitrogen, the remaining three being carbon, one of Y & Z being ethylidene, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R 8 hydrogen or a lone pair of electrons. 52. The method of claim 1 wherein n = 0, with any two of A, B, D or E aε nitrogen, the remaining two being carbon, one of Y & Z being ethylidene, X = NH, Ar a benzene ring, optionally εubstituted, and R 5 -R B hydrogen or a lone pair of electrons. 53. The method of claim 1 wherein n = 0 or 1, A-E being carbon, one of Y & Z being sulfur, X = NH, Ar a benzene ring, optionally subεtituted, and R 5 -R B hydrogen or a lone pair of electrons. 5 . The method of claim 53 having the ring structure: 55. The method of claim 1 wherein n = 0 or 1, with one of A & B or D & E taken together as oxygen, the remaining pair both being carbon, one of Y & Z being sulfur, X = NH, Ar a benzene ring, optionally substituted, and R s -R 8 hydrogen or a lone pair of electrons. 56. The method of claim 1 wherein n = 0 or 1, with one of A & B or D & E taken together as sulfur, the remaining pair both being carbon, one of Y & Z being sulfur, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R 8 hydrogen or a lone pair of electrons. 57. The method of , claim 1 wherein n = 0 or 1, with one of A & B or D & E taken together as nitrogen, the remaining pair both being carbon, one of Y & Z being sulfur, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R 8 hydrogen or a lone pair or lower alkyl if on nitrogen. 58. The method of claim 1 wherein n = 0 or 1, A & B taken together as oxygen, and E as nitrogen, or D & E taken together as oxygen and A as nitrogen, one of Y & Z being sulfur, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R 8 hydrogen or a lone pair of electrons. 59. The method of claim 1 wherein n = 0 or 1, A & B taken together as sulfur, and E as nitrogen, or D & E taken together as sulfur and A as nitrogen, one of Y & Z being sulfur, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R 8 hydrogen or a lone pair of electrons. 60. The method of claim 59 having the ring structure: 61. The method of claim 1 wherein n = 0, A & B taken together, and E as nitrogen, one of Y & Z being sulfur, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R 8 hydrogen or lower alkyl if on nitrogen or a lone pair of electrons. 62. The method of claim 1 wherein n = 0 or l, A & B taken together as oxygen, and D as nitrogen, or D & E taken together as oxygen and B as nitrogen, one of Y & Z being sulfur, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R 8 hydrogen, lower alkyl, or a lone pair of electrons. 63. The method of claim 1 wherein n = 0 or 1, A & B taken together as sulfur, and D as nitrogen, or D & E taken together as sulfur and B as nitrogen, one of Y & Z being sulfur, X - NH, Ar a benzene ring, optionally substituted, and R s -R 8 hydrogen, lower alkyl, or a lone pair of electrons. 64. The method of claim 1 wherein n = 0 or 1, A & B taken together, and D as nitrogen, or D & E taken together, and B as nitrogen, one of Y & Z being sulfur, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R 8 hydrogen, lower alkyl, or a lone pair of electrons. 65. The method of claim 1 wherein n = 0 or 1, with one of A, B, D or E as nitrogen, the remaining three being carbon, one of Y & Z being sulfur, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R 8 hydrogen or a lone pair of electrons. 66. The method of claim 1 wherein n = 0 or 1, A-E being carbon, one of Y & Z being nitrogen, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R 8 hydrogen, or lower alkyl if on nitrogen. 67. The method of .claim 1 wherein n = 0 or 1, with one of A & B or D & E taken together as oxygen, the remaining pair both being carbon, one of Y & Z being nitrogen, X = NH, Ar a benzene ring, optionally substituted, and R'-R f hydrogen or a lone pair or lower alkyl if on nitrogen. 68. The method of claim 1 wherein n = 0 or 1, with one of A & B or D & E taken together as sulfur, the remaining pair both being carbon, one of Y & Z being nitrogen, Ar a benzene ring, optionally substituted, and R 5 -R 8 hydrogen or a lone pair or lower alkyl if on nitrogen. 69. The method of claim 1 wherein n = 0 or 1, with one of A & B or D & E taken together as nitrogen, the remaining pair both being carbon, one of Y & Z being nitrogen, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R 8 hydrogen or lower alkyl if on nitrogen. 70. The method of claim 1 wherein n = 0 or 1, A & B taken together as oxygen, and E as nitrogen, or D & E taken together as oxygen and A as nitrogen, one of Y & Z being nitrogen, X -= NH, Ar a benzene ring, optionally substituted, and R 5 -R 8 hydrogen or a lone pair or lower alkyl if on nitrogen. 71. The method of claim 70 having the ring structure: 72. The method of claim 1 wherein n = 0 or 1, A & B taken together as sulfur, and E aε nitrogen, or D & E taken together aε sulfur and A aε nitrogen, one of Y & Z being nitrogen, X = NH, Ar a benzene ring, optionally εubεtituted, and R 5 -R 8 hydrogen or a lone pair where appropriate, or lower alkyl if on nitrogen. 73. The method of claim 1 wherein n = 0, A & B taken together, and E as nitrogen, one of Y & Z being nitrogen, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R B hydrogen or lower alkyl if on nitrogen or a lone pair of electrons. 74. The method of claim 1 wherein n = 0 or 1, A & B taken together as oxygen, and D as nitrogen, or D & E taken together as oxygen and B as nitrogen, one of Y & Z being nitrogen, X = NH, Ar a benzene ring, optionally subεtituted, and R 5 -R 8 hydrogen, lower alkyl, or a lone pair of electrons where appropriate. 75. The method of claim 1 wherein n = 0 or 1, A & B taken together as sulfur, and D as nitrogen, or D & E taken together as sulfur and B as nitrogen, one of Y & Z being nitrogen, X = NH, Ar a benzene ring, optionally subεtituted, and R 5 -R 8 hydrogen, lower alkyl, or a lone pair of electrons where appropriate. 76. The method of claim 1 wherein n = 0 or 1, A & B taken together, and D as nitrogen, or D & E taken together, and B as nitrogen, one of Y & Z being nitrogen, X = NH, Ar a benzene ring, optionally subεtituted, and R 5 -R 6 hydrogen, lower alkyl, or a lone pair of electrons where appropriate. 77. The method of claim 1 wherein n = 0 or 1, with one of A, B, D or E aε nitrogen, the remaining three being carbon, one of Y & Z being nitrogen, X = NH, Ar a benzene ring, optionally εubstituted, and ,R 5 -R 8 hydrogen or a lone pair of electrons. 78. The method of claim 1 wherein n = 0 or 1, A-E being carbon, one of Y & Z being oxygen, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R 8 hydrogen or a lone pair of electrons. 79. The method of claim 78 having the ring structure: 80. The method of claim 1 wherein n = 0 or 1, with one of A & B or D & E taken together aε oxygen, the remaining pair both being carbon, one of Y & Z being oxygen, X = NH, Ar a benzene ring, optionally εubεtituted, and R 5 -R 8 hydrogen or a lone pair of electrons. 81. The method of claim 1 wherein n = 0 or 1, with one of A & B or D & E taken together aε εulfur, the remaining pair both being carbon, one of Y & Z being oxygen, X = NH, Ar a benzene ring, optionally substituted, and R s -R 6 hydrogen or a lone pair of electrons. 82. The method of claim 1 wherein n = 0 or 1, with one of A & B or D & E taken together as nitrogen, the remaining pair both being carbon, one of Y & Z being oxygen, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R β hydrogen or a lone pair of electrons where appropriate or lower alkyl if on nitrogen. 83. The method of claim 1 wherein n = 0 or 1, A & B taken together aε oxygen, and E as nitrogen, or D & E taken together as oxygen and A as nitrogen, one of Y & Z being oxygen, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R 8 hydrogen or a lone pair of electrons. 84. The method of claim 1 wherein n = 0 or 1, A & B taken together as sulfur, and E as nitrogen, or D & E taken together as sulfur and A as nitrogen, one of Y & Z being oxygen, X = NH, Ar a benzene ring, optionally substituted, and R s -R 8 hydrogen or a lone pair of electrons. 85. The method of claim 84 having the ring structure 86. The method of claim 1 wherein n = 0, A & B taken together, and E as nitrogen, one of Y & Z being oxygen, X = NH, Ar a benzene ring, optionally substituted, and R--R 6 hydrogen or optionally lower alkyl if on nitrogen or a lone pair of electrons. 87. The method of claim 1 wherein n = 0 or 1, A & B taken together aε oxygen, and D aε nitrogen, or D & E taken together aε oxygen and B as nitrogen, one of Y & Z being oxygen, X = NH, Ar a benzene ring, optionally substituted, and R s -R β hydrogen, lower alkyl, or a lone pair of electrons. 88. The method of claim 1 wherein n - 0 or 1, A & B taken together as sulfur, and D as nitrogen, or D & E taken together as sulfur and B as nitrogen, one of Y & Z being oxygen, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R 8 hydrogen, lower alkyl, or a lone pair of electrons. 89. The method of claim 1 wherein n = 0 or 1, A & B taken together, and D as nitrogen, or D & E taken together, and B as nitrogen, one of Y & Z being oxygen, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R B hydrogen, lower alkyl, or a lone pair of electrons. 90. The method of claim 1 wherein n = 0 or 1, with one of A, B, D or E as nitrogen, the remaining three being carbon, one of Y & Z being oxygen, X = NH, Ar a benzene ring, optionally substituted, and R 5 -R 8 hydrogen or a lone pair of electrons. 91. The method of claim 1 wherein any of the subεtituentε R : , R : , R 3 or R* contain chiral centerε, or in the caεe of R : create chiral centers on the linking atoms, then all stereoisomers thereof both separately and as racemic and/or diastereoisomeric mixtures are included therein. 92. The method of claim 1 wherein the compound is selected from the group consisting of 4-(3- Bromoanilino) benzo [g] quinazoline ; 4 - ( [R] - l - Phenylethylamino) benzo [g] quinazoline ; 4- (3- Bromoanilino) pyrrolo [3 , 2-g] quinazoline ; 4- (3- Bromoanilino) thiazolo [4, 5-g] quinazoline ; 4 - (3 - Bromoanilino) oxazolo [4, 5-g] quinazoline ; 4 - (3 - Bromoanilino) imidazolo [4 , 5-g] quinazoline; 4- (3- Bromoanilino) triazolo [4, 5-g] quinazoline ; 4- (3 - Bromoanilino) -6N-methylimidazolo [4, 5-g] quinazoline; 4- (3 -Bromoanilino) -8N-methylimidazolo[4, 5-g] quinazoline; 4- (3 -Bromoanilino) pyrazolo [2, 3 -g] quinazoline; 4- (3- Bromoanilino) imidazolo [4 , 5-h] quinazoline; 4- (3- Bromoanilino) benzothieno [3 , 2-d] pyrimidine; 4- (3- Bromoanilino) - 8 -nitrobenzothieno [3 , 2-d] yrimidine ,- 8 - Amino - 4 - ( 3 - bromoani 1 ino ) benzothieno [ 3 , 2 - d] pyrimidine ; 4 - ( 3 -Bromoanilino ) - 8 -methoxybenzothieno [3 , 2 -d] pyrimidine ; 4 - (3 -Bromoanilino) thiazolo[4'5' :4,5]thieno[3,2- d] pyrimidine ; 4 - C3 -Bromoanilino) indolo [3 , 2-d] pyrimidine ; 4- (3 -Bromoanilino) indolo [2, 3-d] pyrimidine . 93. A compound of the formula: where: wherein: 1) Y and Z are both C (carbon) , both N or one N and the other C, in which case the ring structure is a linearly fused 6,6 (5 or 6) tricycle, or 2) one of Y and Z is C=C, C=N, whereupon the other one of Y or Z is simply a bond between the two aromatic rings, then the ring structure is a nonlinear 6,6 (5 or 6) tricycle, or 3) one of Y and Z is N, 0 or S, whereupon the other one of Y or Z iε εimply a bond between the two aromatic rings, then the ring εtructure is a fused 6,5 (5 or 6) tricycle; A, B, D and E can all be carbon, or up to two of them can be nitrogen, whereupon the remaining atoms must be carbon, or any two contiguous positions in A-E can be a single heteroatom, N, O or S, forming a five membered fused ring, in which case one of the two remaining atoms must be carbon, and the other can be either carbon or nitrogen, except that the case where A and B taken together, and D and E taken separately are all three nitrogen atoms; X = 0, S, NH or NR 9 , such that R 9 = lower alkyl (1-4 carbon atoms) , OH, NH 2> lower alkoxy (1-4 carbon atoms) or lower monoalkylamino (1-4 carbon atoms) ; R 1 = H or lower alkyl; n = 0, 1 or 2,- if n = 2, R 1 can be independently H or lower alkyl (1-4 carbon atoms) on either linking carbon atom, and both R and S stereocentres on either linker are included; R 2 is lower alkyl (1-4 carbon atoms) , cycloalkyl (3-8 carbon atoms) , lower alkoxy (1-4 carbon atoms) , cycloalkoxy (3-8 carbon atoms) , nitro, halo, lower perfluoroalkyl (1-4 carbon atoms) , hydroxy, lower acyloxy (1-4 carbon atoms; -O-C(O)-R), amino, lower mono or dialkylamino (1-4 carbon atoms) , lower mono or dicycloalkylamino (3-8 carbon atoms) , hydroxymethyl, lower acyl (1-4 carbon atoms; -C(O)R), cyano, lower thioalkyl (1-4 carbon atoms) , lower sulfinylalkyl (1-4 carbon atoms) , lower sulfonylalkyl (1-4 carbon atoms) , thiocycloalkyl (3-8 carbon atoms) , sulfinylcycloalkyl (3-8 carbon atoms) , sulfonylcycloalkyl (3-8 carbon atoms) , mercapto, lower alkoxycarbonyl (1-4 carbon atoms) , cycloalkoxycarbonyl (3-8 carbon atoms) , lower alkenyl (2-4 carbon atoms) , cycloalkenyl (4-8 carbon atoms) , lower alkynyl (2-4 carbon atoms) , or two R 2 taken together can form a carbocyclic ring of 5-7 members; and m = 0-3, wherein Ar is phenyl, thienyl, furanyl, pyrrolyl, pyridyl, pyrimidyl, imidazoyl, pyrazinyl, oxazolyl, thiazolyl, naphthyl, benzothienyl, benzofuranyl, indolyl, quinolinyl, isoquinolinyl and quinazolinyl; R 3 , R 4 , R 5 and R 6 are independently not present, H, lower alkyl (1-4 carbon atoms) , cycloalkyl (3-8 carbon atoms) , lower alkoxy (1-4 carbon atoms) , cycloalkoxy (3-8 carbon atoms) , hydroxy, lower acyloxy (1-4 carbon atoms) , amino, lower mono or dialkylamino (1-4 carbon atoms) , lower mono or dicycloalkylamino (3-8 carbon atoms) , lower alkyl (1-4 carbon atoms) or cycloalkyl (3-8 carbon atoms), carbonato (-OC(O)OR) where R is alkyl of from 1-4 carbon atoms or cycloalkyl of from 3-8 carbon atoms; or ureido or thioureido or N- or 0- linked urethane any one of which is optionally substituted by mono or di-lower alkyl (1-4 carbon atoms) or cycloalkyl (3-8 carbon atoms) ; lower thioalkyl (1-4 carbon atoms) , thiocyclo¬ alkyl (3-8 carbon atoms) , mercapto, lower alkenyl (2-4 carbon atoms), hydrazino, N' -lower alkylhydrazino (1-4 carbon atoms) , lower acylamino (1-4 carbon atoms) , hydroxylamino, lower O-alkylhydroxylamino (1-4 carbon atoms), or taken together can be methylene-, ethylene- or propylenedioxy, or taken together form a fused pyrrolidine, tetrahydrofuranyl, piperidinyl, piper- azinyl, morpholino or thiomorpholino ring; R 7 and R β can be independently aε appropriate, lone pairs of electrons, H, or lower alkyl (1-4 carbon atoms) ; any lower alkyl group substituent on any of the subεtituents in R 3 -R 8 which contain such a moiety can be optionally subεtituted with one or more of hydroxy, amino, lower monoalkylamino, lower dialkylamino, N- pyrrolidyl, N-piperidinyl, N-pyridinium, N-morpholino, N-thiomorpholino or N-piperazino groups; if one or two of A through E are N, then if any of R 3 -R 6 iε on a neighboring C atom to one of the N atomε, that εubstituent cannot be either OH or SH; and R 10 is H or lower alkyl (1-4 carbon atoms) , amino or lower mono- or dialkylamino (1-4 carbon atoms) ; if any of the substitutents R 1 , R 2 , R 3 or R 4 contain chiral centerε, or in the case of R 1 create chiral centers on the linking atoms, then all stereoisomers thereof both separately and aε racemic and/or diastereoisomeric mixtureε are included; with the proviso that the ring containing A-E is aromatic; and with the proviso that if A and B taken together and E are nitrogen, and if neither Y nor Z iε a heteroatom, and if X = NH, and n = 1, and R 1 = H and Ar = Ph, then one of the imidazole nitrogen atomε muεt have a εubεtituent from the R 3 -R 6 group other than lone pair or hydrogen; and with the proviεo that if A-E are carbon, and Y iε a bond, and Z is εulfur, and X = NH, and n = 0, then Ar cannot be unεubstituted phenyl, unsubstituted or substituted pyridyl or unsubstituted or substituted pyrimidyl; or a pharmaceutical salt or hydrate thereof. 94. The compound of claim 93 having the further provisos : that if A-E ar carbon, Y and Z cannot be both carbon or one ethylidene and the other a bond, unless at least one of R 3 -R 6 is not hydrogen; and that if A-E are carbon one of Y and Z cannot be nitrogen, substituted with hydrogen, and the other a bond. 95. The compound of claim 2 wherein the compound is selected from the group consisting of 4- (3- Bromoanilino) pyrrolo [3, 2-g] quinazoline; 4 - ( 3 - Bromoanilino) thiazolo [4, 5-g] quinazoline ; 4 - (3 - Bromoanilino) oxazolo [4, 5-g] quinazoline; 4- (3 - Bromoanilino) imidazolo [4 , 5-g] quinazoline; 4- (3- Bromoanilino) triazolo[4, 5-g] quinazoline; 4- (3 - Bromoanilino) -6N-methylimidazolo [4, 5-g] quinazoline; 4- (3 -Bromoanilino) -8N-methylimidazolo [4, 5-g] quinazoline; 4- ( 3 -Bromoanilino) pyrazolo [2,3-g] quinazoline; 4- (3- Bromoanilino) imidazolo [4 , 5-h] quinazoline; 4- (3- Bromoani lino) benzothieno [3 , 2-d] pyrimidine; 4- (3- Bromoanilino) - 8 -nitrobenzothieno [3, 2-d] pyrimidine; 8- Amino-4- (3 -bromoanilino) benzothieno [3 , 2-d] pyrimidine; 4- (3 -Bromoanilino) -8-methoxybenzothieno [3 , 2-d] pyrimidine; 4 - ( 3 -Bromoanilino) thiazolo[4'5' :4,5]thieno[3,2- d] pyrimidine . 96. A method of inhibiting Erb-B2 or Erb-B3 or Erb-B4 receptor tyrosine kinase by treating, with an effective inhibiting amount, a mammal, in need thereof, a compound of the formula: wherein: 1) Y and Z are both C (carbon) , both N or one N and the other C, in which case the ring structure is a linearly fused 6,6 (5 or 6) tricycle, or 2) one of Y and Z is C=C, C=N, whereupon the other one of Y or Z is simply a bond between the two aromatic rings, then the ring structure is a nonlinear 6,6 (5 or 6) tricycle, or 3) one of Y and Z is N, 0 or S, whereupon the other one of Y or Z is simply a bond between the two aromatic rings, then the ring structure is a fused 6,5 (5 or 6) tricycle; A, B, D and E can all be carbon, or up to two of them can be nitrogen, whereupon the remaining atoms must be carbon, or any two contiguous positions in A-E can be a single heteroatom, N, O or S, forming a five membered fused ring, in which case one of the two remaining atoms must be carbon, and the other can be either carbon or nitrogen, except that the case where A and B taken together, and D and E taken separately are all three nitrogen atoms; X = 0, S, NH or NR 9 , such that R 9 = lower alkyl (1-4 carbon atoms) , OH, NH 2/ lower alkoxy (1-4 carbon atoms) or lower monoalkylamino (1-4 carbon atoms) ; R 1 = H or lower alkyl; n = 0, 1 or 2; if n = 2, R 1 can be independently H or lower alkyl on either linking carbon atom, and both R and S stereocentres on either linker are included; R 2 iε lower alkyl (1-4 carbon atoms) , cycloalkyl (3-8 carbon atoms) , lower alkoxy (1-4 carbon atoms) , cycloalkoxy (3*--8 carbon atoms) , nitro, halo, lower perfluoroalkyl j.1-4 carbon atoms) , hydroxy, lower acyloxy (1-4 carbon atoms; -O-C(O)-R), amino, lower mono or dialkylamino (1-4 carbon atomε) , lower mono or dicycloalkylamino (3-8 carbon atoms) , hydroxymethyl, lower acyl (1-4 carbon atoms; -C(O)R), cyano, lower thioalkyl (1-4 carbon atoms) , lower sulfinylalkyl (1-4 carbon atoms) , lower sulfonylalkyl (1-4 carbon atoms) , thiocycloalkyl (3-8 carbon atoms) , sulfinylcycloalkyl (3-8 carbon atoms) , sulfonylcycloalkyl (3-8 carbon atoms) , mercapto, lower alkoxycarbonyl (1-4 carbon atoms) , cycloalkoxycarbonyl (3-8 carbon atoms) , lower alkenyl (2-4 carbon ' atoms) , cycloalkenyl (4-8 carbon atoms) , lower alkynyl (2-4 carbon atoms) , or two R 2 taken together can form a carbocyclic ring of 5-7 members; and m = 0-3, wherein Ar is phenyl, thienyl, furanyl, pyrrolyl, pyridyl, pyrimidyl, imidazoyl, pyrazinyl, oxazolyl, thiazolyl, naphthyl, benzothienyl, benzofuranyl, indolyl, quinolinyl, isoquinolinyl and quinazolinyl; R 3 , R 4 , R 5 and R 6 are independently not present, H, lower alkyl (1-4 carbon atoms) , cycloalkyl (3-8 carbon atoms) , lower alkoxy (1-4 carbon atoms) , cycloalkoxy (3-8 carbon atoms) , hydroxy, lower acyloxy (1-4 carbon atoms) , amino, lower mono or dialkylamino (1-4 carbon atoms) , lower mono or dicycloalkylamino (3-8 carbon atomε) , lower alkyl (1-4 carbon atoms) or cycloalkyl (3-8 carbon atoms), carbonato (-OC(O)OR) where R is alkyl of from 1-4 carbon atoms or cycloalkyl of from 3-8 carbon atoms; or ureido or thioureido or N- or 0- linked urethane any one of which is optionally substituted by mono or di-lower alkyl (1-4 carbon atoms) or cycloalkyl (3-8 carbon atoms) ; lower thioalkyl (1-4 carbon atoms) , thiocyclo- alkyl (3-8 carbon atoms) , mercapto, lower alkenyl (2-4 carbon atoms) , hydrazino, N' -lower alkylhydrazino (1-4 carbon atoms) , lower acylamino (1-4 carbon atoms) , hydroxylamino, lower 0-alkylhydroxylamino (1-4 carbon atoms) , or taken together can be methylene-, ethylene- or propylenedioxy, or taken together form a fused pyrrolidine, tetrahydrofuranyl, piperidinyl, piper- azinyl, morpholino or thiomorpholino ring; R 7 and R β can be independently as appropriate, lone pairs of electrons, H, or lower alkyl (1-4 carbon atoms) ; any lower alkyl group substituent on any of the substituentε in R 3 -R 8 which contain such a moiety can be optionally substituted with one or more of hydroxy, amino, lower monoalkylamino, lower dialkylamino, N- pyrrolidyl, N-piperidinyl, N-pyridinium, N-morpholino, N-thiomorpholino or N-piperazino groups; if one or two of -A through E are N, then if any of R 3 -R 6 is on a neighboring C atom to one of the N atoms, that substituent cannot be either OH or SH; and R 10 is H or lower alkyl (1-4 carbon atoms) , amino or lower mono- or dialkylamino (1-4 carbon atomε) ,* if any of the εubstitutents R 1 , R 2 , R 3 or R" contain chiral centers, or in the case of R 1 create chiral centers on the linking atomε, then all stereoisomers thereof both separately and as racemic and/or diastereoisomeric mixtures are included; or a pharmaceutical salt or hydrate thereof. 97. A pharmaceutical composition adapted for administration as an inhibitor of the epidermal growth factor receptor family of tyrosine kinases, comprising a therapeutically effective amount of a compound of the following structure in admixture with a pharmaceutically acceptable excipient, diluent or carrier: wherein: 1) Y and Z are both C (carbon) , both N or one N and the other C, in which case the ring structure is a linearly fused 6,6 (5 or 6) tricycle, or 2) one of Y and Z iε C=C, C=N, whereupon the other one of Y or Z is simply a bond between the two aromatic rings, then the ring structure is a nonlinear 6,6 (5 or 6) tricycle, or 3) one of Y and Z is N, 0 or S, whereupon the other one of Y or Z is simply a bond between the two aromatic rings, then the ring structure is a fused 6,5 (5 or 6) tricycle; A, B, D and E can all be carbon, or up to two of them can be nitrogen, whereupon the remaining atoms must be carbon, or any two contiguous positions in A-E can be a single heteroatom, N, 0 or S, forming a five membered fused ring, in which case one of the two remaining atoms must be carbon, and the other can be either carbon or nitrogen, except that the case where A and B taken together, and D and E taken separately are all three nitrogen atoms; X = 0, S, NH or NR 9 , such that R 9 = lower alkyl (1-4 carbon atoms) , OH, NH 2# lower alkoxy (1-4 carbon atoms) or lower monoalkylamino (1-4 carbon atoms) ; R 1 = H or lower alkyl; n = 0, 1 or 2,- if n = 2, R 1 can be independently H or lower alkyl on either linking carbon atom, and both R and S stereocentres on either linker are included; R 2 is lower alkyl (1-4 carbon atoms) , cycloalkyl (3-8 carbon atoms) , lower alkoxy (1-4 carbon atoms) , cycloalkoxy (3-8 carbon atoms) , nitro, halo, lower perfluoroalkyl (1-4 carbon atomε) , hydroxy, lower acyloxy (1-4 carbon atomε; -O-C(O)-R), amino, lower mono or dialkylamino (1-4 carbon atomε) , lower mono or dicycloalkylamino (3-8 carbon atoms) , hydroxymethyl, lower acyl (1-4 carbon atoms; -C(O)R), cyano, lower thioalkyl (1-4 carbon atoms) , lower sulfinylalkyl (1-4 carbon atoms) , lower sulfonylalkyl (1-4 carbon atoms) , thiocycloalkyl (3-8 carbon atoms) , sulfinylcycloalkyl (3-8 carbon atoms) , sulfonylcycloalkyl (3-8 carbon atoms) , mercapto, lower alkoxycarbonyl (1-4 carbon atoms) , cycloalkoxycarbonyl (3-8 carbon atoms) , lower alkenyl (2-4 carbon atoms) , cycloalkenyl (4-8 carbon atoms) , lower alkynyl (2-4 carbon atoms) , or two R 2 taken together can form a carbocyclic ring of 5-7 members; and m = 0-3, wherein Ar is phenyl, thienyl, furanyl, pyrrolyl, pyridyl, pyrimidyl, imidazoyl, pyrazinyl, oxazolyl, thiazolyl, naphthyl, benzothienyl, benzofuranyl, indolyl, quinolinyl, isoquinolinyl and quinazolinyl; R 3 , R 4 , R 5 and R 6 are independently not present, H, lower alkyl (1-4 carbon atoms) , cycloalkyl (3-8 carbon atoms) , lower alkoxy (1-4 carbon atomε) , cycloalkoxy (3-8 carbon atomε) , hydroxy, lower acyloxy (1-4 carbon atoms) , amino, lower mono or dialkylamino (1-4 carbon atomε) , lower mono or dicycloalkylamino (3-8 carbon atomε) , lower alkyl (1-4 carbon atoms) or cycloalkyl (3-8 carbon atoms), carbonato (-OC(O)OR) where R is alkyl of from 1-4 carbon atoms or cycloalkyl of from 3-8 carbon atoms; or ureido or thioureido or N- or 0- linked urethane any one of which is optionally substituted by mono or di-lower alkyl (1-4 carbon atoms) or cycloalkyl (3-8 carbon atoms) ; lower thioalkyl (1-4 carbon atoms) , thiocyclo- alkyl (3-8 carbon atoms) , mercapto, lower alkenyl (2-4 carbon atoms), hydrazino, N'-lower alkylhydrazino (1-4 carbon atoms) , lower acylamino (1-4 carbon atoms) , hydroxylamino, lower 0-alkylhydroxylamino (1-4 carbon atoms), or taken together can be methylene-, ethylene- or propylenedioxy, or taken together form a fused pyrrolidine, tetrahydrofuranyl, piperidinyl, piper- azinyl, morpholino or thiomorpholino ring; R 7 and R β can be independently as appropriate, lone pairs of electrons, H, or lower alkyl (1-4 carbon atoms) ; any lower alkyl group substituent on any of the substituents in R 3 -R 8 which contain such a moiety can be optionally substituted with one or more of hydroxy, amino, lower monoalkylamino, lower dialkylamino, N- pyrrolidyl, N-piperidinyl, N-pyridinium, N-morpholino, N-thiomorpholino or N-piperazino groups; if one or two of A through E are N, then if any of R 3 -R 6 is on a neighboring C atom to one of the N atoms, that substituent cannot be either OH or SH; and R 10 is H or lower alkyl (1-4 carbon atoms) , amino or lower mono- or dialkylamino (1-4 carbon atoms) ; if any of the substitutents R 1 , R 2 , R 3 or R 4 contain chiral centers, or in the caεe of R 1 create chiral centers on the linking atoms, then all stereoisomers thereof both separately and as racemic and/or diastereoisomeric mixtures are included; or a pharmaceutical salt or hydrate thereof. 98. A method of treating cancer by treating, with an effective cancer inhibiting amount, a mammal, in need thereof, a compound of the formula: wherein: 1) Y and Z are both C (carbon) , both N or one N and the other C, in which case the ring structure is a linearly fused 6,6 (5 or 6) tricycle, or 2) one of Y and Z is C=C, C=N, whereupon the other one of Y or Z is simply a bond between the two aromatic rings, then the ring structure is a nonlinear 6,6 (5 or 6) tricycle, or 3) one of Y and Z is N, 0 or S, whereupon the other one of Y or Z is simply a bond between the two aromatic rings, then the ring structure is a fused 6,5 (5 or 6) tricycle; A, B, D and E can all be carbon, or up to two of them can be nitrogen, whereupon the remaining atoms must be carbon, or any two contiguous positions in A-E can be a single heteroatom, N, O or S, forming a five membered fused ring, in which case one of the two remaining atoms must be carbon, and the other can be either carbon or nitrogen, except that the case where A and B taken together, and D and E taken separately are all three nitrogen atoms; X = 0, S, NH or NR 9 , such that R 9 = lower alkyl (1-4 carbon atoms) , OH, NH 2 lower alkoxy (1-4 carbon atoms) or lower monoalkylamino (1-4 carbon atoms) ; R 1 = H or lower alkyl; n = 0, 1 or 2; if n = 2, R 1 can be independently H or lower alkyl (1-4 carbon atoms) on either linking carbon atom, and both R and S stereocentres on either linker are included; R 2' is lower alkyl (1-4 carbon atoms) , cycloalkyl (3-8 carbon atoms) , lower alkoxy (1-4 carbon atoms) , cycloalkoxy (3-8 carbon atoms) , nitro, halo, lower perfluoroalkyl (1-4 carbon atoms) , hydroxy, lower acyloxy (1-4 carbon atoms; -O-C(O)-R), amino, lower mono or dialkylamino (1-4 carbon atoms) , lower mono or dicycloalkylamino (3-8 carbon atoms) , hydroxymethyl, lower acyl (1-4 carbon atoms; -C(O)R), cyano, lower thioalkyl (1-4 carbon atoms) , lower sulfinylalkyl (1-4 carbon atomε) , lower sulfonylalkyl (1-4 carbon atoms) , thiocycloalkyl (3-8 carbon atoms) , sulfinylcycloalkyl (3-8 carbon atoms) , sulfonylcycloalkyl (3-8 carbon atoms) , mercapto, lower alkoxycarbonyl (1-4 carbon atoms) , cycloalkoxycarbonyl (3-8 carbon atoms) , lower alkenyl (2-4 carbon atoms) , cycloalkenyl (4-8 carbon atoms) , lower alkynyl (2-4 carbon atoms) , or two R 2 taken together can form a carbocyclic ring of 5-7 members; and m = 0-3, wherein Ar is phenyl, thienyl, furanyl, pyrrolyl, pyridyl, pyrimidyl, imidazoyl, pyrazinyl, oxazolyl, thiazolyl, naphthyl, benzothienyl, benzofuranyl, indolyl, quinolinyl, isoquinolinyl and quinazolinyl; R 3 , R 4 , R 5 and R 6 are independently not present, H, lower alkyl (1-4 carbon atoms) , cycloalkyl (3-8 carbon atoms) , lower alkoxy (1-4 carbon atoms) , cycloalkoxy (3-8 carbon atoms) , hydroxy, lower acyloxy (1-4 carbon atoms) , amino, lower mono or dialkylamino (1-4 carbon atoms) , lower mono or dicycloalkylamino (3-8 carbon atoms) , lower alkyl (1-4 carbon atoms) or cycloalkyl (3-8 carbon atoms) , carbonato (-OC(O)OR) where R is alkyl of from 1-4 carbon atoms or cycloalkyl of from 3-8 carbon atoms; or ureido or thioureido or N- or O- linked urethane any one of which is optionally substituted by mono or di-lower alkyl (1-4 carbon atoms) or cycloalkyl (3-8 carbon atoms) ; lower thioalkyl (1-4 carbon atoms) , thiocyclo- alkyl (3-8 carbon atomε) , mercapto, lower alkenyl (2-4 carbon atoms) , hydrazino, N' -lower alkylhydrazino (1-4 carbon atoms) , lower acylamino (1-4 carbon atoms) , hydroxylamino, lower O-alkylhydroxylamino (1-4 carbon atoms) , or taken together can be methylene-, ethylene- or propylenedioxy, or taken together form a fused pyrrolidine, tetrahydrofuranyl, piperidinyl, piper- azinyl, morpholino or thiomorpholino ring; R 7 and R β can be independently as appropriate, lone pairs of electrons, H, or lower alkyl (1-4 carbon atoms) ; any lower alkyl group εubstituent on any of the substituents in R 3 -R 8 which contain such a moiety can be optionally substituted with one or more of hydroxy, amino, lower monoalkylamino, lower dialkylamino, N- pyrrolidyl, N-piperidinyl, N-pyridinium, N-morpholino, N-thiomorpholino or N-piperazino groups; if one or two of A through E are N, then if any of R 3 -R 6 is on a neighboring C atom to one of the N atoms, that substituent cannot be either OH or SH; and R 10 is H or lower alkyl (1-4 carbon atoms) , amino or lower mono- or dialkylamino (1-4 carbon atoms) ; if any of the substitutents R 1 , R 2 , R 3 or R 4 contain chiral centers, or in the case of R 1 create chiral centers on the linking atoms, then all stereoisomers thereof both separately and as racemic and/or diastereoisomeric mixtures are included; or a pharmaceutical salt or hydrate thereof. 99. A method of treating psoriasis by treating, with an effective psoriasiε inhibiting amount, a mammal, in need thereof, a compound of the formula: wherein: 1) Y and Z are both C (carbon) , both N or one N and the other C, in which case the ring structure is a linearly fused 6,6 (5 or 6) tricycle, or 2) one of Y and Z is C=C, C=N, whereupon the other one of Y or Z is simply a bond between the two aromatic rings, then the ring structure is a nonlinear 6,6 (5 or 6) tricycle, or 3) one of Y and Z is N, 0 or S, whereupon the other one of Y or Z is simply a bond between the two aromatic rings, then the ring structure is a fused 6,5 (5 or 6) tricycle; A, B, D and E can all be carbon, or up to two of them can be nitrogen, whereupon the remaining atoms must be carbon, or any two contiguous positions in A-E can be a single heteroatom, N, 0 or S, forming a five membered fused ring, in which case one of the two remaining atoms must be carbon, and the other can be either carbon or nitrogen, except that the case where A and B taken together, and D and E taken separately are all three nitrogen atoms; X = 0, S, NH or NR 9 , such that R 9 = lower alkyl (1-4 carbon atoms) , OH, NH 2/ lower alkoxy (1-4 carbon atoms) or lower monoalkylamino (1-4 carbon atoms) ; R 1 = H or lower alkyl; n = 0, 1 or 2,- if n = 2, R 1 can be independently H or lower alkyl on either linking carbon atom, and both R and S stereocentres on either linker are included; R 2 is lower alkyl (1-4 carbon atoms) , cycloalkyl (3-8 carbon atoms) , lower alkoxy (1-4 carbon atoms) , cycloalkoxy (3-8 carbon atoms) , nitro, halo, lower perfluoroalkyl (1-4 carbon atoms) , hydroxy, lower acyloxy (1-4 carbon atoms; -O-C(O)-R), amino, lower mono or dialkylamino (1-4 carbon atoms) , lower mono or dicycloalkylamino (3-8 carbon atoms) , hydroxymethyl, lower acyl (1-4 carbon atoms; -C(O)R), cyano, lower thioalkyl (1-4 carbon atoms) , lower sulfinylalkyl (1-4 carbon atoms) , lower sulfonylalkyl (1-4 carbon atoms) , thiocycloalkyl (3-8 carbon atoms) , sulfinylcycloalkyl (3-8 carbon atoms) , sulfonylcycloalkyl (3-8 carbon atoms) , mercapto, lower alkoxycarbonyl (1-4 carbon atoms) , cycloalkoxycarbonyl (3-8 carbon atoms) , lower alkenyl (2-4 carbon atoms) , cycloalkenyl (4-8 carbon atoms) , lower alkynyl (2-4 carbon atoms) , or two R 2 taken together can form a carbocyclic ring of 5-7 members; and m = 0-3, wherein Ar is phenyl, thienyl, furanyl, pyrrolyl, pyridyl, pyrimidyl, imidazoyl, pyrazinyl, oxazolyl, thiazolyl, naphthyl, benzothienyl, benzofuranyl, indolyl, quinolinyl, isoquinolinyl and quinazolinyl; R 3 , R 4 , R 5 and R 6 are independently not present, H, lower alkyl (1-4 carbon atoms) , cycloalkyl (3-8 carbon atoms) , lower alkoxy (1-4 carbon atoms) , cycloalkoxy (3-8 carbon atoms) , hydroxy, lower acyloxy (1-4 carbon atoms) , amino, lower mono or dialkylamino (1-4 carbon atoms) , lower mono or dicycloalkylamino (3-8 carbon atoms) , lower alkyl (1-4 carbon atoms) or cycloalkyl (3-8 carbon atoms), carbonato (-OC(O)OR) where R iε alkyl of from 1-4 carbon atomε or cycloalkyl of from 3-8 carbon atoms; or ureido or thioureido or N- or O- linked urethane any one of which is optionally substituted by mono or di-lower alkyl (1-4 carbon atoms) or cycloalkyl (3-8 carbon atoms) ; lower thioalkyl (1-4 carbon atoms) , thiocyclo- alkyl (3-8 carbon atoms) , mercapto, lower alkenyl (2-4 carbon atoms), hydrazino, N'-lower alkylhydrazino (1-4 carbon atoms) , lower acylamino (1-4 carbon atoms) , hydroxylamino, lower 0-alkylhydroxylamino (1-4 carbon atoms), or taken together can be methylene-, ethylene- or propylenedioxy, or taken together form a fused pyrrolidine, tetrahydrofuranyl, piperidinyl, piper- azinyl, morpholino or thiomorpholino ring; R 7 and R β can be independently as appropriate, lone pairs of electrons, H, or lower alkyl (1-4 carbon atoms) ; any lower alkyl group substituent on any of the substituents in R 3 -R 8 which contain such a moiety can be optionally substituted with one or more of hydroxy, amino, lower monoalkylamino, lower dialkylamino, N- pyrrolidyl, N-piperidinyl, N-pyridinium, N-morpholino, N-thiomorpholino or N-piperazino groups; if one or two of A through E are N, then if any of R 3 -R 6 is on a neighboring C atom to one of the N atoms, that substituent cannot be either OH or SH; and R 10 is H or lower alkyl (1-4 carbon atoms) , amino or lower mono- or dialkylamino (1-4 carbon atoms) ; if any of the substitutents R 1 , R 2 , R 3 or R 4 contain chiral centers, or in the case of R 1 create chiral centers on the linking atoms, then all stereoisomers thereof both separately and as racemic and/or diastereoisomeric mixtures are included; or a pharmaceutical salt or hydrate thereof. 100. A method of preventing blastocyte implantation by treating, with ' an effective blastocyte implantation inhibiting amount, a mammal, in need thereof, a compound of the formula: wherein: 1) Y and Z are both C (carbon) , both N or one N and the other C, in which case the ring structure is a linearly fused 6,6 (5 or 6) tricycle, or 2) one of Y and Z is C=C, C=N, whereupon the other one of Y or Z is simply a bond between the two aromatic rings, then the ring structure is a nonlinear 6,6 (5 or 6) tricycle, or 3) one of Y and Z is N, 0 or S, whereupon the other one of Y or Z is simply a bond between the two aromatic rings, then the ring structure is a fused 6,5 (5 or 6) tricycle; A, B, D and E can all be carbon, or up to two of them can be nitrogen, whereupon the remaining atoms must be carbon, or any two contiguous positions in A-E can be a single heteroatom, N, 0 or S, forming a five membered fused ring, in which case one of the two remaining atoms must be carbon, and the other can be either carbon or nitrogen, except that the case where A and B taken together, and D and E taken separately are all three nitrogen atoms; X = O, S, NH or NR 9 , such that R 9 = lower alkyl (1-4 carbon atoms) , OH, NH 2/ lower alkoxy (1-4 carbon atoms) or lower monoalkylamino (1-4 carbon atoms) ; R 1 = H or lower alkyl; n = 0, 1 or 2,- if n = 2, R 1 can be independently H or lower alkyl on either linking carbon atom, and both R and S stereocentres on either linker are included; R 2 is lower alkyl (1-4 carbon atoms) , cycloalkyl (3-8 carbon atoms) , lower alkoxy (1-4 carbon atoms) , cycloalkoxy (3-8 carbon atoms) , nitro, halo, lower perfluoroalkyl (1-4 carbon atoms) , hydroxy, lower acyloxy (1-4 carbon atoms; -O-C(O)-R), amino, lower mono or dialkylamino (1-4 carbon atoms) , lower mono or dicycloalkylamino (3-8 carbon atoms) , hydroxymethyl, lower acyl (1-4 carbon atomε; -C(O)R), cyano, lower thioalkyl (1-4 carbon atoms) , lower sulfinylalkyl (1-4 carbon atoms) , lower sulfonylalkyl (1-4 carbon atoms) , thiocycloalkyl (3-8 carbon atoms) , sulfinylcycloalkyl (3-8 carbon atoms) , sulfonylcycloalkyl (3-8 carbon atomε) , mercapto, lower alkoxycarbonyl (1-4 carbon atomε) , cycloalkoxycarbonyl (3-8 carbon atoms) , lower alkenyl (2-4 carbon atoms) , cycloalkenyl (4-8 carbon atoms) , lower alkynyl (2-4 carbon atoms) , or two R 2 taken together can form a carbocyclic ring of 5-7 memberε; and m = 0-3,' wherein Ar is phenyl, thienyl, furanyl, pyrrolyl, pyridyl, pyrimidyl, imidazoyl, pyrazinyl, oxazolyl, thiazolyl, naphthyl, benzothienyl, benzofuranyl, indolyl, quinolinyl, isoquinolinyl and quinazolinyl; R 3 , R 4 , R 5 and R 6 are independently not present, H, lower alkyl (1-4 carbon atoms) , cycloalkyl (3-8 carbon atoms) , lower alkoxy (1-4 carbon atoms) , cycloalkoxy (3-8 carbon atoms) , hydroxy, lower acyloxy (1-4 carbon atoms) , amino, lower mono or dialkylamino (1-4 carbon atoms) , lower mono or dicycloalkylamino (3-8 carbon atoms) , lower alkyl (1-4 carbon atoms) or cycloalkyl (3-8 carbon atoms), carbonato (-OC(O)OR) where R iε alkyl of from 1-4 carbon atoms or cycloalkyl of from 3-8 carbon atoms; or ureido or thioureido or N- or O- linked urethane any one of which is optionally substituted by mono or di-lower alkyl (1-4 carbon atoms) or cycloalkyl (3-8 carbon atoms) ; lower thioalkyl (1-4 carbon atoms) , thiocyclo- alkyl (3-8 carbon atoms) , mercapto, lower alkenyl (2-4 carbon atoms), hydrazino, N' -lower alkylhydrazino (1-4 carbon atoms) , lower acylamino (1-4 carbon atoms) , hydroxylamino, lower 0-alkylhydroxylamino (1-4 carbon atoms), or taken together can be methylene-, ethylene- or propylenedioxy, or taken together form a fused pyrrolidine, tetrahydrofuranyl, piperidinyl, piper- azinyl, morpholino or thiomorpholino ring; R 7 and R 8 can be independently as appropriate, lone pairs of electrons, H, or lower alkyl (1-4 carbon atoms) ; any lower alkyl group substituent on any of the substituents in R 3 -R 8 which contain such a moiety can be optionally substituted with one or more of hydroxy, amino, lower monoalkylamino, lower dialkylamino, N- pyrrolidyl, N-piperidinyl, N-pyridinium, N-morpholino, N-thiomorpholino or N-piperazino groups; if one or two of A through E are N, then if any of R 3 -R 6 is on a neighboring C atom to one of the N atoms, that substituent cannot be either OH or SH; and R 10 is H or lower alkyl (1-4 carbon atoms) , amino or lower mono- or dialkylamino (1-4 carbon atoms) ; if any of the subεtitutents R 1 , R 2 , R 3 or R 4 contain chiral centers, or in the case of R 1 create chiral centerε on the linking atoms, then all stereoisomers thereof both separately and as racemic and/or diastereoisomeric mixtures are included; or a pharmaceutical εalt or hydrate thereof. 101. A contraceptive composition comprising a contraceptively effective amount of a compound of the following formula in admixture with a contraceptively acceptable excipient, diluent or carrier: wherein: 1) Y and Z are both C (carbon) , both N or one N and the other C, in which case the ring structure is a linearly fused 6,6 (5 or 6) tricycle, or 2) one of Y and Z is C=C, C=N, whereupon the other one of Y or Z is simply a bond between the two aromatic rings, then the ring structure is a nonlinear 6,6 (5 or 6) tricycle, or 3)' -one of Y and Z is N, 0 or S, whereupon the other one of Y or Z is εimply a bond between the two aromatic ringε, then the ring εtructure is a fused 6,5 (5 or 6) tricycle; A, B, D and E can all be carbon, or up to two of them can be nitrogen, whereupon the remaining atoms must be carbon, or any two contiguous positions in A-E can be a single heteroatom, N, 0 or S, forming a five membered fused ring, in which case one of the two remaining atoms muεt be carbon, and the other can be either carbon or nitrogen, except that the case where A and B taken together, and D and E taken separately are all three nitrogen atoms; X = O, S, NH or NR 9 , such that R 9 ■= lower alkyl (1-4 carbon atoms) , OH, NH 2 _ lower alkoxy (1-4 carbon atoms) or lower monoalkylamino (1-4 carbon atoms) ; R 1 = H or lower alkyl; n = 0, 1 or 2; if n = 2, R 1 can -be independently H or lower alkyl on either linking carbon atom, and both R and S stereocentres on either linker are included; R 2 iε lower alkyl (1-4 carbon atomε) , cycloalkyl (3-8 carbon atoms) , lower alkoxy (1-4 carbon atoms) , cycloalkoxy (3-8 carbon atoms) , nitro, halo, lower perfluoroalkyl (1-4 carbon atoms) , hydroxy, lower acyloxy (1-4 carbon atoms; -O-C(O)-R), amino, lower mono or dialkylamino (1-4 carbon atoms) , lower mono or dicycloalkylamino (3-8 carbon atoms) , hydroxymethyl, lower acyl (1-4 carbon atoms; -C(O)R) , cyano, lower thioalkyl (1-4 carbon atoms) , lower sulfinylalkyl (1-4 carbon atoms) , lower sulfonylalkyl (1-4 carbon atoms) , thiocycloalkyl (3-8 carbon atoms) , sulfinylcycloalkyl (3-8 carbon atoms) , sulfonylcycloalkyl (3-8 carbon atoms) , mercapto, lower alkoxycarbonyl (1-4 carbon atoms) , cycloalkoxycarbonyl (3-8 carbon atoms) , lower alkenyl (2-4 carbon atoms) , cycloalkenyl (4-8 carbon atoms) , lower alkynyl (2-4 carbon atoms) , or two R 2 taken together can form a carbocyclic ring of 5-7 members; and m = 0-3, wherein Ar is phenyl, thienyl, furanyl, pyrrolyl, pyridyl, pyrimidyl, imidazoyl, pyrazinyl, oxazolyl, thiazolyl, naphthyl, benzothienyl, benzofuranyl, indolyl, quinolinyl, isoquinolinyl and quinazolinyl; R 3 , R 4 , R 5 and R 6 are independently not present, H, lower alkyl (1-4 carbon atoms) , cycloalkyl (3-8 carbon atoms) , lower alkoxy (1-4 carbon atoms) , cycloalkoxy (3-8 carbon atoms) , hydroxy, lower acyloxy (1-4 carbon atoms) , amino, lower mono or dialkylamino (1-4 carbon atoms) , lower mono or dicycloalkylamino (3-8 carbon atoms) , lower alkyl (1-4 carbon atoms) or cycloalkyl (3-8 carbon atoms) , carbonato (-OC(O)OR) where R is alkyl of from 1-4 carbon atoms or cycloalkyl of from 3-8 carbon atoms; or ureido or thioureido or N- or O- linked urethane any one of which is optionally substituted by mono or di-lower alkyl (1-4 carbon atoms) or cycloalkyl (3-8 carbon atoms) ; lower thioalkyl (1-4 carbon atoms) , thiocyclo¬ alkyl (3-8 carbon atoms) , mercapto, lower alkenyl (2-4 carbon atoms) , hydrazino, N' -lower alkylhydrazino (1-4 carbon atoms) , lower acylamino (1-4 carbon atoms) , hydroxylamino, lower O-alkylhydroxylamino (1-4 carbon atoms) , or taken together can be methylene-, ethylene- or propylenedioxy, or taken together form a fused pyrrolidine, tetrahydrofuranyl, piperidinyl, piper- azinyl, morpholino or thiomorpholino ring; R 7 and R β can be independently as appropriate, lone pairs of electrons, H, or lower alkyl (1-4 carbon atoms) ; any lower alkyl group substituent on any of the substituents in R 3 -R 8 which contain such a moiety can be optionally substituted with one or more of hydroxy, amino, lower monoalkylamino, lower dialkylamino, N- pyrrolidyl, N-piperidinyl, N-pyridinium, N-morpholino, N-thiomorpholino or N-piperazino groups; if one or two of A through E are N, then if any of R 3 -R 6 is on a neighboring C atom to one of the N atomε, that substituent cannot be either OH or SH; and R 10 is H or lower alkyl (1-4 carbon atoms) , amino or lower mono- or dialkylamino (1-4 carbon atoms) ; if any of the substitutentε R 1 , R 2 , R 3 or R 4 contain chiral centers, or in the case of R 1 create chiral centers on the linking atoms, then all stereoisomers thereof both separately and as racemic and/or diastereoisomeric mixtures are included; or a pharmaceutical salt or hydrate thereof. 102. A method of treating pancreatitis by treating, with an effective amount inhibiting a mammal, in need thereof, a compound of the formula: wherein: 1) Y and Z are both C (carbon) , both N or one N and the other C, in which case the ring structure is a linearly fused 6,6 (5 or 6) tricycle, or 2) one of Y and Z is C=C, C=N, whereupon the other one of Y or Z is simply a bond between the two aromatic rings, then the ring structure is a nonlinear 6,6 (5 or 6) tricycle, or 3) one of Y and Z is N, 0 or S, whereupon the other one of Y or Z is simply a bond between the two aromatic rings, then the ring structure is a fused 6,5 (5 or 6) tricycle; A, B, D and E can all be carbon, or up to two of them can be nitrogen, whereupon the remaining atoms must be carbon, or any two contiguous positions in A-E can be a single heteroatom, N, 0 or S, forming a five membered fused ring, in which case one of the two remaining atoms must be carbon, and the other can be either carbon or nitrogen, except that the case where A and B taken together, and D and E taken separately are all three nitrogen atoms; X = 0, S, NH or NR 9 , such that R 9 = lower alkyl (1-4 carbon atoms) , OH, NH 2< lower alkoxy (1-4 carbon atoms) or lower monoalkylamino (1-4 carbon atoms) ; R 1 = H or lower alkyl; n = 0, 1 or 2; if n = 2, R 1 can be independently H or lower alkyl (1-4 carbon atoms) on either linking carbon atom, and both R and S stereocentres on either linker are included; R 2 is lower alkyl (1-4 carbon atoms) , cycloalkyl (3-8 carbon atoms) , lower alkoxy (1-4 carbon atoms) , cycloalkoxy (3-8 carbon atoms) , nitro, halo, lower perfluoroalkyl (1-4 carbon atoms) , hydroxy, lower acyloxy (1-4 carbon atoms; -O-C(O)-R), amino, lower mono or dialkylamino (1-4 carbon atoms) , lower mono or dicycloalkylamino (3-8 carbon atoms) , hydroxymethyl, lower acyl (1-4 carbon atoms; -C(O)R), cyano, lower thioalkyl (1-4 carbon atoms) , lower sulfinylalkyl (1-4 carbon atoms) , lower sulfonylalkyl (1-4 carbon atoms) , thiocycloalkyl (3-8 carbon atoms) , sulfinylcycloalkyl (3-8 carbon atoms) , sulfonylcycloalkyl (3-8 carbon atoms) , mercapto, lower alkoxycarbonyl (1-4 carbon atoms) , cycloalkoxycarbonyl (3-8 carbon atoms) , lower alkenyl (2-4 carbon atoms) , cycloalkenyl (4-8 carbon atoms) , lower alkynyl (2-4 carbon atoms) , or two R 2 taken together can form a carbocyclic ring of 5-7 members; and m = 0-3, wherein Ar is phenyl, thienyl, furanyl, pyrrolyl, pyridyl, pyrimidyl, imidazoyl, pyrazinyl, oxazolyl, thiazolyl, naphthyl, benzothienyl, benzofuranyl, indolyl, quinolinyl, isoquinolinyl and quinazolinyl; R 3 , R 4 , R 5 and R 6 are independently not present, H, lower alkyl (1-4 carbon atoms) , cycloalkyl (3-8 carbon atoms) , lower alkoxy (1-4 carbon atoms) , cycloalkoxy (3-8 carbon atoms) , hydroxy, lower acyloxy (1-4 carbon atoms) , amino, lower mono or dialkylamino (1-4 carbon atoms) , lower mono or dicycloalkylamino (3-8 carbon atoms) , lower alkyl (1-4 carbon atoms) or cycloalkyl (3-8 carbon atoms), carbonato (-OC(O)OR) where R is alkyl of from 1-4 carbon atoms or cycloalkyl of from 3-8 carbon atoms; or ureido or thioureido or N- or O- linked urethane any one of which is optionally εubstituted by mono or di-lower alkyl (1-4 carbon atoms) or cycloalkyl (3-8 carbon atoms) ; lower thioalkyl (1-4 carbon atoms) , thiocyclo- alkyl (3-8 carbon atoms) , mercapto, lower alkenyl (2-4 carbon atoms), hydrazino, N' -lower alkylhydrazino (1-4 carbon atoms) , lower acylamino (1-4 carbon atoms) , hydroxylamino, lower 0-alkylhydroxylamino (1-4 carbon atoms), or taken together can be methylene-, ethylene- or propylenedioxy, or taken together form a fused pyrrolidine, tetrahydrofuranyl, piperidinyl, piper- azinyl, morpholino or thiomorpholino ring; R 7 and R β can be independently as appropriate, lone pairs of electrons, H, or lower alkyl (1-4 carbon atoms) ; any lower alkyl group substituent on any of the substituents in R 3 -R 8 which contain such a moiety can be optionally substituted with one or more of hydroxy, amino, lower monoalkylamino, lower dialkylamino, N- pyrrolidyl, N-piperidinyl, N-pyridinium, N-morpholino, N-thiomorpholino or N-piperazino groups; if one or two of A through E are N, then if any of R 3 -R 6 is on a neighboring C atom to one of the N atoms, that substituent cannot be either OH or SH; and R 10 is H or lower alkyl (1-4 carbon atoms) , amino or lower mono- or dialkylamino (1-4 carbon atoms) ; if any of the substitutents R 1 , R 2 , R 3 or R 4 contain chiral centers, or in the case of R 1 create chiral centers on the linking atoms, then all stereoisomers thereof both separately and as racemic and/or diastereoisomeric mixtures are included; or a pharmaceutical salt or hydrate thereof. 103. A method of treating kidney diseaεe by treating, with an effective kidney diεease inhibiting amount, a mammal, in need thereof, a compound of the formula: wherein: 1) Y and Z are both C (carbon) , both N or one N and the other C, in which case the ring structure is a linearly fused 6,6 (5 or 6) tricycle, or 2) one of Y and Z is C=C, C=N, whereupon the other one of Y or Z is simply a bond between the two aromatic rings, then the ring structure is a nonlinear 6,6 (5 or 6) tricycle, or 3) one of Y and Z is N, 0 or S, whereupon the other one of Y or Z is simply a bond between the two aromatic rings, then the ring structure iε a fused 6,5 (5 or 6) tricycle; A, B, D and E can all be carbon, or up to two of them can be nitrogen, whereupon the remaining atoms must be carbon, or any two .contiguous positions in A-E can be a single heteroatom, N, 0 or S, forming a five membered fused ring, in which case one of the two remaining atoms must be carbon, and the other can be either carbon or nitrogen, except that the case where A and B taken together, and D and E taken separately are all three nitrogen atoms,- X = 0, S, NH or NR 9 , such that R 9 -= lower alkyl (1-4 carbon atoms) , OH, NH 2ι lower alkoxy (1-4 carbon atoms) or lower monoalkylamino (1-4 carbon atoms) ; R 1 = H or lower alkyl; n = 0, 1 or 2,- if n = 2, R 1 can be independently H or lower alkyl (1-4 carbon atoms) on either linking carbon atom, and both R and S stereocentres on either linker are included; R 2 iε lower alkyl (1-4 carbon atoms) , cycloalkyl (3-8 carbon atoms) , lower alkoxy (1-4 carbon atoms) , cycloalkoxy (3-8 carbon atoms) , nitro, halo, lower perfluoroalkyl (1-4 carbon atoms) , hydroxy, lower acyloxy (1-4 carbon atoms; -O-C(O)-R), amino, lower mono or dialkylamino (1-4 carbon atoms) , lower mono or dicycloalkylamino (3-8 carbon atoms) , hydroxymethyl, lower acyl (1-4 carbon atoms; -C(O)R), cyano, lower thioalkyl (1-4 carbon atoms) , lower sulfinylalkyl (1-4 carbon atoms) , lower sulfonylalkyl (1-4 carbon atoms) , thiocycloalkyl (3-8 carbon atoms) , sulfinylcycloalkyl (3-8 carbon atoms) , sulfonylcycloalkyl (3-8 carbon atoms) , mercapto, lower alkoxycarbonyl (1-4 carbon atoms) , cycloalkoxycarbonyl (3-8 carbon atoms) , lower alkenyl (2-4 carbon atoms) , cycloalkenyl (4-8 carbon atoms) , lower alkynyl (2-4 carbon atoms) , or two R 2 taken together can form a carbocyclic ring of 5-7 members; and m = 0-3, wherein Ar is phenyl, thienyl, furanyl, pyrrolyl, pyridyl, pyrimidyl, imidazoyl, pyrazinyl, oxazolyl, thiazolyl, naphthyl, benzothienyl, benzofuranyl, indolyl, quinolinyl, isoquinolinyl and quinazolinyl; R 3 , R 4 , R 5 and R 6 are independently not present, H, lower alkyl (1-4 carbon atoms) , cycloalkyl (3-8 carbon atoms) , lower alkoxy (1-4 carbon atoms) , cycloalkoxy (3-8 carbon atoms) , hydroxy, lower acyloxy (1-4 carbon atoms) , amino, lower mono or dialkylamino (1-4 carbon atoms) , lower mono or dicycloalkylamino (3-8 carbon atoms) , lower alkyl (1-4 carbon atoms) or cycloalkyl (3-8 carbon atoms) , carbonato (-OC(O)OR) where R is alkyl of from 1-4 carbon atoms or cycloalkyl of from 3-8 carbon atoms; or ureido or thioureido or N- or 0- linked urethane any one of which is optionally substituted by mono or di-lower alkyl (1-4 carbon atoms) or cycloalkyl (3-8 carbon atoms) ; lower thioalkyl (1-4 carbon atoms) , thiocyclo- alkyl (3-8 carbon atoms) , mercapto, lower alkenyl (2-4 carbon atoms) , hydrazino, N' -lower alkylhydrazino (1-4 carbon atoms) , lower acylamino (1-4 carbon atoms) , hydroxylamino, lower O-alkylhydroxylamino (1-4 carbon atoms) , or taken together can be methylene-, ethylene- or propylenedioxy, or taken together form a fused pyrrolidine, tetrahydrofuranyl, piperidinyl, piper- azinyl, morpholino or thiomorpholino ring; R 7 and R β can be independently as appropriate, lone pairs of electrons, H, or lower alkyl (1-4 carbon atoms) ; any lower alkyl group substituent on any of the substituents in R 3 -R 8 which contain such a moiety can be optionally substituted with one or more of hydroxy, amino, lower monoalkylamino, lower dialkylamino, N- pyrrolidyl, N-piperidinyl, N-pyridinium, N-morpholino, N-thiomorpholino or N-piperazino groups; if one or two of A through E are N, then if any of R 3 -R 6 is on a neighboring C atom to one of the N atoms, that substituent cannot be either OH or SH; and R 10 is H or lower alkyl (1-4 carbon atoms) , amino or lower mono- or dialkylamino (1-4 carbon atoms) ; if any of the substitutents R 1 , R 2 , R 3 or R 4 contain chiral centerε, or in the case of R 1 create chiral centers on the linking atoms, then all stereoisomers thereof both separately and as racemic and/or diastereoisomeric mixtures are included; or a pharmaceutical salt or hydrate thereof.

Inventors: BRIDGES ALEXANDER JAMES, DENNY WILLIAM ALEXANDER, FRY DAVID, KRAKER ALAN, MEYER ROBERT, REWCASTLE GORDON WILLIAM, SHOWALTER HOWARD DANIEL HOLLIS, THOMPSON ANDREW MARK, BRIDGES, ALEXANDER, JAMES, DENNY, WILLIAM, ALEXANDER, FRY, DAVID, KRAKER, ALAN, MEYER, ROBERT, REWCASTLE, GORDON, WILLIAM, SHOWALTER, HOWARD, DANIEL, HOLLIS, THOMPSON, ANDREW, MARK
Applicants: WARNER LAMBERT CO, WARNER-LAMBERT COMPANY
Application year: 1995
Main classification: C07D239
IPC codes: A61K31, A61P1, A61P29, A61P35, A61P43, C07D239, C07D471, C07D473, C07D487, C07D491, C07D495, C07D498, C07D513