MXPA01008114A - Cyclic substituted fused pyrrolocarbazoles and isoindolones - Google Patents

Abstract

The present invention is directed to cyclic substituted fused pyrrolocarbazoles and isoindolones having formula I. The invention also is directed to methods for making and using the cyclic substituted fused pyrrolocarbazoles and isoindolones. The compounds are useful as agents for the regulation of protein kinase.

Description

PIRROLOCARBAZOLES AND FUSIONED ISOINDOLONAS SUBSTITUTED CYCLIC CROSS REFERENCE TO RELATED APPLICATIONS This application claims the priority benefit of the provisional US application to be. No. 60 / 119,834, filed on February 12, 1999, the content of which is hereby incorporated by reference in its entirety.

FIELD OF THE INVENTION The present invention is directed to pyrrolocarbazoles and aryl and heteroaryl-fused, substituted, cyclic isoindolones, which are referred to herein as "fused substituted pyrrolocarbazoles and isoindolones". The invention is also directed to methods for making and using cyclic substituted fused pyrrolocarbazoles and isoindolones.

BACKGROUND OF THE INVENTION Protein kinases play a critical role in the control of cell growth and differentiation. It has been shown that an aberrant expression or mutations in protein kinases leads to uncontrolled cell proliferation, such as growth of malignant tumors, and various defects in the processes of development, including migration and invasion, and angiogenesis. Consequently, protein kinases are critical for the control, regulation and modulation of cell proliferation in * ^ * diseases and disorders associated with proliferation of abnormal cells. Protein kinases have also been implicated as targets in central nervous system disorders, such as Alzheimer's disease, inflammatory disorders, such as, psoriasis, bone diseases, such as, osteoporosis, atherosclerosis, restenosis, thrombosis, metabolic disorders, such as diabetes and infectious diseases, such as viral and fungal infections. One of the most commonly studied routes that involve cell regulation is cellular signaling from recipients in the cell surface to the core. In general, the function of each receptor is determined by its expression pattern, ligand availability and the arrangement of downstream signal transduction pathways that are activated by a particular receptor. An example of this route includes a cascade of kinases, in which members of the factor receptor Growth, tyrosine kinases deliver signals via phosphorylation to other kinases, such as Src tyrosine kinase, and the serine / threonine kinase families Raf, Mek and Erk. Each of these kinases is represented by several family members, who play related but functionally distinct roles. The loss of regulation of the route of Signaling of growth factors is a frequent occurrence in cancer, as well as other disease states. Fearon, Genetic Lesions in Human Cancer (Molecular Lesions in Human Cancer), Molecular Oncology, 1 996, 143- 1 78. The serine / threonine kinase rafl can be activated by the product of known oncogene ras. Raf kinase enzyme positively regulates cell division through the Raf / MEK / ERK protein kinase cascade This activation is the result of cRafl-catalyzed phosphorylation of the cmasa protein, MEK1, which fosfopla and activates the protein ERK phosphokinase kinase and regulates the transcription factors required for cell division Avruch et al, TIBS, 1994 (19) 279-283 cRafl negatively regulates cell death by modulating the activity of Bcl-2, a critical regulator of apoptosis This regulation involves direct phosphorylation of Bcl-2 family members Gajewski and Thompson, Cell, 1996 (87) 619-628? o These aspects of cRafl-mediated regulation of cell proliferation require the kinase activity of cRAfl It has also been reported that the reduction of Raf protein levels correlates with a reduction in tumor growth rate in in vivo tumor mouse models Moma, Johnsto n, Geiger, Muller and Fubro, Nature Medicine, vol 2, no 6, jumo 1996, 668-674 Inhibitors of cRafl kinase activity should therefore provide effective treatment for a wide variety of human cancers Activation of signaling pathways of MAP MAP represents an attractive target for tumor therapy by inhibiting one or more of the kinases involved An additional member of the MAP protein kinase family is the p38 cmasa, alternatively known as the cytokine suppressor drug binding protein or reactivation kinase, RK Activation of this kinase has been implicated in the production of atokines proinflammaps, such as IL-1 and TNF The inhibition of this cmasa could offer, therefore, a treatment for disease states in which the production of deregulated atocins is involved. It has also been shown that the signals mediated by anasas control cell growth, cell death and differentiation. in the cell by regulating the processes of the cell cycle Progression through the cycle of eukaryotic cells is controlled by a family of anasas called acne-dependent anasas (CDKs) The loss of control of CDK regulation is a frequent case in Hyperproliferative diseases and cancer Inhibitors of anasas involved in mediating or maintaining particular disease states represent novel therapies for these disorders Examples of such organisms include the inhibition of Src, raf and acyl-dependent anasas (CDK) 1, 2 and 4 in cancer, CDK2 or PDG FR anasa in restenosis, CDK5 and GSK3 anasas in Alzheimer, c-Src anasa in osteoporosis, GS K-3 anasa in type 2 diabetes, p38 kinase in inflateation, VEGF-R 1 -3 and TIE-1 and -2 anasas in angiogenesis, U L97 in nasa in viral infections, CSF - 1 R anasa in bone and hematopoietic diseases, and Lck anasa in autoimmune diseases and transplant rejection Microbial derived material referred to as "K-252a" is a unique compound, which has gained significant attention over the past years due to the variety of functional activities possessed by K-252a is an alkaloid of molocarbazole, which was originally isolated from a culture of Nocardiosis sp (Kase, H et al 39 J Antibiotics 1 959, 1986) K- - 252a is an inhibitor of several enzymes, including protein anasa C (PKC), which plays a central role in regulating cellular functionalities and trk tyrosine anasa The reported functional activities of K-252a and its depvados are numerous and diverse inhibition of tumors (see US Pat. Nos. 4,877,776 , 4,923,986 and 5,063,330, European publication 238,011 in the name of Nomato), antimicrobial activity (see U.S. Patent No. 4,735,939), inhibition of inflammation (see U.S. Patent No. 4,816,450), treatment of diseases associated with neuronal cells (see patents US 5,461,146, 5,621,100, 5,621,101, and publication l? WIPO WO 94/02488, published on February 3, 1994 in the name of Cephalon, Inc and Kyowa Kakko Kogyo Co Ltd), and treatment of prostate diseases (see US Pat. Nos. 5,516,771, and 5,654427) It has also been reported that K-252a inhibits the production of IL-2 (see Grove, DS et al, Experimental Cell Research 193 175-182, 1991). The reported indolocarbazoles share several common attributes. In particular, each comprises three rings of five members, which all include a portion of nitrogen, staurospopne (derived from Streptomyces sp) and K-252a comprise each one a portion of sugar linked via two N-glycosidic bonds Both K-252a and staurospopna have been studied extensively with respect to their usefulness as therapeutic agents. Mdolocarbazoles are generally lipophilic, which allows their comparative ease for crossing biological membranes and, unlike the protein materials, show a longer half-life m "Although K-252a is normally derived from culture media via a fermentation process, the total synthesis of the natural isomer (+) and the non-natural isomer (-) has been achieved in the which the three chiral sugar carbons have the opposite configurations (see Wood et al, J Am Chem Soc 117 10413, 1995 and WIPO publication WO 97/07081) However, this synthesis is not practical for commercial use In addition to the molocarbazole alkaloids represented by K-252a and staurospopna, small synthetic organic molecules have been prepared, which are biologically active and known as fused pyrrolocarbazoles (see U.S. Patent Nos. 5,475,110 , 5,591,855, 5,594,009, 5,705,511, and 5,616,724) Fused isoindolones are also known, which are molecules that do not contain indole, which can be synthesized chemically de novo (see U.S. Patent No. 5,808,060 and WIPO publication WO 97/21677). Certain macrocyclic bis-indolylmaleimide derivatives have been reported (see, for example, U.S. Patent Nos. 5,710,145, 5,672,618, 5,552,396 and 5,545,636). Indolopyrrolocarbazole sugar derivatives have also been reported (see WIPO publication WO98 / 07433). There is a need for novel classes of compounds that demonstrate active It is found that a class of compounds, referred to herein as cyclic fused substituted pyrrolocarbazoles and isoindolones, are useful as agents for the regulation of protein kinases. Accordingly, the present invention is directed, inter alia, to its use as therapeutic agents for the treatment of prior disorders, as well as other important purposes.

BRIEF DESCRIPTION OF THE INVENTION The present invention is directed to pyrrolocarbazoles and isoindolones to ril and heteroaryl-fused, substituted, cyclic. Exemplary com ponents of the invention have the general Formula I: wherein: ring B and ring F, independently, and each together with the carbon atoms to which they are attached, are selected from the group consisting of: a) a carbocyclic aromatic ring of 6 m unsaturated, in which from 1 to 3 carbon atoms can be replaced by nitrogen atoms; b) a 5-membered unsaturated carbocyclic aromatic ring; and c) an unsaturated 5-membered carbocyclic aromatic ring in which either 1) a carbon atom is replaced with an oxygen, nitrogen or sulfur atom; 2) Two carbon atoms are replaced with a sulfur atom and a nitrogen atom, an oxygen atom and a nitrogen atom; or two nitrogen atoms; or 3) three carbon atoms are replaced with three nitrogen atoms; R1 is selected from the group consisting of: a) H, substituted or unsubstituted alkyl having from 1 to 4 carbons, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroarylalkyl; b) -C (= O) R9, where R9 is selected from the group consisting of alkyl, aryl and heteroaryl; c) -OR10, wherein R10 is selected from the group consisting of H and alkyl having from 1 to 4 carbons; d) -C (= O) NH2, -NR11R12, - (CH2) PNR11R12, - (CH2) pOR10, -O (CH2) pOR10 and -O (CH2) pNR11R12, wherein p is from 1 to 4; and wherein either 1) R11 and R12 are each independently selected from the group consisting of H and alkyl having from 1 to 4 carbons; or 2) R11 and R12 together form a linking group of the formula - (CH2) 2-X1- (CH2) 2-, wherein X1 is selected from the group consisting of -O-, -S- and -CH2-; R2 is selected from the group consisting of H, alkyl having 1 to 4 carbons, -OH, alkoxy having 1 to 4 carbons, -OC (= O) R9, -CO (= O) NR1 R12, -O (CH2) pNR11R12, -O (CH2) pOR10, arylalkyl or substituted unsubstituted having 6 to 10 carbons, and substituted or unsubstituted heteroarylalkyl; R3, R4, R5 and R6 are each independently selected from the group consisting of: a) H, aryl, heteroaryl, F, Cl, Br, I, -CN, CF3, -NO2, -OH, -OR9, -O (CH2) pNR11R12, -OC (= O) R9, -OC (= O) NR11R12, -O (CH2) pOR10, -CH2OR10, -NR11R12, -NR10S (= O) 2R9, -NR10C (= O) R9, b) -CH2OR14, wherein R14 is the residue of an amino acid after the hydroxyl group of the carboxyl group is removed; c) -NR10C (= O) NR11R12, -CO2R2, -C (= O) R2, -C (= O) NR11R12, -CH = NOR2, -CH = NR9, - (CH2) PNR11R12, - (CH2) PNHR14 , or -CH = NNR2R2A, wherein R2A is the same as R2; d) -S (O) and R 2, - (CH 2) pS (O) and R 9, -CH 2 S (O) and R 14, wherein y is 0, 1 or 2; e) alkyl having from 1 to 8 carbons, alkenyl having from 2 to 8 carbons, and alkynyl having 2 to 8 carbons, wherein 1) each alkyl, alkenyl or alkynyl group is unsubstituted; or 2) each alkyl, alkenyl or alkynyl group is substituted with 1 to 3 groups selected from the group consisting of aryl having 6 to 10 carbons, heteroaryl, arylalkoxy, heterocycloalkoxy, hydroxy alkoxy, alkyloxy alkoxy, hydroxyalkylthio, alkoxy alkylthio, F , Cl, Br, I, -CN, -NO2, -OH, -OR9, -X2 (CH2) PNR11R12, -X2 (CH2) pC (= O) NR11R12, X2 (CH2) pOC (= O) NR11R12, - X2 (CH2) pCO2R9, X2 (CH2) pS (O) and R9, X2 (CH2) PNR10C (= O) NR11R12, -OC (= O) R9, -OCONHR2, -O-tetrahydropyranyl, -NR 1R12, -NR10CO2R9, -NR10C (= O) NR11R12, -NHC (= NH) NH2, NR10C (= O) R9, -NR10S (O) 2R9, -S (O) and R9, -CO2R2, -C (= O) NR11R12, -C (= O) R2, -CH2OR10, -CH = NNR2R2A, -CH = NOR2, -CH = NNHCH (N = NH) NH2, -S (= O) 2NR2R2A, -P (= O) (OR10) 2, - OR14, and a monosaccharide having from 5 to 7 carbons, wherein each hydroxyl group of the monosaccharide is independently either unsubstituted or is replaced by H, alkyl having from 1 to 4 carbons, alkylcarbonyloxy having from 2 to 5 carbons, or alkoxy having from 1 to 4 carbons; X2 is O, S or NR10; R7 isrbO where: m is 0-4; G is a link; or alkylene having 1 to 4 cas, wherein the alkylene group is unsubstituted, or substituted with NR11AR12A or OR19; R11A and R12A are ¡g ua | is that R11 and R12.

R19 is selected from the group consisting of H, alkyl, acyl and C (= O) NR H 1111A? AnRl122AA ..

R8 is selected from the group consisting of O (C = O) NR11R12, -CN, acyloxy, alkenyl, -O-CH2-O- (CH2) 2-O-CH3, halogen and R1A, wherein R1A is equal to R1; A and B are independently selected from the group consisting of O, N, S, CHR17, C (OH) R17, C (= O), and CH2 = C; or A and B together can form -CH = CH-; C and D are independently selected from the group consisting of a bond, O, N, S, CHR17, C (OH) R17, C (= O) and CH2 = C; E and F are independently selected from the group consisting of a bond, O, N, S, C (= O), and CH (R17); R17 is selected from the group consisting of H, substituted or unsubstituted alkyl, alkoxycayl, and substituted or unsubstituted alkoxy; wherein: 1) ring J contains 0 to 3 ring heteroatoms; 2) two adjacent hydroxyl groups of any of the J ring can be joined in a dioxolane ring; 3) Two adjacent ring ca atoms of any ring J may be joined to form a fused aryl or heteroaryl ring; 4) two adjacent ring nitrogen atoms of any ring J may be joined to form a fused heterocyclic ring, which may be substituted with 1 or 3 alkyl or aryl groups; provided that: 1) ring J contains at least one ca atom that is saturated; 2) ring J does not contain two adjacent ring O atoms, 3) ring J contains a maximum of two ring C (= O) groups, 4) when G is a bond, ring J can be heteropole, Q is selected from the group consisting of O, S, NR13, NR7A, wherein R7A is the same as R7, CHR15, X3CH (R15) and CH (R15) X3, wherein X3 is selected from the group consisting of -O- , -S-, -CH2-, NR7A and NR13, W is selected from the group consisting of CR18R7 and CHR2, R13 is selected from the group consisting of H, -SO2R9, -CO2R9, -C (= 0) R9, - C (= 0) NR 11 R 12, alkyl of 1-8 cas, alkenyl having 2-8 cas and alkynyl having 2-8 cas, and either 1) the alkyl, alkenyl or alkyl group is unsubstituted, or 2) the alkyl group , alkenyl or alkynyl independently is substituted with 1 to 3 groups selected from the group consisting of 6 to 10 ca atoms, heterolalk, aplaxkoxy, heteroacloalkoxy, hydroxyalkoxy, alkyloxy-alkoxy, hydroxyalkylthio, alkoxy-alkyl io, F, Cl, Br, I, -CN, -N02, -OH, -OR9, -X2 (CH2) PNR11R12, -X2 (CH2) pC (= O) NR11R12, - X / (CH2) pOC (= O) NR11R1 -X2 (CH2) pCO2R? X2 (CH2) pS (O) and R9, X2 (CH2) PNR10C (= O) NR11R12, -OC (= O) R9, -OCONHR2, -O-tetrah? Drop? Lo?, -NR 1R12, -NR10CO2R9, -S (O) and R9, -C02R2, -C (= O) NR11R12, -C (= O) R2, -CH2OR10, -CH = NNR2R2A, -CH = NOR2, -CH = NR9, -CH = NNHCH (N = NH) NH2, -S (= 0) NR2R2A, -P (= O) (OR10) 2, -OR14, and a monosaccharide having from 5 to 7 cas, wherein each hydroxyl group of the monosaccharide is independently either unsubstituted or is replaced by H, alkyl having from 1 to 4 cas, alkylcaloxy having from 2 to 5 cas, and alkoxy having from 1 to 4 cas, R15 is selected from the group consisting of H, OR10, SR10, R7A and R16, R16 is selected from the group consisting of alkyl of 1 to 4 cas, phenyl, naphthyl, aplaxyl having 7 to 15 cas, -SO2R9, -C02R9, -C (= O) R9, alkyl having 1-8 cas, alkenyl having 2 to 8 cas, and alkynyl having 2 to 8 cas, wherein 1) each alkyl, alkenyl or alkyl group is unsubstituted, or 2) each alkyl, alkenyl or alkenyl group is substituted with 1 to 3 groups selected from the group consisting of 6 to 10 cas having heteroca, aplaxkoxy, heteroacloalkoxy, hydroxyalkoxy, alkyloxy alkoxy, hydroxy alkylthio, alkoxy alkylthio, F , Cl, Br, I, -CN, -NO2, - OH -OR £ 1 RD12 -X '(CH2) pC (= O) NR 1"1Rn12 Xz (CH2) pOC (= O) NR11R1, -X (CH2) pCO2R9, X2 (CH2) pS (O) and R9, X2 (CH2) pNR10C (= O) NR11R12, -OC (= O) R9, -OCONHR2, -O-tetrah? Drop? Lo?, -NR11R19, -NR10CO2R9, -S (O) andR9, -CO2R2, - C (= O) NR11R12, -C (= O) R2, -CH2OR10, -CH = NNR R2A, -CH = NOR2, -CH = NR9, -CH = NNHCH (N = NH) NH2, -S (= O ) NR2R2A, -P (= O) (OR10) 2, -OR14, and a monosaccharide having from 5 to 7 carbons, wherein each hydroxyl group of the monosaccharide is independently either unsubstituted or is replaced by H, alkyl having 1 at 4 carbons, alkylcarbonyloxy having from 2 to 5 carbons, and alkoxy having from 1 to 4 carbons, R18 is selected from the group consisting of R2, thioalkyl of 1-4 carbons and halogen, A1 and A2 are selected from the group consisting of of H, H, H, OR2, H, -SR2, H, -N (R2) 2, and a group wherein A1 and A2 together form a portion selected from the group consisting of = O, OS y = NR2, B and B2 are selected from the group consisting of H, H, H, -OR2, H, -SR2, H, -N (R) 2, and a group wherein B1 and B2 together form a selected portion of the group which onsiste de = 0, = S y = NR2, with the proviso that at least one of the pairs A1 and A2, or B1 and B2, form = 0, with the proviso that when Q is NH or N R7A, and in any of the group R7 or R7A m is 0 and G is a bond, R8 is H and R7 or R7A contains a ring oxygen heteroatom at position A in a five or six member ring, then B can not be CHR17, wherein R17 is its substituted or unsubstituted alkyl, and with the additional proviso that when the compound of Formula I contains a group R7 or R7A or both a group R7 or R7A In some preferred embodiments of the compounds of Formula I, A and B are independently selected from the group consisting of O, N, S, CH R17, C (OH) R17, C (= O) and CH2 = C, R17 is selected from the group consisting of H, substituted or unsubstituted alkyl substituted, and substituted or unsubstituted alkoxy, wherein 1) the anyl J contains 0 to 3 ring heteroatoms, 2) two adjacent hydroxyl groups any of the J ring may be bonded to a dioxolane ring, 3) two carbon atoms of any adjacent ring of the J ring may leave to form a fused ring or heteropole ring, provided that 1) ring J contains at least one carbon atom that is saturated, 2) ring J does not contain two ring O atoms adjacent, 3) ring J contains a maximum of two C (= O) ring groups, 4) when G is a bond, ring J can be hetero- lope, and R8 is selected from the group consisting of O (C = O) NR11R12 , acyloxy, alkenyl, -O-CH2-O- (CH2) 2-O-CH3, halogen and R1A, wherein R1A is the same as R1 In some preferred embodiments of the compounds of the invention, R1, R4 and R6 are H In further preferred embodiments of the compounds of the invention, one of Ai, A2 or B B2 is H, H and the other is = 0 Preferably, R1, R4 and R6 are H and one of A ,, A2 or B ?, B2 is H, H and the other is = 0 In further preferred embodiments, R1, R4, R5, R6 and R8 are H In some preferred embodiments, R3 and R5 are independently selected from the group consisting of H, alkoxy, halogen, alkoxyalkyl , alkoxy-alkoxyalkyl and alkoxy-alkoxycarbonyl In some preferred embodiments, Q is NR13, preferably wherein R13 is H or R7A, with H being especially preferred In some preferred embodiments of the compounds of to the invention, W is CH2 or CR18R7, with CR18R7 being preferred. Preferably, R18 is H or lower alkyl. In some preferred embodiments, R7 is a 3, 4, 5 or 6 membered carbocyclic ring, or a 5- or 6-membered heterocyclic ring, which contains one or two ring O, N or S atoms. More preferably, R7 is a heterocyclic ring having a ring, ring, or ring heteroatom. In some especially preferred embodiments, R7 is a 3, 4, 5 or 6 membered heterocyclic ring, which contains a ring O atom. In some preferred embodiments, G is a bond or CH2. In further preferred embodiments, m is 0 or 1. In some preferred embodiments, R 8 is H, OH, halogen, ethenyl, acyloxy, alkoxy, substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, or hydroxyalkyl, with H or OH being preferred. In some preferred embodiments, the compounds of the invention have Formula II: In some preferred embodiments of the compounds of Formula II, R1, R4 and R6 are H. In further preferred embodiments of the compounds of Formula II, one of ALA2 O B1, B2 is H, H and the other is = O. In further preferred embodiments of the compounds of Formula II, R3 and R5 are independently selected from the group consisting of H, alkoxy, halogen, alkoxyalkyl, alkoxy-alkoxyalkyl, and alkoxy-alkoxycarbonyl. Still in further preferred embodiments of the compounds of Formula II, G is a bond or CH2.

In further preferred embodiments of the compounds of Formula II, W is CH2 or CR18R7. Still in further preferred embodiments of the compounds of Formula II, Q is NR13 or NR7A. In further preferred embodiments of the compounds of Formula II, R8 is H, OH, halogen, ethenyl, acyloxy, alkoxy, substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, or hydroxyalkyl. In more preferred embodiments of the compounds of Formula II, R1, R4 and R6 are H, one of ALA2 O B ^ B;, is H, H and the other is = O; R3 and R5 are independently selected from the group consisting of H, alkoxy, halogen, alkoxyalkyl, alkoxy-alkoxyalkyl, and alkoxy-alkoxycarbonyl; G is a bond or CH2; and W is CH2 or CR18R7; R8 is selected from the group consisting of H, OH, halogen, ethenyl, acyloxy, alkoxy, substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, and hydroxyalkyl; and Q is NR13 or NR7A. Preferably, R8 is H or OH. In some even more preferred embodiments of the compounds of Formula II, Q is NR13, where R13 is H, G is a bond; and W is CR18R7, wherein R18 is H or lower alkyl; and R3 and R5 are independently selected from the group consisting of H, alkoxy and alkoxy-alkoxycarbonyl. Preferably, R7 is a 3, 4, 5 or 6 membered carbocyclic ring, or a 5- or 6-membered heterocyclic ring, which contains one or two ring O, N or S atoms. Also preferred are embodiments wherein R7 is a heterocyclic ring having a heteroatom of O, N or S ring, with a heterocyclic ring of 3, 4, 5 or 6 members, with one containing a ring O atom being preferred.

In some particularly preferred embodiments, the constituent variables of the compounds of Formula II are selected in accordance with Table 7, infra. In more preferred additional embodiments of the compounds of Formula II, Q is NR7A; R5 and R8 are H, W is CH2; m is 0; G is a bond or CH; and R3 is independently selected from the group consisting of H, halogen, alkoxyalkyl and alkoxy alkoxyalkyl. Preferably, R7A is a 3, 4, 5 or 6 membered carbocyclic ring, or a 5- or 6-membered heterocyclic ring, which contains one or two ring O, N or S atoms. Also preferred are embodiments wherein R7A is a heterocyclic ring having an O, N or S heteroatom, with a 3, 4, 5 or 6 membered heterocyclic ring, which contains a ring O atom being preferred. In some particularly preferred embodiments, the constituent variables of the compounds of Formula II are selected in accordance with Table 8, infra. In some preferred embodiments of the compounds of Formula II, R1, R3, R4 and R6 are each H, A -, A2 is H, H, B?, B2 is = O; Q is NH, R5 is H or alkoxy; W is CR18R7, where R18 is H, G is a bond; m is 1; R8 is OH or -C (= O) R9, where R9 is alkyl; A is O; B, C and D are each CHR17, where R17 is H, and E and F are each a bond. In particularly preferred embodiments, R 5 is attached at the 10-position. In some especially preferred embodiments, R 5 is alkoxy, with -O-CH 3 being preferred. In further especially preferred embodiments, R8 is -OH. In further preferred embodiments of the compounds of Formula II, R1, R3, R4 and R6 are each H; A ,, A2 is H, H; B?, B2 is = O; Q is NH; R5 is H and is attached at position 10; W is CR18R7 where R18 is H; G is a link; m is 1; R8 is OH or -C (= O) R9, where R9 is alkyl, with -OH being preferred; A is O; B, C and D are each CHR17, where R17 is H; and E and F are each a link. In further preferred embodiments, the compounds of Formula II, R1, R3, R4 and R6 are each H, A?, A2 is H, H; B?, B2 is = O; Q is NH; R5 is H and is attached at position 10; W is CR18R7, where R18 is H; G is a link; m is 1; R8 acyloxy with -O- (C = O) -CH3 being preferred; A is O; B, C and D are each CHR17, where R17 is H; and E and F are each a link. In further preferred embodiments of the compounds of Formula II, R1, R3, R4, R5 and R6 are each H, A?, A2 is H, H; and B?, B2 is = 0. In further preferred embodiments, Q is NR7A and W is CHR17, preferably where R7A and R17 are each cyclopropylmethyl. In some preferred embodiments of the compounds of Formula I, R1, R3, R4, R5 and R6 are each H; A?, A2 is H, H; B - ?, B2 is = O, W is CH2, and Q is NR7A. In further preferred embodiments, G is CH2, m is 0, R8 is -CN and ring J is cyclopropyl. In further preferred embodiments of the compounds of Formula I, R1, R3, R4, R5 and R6 are each H; A ,, A2 is H.H; B - ,, B2 is = O, Q is NH, and W is CR18R7, where R18 is H. In further preferred embodiments, G is CHOH, m is 0, R8 is H, A and B form -CH = CH-, C is CHR17, where R17 is -CH3, D is a bond, E and F are each N. In all further preferred embodiments, E and F join to form a fused heterocyclic ring, which is substituted with 1 aryl group. Preferably, R7 has the formula: In further preferred embodiments of the compounds of Formula I, R1, R3, R4, R5 and R6 are each H, A?, A2 is H, H; B1, B2 is = O, W is CH2, and Q is NR7A, G is ethylene, m is 0, R8 is H, A is NH, B is CHR17, C and D are each a bond, E is CH2 and F is S, preferably wherein R17 is alkoxycarbonyl, with methoxycarbonyl being more preferred. The compounds of the invention are useful, inter alia, for enhancing activities induced by trophic factors of cells that respond to trophic factors, e.g., cholinergic neurons, and may also function as survival promoting agents for other types of neuronal cells, by example, dopaminergic and glutamatergic, and thus, they are beneficial therapeutic and pharmacological agents. The present compounds are also useful in the treatment of disorders associated with decreased ChAT activity or death or injury of motoneurons of the spinal cord, and also have utility in diseases associated with apoptotic cell death of the central and peripheral nervous system, immune system. and in inflammatory diseases. The pyrrolocarbazole and cyclic substituted fused isoindolone compounds described herein may also find utility in the treatment of disease states involving malignant cell proliferation, such as cancer. Thus, also provided according to the present invention are methods for inhibiting a kinase comprising providing a compound of claim 1 in an amount sufficient to result in effective inhibition. Preferably, the kinase is selected from trk kinase, particularly trk A, VEGFR, MLK and FGFR. In some preferred embodiments, the methods of the invention are provided to treat inflammation. In further preferred embodiments, methods are provided for treating or preventing prostate disorders, which comprise administering to a host in need of such treatment or prevention, a therapeutically effective amount of a compound of the invention. In some preferred embodiments, the prostate disorder is prostate cancer or benign prostatic hyperplasia. In further preferred embodiments of the methods of the invention, methods are provided for treating or preventing disorders where VEGFR activity contributes to pathological conditions, comprising providing a compound of the invention in a sufficient amount to result in the receptor of growth factor derived from plaques that come into contact with an effective inhibitory amount of the compound, preferably where the disorder is cancer, endometritis, psoriasis, hemangioblastoma or an ocular disease, and more preferably, wherein the disorder is a solid tumor, a hematopoietic or lymphatic malignancy, or ocular disease, which is preferably, diabetic retinopathy. methods of the invention, methods are provided for treating or preventing disorders where the activity of PDGFR contributes to pathological conditions, comprising providing a compound of the invention in an amount sufficient to result in the platelet-derived growth factor receptor coming into contact with an effective inhibitory amount of the compound In further preferred embodiments of the methods of the invention, methods are provided for treating or preventing neoplasia, re umatoid arthritis, pulmonary fibrosis, myelofibrosis, wound healing to normal, atherosclerosis, or restenosis, which they include administering to a need for such treatment or prevention a therapeutically effective amount of a compound of the invention In preferred embodiments of the methods of the invention, methods are provided for treating or preventing disorders characterized by the aberrant activity of cells responsive to trophic factors, comprising providing a compound of the invention in an amount sufficient to result in the trophic factor cell receptor that comes in contact with a mductive amount of effective compound activity. Still in further preferred embodiments of the methods of the invention, methods are provided for treating or prevent Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, stroke, ischemia, Huntington's disease, dementia for IFAD, epilepsy, multiple sclerosis, peripheral neuropathy, or brain or spinal cord injuries, which comprise administering to a guest d in need of such treatment or prevention, a therapeutically effective amount of a compound of the invention In further preferred embodiments of the methods of the invention, methods are provided for treating or preventing disorders characterized by the aberrant activity of a protein kinase, which comprises administering to a host in need of such treatment or prevention, a therapeutically effective amount of a compound of the invention. In still further preferred embodiments of the methods of the invention, methods are provided for treating or preventing disorders where any of the receptor anasa of vascular endothelial growth factor (VEGFR), tyrosma anasa trkA (trkA), midax lineage anasa (M LK) or fibroplast growth factor receptor anasa (FG FR), contributes to pathological conditions, comprising The method provides a compound of the invention in an amount sufficient to to result in the receptor being contacted with an effective inhibitory amount of the compound In some preferred embodiments of the methods of the invention, methods are provided for treating or preventing a disease mediated by a kinase selected from abl, AKT, bcr-ab1, Blk, Brk, Btk, c-kit, c-met, c-src, CDK1, CDK2, CDK4, CDK6, chkl, chk2, cRafl, CSF1R, CSK, EGFR, ErbB2, ErbB3, ErbB4, ERK (Eph), ERK 2, Fak, Faith, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, FLK-4, Flt-1, Fps, Frk, Fyn, GSK, Hck, IGF-1R, INS-R, Jak, JNK, tau, VEGFR1, VEGFR2, VEGFR3, Lck, Lyn, MEK, p38, PDGFR, PIK, PKC, PYK2, ros, tie!, Tie2, TRK, UL97, Yes and Zap70, the method comprising administering to a patient in need of such treatment or prevention, a pharmaceutically effective amount of a compound of the invention. In further preferred embodiments, methods for treating or preventing disorders are provided, wherein a selected kinase of abl, AKT, bcr-ab1, Blk, Brk, Btk, c-kit, c-met, c-src, CDK1, CDK2, CDK4 , CDK6, chkl, chk2, cRafl, CSF1R, CSK, EGFR, ErbB2, ErbB3, ErbB4, ERK (Eph), ERK2, Fak, fes, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, FLK-4, Flt-1, Fps, Frk, Fyn, GSK, Hck, IGF -1R, INS-R, Jak, JNK, tau, VEGFR1, VEGFR2, VEGFR3, Lck, Lyn, MEK, p38, PDGFR, PIK, PKC, PYK2, ros, tie !, tie2, TRK, UL97, Yes and Zap70, contributes to pathological conditions, the method comprising providing a compound of the invention in a sufficient amount, to result in the receptor being contacted with an effective inhibitory amount of the compound. Methods according to embodiments of the present invention are also provided for treating or preventing a symptom of a disorder where a selected kinase of abl, AKT, bcr-ab1, Blk, Brk, Btk, c-kit, c-met, c -src, CDK1, CDK2, CDK4, CDK6, chkl, chk2, cRafl, CSF1R, CSK, EGFR, ErbB2, ErbB3, ErbB4, ERK (Eph), ERK2, Fak, fes, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5 , Fgr, FLK-4, flt-1, Fps, Frk, Fyn, GSK, Hck, IGF-1 R, I NS-R, Jak, JNK, tau, VEGFR 1, VEG FR2, VEGFR3, Lck, Lyn, MEK , p38, PDGFR, PIK, PKC, PYK2, ros, tie-,, tie2, TRK, UL97, Yes and Zap70, contribute to such a symptom, the method comprising providing a compound of the invention in an amount sufficient to result in the receptor is contacted with an effective inhibiting amount of the compound. The present invention further provides methods for treating or preventing Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, stroke, ischemia, Huntington's disease, SI dementia, epilepsy, multiple sclerosis, peripheral neuropathy, brain or spinal cord injuries, cancer, restenosis, osteoporosis, inflammation, angiogenesis, viral infections, bone or hematopoietic diseases, autoimmune diseases or rejection of transplantation, which comprise administering to a host in need of such treatment or prevention an effective therapeutic amount of a compound of the invention . Methods for the treatment of cancer, which comprise inhibiting one or more of Sr, raf or a cell cycle kinase, are also provided according to the present invention. Preferably, the cell cycle kinase is a cyclin-dependent kinase or a checkpoint kinase. Preferably, the elin-dependent kinase is CDK 1, 2, 4 or 6, and the checkpoint kinase is chk 1 or chk 2. Compositions are described containing the present compounds, and methods for using the present compounds. Also described are methodologies for making apr and isapol-fused, substituted, cyclic pyrrolocarbazoles and isomdolones. Other useful methodologies will be apparent to those skilled in the art, once armed with the present disclosure. These and other features of the compounds of the present invention are expose in more detail later BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a schematic drawing showing a preparation of fused pyrrolocarbazoles and fused isoindolones of protected R1. Figure 2 is a schematic drawing showing a general preparation of a cyclic compound of the invention from an acyclic reagent. Fig. 3 is a schematic drawing showing a general preparation of a cyclic compound of the invention via intramolecular dipolar acloadiation. Figure 4 is a schematic drawing showing another general preparation of a cyclic compound of the invention via intermolecular dipolar acloadiaon. 5 is a schematic drawing showing a general preparation of a cyclic compound of the invention by reaction of a carbamone intermediate with a cyclic ketone, an epoxide, oxirane or azipidine and Michael addition. Figure 6 is a schematic drawing showing a General preparation of a cyclic compound of the invention By means of introducing an appropriately substituted, preferred cyclic intermediate, such as a nucleophile, Figure 7 is a schematic drawing showing a general preparation of a cyclic compound of the invention, by reaction of a carbamone intermediate with highly electrophilic reagents. 8 is a schematic drawing showing a general preparation of a cyclic compound of the invention, using an appropriately substituted, preferred cyclic intermediate, as an electrophile. Figure 9 is a schematic drawing showing a general preparation of a cyclic compound of the invention , wherein the cyclic substituents are formed from an olefinic group. Figure 10 is a schematic drawing showing the preparation of fused pyrrolocarbazoles and isomdolones of protected R1. Figure 11 is a schematic drawing showing the preparation of fused pyrrolocarbazoles protected by N-lactam, resin bound and soluble Figure 12 is a schematic drawing showing a general preparation of a cyclic compound of the invention by reaction of a carbamne intermediate with an acyclic reagent containing an electrophilic C = Y bond, to provide the cyclic substituent directly FIGURE 13 is a schematic drawing showing a general preparation of a cyclic compound of the invention via intramolecular dipolar acloadiaon FIGURE 14 is a schematic drawing showing a general preparation of a cyclic compound of the invention via intermolecular dipolar cycloaddition . Figure 15 is another schematic drawing showing a general preparation of a cyclic compound of the invention showing a general preparation of a cyclic compound of the invention, by the reaction of a carbanion intermediate with a cyclic ketone, an epoxide , oxira no or aziridine, and Michael addition. Figure 1 6 is a schematic drawing showing a general preparation of a cyclic compound of the invention by the introduction of an appropriately substituted, preferred cyclic intermediate, such as a nucleophile. FIG. 17 is another schematic drawing showing a general preparation of a cyclic compound of the invention, by reaction of a carbanion intermediate with highly electrophilic reagents. Figure 18 is another schematic drawing showing a general preparation of a cyclic com position of the invention using an appropriately substituted, preferred cyclic intermediate, such as an electrophile. Figure 1 9 is another schematic drawing showing a general preparation of a cyclic compound of the invention, in which cyclic substituents are formed from an olefinic group.

Fig. 20 is a schematic drawing showing a general preparation of a cyclic compound of the invention, in which the cyclic substituent is formed from an aldehyde intermediate. Figure 21 is another schematic drawing showing a general preparation of a cyclic compound of the invention, in which the cyclic bitumen thereof is formed from an aldehyde intermediate.

DETAILED DESCRIPTION Disclosed herein are pyrrolocarbazoles and fused cyclic substituted isoindolones, which are represented by the following Formula I: wherein: ring B and ring F, independently, and each together with the carbon atoms to which they are attached, are selected from the group consisting of: a) a 6-membered carbocyclic aromatic ring, unsaturated, in which from 1 to 3 carbon atoms can be replaced by nitrogen atoms; b) an unsaturated, 5-membered carbocyclic aromatic ring; and c) an unsaturated, 5-membered carbocyclic aromatic ring in which either 1) a carbon atom is replaced with an oxygen, nitrogen or sulfur atom; 2) Two carbon atoms are replaced with a sulfur atom and a nitrogen atom, an oxygen atom and a nitrogen atom; or two nitrogen atoms; or 3) three carbon atoms are replaced with three nitrogen atoms; R1 is selected from the group consisting of: a) H, substituted or unsubstituted alkyl having from 1 to 4 carbons, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroarylalkyl; e) -C (= O) R9, where R9 is selected from the group consisting of alkyl, aryl and heteroaryl; f) -OR10, wherein R10 is selected from the group consisting of H and alkyl having from 1 to 4 carbons; g) -C (= O) N H2, -NR1 R1 2, - (CH2) PNR1 1 R12, - (CH2) pOR1 0, -0 (CH2) pOR? u and -O (CH2) pN R1 1 R1 J wherein p is from 1 to 4; and wherein either 1) R1 1 and R1 2 are each independently selected from the group consisting of H and alkyl having from 1 to 4 carbons; or 2) R11 and R12 together form a linking group of the formula - (CH2) 2-X1- (CH2) 2-, wherein X1 is selected from the group consisting of -O-, -S- and -CH2-; R2 is selected from the group consisting of H, alkyl having from 1 to 4 carbons, -OH, alkoxy having from 1 to 4 carbons, -OC (= O) R9, - OC (= O) NR11R12, -O (CH2) pNR11R12, -O (CH2) pOR10, substituted or unsubstituted arylalkyl having 6 to 10 carbons, and substituted or unsubstituted heteroarylalkyl; R3, R4, R5 and Rd are each independently selected from the group consisting of: a) H, aryl, heteroaryl, F, Cl, Br, I, -CN, CF3, -NO2, -OH, -OR9, -O (CH2) pNR11R12, -OC (= O) R9, -OC (= O) NR11R12, -O (CH2) pOR10, -CH2OR10, -NR11R12, -NR10S (= O) 2R9, -NR10C (= O) R9, b) -CH2OR14, wherein R14 is the residue of an amino acid after the hydroxyl group of the carboxyl group is removed; c) -NR10C (= O) NR11R12, -CO2R2, -C (= O) R2, -C (= O) NR11R12, -CH = NOR2, -CH = NR9, - (CH2) PNR11R12, - (CH2) PNHR14 , or -CH = NNR2R2A, wherein R2A is the same as R2; d) -S (O) and R 2, - (CH 2) pS (O) and R 9, -CH 2 S (O) and R 14, wherein y is 0, 1 or 2; e) alkyl having from 1 to 8 carbons, alkenyl having from 2 to 8 carbons, and alkynyl having 2 to 8 carbons, wherein 1) each alkyl, alkenyl or alkynyl group is unsubstituted; or 2) each alkyl, alkenyl or alkynyl group is substituted with 1 to 3 groups selected from the group consisting of aryl having 6 to 10 carbons, heteroaryl, arylalkoxy, heterocycloalkoxy, hydroxy alkoxy, alkyloxy alkoxy, hydroxyalkylthio, alkoxy alkylthio, F, Cl, Br, I, -CN, -NO2, -OH, -OR9, -X2 (CH2) PNR11R12, -X2 (CH2) pC (= O) NR11R12, X2 (CH2) pOC (= O) NR11R12, -X2 (CH2) pCO2R9, X2 (CH2) pS (O) and R9, X2 (CH2) pNR10C (= O) NR11R12, -OC (= O) R9, -OCONHR2, -O-tetrahydropyranyl, -NR11R12, -NR10CO2R9, -NR10C (= O) NR11R12, -NHC (= NH) NH2, NR10C (= O) R9, -NR10S (O) 2R9, -S (O) and R9, -CO2R2, -C (= O) NR11R12, -C (= O) R2, -CH2OR10, -CH = NNR2R2A, -CH = NOR2, -CH = NNHCH (N = NH) NH2, -S (= O) 2NR2R2A, -P (= O) (OR10) 2, -OR14, and a monosaccharide having from 5 to 7 carbons, wherein each hydroxyl group of the monosaccharide is independently either unsubstituted or is replaced by H, alkyl having from 1 to 4 carbons, alkylcarbonyloxy having from 2 to 5 carbons, or alkoxy having from 1 to 4 carbons; X2 is O, S or NR10; R7 is where: m is 0-4; G is a link; or alkylene having 1 to 4 carbons, wherein the alkylene group is unsubstituted, or substituted with NR11AR12A or OR19; R11A and R12A are jgUa | is that R11 and R12; R 9 is selected from the group consisting of H, alkyl, acyl and C (= 0) NR1 AR12A; R8 is selected from the group consisting of O (C = O) NR11R12, -CN, acyloxy, alkenyl, -O-CH2-O- (CH2) 2-O-CH3, halogen and R1A, wherein R1A is equal to R1; A and B are independently selected from the group consisting of O, N, S, CHR17, C (OH) R17, C (= O), and CH2 = C; or A and B together can form -CH = CH-; C and D are independently selected from the group consisting of a bond, O, N, S, CHR17, C (OH) R17, C (= O) and CH2 = C; E and F are independently selected from the group consisting of a bond, O, N, S, C (= O), and CH (R17); R17 is selected from the group consisting of H, substituted or unsubstituted alkyl, alkoxycarbonyl, and substituted or unsubstituted alkoxy; wherein: 1) ring J contains 0 to 3 ring heteroatoms; 2) two adjacent hydroxyl groups of any of the J ring can be joined in a dioxolane ring; 3) Two adjacent ring carbon atoms of any ring J may be joined to form a fused aryl or heteroaryl ring; 4) two adjacent ring nitrogen atoms of any ring J may be joined to form a fused heterocyclic ring, which may be substituted with 1 or 3 alkyl or aryl groups; provided that: 1) ring J contains at least one carbon atom that is saturated; 2) ring J does not contain two adjacent ring O atoms; 3) Ring J contains a maximum of two C groups (= O) of ring; 4) when G is a bond, ring J can be heteroaryl; Q is selected from the group consisting of O, S, NR13, NR7A, wherein R7A is the same as R7, CHR15, X3CH (R15) and CH (R15) X3, wherein X3 is selected from the group consisting of -O -, -S-, -CH2-, NR7A and NR13; W is selected from the group consisting of CR18R7 and CHR2; R13 is selected from the group consisting of H, -SO2R9, -CO2R9, -C (= 0) R9, -C (= O) NR 1R12, alkyl of 1-8 carbons, alkenyl having 2-8 carbons and alkynyl having 2 -8 carbons; and either 1) the alkyl, alkenyl or alkynyl group is unsubstituted; or 2) the alkyl, alkenyl or alkynyl group independently is substituted with 1 to 3 groups selected from the group consisting of aryl having from 6 to 10 carbons, heteroaryl, arylalkoxy, heterocycloalkoxy, hydroxyalkoxy, alkyloxy-alkoxy, hydroxyalkylthio, alkoxy-alkylthio, F, Cl, Br, I, -CN, -NO2, -OH, -OR9, -X2 (CH2) pNR1 R12, -X2 (CH2) pC (= O) NR11R12, -X2 (CH2) pOC (= O) NR 11 R 12, -X 2 (CH 2) pCO 2 R 9, X 2 (CH 2) p S (O) and R 9, X 2 (CH 2) PNR 10 C (= O) NR 11 R 12, -OC (= O) R 9, -OCONHR 2, -O-tetrahydropyranyl, -NR 11 R 12, - NR10CO2R9, -S (O) and R9, -CO2R2, -C (= O) NR11R12, -C (= O) R2, -CH2OR10, -CH = NNR2R2A, -CH = NOR2, -CH = NR9, -CH = NNHCH (N = NH) NH2, -S (= O) NR2R2A, -P (= O) (OR10) 2, -OR14, and a monosaccharide having from 5 to 7 carbons, wherein each hydroxyl group of the monosaccharide is independently either unsubstituted or is replaced by H, alkyl having from 1 to 4 carbons, alkylcarbonyloxy having from 2 to 5 carbons, and alkoxy having from 1 to 4 carbons; R15 is selected from the group consisting of H, OR10, SR10, R7A and R16; R16 is selected from the group consisting of alkyl of 1 to 4 carbons; phenyl; naphthyl, arylalkyl having 7 to 15 carbons, -SO2R9, -CO2R9, -C (= O) R9, alkyl having 1-8 carbons; alkenyl having 2 to 8 carbons, and alkynyl having 2 to 8 carbons, wherein 1) each alkyl, alkenyl or alkynyl group is unsubstituted; or 2) each alkyl, alkenyl or alkenyl group is substituted with 1 to 3 groups selected from the group consisting of aryl having 6 to 10 carbons, heteroaryl, arylalkoxy, heterocycloalkoxy, hydroxy alkoxy, alkyloxy alkoxy, hydroxyalkylthio, alkoxy alkylthio, F, Cl, Br, I, -CN, -NO2, -OH, -OR9, -X2 (CH2) PNR11R12, -X2 (CH2) pC (= O) NR11R12, X2 (CH2) pOC (= O) NR11R12, -X2 (CH2) pCO2R9, X2 (CH2) pS (O) and R9, X2 (CH2) PNR10C (= O) NR11R12, -OC (= O) R9, -OCONHR2, -O-tetrahydropyranyl, -NR1 R12, -NR10CO2R9, -S (O) and R9, -CO2R2, -C (= O) NR11R12, -C (= O) R2, -CH2OR10, -CH = NNR2R2A, -CH = NOR2, -CH = NR9, -CH = NNHCH (N = NH) NH2, -S (= O) NR2R2A, -P ( = O) (OR10) 2, -OR14, and a monosaccharide having from 5 to 7 carbons, wherein each hydroxyl group of the monosaccharide is independently either unsubstituted or is replaced by H, alkyl having from 1 to 4 carbons, alkylcarbonyloxy having from 2 to 5 carbons, and alkoxy having from 1 to 4 carbons; R1 8 is selected from the group consisting of R2, thioalkyl of 1-4 carbons and halogen; A1 and A2 are selected from the group consisting of H, H; H, OR2; H, -S R2; H, -N (R2) 2; and a group wherein A1 and A2 together form a portion selected from the group consisting of = O, OS and = NR2; B1 and B2 are selected from the group consisting of H, H; H, -OR2; H, -SR2; H, -N (R2) 2; and a group in which B1 and B2 together form a selected portion of the group consisting of = 0, = S and = NR2; with the condition that at least one of the pairs. A1 and A2, or B1 and B2, form = O; with the proviso that when Q is NH or NR7A, and in any of the group R7 or R7A m is 0 and G is a bond, R8 is H and R7 or R7A contains a ring oxygen heteroatom at the A position in a ring of five or six members, then B can not be CHR1 7, where R17 is substituted or unsubstituted alkyl; and with the additional proviso that when the compound of Formula I contains a group R7 or R7A or both a group R7 and R7A. The compounds of the invention include both diastereomers and enantiomers. Preferred substituted cyclic substituted fused pyrrolocarbazoles and syndindolones are represented by the following formula: The compounds represented by Formula (I) are referred to hereafter as Compound (I), and it is applied to compounds of other numbers of formulas. As used herein, the term "carbocyclic" refers to cyclic groups, in which the ring portion is composed solely of carbon atoms. The terms "heterocycle" and "heterocyclic" refer to cyclic groups, in which the ring portion includes at least one heteroatom, such as O, N or S. As used herein, the term "alkyl" means a linear chain, cyclic or branched chain, having 1 to 8 carbon atoms, such as, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, neopentyl, -ethylpropyl, hexyl, octyl, cyclopropyl and cyclopentyl. The alkyl portion of alkyl-containing groups, such as alkoxy, alkoxycarbonyl and alkylaminocarbonyl groups, has the same meaning as alkyl defined above. Lower alkyl groups, which are preferred, are alkyl groups as defined above, which contain 1 to 4 carbons. The term "alkylene" is intended to include straight or branched chain hydrocarbon chains having at least one carbon-carbon double bond. Examples of alkenyl groups include ethenyl and propenyl groups. As used herein, the term "alkylaryl" is intended to include straight or branched chain hydrocarbon chains having at least one carbon-carbon triple bond. Examples of alkynyl groups include ethynyl and propynyl groups.

The acyl portion of acyl containing moieties, such as acyloxy groups, is intended to include a straight or branched chain alkanoyl group having 1 to 6 carbon atoms, such as formyl, acetyl, propanoyl, butyl, valeryl, pivaloyl or hexanoyl. As used herein, the term "aryl" means a group having 6 to 12 carbon atoms, such as phenyl, biphenyl and naphthyl. Preferred aryl groups include substituted or unsubstituted phenyl and naphthyl groups. The term "heteroaryl", as used herein, denotes an aryl group in which one or more ring carbon atoms are replaced by a heteroatom (i.e., Not carbon), such as, O, N or S. Preferred heteroaplo groups include pyridyl, pyrimidyl, pyrrolyl, furyl, thienyl, imidazolyl, triazolyl, tetrazolyl, quinolyl, isoquinolyl, ídazolilo benzoim, thiazolyl, pyrazolyl, and benzothiazolyl. The term "aralkyl" (or "arylalkyl") is intended to denote a group having from 7 to 15 carbons, which consists of an alkyl group bearing an aryl group. Examples of aralkyl groups include benzyl, phenethyl, benzhydryl and naphthylmethyl groups. alkyl and alkyl portions contained within substituents such as aralkyl, alkoxy, arylalkoxy, hydroxyalkoxy, alkoxy-alkoxy, hydroxy-alkylthio, alkoxy-alk uiltio, alk uilcarboniloxi, hydroxyalkyl and acyloxy may be substituted or unsubstituted groups groups. A substituted alkyl group having 1 to 3 substituents independently selected preferably hydroxy, lower alkoxy, lower alkoxy-alkoxy, substituted lcoxi arylated or unsubstituted lower alkoxy, substituted heteroarylalkoxy or unsubstituted lower alkoxy, aryl substituted or unsubstituted, heteroacloalcoxi substituted or unsubstituted, halogen, carboxyl, lower alcoxicarbomlo, nitro, amino, mono- or di-lower alkylamino, dioxolane, dioxane, dithiolane, dithione, furan, lactone or lactam aplo The substituted groups, substituted aralkyl and substituted heteroaplo have, each, 1 to 3 independently selected substituents, which are preferably lower alkyl, hydroxy, lower alkoxy, carboxy lower alkoxycarbonyl, nitro, amino, mono- or di-lower alkylamino and halogen The heterocyclic groups formed with a nitrogen atom include pi rro I id i ni lo groups, pipepdmilo, pipepdmo, morfolimlo, morfolino, thiomorfolin or, N-metilpiperazimlo, indolyl, isomdolilo, imidazole, imidazoline, oxazole ina, oxazole, tpazol, tiazolma, tlazol, pyrazole, pyrazolone, oxadiazole, iazol TIAD and tpazol heterocyclic groups formed with an oxygen atom they include furan groups, tetrahydrofuran, pyran 1, 3-d? Oxolane, 1,3-d? Oxannane, 1,4-d? Oxannane, 1,3-oxat? Nano, 1,4-oxat? Nano, 1,3-oxat ? olano and Tetrah idropirano the g roups "hydroxyalkyl" are alkyl groups that have a hydroxyl group appended thereto the "hydroxyalkoxy groups" are alkoxy groups that have a hydroxyl group appended thereto halogens include fluorine, chlorine, bromine and iodine As used herein, the term "heteroalalkyl" means a group at alkyl which contains a heteroatom. The term "oxy" denotes the presence of an oxygen atom. Thus, "alkoxy" groups are alkyl groups that are linked through an oxygen atom, and the "carbonylloxy" groups are carbonyl groups that are n united through an oxygen atom. The term "heterocycloalkoxy" means an alkoxy group having a heterocycle group attached to the alkyl portion thereof, and the term "arylalkoxy" means an alkoxy group having an aryl group attached to the alkyl portion thereof. The term "alkylcarbonyloxy" means a group of formula -O-C (= O) -alkyl. As used herein, the term "alkyloxy alkoxy" denotes an alkoxy group that contains an alkyloxy substituent attached to its alkyl portion. The term "alkoxy-alkylthio" means an alkylthio group (ie, a group of the formula -S-alkyl), which contains an alkoxy substituent attached to its alkyl portion. The term "hydroxy-alkylthio" means an alkylthio group (ie, a group of formula -S-alkyl) which contains a hydroxy substituent aided to its alkyl portion. The term "alkoxy alkylthio" means an alkylthio group containing an alkoxy substituent attached to its alkyl portion. As used herein, the term "monosaccharide" has its usual meaning as a simple sugar. As used herein, the term "amino acid" denotes a molecule that contains both an amino group and a carboxyl group. Modalities of amino acids include aa-am inoctates; that is, carboxylic acids of the general formula HOOC-CH (NH2) - (side chain). The side chains of amino acids include portions that occur naturally and occur naturally. The side chains of amino acids that do not occur unnaturally (ie, artificially) are portions that are used in place of side chains of amino acids that occur naturally in, for example, amino acid analogues. See, for example, Lehninger, Biochemistry (Biochemistry), second edition, Worth Publishers, Inc., 1975, pages 73-75, incorporated herein by reference. In some preferred embodiments, the substituent groups for the compounds of formulas I and II include the residue of an amino acid after the removal of the hydroxyl portion of the carboxyl group from the same; that is, groups of formula C (= O) -CH (N H2) - (side chain). The functional groups present in the compounds of Formula I may contain protecting groups. For example, the amino acid side chain substituents of the compounds of Formula I can be substituted with protecting groups, such as benzyloxycarbonyl or t-butoxycarbonyl groups. Protecting groups are known per se as chemical functional groups that can be selectively appended to, and removed from, functionalities, such as hydroxyl groups and carboxyl groups. These groups are present in a chemical compound to render such functionality inert to conditions of chemical reactions, to which the compound is exposed. Any of a variety of protecting groups can be employed with the present invention. One such protective group is the benzyloxycarbonyl group (Cbz; Z). Other preferred protecting groups according to the invention can be found in Greene, T.W. and Wuts, P.G. M., "Protective Groups in Organic Synthesis" (Protective groups in organic synthesis), 2nd ed. , Wiley & Sons, 1991.

The fused substituted pyrrolocarbazole and isoindolone cyclic compounds have obvious important functional pharmacological activities, which find utility in a variety of environments, including both research and therapeutic areas. These derivatives are useful as therapeutic agents. The activities of the compounds show positive effects on the function and / or survival of cells that respond to trophic factors. The effect on the function and / or survival of cells responsive to trophic factors, eg, cells of a neuronal lineage, has been demonstrated using any of the following assays: (1) choline acetyltransferase ("ChAT") assay spinal cord cultured; or (2) assay of ChAT activity of cultured basal forebrain neuron. As used herein, the term "effect," when used to modify the terms "function" and "survival," means a positive or negative alteration or change. An effect, which is positive, can be referred to in the present as an "intensification" or "intensifying" and an effect, which is negative, can be referred to in the present as "inh ibición" or "que inh ibe" . As used herein, the terms "intensify" or "intensify", when used to modify the terms "function" or "survival", mean that the presence of a substituted pyrrolocarbazole or fused isoindolone cyclic compound has a positive effect on the function and / or survival of a cell that responds to trophic factors, compared with a cell in the absence of the compound. For example, and not by way of limitation, with respect to the survival of, for example, a cholinergic neuron, the compound would evidence the intensification of the survival of a cholinergic neuronal population at risk of dying (due to, for example, injury, a disease condition, a degenerative condition or natural progression), when compared to a cholinergic neuronal population not present with such a compound, if the treated population has a comparatively greater period of functionality than the untreated population. As used herein, "inhibit" and "inhibition" means that a specified response of a designated material (eg, enzymatic activity) is comparatively decreased in the presence of a substituted pyrrolocarbazole or fused isoindolone cyclic compound. As used herein, the term "trk" refers to the family of high affinity neurotrophin receptors currently comprising trk A, trk B and trk C, and other membrane associated proteins to which neurotrophin can bind. As used herein, inhibition of VEGFR implies utility in, for example, diseases where angiogenesis plays important roles, such as cancer of solid tumors, endometriosis, diabetic retinopathy, psoriasis, hemangioblastoma, as well as other ocular diseases and cancers. The inhibition of trk involves utility in, for example, diseases of the prostate, such as prostate cancer and benign prostatic hyperplasia and treatment of inflammatory pain. Inhibition of platelet-derived growth factor receptor (PDGFR) implies utility in, for example, various forms of neoplasia, rheumatoid arthritis, pulmonary fibrosis, myelofibrosis, abnormal wound healing, diseases with cardiovascular endpoints, such as atherosclerosis, réstenoses , post-angioplasty restenosis, etc. As used herein, the terms "cancer" and "cancerous" refer to any malignant proliferation of cells in a mammal. Examples include prostate, benign prostatic hyperplasia, ovarian, breast, cerebral, pulmonary, pancreatic, colorectal, gastric, stomach, solids, head and neck carcinoma, neuroblastoma, renal cell carcinoma, lymphoma, leukemia, other recognized malignancies of hematopoietic systems, and other recognized cancers. As used herein, the terms "neuron", "neuronal cell line" and "neuronal cell" include, but are not limited to, a heterogeneous population of neuronal types having single or multiple transmitters and / or single or multiple functions; preferably, these are cholinergic and sensory neurons. As used herein, the phrase "cholinergic neuron" means neurons of the central nervous system (CNS) and peripheral nervous system (PNS), whose neurotransmitter is acetylcholine; examples are neurons of the forebrain basal, striatal and spinal cord. As used herein, the phrase "sensory neuron" includes neurons that respond to environmental signals (e.g., temperature, movement) of, e.g., skin, muscle and joints; An example is a neuron of the dorsal root ganglia.

A "cell responsive to trophic factors," as defined herein, is a cell that includes a receptor, to which a trophic factor can specifically bind; examples include neurons (e.g., cholinergic and sensory neurons) and non-neuronal cells (e.g., monocytes and neoplastic cells). The substituted pyrrolocarbazole and fused isoindolone cyclic compounds described herein find utility in both research and therapeutic environments in, for example, the inhibition of enzymatic activity. For example, in a research setting, the compounds can be used in the development of assays and models for further enhancement of the understanding of roles that inhibition of serine / threonine or tyrosine protein kinase (eg, PKC, trk tyrosine kinase ) play on the mechanical aspects of the disorders and associated diseases. In a therapeutic environment, compounds that inhibit these enzymatic activities can be used to inhibit the deleterious consequences of these enzymes with respect to disorders, such as cancer. As the Examples shown below, the inhibition of the enzymatic activity using the fused pyrrolocarbazole and fused isoindolone cyclic compounds can be determined using, for example, the following tests: 1. Inhibition assay of trkA tyrosine kinase activity; 2. Inhibition of the phosphorylation of trk NGF-stimulated in a whole cell preparation; 3 Endote to vascular growth factor receptor anasa inhibition assay (VEGFR), 4 PKC activity inhibition test, 5 PDGFR inhibition assay 6 Intensification of ChAT activity of the spinal cord. The pyrrolocarbazole compounds and cyclic substituted fused isomdolones described can be used to enhance the function and / or survival of cells of neuronal lineage in a mammal, for example a human In these contexts, the compounds can be used individually or with other fused pyrrolocarbazoles and / or indolocarbazoles, or in combination with other beneficial molecules, which also demonstrate the ability to affect the function and / or survival of a designated cell. The substituted pyrrolocarbazoles and fused cyclic isomdolones of the present invention are useful, inter alia , as therapeutic agents In particular, the compounds are useful for the inhibition of protein anasa The substituted pyrrolocarbazoles and fused isomdolones cyclic can inhibit, for example, selected anasas of abl, AKT, bcr-ab1, Blk, Brk, Btk, c-kit , c-met, c-src, CDK1, CDK2, CDK4, CDK6, chkl, chk2, cRafl, CSF1R, CSK, EG FR, ErbB2, ErbB3, ErbB4, ERK (Eph), ERK2, Fak, Fes, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, FLK-4, Flt-1, Fps, Frk, Fyn, GSK, Hck, IGF-1R, INS-R, Jak, JNK, tau, VEGFR1, VEGFR2, VEGFR3, Lck, Lyn, MEK, p38, PDGFR, PIK, PKC, PYK2, ros, tie-i, t? E2, TRK, UL97, Yes and Zap70 In this way, the properties of the compounds of the present invention are beneficial in therapeutic environments. The activities of the fused substituted pyrrolocarbazoles and isoindolones cyclic to certain enzymes can be exploited to combat the harmful consequences of these enzymes. For example, inhibition of vascular endothelial growth factor receptor (VEGFR) implies utility in, for example, diseases where angiogenesis plays important roles, such as cancer (e.g., solid tumors and hematopoietic / lymphatic malignancies), endometriosis, Diabetic retinopathy, psoriasis, hemangioblastoma, as well as other eye diseases and cancers. The inhibition of trk implies utility in, by. example, diseases of the prostate, such as prostate cancer and benign prostatic hyperplasia, and treatment of inflammatory pain. Inhibition of the platelet-derived growth factor receptor (PDGFR) implies utility in, for example, various forms of neoplasia, rheumatoid arthritis, pulmonary fibrosis, myelofibrosis, abnormal wound healing, diseases with cardiovascular endpoints, such as atherosclerosis, restenosis , post-angiotomy and similar restenosis. Inhibition of mixed lineage kinase (MLK) implies utility in, for example, Alzheimer's disease; disorders of motor neurons (eg, amyotrophic lateral sclerosis); Parkinson's disease; cerebrovascular disorders (eg, stroke, ischemia); Huntington's disease; dementia due to AIDS; epilepsy; multiple sclerosis; peripheral neuropathies (for example, those that affect DRG neurons in peripheral neuropathy associated with chemotherapy) including diabetic neuropathy, disorders induced by excitatory amino acids; and disorders associated with concussive or penetrating injuries of the brain or spinal cord. Inhibition of fibroplast growth factor receptor (FGFR) kinase implies utility in, for example, restenosis, post-angioplasty restenosis, atherosclerosis, pulmonary fibrosis, various cancers including, but not limited to, prostate cancer, breast cancer , healing of normal wounds and benign prosthetic hypertrophy. The activities of pyrrolocarbazoles and fused cyclic substituted isoindolones can also have positive effects on the function and survival of cells that respond to trophic factors by promoting the survival of neurons. With respect to the survival of a cholinergic neuron, for example, the compound can preserve the survival of a cholinergic neuronal population at risk of dying (due, for example, to injury, a disease condition, a degenerative condition or natural progression), when compared to a cholinergic neuronal population not presented with such a compound, if the treated population has a comparatively longer period of function than the untreated population. A variety of neurological disorders are characterized by neuronal cells, which are dying, are injured, are functionally compromised, are experiencing axonal degeneration, are at risk of dying, etc. These disorders include, but are not limited to: Alzheimer's disease; disorders of motor neurons (eg, amyotrophic lateral sclerosis); Parkinson's disease; cerebrovascular disorders (eg, stroke, ischemia); Huntington's disease; dementia due to AIDS; epilepsy; multiple sclerosis; peripheral neuropathies (for example, those that affect DRG neurons in peripheral neuropathy associated with chemotherapy) including diabetic neuropathy; disorders induced by amioacid excitators; and disorders associated with concussive or penetrating injuries of the brain or spinal cord. Additionally, inhibition of Src, raf, and cell cycle cells, such as cyclin-dependent kinases (CDK) 1, 2, 4 and 6, and checkpoint kinases (such as, chk 1 and chk 2) can be useful for the treatment of cancer. The regulation of CDK2 kinase can be useful for the treatment of restenosis. The regulation of one or more of CDK5 or GSK3 kinases may be useful for the treatment of Alzheimer. The regulation of one or more cSrc kinase may be useful for the treatment of osteoporosis. The regulation of one or more of GSK-3 kinase can be useful for the treatment of type-2 diabetes. The regulation of one or more of p38 kinase may be useful for the treatment of inflammation. The regulation of one or more of TIE-1, or TIE-2 kinases can be useful for the treatment of angiogenesis. The regulation of one or more of U L97 kinase may be useful for the treatment of viral infections. The regulation of one or more of CS F-1 R kinase can be useful for the treatment of bone and hematopoietic diseases. The regulation of one or more of Lck kinase may be useful for the treatment of autoimmune diseases and transplant rejection. Topo-I or Topo II topoisomerase regulation may be useful for the treatment of cancer.

ChAT catalyzes the synthesis of the neurotransmitter acetylcholine, and is considered an enzymatic marker for a functional cholinergic neuron. A functional neuron is also capable of survival. The survival of neurons is tested by quantifying the specific uptake and enzymatic conversion of a dye (for example, AMA-match) by living neurons. Due to their varied utilities, the substituted pyrrolocarbazole and fused isoindole cyclic compounds described herein find utility in a variety of environments, e.g., research. The compounds can be used in the development of in vitro models of survival, function, neuronal cell identification, or for the classification of other synthetic compounds, which have activities similar to those of the fused substituted pyrrolocarbazole and isoindolone cyclic compounds. In this manner, the compounds provided by this invention are useful as standard or reference compounds for use in tests or assays to determine the activity of a person in a pharmaceutical research program, and / or can otherwise be used in a research environment to investigate, define and determine molecular objectives associated with functional responses. For example, by radiolabelling a substituted pyrrolocarbazole or fused isoindolone cyclic compound, associated with a specific cellular function (eg, mitogenesis), the target entity to which the derivative binds can be identified, isolated and purified for characterization.

The compounds are useful, inter alia, not only to intensify the activities induced by trophic factors of cells that respond to trophic factors, for example, cholinergic neurons, but can also function as survival promoting agents for other types of neuronal cells, for example , dopaminergic or glutamatergic. The growth factor can regulate the survival of neurons by signaling cascades downstream of the small GTP binding proteins ras, rae and cdc42 (Denhardt, D.T., Biochem J., 1996, 318, 729). Specifically, ras activation leads to phosphorylation and activation of extracellular receptor activated kinase (ERK), which has been linked to differentiation and biological growth processes. The stimulation of rac / cdc42 leads to an increase in the activation of JNK and p38, responses that are associated with tension, apoptosis and inflammation. Although the responses of growth factors are mainly via the ERK pathway, affecting the latter processes can lead to alternating mechanisms of neuronal survival, which can mimic growth factors that enhance the survival properties (Xia et al., Science, 1 995, 270, 1 326). The compounds can also function as survival promoters for neuronal and non-neuronal cells by mechanisms related to, but also different from, growth factor-mediated survival, for example, inhibition of the MAPK pathways of JNK and p38, which they can lead to survival by inhibiting apoptotic cell death processes.

The present compounds are useful in the treatment of disorders associated with decreased ChAT activity or death, injury to motoneurons of the spinal cord, and also have utility in, for example, diseases associated with apoptotic cell death of the central nervous system and peripheral, immune system and in inflammatory diseases. The pyrrolocarbazole and cyclic substituted fused isoindolone compounds described herein may also find utility in the treatment of disease states, which involve proliferation of malignant cells, such as, many cancers. As an additional illustration, the compounds can be used in the development of tests and models for further intensification of the understanding of the roles that inhibition plays in the mechanical aspects of associated disorders and diseases. In this way, the compounds of the present invention are useful as diagnostic reagents in diagnostic assays, such as the assays described herein. The pharmaceutically acceptable salts of the compounds (I) include pharmaceutically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts and amino acid addition salts. Examples of the acid addition salts are inorganic acid addition salts, such as hydrochloride, sulfate and phosphate and organic acid addition salts, such as acetate, maleate, fumarate, tartrate, citrate and lactate; examples of the metal salts are alkali metal salts, such as, lithium salt, sodium salt and potassium salt, alkaline earth metal salts, such as magnesium salt and calcium salt, aluminum salt and zinc salt; examples of ammonium salts are ammonium salt and tetramethylammonium salt; examples of organic mine addition salts are salts with morpholine and pyperidine; and examples of the amino acid addition salts are salts with glycine, phenylalanine, glutamic acid and lysine. The compounds provided herein can be formulated into pharmaceutical compositions by admixture with pharmaceutically acceptable non-toxic carriers and excipients. Such compositions can be prepared for use in parenteral administration, in particular in the form of liquid solutions or suspensions; or oral administration, in particular in the form of tablets or capsules; or intranasally, in particular in the form of powders, nasal drops or aerosols; or dermally, via, for example, transdermal patches. The composition can be conveniently administered in unit dosage form and can be prepared by any of the methods well known in the pharmaceutical art, for example, as described in Remington's Pharmaceutical Sciences (Mack Publ. Co., Easton, PA, 1 980). Formulations for parenteral administration may contain as common excipients, water or sterile saline, polyalkylene glycols, such as polyethylene glycol, hydrogenated oils and naphthalenes, of plant origin and the like. In particular, the lactide polymer, lactide / g licolide copolymer, or biodegradable, biodegradable polyoxyethylene-polyoxypropylene copolymers can be useful excipients for controlling the release of the active compounds. Other potentially useful parenteral delivery systems for these active compounds include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems and liposomes. The formulations for administration by inhalation contain as excipients, for example, lactose, or they can be aqueous solutions containing, for example, polyoxyethylene-9-the uryl ether, glycocholate and deoxycholate, or oily solutions for administration in the form of nasal drops, or as a gel to be applied intranasally. Formulations for parenteral administration may also include glycocholate for buccal administration, a salicylate for rectal administration, or citric acid for vaginal administration. Formulations for transdermal patches are preferably lipophilic emulsions. The compounds of this invention can be employed as the sole active agent in a pharmaceutical composition. Alternatively, they can be used in combination with other active ingredients, for example, other growth factors that facilitate neuronal survival or axonal regeneration in diseases or disorders. The compounds of Formula I and pharmaceutically acceptable salts thereof can be administered orally or non-orally, for example, as an ointment or an injection. The concentrations of the compounds of this invention in a therapeutic composition may vary. The concentration will depend on factors, such as the total dosage of the drug to be administered, the chemical characteristics (for example, hydrophobicity) of the compounds used, the route of administration, the age, body weight and symptoms of a patient. , etc. The compounds of this invention are usually provided in an aqueous physiological buffer solution containing about 0.1 to 10% w / v of compound for parenteral administration. The normal dose ranges are from about 1 mg to about 1 mg / g. kg of body weight per day, a preferred range of doses is from approximately 0 01 mg / kg to 100 mg / kg of body weight per day, and preferably about 0 1 to 20 mg / kg one to four times a day A preferred dosage of drug to be administered is likely to depend on variables such as, the type and degree of disease progression or disorder, the state of overall health of the particular patient, the relative biological efficacy of the selected compound, the formulation of the excipient of the compound and its route of administration. The compounds of Formula I and pharmaceutically acceptable salts of the same can be administered alone, or in the form of various pharmaceutical compositions, according to the pharmacological activity and the purpose of the administration. The pharmaceutical compositions according to the present invention can be prepared by uniformly mixing an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, as an active ingredient, with a pharmaceutically acceptable carrier The carrier can take a wide range of forms according to the forms of composition suitable for administration It is desired that such pharmaceutical compositions are prepared in a unit dosage form suitable for oral or non-oral administration Forms for non-oral administration include ointment and injection Tablets may be prepared using excipients, such as lactose, glucose, sucrose, mamthol and methyl cellulose, disintegrating agents such as sodium hydroxide, sodium alginate, carboxymethyl cel or calcium slab and crystalline cellulose, lubricants, such as magnesium stearate and talc, binders, such as gelatin, polyvinyl alcohol, polyvinyl pyrrolidone, hydroxypropyl cellulose and methyl cellulose, surfactants, such as sucrose fatty acid ester and sorbitol fatty acid ester and the like, in a conventional manner It is preferred that each tablet contain 15- 300 mg of the active ingredient Granules can be prepared using excipients, such as lactose and sucrose, disintegrating agents, such as starch, binders, such as gelatin, and the like in a conventional manner Powders can be prepared using excipients, such as lactose and mannitol, and the like in a conventional manner Capsules can be prepared using gelatin, water, sucrose, gum arabic, sorbitol, glycepna, crystalline cellulose, magnesium stearate, talc and the like in a conventional manner It is preferred that each capsule contains 1 5-300 mg of the active ingredient Syrup preparations can be made using sugars , such as sucrose, water, ethanol and the like, in a conventional manner. It can be prepared unguent using ointment bases, such as vaseline, liquid paraffin, lanolin and macrogol, emulsifiers, such as, sodium lactate upl, chloride of benzalcomo, mono-fatty acid ester of sorbitan, sodium carboxymethyl cellulose and gum arabic, and the like in a conventional manner can injectable preparations are made using solvents, such as water, physiological saline, vegetable oils (e.g., olive oil and peanut oil), ethyl oleate and propylene glycol, solubilizing agents, such as sodium benzoate, sodium salicylate and urethane, isotonicity agents, such as sodium chloride and glucose, preservatives, such as phenol, cresol, p-hydroxybenzoic ester and chlorobutanol, anti-oxidants, such as ascorbic acid and sodium pyrosulfite and simvastatins in a conventional manner The invention is illustrated additionally by way of the following examples, which are intended to elucidate the invention. These examples are not intended to be, nor will they be interpreted as, limiting the scope of the description EXAMPLES EXAMPLE 1 I nhi bination of trkA tyrosine cyanase activity Compounds of pyrrolocarbazoles and selected cyclic substituted fused isoindolones were tested for their ability to inhibit the cytoplasmic domain anasa activity of human trkA expressed in baculovirus, using an assay based on ELISA, as previously described (Angeles et al, Anal Biochem 236 49-55, 1996) Briefly, the 96-well microtiter plate was coated with substrate solution (phospholipase fusion protein 5). recombinant C-? 1 / glutathione S-transferase) (Rotin et al., EMBO J., 11: 559-567, 1992). Inhibition studies were performed in 100 μl of assay mixtures containing 50 mM Hepes, pH 7.4, 40 μM ATP, 10 mM MnCl 2, 0.1% BSA, 2% DMSO and various concentrations of inhibitor. The reaction was initiated by the addition of trkA kinase and allowed to proceed for 15 minutes at 37 ° C. Then an antibody to phosphotyrosine (UBI) was added, followed by an antibody conjugated by secondary enzyme, goat anti-mouse IgG labeled with alkaline phosphatase (Bio-Rad). The activity of the bound enzyme was measured via an amplified detection system (Gibco-BRL). The inhibition data were analyzed using the sigmoidal dose response equation (variable slope) in GraphPad Prism. The concentration that resulted in 50% inhibition of kinase activity is referred to as "IC50". The results are summarized in Table 1.

Table 1 Inhibitory effects of cyclic substituted fused pyrrolocarbazoles and isoindolones on trkA kinase activity fifteen twenty 20 EXAMPLE 2 I nhi bition of NGF-stimulated trk phosphorylation in a whole cell preparation Inhibition of NKF-stimulated phosphorylation of trk by selected cyclic substituted fused pyrrolocarbazole and fused isoindolone compounds was performed using a modified procedure, as described above, of that previously described (see U.S. Patent No. 5, 516,771). NI H3T3 cells transfected with trkA were grown in 1 00 mm plates. Subconfluent cells were stripped of serum by replacing media with compound containing DMEM with 0.05% serum free BSA (100 nM and 1 μM) or DMSO (added to controls) for one hour at 37 ° C. Then NG F (Harlan / Bioproducts for Science) was added to the cells at a concentration of 10 ng / ml for 5 minutes. The cells were lysed in buffer containing detergent and protease inhibitors. Clarified cell lysates were normalized to protein using the BCA method and immunoprecipitated with anti-trk antibody. The polyclonal anti-trk antibody was prepared against a peptide corresponding to the 14 amino acids at the carboxyl terminus of trk (Martin-Zanca et al., Mol.Cell. Biol. 9: 24-33, 1989). Immune complexes were harvested on the Protein A Sepharose beads (Sigma Cehm Co., St. Louis, MO), separated by SDS polyacrylamide gel electrophoresis (SDS-PAGE) and transferred to a polyvinylidene difluoride membrane. (PVDF). The membranes were immunoblotted with anti-phosphotyrosine antibody (UBI), followed by incubation with goat anti-mouse IgG coupled to horseradish peroxidase (Bio-Rad Laboratories, Hercules, CA). The phosphorylated proteins were visualized using ECL (Amersham Life Science, ln., Arlington Heíghts, I L). The area of the trk protein band was measured and compared with NGF-stimulated control. The inhibition rating system used, based on the percentage of decrease in the trk protein band, was as follows: 0 = no decrease; 1 = 1 -25%; 2 = 26-49%; 3 = 50-75%; 4 = 76-100%. The results are shown below in Table 2.

Table 2 Effects of cyclic substituted fused pyrrolocarbazoles and isoindolones on the phosphorylation of NGF-stimulated trka in NIH3T3 cells EXAMPLE 3 Inhibition of vascular endothelial growth factor receptor kinase activity Fused pyrrolocarbazole and fused isoindolone cyclic compounds were examined for their inhibitory effects on the kinase activity of the VEGF receptor kinase domain expressed by baculovirus (human flk-1), KDR, VEGFR2,) using the procedure described for the ELISA assay of trkA kinase described above. The kinase reaction mixture, consisting of 50 mM Hepes, pH 7.4, 40 μM ATP, 10 mM MnCl 2, 0.1% BSA, 2% DMSO and various concentrations of inhibitor, was transferred to plates coated with PLC-γ / GST. VEGFR kinase was added and the reaction was allowed to proceed for 15 min at 37 ° C. The detection of phosphorylated product was achieved by the addition of anti-phosphotyrosine antibody (UBI). A conjugated antibody was delivered with secondary enzyme to capture the phosphorylated PLC-α / GST-antibody complex. The activity of the bound enzyme was measured via an amplified detection system (Gibco-BRL). The inhibition data were analyzed using the sigmoidal dose response equation (variable slope) in GraphPad Prism. The results are summarized in Table 3.

Table 3 bitory effects of cyclic substituted fused pyrrolocarbazoles and isoindolones on the activity of VEGF receptor kinase twenty Example 4 bition of protein kinase C activity Protein kinase C activity was assessed using the Millipore Multiscreen TCA "plate" assay as described in Pitt, A.M. and Lee, C. (J. Biomol. Screening, 1: 47-51, 1996). The tests were carried out in I0 96-well Mulstiscreen-DP plates (Millipore). Each 40 ml of assay mixture contained 20 mM Hepes, pH 7.4, 10 mM MgCl2, 2.5 mM EGTA, 2.5 mM CaCl2, 80 mg / ml phosphatidyl serine, 3.2 mg / ml diolein, 200 mg / ml histamine H- 1 (Fluka), 5 mM [? -32P] ATP, 1.5 ng of protein kinase C (UBI, mixed isozymes of a, b, g), 0.1% BSA, 2% DMSO and fused substituted pyrrolocarbazole cyclic test compound. The reaction was allowed to proceed for 10 min at 37 ° C, then it was quenched by adding ice cold 50% trichloroacetic acid. The plates were allowed to equilibrate for 30 min at 4 ° C, then washed with 25% ice-cold TCA. The scintillation cocktail was added to the plates and the radioactivity was determined using the Wallas MicroBeta 1450 PLUS scintillation counter. The IC50 values were calculated by fitting the data to the sigmoidal dose response equation (variable slope) in GraphPad Prism. The results are summarized in Table 4.

Table 4 bitory effects of cyclic substituted fused pyrrolocarbazoles and isoindolones on protein kinase C activity Example 5 bition of platelet-derived growth factor receptor kinase activity Fused pyrrolocarbazole and cyclic substituted fused isomdolone compounds were examined for their bitory effects on the anasa domain activity of baculovirus expressed PDGFβ receptor, using the ELISA of trkA anasa described above The assays were performed on 96-well microtitre plates, coated with substrate (PLC -? / GST) Each 100 μl of reaction mixture contained 50 mM HEPES, pH 74, 20 μM ATP, 10 mM MnCl2, 01 % BSA, 2% DMSO and various concentrations of bitor The reaction was initiated by the addition of recombinant prefosphophedylated human enzyme (10 ng / ml of PDGFRβ) and the pre-phosphoproteced enzyme was allowed to proceed for 15 minutes at 37 ° C. used by incubation of the anasa in buffer containing 20 μM ATP and 10 mM MnCl2 for 1 hour at 4 ° C the detection of phospho-product was made after addition anti-phosphotyrosm antibody conjugated with horseradish peroxidase (HRP) (UBI) The substrate solution of HRP containing 33 55'-tetramet? lbenc? d? na and hydrogen peroxide was subsequently added and the plates were incubated for 10 min. minutes at room temperature. The reaction was quenched with acid and the resulting absorbance was read at 450 nm using a Microplate Bio-Kinetics reader (Bio-Teck I nstrument EL 31 2e). The bition data were analyzed using the sigmoid dose response equation (variable slope) in G raph Pad Prism. The results are summarized in Table 5.

Table 5 bitory effects of pyrrolocarbazoles PDGFRß and cyclic substituted fused isoindolones Example 6 I nstallation of Spinal Cord ChAT Activity As discussed earlier, ChAT is a specific biochemical marker for functional cholinergic neurons. Cholinergic neurons represent a major cholinergic entry in the hippocampal formation, olfactory nucleus, interpeduncular nucleus, cortex, amygdala, and parts of the thalamus. In the spinal cord, motor neurons are inert neurons, which contain ChAT (Phelps et al., J, Comp.Neurol. 273: 459-472 (1988)). The activity of ChAT has been used to study the effects of neurotrophins (for example, NGF or NT-3) on the survival and / or function of cholinergic neurons. The ChAT assay also serves as an indication of the regulation of ChAT levels within cholinergic neurons. The fused substituted pyrrolocarbazole and isoindolone cyclic compounds increased ChAT activity in the dissociated rat embryonic spinal cord culture assay (Table 6). For example, in these tests, a compound was added directly to a distally divided spinal cord. The compounds with which the ChAT activity increased at least 1 20% of the control activity were considered active. The results are summarized in Table 6.

Table 6 Intensification of Spinal Cord ChAT Activity by Cyclic Substituted Fused Isocyanol and Rifolocarbazoles Methods: Fetal rat spinal cord cells were dissociated and experiments were performed as described (Smith et al., J. Cell Biology 101: 1608-1621 (1985); Glicksman et al., J. Neurochem. 61: 210- 221 (1993)). Dissociated cells from spinal cord dissected from rats (embryonic day 14-15) were prepared by standard tripisine dissociation techniques (Smith et al., Supra). Cells were plated at 6 x 10 5 cells / cm 2 in plastic tissue culture wells coated with poly-l-ornithine in serum free N 2 medium supplemented with 0.05% bovine serum albumin (BSA) (Bottenstein et al., PNAS USA 76: 514-517 (1979)). The cultures were incubated at 37 ° C in a humidified atmosphere of 5% CO2 / 95% air for 48 hours. The activity of ChAT was measured after 2 days in vitro using a modification of the Fonnum procedure (Fonnum, J. Neurochem, 24: 407-409 (1975)) according to McManaman et al. and Glicksman et al. (McManaman et al., Developmental Biology 125: 311-320 (1988); Glicksman et al., J. Neurochem., Supra). The compounds of Formula II described in the examples are listed in Tables 7 and 8. In Table 7, the values for R1, R4 and R6 are H; Q is NH (except for compounds II-68 and II-69, where Q is NC (= O) NHEt) and G is a bond. In Table 8, R1, R4, R5, R6 and R8 are H, W is CH2, m is equal to 0 and G is CH2. Compounds 11-64 to II-67 are described in Table 9. In Table 9, R1, R3, R4, R5 and R6 are H; A1.A2 is H, H; and B1, B2 is O. or a 20 Table 8 fifteen twenty oo fifteen twenty Table 9 General description of the synthetic processes and examples The general synthetic route used to prepare the cyclic substituted fused pyrrolocarbazoles of this invention is shown in Figs. 2 to 12. The general procedures for synthesis of the fused pyrrolocarbazoles (3) / (47) can performed as described in U.S. Pat. 5, 705, 51 1 and U.S. Patent No. 4, 923, 986, the descriptions of which are incorporated herein by reference in their entirety. When R1 is H, the lactam nitrogen of the fused pyrrolocarbazoles (3) 1 (47) is protected with an appropriate protecting group which leads to (4) 1 (48). The protected compounds are treated with an appropriate base in anhydrous organic solvent (s), which results in the generation of a dark red solution, which is believed to be carbanion. The reaction of the carbanion with a reagent containing an electrophilic C = Y bond provides either a cyclic substituent directly (as shown in Figures 2, 5, 7, 12, 15 and 17), or an acyclically formed derivative initially ( 6), (14), (53) or (60), which is subsequently converted to a cyclic substituent (as shown in Figures 3, 4, 13 and 14). An appropriately substituted, preformed cyclic derivative can be used either as a nucleophile (as shown in Figures 6 and 16), or as an electrophile (as shown in Figures 8 and 18). The cyclic substituents can be formed from an olefinic group, as shown in Figures 9 and 1 9. Either an acid or base catalyzed process is used to perform the lactam nitrogen protection strategy (shown in the Figures). 1, 1 0 and 1 1). The acid catalyzed reaction can be carried out with a resin-bound reagent, which allows immobilization of the pyrrolocarbazole (47) to a polymer support, such as a Rink acid resin, based on polystyrene (Figure 11), which provides (50) ). Alternatively, the acid-catalyzed reaction can be carried out with a soluble reagent, for example, 4,4'-dimethoxybenzhydrol to produce a compound (49) (Figure 11). The silyl protected compound (51) is produced under base catalysis (Figure 11). The reaction of the carbanion derived from (4) 1 (48) with a ketone / aldehyde? -functionalized, [figure 2/12], provides an acyclical intermediary (6) 1 (53). The closure of the ring to provide (Z) / (5) normally occurs in situ when the cyclization leads to a product of 5 members (and occasionally to one of 6 members) and when the group Z is an ester or a halide, such as chloride or bromide. For cases when ring closure leads to a cyclic product of six or more members, the initially isolated acyclic derivative (6) 1 (53) is subsequently treated with a base that provides the cyclic product, (L) / (54) . The acyclic intermediates (6) 1 (53), derived from the reaction with an aldehyde, on oxidation, provide an intermediate of ketone (9) 1 (56). When the group Z is another carbonyl containing group (eg, a tertiary amide), the reaction with a hydrazine (or urea) leads to the formation of heterocyclic derivatives, such as dihydro-pyrazole, pyrazole, pyridazinone, pyridazine dione or phthalazine diona, etc. (or dihydro-pyrimidone / dione, pyrimidone / dione and / or homologs, etc.). However, when the group Z is an olefin (or an ethylenic group), the reaction of the keto-intermediary (9) / (56), with an N-alkyl hydroxylamine, provides a nitrone, which subsequently leads to a product cyclic derivative of an intramolecular dipolar cycloaddition reaction (Fig. 371 3). The secondary alcohol (14) 1 (60), produced from the reaction with aldehyde (13), is oxidized to the ketone (15) 1 (61), which in turn is converted to the corresponding nitrone (16) 1 (62) (Figure 4/14) The reaction of this nitrone with an olefinic or acetylenic compound provides a cyclic derivative (17) 1 (63) The mono- or dialkylation of the ammonium derivative (s) derived from (4) 1 (48) , provide fused pyrrolocarbazole containing olefin (41) 1 (79) or (44) 1 (82), respectively (Figure 9/1 9) The group C = C (olefin) is subsequently converted to a cyclic derivative via a reaction of analogous dipolar cycloaddition analogously with a mtphoxide, n itrona or azide A cyclic group A directly linked to the carbazole nucleus is obtained (Figures 7/1 7) by reaction of carbanion derived from (I) l (48) with reagents highly electrophilic, such as, N-acyl pipdinium compounds (30) [or pipdma N-oxide] Dihydro derivatives (31) / ( 71) or (32) 1 (72) are converted to either the corresponding saturated cyclic analogues (35) or (36) 1 (75) or (76), or are aromatized to the corresponding heterocyclic derivatives (33) or (34) ) 1 (73) or (74) In a similar manner, the reaction of (4) 1 (48) with a cyclic myrone (37) gives the saturated heterocyclic derivatives (38) 1 (77) The cyclic substituents are obtained by reaction of the carban ion derived from (4) 1 (48) with a cyclic ketone (18) (Figures 5/15), which may optionally contain a wide variety of functional groups (see examples section). Otherwise, the reaction of the carban ion derived from (4) 1 (48) with an epoxide, oxirane or an azipdma (Figures 5/15) produce cyclic substituents represented by [21) 1 (65) Carbanion derived from (4) 1 (48) also reacts with highly activated acyl derivatives (22) (Figures 5715) to provide cyclic derivatives (23) 1 (66) If the EWG in these products (23) 1 (66) is a function of ter, further reaction with a hydrazine (or urea) leads to the formation of heterocyclic derivatives, such as, dihydro-pyrazole, pyrazole, pipdazinone, pipdazine dione, phthalazine dione, etc. (or dihydro-pipmidone, dihydro-pipmidone idona, ppmidone / dione, or homologs, etc.) The cyclic substituents are obtained by additional derivatization of the key aldehyde intermediate (90) 1 (99), either with (i) a difunctional reagent (91), such as amino-alcohol, ammo -diol diol, dithioles or diammas [(path (a) in Figures (20/21)], or (n) via Diels-Alder reaction with a diene (93), as shown by path (b) in the Figure (20/21) These cyclic substituents may optionally contain a wide variety of functional groups, either present in the difunctional reagent (91) or the diene, or alternatively, by further operation of the olefam group present in (94) 1 (101) to provide (95) 1 (102) Finally, a cyclic substituent is introduced by coupling an alkylating agent carrying an appropriately substituted cyclic group (Figure 8/18) with the carbanion derived from (4) 1 (48) When Q = NH, this reaction is facilitated by the presence of a tertiary amine base , an inorganic base, such as alkali metal carbonate, alkali metal alkoxide, alkali metal hydride or by the use of an alkyl lithium or a Gpgnard base In a majority of the approaches described above for the preparation of fused pyrrolocarbazole containing substituents cyclic, the carbanion derived from (4) 1 (48) is used. Meanwhile, as described in Figures 20 and 21, it is the nucleophile of nitrogen that is used for functionalization to provide pyrrolocarbazole. used containing cyclic substituents. However, a route where the fused pyrrolocarbazole (4) 1 (48) serves as an electrophile is indicated in Figure 6/16. The methylene group of the fused pyrrolocarbazole (4) 1 (48) is oxidized to provide an electrophilic ketone [25) 1 (68). The addition of the anion (27) derived from a cyclic reagent (26) to the C = O of (25) 1 (68), provides a substituted cyclic product (29) 1 (69), which also contains a hydroxyl group in the position benzyl, as shown. This hydroxyl group is replaced by H, F, SR, OR or NRR '. Additionally, when Q = NH and W is a cyclic substituent, as described above, these analogs can be treated with an appropriately functionalized isocyanate, to provide fused pyrrolocarbazoles containing cyclic substituents, where Q = NC (= O) NHR '. The examples below provide the synthesis of a representative set of specific compounds, using the general procedures described above.

Example 7 Preparation of Rink Resin Attached Intermediates (50a), (50b) and (50c) (Figure 11) Example 7A A three-necked round bottom flask equipped with an overhead mechanical stirrer and a Dean-Stark trap was loaded sequentially with a Rink acid resin (51b, R '= OMe, R "= polymer) (10.00 g, 0.64 mmol / g), 1-methyl-2-pyrrolidioneone (80 ml), benzene (350 ml), ( 47a) [A1, A2 = H2, B1, B2 = O, R3 = R4 = R5 = R6 = H, Q = NH] (3.00 g) and p-toluenesulfonic acid (1.00 g) The reaction mixture was heated to reflux for 20 hours, cooled and filtered.The resin was washed with THF (5 x 175 ml) and the filtrate was left aside.The resin was then washed sequentially with DMSO (4 x 100 ml), 2% aqueous NaHCO3. (4 x 100 ml), water (4 x 100 ml), DMSO (2 x 200 ml), THF (4 x 100 ml) and ethyl acetate (4 x 100 ml) The resin was dried under vacuum (24 hours) ) to give 11.70 g (0.47 mmol / g) of resin (50a)) [A1, A2 = H2, B1, B2 = O, R3 = R4 = 45 = R6 = H)]. The original THF washes After evaporation, the residue was diluted with water (750 ml) and the resulting precipitate was filtered and washed sequentially with water, 2% aqueous NaHCO2 (4 x 100 ml) and water (4 x 100 ml). After drying under vacuum, 1.28 g of (47a) was recovered.

Example 7B In a similar manner, (47b) [A1, AB = H2, B1, B2 = O, R3 = R4 = R5 = H, R6 = 10-OMe, Q = NH], (1.02 g) was coupled to the Rink acid resin (51b) (3.12 g) to give 3.70 g (0.46 mmol / g) of compound bound to the resin, (50b), together with recovered starting material (47b) (0.44 g).

Example 7C In a similar manner, (47c) [A1, A2 = O, B1, B2 = H2, RE = R4 = R5 = R7 = H, Q = NH], (0.5 g) was coupled to the acid resin of Rink (51b) (1.52 g) to give the resin bound compound, (50c), (1.58 g).

Example 7D Preparation of intermediate (49a) (Figure 11) A three-necked round bottom flask equipped with an overhead mechanical stirrer and a Dean-Stark trap was charged sequentially with DMB-OH (5 a) (2.44 g, 10 mmol) ), 1-methyl-2-pyrrolidone (30 ml), benzene (270 ml), (47a) (3.10 g, 10 mmol) and p-toluenesulfonic acid (1.90 g, 10 mmol). The reaction mixture was heated to reflux. After 2 h, the reaction mixture becomes homogeneous, and the heating is continued for another 2 h. The reaction mixture was cooled to room temperature, diluted with EtOAc (200 ml), washed with saturated aqueous NaHCO3 solution (4 x 100 ml), water (4 x 100 ml) and the organic layer was dried over anhydrous MgSO4. , it was filtered and concentrated in vacuo. The residue was triturated with EtOAc / hexane and the resulting solid was filtered and dried under high vacuum to give (49a) [A1, A2 = H2, B1, B2 = O, R3 = R4 = R5 = R6 = H, Q = NH, R '= R "= H], (5.2 g, 98%).

Example 8 General synthesis of cyclic derivatives by solid phase chemistry (SPS). To a suspension of (50a) or (50b) or (50c) (50 mg) in THF (2 ml) was added a 1.0 M solution of EtMgBr (1.0 ml in THF) and the reaction was stirred for 1 h before the reaction. addition of HMPA (0.5 ml). After stirring for 10 min, the electrophile (for example, aldehyde, ketone, epoxide, etc.) (-10-15 mmoles) was added and the reaction was stirred for 20 h. The reaction was quenched with 10% aqueous NH CI (5 mL) and filtered. The resin was washed successively with 10% aqueous NH4CI (3 x 10 ml), water (3 x 10 ml), THF (3 x 10 ml), DMF (3 x 10 ml), water (3 x 10 ml), THF (3 x 10 ml) and ether (3 x 10 ml). The resin was dried under vacuum, taken up in methylene chloride (15 ml) and treated with trifluoroacetic acid (0.15 ml). After stirring for 1 h, the reaction was filtered and the filtrate was evaporated. The resulting residue was analyzed by analytical HPLC (see description of methods below) and those samples less than 80% pure were purified by preparative HPLC (Zorbax RX-8, 4 x 25 cm, levigated with MeCN / water containing 0.1% acid trifluoroacetic, gradient). The appropriate fractions were neutralized with NaHCO3 and extracted into methylene chloride (3 x 50 ml) and dried over MgSO4. The desired compounds were obtained after filtration and evaporation of solvent.

Analytical HPLC methods: Method A: Column: Analytical RX-C8 Zorbax, 4.6 mm x 250 mm. Conditions: 10% MeCN - > 100% MeCN (p / 0.1% TFA) over 40 minutes. Method B: Column: Vydac analytical C8, 4.6 mm x 150 mm '. Conditions: 35% MeCN - 60% MeCN (p / 0.1% TFA) over 20 minutes. letodo C Analytical RX-C8 column Zorbax, 46 mm x 150 mm Conditions 10% MeCN • »100% MeCN (p / 01% TFA) over 20 minutes letodo D Analytical RX-C8 column Zorbax, 46 mm x 250 mm 10% MeCN conditions - > 100% MeCN (p / 01% TFA) over 40 minutes Example 9 Preparation of compound 11-01 a A solution of (47a) (202 g, 65 mmol) in DMF (200 ml) was heated (oil bath at 155 ° C) under vacuum and the solvent was reduced by distillation (-70 ml) After cooling to room temperature, the nitrogen was bled in the system and the distillation head was replaced with a septum and bubbler. N 2 Sodium hydride (274 mg, 8 15 mmol of a 60% dispersion in mineral oil) was added in one portion and the reaction was then heated to 55 ° C and stirred for 1 h Then added (+/-) glycidyl mesylate (1 69 g, 815 mmol) and the reaction was stirred for an additional 15 h at 55 ° C. The oil bath was stirred and the reaction was stirred at room temperature for 24 h. The crude mixture was filtered and the liquor The mother was concentrated and triturated with diethyl ether / methanol. The solid was collected by filtration and washed with water and dried to give the desired product 11-01 a as a pale green solid (1.7 g, 462 mmol, 71%), which had the following spectral properties 300 MHz 1H NMR (DMSO d6) d 950 (d, 1), 858 (s, 1), 801 (d, 1) 774 (d, 1), 768 (d, 1), 750 (dd, 1), 744-731 (m, 3), 518 (m, 1), 495 (s, 2), 4.74 (dd, 1), 4.50 (s, 2), 3.53 (m, 1H), 2.8 (t, 1), 2.48 (m, 1H); ESI MS caled for C 24 H 18 N 2 O 2 (M + H) 367.44, found 367.14.

Example 10 Preparation of compound 11-01 b A solution of (47a) (320 g, 1.1 mmol) in DMF (35 ml) was heated (oil bath at 155 ° C) under vacuum and the solvent was reduced by distillation (-15 ml). After cooling to room temperature, the nitrogen was bled in the system and the distillation head was replaced with a N2 septum and sparger. Sodium hydride (49 mg, I 1 mmol of a 60% dispersion in mineral oil) in one portion and the reaction was stirred for 1 h at room temperature. Then 2-R (-) glycidyl tosylate (283 g, 1.24 mmol) was added and the reaction was stirred an additional 18 h at 60 ° C. The oil bath was removed and the reaction was stirred at room temperature for 4 h. The crude mixture was dried, triturated with diethyl ether / methanol and then taken up in THF and filtered. The THF filtrate was concentrated and the resulting solid was triturated with diethyl ether / methanol and dried to give the desired product 11 -01 b (155 mg, 042 mmol, 37%) as a greenish solid. Concentration and additional crushing of the mother liquor provided an additional amount of the product I I -01 b (90 mg). The product 11-01 b had the following spectral properties: 300 MHz 1 H NMR (DMSO dβ) d 9.50 (d, 1), 8.58 (s, 1), 8.01 (d, 1), 774 (d, 1), 7.68 (d, 1), 75.0 (dd, 1), 7.44-7.31 (m, 3), 5.18 (m, 1), 4.95 (s, 2), 474 (dd, 1), 4.50 (s, 2), 3.53 (m, 1), 2.8 (t, 1), 2.48 (m, 1).

Example 11 Preparation of compound 11-01 c This compound was prepared using the same procedure as II-01 b using (47a) (300 mg, 0.97 mmol), NaH (46 mg, 0.97 mmol) and 2-S (+) - glycidyl tosylate (265 mg, 1.2 mmol) in DMF (10 ml). The desired product was obtained (277 mg, 0.76 mmol, 78%), which had the following spectral properties: 300 MHz 1 H NMR (DMSO d 6) d 9.50 (d, 1), 8.60 (s, 1), 8.02 (d , 1), 7.78 (d, 1), 7.68 (d, 1), 7.53 (t, 1), 7.44-7.38 (m, 3), 5.20 (m, 1), 4.95 (s, 2), 4.74 ( dd, 1), 4.50 (s, 2), 3.53 (m, 1H), 2.8 (t, 1), 2.48 (m, 1H).

Example 12 Preparation of compound 11 -02 Following the general SPS procedure as described in Example 8, (50a) (50 mg) was reacted with l-benzyl-4-piperidone to provide 9 mg of the desired compound, which had the following physical properties: HPLC: R, = 21.36 min. (Method D). MS: 500 (M + H). 1H NMR (DMSOd6): d 11.13 (s, 1H), 9.40 (d, J = 7.57 Hz, 1H), 8.57 (s, 1H), 7.95 (d, J = 7.81 Hz, 1H), 7.6-7.11 (series of m, 11H), 4.90 (s, 2H), 4.88 (s, 1H), 4.49 (s br, 2H), 3.66-1.03 (series of m, 8H).

Example 13 Preparation of compound 11 -03 Following the general SPS procedure as described in Example 8, (50a) (50 mg) was reacted with tetrahydro-4H-pyranone to provide 11 mg of the desired compound, which had the following physical properties HPLC Rt = 2385 min (Method D) MS 411 (M + H) 1H NMR (DMSOd6) d 11 07 (s, 1H), 942 (d, J = 759 Hz, 1H), 852 (s, 1H ), 79-722 (series of m, 7H), 489 (s, 2H), 439 (s, 1H), 36-083 (series of m, 8H) Example 14 Preparation of compound II-04 Following the general SPS procedure as described in Example 8, (50a) (50 mg) was reacted with 5-chloro-penan-2-one to provide 10 mg of the desired compound as a set of diastereomers, which had the following physical properties HPLC Rt = 321 min and 330 min (Method A) MS 395 (M + H) Example 15 Preparation of compound 11 -05 Following the general SPS procedure as described in Example 8, (50a) (50 mg) was reacted with methyl 2-keto-hexonoate [which was prepared according to a procedure of literature by EJ Corey, et al, Tett Letters, 1985, 3919-22], to provide 6 mg of the desired compound as a set of diastereomers, which had the following physical properties HPLC R, = 255 mm and 260 mm (Method A) MS 409 (M + H), 431 (M + Na) EXAMPLE 16 PREPARATION OF COMPOUND 11-06 Following the general SPS procedure as described in Example 8, (50a) (50 mg) was reacted with methyl 2-keto-pentanoate [which was prepared in accordance with a literature procedure by C. Hershburg, Org. Syn. , 1955, 627], to provide 6 mg of the desired compound as a set of diastereomers, which had the following physical properties: HPLC: Rt = 24.1 min and 25.6 min. (Method A). MS: 395 (M + H).

Example 1 Preparation of compound II-07 Following the general SPS procedure as described in Example 8, (50a) (50 mg) was reacted with 4-chloro-butyraldehyde [which was prepared in accordance with a literature procedure of ME Kuehene et al. , J. Org. Chem. 1 981, 46, 2002-09], to provide 6.9 mg of the desired compound as a set of diastereomers, which had the following physical properties: H PLC: Rt = 28.6 min and 30.0 min. (Method A). MS: 381 (M + H).

Example 18 Preparation of compound II-08 Following the general SPS procedure as described in Example 8, (50a) (50 mg) was reacted with 4-chloro-4'-fluorobutyrophenone to provide 0.1 mg of the desired compound as a set of diastereomers, which had the following physical properties HPLC R, = 328 min and 350 min (Method A) MS 475 (M + H) Example 19 Preparation of compound II-09 Following the general SPS procedure as described in Example 8, (50a) (50 mg) was reacted with 4-chloro- (2-t? Of? N? L) but? ronona to provide 76 mg of the desired compound as a set of diastereomers, which had the following physical properties HPLC R, = 31 5 min and 348 min (Method A) MS 463 (M + H) Example 20 Preparation of compound 11-10 Following the general SPS procedure as described in Example 8, (50a) (50 mg) was reacted with 1-met? L-4-p? Per? Dona to provide 6 mg of the desired compound as a set of diastereomers, which had the following physical and spectral HPLC properties R, = 1666 min (Method D) MS 424 (M + H) 1HNMR (DMSOd6) d 11 16 (s, 1H), 945 (d, J = 773 Hz, 1H), 862 (s, 1H), 801 ( d, J = 762 Hz, 1H), 77-725 (sene of m, 6H), 494 (s, 2H), 454 (s, 1H), 38-1 9 (syne of m, 11H) Example 21 Preparation of compound 11-11 Following the general SPS procedure as described in Example 8, (50a) (50 mg) was reacted with 3,4-epoxy-tetrahydrothiophene to provide 7 mg of the desired compound as a whole of diastereomers, which had the following physical and spectral properties: HPLC: Rt (major diastereomer) = 27.19 min, Rt (minor diastereomer) = 27.34 min. (Method D). Diastereomeric ratio: -60: 40. MS: 413 (M + H). 1HNMR (DMSO dβ) d 11.21 and 11.1 (2s, 1H), 9.43 (m, 1H), 8.55 (2s, 1H), 7.96-7.11 (series of m, 7H), 4.89 (s, 2H), 4.67 (s) , 1H), 3.00-1.3 (series of m, 6H).

Example 22 Preparation of compound 11-12 Following the general SPS procedure as described in Example 8, (50a) (50 mg) was reacted with 6-bromo-hexan-2-one [which was prepared in accordance with a literature procedure by Flannery et al., J. Org. Chem. 1972, 37, 2803], and the crude product was purified by preparative TLC, to provide 2.5 mg of the desired compound as a set of diastereomers, which had the following physical properties: HPLC: Rt = 33.9 min and 34.1 min. (Method A). MS: 409 (M + H).

Example 23 Preparation of compound 11-13 Following the general SPS procedure as described in Example 8, (50a) (50 mg) was reacted with 5-bromo-pentan-1-al [which was prepared in accordance with a literature procedure of ME Kuehene et al. J. Org. Chem. 1981, 46, 2002-09], to provide 8.8 mg of the desired compound as a set of diastereomers, which had the following physical properties: HPLC: Rt = 31.3 min and 35.4 min. (Method A). MS: 395 (M + H).

Example 24 Preparation of compound 11-14 Following the general SPS procedure as described in Example 8, (50a) (50 mg) was reacted with tetrahydrothiopyran-4-one to provide 8.8 mg of the desired compound, which had the following physical properties: HPLC: Rt = 28.21 min. (Method D). MS: 427 (M + H).

Example 25 Preparation of compound 11-15 Following the general SPS procedure as described in Example 8, (50a) (50 mg) was reacted with β-tetralone to provide 8 mg of the desired compound as a set of diastereomers, the which had the following physical properties: HPLC: Rt (major diastereomer) = 32.83 min and Rt (minor diastereomer) = 32.38 min. (Method D). Diastereomeric ratio -55: 45. MS: 457 (M + H).

Example 26 Preparation of compound 11-16 Following the general SPS procedure as described in Example 8, (50a) (50 mg) was reacted with 1-ethyl-3-piperidone to provide 8 mg of the desired compound as a whole of diastereomers, which had the following physical and spectral properties: HPLC: Rt (major diastereomer) = 18.36 min, Rt (minor diastereomer) = 17.83 min. (Method D). Diastereomeric proportion: 57:43. MS: 438 (M + H). 1HNMR (DMSO d6): d 11.32 and 11.16 (s, 1H), 9.46 (m, 1H), 8.7 (m, 1H), 8.01 (d, J = 7.71 Hz, 1H), 7.78-7.25 (series of m, 6H), 4.95 (overlapping s, 2H), 4.60 and 4.57 (2s, 1H), 3.8-0.8 (series of m, 13H).

Example 27 Preparation of compound 11-17 Following the general SPS procedure as described in Example 8, (50a) (50 mg) was reacted with 2- (N-morpholinomethyl) cyclopentanone to provide 8 mg of the desired compound as a set of diastereomers, which had the following physical and spectral properties: HPLC: R, ( major diastereomer) = 18.37 min, R, (minor diastereomer) = 19.81 min. (Method D). Diastereomeric ratio: 80: 20. MS: 494 (M + H). 1HNMR (highest, DMSO d6): d 11.07 (s, 1H), 9.44 (d, J = 7.63 Hz, 1H), 8.59 (s, 1H), 7.99-7.09 (series of m, 7H), 4.93 (s, 2H), 4.68 (s, 1H), 4.0-1.1 (series of m, 17H).

Example 28 Preparation of Compound 11-18 Following the general SPS procedure as described in Example 8, (50a) (50 mg) was reacted with cyclobutanone to provide 6 mg of the desired compound, which had the following physical properties and HPLC spectra Rt = 2742 min (Method D) MS 381 (M + H) HNMR (DMSO d6) d 11 07 (s, 1H), 943 (dJ = 768 Hz, 1H), 852 (s, 1H), 793 (d, J = 778 Hz, 1H), 779 (d, J = 744 Hz, 1H), 767 (d, J = 808 Hz, 1H), 74-714 (m, 4H), 489 (s, 2H) ), 436 (s, 1H), 27-08 (sene of m, 6H) Example 29 Preparation of compound 11-19 Following the general SPS procedure as described in Example 8, (50a) (50 mg) was reacted with 1,7-d? Chloro heptan-4-one to provide 76 mg of the desired compound as a set of diastereomers, which had the following physical properties HPLC Rt = 340 min and 353 min (Method A) MS 457/459 (M + H) Example 30 Preparation of compound 11 -20 and 11 -32 Following the general SPS procedure as described in Example 8, (50a) (50 mg) was reacted with 5-chloro- (1-p? Val?) -pentan-2-one [which was prepared according to a literature method of P Knochel et al. J Org Chem 1993, 58, 588-99] and the crude product was triturated with acetomtplo, to provide 53 mg of the desired compound as a set of diastereomers, which had the following physical properties HPLC Rt = 344 mm and 359 min (Method A) MS 495 (M + H) Acetonitopher mother liquor was purified via chromatography (reverse phase C-8 column) with 60% MeCN-40% water containing 01% TFA, to provide 11 -32 (R18 = Et) Example 31 Preparation of compound 11-21 A solution of product 11-20 (20 mg) in THF (2 ml) was treated with a solution of L? BH4 in THF (05 ml, 2M solution) at room temperature for 30 min. The reaction mixture was quenched with 1N HCl (2 mL), EtOAc was added and the reaction mixture was stirred for 1 h. The reaction mixture was neutralized with aqueous NaHCO3 solution, and the organic phase was separated, washed with brine, dried over anhydrous Na2SO and concentrated in vacuo. The residue was taken up in toluene with minimal amounts of THF to provide a clear solution, which was filtered through a silica cushion and levigated with 50% THF-toluene and evaporated to provide anhydrous. -21 as a mixture of diastereomers, which had the following physical properties HPLC Rt = 249 mm and 267 mm (Method A) MS 411 (M + H) Example 32 Preparation of compound 11-22 To a solution of alcohol 11-21 (5 mg) in CH 2 Cl 2 (2 ml) was added Et 3 N (15 μl), acetic anhydride (10 μl) and a crystal of N, N-dimethylaminopipdine The reaction mixture was stirred at room temperature for 30 min, quenched with aqueous NaHCO3 solution and extracted into EtOAc. The organic layer was washed with 1N HCl solution, brine and then dried over anhydrous MgSO. The concentrate in vacuo provided 11- 22 as a mixture of diastereomers, which had the following physical properties HPLC Rt = 292 min and 30 min (Method A) MS 453 (M + H) and 475 (M + Na) Example 33 Preparation of Compound 11-23 Following the general SPS procedure as described in Example 8, (50a) (50 mg) was reacted with dietoxy butyraldehyde [which was prepared according to a literature procedure of LA Paquette et al, Am Chem Soc, 1997, 119, 9662], to provide 62 mg of the desired compound, which had the following physical properties HPLC R, = 232 min (Method A) MS 397 (M + H) Example 34 Preparation of compound 11-24 Following the general SPS procedure as described in Example 8, (50a) (50 mg) was reacted with 1-acetl-4-p-rpepdone to provide 6 mg of the compound desired, which had the following physical and spectral properties HPLC Rt = 21 06 min (Method D) MS 452 (M + H) 1HNMR (DMSO dβ) d 11 06 (2s, 1H), 941 (d, J = 753 Hz , 1H), 853 (s, 1H), 794 (d, J = 759 Hz, 1H), 77-71 one sene of m, 7H), 489 (s, 2H) 45-05 (one sene of sym, 12H ) Example 35 Preparation of compound 11-25 To a solution of ethyl vinyl ether (30 ml) in THF (14 ml) at -78 ° C under argon atmosphere, ter-BuLi (120 ml, 1 7M in pentane) was added. The reaction mixture was heated at -40 ° C for 10 min, then at room temperature for 5 min, cooled again to -78 ° C and added to a suspension of CuBr DMS (205 g) in THF (7 ml) maintained at -40 ° C After 30 min, 1,3-dichloroisobutene (30 ml) was rapidly added and the reaction was allowed to warm gradually to room temperature and was stirred for 4 h. The reaction mixture was quenched with sodium chloride solution. NH CI 10%. This mixture was filtered and the solid was washed with ether. The organic layer was washed with aqueous NaHCO3 solution, brine and dried over MgSO4 and concentrated in vacuo. The residue was taken up in methanol (15 ml) and concentrated in vacuo. treated with HCl (04 ml) When starting material was not evident by TLC, the solvent was removed in vacuo, the residue was treated with aqueous NaHCO3 and the mixture was extracted with ether (3 x 30 ml) The ether layer was washed with brine and dried over anhydrous MgSO4 and concentrated in vacuo Residual material was purified on silica gel and eluted with 20% of EtOAc in hexane to produce 3-acet? l-4-chloro-? -butene Following the general SPS procedure as described in Example 8, (50a) (50 mg) was reacted with 3-acetyl-4-chloroisobutene (as described above), to provide 215 mg of the desired compound, which had the following physical properties HPLC Rt = 340 min and 349 min (Method A) MS 407 (M + H) Example 36 Preparation of compound II-26 A slurry of compound 11 -25 bound to ream (before cutting the product 11-25 with TFA) in THF (10 ml) was treated with OsO solution (100 μl of 01M solution in CCI4 ), N-methyl morpholine N-oxide (50 mg) and water (100 μl) After stirring overnight, the reaction mixture was quenched with 10% NH CI solution, the ream was washed and the product was resin free as described in Example 8, to produce compound 11-26 as a mixture of diastereomers, which had the following physical properties HPLC Rt = 200 min and 21 2 mm (Method A) MS 441 (M + H ) Example 37 Preparation of compound II-27 A portion of product II-26 (2 mg) was taken up in THF (4 ml) and treated with water (15 ml) and NalO 4 (50 mg) at room temperature during -16 h The reaction was quenched with aqueous NaHCO3 solution and extracted into EtOAc. The organic layer was dried over MgSO4, filtered and concentrated in vacuo to provide II-27 as a mixture of diastereomers, which had the following physical properties HPLC Rt = 273 min and 282 mm (Method A) MS 431 (M + Na) Example 38 Preparation of Compound 11-28 To a mixture of N, Od? Meth? Hydroxylamine hydrochloride (130 g) in CH2Cl2 (500 mL) at 0 ° C, Et3N (36 mL) and 5-chlorovaleral chloride were added. The reaction mixture was warmed to room temperature and stirred for 2 h. The reaction was quenched with aqueous NaHCO3 solution, washed with 1N HCl solution and brine. The organic layer was dried over anhydrous MgSO4, filtered, concentrated in vacuo. and the residue was distilled @ 01 mm Hg (78-81 ° C) To a solution of the amide (20 g) in THF (15 ml) at -78 ° C, a solution of magnesium vinyl bromide ( 17 ml, 1M solution), the mixture was heated at 0 ° C for 1 h and then stirred at room temperature for 30 mm. The reaction mixture was cooled back to 0 ° C and quenched with ice cold 1N HCl. The product was extracted with ether, dried over MgSO, filtered and concentrated to -8 ml volume Following the general SPS procedure as described in Example 8, (50a) (50 mg) was reacted with 6-chloro-3-hex-1-eneone ether solution to provide 52 mg of the desired compound II-28 as a mixture of diastereomers, which had the following physical properties HPLC Rt = 324 min and 356 min (Method A) MS 407 (M + H) Example 39 Preparation of compound 11-29 A suspension of compound 11-28 bound to resin during cutting of product 11-27 with TFA) in THF (10 ml) was treated with OsO4 solution (100 μl of 0.1M solution in CCI4) n-methyl morpholine N-oxide (50 mg) and water (100 μl). The reaction mixture was protected from light with aluminum foil and stirred overnight. The reaction mixture was quenched with 10% NH 4 Cl solution and the resin was washed and the product was freed from the resin as described in Example 8. The crude diol was purified via preparative thin layer chromatography (60% THF in toluene) to provide the product, II-29, which had the following physical properties: HPLC: R, = 21.6 min. (Method A). MS: 441 (M + H) and 463 (M + Na).

Example 40 Preparation of compounds ll-30a and ll-30b Compound (II-04) (two diastereomers) was purified as previously described and each diastereomer was isolated by preparative HPLC as described in the General Synthesis. A diastereomer had HPLC Rt = 32.1 min (Method A) and MS = 395 (M + H); and the other had an HPLC R, = 33.0 min. (Method A) and MS = 395 (M + H).

Example 41 Preparation of compound 11-31 Following the general SPS procedure as described in Example 8, (50a) (50 mg) was reacted with ethyl 5,7,9-trioxa-3-oxo decanoate [ which was prepared according to a literature procedure of O Kalmnkovick et al, Tett Lett, 1996, 10956], to provide 16 mg of lactones 11-31, as a mixture of diastereomers, which had the following physical properties HPLC Rt = 24 1 min and 252 min (Method A) MS 469 (M + H) and 491 (M + Na) Example 42 Preparation of compound II-33 A portion (10 mg) of the MOM-ether (11-31) was taken up in methanol (4 ml), treated with a few drops of 6N HCl solution and heated to 55 ° C. 2h The solvent was removed by rotary evaporation and the crude product was purified by TLC preparer with 50% THF / toluene to provide 1 mg of hydroxy lactones (II-33) as a mixture of diastereomers, which had the following physical properties HPLC R , = 196 min and 198 min (Method A) MS 425 (M + H) and 447 (M + Na) Example 43 Preparation of compound 11-34 A solution of pivalate 11-32 (5 mg) in THF (5 ml) was added to a solution of L? BH4 in THF (1 ml, 2M solution) and the reaction mixture was stirred. at room temperature for 5 h, quenched with 1N HCl (2 ml) and taken up in EtOAc The reaction mixture was neutralized with aqueous NaHCO3 solution, the organic phase was separated, washed with brine, dried over anhydrous Na2SO, filtered and concentrated in vacuo. The residue was taken up in toluene with minimal amounts of THF to provide a clear solution and purified by column chromatography on silica gel (eluted with 55% THF in toluene) to give 11-34 ( 334 mg), which had the following physical properties HPLC Rt = 253 min (Method A) MS 439 (M + H) Example 44 Preparation of compound 11-35 and 11-36 Following the general SPS procedure as described in Example 8, (50a) (500 mg) was reacted with 5-chloro- (1-p? Val?) -pentan-2-one [see the preparation of II-20, above] and the crude product was purified , the individual diastereomers were separated via semi-preparative HPLC (C-8 reverse phase column, levigated with 60% MeCN in water containing 01% TFA) The minor isomer (HPLC Rt = 337 min) and the major isomer ( HPLC R, = 3523 min) (Method A) MS 495 (M + H) A small amount of the analog of R18 = Et II-32 was also isolated (HPLC R, = 370 min) The minor isomer (37 mg) in THF (1 ml) was treated with a solution of L? BH4 (05 ml, 2M) and stirred at room temperature overnight The reaction mixture was extracted with EtOAc, the organic layer was washed with 1N NaOH solution, brine and dried over anhydrous MgSO Following filtration and solvent removal by rotary evaporation, alcohol 11-35 (24 mg) was isolated, which had the following physical properties HPLC R, = 252 min (Method A) MS 411 ( M + H) The major isomer (39.5 mg) in THF (2 μl) was treated with a solution of LiBH4 (2 ml, 2M) and stirred at room temperature overnight. The reaction mixture was extracted with EtOAc, the organic layer was washed with 1 N NaOH solution, brine and dried over anhydrous MgSO 4. Following filtration and solvent removal by rotary evaporation, alcohol 11 -36 (27.3 mg) was isolated, which had the following physical properties: H PLC: R, = 23.7 min (Method A). MS: 41 1 (M + H).

EXAMPLE 45 Preparation of Compound II-37 Following the general SPS procedure as described in Example 8, (50a) (25 mg) was reacted with 5-chloro-pentan-2-one to provide 2.3 mg of the desired compound as a mixture of diastereomers, which had the following physical properties: HPLC: R, = 32.2 and 33.2 min. (Method A). MS: 395 (M + H).

EXAMPLE 46 Preparation of Compound 11 -38 Following the general SPS procedure as described in Example 8, (50a) (50 mg) was reacted with diethoxybutyraldehyde [similar to the procedure described for II-23]. The crude product following the TFA treatment was purified by reverse phase column chromatography of C-8 and underwent hydrolysis on settling in the HPLC solvent [55% MeCN-45% water with 0.01% TFA]. The solvent was removed via rotary evaporation to provide a product, which had the following physical properties HPLC Rt = 223 min (Method A) MS 397 (M + H) Example 47 Preparation of compound 11-39 To a stirred suspension of (47a) (87 mg, 0280 mmol) in acetonitoplo (20 ml) at room temperature under nitrogen, 2-chloromethylcyclobutanone (399 mg, 0336 mmol) was added, followed by DBU (461 ml, 0308 mmol). The reaction mixture was refluxed for 42 h DMF was added to solubilize the reaction mixture, chloromethylcyclobutanone (1 eq) was added and the mixture was heated to reflux for 30 min. An additional 1 eq. Of 2-chloromet? Lc? Clobutanone was added and the reaction mixture was heated to reflux for overnight, cooled to room temperature, diluted with ethyl acetate (50 ml), then washed with water (4 x 25 ml) The organic layer was dried (MgSO), filtered and concentrated in vacuo to produce a thin film, which upon further drying, solidified (90 mg, 82% yield) MS (ES +) m / e 415 (M + Na) +, 1 H NMR (CDCl 3, 300 MHz) d 93 (m, 1H ), 228 (m, 1H), 309 (dd, 2H), 374 (m, 4H), 388 (m, 1H), 446 (d, 1H, J = 17 1), 468 (d, 1H, J = 17 1), 721-748 (m, 6H), 763 (d, 1H), 84 3 (s, 1H), 935 (1H, d) Example 48 Preparation of compound ll-40a and ll-40b The reaction was performed as described for II-38, except that the crude product (after ream cutting) was purified via column chromatography on silica gel (2: 1 toluene / EtOAc). Two isomeric ethyl acetals, ll-40a and ll-40b, were isolated and had the following physical properties: HPLC: Rt = 32.3 and 30.4 min, respectively (Method A). MS: 425 (M + H).

Example 49 Preparation of compound 11-41 To a stirred solution of 11-39 (63 mg, 0.161 mmol) in THF (8 ml) under nitrogen at 0 ° C, lithium borohydride (96 ml, 0.193 mmol) was added as of drops. The reaction was stirred at 0 ° C for 30 min, then warmed to room temperature for 2 h. The reaction was cooled to 0 ° C and quenched with methanol. The mixture was stirred for 30 min at room temperature. The solvent was removed in vacuo leaving a whitish solid. The product was isolated by flash chromatography on silica gel using EtOAc (100%) to give a white residue (5 mg, 8% yield). MS (ES +): m / e 394 (M + H); 1 H NMR (CDCl 3, 300 MHz): d 2.34 (m, 2 H), 3.43 (m, 1 H), 3.60 (dd, 1 H), 3.83 (dd, 1 H), 3.83 (dd, 1 H), 3.89 (s, 2 H) ), 3.98 (d, 2H), 4.26-4.34 (m, 2H), 4.75 (s, 2H), 7.31-7.60 (m, 6H), 7.72 (d, 1H), 8.54 (s, 1H), 9.38 ( dd, 1H).

Example 50 Preparation of compound 11 -42 Following the general SPS procedure as described in Example 8, (50a) (50 mg) was reacted with β-lactone to provide 4.5 mg of the desired compound, which had the following physical properties HPLC Rt = 141 min (mixture of diastereomers) (Method A) MS 379 (M -OH) + Example 51 Preparation of compound 11-43 Following the general SPS procedure as described in Example 8, (50a) (50 mg) was reacted with 3,4-oxo-tetrahydrofuran [which was prepared in accordance with a literature method by Hawkins et al, J Chem Soc 1959, 248] and the crude product was purified by semi-preparative HPLC, to provide 1 mg of the desired compound, which had the following physical properties HPLC Rt = 147 min (mixture of diastereomers) (Method A) MS 395 (M + H) Example 52 Preparation of compound II-44 Following the general SPS procedure as described in Example 8, (50a) (50 mg) was reacted with 1,5-d-chloropentan-2-one [which was prepared from according to a literature method of L Hart et al, J Org Chem 1959, 24, 1261], to provide 65 mg of chloromethyltetrahydrofuran derivative 11-44, as a mixture of diastereomers, which had the following physical properties HPLC R, = 153 mm (mixture of diastereomers) (Method A) MS 429 (M + H) Example 53 I 10 Preparation of compound ll-45a, 11-45b and 11 -46 Following the general SPS procedure as described in Example 8, (50a) (50 mg) was reacted with 2-formyl-3,5-chloro -dimethoxy-benzyl [which was prepared according to a literature method of GM Makara et al, J Org Chem 1995, 60, 717], to provide a crude product, which was purified (and the diastereomers were separated) by Semi-preparative HPLC to produce individual diastereomers ll-45a (68 mg) and ll-45b (59 mg), respectively These products had the following physical properties HPLC R, = 138 min (ll-45a) and 159 min (ll-45b) ) (Method C) MS 511 (M + Na) In addition, an ethyl transfer product, 11-46 (analog of R18 = Et) was also isolated and had the following physical properties HPLC Rt = 150 min (Method C) MS 539 (M + Na) Example 54 Preparation of compound 11 -47 Following the general SPS procedure as described in Example 8, (50a) (50 mg) was reacted with 3,3-d? Met? L-4-oxo-β-lactone to provide 101 mg of the desired compound as a mixture of diastereomers, which had the following physical properties HPLC R, = 132 min and 143 min (Method C) MS 439 (M + H) + Example 55 Preparation of compound 11 -48 Following the general SPS procedure as described in Example 8, (50a) (50 mg) was reacted with 2,3-O-isopropylidene-D-erythronolactone to provide 4.1 mg of the compound desired as a mixture of diastereomers, which had the following physical properties: HPLC: R, = 12.9 and 13.6 min. (Method C). MS: 469 (M + H) +.

Example 56 Preparation of compound II-49 Following the general SPS procedure as described in IO Example 8, (50a) (125 mg) was reacted with 3-formyl-N-dimethylpropionamide and 20 mg of the hydroxyamide intermediate were isolated in the usual manner from the solid phase reaction. This alcohol (10 mg) was oxidized with Dess-Martin periododinan (105 mg) in dichloromethane (5 ml) at 0 ° C for 30 min. The reaction mixture was washed with Na 2 S 2 O 3 I5 aqueous, aqueous NaHCO3 and brine, and dried over anhydrous MgSO4 before filtration and concentration in vacuo. The resulting keto-amide was taken up in methanol (5 ml), hydrazine hydrate (1 ml) was added and the mixture was heated to reflux for 2 h. After the solvent was removed in vacuo, the residue was taken up in CH 2 Cl 2 and washed with water, brine and dried over anhydrous MgSO 4. After filtration and solvent removal by rotary evaporation, 4.9 mg of the desired product was obtained, which had the following physical properties: HPLC: R, = 10.3 min. (Method C). MS: 407 (M + H) +. j ... Example 57 P reparation of comm. 11-50 Following the general SPS procedure as described in Example 8, (50a) (50 mg) was reacted with 1,4-d? Oxasp? Ro [4.5] decan-ona to provide 4 mg of the desired compound as a mixture of diastereomers, which had the following physical properties H PLC R, = 14 0 mm (Method C) MS 409 (M + H) Example 58 Preparation of compound 11-51 a, 11-51 be, 11-51 d (Preparation of (1, 1 -d? Ethoxy? Ethoxy?) Acetone) To a cold (0 ° C) suspension of NaH (2 68 g, 60%) in THF (150 ml) was added a solution of 1,1-d? Ethoxy? Ethanol [which was prepared according to the literature procedure of Zirkle, CL et al J. Org Chem 1 961 , 26, 395-407] (9.00 g) in THF (20 ml) and the reaction mixture was stirred at room temperature for 1 hour before adding methylene chloride (8.0 ml). it was refluxed overnight, cooled and filtered through a plug of celite. The solvent was removed by rotary evaporation and the residue was purified by column chromatography (silica, 20% ether / hexane) to give 1.1. -dietoxyethyl lmetalyl ether (1, 5, 90%) Ozonolysis of a cooled solution (-30 ° C) of this ether (6 00 g) in EtOAc (80 ml) was carried out until no starting material was detectable by TLC ( 1 hour ) At this time, the reaction was purged with oxygen, treated with Pd (OH) 2 (150 mg) and stirred under a hydrogen atmosphere overnight. The catalyst was filtered and the filtrate was concentrated by rotary evaporation. The residue The resulting product was purified by column chromatography (silica, 20% EtOAc / hexane) to give (1,1-diethoxy-ethoxy) acetone (4.53 g, 82%). Following the general SPS procedure as described in Example 8, (50a) (50 mg) was reacted with (1,1-diethoxyethoxy) acetone [as described above]. A portion of the product (6.5 mg) was fractionated by semi-preparative HPLC (reverse phase of C-8 and levigated with 65% MeCN-water containing 0.1% TFA). The isolated isomeric products were: ll-51a (0.53 mg, HPLC: R, = 15.0 min). MS: 455 (M + H), II-51bc (1.25 mg, HPLC: Rt = 15.3 min and 15.4 min). MS: 477 (M + Na) and 11-51 d (1.31 mg, HPLC: R, = 15.8 min) (Method C) MS: 477 (M + Na).

Example 59 Preparation of compound 11 -52 The crude reaction products (10.5 mg), obtained according to the preparation of ll-40a and ll-40b, were taken up in methylene chloride (20 ml) and treated with BF3 etherate (20 μl). After shaking during 2. 5 hours, the solution was washed with saturated aqueous NaHCO3 and brine before being dried over MgSO. After filtration and solvent removal by rotary evaporation, the residue was taken up in THF (2 ml) and treated with NBS (4.5 mg). After stirring overnight, additional NBS (4.5 mg) was added and the reaction was stirred for another 2.5 h.

The crude product was filtered through a short C-18 column (cartridge SEP-PAK) and was levigated with increasing step gradients of 5% 65% -75% MeCN-water containing 0.1% TFA. The appropriate fractions were deposited, neutralized with aqueous NaHCO3 and extracted with CH2CI2 and dried over anhydrous MgSO4. After filtration and solvent removal by rotary evaporation, a mixture of bromides (5 mg) was provided to the mixtures of the bromides. (5 mg) in methoxyethanol (2 ml) was added Et3N (37 μl) and 5 PdCI2 (Ph3P) 2 (15 mg), and the mixture was heated under carbon monoxide atmosphere for 30 min. The reaction mixture was cooled and extracted with EtOAc and the organic layer was washed with water. The aqueous layer was extracted several times with EtOAc and the combined organic layers were washed with saline, aqueous NaHCO3, 1 N HCl and brine, and dried over MgSO1O. filtration and concentration under vacuum yielded = 11 mg of 11 -52 as a mixture of HPLC diastereomers Rt = 1397 m in and 14 12 m in (Method C) MS 557 (M + H), 579 (M + Na) Example 60 Preparation of compound 11-53 Following the general SPS procedure as described in Example 8, (50a) (50 mg) was reacted with 5-chloro- (1-p? Val? L) -pentan- 2-one [as described above for 11 -20] and the major product, a single diastereomer, was isolated via H PLC semi-primer (reverse phase 0 column of C-8, levigated with 75% MeCN in water containing 0 1% TFA) H PLC R, = 1 7 2 m in (Method A) The pivalate (5 mg) in TH F (2 ml) was treated with a solution of L? BH (2 mL 2M) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with 1 N HCl and extracted with EtOAc. The organic layer was washed with 1 N NaOH solution, brine and dried. dried over anhydrous MgSO 4. Filtration and concentration in vacuo gave the alcohol 11-53 (3.2 mg). HPLC: R, = 12.0 min (Method A). MS: 441 (M + H).

Example 61 Preparation of compound II-54 Following the general SPS procedure as described in Example 8, (50a) (50 mg) was reacted with diethoxybutyraldehyde. This experimental protocol is similar to that used for the preparation of compounds 11-23, ll-40a and ll-40b, as described above. The crude product (following the TFA treatment) was purified by reverse phase column chromatography of C-8, the appropriate fractions were deposited and neutralized with solid NaHCO3, before being extracted into EtOAc. The organic layer was washed with brine and dried over MgSO, filtered and concentrated in vacuo to yield = 17.2 mg. HPLC Rt = 14.8 min. (Method C). MS: 455 (M + H).

Example 62 Preparation of compound ll-55a and 11 -55 b Following the general SPS procedure as described in Example 8, (50a) (145 mg) was reacted with 2-ethoxycarbonyl-2-cyclopentenone [which was prepared according to a literature procedure of H.J. Reich et al., J. Am. Chem. Soc. 1975, 97, 5434-47]. The crude product was purified by HPLC, which was prepared (C8, 65% CH3CN-35% water containing 0.1% TFA) to give ll-55a (1.98 mg) HPLC: R, = 12.1 min. (Method C). MS: 465 (M + H) and ll-55b (7.35 mg) HPLC: R, = 14.1 min and 15.6 min (Method C). MS: 465 (M + H).

Example 63 Preparation of compound II -56 A sample of example ll-55a (7 mg) was treated with sodium cyanide in DMSO at 145 ° C) for 1 hr to yield imide derivative 11-56. Yield: 4.93 mg. HPLC: R, = 13.6 min. (Method C). MS: 519.

Example 64 Preparation of compound II-57 To a solution of THF (10 ml) of ll-01a (200 mg, 0.54 mmol) was added NBS (116 mg, 0.65 mmol). The reaction was stirred at room temperature for 24 h. The solvent was removed via rotary evaporation and the remaining brown solid was stirred with methanol (5 ml) for 0.5 h. The suspension was filtered and washed with methanol, leaving 215 mg (0.48 mmol, 89%) of the desired product, which had the following spectral properties: 300 MHz 1 H NMR (DMSO d 6) d 9.52 (d, 1), 8.65 ( s, 1), 8.621 (s, 1), 8.15 (s, 1), 7.78-7.62 (m, 2), 7.44-7.38 (m, 2), 5.20 (m, 1H), 4.95 (s, 2) , 4.74 (dd, 1), 4.50 (s, 2), 3.53 (m, 1), 2.8 (t, 1), 2.48 (m, 1).

Example 65 Preparation of compound 11 -58 To a suspension of (47a) (1 g, 3.2 mmol) in THF (40 ml) was added NBS (632 mg, 3.5 mmol). The reaction was stirred at room temperature for 18 h. The solvent was removed under vacuum and the resulting yellow-orange solid was suspended in methanol (50 ml). The paste was filtered and the solid was washed with more methanol. After drying, the bromine compound (R3 = Br) (1.09 g, 2.8 mmol, 88% yield) was recovered as a pale yellow solid: (ESI (M + H) 388.2, 390.2 m / e). To a solution of the above bromide (1.09 g, 2.8 mmol) was added 4,4'-dimethoxybenzhydrol (818 mg, 3.4 mmol) and p-toluenesulfonic acid (532 mg, 2.8 mmol) in benzene (60 ml) and N-methylpyrrolidinone. (6 ml) were heated to reflux. After 24 h, the reaction was allowed to cool to room temperature and diluted with ethyl acetate (200 ml). The organic layer was washed with NaHCO3 (2x), H2O (2x) and brine (2x), dried over anhydrous MgSO4, filtered and the solvent removed in vacuo. The crude material was purified via column chromatography (10% EtOAc-hexane) to provide the desired DMB-protected 3-bromoindol derivative (1.5 g, 2.4 mmol, 87% yield) as an orange solid: (ESII-MS (M + H) 616.5 m / e). A 250 ml sealable tube was charged with the 3-bromo compound protected with DMB (1.5 g, 2.4 mmol), bis (triphenylphosphinyl) palladium dichloride (100 mg, 0.14 mmol), anhydrous sodium acetate (3.9 g, 4.8 mmol) and methoxyethanol (50 ml). The tube was evacuated alternately and filled with CO, leaving it under a CO atmosphere. It was then lowered in an oil bath at 150 ° C. After 4 h, the tube was cooled to room temperature and recharged with CO. This was repeated once more with the reaction proceeding a total of 10 h. The reaction was diluted with ethyl acetate (250 ml), washed with water, dried over anhydrous MgSO 4, filtered and dried in vacuo. The residue was triturated with methanol to give the 3-carboxy compound (1.29 g, 2.02 mmol, 84% yield) as a yellow solid: ESII-MS (M + H) 639.6 m / e. To a solution of the above ester (1.2 g, 1.9 mmol) in methylene chloride (20 ml) was added thioanisole (1 ml) followed by TFA (4 ml). After stirring for 1 h at room temperature, the reaction mixture was evaporated to dryness and the residue was suspended in diethyl ether. The suspension was filtered and the solid was washed with diethyl ether until the filtrate was colorless. The deprotected ester (636 mg, 1.54 mmol) was isolated as an off-white solid (ESII-MS (M + H) 413.4 m / e). The above ester (500 mg, 1.2 mmol) was suspended in methylene chloride (15 ml) and a solution of diisobutylaluminum hydride in methylene chloride (5.5 ml, 5.5 mmol, 1.0 M) was added. After 2 h at room temperature, the reaction was quenched with methanol. The solvent was removed by rotary evaporation and water was added to the residue. The paste was filtered and the solid allowed to dry. The desired product [A1, A2 = H2, B1, B2 = O, R3 = CH3OH, R4 = R5 = R6 = H, Q = NH] (367 mg, 1.08 mmol) was obtained as a pale yellow solid: ESII-MS (M + H) 341.3 m / e. To a suspension of the previous alcohol (430 mg, 1.2 mmol) in alcohol 2-methoxyethyl (25 ml), in a sealable tube, trifluoroacetic anhydride (340 μl, 2.4 mmol) was added. The reaction mixture was heated at 70 ° C for 15 h. The tube was cooled and water was added to the reaction vessel. After stirring for 1 h, the suspension was filtered affording the desired ether [A1, A2 = H2, B1, B2 = O; R3 = CH2OCH2CH2OCH3, R4 = R5 = R6 = H, Q = NH] (370 mg, 093 mmol, 77% yield) as a solid orange ESII-MS (M + H) 3995 m / e The above ether (370 mg , 093 mmol) was dissolved in DMF (20 ml) The solvent was reduced in vacuo at -50% (30 mmHg). Hydride was added.

Sodium (45 mg, 003 mmol of a 60% dispersion in mineral oil) in one portion and the reaction was stirred for 1 h at room temperature. Then gdcidyl mesylate (170 mg) was added., 1 mmol) and the reaction was stirred an additional 18 h at 60 ° C. The crude reaction mixture was stirred at room temperature for 4 h, filtered and concentrated on column chromatography (50% EtOAc-hexane). 10% MeOH-EtOAc) provided the desired product II-58 (90 mg, 02 mmol, 22%) 300 MHz 1 H NMR (DMSO dβ) d 950 (d, 1), 860 (s, 1), 795 (s , 1), 780-731 (m, 5), 5 18 (m, 1H), 490 (s, 2), 474 (dd, 1), 465 (s, 2), 450 (s, 2), 362 (d, 2), 353 (m, 1), 350 (d, 2), 325 (s 3), 28 (t, 1), 248 (m, 1) I5 Example 66 Preparation of compound 11 -59 [Figure 16] To a well stirred solution of (49a) (14 g, 41 mmol) in 260 ml of benzene, MnO2 (216 g, 248 mmol) was added and the mixture was heated at 0 reflux for 18 h. The reaction mixture The filtrate was filtered through a pad of cedta, washed with inert THF (5 x 20 ml) and the filtrate was concentrated in vacuo. The crude product was triturated with MeOH, filtered, washed with cold MeOH and dried to obtain the derivative of indanone (68a) (1 13 g, 85% yield) HPLC (Method C) Rt = 1724 min To a magnetically stirred suspension of (68a) (005 g, 009 mmol) in anhydrous THF (10 mL), was added Cyclopentylmagnesium bromide (2M solution in Et 2 O), (0079 g, 5 mmol) at 0 ° C under argon atmosphere After 15 min, the reaction mixture was quenched with saturated aqueous NH 4 Cl solution and the phases were separated. The aqueous phase it was extracted with EtOAc (3 x 7 ml), the combined organic extracts were washed with water and brine, dried over MgSO and concentrated in vacuo to give the HPLC addition product (Method C) Rt = 1736 min, MS = 621 (M + H), 643 (M + Na) To a well stirred solution of the product (0035 g, 0056 mmol) in a mixture of CH 2 Cl 2 (10 mL) and Et 3 S α (6 mL), tpfluoroacetic acid (1%) was added. ml) at room temperature After 1 h, the reaction mixture was concentrated in vacuo to give the crude product Purification of the crude product by chromatography Flash chromatography on silica gel provided 11-59 (91 mg, 42% yield) HPLC (Method C) Rt = 1569 min, MS 379 (M + H) Example 67 Preparation of compound 11-60 [Figure 16] To a magnetically stirred solution of lithium b? S (tpmet? Ls? L? L) am? Da (1M solution in THF), (021 mL, 266 mmol) in anhydrous THF (5 mL), α-butyrolactone (100 mg, 1 26 mmol) was added at -78 ° C under argon atmosphere After stirring for 45 min. min at -78 ° C, the solution of the enolate was transferred via a cannula to a solution of (68a) (70 mg, 012 mmol) in anhydrous THF (5 ml) at -78 ° C following the addition of the enolate solution , the temperature of the reaction was raised to 0 ° C over a period of 2 h. The cold 0 ° C reaction mixture was quenched with saturated aqueous NH 4 Cl solution and the phases were separated. The aqueous phase was extracted with EtOAc (3 x 25 ml) and the combined organic extracts were washed with water, brine, dried over MgSO 4 and concentrated in vacuo to give the crude product. The crude product was triturated with EtOAc, filtered and washed with EtOAc. Purification of the solid by flash chromatography on silica gel gave the addition product (16 mg, 18% yield). HPLC (Method C) Rt = 15.47 min; MS: 637 (M + H), 659 (M + Na). To a well-stirred solution of the above product (15 mg, 0.023 mmol) in a mixture of CH2Cl2 (5 mL) and Et3SiH (5 mL), trifluoroacetic acid (0.6 mL) was added at room temperature. After 1 h, the reaction mixture was concentrated in vacuo to yield the crude product. The crude product was repeatedly evaporated from EtOAc (3 x 10 ml). The crude product was triturated with hexane and the solid was filtered and washed with hexane, and dried to provide 11-60 (9 mg, 100% yield). HPLC (Method C) Rt = 11.00 min; MS: Obs: 433 (M + K).

Example 68 Preparation of compound 11-61 The alcohol intermediate [A1, A2 = H2, B1lB2 = O, R3 = CH2OH, R4 = R5 = R6 = H, Q = NH] described for the synthesis of compound II-58, (360 mg, 0.9 mmol) was placed in a sealable tube with ethanol (15 ml). To this suspension was added trifluoroacetic anhydride (254 μl, 1.8 mmol). The reaction was heated at 70 ° C for 15 h. The tube was cooled and the contents transferred to a round bottom flask. The solvent was evaporated and the solid was triturated with methanol to provide the desired ether (239 mg, 0.65 mmol, 72% yield) as an orange solid. (ESII-MS (M + H) 369.3 m / e). Compound 11-61 was prepared using the same procedure as described above for 11 -58 using ether [A1, A2 = H2, B1, B2 = O, R3 = CH2OCH2CH3, R4 = R5 = R6 = H, Q = NH ] (122 mg, 0.33 mmol), NaH (16 mg, 0.33 mmol) and glycidyl mesylate (76 mg, 0.5 mmol) in DMF (10 mL), A total of 103 mg (0.24 mmol, 73%) was obtained. desired product, which had the following spectral properties: 300 MHz 1H NMR (DMSO d6) d 9.52 (d, 1), 8.60 (s, 1), 8.60 (s, 1), 7.96 (s, 1), 7.78- 7.62 (m, 2), 7.44-7.38 (m, 2), 5.20 (m, 1H), 4.95 (s, 2), 4.78 (dd, 1), 4.62 (s, 2), 4.5 (s, 2) , 3.54 (q, 2), 3.52 (t, 2), 2.78 (t, 1), 2.48 (m, 1), 1.20 (t, 3).

Example 69 Preparation of compound II-62 To a solution of (47a) (290 mg, 0.94 mmol) in dry DMF (15 ml) was added sodium hydride (45 mg, 0.94 mmol of a 60% dispersion in mineral oil) in one portion. After stirring at RT for 1 h, 2-tetrahydrofurfuryl mesylate (200 mg, 1.1 mmol) was added and the reaction was stirred for 24 h at room temperature. The reaction was heated to 60 ° C (oil bath temperature) for 24 h and then stirred at room temperature for 72 h. The reaction was filtered and the precipitate was washed with diethyl ether. The solvents were concentrated and the residue was triturated with 1: 1 diethyl ether / methanol and the solid was collected. The resulting tan solid was purified by column chromatography (20% EtOAc-CH 2 Cl 2) to give the desired product (140 mg): mp; 250 ° C, 1 H NMR (300 MHz, DMSO-d 6) d 9.52 (d, 1), 8.58 (s, 1), 8.01 (d, 1), 7.76 (d, 1), 7.68 (d, 1), 7.50 (dd, 1), 7.44-7.31 (m, 3H), 4.95 (m, 1H), 4.80 (m, 2), 4.50 (s, 2), 4.23 (m, 2), 3.75 (q, 1) , 3.56 (q, 1), 1.80 (m, 4); MS (ES +) 395 (M + 1).

Example 70 Preparation of compound II-63 This compound was prepared by essentially the same procedure as described for 11-62 from (47a) (280 mg, 0.9 mmol), sodium hydride (60% dispersion in mineral oil) (42 mg, 0.9 mmol) and 2-tetrahydrofurfuplo mesylate (200 mg, 1.1 mmol). Additional NaH and mesylate (50 mg) were added after 72 h at room temperature and the reaction was heated at 100 ° C for 24 h. The crude mixture was filtered and the precipitate was washed with DMF. The solvents were concentrated and the resulting solid was triturated with methanol and collected. The crude product was purified by HPLC (60% CH3CH-H2O 0.1% TFA) to give the desired product: mp > 250 ° C, H NMR (300 MHz, DMSO-de) d 9.54 (d, 1), 8.61 (s, 1), 8.05 (d, 1), 7.80 (d, 1), 7.70 (d, 1), 7.58 (dd, 1), 7.44-7.31 (m, 3), 4.95 (m, 1), 4.75 (m, 2), 4.56 (s, 2), 4.00 (m, 2), 3.6 (m, 2) , 1.95 (m, 1), 1.80 (m, 2); ESI MS (ES +) 395 (M + 1).

Example 71 Preparation of compound 11-64 Following the general SPS procedure as described in Example 8, (50a) (50 mg) was reacted with sorbic aldehyde, except that the resin was not treated with TFA, to provide the product of aldol bound to resin (50d) To a suspension of 4-phenol-1, 2,4-tpazol-na-3,5-dione (100 mg, 057 mmol) in 1 ml of tetrahydrofuran dichloromethane (11) at -60 ° C, the resin (50d) (0025 mmol) was added. The reaction mixture was stirred for 1 h in a cold bath, the cooling bath was stirred and the mixture was stirred at room temperature for an additional 05 h. it was filtered and worked up as described in Example 8, to provide compound 11-64, [crystalline solid (15 mg)], as a mixture of HPLC diastereomers (Method D) R, = 249, 257, 264, 276 , 282, 286, 292 min, MS 582 (M + H) Example 72 Preparation of Compound 11 -65 To the resin (50a) (50 mg, 0025 mmol) in 025 mL of anhydrous tetrahydrofuran under argon, a 1 O M solution of ethyl agnesium bromide (08 mL, 08 mmol) was added in tetrahydrofuran at room temperature The reaction mixture was stirred gently with magnetic stirring for 45 mm. Hexamethylphosphoramide (10 ml) was added via syringe over one minute and stirring was continued for an additional 10 min. (bromomet? l) c? clopropane ( 10 mL, in large excess) by syringe in one portion and the reaction was stirred for 3 h. The reaction was then heated to reflux for 16 h. The reaction was quenched by the addition of saturated ammonium chloride solution (5 mL). The resin it was removed from the supernatant by filtration on filter paper (Coors funnel) and washed successively with (3 x 10 ml portion of) water, N, Nd? meth? lformamide, tetrahydrofuran, isopropanol, ethyl ether and dichloromethane. allowed the resulting ream to dry briefly in the air stream and then transferred to a round bottom flask and treated with a 1% solution of trifluoroacetic acid in dichloromethane (10 ml) with stirring for one hour. The organics were separated from the spent resin by filtration, using (10 ml) of dichloromethane as a chaser. The organics were concentrated; Anhydrous toluene (10 ml) was added to the flask and the residual water was removed by a second concentration. The solid was dried under vacuum to give compound II-65, 12 mg as a yellow crystal. HPLC (Method D) Rt = 251 min, MS 419 M + H) Example 73 Preparation of compound 11-66 Compound (47a) (50 mg, 0.16 mmol) was dissolved in anhydrous N, N-dimethylformamide (10 ml) in a flared round bottom flask, equipped with a distillation apparatus short path Approximately 3 ml of the DMF was removed by distillation at 40 ° C using high vacuum (1-2 mm Hg) to remove any contaminating water. The solution was cooled to room temperature and sodium hydride (70 mg, 0.18 mmol, 60%) was added. of dispersion in mineral oil). The mixture was heated at 50 ° C for 30 min to ensure a complete generation of 1-cyano-1- (p-toluenesulfon? Lox? Met? L) c? Clopropane ammonium (45 mg), 0177 mmol) prepared from the tosylation of 1-c? Ano-1-hydroxymethylcyclopropane (using p-toluenesulfonic anhydride and pipdine in dichloromethane), was added and the heating was continued at 50-60 ° C for 18 h. it was quenched by the addition of vain drops of water and concentrated in vacuo. The resulting solid was redissolved in N, Nd? met? lformamide (1 ml) and filtered through a cotton plug. High performance liquid chromatography. , preparation, in a reversed phase column of C8 (55% acetomthole water), gave 6 mg of the desired compound II-66 HPLC (Method C) Rt = 135 mm, MS 390 (M + H) Example 74 Preparation of compound II-67 (via scheme 20) A mixture of compound (47a) (1 5 g, 48 mmol), tert-butyl acrylate (15 ml, 10 mmol), DBU (11 drops) and tert. -butanol (2 ml) in anhydrous acetomotol (50 ml), refluxed under argon for 5 days. The reaction mixture was cooled to room temperature and ether (27 ml) was added to the reaction mixture at 0 ° C, it was filtered, washed with ether (3 x 10 ml) and dried to give the Michael addition product (96a) [R18 = R23 =, R '= tert-butyl] (1 55 g, 73% yield) HPLC (method D) Rt 31 54 To a well stirred suspension of the tert-butyl ester (96a) (1 55 g, 35 mmol) in 2 ml of methylene chloride, tpfluoroacetic acid (15 ml) was added at room temperature The mixture was further stirred for 1 h at room temperature and TFA and methylene chloride were removed under vacuum, azeotroped with toluene (3 x 15 ml) and dried under vacuum to obtain the acid (97a) [R18 = R23 = H ], (1 .4 g, 99% yield). HPLC (method D): R t = 22.89 min. To a well-stirred mixture of BOP (0.165 g, 0.37 mmol), HOBt (0.040 g 0.029 mmol) in DMF (8 ml) was cooled to 5 ° C, Et3N (24 drops) and the acid (97a) (0.1 g, 0.26 mmol) were added. The resulting mixture was further stirred at 5 ° C for 30 min, then benzyl mercaptan (15 drops) was added. The reaction mixture was further stirred at room temperature for 15 h and quenched with water (50 ml). The solid was filtered, washed with water (3 x 10 ml) and dried to give thio-ester (98a) [R18 = R23 = H, R "= Bn], (0.145 g, 99% yield), HPLC (method D): Rt = 32.22 min MS: 489 (M + H) and 511 (M + Na) To a well-stirred solution of thio-ester (98a) (40 mg, 0.081 mmol) in a mixture of NMP (6 ml) and acetone (6 ml), Pd / C (10%), (100 mg) and Et3SiH (1 ml) were added.The reaction mixture was heated at 55 ° C for 45 min, filtered at from a celite pad, it was washed with acetone and the filtrate was concentrated to give crude aldehyde (99a) [R18 = R23 = H] (10 mg, 33% yield); HPLC (method D): Rt = 23.50 min The crude aldehyde (99a) was used directly for the following reaction: To a well stirred mixture of aldehyde (99a) (10 mg, 0.027 mmol) and cysteine methyl ester hydrochloride (20 mg, 0.116 mmol) in 1-methyl. -2-pyrrolidinone (3 ml), triethylamine (20 drops) was added at room temperature The mixture was stirred at room temperature for 24 h , then quenched with 2M sodium bicarbonate solution (10 ml) and extracted with ethyl acetate (3 x 7 ml) The combined organic layer was washed with water, brine, dried over anhydrous Na2SO4 and concentrated in vacuo to give provide a crude product, which was purified by the semi-prep HPLC method to provide compound 11-67, 26 mg, 16% yield, 95% purity, HPLC (method D) Rt = 2314 mm, MS 484 (M + H) and 506 (M + Na) Example 75 Preparation of compounds II-68 and 11 -69 To a solution of II-35 and 11 -36 (2 mg, mixture of diastereomers) in THF (1 ml), ethyl isocyanate (30 μl) was added after stirring overnight, the mixture was quenched with methanol (1 ml) and the solvent was removed by evaporation. The resulting residue was purified by preparative TLC (toluene / EtOAc, 1/1) and two bands were isolated. The less polar band provided the compound II-68 [HPLC Rt = 1701 min (Method A), MS 553 (M + H) and 575 (M + Na)], and the polar band provided compound 11-69 [HPLC Rt = 1474 mm (method A) , MS 482 (M + H) and 520 (M + Na)] It is intended that each of the patents, applications and printed publications mentioned in this patent document are hereby incorporated by reference in their entirety. As those skilled in the art, will appreciate, numerous changes and modifications can be made to the preferred embodiments of the invention without departing from the spirit u of the invention It is intended that all such variations fall within the scope of the invention

Claims (1)

1. Claims 1 . A comm that has the Formula I: wherein: ring B and ring F, independently, and each together with the carbon atoms to which they are attached, are selected from the group consisting of: a) an unsaturated, 6-membered carbocyclic aromatic ring wherein from 1 to 3 carbon atoms can be replaced by nitrogen atoms; b) an unsaturated, 5-membered carbocyclic aromatic ring; and c) an unsaturated, 5-membered carbocyclic aromatic ring in which either 1) a carbon atom is replaced with an oxygen, nitrogen or sulfur atom; 2) Two carbon atoms are replaced with a sulfur atom and a nitrogen atom, an oxygen atom and a nitrogen atom; or two nitrogen atoms; or 3) three carbon atoms are replaced with three nitrogen atoms, R1 is selected from the group consisting of a) H, substituted or unsubstituted alkyl having from 1 to 4 carbons, substituted or unsubstituted aplo, substituted or unsubstituted alkyl-substituted , substituted or unsubstituted heteroample, or substituted or unsubstituted heteroalalkyl, h) -C (= O) R9, where R9 is selected from the group consisting of alkyl, aplo and heteroaplo, i) -OR10, wherein R10 is selected from the group which consists of H and alkyl having from 1 to 4 carbons, j) -C (= O) NH2, -NR11R12, - (CH2) PNR11R12, - (CH2) pOR10, -O (CH2) POR10 and -O (CH2) pNR11R12, wherein p is from 1 to 4, and wherein either 1) R11 and R12 are each independently selected from the group consisting of H and alkyl having from 1 to 4 carbons, or 2) R 1 and R 12 together form a linking group of the formula - (CH 2) 2 -X 1 - (CH 2) 2-, wherein X 1 is selected from the group consisting of -O-, -S- and -CH2-, R2 is selected from the group consisting of H, alkyl having from 1 to 4 carbons, -OH, alkoxy having from 1 to 4 carbons, -OC (= O) R9, -OC (= 0) NR11R12, -O (CH2) pNR11R12, -0 (CH2) pOR10, substituted or unsubstituted anlalkyl having from 6 to 10 carbons, and substituted or unsubstituted heteroaplakyl, R3, R4, R5 and R6 are each independently selected from the group consisting of a) H, aplo, heteropole, F, Cl, Br, I, -CN, CF3, -NO2, -OH, -OR9, -O (CH2) pNR11R12, -OC (= O) R9, -OC (= O ) NR 11 R 12, -O (CH 2) p OR 10, -CH 2 OR 10, -NR 1 R 12, -NR 10 S (= O) 2 R 9, -NR 10 C (= O) R 9, b) -CH 2 OR 14, wherein R 14 is the residue of an amino acid after that the hydroxyl group of the carboxyl group is removed, c) -NR10C (= O) NR11R12, -CO2R2, -C (= O) R2, -C (= O) NR11R12, -CH = NOR2, -CH = NR9, - (CH2) PNR11R12, - (CH2) PNHR14, or -CH = NNR R2A, wherein R2A is the same as R2, d) -S (O) and R2, - (CH2) pS (0) and R9, -CH2S (O) and R14, wherein y is 0, 1 or 2, e) alkyl having from 1 to 8 carbons, alkenyl having from 2 to 8 carbons, and alkynyl having from 2 to 8 carbons, wherein 1) each alkyl, alkenyl or alkynyl group is unsubstituted, or 2) each alkyl, alkenyl or alkyloyl group is substituted with 1 to 3 groups selected from the group consisting of 6 to 10 carbon atoms, heterolayl, aplaxkoxy, heterocycloalkoxy, hydroxyalkoxy, alkyloxy alkoxy, hydroxyalkylthio alkoxy alkylthio , F, Cl, Br, I, -CN, -NO2, -OH -OR9 -X2 (CH2) PNR11R12, -X2 (CH2) pC (= O) NR11R12, X2 (CH2) pOC (= O) NR11R12, - X2 (CH2) pCO2R9, X2 (CH2) pS (O) and R9, X2 (CH2) PNR10C (= O) NR11R12, -OC (= O) R9, -OCONHR2, -O-tetrah? Drop? Ran? L, -NR11R12, -NR10CO2R9, -NR10C (= O) NR11R12, -NHC ( = NH) NH2, NR10C (= O) R9, -NR10S (O) 2R9, -S (O) and R9, -CO2R2, -C (= O) NR11R12, -C (= O) R2, -CH2OR10, -CH = NNR2R2A, -CH = NOR2, -CH = NNHCH (N = NH) NH2, -S (= O) 2NR2R2A, -P (= O) (OR 0) 2, -OR14, and a monosaccharide having from 5 to 7 carbons, wherein each hydroxyl group of the monosaccharide is independently either unsubstituted or is replaced by H, alkyl having from 1 to 4 carbons, alkylcarbonyloxy having from 2 to 5 carbons, or alkoxy having from 1 to 4 carbons; X2 is O, S or NR10; R7 is where: m is 0-4; G is a link; or alkylene having 1 to 4 carbons, wherein the alkylene group is unsubstituted, or substituted with NR11AR12A or OR19; R11A and R12A are g ua | TS q ue R11 and R12. R19 is selected from the group consisting of H, alkyl, acyl and C (= O) NR11AR12A; R8 is selected from the group consisting of O (C = O) NR11R12, -CN, acyloxy, alkenyl, -O-CH2-O- (CH2) 2-O-CH3, halogen and R1A, wherein R1A is equal to R1; A and B are independently selected from the group consisting of O, N, S, CHR17, C (OH) R17, C (= O), and CH2 = C; or A and B together can form -CH = CH-; C and D are independently selected from the group consisting of a bond, O, N, S, CHR1 7, C (OH) R1 7, C (= 0) and CH2 = C; E and F are independently selected from the group consisting of a bond, O, N, S, C (= O), and CH (R1 7); R1 7 is selected from the group consisting of H, substituted or unsubstituted alkyl, alkoxycarbonyl, and substituted or unsubstituted alkoxy; wherein: 1) the an il lo J contains 0 to 3 ring heteroatoms; 2) Two adjacent hydroxyl groups of any of the J ring may leave in a dioxolane ring; 3) two adjacent ring carbon atoms of any one of the N can be removed to form a fused aryl or heteroaryl ring; 4) Two adjacent ring nitrogen atoms of any ring J may be joined to form a fused heterocyclic ring, which may be substituted with 1 or 3 alkyl or aryl groups; provided that: 1) ring J contains at least one carbon atom that is saturated; 2) ring J does not contain two adjacent ring O atoms; 3) Ring J. Contain a maximum of two groups C (= O) of a nil lo; 4) when G is a lace, ring J may be heteroaryl; Q is selected from the group consisting of O, S, NR13, NR7A, wherein R7A is the same as R7, CHR15, X3CH (R15) and CH (R15) X3, wherein X3 is selected from the group consisting of -O -, -S-, -CH2-, NR7A and NR13; W is selected from the group consisting of CR18R7 and CHR2; R13 is selected from the group consisting of H, -SO2R9, -CO2R9, -C (= O) R9, -C (= O) NR11R12, alkyl of 1-8 carbons, alkenyl having 2-8 carbons and alkynyl having 2-8 carbons; and either 1) the alkyl, alkenyl or alkynyl group is unsubstituted; or 2) the alkyl, alkenyl or alkynyl group independently is substituted with 1 to 3 groups selected from the group consisting of 6 to 10 carbon atoms, heterolayl, arylalkoxy, heterocycloalkoxy, hydroxy alkoxy, alkyloxy alkoxy, hydroxyalkylthio, alkoxy alkylthio, F, Cl, Br, I, -CN, -N02, -OH, -OR9, -X2 (CH2) pNR11R12, -X2 (CH2) pC (= O) NR11R12, -X2 (CH2) pOC (= O) NR11R12 , -X2 (CH2) pCO2R9, X2 (CH2) pS (O) and R9, X2 (CH2) PNR10C (= O) NR11R12, -OC (= O) R9, -OCONHR2, -O-tetrahydropyranyl, -NR11R12, -NR10CO2R9 , -S (O) and R9, -CO2R2, -C (= O) NR11R12, -C (= O) R2, -CH2OR10, -CH = NNR2R2A, -CH = NOR2, -CH = NR9, -CH = NNHCH ( N = NH) NH2, -S (= 0) NR2R2A, -P (= O) (OR10) 2, -OR14, and a monosaccharide having from 5 to 7 carbons, wherein each hydroxyl group of the monosaccharide is independently either substituted or is replaced by H, alkyl having from 1 to 4 carbons, alkylcarbonyloxy having from 2 to 5 carbons, and alkoxy having from 1 to 4 carbons; R15 is selected from the group consisting of H, OR10, SR10, R7A and R16, R is selected from the group consisting of alkyl of 1 to 4 carbons; phenyl; naphtyl, arylalkyl having 7 to 15 carbons, -SO2R9, -C02R9, -C (= O) R9, alkyl having 1-8 carbons; alkenyl having 2 to 8 carbons, and alkynyl having 2 to 8 carbons, wherein 1) each alkyl, alkenyl or alkynyl group is unsubstituted; or 2) each alkyl, alkenyl or alkenyl group is substituted with 1 to 3 groups selected from the group consisting of aryl having 6 to 10 carbons, heteroaryl, arylalkoxy, heterocycloalkoxy, hydroxy alkoxy, alkyloxy alkoxy, hydroxyalkylthio, alkoxy alkylthio, F, Cl, Br, I, -CN, -NO2, -OH, -OR9, -X2 (CH2) PNR11R12, -X2 (CH2) pC (= O) NR11R12, X (CH2) pOC (= O) NR 1111 rR-, 12 -X2 (CH2) pCO2R? X2 (CH2) pS (O) yRE X2 (CH2) PNR10C (= O) NR11R12, -OC (= O) R9, -OCONHR2, -O-tetrahydropyranyl, -NR11R12, -NR10CO2R9, -S (O) and R9, -CO2R2, -C (= O) NR11R12 , -C (= O) R2, -CH2OR10, -CH = NNR2R2A, -CH = NOR2, -CH = NR9, -CH = NNHCH (N = NH) NH2, -S (= 0) NR2R2A, -p (= ?) (OR10) 2, -OR14, and a monosaccharide having from 5 to 7 carbons, wherein each hydroxyl group of the monosaccharide is independently either unsubstituted or is replaced by H, alkyl having from 1 to 4 carbons, alkylcarbonyloxy having from 2 to 5 carbons, and alkoxy having 1 to 4 carbons; R18 is selected from the group consisting of R2, thioalkyl of 1-4 carbons and halogen; A1 and A2 are selected from the group consisting of H, H; H, OR2; H, -SR2; H, -N (R2) 2; and a group wherein A1 and A2 together form a portion selected from the group consisting of = O, OS and = NR2; B1 and B2 are selected from the group consisting of H, H, H, -OR2, H, -SR2, H, -N (R2) 2, and a group wherein B1 and B2 together form a selected portion of the group that consists of = 0, = S and = NR2, with the proviso that at least one of the countries A1 and A2, or B1 and B2, form = 0, with the proviso that when Q is NH or NR7A, and in any of the group R7 or R7A m is 0 and G is a bond, R8 is H and R7 or R7A contains a ring oxygen heteroatom at position A in a five or six member ring, then B can not be CHR17, wherein R1 7 is substituted or unsubstituted alkyl, and with the additional proviso that when the compound of Formula I contains a group R7 or R7A or both a group R7 and R7A2 The compound of claim 1, wherein A and B are independently selected from the group consisting of O, N, S, CHR17, C (OH) R17, C (= O) and CH2 = C, R1 7 is selected from the group consisting of H, substituted or unsubstituted alkyl , and alkoxy substitute whether or not substituted, wherein 1) the anion contains 0 to 3 ring heteroatoms, 2) two adjacent hydroxyl groups of any ring J may be attached to a dioxolane ring, 3) two adjacent ring carbon atoms One of the rings J may leave to form a fused ring or heteropole, provided that 1) ring J contains at least one carbon atom that is saturated, 2) ring J does not contain two adjacent ring O atoms. , 3) ring J contains a maximum of two C (= O) ring groups, 4) when G is a bond, ring J can be hetero- lope, and R8 is selected from the group consisting of O (C = O) NR 11 R 12, acyloxy, alkenyl, -O-CH 2 -O- (CH 2) 2-O-CH 3, halogen and R 1 A, wherein R 1 A is the same as R 1 3 The compound of claim 2, wherein R 1, R 4 and R 6 are H The compound of claim 2, wherein one of Ai, A2 or B?, B2 is H, H and the other is = O 5 The compound of claim 3, wherein one of Ai, A2 or B?, B 2 is H, H and the other is = O 6 The compound of claim 2, wherein R1, R4, R5, R6 and R8 are H The compound of claim 2, wherein R3 and R5 are independently selected from the group consisting of H, alkoxy, halogen, alkoxyalkyl, alkoxy-alkoxyalkyl, and alkoxy-alkoxycarbonyl. The compound of claim 2, wherein Q is NR13. The compound of claim 8, wherein, preferably R13 is H or R7A The compound of claim 9, wherein R13 is H 11 The compound of claim 2, wherein W is CH2 or CR18R7 The compound of claim 11, wherein W is CR18R7. The compound of claim 12, wherein R18 is H or lower alkyl 14. The compound of claim 2, wherein R7 is a 3, 4, 5 or 6 membered carbocyclic ring, or a 5- or 6-membered heterocyclic ring, which contains one or two ring O, N or S atoms. 15. The compound of claim 14, wherein R7 is a heterocyclic ring having a ring, ring, or ring heteroatom. 16. The compound of claim 15, wherein R7 is a 3, 4, 5 or 6 membered heterocyclic ring, which contains a ring O atom. 17. The compound of claim 2, wherein G is a bond or CH2. 18. The compound of claim 2, wherein m is 0 or 1. 19. The compound of claim 2, wherein R8 is H, OH, halogen, ethenyl, acyloxy, alkoxy, substituted or unsubstituted phenyl, heteroaryl substituted or not substituted, or hydroxyalkyl. 20. The compound of claim 19, wherein R8 is H or OH. 21. The compound of claim 2, having the Formula II: 2. The compound of claim 21, wherein R1, R4 and R6 are H. The compound of claim 21, wherein one of A1, A2 or B?, B2 s H, H and the other is = O. The compound of claim 21, wherein R3 and R5 are independently selected from the group consisting of H, alkoxy, halogen, alkoxyalkyl, alkoxy-alkoxyalkyl, and alkoxy-alkoxycarbonyl The compound of claim 21, wherein G is a bond or CH2 26 The compound of claim 21, wherein W is CH2 or CR18R7 The compound of claim 21, wherein Q is NR13 or NR7A The compound of claim 21, wherein R8 is H, OH, halogen, ethenyl, acyloxy, alkoxy, substituted or unsubstituted phenyl, substituted or unsubstituted heteroala, or hydroxyalkyl. The compound of claim 21, wherein R1, R4 and R6 are H, one of At, A2 or B!, B2 is H, H and the other is = O, R3 and R5 are independently selected from the group consisting of H, alkoxy, halogen, alkoxyalkyl, alkoxy-alkoxyalkyl and alkoxy-alkoxycarbonyl, G is a bond or CH2, and W is CH2 or CR18R7, R8 is selected from the group consisting of H, OH, halogen, etemol, acyloxy, alkoxy, substituted or unsubstituted phenyl, substituted or unsubstituted hetero-pyl, and hydroxyalkyl, and Q is NR13 or NR7A The compound of claim 29, wherein R8 is H or OH The compound of claim 21, wherein Q is NR13, where R13 is H, G is a bond, and W is CR18R7, where R18 is H or lower alkyl, and R3 and R5 are independently selected from the group consisting of H, alkyl oxy and alkoxy alkoxycarbonyl The compound of claim 31, wherein R7 is a carbocyclic ring of 3, 4, 5 or 6 members, or a heterocyclic ring of 5 or 6 m members, which contains one or two O atoms. , N or S of ring 33 The compound of claim 31, wherein R7 is a heterocyclic ring having an O, N or S ring heteroatom. The compound of claim 31, wherein R7 is a heterocyclic ring of 3. , 4, 5 or 6 members, which contains an O ring atom The compound of claim 31, wherein the constituent variables of the compounds of Formula II are selected according to Table 7 The compound of claim 31 , wherein R8 is H or OH The compound of claim 21, wherein Q is NR7A, R5 and R8 are H, W is CH2, m is 0, G is a bond or CH2, and R3 is selected independently of the A group consisting of H, halogen, alkoxyalkyl, and alkoxy-alkoxy-loq. of claim 37, wherein R7A is a 3, 4, 5 or 6 membered carbocyclic ring, or a 5 or 6 membered heterocyclic ring, which contains one or two ring O, N or S atoms The compound of claim 37, wherein R7A is a heterocyclic ring having an heteroatom of O, N or S The compound of claim 37, wherein R7A is a 3, 4, 5 or 6 membered heterocyclic ring, which contains an atom of O of ring 41 The compound of claim 37, wherein the constituent variables of the compounds of Formula II are selected according to Table 8, supra. The compound of claim 21, wherein R1, R3, R4 and R6 are each H, A?, A2 is H, H, B?, B2 is = O, Q is NH, R5 is H or alkoxy, W is CR18R7, where R18 is H, G is a bond, m is 1, R8 is OH or -C (= O) R9, where R9 is alkyl, A is O, B, C and D are each CHR17, where R17 is H, and E and F are each a link [Compounds II-53, 11 -36 and II-22] The compound of claim 42, wherein R5 is attached at the position of 44. The compound of claim 43, wherein R5 is alkoxy. The compound of claim 43, wherein R5 is -O-CH3. claim 43, wherein R8 is -OH 47 The compound of claim 43, wherein R5 is H 48 The compound of claim 47, wherein R8 is -OH 49 The compound of claim 43, wherein Rs is H and R8 is -OC (= O) -alkyllo The compound of claim 49, wherein R8 is -O- (C = O) -CH3 The compound of claim 21, wherein R1, R3, R4 and R6 are each H, A?, A2 is H, H, B?, B2 is = O 52 The compound of claim 51, wherein Q is NR7A and W is CHR17 53 The compound of claim 52, wherein R7A and R17 are each cyclopropylmethyl 54. The compound of claim 1, wherein R1, R3, R4, R5 and R6 are each H; A!, A2 is H, H; B?, B2 is = O, W is CH2, and Q is NR7A. 55. The compound of claim 54, wherein R7A is G is CH2, m is 0, R8 is -CN and ring J is cyclopropyl. 56. The compound of claim 1, wherein R1, R3, R4, R5 and R6 are each H; A?, A2 is H, H; B?, B2 is = O, Q is NH, and W is CR18R7, where R18 is H. 57. The compound of claim 56, wherein G is CHOH, m is 0, R8 is H, A and B form - CH = CH-, C is CHR17, where R17 is -CH3, D is a bond, E and F are each N. 58. The compound of claim 57, wherein E and F are joined to form a fused heterocyclic ring, which is substituted with 1 aryl group. 59. The compound of claim 58, wherein R7 has the formula: 60. The compound of claim 54, wherein G is ethylene, m is 0, R8 is H, A is NH, B is CHR17, C and D are each a bond, E is CH2 and F is S. 61. The compound of claim 60, wherein R17 is alkoxycarbonyl 62 The compound of claim 61, wherein R17 methoxycarbonyl A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier. A pharmaceutical composition for treating or preventing prostate disorders, comprising a compound of claim 1 and a pharmaceutically acceptable carrier. Claim 23, wherein the prostate disorder is prostate cancer or benign prostatic hyperplasia. 66 A pharmaceutical composition for treating or preventing neoplasia, rheumatoid arthritis, pulmonary fibrosis, myelofibrosis, abnormal wound healing, atherosclerosis, or restenosis, comprising a compound of claim 1 and a pharmaceutically acceptable carrier 67 A pharmaceutical composition for treating or preventing Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, stroke, schema, Huntington's disease, dementia for SI DA, epilepsy, sclerosis multiple, neuropat to peripheral, or lesions of the brain or spinal cord, comprising a com position of claim 1 and a pharmaceutically acceptable carrier. A method for inhibiting a substance comprising providing a com position of claim 1 in an amount sufficient to result in Effective nhi bition 69 The method of claim 68, wherein the kinase is selected to result in effective inhibition 70. The method for inhibiting trk kinase activity, comprising providing a compound of claim 1 in a sufficient amount to result in in effective inhibition. 71 The method of claim 70, wherein the trk kinase is trk A. 72. The method of claim 70, wherein the compound of claim 1 is provided to treat inflammation. 73. A method for treating or preventing prostate disorders, which comprises administering to a host in need of such treatment or prevention, a therapeutically effective amount of a compound of claim 1. 74. The method of claim 73, wherein the prostate disorder is prostate cancer or benign prostatic hyperplasia. 75. A method for treating or preventing disorders where VEG FR activity contributes to pathological conditions, comprising providing a compound of claim 1 in an amount sufficient to result in the platelet-derived growth factor receptor coming into contact with a effective inhibitory amount of the compound. 76. The method of claim 75, wherein the disorder is cancer, endometriosis, psoriasis, hemangioblastoma or an ocular disease. 77. The method of claim 75, wherein the disorder is cancer. 78. The method of claim 77, wherein the disorder is a solid tumor or a hematopoietic or lymphatic malignancy. 79. The method of claim 75, wherein the disorder is an ocular disease. 80. The method of claim 79, wherein the ocular disease is diabetic retinopathy. 81 A method for treating or preventing disorders, wherein the PDGFR activity contributes to pathological conditions, comprising providing a compound of claim 1 in an amount sufficient to result in the platelet-derived growth factor receptor being contacted with an inhibitory amount. effective of the commission. 82. A method for treating or preventing neoplasia, rheumatoid arthritis, pulmonary fibrosis, myelofibrosis, abnormal wound healing, atherosclerosis, or restenosis, which comprises administering to a host in need of such treatment or prevention, a therapeutically effective amount of a compound of claim 1. 83. A method to treat or prevent disorders characterized by the aberrant activity of cells that respond to trophic factors, comprising providing a compound of claim 1 in an amount sufficient to result in the cellular receptor of trophic factors being contacted with an inducing amount of effective activity of the compound. 84. A method to treat or prevent Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, stroke, ischemia, H untington's disease, AIDS dementia, epilepsy, multiple sclerosis, peripheral neuropathy, or brain or marrow lesions spinal, which comprises administering to a host in need of such treatment or prevention, a therapeutically effective amount of a compound of claim 1. 85. A method for treating or preventing disorders characterized by the aberrant activity of a protein kinase, which comprises administering to a host in need of such treatment or prevention, a therapeutically effective amount of a compound of claim 1. 86. A method for treating or prevent disorders, where either the vascular endothelial growth factor receptor (VEGFR), trkA tyrosine kinase (trkA), mixed lineage kinase (MLK) or the fibroplast growth factor receptor kinase (FGFR) contribute to pathological conditions, the method comprising providing a compound of claim 1 in an amount sufficient to result in the receptor being contacted with an effective inhibitory amount of the compound. 87. A method for treating or preventing a disease mediated by a selected kinase of abl, AKT, bcr-ab1, Blk, Brk, Btk, c-kt, c-met, c-src, CDK1, CDK2, CDK4, CDK6, chkl, chk2, cRafl, CSF1R, CSK, EGFR, ErbB2, ErbB3, ErbB4, ERK (Eph), ERK2, Fak, fes, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, FLK-4, flt-1, Fps, Frk, Fyn, GSK, Hck, IGF-1R, INS-R, Jak, JNK, tau, VEGFR1, VEGFR2, VEGFR3, Lck, Lyn, MEK, p38, PDGFR, PIK, PKC, PYK2, ros, tie, , tie2, TRK, UL97, Yes and Zap70, the method comprising administering to a patient in need of such treatment or prevention, a pharmaceutically effective amount of a compound of claim 1. 88. A method for treating or preventing disorders, wherein a Selected kinase of abl, AKT, bcr-ab1, Blk, Brk, Btk, c-kit, c-met, c-src, CDK1, CDK2, CDK4, CDK6, chkl, chk2, cRafl, CSF1R, CSK, EGFR, ErbB2 , ErbB3, ErbB4, ERK (Eph), ERK 2, Fak, fes, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, FLK-4, flt-1, Fps, Frk, Fyn, GSK, Hck, IGF-1R , INS-R, Jak, JNK, tau, VEGFR1, VEGFR2, VEGFR3, Lck, Lyn, MEK, p38, PDGFR, PIK, PKC, PYK2, ros, tie, tie2, TRK UL97, Yes and Zap70, contribute to pathological conditions, the method comprising providing a compound of claim 1 in a sufficient amount, to result in the receptor being contacted with an effective inhibiting amount of the compound. 89. A method for treating or preventing a symptom of a disorder, wherein a selected kinase of abl, AKT, bcr-ab1, Blk, Brk, Btk, c-kt, c-met, c-src, CDK1, CDK2, CDK4 , CDK6, chkl, chk2, cRafl, CSF1R, CSK, EGFR, ErbB2, ErbB3, ErbB4, ERK (Eph), ERK2, Fak, fes, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, FLK-4, flt -1, Fps, Frk, Fyn, GSK, Hck, IGF-1R, INS-R, Jak, JNK, tau, VEGFR1, VEGFR2, VEGFR3, Lck, Lyn, MEK, p38, PDGFR, PIK, PKC, PYK2, ros , tie2, TRK UL97, Yes and Zap70, contributes to such a symptom, the method comprising providing a compound of claim 1 in an amount sufficient to result in the receptor being contacted with an effective inhibitory amount of the compound. 90. A method to treat or prevent Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, stroke, ischemia, Huntington's disease, AIDS dementia, epilepsy, multiple sclerosis, peripheral neuropathy, brain or spinal cord injuries, cancer, restenosis , osteoporosis, inflammation, angiogenesis, viral infections, bone or hematopoietic diseases, autoimmune diseases or rejection of transplants, which comprises administering to a host in need of such treatment or prevention, a therapeutically effective amount of a compound of claim 1. 91 A method for the treatment of cancer, which comprises inhibiting one or more of Src, raf, a checkpoint kinase or a cyclin-dependent kinase. 92. The method of claim 91, wherein the kinase dependent kinase is CDK 1, 2, 4 or 6. 93. The method of claim 91, wherein the checkpoint kinase is chk 1 or chk 2. 94. The method of claim 91, which comprises inhibiting Src or raf. SUMMARY The present invention is directed to cyclic substituted fused pyrrolocarbazoles and isoindolones having the formula I. The invention is also directed to methods for making and using the pyrrolocarbazoles and Fused cyclic substituted fused soindolones. The compounds are useful as agents for the regulation of protein kinase.