TWI553010B - Heterocyclic pyrazole compounds, method for preparing the same and use thereof - Google Patents

Description

Heterocyclic pyrazole compound, preparation method and use thereof

This invention relates to novel heterocyclic pyrazole compounds and hydrates, solvates, prodrugs or pharmaceutically acceptable salts thereof. These compounds are receptor tyrosine kinase (RTK) inhibitors and have the efficacy of treating, preventing or ameliorating RTK related diseases.

More than 500 unique kinases are encoded in the human genome. Protein kinases are enzymes that catalyze the phosphorylation of hydroxyl groups on tyrosine, serine and threonine residues of proteins. Xianxin protein kinase plays an important role in the signal transduction pathways that regulate a variety of cellular functions such as cell cycle, cell growth, cell differentiation, cell death (apoptosis) and tissue/organ body formation. Abnormal or overactive or dysregulated activity of protein kinases have been observed in a number of disease conditions, including benign and malignant proliferative disorders as well as inflammatory and immune system disorders. Therefore, protein kinases are the therapeutic targets of concern for the treatment of diseases.

For example, dysregulation of the activity of the receptor tyrosine kinase of the platelet growth factor receptor (PDGFR) family has been implicated in a variety of proliferative disorders. Amplification or up-regulation of PDGFR genes occurs in patients with gliomas or sarcomas. The constitutive activation of PDGFRα has been found in patients with chronic myelomonocytic leukemia (CML). Functional mutations and small deletions of the PDGFRα gene have also been found in patients with gastrointestinal tumors (GIST) and idiopathic eosinophilia. PDGFRβ has been found to be expressed in the tumor stroma of most solid tumors, thereby making this receptor an anti-tumor therapy Potential target. PDGFRβ has also been shown to be expressed in tumor vascular structures, and studies have shown that PDGFR-β inhibition is a mechanism of anti-angiogenic therapy.

The second member of the PDGFR family, FLT3 (also known as Flk2), plays an important role in the proliferation and differentiation of hematopoietic stem cells, and activating mutations or overexpression of this receptor are found in AML. Discovered by more than twelve known FLT3 inhibitors in the study, some of which have shown potential for clinical effects of AML. The FLT3 receptor is also expressed in most dendritic progenitor cells, and stimulation of this receptor triggers the proliferation and differentiation of these progenitor cells into dendritic cells (DC). Since dendritic cells are the major initiators of T cell-mediated immune responses, including autoreactive immune responses, inhibition of FLT3 is a mechanism for down-regulating DC-mediated inflammatory and autoimmune responses. One study showed that the FLT3 inhibitor CEP-701 is effective in reducing myelin loss in experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. High levels of FLT3 ligands are found in the serum of patients with Langerhans cell histiocytosis and systemic lupus erythematosus, thereby further enabling FLT3 signaling and their autoimmune diseases Deregulation of dendritic cell progenitors.

Kit (or stem cell factor receptor or SCFR) is another member of the PDGFR family, and the presence of kit mutations is a key diagnostic marker for gastrointestinal matrix tumors (GIST). Gleevec (imatinib mesylate or STI571) is the first FDA-recognized receptor tyrosine kinase (RTK) inhibitor for c-Abl-mediated chronic myeloid leukemia, which was approved by the FDA in 2002. Kit-mediated GIST and establishment of molecular-based Kit inhibition to treat GIST. Functional mutations are also associated with mast cells/myeloid leukemia and fine sperm Cell carcinoma/analogous cell tumor is associated. Kit mutations have also been identified in certain melanomas and are recognized as potential therapeutic targets for melanoma.

Thus, pharmacological modulation of one or more kinases will be useful for slowing or halting the disease, such as cancer induced by inappropriate cell proliferation. Currently, a variety of protein kinase inhibitors have been developed and are widely used in clinical applications.

Including WO 99/55335, WO 00/27822, WO 00/59901, US 6,297,238 B1, US 6,245,796 B1, WO 01/87846 A2, US 6,462,036 B1, WO 2004/080973 A1, US 7,485,730, EP 1602658 A1, US 2007/ Related patents of 173,488 A1 and US 7,468,371 B2 are incorporated herein by reference.

However, protein kinase inhibitors still have considerable demand in this technology, especially the class III receptor tyrosine kinase (RTK) family, such as FLT3 kinase, c-KIT kinase and inhibitor of PDGFR kinase, which have therapeutic, Prevent or improve the efficacy of RTK-related diseases.

One embodiment of the invention provides a compound of formula (I): Or a hydrate, solvate, prodrug or pharmaceutically acceptable salt thereof, wherein R ¹ , R ² , X, Y, ring A, R ³ and R ⁴ are as defined in the specification and the claims.

a compound of formula (I) and a hydrate, solvate, prodrug or pharmaceutically acceptable thereof The salt received is an RTK inhibitor and has the efficacy of treating diseases and conditions mediated by receptor tyrosine kinase (RTK).

In another embodiment of the present invention, there is provided a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a hydrate, solvate, prodrug or pharmaceutically acceptable salt thereof, and a medicament A school-acceptable carrier.

Another embodiment of the invention provides a method of treating a disease and condition mediated by a receptor tyrosine kinase in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of formula (I) or hydration thereof A solvate, prodrug or pharmaceutically acceptable salt.

The present invention relates to a compound of formula (I): Wherein: R ¹ and R ² independently represent hydrogen, halo, cyano, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, -(CH ₂ ) _m OR _a , -( CH ₂ ) _m NR _a R _b , -NR _a R _b , -OR _a , SR _b , -CO ₂ R _a , -NR _a CO-(CH ₂ ) _nm NR _a R _b , -CONR _a R _b , - CONR _a -(CH ₂ ) _m NR _a R _b , aryl, heteroaryl or heterocyclic group wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, OR _a , The SR _b , aryl, heteroaryl and heterocyclic group are optionally one or more substituents selected from the group consisting of 1 to 3 substituents selected from below, or more preferably 1 or 2 selected from the group consisting of Substituents substituted: halo, hydroxy, alkyl, haloalkyl, alkoxy, amine, cycloalkyl, aralkyl, aryl, heteroaryl, heterocyclyl, heterocyclyl-alkyl and -CONH-heteroaryl; X represents alkyl, alkenyl, alkyl-carbonyl, alkenyl-carbonyl, carbonyl, oxygen, -C=NOR _c ; Y represents a direct bond, an alkyl group, an alkenyl group or -NH-; ring A represents aryl, heteroaryl or heterocyclic; R ³ and R ⁴ independently represent hydroxy, hydrogen, halo, nitro, cyano, amine, pendant oxy (ox o), alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, aryl, alkylaryl, NR _a R _b , -NH-aryl, heteroaryl, alkenyl- Aryl, S(O) _n -heterocyclyl, -NH-heterocyclyl or heterocyclyl, wherein the alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, aryl, aryl Alkyl, -NH-aryl, heteroaryl, alkenyl-aryl, S(O) _n -heterocyclyl, -NH-heterocyclyl and heterocyclyl are optionally selected from one or more selected from the group consisting of Substituents, preferably 1 to 3 or more preferably 1 or 2 substituents selected from the group consisting of amine, cyano, halo, haloalkyl, hydroxy, alkyl, alkoxy and haloalkoxy R _a and R _{b are} independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocyclic, or R _a and R _b a heteroaryl or heterocyclic group formed together with an oxygen, nitrogen or sulfur atom to which it is bonded; R _c represents hydrogen or an alkyl group, m is 0, 1, 2 or 3; and n is 0, 1 or 2, or A hydrate, solvate, prodrug or pharmaceutically acceptable salt.

In the present specification, the term "hydrogen" means a hydrogen atom moiety (-H) instead of H ₂ .

The term "halo" or "halogen" means fluoro, chloro, bromo or iodo. Preferred "halogen" groups are fluorine, chlorine or bromine.

The term "haloalkyl" means an alkyl group substituted with one or more of the same or different halogen atoms. Examples of "haloalkyl" are 1-fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl and 2,2,2-trifluoroethyl. The most preferred "haloalkyl" is trifluoromethyl.

The term "alkyl" refers to a branched or straight-chain monovalent alkyl group having from 1 to 12 carbon atoms, alternatively from 1 to 8 carbon atoms, or from 1 to 6 carbon atoms. In some embodiments, the alkyl group has from 1 to 4 carbon atoms. In some embodiments, the alkyl group has 2 to 12 carbon atoms, alternatively 2-8 carbon atoms, or 2-6 carbon atoms. In some embodiments, the alkyl group has from 2 to 4 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, t-butyl, pentyl, hexyl, and the like.

The term "alkenyl" means an unsaturated straight or branched chain chain having one or more carbon-carbon double bonds and having from 2 to 12 carbon atoms, or from 2 to 8 carbon atoms, or from 2 to 6 carbon atoms. Family group. In some embodiments, the alkenyl group has 2 to 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, and hexenyl.

The term "alkynyl" means an unsaturated straight or branched chain chain having one or more carbon-carbon bonds and having from 2 to 12 carbon atoms, or from 2 to 8 carbon atoms, or from 2 to 6 carbon atoms. Family group. In some embodiments, an alkynyl group has 2 to 4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, Butynyl, pentynyl and hexynyl.

The term "alkylene" or "alkenyl" refers to an alkyl or alkenyl group, as defined above, respectively, positioned between two other chemical groups and used to attach the two chemical groups. Examples of alkylene groups include, but are not limited to, methylene, ethyl, propyl and butyl. Examples of alkenyl groups include, but are not limited to, vinyl, propylene, and butenyl groups.

The term "alkoxy" means a group R'-O-, wherein R' is alkyl as defined above. Representative alkoxy groups include methoxy, ethoxy, isopropoxy, tert-butoxy and the like.

The term "cycloalkyl" means a saturated monocyclic, bicyclic ring having from about 3 to 15 carbons, or from 3 to 12 carbons, or from 3 to 8 carbons, or from 3 to 6 carbons, or 5 or 6 carbons. a tricyclic or polycyclic hydrocarbon group. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl and the like.

The term "cycloalkenyl" means having one or more carbon-carbon double bonds and having from about 3 to 15 carbons, or from 3 to 12 carbons, or from 3 to 8 carbons, or from 3 to 6 carbons, or 5 or 6 carbon-unsaturated monocyclic, bicyclic, tricyclic or polycyclic hydrocarbon groups. Examples of "cycloalkenyl" include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and the like.

The term "aryl" is used to mean a monocyclic, bicyclic, tricyclic or polycyclic aromatic moiety comprising from 1 to 3 aromatic rings. In some embodiments, the aryl group is a C ₆ -C ₁₄ aromatic moiety, or the aryl group is a C ₆ -C ₁₂ aryl group, or the aryl group is a C ₆ -C ₁₀ aryl group, or a C ₆ aryl group. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthryl and anthracenyl.

The term "heteroaryl" is used to mean having 5 to 14 ring atoms, or 5, 6, 9 or 10 ring atoms; having, for example, 6, 10 or 14 π electrons shared in a ring array; There are one or more, for example 1, 2 or 3, monocyclic, bicyclic, tricyclic or polycyclic groups independently selected from the group consisting of N, O and S. More specifically, the term "heteroaryl" includes, but is not limited to, pyridyl, oxy-pyridyl, furyl, thienyl, thiazolyl, isothiazolyl, triazolyl, imidazolyl, isoxazolyl , pyrrolyl, pyrimidinyl, pyrazolyl, pyrazinyl, pyrimidinyl, benzofuranyl, tetrahydrobenzofuranyl, isobenzofuranyl, benzothiazolyl, benzisothiazolyl, benzotrien Azyl, fluorenyl, isodecyl, benzoxazolyl, quinolyl, tetrahydroquinolyl, isoquinolyl, benzimidazolyl, benzisoxazolyl or benzothienyl, Imidazolium [1,2-a]-pyridyl, imidazolium [2,1-b]thiazolyl and derivatives thereof. The most preferred heteroaryl groups are pyridyl, thienyl, furyl and pyrrolyl.

The term "heterocyclyl" is used to mean having from about 3 to about 14 atoms, or from 3 to 12 atoms, or from 3 to 10 atoms, or from 3 to 8 atoms, or from 4 to 7 atoms, or 5 or A monocyclic, bicyclic or polycyclic structure of 6 atoms in which one or more atoms, for example 1, 2 or 3, are independently selected from the group consisting of N, O and S, and the remaining ring constituent atoms are carbon atoms. The ring structure can be a saturated or unsaturated ring, but not an aromatic ring. Examples of heterocyclic groups include, but are not limited to, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-sided oxypyrrolidinyl, 4-piperidyl Pyridone, pyrrolidinyl, carbendidyl, pentanosyl, oxiranyl, oxetanyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydropyridyl , tetrahydropyrimidinyl, tetrahydrothiopyranium, tetrahydrothiopyranium, morpholinyl, thiomorpholinyl, Thiomorpholine, thiomorpholinium, 1,3-dioxolane, tetrahydrofuranyl, dihydrofuranyl-2-one, tetrahydrothiophenyl, and tetrahydro-1,1-di Oxythiophenyl group. A preferred heterocyclic group is piperidinyl.

The term "aralkyl" is intended to mean a group comprising an aryl group covalently bonded to an alkyl group. If an aralkyl group is described as "optionally substituted", it is contemplated that one or both of the aryl and alkyl moieties can be independently substituted or unsubstituted as appropriate. In some embodiments, the aralkyl group is a (C ₁ -C ₆ )alkyl (C ₆ -C ₁₀ ) aryl group including, but not limited to, benzyl, phenethyl, and naphthylmethyl. In short, when written as "arylalkyl", the term and its related terms are intended to mean that the order of the group in the compound is "aryl-alkyl". Similarly, "alkyl-aryl" is intended to mean that the order of the group in the compound is "alkyl-aryl".

As used herein, the term "pharmaceutically acceptable salt" is intended to mean a salt that retains the desired biological activity of the compound identified above and exhibits minimal or no undesirable toxicological effects. Examples of such salts are the salts of the compounds of formula (I) with physiologically compatible acids: inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfurous acid or phosphoric acid; or organic acids such as methanesulfonic acid, Toluenesulfonic acid, acetic acid, lactic acid, trifluoroacetic acid, citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid or salicylic acid.

The term "hydrate" refers to a complex in which one or more solvent molecules are water, and includes monohydrates, hemihydrates, dihydrates, hexahydrates, and the like. The terms "solvate" and "hydrate" are well known to those skilled in the art. The term "solvate" refers to a molecular complex or a non-stoichiometric amount of a molecular complex of a compound with one or more solvent molecules. Molecular complex of a compound or a compound moiety with a solvent (for example, electrostatic force, van der Waals or hydrogen bonding) is stable. Those skilled in the art of organic chemistry will appreciate that many compounds can form such complexes with the solvent they are obtained from, prepared from, or synthesized from or precipitated from. Techniques for preparing such solvates are well known in the art (see, e.g., Britain, Polymorphism in Pharmaceutical Industry, Wilen, Weinheim, Germany, 2006).

In certain embodiments, the solvent is an inorganic solvent (eg, water). In certain embodiments, the solvent is an organic solvent (such as, but not limited to, alcohols (such as (but without limitation) methanol, ethanol, isopropanol, and the like), acetic acid, ketones, esters, and analog). In certain specific aspects, the solvent is conventional in the pharmaceutical arts and is known to be non-toxic to the recipient of the solvent (e.g., water, ethanol, and the like) without interfering with the biological activity of the solute.

The term "prodrug" is intended to mean a compound that is covalently bound to a carrier, and when the prodrug is administered to a mammalian subject, the active ingredient in the prodrug can be released. The release of the active ingredient occurs in vivo. Prodrugs can be prepared according to techniques well known in the art. Such techniques generally modify the appropriate functional groups on the provided compounds. However, such functional groups can be restored to the original functional group after routine manipulation or in vivo. Prodrugs of the compounds of the invention include those in which a hydroxyl, amine, carboxyl or similar group is modified. Examples of prodrugs include, but are not limited to, esters (eg, formate, acetate, propionate, butyrate, acrylate, ethyl succinate, and benzoate derivatives), carbamates (such as N,N-dimethylaminocarbonyl on the hydroxyl or amine functional group of the compound of the invention), guanamine (such as trifluoroethylene ammonia) Base, vinylamine based extreme analogs) and analogs thereof. Upon administration to an individual, the prodrug is chemically converted by metabolic or chemical means to produce a compound of the invention.

The present invention provides a preferred embodiment of the compound of formula (I) wherein: R ¹ and R ² independently represent hydrogen, alkyl, halo, cyano, -NR _a CO-(CH ₂ ) _m NR _a R _b , -CONR _a R _b , -CONR _a -(CH ₂ ) _m NR _a R _b , -(CH ₂ ) _m OR _a , -(CH ₂ ) _m NR _a R _b , aryl, heteroaryl or heterocyclic a group wherein the alkyl group, heteroaryl group, aryl group and heterocyclic group are optionally substituted with one or more substituents selected from the group consisting of 1 to 3 substituents selected from the group consisting of halo, hydroxy, Alkoxy, amino, heterocyclyl-alkyl and -CONH-heteroaryl; X represents C _1-3 alkyl or carbonyl; Y represents a direct bond or -NH-; ring A represents phenyl, pyridyl , pyrimidinyl or furyl; R ³ and R ⁴ independently represent an amine group, a halogen group, a hydroxyl group, a nitro group, a pendant oxy group, a C _1-4 alkyl group, a C _1-4 alkoxy group, a halogen group-C _{1 -4} alkyl, phenyl, C _1-3 alkenyl-phenyl, NR _a R _b , -NH-phenyl, S(O) ₂ -piperidinyl, -NH-pyridyl, piperazinyl, Pyrrolidinyl or morpholinyl, wherein the C _1-4 alkyl group, C _1-4 alkoxy group, halo-C _1-4 alkyl group, phenyl group, C _1-3 alkylene group-phenyl group, NH- phenyl, S (O) ₂ - piperidinyl, -NH- pyrazole Yl, piperazinyl, morpholinyl and pyrrolidinyl are optionally substituted with 1-2 substituents selected from the substituent group: halo, hydroxy, C _1-4 alkyl, C _1-4 alkoxy, amino , cyano, halo-C _1-4 alkyl and halo-C _1-4 alkoxy; R _a and R _{b are} independently hydrogen, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, C _3-15 cycloalkyl, C _3-15 cycloalkenyl, aryl, heteroaryl or heterocyclic, or R _a and R _b The oxygen, nitrogen or sulfur atom of the knot together form a morpholinyl, piperidinyl, piperazinyl, methylpiperazinyl, thiomorpholinyl or pyrrolidinyl group; and m is 0, 1 or 2, or hydrated thereof A solvate, prodrug or pharmaceutically acceptable salt.

The present invention provides another preferred embodiment of the compound of formula (I) or a hydrate, solvate, prodrug or pharmaceutically acceptable salt thereof, wherein X represents a methylene group.

The present invention provides another preferred embodiment of the compound of formula (I) or a hydrate, solvate, prodrug or pharmaceutically acceptable salt thereof, wherein X represents a carbonyl group.

The present invention provides another preferred embodiment of the compound of formula (I) or a hydrate, solvate, prodrug or pharmaceutically acceptable salt thereof, wherein Y represents a direct bond.

The present invention provides another preferred embodiment of the compound of formula (I) or a hydrate, solvate, prodrug or pharmaceutically acceptable salt thereof, wherein Y represents -NH-.

The present invention provides another preferred embodiment of the compound of formula (I), or a hydrate, solvate, prodrug or pharmaceutically acceptable salt thereof, wherein ring A is phenyl.

The present invention provides another preferred embodiment of the compound of formula (I) or a hydrate, solvate, prodrug or pharmaceutically acceptable salt thereof, wherein ring A is pyridyl.

The present invention provides a compound of formula (I) or a hydrate, solvate, prodrug thereof or Another preferred embodiment of a pharmaceutically acceptable salt wherein Ring A is a furyl group.

The present invention provides another preferred embodiment of the compound of the formula (I) or a hydrate, solvate, prodrug or pharmaceutically acceptable salt thereof, wherein R ³ and R ⁴ independently represent an amine group or a halogen group , hydroxy, nitro, pendant oxy, methoxy, trifluoromethyl, trifluoromethoxy, phenyl, styryl-phenyl, styrene-phenyl, -NH-phenyl, S(O ₂ -piperidinyl, -NH-pyridyl, piperazinyl, pyrrolidinyl or morpholinyl, wherein the phenyl, -NH-phenyl, S(O) ₂ -piperidinyl, -NH-pyridine The base, piperazinyl, pyrrolidinyl and morpholinyl are optionally substituted by 1 to 2 substituents selected from the group consisting of halo, hydroxy, methyl, methoxy, amine, cyano, trifluoromethyl And trifluoromethoxy.

The present invention provides another preferred embodiment of the compound of formula (I) or a hydrate, solvate, prodrug or pharmaceutically acceptable salt thereof, ring A together with R ³ and R ⁴ to form a phenyl group, 2 -Bromo-phenyl, 3-bromo-phenyl, 4-bromo-phenyl, 2-chloro-phenyl, 3-chloro-phenyl, 4-chloro-phenyl, 2,3-dichloro-phenyl , 2,4-dichloro-phenyl, 3,4-dichloro-phenyl, 3,5-dichloro-phenyl, 2-fluoro-phenyl, 3-fluoro-phenyl, 4-fluoro-benzene Base, 4-iodo-phenyl, phenylamine, 2-methoxy-phenyl, 3-methoxy-phenyl, 4-methoxy-phenyl, 2,4-dimethoxy-benzene , 3,4-dimethoxy-phenyl, 4-nitro-phenyl, 4-amino-phenyl, 2-trifluoromethyl-phenyl, 3-trifluoromethyl-phenyl, 4-Trifluoromethyl-phenyl, 3,5-bis-trifluoromethyl-phenyl, phenyl-(4-fluoro-phenyl)-amine, phenyl-(4-methoxy-phenyl )-amine, biphenyl-4-phenol, 3-methoxy-biphenyl-4-phenol, phenylamino-phenol, phenol, 4-styryl-phenyl, phenyl]-benzene-1, 4-Diamine, 3',4'-dimethoxy-biphenyl-4-yl, biphenyl-4-carbonitrile, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 6 -Bromo-pyridin-3-yl, phenyl-pyridin-3-yl, phenyl-pyridine- 4-yl, 1-oxy-pyridin-3-yl, 1-oxy-pyridin-4-yl, pyridin-2-ylamine, pyridin-3-ylamine, pyridin-4-ylamine, 4-pyrrole Pyridin-1-yl-phenyl, furan-3-yl, 3',5'-dichloro-biphenyl-4-yl, 4'-trifluoromethyl-biphenyl-4-yl, phenyl-( 3-fluoro-phenyl)-amine, 4-(piperidin-1-sulfonyl)-phenyl, 4-(4-methyl-piperazin-1-yl)-phenyl or 4-morpholine- 4-yl-phenyl.

Specific examples of the compound of the formula (II) include: 6-(4-bromo-phenyl)-5,7-dihydro-1-thio-4,5-diaza-cyclopentadienyl[a]fluorenecyclopentane Diene, 4-(4,7-dihydro-1-thio-4,5-diaza-cyclopentadienyl[a]indolecyclopentadienyl-6-yl)-phenylamine hydrochloride, 6-(3-methoxy-phenyl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]noncyclopentadiene, 6-(2, 4-dimethoxy-phenyl)-4,7-dihydro-1-thio-4,5-diaza-cyclopentadienyl[a]noncyclopentadiene, 6-(4-nitro -phenyl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]noncyclopentadiene, 6-phenyl-4,7-dihydro-1 - sulfur-4,5-diaza-cyclopentadienyl[a]indolecyclopentadiene, [4-(4,7-dihydro-1-thio-4,5-diaza-cyclopentadiene)幷[a]幷cyclopentadienyl-6-yl)-phenyl]-(4-fluoro-phenyl)-amine, [4-(4,7-dihydro-1-sulfo-4,5-di Nitrogen-cyclopentadienyl[a]indolecyclopentadienyl-6-yl)-phenyl]-(4-methoxy-phenyl)-amine, 4'-(4,7-dihydro-1 -sulfur-4,5-diaza-cyclopentadienyl[a]indolecyclopentadiene-6- 3-methoxy-biphenyl-4-phenol, 3-[4-(4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]fluorene ring Pentadiene-6-yl)-phenylamino]-phenol, 4'-(4,7-dihydro-1-thio-4,5-diaza-cyclopentadienyl[a]indole Diene-6-yl)-biphenyl-4-phenol, 6-(4-styryl-phenyl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadiene幷[a]幷cyclopentadiene, N-[4-(4,7-dihydro-1-thio-4,5-diaza-cyclopentadienyl[a]indolecyclopentadiene-6- Benzyl]-phenyl-1,4-diamine, 6-(3',4'-dimethoxy-biphenyl-4-yl)-4,7-dihydro-1-thio-4 ,5-diaza-cyclopentadienyl[a]indolecyclopentadiene, 4'-(4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]幷cyclopentadienyl-6-yl)-biphenyl-4-carbonitrile, 6-pyridin-3-yl-4,7-dihydro-1-thio-4,5-diaza-cyclopentadiene [a] Cyclopentadiene, 6-furan-3-yl-4,7-dihydro-1-thio-4,5-diaza-cyclopentadienyl[a]noncyclopentadiene, 4 ,7-Dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]indolecyclopentadiene, 6-(3',5'-dichloro-biphenyl-4-yl) -4,7-dihydro-1-thio-4,5-diaza-cyclopentadienyl[a]indolecyclopentadiene, 6-(4'-trifluoromethyl-biphenyl-4-yl )-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]fluorene ring Pentadiene, 2-bromo-6-phenyl-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]noncyclopentadiene, 6-(1-oxy-pyridin-3-yl)-4,7-dihydro-1-thio-4,5-diaza-cyclopentadienyl[a]noncyclopentadiene, 2-bromo -6-(4-bromo-phenyl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]noncyclopentadiene, 2-bromo-6- (4-methoxy-phenyl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl ruthenium [a]noncyclopentadiene, 6-(3-fluoro- Phenyl)-4,7-dihydro-1-thio-4,5-diaza-cyclopentadienyl[a]noncyclopentadiene,6-(3-chloro-phenyl)-4,7 -Dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]indolecyclopentadiene,6-(4-fluoro-phenyl)-4,7-dihydro-1-sulfide -4,5-diaza-cyclopentadienyl hydrazone [a] fluorene cyclopentadiene, 6-(2-fluoro-phenyl)-4,7-dihydro-1-thio-4,5-diaza -cyclopentadienyl hydrazone [a] fluorene cyclopentadiene, 6-(3,5-bis-trifluoromethyl-phenyl)-4,7-dihydro-1-thio-4,5-diaza -cyclopentadienyl hydrazone [a] fluorene cyclopentadiene, 6-(2-bromo-phenyl)-4,7-dihydro-1-thio-4,5-diaza-cyclopentadienyl hydrazine [ a] indole cyclopentadiene, 6-(3-bromo-phenyl)-4,7-dihydro-1-thio-4,5-diaza-cyclopentadienyl[a]noncyclopentadiene ,6-(3-chloro-phenyl)-4H-1-thio-4,5-diaza-cyclopentadienyl[a]indolecyclopentadien-7-one, 6-(2-methoxy Base-phenyl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl hydrazone [a]幷cyclopentadiene, 6-(4-Amino-phenyl)-4H-1-thio-4,5-diaza-cyclopentadienyl[a]indolecyclopentadien-7-one, 6-(3,5- Dichloro-phenyl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]noncyclopentadiene, 6-pyridin-2-yl-4,7 -Dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]noncyclopentadienyl hydrochloride, 3-(4,7-dihydro-1-sulfo-4,5- Diazo-cyclopentadienyl[a]indolecyclopentadienyl-6-yl)-phenylamine hydrochloride, 6-pyridin-4-yl-4,7-dihydro-1-sulfo-4, 5-diaza-cyclopentadienyl hydrazone [a] fluorene cyclopentadienyl hydrochloride 6-(1-oxy-pyridin-4-yl)-4,7-dihydro-1-sulfo-4,5 -diaza-cyclopentadienyl[a]indolecyclopentadiene,6-(6-bromo-pyridin-3-yl)-4,7-dihydro-1-sulfo-4,5-diaza- Cyclopentadienyl hydrazone [a] fluorene cyclopentadiene, 6-(4-methoxy-phenyl)-2-phenyl-4,7-dihydro-1-thio-4,5-diaza- Cyclopentadienyl hydrazone [a] fluorene cyclopentadiene, 5-(4,7-dihydro-1-thio-4,5-diaza-cyclopentadienyl[a]fluorenecyclopentadiene-6 -yl)-pyridin-2-ylamine hydrochloride, 2-bromo-6-(6-bromo-pyridin-3-yl)-4,7-dihydro-1-sulfo-4,5-diaza- Cyclopentadienyl ruthenium [a] fluorene cyclopentadiene, 6-(4-amino-phenyl)-4H-1-thio-4,5-diaza-cyclopentadienyl ruthenium [a] fluorene cyclopentane Dien-7-one, 6-(6-bromo-pyridine-3- ) -4H-1- 4,5-sulfur-nitrogen - Bing cyclopenta [a] cyclopenta Bing-7-one, 6-(4-methoxy-phenyl)-2-pyridin-4-yl-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]indole Diene, 6-(4-methoxy-phenyl)-2-pyridin-3-yl-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienium[a] Cyclopentadiene, 2-(4-fluoro-phenyl)-6-(4-methoxy-phenyl)-4,7-dihydro-1-thio-4,5-diaza-cyclopentyl Diene oxime [a] fluorene cyclopentadiene, 2-(3,4-difluoro-phenyl)-6-(4-methoxy-phenyl)-4,7-dihydro-1-thio- 4,5-diaza-cyclopentadienyl ruthenium [a] fluorene cyclopentadiene, 2,6-bis-(4-methoxy-phenyl)-4,7-dihydro-1-thio-4 ,5-diaza-cyclopentadienyl[a]decenecyclopentadiene, 2-(3,4-dimethoxy-phenyl)-6-(4-methoxy-phenyl)-4 ,7-Dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]noncyclopentadiene, 2-methoxy-4-[6-(4-methoxy-benzene -4,7-dihydro-1-thio-4,5-diaza-cyclopentadienyl[a]noncyclopentadien-2-yl]-phenol, 6-(4-methoxy -phenyl)-2-(6-methoxy-pyridin-3-yl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]indole Diene, 2-furan-3-yl-6-(4-methoxy-phenyl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl hydrazone [a] Cyclopentadiene, 5-[6-(4-methoxy-phenyl)-4,7-dihydro-1- -4,5-diaza-cyclopentadienyl[a]decenecyclopentadien-2-yl]-pyridin-2-ylamine, 5-[6-(4-methoxy-phenyl)- 4,7-Dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]decenecyclopentadien-2-yl]-pyrimidin-2-ylamine, 6-(4-A Oxy-phenyl)-2-pyridin-3-yl-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]noncyclopentadiene, 6-[4-(4-Methyl-piperazin-1-yl)-phenyl]-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]幷Cyclopentadiene, 5-[6-(4-methoxy-phenyl)-4,7-dihydro-1-thio-4,5-diaza-cyclopentadienyl[a]indole Dien-2-yl]-pyridin-2-ylamine, 6-(4-methoxy-phenyl)-2-[6-(4-methyl-piperazin-1-yl)-pyridine-3 -yl]-4,7-dihydro-1-thio-4,5-diaza-cyclopentadienyl hydrazone [a] fluorene cyclopentadiene, 5-[6-(4-methoxy-phenyl) -4,7-Dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]decenecyclopentadien-2-yl]-pyridin-2-ylamine, N-{5 -[6-(4-methoxy-phenyl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]indolyl-2-yl ]-pyridin-2-yl}-2-pyrrolidin-1-yl-acetamide, 2-(3-fluoro-4-methoxy-phenyl)-6-(4-methoxy-phenyl -4,7-Dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]noncyclopentadiene, 6-(4-pyrrolidin-1-yl-phenyl)- 4,7-Dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]noncyclopentadiene, 6-(4-morpholin-4-yl-phenyl)-4, 7-Dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]indolecyclopentadiene, 3-[6-(4-methoxy-phenyl)-4,7- Dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]decenecyclopentadien-2-yl]-phenyl ,2-(6-Amino-pyridin-3-yl)-6-(4-methoxy-phenyl)-4H-1-thio-4,5-diaza-cyclopentadienium[a] Cyclopentadien-7-one, N-{5-[6-(4-methoxy-phenyl)-4,7-dihydro-1-thio-4,5-diaza-cyclopentane Alkene [a]indolecyclopentadien-2-yl]-pyridin-2-yl}-2-pyrrolidin-1-yl-acetamide hydrochloride, 5-[6-(4-morpholin-4-yl-phenyl)-4,7-dihydro-1-thio-4,5-diaza-cyclopentadienyl[a]noncyclopentadiene 2-yl]-pyridin-2-ylamine hydrochloride, 5-{6-[4-(4-methyl-piperazin-1-yl)-phenyl]-4,7-dihydro-1 - sulfur-4,5-diaza-cyclopentadienyl[a]decenecyclopentadien-2-yl}-pyridin-2-ylamine hydrochloride, 6-[4-(4-methyl- Piperazin-1-yl)-phenyl]-2-pyridin-3-yl-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]fluorenecyclopentane Alkyl hydrochloride, 5-[6-(4-methoxy-phenyl)-4,7-dihydro-1-thio-4,5-diaza-cyclopentadienyl[a]indole Dien-2-yl]-pyridin-3-ylamine hydrochloride, 4-[2-(6-amino-pyridin-3-yl)-4,7-dihydro-1-sulfo-4,5 -diaza-cyclopentadienyl[a]indolecyclopentadienyl-6-yl]-phenol, 4-(4,7-dihydro-1-thio-4,5-diaza-cyclopentadiene幷[a]幷cyclopentadienyl-6-yl)-phenol, [4-(4,7-dihydro-1-thio-4,5-diaza-cyclopentadienyl[a]fluorenecyclopenta Dien-6-yl)-phenyl]-(3-fluoro-phenyl)-amine, [4-(4,7-dihydro-1-thio-4,5-diaza-cyclopentadienium fluorene [a] Cyclopentadienyl-6-yl)-phenyl]-(4-methoxy-phenyl)-amine, (4-bromo-phenyl)-(4,7-dihydro-1- Sulfur-4,5-diaza-cyclopentadienyl[a]indolecyclopentadienyl-6-yl)-amine, (2, 4-dichloro-phenyl)-(4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]indolecyclopentadienyl-6-yl)-amine, 4,7-Dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]indolecyclopentadienyl-6-yl)-(4-iodo-phenyl)-amine, (4 ,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]indolecyclopentadienyl-6-yl)-(4-methoxy-phenyl)-amine, (4,7-Dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]indolecyclopentadienyl-6-yl)-(3,4-dimethoxy-phenyl )-amine, (3-chloro-phenyl)-(4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]noncyclopentadienyl-6-yl) -amine, (4,7-dihydro-1-thio-4,5-diaza-cyclopentadienyl[a]indolecyclopentadienyl-6-yl)-(3-methoxy-phenyl -amine, (4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]indolecyclopentadienyl-6-yl)-(3-trifluoromethyl- Phenyl)-amine, (4,7-dihydro-1-thio-4,5-diaza-cyclopentadienyl[a]indolecyclopentadienyl-6-yl)-(3-fluoro-benzene Amine, (2-chloro-phenyl)-(4,7-dihydro-1-thio-4,5-diaza-cyclopentadienyl[a]noncyclopentadienyl-6-yl )-amine, (4-chloro-phenyl)-(4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]noncyclopentadienyl-6-yl) -amine, (4,7-dihydro-1-thio-4,5-diaza-cyclopentadienyl[a]indolecyclopentadienyl-6-yl)-(4-trifluoromethyl-benzene Amine, (3-bromo-phenyl)-(4,7-dihydro-1-thio-4,5-diaza-cyclopentadienyl[a]noncyclopentadienyl-6-yl )-amine, (4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]indolecyclopentadienyl-6-yl)-(2-trifluoromethyl- Phenyl)-amine, (4,7-dihydro-1-thio-4,5-diaza-cyclopentadienyl hydrazone [a幷cyclopentadienyl-6-yl)-(2-methoxy-phenyl)-amine, (4,7-dihydro-1-thio-4,5-diaza-cyclopentadienyl hydrazine [ a] indole cyclopentadienyl-6-yl)-(4-trifluoromethoxy-phenyl)-amine, (4,7-Dihydro-1-thio-4,5-diaza-cyclopentadienyl[a]indolecyclopentadienyl-6-yl)-(2-trifluoromethoxy-phenyl) -amine, (3,5-dichloro-phenyl)-(4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]noncyclopentadiene-6- Amine, (2,4-dichloro-phenyl)-(4,7-dihydro-1-thio-4,5-diaza-cyclopentadienyl[a]indolecyclopentadiene- 6-yl)-amine, (3,4-dichloro-phenyl)-(4,7-dihydro-1-thio-4,5-diaza-cyclopentadienyl[a]fluorenecyclopentane Ace-6-yl)-amine, (2,3-dichloro-phenyl)-(4,7-dihydro-1-thio-4,5-diaza-cyclopentadienyl[a]fluorene ring Pentadien-6-yl)-amine, and (4,7-dihydro-1-thio-4,5-diaza-cyclopentadienyl[a]indolecyclopentadienyl-6-yl)- [4-(Piperidine-1-sulfonyl)-phenyl]-amine, and hydrates, solvates, prodrugs or pharmaceutically acceptable salts thereof.

The compound of formula (I) can generally be prepared according to Scheme 1 shown below. Tautomers and solvates (e.g., hydrates) of the compounds of formula (I) are also included within the scope of the invention. Methods of solvation are well known to those skilled in the art. Accordingly, the compounds of the present invention may be in the form of a free state, a hydrate or a salt, and may be obtained by the method exemplified in Scheme 1 below:

Process 1 method 1

Method-2

Method-3

Method-4

In Method-1, 5,6-dihydro-cyclopentadienyl hydrazone [b]thiophen-4-one (1), which is commercially available or prepared, is treated with an ester (2) and sodium hydride to provide a compound (3). ). Compound (3) may be subjected to heat treatment with hydrazine and acetic acid to provide compound (4).

In Method-2, 5,6-dihydro-cyclopentadienyl hydrazone [b]thiophene-4-one (1) obtained or prepared is isothiocyanate (5), THF and bis (trimethyl) The base alkyl) alkoxide is treated at ambient temperature. After 30 minutes, the mixture can be combined with amine and acetic acid to provide compound (6).

In the method -3, the compound (4) can be subjected to heat treatment to provide the compound (7) with bromine and acetic acid. Compound (7) can be treated with sodium hydride and 2-(trimethylsulfonyl)ethoxymethyl chloride to give compound (8). Compound (8) can be further treated under Heck, Suzuki or Stille conditions to obtain a compound as defined herein. Fang The benzyl- or heteroaryl-boronic acid and borate esters are commercially available or can be prepared by methods of the scientific literature of synthetic organic chemistry. The compound (8) may be obtained by an arylboronic acid or a heteroarylboronic acid obtained by a conventional method, a palladium source such as bis(triphenylphosphine)palladium(II) dichloride, and a base such as sodium carbonate. Treatment at 80 ° C to provide compound (10). Compound (10) can be hydrolyzed in a solvent such as methanol with heat treatment to provide compound (11).

In the method-4, the compound (11) can be treated with cesium carbonate in DMF at ambient temperature to provide the compound (12).

The compounds of formula (I) are useful in the treatment of diseases and conditions mediated by receptor tyrosine kinase. In certain embodiments, the compounds of the invention are inhibitors of one or more Class III receptor tyrosine kinases, such as FLT3 kinase, c-KIT kinase, and PDGFR kinase. For example, the compounds of the invention may be used to treat hematopoietic malignancies, cancers (eg, lung, liver, pancreas, ovary, thyroid, bladder or colon), melanoma, bone marrow diseases (eg, myeloid leukemia, multiple myeloma, and red blood cells) Leukemia), adenomas (such as colonic villus adenoma), sarcomas (such as osteosarcoma), autoimmune diseases, allergic reactions, organ transplant rejection syndromes, and combinations thereof. Examples of hematopoietic malignancies include, for example, leukemia, lymphoma (non-Hodgkin's lymphoma), Kejiejin's disease (also known as Kejiejin's lymphoma), and myeloma (such as , acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), chronic Promyelocytic leukemia (CPL), acute undifferentiated leukemia (AUL), undifferentiated large cell leukemia (ALCL), anterior lymphocytic leukemia (PML), juvenile granulocyte mononuclear leukemia Disease (JMML), adult T-cell ALL, AML (AML/TMDS) with trilineage myelodysplasia, mixed leukemia (MLL), myelodysplastic syndrome (MDSs), myeloproliferative disease (MPD) ) and multiple myeloma (MM).

As used herein, "treatment" or "medical" includes the prevention and treatment of a condition.

Another aspect of the invention provides a method of treating a disease and condition mediated by a receptor tyrosine kinase in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of formula (I) or a hydrate thereof, a solvate, prodrug or pharmaceutically acceptable salt.

The individual to be administered is a mammal, preferably a human.

The term "therapeutically effective amount" means that when a compound is administered to an individual in need of such treatment, the amount of the compound is sufficient to (i) treat or prevent a particular disease or condition mediated by one or more receptor tyrosine kinases. Or a condition, (ii) reducing, ameliorating or removing one or more symptoms of a particular disease, condition or condition, or (iii) preventing or delaying the occurrence of one or more symptoms of a particular disease, condition or condition. The determination of a therapeutically effective amount is a matter of skill in the art. The compound of the formula (I) or a hydrate, solvate, prodrug or pharmaceutically acceptable salt thereof can be administered in a single dose or in multiple doses. The physician can determine the delivery dose of the compound of formula (I) depending on the form and severity of the condition to be treated, the particular compound to be administered, the route of administration, the condition being treated, and the individual to be treated.

Accordingly, the present invention also relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a hydrate, solvate, prodrug or pharmaceutically thereof thereof Acceptable salts, and pharmaceutically acceptable carriers.

The term "pharmaceutically acceptable carrier" is intended to include any and all concomitant drug delivery materials, including solvents, dispersion vehicles, coatings, antibacterial and antifungal agents, isotonic and delayed absorbents, and others. Substances and compounds that can be accompanied by drug delivery. In addition to any conventional vehicle or agent that is incompatible with the active compound, an evaluation is made when it is used in the compositions of the present invention. Supplementary active compounds can also be incorporated into the compositions.

The pharmaceutical compositions of the present invention may also include pharmaceutically acceptable excipients which are useful in the preparation of pharmaceutical compositions which are generally safe, non-toxic (whether biological or otherwise undesirable), and include veterinary An acceptable excipient for use on human and human medicine.

The compound or pharmaceutical composition of the present invention can be administered to a subject in need thereof by any suitable route, for example, parenterally, topically, rectally, nasally, buccally, transvaginally, transdermally, by way of example. Inhalation, administration by injection or perfusion, by spraying or via implantation of a reservoir. Preferably, the compound is administered orally or by injection or perfusion (e.g., via intravenous).

The compounds or pharmaceutical compositions of the invention may be used alone or in combination with one or more additional therapies for the treatment of the above mentioned conditions. For example, in anticancer therapy, it may be combined with other chemotherapeutic agents, hormones or antibody agents, and may be combined with surgical therapy, radiation therapy or a combination thereof. Thus, a combination therapy according to the invention comprises administering at least one compound or pharmaceutical composition of the invention, and using at least one other method of treatment. Preferably, the combination therapies of the invention comprise administering a compound or pharmaceutical composition of the invention and at least one second medical agent, preferably an anti-neoplastic agent. Compound of the invention Alternatively, the pharmaceutical composition and the second medical agent may be delivered together or separately, and when delivered separately, they may be delivered simultaneously or in any order. To achieve the desired combination, the amount of the compound of formula (I) and the second therapeutic agent and the associated delivery time can be selected.

Anticancer agents can induce anticancer effects in cell cycle-specific behavior, such as phase specificity and function in the specific phase of the cell cycle, or bind to DNA and produce a role in non-cell cycle specific behavior (ie, non- Cell cycle specificity and regulated by other mechanisms).

Anticancer agents can include the following: (1) cell cycle specific anticancer agents include, but are not limited to, diiterpenoids (such as paclitaxel and its docetaxel analogs); vinca alkaloids (eg vinblastine, vincristine, vindesine and inorelbine); epipodophyllotoxins (eg etoposide and sneaky) "teniposide"; fluoropyrimidines, such as 5-5-fluorouracil and fluorodeoxyuridine; antimetabolites such as allopurinol, fludurabine , methotrexate, cladrabine, cytarabine, mercaptopurine, and thioguanine; and camptothecins, such as 9- Aminocamptothecin, irinotecan, topotecan, CPT-11 and 7-(4-methylperidine - methylene)-10,11-extended ethyldioxy-20-camptothecin in various optical forms; (2) cytotoxic chemotherapeutic agents, including but not limited to alkylating agents such as nitrogen mustard amphetamine Acid (melphalan), chlorambucil, cyclophosphamide, mechlorethamine, hexamethylmelamine, butyl sulfonate (busulfan), carmustine ( Carmustine), lomustine and dacarbazine; anti-cancer antibodies such as doxorubicin, daunomycin, epirubicin, idaruubi Idarubicin, mitomycin-C, dacttainomycin, and mithramycin; and platinum coordination complexes, such as cisplatin, carboplatin Carboplatin and oxaliplatin; and (3) other chemotherapeutic agents, including but not limited to, anti-emotional hormones such as tamoxifen (tomixefen) and toremifene (toremifene) , raloxifene, droloxifene, and iodoxyfene; progesterone, such as acetate Megastrol acetate; aromatase inhibitors such as anastrozole, letrazole, vorazole and exemestane; antiandrogens such as statin (flutamide), nilutamide, bicalutamide, and cyproterone acetate; LHRH agonists and antagonists, such as goserelin acetate and leuprolide Luprolide; a testosterone 5[α]-dihydroreductase inhibitor, such as finasteride; a metalloproteinase inhibitor, such as marimastat; antiprogestogens; urokinase Inhibitors of serine activin receptor function; inhibitors of growth factor function, such as hepatocyte growth factor, erb-B2, erb-B4, epithelial growth factor receptor, platelet-derived growth factor receptor (PDGFR), vascular endothelial growth Inhibitors of the function of factor receptors (VEGFR and TIE-2 (in addition to the VEGFR and TIE-2 inhibitors described herein); and other tyrosine kinase inhibitors, such as inhibitors of CDK2 and CDK4 inhibition Agent.

The following specific examples are to be construed as illustrative only. And in no case does it limit the remainder of the disclosure. It will be appreciated by those skilled in the art that the present invention is not limited to the examples used as illustrative examples, and all forms of the above disclosure are included.

Example Example 1

6-(4-Bromo-phenyl)-5,7-dihydro-1-thio-4,5-diaza-cyclopentadienyl[a]noncyclopentadiene

5,6-Dihydro-cyclopentadienium [b]thiophen-4-one (3.34 g, 24.2 mmol) in 40 mL of THF was treated with NaH (60%, 1.45 g, 36.3 mmol). After the addition of 4-bromo-benzoic acid phenyl ester (6.7 g, 24.2 mmol), the reaction mixture was heated to 100 ° C for 8 hours. The solution was cooled to room temperature and poured into water. The resulting mixture was acidified with concentrated HCl and extracted with ethyl acetate. The organic layer was collected, dried over MgSO _{4 (s)} and evaporated. The resulting precipitate was collected and recrystallized from ethanol to give the corresponding 5-(4-bromo-phenyl)-5,6-dihydro-cyclopentadienyl[b]thiophen-4-one as a yellow solid. 5.4 g, 16.9 mmol), yield 70%.

5-(4-Bromo-phenyl)-5,6-dihydro-cyclopentadienyl hydrazide [b]thiophen-4-one (8.0 g, 25 mmol), hydrazine monohydrate (4.8 mL, 150 mmol), glacial acetic acid (1.8 mL) and ethanol (45 mL) were heated to 100 ° C under nitrogen for 4 h. The mixture was cooled to 25 ° C and concentrated under reduced pressure to give a solid which was recrystallised from ethanol to give the corresponding 6-(4-bromo-phenyl)-5,7-dihydro- 1-Sulpho-4,5-diaza-cyclopentadienyl[a]indolecyclopentadiene (7.6 g, 24.2 mmol), yield 97%.

MS (ESI) m/z: 318.0 (M+H) ⁺ . ¹ H NMR (DMSO - d ₆ ): 13.04 (s, 1 H), 7.71 (s, 4 H), 7.60 (d, 1 H,) , 7.29 (d, 1 H), 3.90 (s, 3 H).

Example 2

4-(4,7-Dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]indolecyclopentadienyl-6-yl)-phenylamine hydrochloride

Add NaH (60%, 0.48 g, 12.0 mmol) to 6-(4-bromo-phenyl)-4,7-dihydro-1-thio-4,5-diaza-cyclopentane at 0 °C A solution of diene[a]indolecyclopentadiene (3.1 g, 9.7 mmol) in THF (15 ml). Further, SEM-Cl (90%, 2.4 ml, 12 mmol) was added to the reaction mixture, and the mixture was stirred at 0 ° C for 30 minutes, and then heated to 80 ° C and stirred for 2 hours. The solution was cooled to room temperature and poured into ice water. The resulting mixture was extracted with ethyl acetate. The organic layer was collected and rinsed with saturated aqueous NH ₄ Cl, to MgSO _{4 (s)} sulfate, and concentrated under reduced pressure. The oily residue was purified by gravity column chromatography (20% EtOAc in hexane) to afford 6-(4-bromo-phenyl)-4-(2-trimethyldecane-ethoxymethyl)- 4,7-Dihydro-1-thio-4,5-diaza-cyclopenta[a]indolecyclopentadiene (3.0 g, 6.7 mmol) as a brown solid, yield 69%.

The corresponding intermediate 6-(4-bromo-phenyl)-4-(2-trimethyldecane-ethoxymethyl)-4,7-dihydro-1-sulfo-4,5-diaza -cyclopenta[a]noncyclopentadiene (0.45 g, 1.0 mmol), acetamide (0.15 g, 2.5 mmol), Cs ₂ CO ₃ (2 M, 3.0 mL), Xantphos (0.45 g, A mixture of 1.0 mmol) and Pd(OAc) ₂ (22 mg, 0.1 mmol) in dioxane (5 mL) was heated to 100 ° C for 8 h. The mixture was cooled to room temperature and extracted with ethyl acetate. The desired product N-{4-[4-(2-trimethyldecane-ethoxymethyl)-4,7-di was obtained as a brown solid. Hydrogen-1-sulfo-4,5-diaza-cyclopentadienyl[a]decenecyclopentadienyl-6-yl]-phenyl}-acetamide, yield 71%.

N-{4-[4-(2-Trimethyldecane-ethoxymethyl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a] Indole cyclopentadienyl-6-yl]-phenyl}-acetamidamine (0.21 g, 0.5 mmol) was dissolved in EtOAc EtOAc (EtOAc) The reaction mixture was heated to 100 ° C for 4 hours. The solution was cooled to room temperature, and the obtained precipitate was filtered, washed with methanol, and then obtained under reduced pressure to give the corresponding 4-(4,7-dihydro-1-sulfo-4,5- as a yellow solid. Diazo-cyclopentadienyl[a]indolecyclopentadienyl-6-yl)-phenylamine hydrochloride (0.12 g, 0.42 mmol), yield 84%.

MS (ESI) m / z: 290.0 (M + H) + .1H NMR (DMSO- d 6): 7.88 (d, 2 H), 7.62 (d, 1 H), 7.46 (d, 2 H), 7.29 (d, 1 H), 3.94 (s, 2 H).

Example 3

6-(3-methoxy-phenyl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]noncyclopentadiene

5,6-Dihydro-cyclopenta[b]thiophen-4-one (3.34 g, 24.2 mmol) in 40 mL THF was treated with NaH (60%, 0.5 g, 12.4 mmol). After the addition of 4-methoxy-benzoic acid phenyl ester, the reaction mixture was heated to 100 ° C for 8 hours. The solution was cooled to room temperature and poured into water. The product mixture was acidified with cone. EtOAc (EtOAc)EtOAc. The organic layer was taken, dried over EtOAc EtOAc _m . The resulting precipitate was collected and recrystallized from ethanol to give the corresponding 6-(4-methoxy-phenyl)-4,7-dihydro-1-thio-4,5-diaza-cyclopentadiene [ a] Cyclopentadiene (3.4 g, 12.5 mmol) in lemon yellow solid with a yield of 89%.

6-(4-Methoxy-phenyl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]indolecyclopentadiene (2.72 g, 10 Methyl) monoamine hydrate (4.8 mL, 150 mmol), glacial acetic acid (1.8 mL) and ethanol (45 mL) were heated to 100 ° C under nitrogen for 4 h. The mixture was cooled to 25 ° C and concentrated under reduced pressure to give a solid, which was recrystallised from ethanol to give the corresponding 6-(4-methoxy-phenyl)-4,7-dihydro- 1-Sulpho-4,5-diaza-cyclopentadienyl[a]indolecyclopentadiene (2.65 g, 9.9 mmol), yield 99%.

MS (ESI) m/z: 269.0 (M+H) ⁺ . ¹ H NMR (DMSO - d ₆ ): 12.90 (s, 1 H), 7.59 (d, 1 H), 7.41 (d, 1H), 7.28 -7.34 (m, 3 H), 6.92 (d, 1 H), 3.91 (s, 2 H), 3.83 (s, 3 H).

Example 4

6-(2,4-Dimethoxy-phenyl)-4,7-dihydro-1-thio-4,5-diaza-cyclopentadienyl[a]noncyclopentadiene

5,6-Dihydro-cyclopenta[b]thiophen-4-one (3.34 g, 24.2 mmol) in 40 mL THF was treated with NaH (60%, 1.45 g, 12.4 mmol). After the addition of 2,4-dimethoxy-benzoic acid phenyl ester, the reaction mixture was heated to 100 ° C for 8 hours. The solution was cooled to room temperature and poured into water. The product mixture was acidified with cone. EtOAc (EtOAc)EtOAc. The organic layer was taken, dried over EtOAc EtOAc _m . The resulting precipitate was collected and recrystallized from ethanol to give the corresponding 5-(2,4-dimethoxy-phenyl)-5,6-dihydro-cyclopenta[b]thiophen-4-one ( 2.0 g, 6.6 mmol) of a brown solid, yield 47%.

5-(2,4-Dimethoxy-phenyl)-5,6-dihydro-cyclopenta[b]thiophen-4-one (1.12 g, 3.69 mmol), hydrazine monohydrate ( 0.7 mL, 22 mmol), glacial acetic acid (0.6 mL) and ethanol (10 mL) were heated to 100 ° C under nitrogen for 4 h. The mixture was cooled to 25 ° C and concentrated under reduced pressure to give a solid which crystallised from ethanol to give the corresponding 6-(2,4-dimethoxy-phenyl)-4,7 as a yellow solid. -Dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]indolecyclopentadiene (2.5 g, 3.1 mmol) in 85% yield.

MS (ESI) m / z: . 299.0 (M + H) + 1 H NMR (DMSO- d 6): 12.43 (s, 1 H), 7.58 (s, 1 H), 7.56 (d, 1 H), 6.69 (s, 1 H), 6.65 (d, 1 H), 3.91 (s, 3 H), 3.81 (s, 3 H), 3.78 (s, 2 H).

Example 5

6-(4-Nitro-phenyl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]indolecyclopentadiene

5,6-Dihydro-cyclopenta[b]thiophen-4-one (3.34 g, 24.2 mmol) in 40 mL THF was treated with NaH (60%, 1.45 g, 36.25 mmol). After the addition of 2,4-dimethoxy-benzoic acid phenyl ester, the reaction mixture was heated to 100 ° C for 8 hours. The solution was cooled to room temperature and poured into water. The product mixture was acidified with cone. EtOAc (EtOAc)EtOAc. The organic layer was taken, dried over EtOAc EtOAc _m . The resulting precipitate was collected and recrystallized from ethanol to give the corresponding 5-(4-nitro-phenyl)-5,6-dihydro-cyclopenta[b]thiophen-4-one (2.8 g, 9.7 Mmol) of brown solid, yield 69%

5-(4-Nitro-phenyl)-5,6-dihydro-cyclopenta[b]thiophen-4-one (2.0 g, 6.9 mmol), hydrazine monohydrate (1.32 mL, 10.4) Methyl acetate, glacial acetic acid (0.62 mL) and ethanol (15 mL) were heated to 100 ° C under nitrogen for 4 h. The mixture was cooled to 25 ° C and concentrated under reduced pressure to give a solid, which was recrystallized from ethanol to give the corresponding 6-(4-nitro-phenyl)-4,7-dihydro-1 as a yellow solid. - Sulfur-4,5-diaza-cyclopentadienyl[a]indolecyclopentadiene (2.0 g, 6.3 mmol) in 92% yield.

MS (ESI) m / z: 284.0 (M + H) +.

Example 6

6-phenyl-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]noncyclopentadiene

5,6-Dihydro-cyclopenta[b]thiophen-4-one (3.34 g, 24.2 mmol) in 40 mL THF was treated with NaH (60%, 1.45 g, 36.25 mmol). After the addition of phenyl benzoate, the reaction mixture was heated to 100 ° C for 8 hours. The solution was cooled to room temperature and poured into water. The product mixture was acidified with cone. EtOAc (EtOAc)EtOAc. The organic layer was taken, dried over EtOAc EtOAc _m . The resulting precipitate was collected and recrystallized from ethanol to give a white solid corresponding to 5-benzylidenyl-5,6-dihydro-cyclopenta[b]thiophen-4-one (4.3 g, 17.7 mmol). The yield was 73%.

5-Benzylmercapto-5,6-dihydro-cyclopenta[b]thiophen-4-one (2.42 g, 10.0 mmol), hydrazine monohydrate (1.92 mL, 60 mmol), glacial acetic acid (2.7 (mL) and ethanol (15 mL) were heated to 100 ° C under nitrogen for 4 hours. The mixture was cooled to 25 ° C and concentrated under reduced pressure to give a solid, which was recrystallised from ethanol to give the corresponding 6-phenyl-4,7-dihydro-1-sulfo-4,5- as a white solid. Diazo-cyclopentadienyl[a]indolecyclopentadiene (2.4 g, 8.0 mmol) in 80% yield.

MS (ESI) m / z: 239.0 (M + H) +.

Example 7

[4-(4,7-Dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]indolecyclopentadienyl-6-yl)-phenyl]-(4-fluoro- Phenyl)-amine

Add NaH (60%, 0.48 g, 12.0 mmol) to 6-(4-bromo-phenyl)-4,7-dihydro-1-thio-4,5-diaza-cyclopentane at 0 °C A solution of diene[a]indolecyclopentadiene (3.1 g, 9.7 mmol) in THF (15 ml). Further, SEM-Cl (90% purity, 2.4 ml, 12 mmol) was added to the reaction mixture, and the obtained mixture was stirred at 0 ° C for 30 minutes, and then heated to 80 ° C for further 2 hours. The solution was cooled to room temperature and poured into ice water. The resulting mixture was extracted with ethyl acetate. The organic layer was collected and rinsed with saturated aqueous NH ₄ Cl, to MgSO _{4 (s)} sulfate, and concentrated under reduced pressure. The oily residue was purified by gravity column chromatography (20% EtOAc in hexane) to afford 6-(4-bromo-phenyl)-4-(2-trimethyldecane-ethoxymethyl)- 4,7-Dihydro-1-thio-4,5-diaza-cyclopenta[a]indolecyclopentadiene (3.0 g, 6.7 mmol) as a brown solid, yield 69%.

The corresponding intermediate 6-(4-bromo-phenyl)-4-(2-trimethyldecane-ethoxymethyl)-4,7-dihydro-1-sulfo-4,5-diaza -cyclopenta[a]noncyclopentadiene (0.45 g, 1.0 mmol), 4-fluoro-aniline (0.27 g, 2.5 mmol), Cs ₂ CO ₃ (2 M, 3.0 mL), Xantphos (58 The mixture of mg, 0.1 mmol) and Pd(OAc) ₂ (22 mg, 0.1 mmol) in dioxane (5 mL) was heated to 100 ° C for 8 h. The mixture was cooled to room temperature and extracted with ethyl acetate. The desired product (4-fluoro-phenyl)-{4-[4-(2-trimethyldecane-ethoxymethyl) was obtained as a brown solid (m.). -4,7-Dihydro-1-thio-4,5-diaza-cyclopenta[a]indolecyclopentadienyl-6-yl]-phenyl}-amine, yield 69%.

(4-Fluoro-phenyl)-{4-[4-(2-trimethyldecane-ethoxymethyl)-4,7-dihydro-1-sulfo-4,5-diaza-ring The pentadienyl [a] indole cyclopentadienyl-6-yl]-phenyl}-amine (0.25 g, 0.5 mmol) was dissolved in MeOH then EtOAc (EtOAc) The reaction mixture was heated to 100 ° C for 4 hours. The solution was cooled to room temperature, and the obtained precipitate was filtered, washed with methanol, and then concentrated under reduced pressure to give the corresponding [4-(4,7-dihydro-1-sulfo-4) as a white solid. 5-diaza-cyclopentadienyl[a]indolecyclopentadienyl-6-yl)-phenyl]-(4-fluoro-phenyl)-amine (0.14 g, 0.42 mmol), yield 85% .

MS (ESI) m / z: 348.0 (M + H) +.

Example 8

[4-(4,7-Dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]indolecyclopentadienyl-6-yl)-phenyl]-(4-methoxy Base-phenyl)-amine

Add NaH (60%, 0.48 g, 12.0 mmol) to 6-(4-bromo-phenyl)-4,7-dihydro-1-thio-4,5-diaza-cyclopentane at 0 °C A solution of diene-[a]noncyclopentadiene in THF (15 ml). Further, SEM-Cl (90% purity, 2.4 ml, 12 mmol) was added to the reaction mixture, and the obtained mixture was stirred at 0 ° C for 30 minutes, and then heated to 80 ° C for further 2 hours. The solution was cooled to room temperature and poured into ice water. The resulting mixture was extracted with ethyl acetate. The organic layer was collected and rinsed with saturated aqueous NH ₄ Cl, to MgSO _{4 (s)} sulfate, and concentrated under reduced pressure. The oily residue was purified by gravity column chromatography (20% EtOAc in hexane) to afford 6-(4-bromo-phenyl)-4-(2-trimethyldecane-ethoxymethyl)- 4,7-Dihydro-1-thio-4,5-diaza-cyclopenta[a]indolecyclopentadiene (3.0 g, 6.7 mmol) as a brown solid, yield 69%.

The corresponding intermediate 6-(4-bromo-phenyl)-4-(2-trimethyldecane-ethoxymethyl)-4,7-dihydro-1-sulfo-4,5-diaza -cyclopenta[a]noncyclopentadiene (0.45 g, 1.0 mmol), 4-fluoro-aniline (0.27 g, 2.5 mmol), Cs ₂ CO ₃ (2 M, 3.0 mL), Xantphos (58 The mixture of mg, 0.1 mmol) and Pd(OAc) ₂ (22 mg, 0.1 mmol) in dioxane (5 mL) was heated to 100 ° C for 8 h. The mixture was cooled to room temperature and extracted with ethyl acetate. The desired product (4-fluoro-phenyl)-{4-[4-(2-trimethyldecane-ethoxymethyl) was obtained as a brown solid (m.). -4,7-Dihydro-1-thio-4,5-diaza-cyclopenta[a]indolecyclopentadienyl-6-yl]-phenyl}-amine, yield 60%.

(4-Methoxy-phenyl)-{4-[4-(2-trimethyldecane-ethoxymethyl)-4,7-dihydro-1-sulfo-4,5-diaza -cyclopentadienyl[a]indolecyclopenta-6-yl]-phenyl}-amine (0.25 g, 0.5 mmol) was dissolved in MeOH then EtOAc (EtOAc) The reaction mixture was heated to 100 ° C for 4 hours. The solution was cooled to room temperature, and the obtained precipitate was filtered, washed with methanol, and then concentrated under reduced pressure to afford corresponding [4-(4,7-dihydro-1-thio-4) as a white solid. ,5-diaza-cyclopentadienyl[a]indolecyclopentadienyl-6-yl)-phenyl]-(4-methoxy-phenyl)-amine (0.14 g, 0.42 mmol), The rate is 80%.

MS (ESI) m / z: 348.0 (M + H) +.

Example 9

4'-(4,7-Dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]indolecyclopenta-6-yl)-3-methoxy-biphenyl- 4-phenol

Add NaH (60%, 0.48 g, 12.0 mmol) to 6-(4-bromo-phenyl)-4,7-dihydro-1-thio-4,5-diaza-cyclopentane at 0 °C A solution of diene[a]indolecyclopentadiene (3.1 g, 9.7 mmol) in THF (15 ml). Further, SEM-Cl (90% purity, 2.4 ml, 12 mmol) was added to the reaction mixture, and the obtained mixture was stirred at 0 ° C for 30 minutes, and then heated to 80 ° C for further 2 hours. The solution was cooled to room temperature and poured into ice water. The resulting mixture was extracted with ethyl acetate. The organic layer was collected and rinsed with saturated aqueous NH ₄ Cl, to MgSO _{4 (s)} sulfate, and concentrated under reduced pressure. The oily residue was purified by gravity column chromatography (20% EtOAc in hexane) to afford 6-(4-bromo-phenyl)-4-(2-trimethyldecane-ethoxymethyl)- 4,7-Dihydro-1-thio-4,5-diaza-cyclopenta[a]indolecyclopentadiene (3.0 g, 6.7 mmol) as a brown solid, yield 69%.

The corresponding intermediate 6-(4-bromo-phenyl)-4-(2-trimethyldecane-ethoxymethyl)-4,7-dihydro-1-sulfo-4,5-diaza -cyclopenta[a]noncyclopentadiene (0.3 g, 0.9 mmol), 3,4-dimethoxyphenylboronic acid (0.24 g, 1.5 mmol), Na ₂ CO ₃ (2 M, 2.7 mL) and _{Pd (PPh 3) 2 Cl 2} (8 mg, 0.075 mmol) in toluene / ethanol (1: the mixture was heated to 100 deg.] C 1,6 mL) and maintained in the 8 hours. The solution was cooled to room temperature and extracted with ethyl acetate. The desired product (3,4-dimethyl-phenyl)-{4-[4-(2-trimethyldecane-B) was obtained as a brown solid. Oxymethyl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopenta[a]indolecyclopentadienyl-6-yl]-phenyl}-amine, produced The rate is 42%.

(3,4-Dimethyl-phenyl)-{4-[4-(2-trimethyldecane-ethoxymethyl)-4,7-dihydro-1-sulfo-4,5- Diazo-cyclopenta[a]noncyclopentadienyl-6-yl]-phenyl}-amine (0.5 g, 0.13 mmol) was dissolved in MeOH then EtOAc (EtOAc) . The reaction mixture was heated to 100 ° C for 4 hours. The solution was cooled to room temperature, and the obtained precipitate was filtered, washed with methanol, and then obtained under reduced pressure to obtain corresponding 4'-(4,7-dihydro-1-sulfo-4,5 as a brown solid. - Diazo-cyclopentadienyl[a]indolecyclopentadien-6-yl)-3-methoxy-biphenyl-4-phenol (0.34 g, 0.09 mmol), yield 67%.

MS (ESI) m / z: . 360.0 (M + H) + 1 H NMR (DMSO- d 6): 7.63 (d, 2 H), 7.61 (s, 1 H), 7.28 (d, 1 H), 7.10 (d, 2 H), 7.01 (d, 2 H), 6.91 (d, 2 H), 3.92 (s, 2 H), 3.73 (s, 3 H).

Example 10

3-[4-(4,7-Dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]indolecyclopentadienyl-6-yl)-phenylamino]-phenol

Add NaH (60%, 0.48 g, 12.0 mmol) to 6-(4-bromo-phenyl)-4,7-dihydro-1-thio-4,5-diaza-cyclopentane at 0 °C A solution of diene[a]indolecyclopentadiene (3.1 g, 9.7 mmol) in THF (15 ml). Further, SEM-Cl (90% purity, 2.4 ml, 12 mmol) was added to the reaction mixture, and the obtained mixture was stirred at 0 ° C for 30 minutes, and then heated to 80 ° C for further 2 hours. The solution was cooled to room temperature and poured into ice water. The resulting mixture was extracted with ethyl acetate. The organic layer was collected and rinsed with saturated aqueous NH ₄ Cl, to MgSO _{4 (s)} sulfate, and concentrated under reduced pressure. The oily residue was purified by gravity column chromatography (20% EtOAc in hexane) to afford 6-(4-bromo-phenyl)-4-(2-trimethyldecane-ethoxymethyl)- 4,7-Dihydro-1-thio-4,5-diaza-cyclopenta[a]indolecyclopentadiene (3.0 g, 6.7 mmol) as a brown solid, yield 69%.

The corresponding intermediate 6-(4-bromo-phenyl)-4-(2-trimethyldecane-ethoxymethyl)-4,7-dihydro-1-sulfo-4,5-diaza -cyclopenta[a]noncyclopentadiene (0.45 g, 1.0 mmol), 3-amino-phenol (0.27 g, 2.5 mmol), Cs ₂ CO ₃ (2 M, 3.0 mL), Xantphos ( A mixture of 58 mg, 0.1 mmol) and Pd(OAc) ₂ (22 mg, 0.1 mmol) in dioxane (5 mL) was heated to 100 ° C for 8 h. The solution was cooled to room temperature and extracted with ethyl acetate. The desired product, 3-{4-[4-(2-trimethyldecane-ethoxymethyl)-4,7-di, was obtained as a brown solid. Hydrogen-1-sulfo-4,5-diaza-cyclopenta[a]indolecyclopentadienyl-6-yl]-anilino}-phenol, yield 60%.

3-{4-[4-(2-Trimethyldecane-ethoxymethyl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a] Indole cyclopentadienyl-6-yl]-anilino}-phenol (0.24 g, 0.5 mmol) was dissolved in MeOH then EtOAc (EtOAc) The reaction mixture was heated to 100 ° C for 4 hours. The solution was cooled to room temperature, and the obtained precipitate was filtered, washed with methanol, and then obtained under reduced pressure to give the corresponding 3-[4-(4,7-dihydro-1-sulfo-4) as a yellow solid. ,5-diaza-cyclopentadienyl[a]noncyclopentadienyl-6-yl)-phenylamino]-phenol (0.15 g, 0.44 mmol), yield 88%.

MS (ESI) m / z: 346.0 (M + H) +.

Example 11

4'-(4,7-Dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]indolecyclopentadienyl-6-yl)-biphenyl-4-phenol

Add NaH (60%, 0.48 g, 12.0 mmol) to 6-(4-bromo-phenyl)-4,7-dihydro-1-thio-4,5-diaza-cyclopentane at 0 °C A solution of diene[a]indolecyclopentadiene (3.1 g, 9.7 mmol) in THF (15 ml). Further, SEM-Cl (90% purity, 2.4 ml, 12 mmol) was added to the reaction mixture, and the obtained mixture was stirred at 0 ° C for 30 minutes, and then heated to 80 ° C for further 2 hours. The solution was cooled to room temperature and poured into ice water. The resulting mixture was extracted with ethyl acetate. The organic layer was collected and rinsed with saturated aqueous NH ₄ Cl, to MgSO _{4 (s)} sulfate, and concentrated under reduced pressure. The oily residue was purified by gravity column chromatography (20% EtOAc in hexane) to afford 6-(4-bromo-phenyl)-4-(2-trimethyldecane-ethoxymethyl)- 4,7-Dihydro-1-thio-4,5-diaza-cyclopenta[a]indolecyclopentadiene (3.0 g, 6.7 mmol) as a brown solid, yield 69%.

The corresponding intermediate 6-(4-bromo-phenyl)-4-(2-trimethyldecane-ethoxymethyl)-4,7-dihydro-1-sulfo-4,5-diaza -cyclopenta[a]noncyclopentadiene (0.3 g, 0.9 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan 2-yl)phenol (0.33 g, 1.5 mmol), Na ₂ CO ₃ (2 M, 3.0 mL) and Pd(PPh ₃ ) ₂ Cl ₂ (22 mg, 0.1 mmol) in toluene/ethanol (1:1, The mixture in 6 mL) was heated to 100 ° C for 8 hours. The solution was cooled to room temperature and extracted with ethyl acetate. The title product 4'-[4-(2-trimethyldecane-ethoxymethyl)-4,7-dihydro-branched was obtained as a brown solid. 1-sulfo-4,5-diaza-cyclopenta[a]indolecyclopenta-6-yl]-biphenyl-4-phenol, yield 52%.

4'-[4-(2-Trimethyldecane-ethoxymethyl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopenta[a]fluorene ring Pentadien-6-yl]-biphenyl-4-phenol (0.06 g, 0.13 mmol) was dissolved in MeOH then EtOAc (EtOAc) The reaction mixture was heated to 100 ° C for 4 hours. The solution was cooled to room temperature, and the obtained precipitate was filtered, washed with methanol, and then obtained under reduced pressure to obtain corresponding 4'-(4,7-dihydro-1-sulfo-4,5 as a brown solid. - Diazo-cyclopentadienyl[a]indolecyclopentadienyl-6-yl)-biphenyl-4-phenol (0.03 g, 0.08 mmol), yield 61%.

MS (ESI) m / z: . 331.0 (M + H) + 1 H NMR (DMSO- d 6): 7.86 (d, 2 H), 7.73 (d, 2 H), 7.63 (d, 1 H), 7.57 (d, 2 H), 7.30 (d, 1 H), 6.89 (d, 2 H), 3.99 (s, 2 H).

Example 12

6-(4-styryl-phenyl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]noncyclopentadiene

Add NaH (60%, 0.48 g, 12.0 mmol) to 6-(4-bromo-phenyl)-4,7-dihydro-1-thio-4,5-diaza-cyclopentane at 0 °C A solution of diene[a]indolecyclopentadiene (3.1 g, 9.7 mmol) in THF (15 ml). Further, SEM-Cl (90% purity, 2.4 ml, 12 mmol) was added to the reaction mixture, and the obtained mixture was stirred at 0 ° C for 30 minutes, and then heated to 80 ° C for further 2 hours. The solution was cooled to room temperature and poured into ice water. The resulting mixture was extracted with ethyl acetate. The organic layer was collected and rinsed with saturated aqueous NH ₄ Cl, to MgSO _{4 (s)} sulfate, and concentrated under reduced pressure. The oily residue was purified by gravity column chromatography (20% EtOAc in hexane) to afford 6-(4-bromo-phenyl)-4-(2-trimethyldecane-ethoxymethyl)- 4,7-Dihydro-1-thio-4,5-diaza-cyclopenta[a]indolecyclopentadiene (3.0 g, 6.7 mmol) as a brown solid, yield 69%.

The corresponding intermediate 6-(4-bromo-phenyl)-4-(2-trimethyldecane-ethoxymethyl)-4,7-dihydro-1-sulfo-4,5-diaza -cyclopenta[a]noncyclopentadiene (1.46 g, 3.2 mmol), trans-β-styrene boronic acid (0.7 g, 4.9 mmol), Na ₂ CO ₃ (2 M, 7 mL) and A mixture of Pd(PPh ₃ ) ₂ Cl ₂ (300 mg, 0.26 mmol) in toluene/ethanol (1:1, 20 mL) was heated to 100 ° C and maintained for 8 hours. The solution was cooled to room temperature and extracted with ethyl acetate. The desired product 6-(4-styryl-phenyl)-4-(2-trimethyldecane-ethoxymethyl) as a yellow solid was obtained by chromatography (30%EtOAc) 4,7-Dihydro-1-sulfo-4,5-diaza-cyclopenta[a]noncyclopentadiene, yield 68%.

6-(4-styryl-phenyl)-4-(2-trimethyldecane-ethoxymethyl)-4,7-dihydro-1-sulfo-4,5-diaza-ring The pentadienyl[a]indolecyclopentadiene (0.15 g, 0.3 mmol) was dissolved in MeOH then EtOAc (EtOAc) The reaction mixture was heated to 100 ° C for 4 hours. The solution was cooled to room temperature, and the obtained precipitate was filtered, washed with methanol, and then obtained under reduced pressure to give corresponding 6-(4-styryl-phenyl)-4,7- Hydrogen-1-sulfo-4,5-diaza-cyclopentadienyl[a]indolecyclopentadiene (0.1 g, 0.27 mmol), yield 89%.

MS (ESI) m / z: . 341.0 (M + H) + 1 H NMR (DMSO- d 6): 7.80 (d, 2 H), 7.74 (d, 2 H), 7.63 (d, 2 H), 7.61 (s, 1 H), 7.29-7.41 (m, 6 H), 3.96 (s, 2 H).

Example 13

N-[4-(4,7-Dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]indolecyclopentadienyl-6-yl)-phenyl]-benzene-1 4-diamine

Add NaH (60%, 0.48 g, 12.0 mmol) to 6-(4-bromo-phenyl)-4,7-dihydro-1-thio-4,5-diaza-cyclopentane at 0 °C A solution of diene[a]indolecyclopentadiene (3.1 g, 9.7 mmol) in THF (15 ml). Further, SEM-Cl (90% purity, 2.4 ml, 12 mmol) was added to the reaction mixture, and the obtained mixture was stirred at 0 ° C for 30 minutes, and then heated to 80 ° C for further 2 hours. The solution was cooled to room temperature and poured into ice water. The resulting mixture was extracted with ethyl acetate. The organic layer was collected and rinsed with saturated aqueous NH ₄ Cl, to MgSO _{4 (s)} sulfate, and concentrated under reduced pressure. The oily residue was purified by column chromatography (20%EtOAcEtOAcEtOAc) elute Methyl)-4,7-dihydro-1-thio-4,5-diaza-cyclopenta[a]indolecyclopentadiene (3.0 g, 6.7 mmol), yield 69%.

The corresponding intermediate 6-(4-bromo-phenyl)-4-(2-trimethyldecane-ethoxymethyl)-4,7-dihydro-1-sulfo-4,5-diaza -cyclopenta[a]noncyclopentadiene (0.5 g, 1.0 mmol), 4-nitro-aniline (0.35 g, 2.5 mmol), Cs ₂ CO ₃ (2 M, 3.0 mL), Xantphos ( A mixture of 58 mg, 0.1 mmol) and Pd(OAc) ₂ (22 mg, 0.1 mmol) in dioxane (5 mL) was heated to 100 ° C for 8 h. The solution was cooled to room temperature and extracted with ethyl acetate. The desired product (4-nitro-phenyl)-{4-[4-(2-trimethyldecane-ethoxymethyl) was obtained as a brown solid (m.p. -4,7-Dihydro-1-thio-4,5-diaza-cyclopenta[a]indolecyclopentadienyl-6-yl]-phenyl}-amine, yield 71%.

(4-Nitro-phenyl)-{4-[4-(2-trimethyldecane-ethoxymethyl)-4,7-dihydro-1-sulfo-4,5-diaza-ring Pentadieno[a]indolecyclopentadienyl-6-yl]-phenyl}- The amine (0.25 g, 0.5 mmol) was dissolved in MeOH then EtOAc (EtOAc) The reaction mixture was heated to 100 ° C for 4 hours. The solution was cooled to room temperature, and the obtained precipitate was filtered, washed with methanol, and then evaporated to dryness to give the corresponding N-[4-(4,7-dihydro-1-sulfo-4) as a yellow solid. ,5-diaza-cyclopentadienyl[a]indolecyclopentadienyl-6-yl)-phenyl]-benzene-1,4-diamine (0.14 g, 0.4 mmol), yield 80%.

MS (ESI) m / z: 381.0 (M + H) +.

Example 14

6-(3',4'-dimethoxy-biphenyl-4-yl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]fluorene ring Pentadiene

Add NaH (60%, 0.48 g, 12.0 mmol) to 6-(4-bromo-phenyl)-4,7-dihydro-1-thio-4,5-diaza-cyclopentane at 0 °C A solution of diene[a]indolecyclopentadiene (3.1 g, 9.7 mmol) in THF (15 ml). Further, SEM-Cl (90% purity, 2.4 ml, 12 mmol) was added to the reaction mixture, and the obtained mixture was stirred at 0 ° C for 30 minutes, and then heated to 80 ° C for further 2 hours. The solution was cooled to room temperature and poured into ice water. The resulting mixture was extracted with ethyl acetate. The organic layer was collected and rinsed with saturated aqueous NH ₄ Cl, to MgSO _{4 (s)} sulfate, and concentrated under reduced pressure. The oily residue was purified by column chromatography (20%EtOAcEtOAcEtOAc) elute Methyl)-4,7-dihydro-1-thio-4,5-diaza-cyclopenta[a]indolecyclopentadiene (3.0 g, 6.7 mmol), yield 69%.

The corresponding intermediate 6-(4-bromo-phenyl)-4-(2-trimethyldecane-ethoxymethyl)-4,7-dihydro-1-sulfo-4,5-diaza -cyclopenta[a]noncyclopentadiene (0.5 g, 1.0 mmol), 3,4-dimethoxyphenylboronic acid (0.276 g, 1.5 mmol), Na ₂ CO ₃ (2 M, 2.5 mL) and _{Pd (PPh 3) 2 Cl 2} (87 mg, 0.7 mmol) in (1 toluene / ethanol: the mixture was heated to 100 deg.] C 1,6 mL) and maintained in the 8 hours. The solution was cooled to room temperature and extracted with ethyl acetate. The desired product 6-(3',4'-dimethoxy-biphenyl-4-yl)-4-(2-tri) was obtained as a brown solid. Methyl decane-ethoxymethyl)-4,7-dihydro-1-thio-4,5-diaza-cyclopenta[a]noncyclopentadiene in a yield of 68%.

6-(3',4'-Dimethoxy-biphenyl-4-yl)-4-(2-trimethyldecane-ethoxymethyl)-4,7-dihydro-1-sulfo -4,5-Dinitro-cyclopenta[a]indolecyclopentadiene (0.52 g, 1.0 mmol) was dissolved in MeOH then EtOAc (EtOAc) The reaction mixture was heated to 100 ° C for 4 hours. The solution was cooled to room temperature, and the obtained precipitate was filtered, washed with methanol, and then concentrated under reduced pressure to give the corresponding 6-(3',4'-dimethoxy-biphenyl- 4-yl)-4,7-dihydro-1-thio-4,5-diaza-cyclopentadienyl[a]indolecyclopentadiene (0.3 g, 0.8 mmol), yield 80%.

MS (ESI) m / z: 375.0 (M + H) + (DMSO- d 6):. 7.89 (d, 2 H), 7.81 (d, 2 H), 7.65 (d, 1 H), 7.26-7.31 (m, 3 H), 7.03 (d, 1 H), 4.00 (s, 2 H), 3.87 (s, 3 H), 3.79 (s, 3 H).

Example 15

4'-(4,7-Dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]indolecyclopentadienyl-6-yl)-biphenyl-4-carbonitrile

Add NaH (60%, 0.48 g, 12.0 mmol) to 6-(4-bromo-phenyl)-4,7-dihydro-1-thio-4,5-diaza-cyclopentane at 0 °C A solution of diene[a]indolecyclopentadiene (3.1 g, 9.7 mmol) in THF (15 ml). Further, SEM-Cl (90% purity, 2.4 ml, 12 mmol) was added to the reaction mixture, and the obtained mixture was stirred at 0 ° C for 30 minutes, and then heated to 80 ° C for further 2 hours. The solution was cooled to room temperature and poured into ice water. The resulting mixture was extracted with ethyl acetate. The organic layer was collected and rinsed with saturated aqueous NH ₄ Cl, to MgSO _{4 (s)} sulfate, and concentrated under reduced pressure. The oily residue was purified by gravity column chromatography (20% EtOAc in hexane) to afford 6-(4-bromo-phenyl)-4-(2-trimethyldecane-ethoxymethyl)- 4,7-Dihydro-1-thio-4,5-diaza-cyclopenta[a]indolecyclopentadiene (3.0 g, 6.7 mmol) as a brown solid, yield 69%.

The corresponding intermediate 6-(4-bromo-phenyl)-4-(2-trimethyldecane-ethoxymethyl)-4,7-dihydro-1-sulfo-4,5-diaza -cyclopenta[a]noncyclopentadiene (0.4 g, 0.9 mmol), 4-cyanophenylboronic acid (0.2 g, 1.35 mmol), Na ₂ CO ₃ (2 M, 2.0 mL) and Pd A mixture of (PPh ₃ ) ₂ Cl ₂ (8 mg, 0.075 mmol) in toluene/ethanol (1:1, 6 mL) was warmed to 100 ° C and maintained for 8 hours. The solution was cooled to room temperature and extracted with ethyl acetate. The title product 4'-[4-(2-trimethyldecane-ethoxymethyl)-4,7-dihydro-branched was obtained as a brown solid. 1-Sulpho-4,5-diaza-cyclopenta[a]indolene, yield 50%.

4'-[4-(2-Trimethyldecane-ethoxymethyl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopenta[a]fluorene ring Pentadiene (0.23 g, 0.5 mmol) was dissolved in MeOH then EtOAc (EtOAc) The reaction mixture was heated to 100 ° C for 4 hours. The solution was cooled to room temperature, and the obtained precipitate was filtered, washed with methanol and then evaporated Corresponding to 4'-(4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]indolecyclopentadienyl-6-yl)-biphenyl-4-carbonitrile ( 0.14 g, 0.42 mmol), yield 83%.

MS (ESI) m/z: 340.0 (M+H) ⁺ . ¹ H NMR (DMSO - d ₆ ): 7.90-7.97 (m, 8 H), 7.63 (d, 1 H), 7.30 (d, 1 H) ), 3.98 (s, 2 H).

Example 16

6-pyridin-3-yl-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]noncyclopentadiene

5,6-Dihydro-cyclopenta[b]thiophen-4-one (3.34 g, 24.2 mmol) in 40 mL THF was treated with NaH (60%, 1.45 g, 36.25 mmol). After the addition of ethyl nicotinic acid, the reaction mixture was heated to 100 ° C for 8 hours. The solution was cooled to room temperature and poured into water. The product mixture was acidified with cone. EtOAc (EtOAc)EtOAc. The organic layer was taken, dried over EtOAc EtOAc _m . The resulting precipitate was collected and recrystallized from ethanol to give the corresponding 5-(pyridine-3-carbonyl)-5,6-dihydro-cyclopenta[b]thiophen-4-one (1.23 g) as a red solid. , 5 mmol), yield 35%.

5-(Pyridin-3-carbonyl)-5,6-dihydro-cyclopenta[b]thiophen-4-one (1.23 g, 5 mmol), hydrazine monohydrate (0.38 mL, 7.5 mmol) Glacial acetic acid (0.9 mL) and ethanol (15 mL) were heated to 100 ° C under nitrogen for 4 h. The mixture was cooled to 25 ° C and concentrated under reduced pressure to give a solid, which was recrystallised from ethanol to give the corresponding 6-pyridin-3-yl-4,7-dihydro-1-sulfide as a white solid. -4,5-diaza-cyclopentadienyl[a]indolecyclopentadiene (0.5 g, 2 mmol), yield 40%.

MS (ESI) m / z: . 240.0 (M + H) + 1 H NMR (DMSO- d 6): 13.14 (s, 1 H), 8.90 (s, 1 H), 8.55 (d, 1 H), 8.14 (d, 1 H), 7.60 (d, 1 H), 7.52 (s, 1 H), 7.30 (s, 1 H), 3.96 (s, 2 H).

Example 17

6-furan-3-yl-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]indolecyclopentadiene

5,6-Dihydro-cyclopenta[b]thiophen-4-one (3.34 g, 24.2 mmol) in 40 mL THF was treated with NaH (60%, 0.8 g, 36.25 mmol). After the addition of ethyl furan-3-carboxylate, the reaction mixture was heated to 100 ° C for 8 hours. The solution was cooled to room temperature and poured into water. The product mixture was acidified with cone. EtOAc (EtOAc)EtOAc. The organic layer was taken, dried over EtOAc EtOAc _m . The resulting precipitate was collected and recrystallized from ethanol to give the corresponding 5-(furan-3-carbonyl)-5,6-dihydro-cyclopenta[b]thiophen-4-one (0.9 g, 38 mmol). The brown solid was 27%.

5-(Furan-3-carbonyl)-5,6-dihydro-cyclopenta[b]thiophen-4-one (0.9 g, 38 mmol), hydrazine monohydrate (1.9 mL, 58 mmol) Glacial acetic acid (0.69 mL) and ethanol (10 mL) were heated to 100 ° C under nitrogen for 4 hours. The mixture was cooled to 25 ° C and concentrated under reduced pressure to give a solid, which was recrystallised from ethanol to give the corresponding 6-furan-3-yl-4,7-dihydro-1-sulfon as a white solid. -4,5-diaza-cyclopentadienyl[a]indolecyclopentadiene (0.53 g, 23 mmol), yield 61%.

MS (ESI) m / z: . 229.0 (M + H) + 1 H NMR (DMSO- d 6): 12.76 (s, 1 H), 8.10 (s, 1 H), 7.81 (s, 1 H), 7.58 (d, 1 H), 7.27 (d, 2 H), 6.91 (s, 1 H), 3.76 (s, 2 H).

Example 18

6-(3',5'-Dichloro-biphenyl-4-yl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]fluorenecyclopentane Alkene

Add NaH (60%, 0.48 g, 12.0 mmol) to 6-(4-bromo-phenyl)-4,7-dihydro-1-thio-4,5-diaza-cyclopentane at 0 °C A solution of diene[a]indolecyclopentadiene (3.1 g, 9.7 mmol) in THF (15 ml). Further, SEM-Cl (90% purity, 2.4 ml, 12 mmol) was added to the reaction mixture, and the obtained mixture was stirred at 0 ° C for 30 minutes, and then heated to 80 ° C for further 2 hours. The solution was cooled to room temperature and poured into ice water. The resulting mixture was extracted with ethyl acetate. The organic layer was collected and rinsed with saturated aqueous NH ₄ Cl, to MgSO _{4 (s)} sulfate, and concentrated under reduced pressure. The oily residue was purified by gravity column chromatography (20% EtOAc in hexane) to afford 6-(4-bromo-phenyl)-4-(2-trimethyldecane-ethoxymethyl)- 4,7-Dihydro-1-thio-4,5-diaza-cyclopenta[a]indolecyclopentadiene (3.0 g, 6.7 mmol) as a brown solid, yield 69%.

The corresponding intermediate 6-(4-bromo-phenyl)-4-(2-trimethyldecane-ethoxymethyl)-4,7-dihydro-1-sulfo-4,5-diaza -cyclopenta[a]noncyclopentadiene (1.46 g, 32 mmol), 3,5-dichlorophenylboronic acid (0.94 g, 49 mmol), Na ₂ CO ₃ (2 M, 7 mL) A mixture of Pd(PPh ₃ ) ₂ Cl ₂ (30 mg, 0.26 mmol) in toluene/ethanol (1:1, 18 mL) was heated to 100 ° C for 8 h. The solution was cooled to room temperature and extracted with ethyl acetate. The desired product 6-(3',5'-dichloro-biphenyl-4-yl){4-[4-(2-) was obtained as a brown solid. Trimethyldecane-ethoxymethyl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopenta[a]noncyclopentadiene, yield 53%.

6-(3',5'-Dichloro-biphenyl-4-yl){4-[4-(2-trimethyldecane-ethoxymethyl)-4,7-dihydro-1- Sulfur-4,5-diaza-cyclopenta[a]indolecyclopentadiene (0.14 g, 0.27 mmol) was dissolved in MeOH then EtOAc (EtOAc) The reaction mixture was heated to 100 ° C for 4 hours. The solution was cooled to room temperature, and the obtained precipitate was filtered, washed with methanol, and then concentrated under reduced pressure to give the corresponding 6-(3',5'-dichloro-biphenyl-4- 4,7-Dihydro-1-thio-4,5-diaza-cyclopentadienyl[a]indolecyclopentadiene (0.06 g, 0.15 mmol), yield 58%.

MS (ESI) m / z: . 383.0 (M + H) + 1 H NMR (DMSO- d 6): 7.90 (q, 4 H), 7.62 (d, 1 H), 7.54 (d, 2 H), 7.30 (d, 1 H), 7.25 (d, 1 H), 3.97 (s, 2 H).

Example 19

6-(4'-trifluoromethyl-biphenyl-4-yl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]noncyclopentadiene

Add NaH (60%, 0.48 g, 12.0 mmol) to 6-(4-bromo-phenyl)-4,7-dihydro-1-thio-4,5-diaza-cyclopentane at 0 °C A solution of diene[a]indolecyclopentadiene (3.1 g, 9.7 mmol) in THF (15 ml). Further, SEM-Cl (90% purity, 2.4 ml, 12 mmol) was added to the reaction mixture, and the obtained mixture was stirred at 0 ° C for 30 minutes, and then heated to 80 ° C for further 2 hours. The solution was cooled to room temperature and poured into ice water. The resulting mixture was extracted with ethyl acetate. The organic layer was collected and rinsed with saturated aqueous NH ₄ Cl, to MgSO _{4 (s)} sulfate, and concentrated under reduced pressure. The oily residue was purified by column chromatography (20%EtOAcEtOAcEtOAc) elute Methyl)-4,7-dihydro-1-thio-4,5-diaza-cyclopenta[a]indolecyclopentadiene (3.0 g, 6.7 mmol), yield 69%.

The corresponding intermediate 6-(4-bromo-phenyl)-4-(2-trimethyldecane-ethoxymethyl)-4,7-dihydro-1-sulfo-4,5-diaza -cyclopenta[a]noncyclopentadiene (1.34 g, 3 mmol), 4-trifluoromethylphenylboronic acid (0.85 g, 49 mmol), Na ₂ CO ₃ (2 M, 7 mL) A mixture of Pd(PPh ₃ ) ₂ Cl ₂ (30 mg, 4.5 mmol) in toluene/ethanol (1:1, 18 mL) was heated to 100 ° C for 8 h. The solution was cooled to room temperature and extracted with ethyl acetate. The desired product 6-(4'-trifluoromethyl-biphenyl-4-yl)-4-(2-trimethyldecane) was obtained as a brown solid. -Ethoxymethyl)-4,7-dihydro-1-thio-4,5-diaza-cyclopenta[a]noncyclopentadiene in a yield of 35%.

6-(4'-Trifluoromethyl-biphenyl-4-yl)-4-(2-trimethyldecane-ethoxymethyl)-4,7-dihydro-1-sulfo-4, 5-Dinitro-cyclopenta[a]indolecyclopentadiene (0.14 g, 0.27 mmol) was dissolved in MeOH then EtOAc (EtOAc) The reaction mixture was heated to 100 ° C for 4 hours. The solution was cooled to room temperature, and the obtained residue was filtered, washed with methanol, and then concentrated under reduced pressure to give the corresponding 6-(4'-trifluoromethyl-biphenyl-4-yl group as a brown solid. -4,7-Dihydro-1-thio-4,5-diaza-cyclopentadienyl[a]indolecyclopentadiene (0.04 g, 0.1 mmol), yield 38%.

MS (ESI) m / z: . 383.0 (M + H) + 1 H NMR (DMSO- d 6) :( m, 8 H), 7.62 (d, 1 H), 7.31 (d, 1 H), 3.97 (s, 2 H).

Example 20

(4-bromo-phenyl)-(4,7-dihydro-1-thio-4,5-diaza-cyclopentadienyl[a]indolecyclopentadienyl-6-yl)-amine

5,6-dihydro-cyclopenta[b]thiophen-4-one (1.0 g, 7.4 mmol) and 1-bromo-4-isothiocyanato-benzene in THF (2.0 mL) A mixture of 1.5 g, 7.2 mmol) was added dropwise at room temperature with lithium hexamethyldihydroethane (7.0 mL, 7.2 mmol). The reaction mixture was stirred for 8 hours. To the reaction mixture was added hydrazine monohydrate (0.4 mL, 7.9 mmol) and glacial acetic acid (0.5 mL), which was then stirred at reflux temperature for 24 hours. The product mixture was taken up in water (30 mL) andEtOAc. Purification by gravity column chromatography (50% EtOAc in hexanes) afforded the desired product (4-bromo-phenyl)-(4,7-dihydro-1-sulfo-4,5-diaza - cyclopentadienyl [a] indole cyclopentadienyl-6-yl)-amine in a yield of 32%.

MS (ESI) m / z: . 332.0 (M + H) + 1 H NMR (CDCl 3): 7.36-7.32 (m, 3 H), 7.19 (d, 1 H), 6.89 (d, 2 H), 3.46(s, 2 H).

Example 21

(2,4-dichloro-phenyl)-(4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]noncyclopentadienyl-6-yl)- amine

5,6-dihydro-cyclopenta[b]thiophen-4-one (1.0 g, 7.4 mmol) and 2,4-dichloro-1-isothiocyanato in THF (2.0 mL) A mixture of benzene (1.5 g, 7.2 mmol) was added dropwise lithium hexamethyldihydroethane (7.0 mL, 7.2 mmol) at room temperature. The reaction mixture was stirred for 8 hours. To the reaction mixture was added hydrazine monohydrate (0.4 mL, 7.9 mmol) and glacial acetic acid (0.5 mL), which was then stirred at reflux temperature for 24 hours. The product mixture was taken up in water (30 mL) andEtOAc. Purification by gravity column chromatography (50% EtOAc in hexanes) -diaza-cyclopentadienylhydrazone [a]幷 Cyclopentadienyl-6-yl)-amine in 33% yield.

MS (ESI) m / z: . 322.0 (M + H) + 1 H NMR (DMSO- d 6): 7.92 (s, 1 H), 7.57 (d, 1 H), 7.50 (d, 1 H), 7.25-7.21 (m, 2 H), 3.51 (s, 2 H).

Example 22

(4,7-Dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]noncyclopentadienyl-6-yl)-(4-iodo-phenyl)-amine

5,6-dihydro-cyclopenta[b]thiophen-4-one (1.0 g, 7.4 mmol) and 1-iodo-4-isothiocyanato-benzene in THF (2.0 mL) A mixture of 1.5 g, 7.2 mmol) was added dropwise at room temperature with lithium hexamethyldihydroethane (7.0 mL, 7.2 mmol). The reaction mixture was stirred for 8 hours. To the reaction mixture was added hydrazine monohydrate (0.4 mL, 7.9 mmol) and glacial acetic acid (0.5 mL), which was then stirred at reflux temperature for 24 hours. The product mixture was taken up in water (30 mL) andEtOAc. Purification by gravity column chromatography (50% EtOAc in hexanes) afforded the desired product (4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadiene[a] as a brown solid. Indole cyclopentadienyl-6-yl)-(4-iodo-phenyl)-amine, yield 32%.

MS (ESI) m/z: 380.0 (M+H) ⁺ . ¹ H NMR (DMSO - d ₆ ): 12.10 (s, 1 H), 8.57 (br, 1 H), 7.56-7.47 (m, 3 H ), 7.18 (d, 2 H), 6.72 (d, 1 H), 3.50 (s, 2 H).

Example 23

(4,7-Dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]indolecyclopentadienyl-6-yl)-(4-methoxy-phenyl)-amine

5,6-dihydro-cyclopenta[b]thiophen-4-one (1.0 g, 7.4 mmol) and 1-isothiocyanato-4-methoxy- in THF (2.0 mL) a mixture of benzene (1.5 g, 7.2 mmol), lithium hexamethyldihydroethane was added dropwise at room temperature (7.0 mL, 7.2 mmol). The reaction mixture was stirred for 8 hours. To the reaction mixture was added hydrazine monohydrate (0.4 mL, 7.9 mmol) and glacial acetic acid (0.5 mL), which was then stirred at reflux temperature for 24 hours. The product mixture was taken up in water (30 mL) andEtOAc. Purification by gravity column chromatography (50% EtOAc in hexanes) afforded the desired product (4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadiene[a] as a brown solid. Indole cyclopentadienyl-6-yl)-(4-methoxy-phenyl)-amine, yield 34%.

MS (ESI) m / z: . 284.0 (M + H) + 1 H NMR (DMSO- d 6): 11.88 (s, 1 H), 8.04 (s, 1 H), 7.54 (d, 1 H), 7.17 (d, 1 H), 6.82 (d, 2 H), 3.69 (s, 3 H), 3.43 (s, 2 H).

Example 24

(4,7-Dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]indolecyclopentadienyl-6-yl)-(3,4-dimethoxy-phenyl )-amine

5,6-dihydro-cyclopenta[b]thiophen-4-one (1.0 g, 7.4 mmol) and 4-isothiocyanato-1,2-methoxy in THF (2.0 mL) A mixture of benzyl-benzene (1.5 g, 7.2 mmol) was added dropwise lithium hexamethyldihydroethane (7.0 mL, 7.2 mmol) at room temperature. The reaction mixture was stirred for 8 hours. To the reaction mixture was added hydrazine monohydrate (0.4 mL, 7.9 mmol) and glacial acetic acid (0.5 mL), which was then stirred at reflux temperature for 24 hours. The product mixture was taken up in water (30 mL) andEtOAc. Purification by gravity column chromatography (50% EtOAc in hexanes) afforded the desired product (4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadiene[a] as a brown solid. Indole cyclopentadienyl-6-yl)-(3,4-dimethoxy-phenyl)-amine in a yield of 30%.

MS (ESI) m / z: . 314.0 (M + H) + 1 H NMR (DMSO- d 6): 11.92 (s, 1 H), 8.086 (s, 1 H), 7.54 (d, 1 H), 7.17 (d, 1 H), 6.83 (s, 1 H), 6.81 (s, 1 H), 3.72 (s, 3 H), 3.68 (s, 3 H), 3.46 (s, 2 H).

Example 25

(3-chloro-phenyl)-(4,7-dihydro-1-thio-4,5-diaza-cyclopentadienyl[a]indolecyclopentadienyl-6-yl)-amine

5,6-dihydro-cyclopenta[b]thiophen-4-one (1.0 g, 7.4 mmol) and 1-chloro-3-isothiocyanato-benzene in THF (2.0 mL) A mixture of 1.5 g, 7.2 mmol) was added dropwise at room temperature with lithium hexamethyldihydroethane (7.0 mL, 7.2 mmol). The reaction mixture was stirred for 8 hours. To the reaction mixture was added hydrazine monohydrate (0.4 mL, 7.9 mmol) and glacial acetic acid (0.5 mL), which was then stirred at reflux temperature for 24 hours. The product mixture was taken up in water (30 mL) andEtOAc. Purification by gravity column chromatography (50% EtOAc in EtOAc) - cyclopentadienyl [a] indole cyclopentadienyl-6-yl)-amine in a yield of 30%.

MS (ESI) m / z: . 288.0 (M + H) + 1 H NMR (DMSO- d 6): 12.05 (s, 1 H), 8.67 (s, 1 H), 7.57 (d, 1 H), 7.20 (t, 2 H), 6.75 (d, 1 H), 3.51 (s, 2 H).

Example 26

(4,7-Dihydro-1-thio-4,5-diaza-cyclopentadienyl[a]indolecyclopentadienyl-6-yl)-(3-methoxy-phenyl)-amine

5,6-dihydro-cyclopenta[b]thiophen-4-one (1.0 g, 7.4 mmol) and 1-isothiocyanato-3-methoxy- in THF (2.0 mL) A mixture of benzene (1.5 g, 7.2 mmol) was added dropwise lithium hexamethyldihydroethane (7.0 mL, 7.2 mmol) at room temperature. The reaction mixture was stirred for 8 hours. Add monohydrate hydrazine (0.4 mL, 7.9 mmol) and glacial acetic acid (0.5 mL) to the reaction mixture. In the mixture, it was further heated at reflux temperature for 24 hours. The product mixture was taken up in water (30 mL) andEtOAc. Purification by gravity column chromatography (50% EtOAc in hexanes) afforded the desired product (4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadiene[a] as a brown solid. Indole cyclopentadienyl-6-yl)-(3-methoxy-phenyl)-amine, yield 32%.

MS (ESI) m / z: . 284.0 (M + H) + 1 H NMR (DMSO- d 6): 12.06 (s, 1 H), 8.351 (s, 1 H), 7.55 (d, 1 H), 7.19 (s, 1 H), 7.09 (t, 2 H), 6.32 (d, 1 H), 3.70 (s, 3 H), 3.49 (s, 2 H).

Example 27

3-bromo-6-phenyl-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]indolecyclopentadiene

Add bromide to ice in 6-phenyl-4,7-dihydro-1-thio-4,5-diaza-cyclopentadienyl[a]indolecyclopentadiene (0.12 g, 0.5 mmol) A solution of acetic acid (0.5 mL of a 3 M solution). The reaction mixture was heated to 80 ° C for 12 hours. The solution was cooled to room temperature and poured into ice water. The resulting precipitate was filtered and washed with water to give the corresponding 3-bromo-6-phenyl-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl fluorene as a yellow solid. a] indole cyclopentadiene (0.14 g, 0.44 mmol) in 88% yield.

MS (ESI) m / z: . 317.0 (M + H) + 1 H NMR (DMSO- d 6): 7.78 (q, 2 H), 7.50 (t, 3 H), 7.34 (t, 1 H), 3.92 (s, 2 H).

Example 28

6-(1-oxy-pyridin-3-yl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]noncyclopentadiene

6-Pyridin-3-yl-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]pyrene Cyclopentadiene (0.24 g, 1.0 mmol) was dissolved in dichloromethane (5 mL) and then 3-chloroperoxybenzoic acid (purity: 75%, 0.5 g, 2 mmol). The mixture was stirred at ambient temperature for 8 hours. The dichloromethane was removed under reduced pressure and the residue was washed with 2M sodium bicarbonate. The precipitate was filtered, collected, washed with water and evaporated to dryness to give the corresponding 6-(1-oxy-pyridin-3-yl)-4,7-dihydro-1-sulfo-4,5 as a white solid. - Diazo-cyclopentadienyl[a]indolecyclopentadiene (0.21 g, 0.8 mmol) in 80% yield.

MS (ESI) m / z: . 256.0 (M + H) + 1 H NMR (DMSO- d 6): 13.20 (s, 1 H), 8.60 (s, 1 H), 8.20 (d, 1 H), 7.39 (d, 1 H), 7.61 (d, 1 H), 7.54 (t, 1 H), 7.28 (d, 1 H), 3.95 (s, 2 H).

Example 29

(4,7-Dihydro-1-thio-4,5-diaza-cyclopentadienyl[a]indolecyclopentadienyl-6-yl)-(3-trifluoromethyl-phenyl)- amine

5,6-dihydro-cyclopenta[b]thiophen-4-one (1.0 g, 7.4 mmol) and 1-isothiocyanato-3-trifluoromethyl in THF (2.0 mL) A mixture of benzene (1.5 g, 7.2 mmol) was added dropwise lithium hexamethyldihydroethane (7.0 mL, 7.2 mmol) at room temperature. The reaction mixture was stirred for 8 hours. To the reaction mixture was added hydrazine monohydrate (0.4 mL, 7.9 mmol) and glacial acetic acid (0.5 mL), which was then stirred at reflux temperature for 24 hours. The product mixture was taken up in water (30 mL) andEtOAc. Purification by gravity column chromatography (50% EtOAc in hexanes) afforded the desired product (4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadiene[a] as a brown solid. Indole cyclopentadienyl-6-yl)-(3-trifluoromethyl-phenyl)-amine, yield 34%.

MS (ESI) m / z: 322.0 (M + H) +.

Example 30

(4,7-Dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]indolecyclopentadienyl-6-yl)-(3-fluoro-phenyl)-amine

5,6-dihydro-cyclopenta[b]thiophen-4-one (1.0 g, 7.4 mmol) and 1-fluoro-3-isothiocyanato-benzene (THF) in THF (2.0 mL) A mixture of 1.5 g, 7.2 mmol) was added dropwise at room temperature with lithium hexamethyldihydroethane (7.0 mL, 7.2 mmol). The reaction mixture was stirred for 8 hours. To the reaction mixture was added hydrazine monohydrate (0.4 mL, 7.9 mmol) and glacial acetic acid (0.5 mL), which was then stirred at reflux temperature for 24 hours. The product mixture was taken up in water (30 mL) andEtOAc. Purification by gravity column chromatography (50% EtOAc in hexanes) afforded the desired product (4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadiene[a] as a brown solid. Indole cyclopentadienyl-6-yl)-(3-fluoro-phenyl)-amine, yield 33%.

MS (ESI) m / z: 273.0 (M + H) +.

Example 31

(2-Chloro-phenyl)-(4,7-dihydro-1-thio-4,5-diaza-cyclopentadienyl[a]indolecyclopentadienyl-6-yl)-amine

5,6-dihydro-cyclopenta[b]thiophen-4-one (1.0 g, 7.4 mmol) and 1-chloro-2-isothiocyanato-benzene (THF) in THF (2.0 mL) A mixture of 1.5 g, 7.2 mmol) was added dropwise at room temperature with lithium hexamethyldihydroethane (7.0 mL, 7.2 mmol). The reaction mixture was stirred for 8 hours. To the reaction mixture was added hydrazine monohydrate (0.4 mL, 7.9 mmol) and glacial acetic acid (0.5 mL), which was then stirred at reflux temperature for 24 hours. The product mixture was taken up in water (30 mL) andEtOAc. Gravity column chromatography (50% Purification of EtOAc in hexanes afforded (2-chloro-phenyl)-(4,7-dihydro-1-thio-4,5-diaza-cyclopentadienyl[a] as a brown solid. Indole cyclopentadienyl-6-yl)-amine in a yield of 30%.

MS (ESI) m / z: 289.0 (M + H) +.

Example 32

(4-chloro-phenyl)-(4,7-dihydro-1-thio-4,5-diaza-cyclopentadienyl[a]indolecyclopentadienyl-6-yl)-amine

5,6-dihydro-cyclopenta[b]thiophen-4-one (1.0 g, 7.4 mmol) and 1-chloro-4-isothiocyanato-benzene (THF) in THF (2.0 mL) A mixture of 1.5 g, 7.2 mmol) was added dropwise at room temperature with lithium hexamethyldihydroethane (7.0 mL, 7.2 mmol). The reaction mixture was stirred for 8 hours. To the reaction mixture was added hydrazine monohydrate (0.4 mL, 7.9 mmol) and glacial acetic acid (0.5 mL), which was then stirred at reflux temperature for 24 hours. The product mixture was taken up in water (30 mL) andEtOAc. Purification by gravity column chromatography (50% EtOAc in hexanes) - cyclopentadienyl [a] indole cyclopentadienyl-6-yl)-amine in a yield of 35%.

MS (ESI) m / z: 289.0 (M + H) +.

Example 33

2-bromo-6-(4-bromo-phenyl)-4,7-dihydro-1-thio-4,5-diaza-cyclopentadienyl[a]noncyclopentadiene

6-(4-Bromo-phenyl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]indolecyclopentadiene (0.16 g, 0.5 mmol) Add to a solution of bromide in glacial acetic acid (0.5 mL of 3 M solution). Heat the reaction mixture to 80 ° C and maintain 12 hours. The solution was cooled to room temperature and poured into ice water. The resulting precipitate was filtered and washed with water to give the corresponding 2-bromo-6-(4-bromo-phenyl)-4,7-dihydro-1-sulfo-4,5-diazide as a yellow solid. Cyclopentadienyl[a]indolecyclopentadiene (0.18 g, 0.47 mmol), yield 93%.

MS (ESI) m/z: 395.0 (M+H) ⁺ . ¹ H NMR (DMSO - d ₆ ): 7.69 (s, 4 H), 7.48 (s, 1 H), 3.88 (s, 2 H)

Example 34

2-bromo-6-(4-methoxy-phenyl)-4,7-dihydro-1-thio-4,5-diaza-cyclopentadienyl[a]noncyclopentadiene

6-(4-Methoxy-phenyl)-4,7-dihydro-1-thio-4,5-diaza-cyclopentadienyl[a]indenecyclopentadiene (0.13 g, 0.5 Methyl) was added to a solution of bromide in glacial acetic acid (0.5 mL of a 3 M solution). The reaction mixture was heated to 80 ° C for 12 hours. The solution was cooled to room temperature and poured into ice water. The resulting precipitate was filtered and washed with water to give the corresponding 2-bromo-6-(4-methoxy-phenyl)-4,7-dihydro-1-sulfo-4,5- Nitrogen-cyclopentadienyl[a]indolecyclopentadiene (0.18 g, 0.47 mmol), yield 91%.

MS (ESI) m / z: . 347.0 (M + H) + 1 H NMR (DMSO- d 6): 7.69 (d, 2 H), 7.64 (s, 1 H), 7.47 (s, 1 H), 7.08 (d, 2 H), 3.88 (s, 2 H), 3.80 (s, 3 H).

Example 35

(4,7-Dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]indolecyclopentadienyl-6-yl)-(4-trifluoromethyl-phenyl)- amine

5,6-dihydro-cyclopenta[b]thiophen-4-one (1.0 g, 7.4 mmol) and 1-isothiocyanato-4-trifluoromethoxy- in 2.0 mL THF - a mixture of benzene (1.5 g, 7.2 mmol), lithium hexamethyldihydroethane was added dropwise at room temperature (7.0 mL, 7.2 mmol). The reaction mixture was stirred for 8 hours. To the reaction mixture was added hydrazine monohydrate (0.4 mL, 7.9 mmol) and glacial acetic acid (0.5 mL), which was then stirred at reflux temperature for 24 hours. The product mixture was taken up in water (30 mL) andEtOAc. Purification by gravity column chromatography (50% EtOAc in hexanes) afforded the desired product (4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadiene[a] as a brown solid. Indole cyclopentadienyl-6-yl)-(4-trifluoromethyl-phenyl)-amine in a yield of 30%.

MS (ESI) m/z: 322.0 (M+H) ⁺ . ¹ H NMR (CDCl ₃ ): 7.43 (d, 2 H), 7.25 (d, 1 H), 7.02 (d, 1 H), 6.96 ( d, 2 H), 3.21 (s, 2 H).

Example 36

(3-bromo-phenyl)-(4,7-dihydro-1-thio-4,5-diaza-cyclopentadienyl[a]indolecyclopentadienyl-6-yl)-amine

5,6-dihydro-cyclopenta[b]thiophen-4-one (1.0 g, 7.4 mmol) and 1-bromo-3-isothiocyanato-benzene (THF) in THF (2.0 mL) A mixture of 1.5 g, 7.2 mmol) was added dropwise at room temperature with lithium hexamethyldihydroethane (7.0 mL, 7.2 mmol). The reaction mixture was stirred for 8 hours. To the reaction mixture was added hydrazine monohydrate (0.4 mL, 7.9 mmol) and glacial acetic acid (0.5 mL), which was then stirred at reflux temperature for 24 hours. The product mixture was taken up in water (30 mL) andEtOAc. Purification by gravity column chromatography (50% EtOAc in hexanes) - cyclopentadienyl [a] indole cyclopentadienyl-6-yl)-amine in a yield of 34%.

MS (ESI) m / z: 333.0 (M + H) +.

Example 37

[4-(4,7-Dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]indolecyclopentadienyl-6-yl)-phenyl]-(3-fluoro- Phenyl)-amine

Add NaH (60%, 0.48 g, 12.0 mmol) to 6-(4-bromo-phenyl)-4,7-dihydro-1-thio-4,5-diaza-cyclopentane at 0 °C A solution of diene[a]indolecyclopentadiene (3.1 g, 9.7 mmol) in THF (15 ml). Further, SEM-Cl (60%, 2.4 ml, 12 mmol) was added to the reaction mixture, and the obtained mixture was stirred at 0 ° C for 30 minutes, and then heated to 80 ° C and stirred for 2 hours. The solution was cooled to room temperature and poured into ice water. The resulting mixture was extracted with ethyl acetate. The organic layer was collected and rinsed with saturated aqueous NH ₄ Cl, to MgSO _{4 (s)} sulfate, and concentrated under reduced pressure. The oily residue was purified by gravity column chromatography (20% EtOAc in hexane) to afford 6-(4-bromo-phenyl)-4-(2-trimethyldecane-ethoxymethyl)- 4,7-Dihydro-1-thio-4,5-diaza-cyclopenta[a]indolecyclopentadiene (3.0 g, 6.7 mmol) as a brown solid, yield 69%.

The corresponding intermediate 6-(4-bromo-phenyl)-4-(2-trimethyldecane-ethoxymethyl)-4,7-dihydro-1-sulfo-4,5-diaza -cyclopenta[a]noncyclopentadiene (0.45 g, 1.0 mmol), 3-fluoro-phenylamine (0.28 g, 2.5 mmol), Cs ₂ CO ₃ (2 M, 3.0 mL), Xantphos (58 mg, 0.1 mmol), and a mixture of Pd(OAc) ₂ (22 mg, 0.1 mmol) in dioxane (5 mL) was heated to 100 ° C for 8 h. The mixture was cooled to room temperature and extracted with ethyl acetate. The desired product (3-fluoro-phenyl)-{4-[4-(2-trimethyldecane-ethoxymethyl) was obtained as a brown solid (m.). -4,7-Dihydro-1-thio-4,5-diaza-cyclopenta[a]indolecyclopentadienyl-6-yl]-phenyl}-amine, yield 49%.

(3-Fluoro-phenyl)-{4-[4-(2-trimethyldecane-ethoxymethyl)-4,7-di Hydrogen-1-sulfo-4,5-diaza-cyclopenta[a]noncyclopentadienyl-6-yl]-phenyl}-amine (0.24 g, 0.5 mmol) was dissolved in methanol Treat with concentrated hydrochloric acid (0.16 mL, 5 mmol). The reaction mixture was heated to 100 ° C for 4 hours. The solution was cooled to room temperature, and the obtained residue was filtered, washed with methanol, and then concentrated under reduced pressure to give the corresponding [4-(4,7-dihydro-1-sulfo-4) as a yellow solid. 5-diaza-cyclopentadienyl hydrazide [a] fluorene cyclopentadienyl-6-yl)-phenyl]-(3-fluoro-phenyl)-amine (0.14 g, 0.40 mmol), yield 79% .

MS (ESI) m/z: 349.0 (M+H) ⁺ . ¹ H NMR (DMSO - d ₆ ): 7.72 (d, 2 H), 7.64 (d, 1 H), 7.30-7.22 (m, 4 H) ), 6.94 (d, 2 H), 6.65 (d, 1 H), 3.95 (s, 2 H).

Example 38

6-(3-Fluoro-phenyl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]indolecyclopentadiene

5,6-Dihydro-cyclopenta[b]thiophen-4-one (2.1 g, 15.0 mmol) in 15 mL THF was treated with NaH (60%, 1.5 g, 36 mmol). After the addition of ethyl 4-fluoro-benzoate, the reaction mixture was heated to 100 ° C for 8 hours. The solution was cooled to room temperature and poured into water. The product mixture was acidified with cone. EtOAc (EtOAc)EtOAc. The organic layer was taken, dried over EtOAc EtOAc _m . The resulting precipitate was collected and recrystallized from ethanol to give the corresponding 5-(2-fluoro-benzylidenyl)-5,6-dihydro-cyclopenta[b]thiophen-4-one (0.56 g, 2.15 mmol) of a brown solid in 15% yield.

5-(2-Fluoro-benzylidenyl)-5,6-dihydro-cyclopenta[b]thiophen-4-one (0.56 g, 2.15 mmol), hydrazine monohydrate (0.16 mL, 3.2 mmol), glacial acetic acid (0.38 mL) and ethanol (10 mL) were heated to 100 ° C in nitrogen and maintained 4 hours. The mixture was cooled to 25 ° C and concentrated under reduced pressure to give a solid, which was recrystallised from ethanol to give the corresponding 6-(3-fluoro-phenyl)-4,7-dihydro-1 as a yellow solid. - Sulfur-4,5-diaza-cyclopentadienyl[a]indolecyclopentadiene (0.45 g, 17.5 mmol) in 81% yield.

MS (ESI) m/z: 258.0 (M+H) ⁺ . ¹ H NMR (DMSO - d ₆ ): 13.06 (s, 1 H), 7.61 - 7.54 (m, 4 H), 7.29 (s, 1 H) ), 7.20 (t, 1 H), 3.93 (s, 2 H).

Example 39

6-(3-Chloro-phenyl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]indolecyclopentadiene

5,6-Dihydro-cyclopenta[b]thiophen-4-one (2.1 g, 15.0 mmol) in 10 mL THF was treated with NaH (60%, 0.73 g, 18 mmol). After the addition of 3-chloro-benzoic acid methyl ester, the reaction mixture was heated to 100 ° C for 8 hours. The solution was cooled to room temperature and poured into water. The product mixture was acidified with cone. EtOAc (EtOAc)EtOAc. The organic layer was taken, dried over EtOAc EtOAc _m . The resulting precipitate was collected and recrystallized from ethanol to give the corresponding 5-(4-chloro-benzylidenyl)-5,6-dihydro-cyclopenta[b]thiophen-4-one (0.9 g, 3.3 mmol) of a brown solid with a yield of 45%.

5-(4-Chloro-benzylidene)-5,6-dihydro-cyclopenta[b]thiophen-4-one (0.9 g, 3.3 mmol), hydrazine monohydrate (0.24 mL, 4.9 mmol), glacial acetic acid (0.6 mL) and ethanol (10 mL) were heated to 100 ° C under nitrogen for 4 h. The mixture was cooled to 25 ° C and concentrated under reduced pressure to give a solid, which was recrystallised from ethanol to give the corresponding 6-(3-chloro-phenyl)-4,7-dihydro-1 as a yellow solid. - sulfur-4,5-diaza-cyclopentadienyl[a]noncyclopentadiene (0.64 g, 2.3 mmol), yield 71%.

MS (ESI) m / z: . 274.0 (M + H) + 1 H NMR (DMSO- d 6): 13.07 (s, 1 H), 7.83 (s, 1 H), 7.71 (d, 1 H), 7.60 (d, 1 H), 7.54 (t, 1 H), 7.43 (d, 1 H), 7.30 (d, 1 H), 3.95 (s, 2 H).

Example 40

6-(4-Fluoro-phenyl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]indolecyclopentadiene

5,6-Dihydro-cyclopenta[b]thiophen-4-one (2.1 g, 15.0 mmol) in 15 mL THF was treated with NaH (60%, 1.5 g, 36 mmol). After the addition of ethyl 3-fluoro-benzoate, the reaction mixture was heated to 100 ° C for 8 hours. The solution was cooled to room temperature and poured into water. The product mixture was acidified with cone. EtOAc (EtOAc)EtOAc. The organic layer was taken, dried over EtOAc EtOAc _m . The resulting precipitate was collected and recrystallized from ethanol to give the corresponding 5-(4-fluoro-benzylidenyl)-5,6-dihydro-cyclopenta[b]thiophen-4-one (0.56 g, 2.1 mmol) of a brown solid with a yield of 14%.

5-(4-Fluoro-benzylidenyl)-5,6-dihydro-cyclopenta[b]thiophen-4-one (0.56 g, 2.1 mmol), hydrazine monohydrate (0.15 mL, 3.1 mmol), glacial acetic acid (0.5 mL) and ethanol (10 mL) were heated to 100 ° C under nitrogen for 4 h. The mixture was cooled to 25 ° C and concentrated under reduced pressure to give a solid, which was recrystallised from ethanol to give the corresponding 6-(4-fluoro-phenyl)-4,7-dihydro-1- Sulfur-4,5-diaza-cyclopentadienyl[a]indolecyclopentadiene (0.45 g, 1.7 mmol) in 81% yield.

MS (ESI) m/z: 258.0 (M+H) ⁺ . ¹ H NMR (DMSO - d ₆ ): 12.97 (s, 1 H), 7.80 (t, 2 H), 7.60 (d, 1 H) , 7.38-7.29 (m, 3 H), 3.90 (s, 2 H).

Example 41

6-(2-Fluoro-phenyl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]noncyclopentadiene

5,6-Dihydro-cyclopenta[b]thiophen-4-one (2.1 g, 15.0 mmol) in 15 mL THF was treated with NaH (60%, 1.5 g, 36 mmol). After the addition of ethyl 3-fluoro-benzoate, the reaction mixture was heated to 100 ° C for 8 hours. The solution was cooled to room temperature and poured into water. The product mixture was acidified with cone. EtOAc (EtOAc)EtOAc. The organic layer was taken, dried over EtOAc EtOAc _m . The resulting precipitate was collected and recrystallized from ethanol to give the corresponding 5-(2-fluoro-benzylidenyl)-5,6-dihydro-cyclopenta[b]thiophen-4-one (0.56 g, 2.1 mmol) of a brown solid with a yield of 14%.

5-(2-Fluoro-benzylidene)-5,6-dihydro-cyclopenta[b]thiophen-4-one (0.56 g, 2.1 mmol), hydrazine monohydrate (0.15 mL, 3.1 mmol), glacial acetic acid (0.5 mL) and ethanol (10 mL) were heated to 100 ° C under nitrogen for 4 h. The mixture was cooled to 25 ° C and concentrated under reduced pressure to give a solid, which was recrystallised from ethanol to give the corresponding 6-(2-fluoro-phenyl)-4,7-dihydro-1- Sulfur-4,5-diaza-cyclopentadienyl[a]indolecyclopentadiene (0.45 g, 1.7 mmol) in 81% yield.

MS (ESI) m / z: . 258.0 (M + H) + 1 H NMR (DMSO- d 6): 12.94 (s, 1 H), 7.84 (s, 1 H), 7.59 (d, 1 H), 7.43-7.30 (m, 4 H), 3.83 (s, 2 H).

Example 42

(4,7-Dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]noncyclopentadiene-6- Base)-(2-trifluoromethyl-phenyl)-amine

5,6-dihydro-cyclopenta[b]thiophen-4-one (1.0 g, 7.4 mmol) and 1-isothiocyanato-2-trifluoromethyl in THF (2.0 mL) A mixture of benzene (1.5 g, 7.2 mmol) was added dropwise lithium hexamethyldihydroethane (7.0 mL, 7.2 mmol) at room temperature. The reaction mixture was stirred for 8 hours. To the reaction mixture was added hydrazine monohydrate (0.4 mL, 7.9 mmol) and glacial acetic acid (0.5 mL), which was then stirred at reflux temperature for 24 hours. The product mixture was taken up in water (30 mL) andEtOAc. Purification by gravity column chromatography (50% EtOAc in hexanes) afforded the desired product (4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadiene[a] as a brown solid. Indole cyclopentadienyl-6-yl)-(2-trifluoromethyl-phenyl)-amine, yield 33%.

MS (ESI) m / z: . 323.0 (M + H) + 1 H NMR (DMSO- d 6): 12.11 (s, 1 H), 7.56 (d, 2 H), 7.48 (t, 2 H), 7.21 (d, 1 H), 6.94 (d, 1 H), 3.46 (s, 2 H).

Example 43

6-(3,5-bis-trifluoromethyl-phenyl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]noncyclopentadiene

5,6-Dihydro-cyclopenta[b]thiophen-4-one in 13 mL THF was treated with NaH (60%, 1.1 g, 27 mmol). After the addition of 3,5-bis-trifluoromethyl-benzoic acid ethyl ester, the reaction mixture was heated to 100 ° C for 8 hours. The solution was cooled to room temperature and poured into water. The product mixture was acidified with cone. EtOAc (EtOAc)EtOAc. The organic layer was taken, dried over EtOAc EtOAc _m . The resulting precipitate was collected and recrystallized from ethanol to give the corresponding 5-(3,5-bis-trifluoromethyl-benzylidenyl)-5,6-dihydro-cyclopenta[b]thiophene- 4-ketone (1.07 g, 4.1 mmol) as a yellow solid.

5-(3,5-Bis-Trifluoromethyl-benzylidene)-5,6-dihydro-cyclopenta[b]thiophen-4-one (1.07 g, 4.1 mmol), single Hydrazine hydrate (0.3 mL, 6.2 mmol), glacial acetic acid (0.8 mL) and ethanol (10 mL) were heated to 100 ° C under nitrogen for 4 h. The mixture was cooled to 25 ° C and concentrated under reduced pressure to give a solid, which was recrystallised from ethanol to give the corresponding 6-(3,5-bis-trifluoromethyl-phenyl) as a white solid. 4,7-Dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]indolecyclopentadiene (0.58 g, 1.5 mmol), yield 37%. MS (ESI) m/z: (M+H) ⁺ . ¹ H NMR (DMSO - d ₆ ): 13.34 (s, 1 H), 8.36 (s, 1 H), 8.32 (s, 1 H), 8.10 (s, 1 H), 7.62 (d, 1 H), 7.31 (d, 1 H), 4.04 (s, 2 H).

Example 44

6-(2-bromo-phenyl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]noncyclopentadiene

5,6-Dihydro-cyclopenta[b]thiophen-4-one (2.1 g, 15.0 mmol) in 15 mL THF was treated with NaH (60%, 1.5 g, 36 mmol). After the addition of 2-bromo-benzoic acid phenyl ester, the reaction mixture was heated to 100 ° C for 8 hours. The solution was cooled to room temperature and poured into water. The product mixture was acidified with cone. EtOAc (EtOAc)EtOAc. The organic layer was taken, dried over EtOAc EtOAc _m . The resulting precipitate was collected and recrystallized from ethanol to give the corresponding 5-(2-bromo-benzylidenyl)-5,6-dihydro-cyclopenta[b]thiophen-4-one (2.5 g, 8.2 mmol) of a yellow solid with a yield of 58%.

5-(2-Bromo-benzylidenyl)-5,6-dihydro-cyclopenta[b]thiophen-4-one (2.5 g, 8.2 mmol), hydrazine monohydrate (0.6 mL, 1.2 mmol), ice vinegar The acid (1.5 mL) and ethanol (30 mL) were heated to 100 ° C under nitrogen for 4 h. The mixture was cooled to 25 ° C and concentrated under reduced pressure to give a solid, which was recrystallised from ethanol to give the corresponding 6-(2-bromo-phenyl)-4,7-dihydro- 1-Sulpho-4,5-diaza-cyclopentadienyl[a]indolecyclopentadiene (0.8 g, 2.5 mmol) in 30% yield.

MS (ESI) m / z: . 320.0 (M + H) + 1 H NMR (DMSO- d 6): 12.75 (s, 1 H), 7.78 (d, 1 H), 7.58 (d, 2 H), 7.50 (t, 1 H), 7.39 (d, 1 H), 7.29 (d, 1 H), 3.74 (s, 2 H).

Example 45

(4,7-Dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]indolecyclopentadienyl-6-yl)-(2-methoxy-phenyl)-amine

5,6-dihydro-cyclopenta[b]thiophen-4-one (1.0 g, 7.4 mmol) and 1-isothiocyanato-2-methoxy- in THF (2.0 mL) A mixture of benzene (1.5 g, 7.2 mmol) was added dropwise lithium hexamethyldihydroethane (7.0 mL, 7.2 mmol) at room temperature. The reaction mixture was stirred for 8 hours. To the reaction mixture was added hydrazine monohydrate (0.4 mL, 7.9 mmol) and glacial acetic acid (0.5 mL), which was then stirred at reflux temperature for 24 hours. The product mixture was taken up in water (30 mL) andEtOAc. Purification by gravity column chromatography (50% EtOAc in hexanes) afforded the desired product (4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadiene[a] as a brown solid. Indole cyclopentadienyl-6-yl)-(2-trifluoromethyl-phenyl)-amine, yield 33%.

MS (ESI) m / z: 285.0 (M + H) + 1 H NMR (CDCl 3):. 7.29 (s, 1 H), 7.20 (d, 1 H), 7.14 (t, 1 H), 6.92- 6.87 (m, 3 H), 3.87 (s, 3 H), 3.49 (s, 2 H).

Example 46

(4,7-Dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]noncyclopentadiene-6- (-)-(4-trifluoromethoxy-phenyl)-amine

5,6-dihydro-cyclopenta[b]thiophen-4-one (1.0 g, 7.4 mmol) and 1-isothiocyanato-4-trifluoromethoxy in THF (2.0 mL) A mixture of benzyl-benzene (1.5 g, 7.2 mmol) was added dropwise lithium hexamethyldihydroethane (7.0 mL, 7.2 mmol) at room temperature. The reaction mixture was stirred for 8 hours. To the reaction mixture was added hydrazine monohydrate (0.4 mL, 7.9 mmol) and glacial acetic acid (0.5 mL), which was then stirred at reflux temperature for 24 hours. The product mixture was taken up in water (30 mL) andEtOAc. Purification by gravity column chromatography (50% EtOAc in hexanes) afforded the desired product (4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadiene[a] as a brown solid. Indole cyclopentadienyl-6-yl)-(4-trifluoromethoxy-phenyl)-amine, yield 33%.

MS (ESI) m/z: 339.0 (M+H) ⁺ . ¹ H NMR (CDCl ₃ ): 7.23 (d, 1 H), 7.07 (d, 2 H), 7.02 (d, 1 H), 6.93 ( d, 2 H), 3.19 (s, 2 H).

Example 47

6-(3-Bromo-phenyl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]noncyclopentadiene

5,6-Dihydro-cyclopenta[b]thiophen-4-one (2.1 g, 15.0 mmol) in 15 mL THF was treated with NaH (60%, 1.5 g, 36 mmol). After the addition of 3-bromo-benzoic acid phenyl ester, the reaction mixture was heated to 100 ° C for 8 hours. The solution was cooled to room temperature and poured into water. The product mixture was acidified with cone. EtOAc (EtOAc)EtOAc. The organic layer was taken, dried over EtOAc EtOAc _m . The resulting precipitate was collected and recrystallized from ethanol to give the corresponding 5-(3-bromo-benzylidenyl)-5,6-dihydro-cyclopenta[b]thiophen-4-one as a brown solid. (2.5 g, 8.2 mmol), yield 58%.

5-(3-Bromo-benzylidenyl)-5,6-dihydro-cyclopenta[b]thiophen-4-one (2.5 g, 8.2 mmol), hydrazine monohydrate (0.6 mL, 1.2 mmol), glacial acetic acid (1.5 mL) and ethanol (30 mL) were heated to 100 ° C under nitrogen for 4 h. The mixture was cooled to 25 ° C and concentrated under reduced pressure to give a solid, which was crystallised from ethanol to give the corresponding 6-(3-bromo-phenyl)-4,7-dihydro-1- Sulfur-4,5-diaza-cyclopentadienyl[a]indolecyclopentadiene (0.8 g, 2.5 mmol) in 30% yield.

MS (ESI) m / z: 317.0 (M + H) +.

Example 48

(4,7-Dihydro-1-thio-4,5-diaza-cyclopentadienyl[a]indolecyclopentadienyl-6-yl)-(2-trifluoromethoxy-phenyl) -amine

5,6-dihydro-cyclopenta[b]thiophen-4-one (1.0 g, 7.4 mmol) and 1-isothiocyanato-2-trifluoromethoxy in THF (2.0 mL) A mixture of benzyl-benzene (1.6 g, 7.4 mmol) was added dropwise lithium hexamethyldiphenyl hydride (7.0 mL, 7.2 mmol) at room temperature. The reaction mixture was stirred for 8 hours. To the reaction mixture was added hydrazine monohydrate (0.4 mL, 7.9 mmol) and glacial acetic acid (0.5 mL), which was then stirred at reflux temperature for 24 hours. The resulting mixture was added to water (30 mL) and then evaporated. Purification by gravity column chromatography (50% EtOAc in hexanes) afforded the desired product (4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadiene[a] as a brown solid. Indole cyclopentadienyl-6-yl)-(2-trifluoromethoxy-phenyl)-amine, yield 33%.

MS (ESI) m / z: 339.0 (M + H) +.

Example 49

(3,5-Dichloro-phenyl)-(4,7-dihydro-1-thio-4,5-diaza-cyclopentadienyl[a]indolecyclopentadienyl-6-yl)- amine

5,6-dihydro-cyclopenta[b]thiophen-4-one (1.0 g, 7.4 mmol) and 1,3-dichloro-5-isothiocyanato in THF (2.0 mL) A mixture of benzene (1.2 g, 7.4 mmol) was added dropwise lithium hexamethyldihydroethane (7.0 mL, 7.2 mmol). The reaction mixture was stirred for 8 hours. To the reaction mixture was added hydrazine monohydrate (0.4 mL, 7.9 mmol) and glacial acetic acid (0.5 mL), which was then stirred at reflux temperature for 24 hours. The product mixture was taken up in water (30 mL) andEtOAc. Purification by gravity column chromatography (50% EtOAc in hexanes) afforded the desired product (3,5-dichloro-phenyl)-(4,7-dihydro-1-sulfo-4,5 as a brown solid. - Diazo-cyclopentadienyl [a] indolecyclopenta-6-yl)-amine in a yield of 30%.

MS (ESI) m / z: 323.0 (M + H) + 1 H NMR (CDCl 3):. 7.28 (d, 1 H), 7.04 (d, 1 H), 6.89 (s, 3 H), 3.02 ( s, 2 H).

Example 50

6-(3-Chloro-phenyl)-4H-1-thio-4,5-diaza-cyclopentadienyl[a]indolecyclopentadien-7-one

6-(3-Chloro-phenyl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopenta[b]indolecyclopentane in DMF (10 mL) ene (0.27 g, 1.0 mmol) and (3.26 g, 10 mmol) of the mixture CsCO _3, was stirred at ambient temperature and the oxygen molecule. The reaction mixture was stirred for 12 hours. The mixture was poured into ice water, rinsed with water, and the solvent was evaporated to give the corresponding 6-(3-chloro-phenyl)-4H-1-thio-4,5-diaza-cyclopentadienyl oxime as an orange solid. [a] Cyclopentadien-7-one, 96% yield.

MS (ESI) m / z: . 288.0 (M + H) + 1 H NMR (DMSO- d 6): 13.57 (s, 1 H), 8.20 (s, 1 H), 8.07 (q, 2 H), 7.60-7.54 (m, 2 H), 7.28 (d, 1 H).

Example 51

6-(2-methoxy-phenyl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]noncyclopentadiene

5,6-Dihydro-cyclopenta[b]thiophen-4-one (2.1 g, 15.0 mmol) in 15 mL THF was treated with NaH (60%, 1.5 g, 36 mmol). After the addition of 2-methoxy-benzoic acid phenyl ester, the reaction mixture was heated to 100 ° C for 8 hours. The solution was cooled to room temperature and poured into water. The product mixture was acidified with cone. EtOAc (EtOAc)EtOAc. The organic layer was taken, dried over EtOAc EtOAc _m . The resulting precipitate was collected and recrystallized from ethanol to give the corresponding 5-(2-methoxy-benzylidenyl)-5,6-dihydro-cyclopenta[b]thiophen-4-one (2.53 g, 8.3 mmol) of a yellow solid, yield 59%.

5-(2-Methoxy-benzylidenyl)-5,6-dihydro-cyclopenta[b]thiophen-4-one (2.53 g, 8.3 mmol), hydrazine monohydrate (0.65 mL, 12 mmol), glacial acetic acid (1.5 mL) and ethanol (20 mL) were heated to 100 ° C under nitrogen for 4 h. The mixture was cooled to 25 ° C and concentrated under reduced pressure to give a solid, which was recrystallised from ethanol to give the corresponding 6-(2-methoxy-phenyl)-4,7- Hydrogen-1-sulfo-4,5-diaza-cyclopentadienyl[a]indolecyclopentadiene (2 g, 7.4 mmol), yield 89%.

MS (ESI) m / z: . 270.0 (M + H) + 1 H NMR (DMSO- d 6): 12.60 (s, 1 H), 7.66 (d, 1 H), 7.57 (d, 1 H), 7.36 (d, 1 H), 7.34 (s, 1 H), 7.29 (d, 1 H), 7.14 (d, 1 H), 7.06 (t, 1 H), 3.93 (s, 3 H), 3.82 ( s, 2 H).

Example 52

(2,4-dichloro-phenyl)-(4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]noncyclopentadienyl-6-yl)- amine

5,6-dihydro-cyclopenta[b]thiophen-4-one (1.0 g, 7.4 mmol) and 2,4-dichloro-5-isothiocyanato in THF (2.0 mL) A mixture of benzene (1.2 g, 7.4 mmol) was added dropwise lithium hexamethyldihydroethane (7.0 mL, 7.2 mmol). The reaction mixture was stirred for 8 hours. To the reaction mixture was added hydrazine monohydrate (0.4 mL, 7.9 mmol) and glacial acetic acid (0.5 mL), which was then stirred at reflux temperature for 24 hours. The product mixture was taken up in water (30 mL) andEtOAc. Purification by gravity column chromatography (50% EtOAc in hexanes) - Diazo-cyclopentadienyl [a] indolecyclopenta-6-yl)-amine in a yield of 30%.

MS (ESI) m/z: 323.0 (M+H) ⁺ . ¹ H NMR (CDCl ₃ ):7.33-7.31 (m, 2 H), 7.14-7.09 (m, 3 H), 6.33 (brs, 1 H) ), 3.46 (s, 2 H).

Example 53

(3,4-Dichloro-phenyl)-(4,7-dihydro-1-thio-4,5-diaza-cyclopentadienyl[a]indolyl-6-yl)- amine

5,6-dihydro-cyclopenta[b]thiophen-4-one (1.0 g, 7.4 mmol) and 3,4-dichloro-5-isothiocyanato in THF (2.0 mL) A mixture of benzene (1.2 g, 7.4 mmol) was added dropwise lithium hexamethyldihydroethane (7.0 mL, 7.2 mmol). The reaction mixture was stirred for 8 hours. To the reaction mixture was added hydrazine monohydrate (0.4 mL, 7.9 mmol) and glacial acetic acid (0.5 mL), which was then stirred at reflux temperature for 24 hours. Mix the product After adding water (30 mL), it was extracted with ethyl acetate. Purification by gravity column chromatography (50% EtOAc in hexanes) toield of the desired product (3,4-dichloro-phenyl)-(4,7-dihydro-1-thio-4,5 - Diazo-cyclopentadienyl [a] indolecyclopenta-6-yl)-amine in a yield of 30%.

MS (ESI) m/z: 323.0 (M+H) ⁺ . ¹ H NMR (CDCl ₃ ): 7.31 (d, 1 H), 7.25 (d, 1 H), 7.11 (d, 1 H), 7.08 ( d, 1 H), 6.77 (d, 1 H), 6.16 (brs, 1 H), 3.44 (s, 2 H).

Example 54

(2,3-dichloro-phenyl)-(4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]indolecyclopentadienyl-6-yl)- amine

5,6-dihydro-cyclopenta[b]thiophen-4-one (1.0 g, 7.4 mmol) and 2,3-dichloro-5-isothiocyanato in THF (2.0 mL) A mixture of benzene (1.2 g, 7.4 mmol) was added dropwise lithium hexamethyldihydroethane (7.0 mL, 7.2 mmol). The reaction mixture was stirred for 8 hours. To the reaction mixture was added hydrazine monohydrate (0.4 mL, 7.9 mmol) and glacial acetic acid (0.5 mL), which was then stirred at reflux temperature for 24 hours. The product mixture was taken up in water (30 mL) andEtOAc. Purification by gravity column chromatography (50% EtOAc in hexanes) - Diazo-cyclopentadienyl [a] indolecyclopenta-6-yl)-amine in a yield of 30%.

MS (ESI) m/z: 322.0 (M+H) ⁺ . ¹ H NMR (CDCl ₃ ): 7.32 (d, 1 H), 7.26 (d, 1 H), 7.18 (d, 2 H), 7.07 ( d, 1 H), 6.51 (brs, 1 H), 3.48 (s, 2 H).

Example 55

(4,7-Dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]indolecyclopentadienyl-6-yl)-[4-(piperidine-1-sulfonyl) )-phenyl]-amine

5,6-dihydro-cyclopenta[b]thiophen-4-one (1.0 g, 7.4 mmol) and 1-(4-isothiocyanato-benzenesulfonate in THF (2.0 mL) A mixture of piperidine (2.0 g, 7.4 mmol) was added dropwise lithium hexamethyldihydroethane (7.0 mL, 7.2 mmol). The reaction mixture was stirred for 8 hours. To the reaction mixture was added hydrazine monohydrate (0.4 mL, 7.9 mmol) and glacial acetic acid (0.5 mL), which was then stirred at reflux temperature for 24 hours. The product mixture was taken up in water (30 mL) andEtOAc. Purification by gravity column chromatography (50% EtOAc in hexanes) afforded the desired product (4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadiene[a] as a brown solid. Indole cyclopentadienyl-6-yl)-[4-(piperidin-1-sulfonyl)-phenyl]-amine, yield 29%.

MS (ESI) m / z: 401.0 (M + H) + 1 H NMR (CDCl 3):. 7.63 (d, 2 H), 7.31 (d, 1 H), 7.11 (t, 3 H), 5.30 ( s, 2 H), 2.98-2.95 (m, 4 H), 1.66-1.62 (m, 4 H), 1.43-1.41 (m, 2 H).

Example 56

6-(4-Amino-phenyl)-4H-1-thio-4,5-diaza-cyclopentadienyl[a]indolecyclopentadien-7-one

4-(4,7-Dihydro-1-thio-4,5-diaza-cyclopenta[b]indolecyclopentadienyl-6-yl)-phenyl in DMF (10 mL) amine (0.25 g, 1.0 mmol) and (3.26 g, 10 mmol) of the mixture CsCO _3, was stirred at ambient temperature and the oxygen molecule. The reaction mixture was stirred for 12 hours. The mixture was poured into ice water, rinsed with water and then evaporated to give the corresponding 6-(4-amino-phenyl)-4H-1-thio-4,5-diaza-cyclopentadiene as a brown solid. [a] Cyclopentadien-7-one (2.49 g, 9.3 mmol), yield 93%.

MS (ESI) m / z: . 268.0 (M + H) + 1 H NMR (DMSO- d 6): 12.95 (s, 1 H), 8.01 (d, 1 H), 7.85 (d, 2 H), 7.26 (d, 1 H), 6.64 (d, 2 H), 5.82 (brs, 2 H).

Example 57

6-(3,5-Dichloro-phenyl)-4,7-dihydro-1-thio-4,5-diaza-cyclopentadienyl[a]noncyclopentadiene

5,6-Dihydro-cyclopenta[b]thiophen-4-one (2.1 g, 15.0 mmol) in 15 mL THF was treated with NaH (60%, 1.5 g, 36 mmol). After the addition of 3,5-dichloro-benzoic acid ethyl ester, the reaction mixture was heated to 100 ° C for 8 hours. The solution was cooled to room temperature and poured into water. The product mixture was acidified with cone. EtOAc (EtOAc)EtOAc. The organic layer was taken, dried over EtOAc EtOAc _m . The resulting precipitate was collected and recrystallized from ethanol to give the corresponding 5-(3,5-dichloro-benzylidenyl)-5,6-dihydro-cyclopenta[b]thiophen-4-one ( 1.5 g, 4.8 mmol) of a brown solid, yield 34%.

5-(3,5-Dichloro-benzylidenyl)-5,6-dihydro-cyclopenta[b]thiophen-4-one (1.5 g, 4.8 mmol), monoamine hydrazine ( 0.65 mL, 12 mmol), glacial acetic acid (1.5 mL) and ethanol (20 mL) were heated to 100 ° C under nitrogen for 4 h. The mixture was cooled to 25 ° C and concentrated under reduced pressure to give a solid, which was recrystallised from ethanol to give the corresponding 6-(3,5-dichloro-phenyl)-4,7- as a yellow solid. Dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]indolecyclopentadiene (1.33 g, 4.3 mmol) in 90% yield.

MS (ESI) m / z: . 307.0 (M + H) + 1 H NMR (DMSO- d 6): 13.13 (s, 1 H), 7.77 (s, 2 H), 7.60 (d, 2 H), 7.29 (d, 1 H), 3.97 (s, 2 H).

Example 58

6-pyridin-2-yl-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]fluorene ring Pentadiene

5,6-Dihydro-cyclopenta[b]thiophen-4-one (1.66 g, 12 mmol) in 40 mL of THF was treated with NaH (60%, 2.4 g, 17 mmol). After the addition of ethyl nicotinic acid (0.3 g, 20 mmol), the reaction mixture was heated to 100 ° C for 8 h. The solution was cooled to room temperature and poured into water. The product mixture was acidified with cone. EtOAc (EtOAc)EtOAc. The organic layer was taken, dried over EtOAc EtOAc _m . The resulting precipitate was collected and recrystallized from ethanol to give the corresponding 5-(pyridine-2-carbonyl)-5,6-dihydro-cyclopenta[b]thiophen-4-one (1.23 g) as a red solid. , 8 mmol), yield 55%.

5-(Pyridin-2-carbonyl)-5,6-dihydro-cyclopenta[b]thiophen-4-one (1.19 g, 8 mmol), hydrazine monohydrate (0.6 mL, 12 mmol) Glacial acetic acid (1.4 mL) and ethanol (20 mL) were heated to 100 ° C under nitrogen for 4 h. The mixture was cooled to 25 ° C and concentrated under reduced pressure to give a solid, which was recrystallised from ethanol to give the corresponding 6-pyridin-2-yl-4,7-dihydro-1-sulfide as a white solid. -4,5-diaza-cyclopentadienyl[a]indolecyclopentadiene (0.94 g, 3.9 mmol), yield 49%.

MS (ESI) m / z: 239.8 (M + H) + .H NMR (DMSO- d 6): 13.16 (s, 1 H), 8.66 (d, 1 H), 7.93 (t, 1 H), 7.76 (d, 1 H), 7.60 (d, 1 H), 7.36 (t, 1 H), 7.29 (d, 1 H), 3.93 (s, 2 H).

Example 59

3-(4,7-Dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]indolecyclopentadienyl-6-yl)-phenylamine hydrochloride

Add NaH (60%, 0.6 g, 12.0 mmol) to 6-(3-bromo-phenyl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentane at 0 °C A solution of diene[a]indolecyclopentadiene (3.1 g, 9.7 mmol) in THF (15 ml). Further, SEM-Cl (2.5 ml, 12 mmol) was added to the reaction mixture, and the mixture was stirred at 0 ° C for 30 minutes, and then heated to 80 ° C and stirred for 2 hours. The solution was cooled to room temperature and poured into ice water. The resulting mixture was extracted with ethyl acetate. The organic layer was collected and rinsed with saturated aqueous NH ₄ Cl, to MgSO _{4 (s)} sulfate, and concentrated under reduced pressure. The oily residue was purified by gravity column chromatography (20% EtOAc in hexane) to afford 6-(3-bromo-phenyl)-4-(2-trimethyldecane-ethoxymethyl)- 4,7-Dihydro-1-thio-4,5-diaza-cyclopenta[a]indolecyclopentadiene (3.0 g, 6.7 mmol) as a brown solid, yield 70%.

The corresponding intermediate 6-(3-bromo-phenyl)-4-(2-trimethyldecane-ethoxymethyl)-4,7-dihydro-1-sulfo-4,5-diaza -cyclopenta[a]noncyclopentadiene (0.45 g, 1.0 mmol), acetamide (0.15 g, 2.5 mmol), Cs ₂ CO ₃ (2 M, 3.0 mL), Xantphos (58 mg, A mixture of 0.1 mmol) and Pd(OAc) ₂ (22 mg, 0.1 mmol) in dioxane (5 mL) was heated to 100 ° C for 8 h. The mixture was cooled to room temperature and extracted with ethyl acetate. The desired product N-{3-[4-(2-trimethyldecane-ethoxymethyl)-4,7-di was obtained as a brown solid. Hydrogen-1-sulfo-4,5-diaza-cyclopenta[a]indolenecyclopenta-6-yl]-phenyl}-acetamide, yield 75%.

N-{3-[4-(2-Trimethyldecane-ethoxymethyl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopenta[a] The indole cyclopentadienyl-6-yl]-phenyl}-acetamide (0.21 g, 0.5 mmol) was dissolved in MeOH thenEtOAc. The reaction mixture was heated to 100 ° C for 4 hours. Cool the solution To the room temperature, the resulting precipitate was filtered off, washed with methanol, and then obtained under reduced pressure to give the corresponding 3-(4,7-dihydro-1-sulfo-4,5-diazide as a yellow solid. Cyclopentadienyl[a]indolecyclopentadienyl-6-yl)-phenylamine hydrochloride (0.12 g, 0.41 mmol), yield 81%.

MS (ESI) m / z: 254.0 (M + H) +.

Example 60

6-pyridin-4-yl-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]noncyclopentadiene

5,6-Dihydro-cyclopenta[b]thiophen-4-one (1.66 g, 12 mmol) in 40 mL THF was treated with NaH (60%, 0.7 g, 17 mmol). After the addition of ethyl isonicotinate (0.3 g, 20 mmol), the reaction mixture was heated to 100 ° C for 8 h. The solution was cooled to room temperature and poured into water. The product mixture was acidified with cone. EtOAc (EtOAc)EtOAc. The organic layer was taken, dried over EtOAc EtOAc _m . The resulting precipitate was collected and recrystallized from ethanol to give the corresponding 5-(pyridine-4-carbonyl)-5,6-dihydro-cyclopenta[b]thiophen-4-one (1.78 g, 7.3 mmol). The red solid was 61%.

5-(Pyridin-4-carbonyl)-5,6-dihydro-cyclopenta[b]thiophen-4-one (1.95 g, 8 mmol), hydrazine monohydrate (0.6 mL, 12 mmol) Glacial acetic acid (1.4 mL) and ethanol (20 mL) were heated to 100 ° C under nitrogen for 4 h. The mixture was cooled to 25 ° C and concentrated under reduced pressure to give a solid, which was crystallised from ethanol to give the corresponding 6-pyridin-4-yl-4,7-dihydro-1-sulfide as a white solid. 4,5-Diazin-cyclopentadienyl[a]indolecyclopentadiene (1.16 g, 4.2 mmol), yield 53%.

MS (ESI) m / z: . 239.6 (M + H) + 1 H NMR (DMSO- d 6): 13.32 (s, 1 H), 8.67 (s, 2 H), 7.71 (d, 2 H), 7.62 (d, 1 H), 7.31 (s, 1 H), 3.97 (s, 2 H).

Example 61

6-(1-oxy-pyridin-4-yl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]noncyclopentadiene

6-Pyridin-4-yl-4,7-dihydro-1-thio-4,5-cyclopenta[a]cyclopentadiene (0.24 g, 1.0 mmol) was dissolved in dichloromethane (5 (mL), then added 3-chloroperoxybenzoic acid (15 mL). The mixture was stirred at ambient temperature for 8 hours. The dichloromethane was removed under reduced pressure and the residue was washed with 2M sodium hydrogen carbonate. The precipitate was collected by filtration, washed with water, dried and evaporated to give the corresponding 6-(1-oxy-pyridin-4-yl)-4,7-dihydro-1-sulfene as a white solid. 4,5-Dinitro-cyclopentadienyl[a]indolecyclopentadiene (0.23 g, 0.9 mol), yield 90%.

MS (ESI) m / z: . 256.0 (M + H) + 1 H NMR (DMSO- d 6): 13.20 (s, 1 H), 8.31 (s, 2 H), 7.71 (d, 2 H), 7.60 (d, 2 H), 7.29 (s, 1 H), 3.928 (s, 2 H).

Example 62

[4-(4,7-Dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]indolecyclopentadienyl-6-yl)-phenyl]-pyridin-4-yl -amine hydrochloride

The corresponding intermediate 6-(4-bromo-phenyl)-4-(2-trimethyldecane-ethoxymethyl)-4,7-dihydro-1-sulfo-4,5-diaza -cyclopenta[a]noncyclopentadiene (0.45 g, 1.0 mmol), pyridin-4-yl-amine (0.24 g, 2.5 mmol), Cs ₂ CO ₃ (2 M, 3.0 mL), Xantphos (58 mg, 0.1 mmol) and a mixture of Pd(OAc) ₂ (22 mg, 0.1 mmol) in dioxane (5 mL) were heated to 100 ° C for 8 h. The solution was cooled to room temperature and extracted with ethyl acetate. The desired product pyridin-4-yl-{4-[4-(2-trimethyldecane-ethoxymethyl)-4 was obtained as a brown solid. , 7-Dihydro-1-sulfo-4,5-diaza-cyclopenta[a]indolecyclopentadienyl-6-yl]-phenyl}-amine, yield 66%.

Pyridin-4-yl-{4-[4-(2-trimethyldecane-ethoxymethyl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadiene And [a] indole cyclopentadienyl-6-yl]-phenyl}-amine (0.23 g, 0.5 mmol) was dissolved in MeOH thenEtOAc. The reaction mixture was heated to 100 ° C for 4 hours. The solution was cooled to room temperature, and the obtained precipitate was filtered, washed with methanol, and then concentrated under reduced pressure to give the corresponding [4-(4,7-dihydro-1-sulfo-4) as a yellow solid. 5-diaza-cyclopentadienyl hydrazide [a] fluorene cyclopentadienyl-6-yl)-phenyl]-pyridin-4-yl-amine hydrochloride (0.13 g, 0.36 mmol), yield 71 %.

MS (ESI) m/z: 331.0 (M+H) ⁺ . ¹ H NMR (DMSO- d ₆ ): 13.91 (s, 1 H), 10.923 (s, 1 H), 8.30 (d, 2 H), 7.88 (d, 2 H), 7.61 (d, 1 H), 7.48 (d, 2 H), 7.29 (d, 1 H), 7.21. (d, 2 H), 3.93 (s, 2 H).

Example 63

[4-(4,7-Dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]indolecyclopentadienyl-6-yl)-phenyl]-pyridin-3-yl -amine

The corresponding intermediate 6-(4-bromo-phenyl)-4-(2-trimethyldecane-ethoxymethyl)-4,7-dihydro-1-sulfo-4,5-diaza -cyclopenta[a]noncyclopentadiene (0.45 g, 1.0 mmol), pyridin-3-yl-amine (0.24 g, 2.5 mmol), Cs ₂ CO ₃ (2 M, 3.0 mL), Xantphos (58 mg, 0.1 mmol) and a mixture of Pd(OAc) ₂ (22 mg, 0.1 mmol) in dioxane (5 mL) were heated to 100 ° C for 8 h. The solution was cooled to room temperature and extracted with ethyl acetate. The desired product, pyridin-3-yl-{4-[4-(2-trimethyldecane-ethoxymethyl)-4, was obtained as a brown solid. , 7-Dihydro-1-sulfo-4,5-diaza-cyclopenta[a]noncyclopentadienyl-6-yl]-phenyl}-amine, yield 71%.

Pyridin-3-yl-{4-[4-(2-trimethyldecane-ethoxymethyl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadiene And [a] indole cyclopentadienyl-6-yl]-phenyl}-amine (0.23 g, 0.5 mmol) was dissolved in MeOH thenEtOAc. The reaction mixture was heated to 100 ° C for 4 hours. The solution was cooled to room temperature, and the obtained precipitate was filtered, washed with methanol, and then concentrated under reduced pressure to give the corresponding [4-(4,7-dihydro-1-sulfo-4,5) as a yellow solid. - Diazo-cyclopentadienyl[a]indolecyclopentadienyl-6-yl)-phenyl]-pyridin-3-yl-amine (0.13 g, 0.36 mmol), yield 80%.

MS (ESI) m / z: . 331.0 (M + H) + 1 H NMR (DMSO- d 6): 9.76 (s, 1 H), 8.51 (d, 1 H), 8.27 (d, 1 H), 8.16(d,1 H),7.86(q,1 H),.7.80(d,2 H), 7.61(d,1 H), 7.39(d,2 H), 7.29(d,1 H), 3.92 (s, 2 H).

Example 64

6-(6-Bromo-pyridin-3-yl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]indolecyclopentadiene

5,6-Dihydro-cyclopentadienium [b]thiophen-4-one (1.38 g, 10 mmol) in 30 mL of THF was treated with NaH (60%, 0.6 g, 15 mmol). After the addition of 6-bromo-nicotinic acid ethyl ester (2.3 g, 10 mmol), the reaction mixture was heated to 100 ° C for 8 hours. The solution was cooled to room temperature and poured into water. The resulting mixture was acidified with concentrated HCl and extracted with ethyl acetate. The organic solution was collected, dried over MgSO _{4 (s)} and evaporated. The resulting precipitate was collected and recrystallized from ethanol to give the corresponding 5-(6-bromo-pyridyl-3-carbonyl)-5,6-dihydro-cyclopentadienyl[b]thiophene as a red solid. 4-ketone 2.28 g, 7.1 mmol), yield 71%.

5-(6-Bromo-pyridyl-3-carbonyl)-5,6-dihydro-cyclopentadienyl[b]thiophen-4-one (1.29 g, 4 mmol), hydrazine monohydrate ( 0.6 mL, 12 mmol), glacial acetic acid (1.4 mL) and ethanol (20 mL) were heated to 100 ° C under nitrogen for 4 h. The mixture was cooled to 25 ° C and concentrated under reduced pressure to give a solid, which was crystallised from ethanol to give the corresponding 6-(6-bromo-pyridin-3-yl)-4,7- Hydrogen-1-sulfo-4,5-diaza-cyclopentadienyl[a]indolecyclopentadiene (0.83 g, 2.6 mmol) in 65% yield.

MS (ESI) m / z: . 317.9 (M + H) + 1 H NMR (DMSO- d 6): 13.18 (s, 1 H), 8.78 (d, 1 H), 8.08 (d, 1 H), 7.80 (d, 1 H), 7.60 (d, 1 H), 7.30 (d, 1 H), 3.95 (s, 2 H).

Example 65

6-(4-methoxy-phenyl)-2-phenyl-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]noncyclopentadiene

Add NaH (60%, 1.3 g, 33 mmol) to 2-bromo-6-(4-methoxy-phenyl)-4,7-dihydro-1-sulfo-4,5 at 0 °C a solution of diaza-cyclopenta[a]indolecyclopentadiene (8.3 g, 24 mmol) in THF (15 ml). Further, SEM-Cl (5.6 ml, 28 mmol) was added to the reaction mixture, and the obtained mixture was stirred at 0 ° C for 30 minutes, and then heated to 80 ° C and stirred for 2 hours. The solution was cooled to room temperature and poured into ice water. The resulting mixture was extracted with ethyl acetate. The organic layer was collected and rinsed with saturated aqueous NH ₄ Cl, to MgSO _{4 (s)} sulfate, and concentrated under reduced pressure. The oily residue was purified by gravity column chromatography (20% EtOAc in hexane) to afford 2-bromo-6-(4-methoxy-phenyl)-4-(2-trimethyldecane-ethyl Oxymethyl)-4,7-dihydro-1-thio-4,5-diaza-cyclopenta[a]indolecyclopentadiene (9.0 g, 19.0 mmol) as a brown solid, yield 79%.

The corresponding intermediate 2-bromo-6-(4-methoxy-phenyl)-4-(2-trimethyldecane-ethoxymethyl)-4,7-dihydro-1-sulfo- 4,5-diaza-cyclopenta[a]indolene (0.3 g, 0.63 mmol), phenylboronic acid (0.12 g, 9.4 mmol), Na ₂ CO ₃ (2 M, 1.5 mL) A mixture of Pd(PPh ₃ ) ₂ Cl ₂ (58 mg, 0.05 mmol) in toluene/ethanol (1:1, 4.0 mL) was heated to 100 ° C for 8 h. The solution was cooled to room temperature and extracted with ethyl acetate. The desired product, 2-bromo-6-(4-methoxy-phenyl)-4-(2-trimethylnonane), was obtained as an orange solid from EtOAc (EtOAc) Ethoxymethyl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopenta[a]indolecyclopentadiene in a yield of 58%.

2-Bromo-6-(4-methoxy-phenyl)-4-(2-trimethyldecane-ethoxymethyl)-4,7-dihydro-1-sulfo-4,5- Diazo-cyclopenta[a]indolecyclopentadiene (0.12 g, 0.25 mmol) was dissolved in MeOH then EtOAc (EtOAc (EtOAc) The reaction mixture was heated to 100 ° C for 4 hours. The solution was cooled to room temperature, and the obtained precipitate was filtered, washed with methanol, and then evaporated to give the corresponding 6-(4-methoxy-phenyl)-2-phenyl- 4,7-Dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]indolecyclopentadiene (0.04 g, 0.11 mmol), yield 46%.

MS (ESI) m/z: 345.0 (M+H) ⁺ . ¹ H NMR (DMSO - d ₆ ): 7.75-7.70 (m, 5 H), 7.44 (t, 2 H), 7.32 (t, 1 H) ), 7.08 (d, 2 H), 3.96 (s, 2 H), 3.80 (s, 3 H).

Example 66

5-(4,7-Dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]indolecyclopentadienyl-6-yl)-pyridin-2-ylamine hydrochloride

Add NaH (60%, 0.6 g, 12.0 mmol) to 6-(6-bromo-pyridin-3-yl)-4,7-dihydro-1-sulfo-4,5-diazepine at 0 °C a solution of cyclopenta[a]indolecyclopentadiene (3.1 g, 9.7 mmol) in THF (15 ml). Further, SEM-Cl (2.5 ml, 12 mmol) was added to the reaction mixture, and the mixture was stirred at 0 ° C for 30 minutes, and then heated to 80 ° C and stirred for 2 hours. The solution was cooled to room temperature and poured into ice water. The resulting mixture was extracted with ethyl acetate. The organic layer was collected and rinsed with saturated aqueous NH ₄ Cl, to MgSO _{4 (s)} sulfate, and concentrated under reduced pressure. The oily residue was purified by gravity column chromatography (20% EtOAc in hexane) to afford 6-(6-bromo-pyridin-3-yl)-4-(2-trimethyldecane-ethoxy 4-)7-Dihydro-1-thio-4,5-diaza-cyclopenta[a]indolecyclopentadiene (3.0 g, 6.7 mmol) as a brown solid, yield 70%.

The corresponding intermediate 6-(6-bromo-pyridin-3-yl)-4-(2-trimethyldecane-ethoxymethyl)-4,7-dihydro-1-sulfo-4,5 - diaza-cyclopenta[a]noncyclopentadiene (0.45 g, 1.0 mmol), acetamide (0.15 g, 2.5 mmol), Cs ₂ CO ₃ (2 M, 3.0 mL), Xantphos ( A mixture of 58 mg, 0.1 mmol) and Pd(OAc) ₂ (22 mg, 0.1 mmol) in dioxane (5 mL) was heated to 100 ° C for 8 h. The solution was cooled to room temperature and extracted with ethyl acetate. The desired product N-{5-[4-(2-trimethyldecane-ethoxymethyl)-4,7-di was obtained as a brown solid. Hydrogen-1-sulfo-4,5-diaza-cyclopenta[a]noncyclopentadien-6-yl]-pyridin-2-yl}-acetamide, yield 71%.

N-{5-[4-(2-trimethyldecane-ethoxymethyl)-4,7-dihydro-1-sulfo- 4,5-diaza-cyclopenta[a]noncyclopentadienyl-6-yl]-pyridin-2-yl}-acetamide (0.21 g, 0.5 mmol) dissolved in methanol and then concentrated Treatment with hydrochloric acid (0.16 mL, 5 mmol). The reaction mixture was heated to 100 ° C for 4 hours. The solution was cooled to room temperature, and the obtained precipitate was filtered, washed with methanol, and then obtained under reduced pressure to give the corresponding 5-(4,7-dihydro-1-sulfo-4,5- as a yellow solid. Diazo-cyclopentadienyl[a]indolecyclopentadienyl-6-yl)-pyridin-2-ylamine hydrochloride (0.13 g, 0.45 mmol), yield 90%.

MS (ESI) m / z: 291.0 (M + H) +.

Example 67

2-bromo-6-(6-bromo-pyridin-3-yl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]noncyclopentadiene

6-(6-Bromo-pyridin-3-yl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]indenecyclopentadiene (0.16 g, A solution of bromide in glacial acetic acid (0.5 mL of a 3 M solution) was added to 0.5 mmol). The reaction mixture was heated to 80 ° C for 12 hours. The solution was cooled to room temperature and poured into ice water. The resulting precipitate was filtered and washed with water to give corresponding 2-bromo-6-(6-bromo-pyridin-3-yl)-4,7-dihydro-1-sulfo-4,5- as a yellow solid. Diazo-cyclopentadienyl ruthenium [a] fluorene cyclopentadiene (0.18 g, 0.48 mol), yield 95%.

MS (ESI) m / z: . 396.0 (M + H) + 1 H NMR (DMSO- d 6): 8.76 (d, 1 H), 8.07 (q, 1 H), 7.79 (d, 1 H), 7.48 (s, 1 H), 3.93 (s, 2 H).

Example 68

6-(6-bromo-pyridin-3-yl)-4H-1-thio-4,5-diaza-cyclopentadienyl[a]indolecyclopentadien-7-one

6-(6-Bromo-pyridin-3-yl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]pyrene in DMF (10 mL) A mixture of cyclopentadiene (0.32 g, 1.0 mmol) and Cs ₂ CO ₃ (2 M, 3.0 mL) was stirred at ambient temperature and in the presence of oxygen molecules. The reaction mixture was stirred for 12 hours. Finally, the mixture was poured into ice water, followed by rinsing with an aqueous solution and volatilizing the solvent to give the corresponding 6-(6-bromo-pyridin-3-yl)-4H-1-sulfo-4,5 as an orange solid. - Diazo-cyclopentadienyl[a]indolecyclopentadien-7-one (0.31 g, 0.92 mmol), yield 92%.

MS (ESI) m / z: . 332.1 (M + H) + 1 H NMR (DMSO- d 6): 13.65 (s, 1 H), 9.05 (d, 1 H), 8.31 (q, 1 H), 8.10 (d, 1 H), 7.89 (d, 1 H), 7.29 (d, 1 H).

Example 69

6-(4-methoxy-phenyl)-2-pyridin-4-yl-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]indole Diene

Add NaH (60%, 1.3 g, 33.0 mmol) to 2-bromo-6-(4-methoxy-phenyl)-4,7-dihydro-1-sulfo-4,5 at 0 °C a solution of diaza-cyclopenta[a]indolecyclopentadiene (8.3 g, 24.0 mmol) in THF (40 ml). Further, SEM-Cl (5.6 ml, 28 mmol) was added to the reaction mixture, and the obtained mixture was stirred at 0 ° C for 30 minutes, and then heated to 80 ° C and stirred for 2 hours. The solution was cooled to room temperature and poured into ice water. The resulting mixture was extracted with ethyl acetate. The organic layer was collected and rinsed with saturated aqueous NH ₄ Cl, to MgSO _{4 (s)} sulfate, and concentrated under reduced pressure. The oily residue was purified by gravity column chromatography (20% EtOAc in hexane) to afford 2-bromo-6-(4-methoxy-phenyl)-4-(2-trimethyldecane-ethyl Oxymethyl)-4,7-dihydro-1-thio-4,5-diaza-cyclopenta[a]indolecyclopentadiene (9.0 g, 18 mmol) as a brown solid, yield 79%.

The corresponding intermediate 2-bromo-6-(4-methoxy-phenyl)-4-(2-trimethyldecane-ethoxymethyl)-4,7-dihydro-1-sulfo- 4,5-diaza-cyclopenta[a]indenecyclopentadiene (0.76 g, 1.5 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2] Dioxaborolan-2-yl)-pyridine (0.3 g, 2.3 mmol), Na ₂ CO ₃ (2 M, 3.7 mL) and Pd(PPh ₃ ) ₂ Cl ₂ (14.6 mg, 0.012 mmol) in toluene The mixture in /ethanol (1:1, 6 mL) was heated to 100 ° C for 8 hours. The mixture was cooled to room temperature and extracted with ethyl acetate. The desired product 6-(4-methoxy-phenyl)-2-pyridin-4-yl-4-(2-trimethyl) was obtained as a brown solid (m.). Pyridinium-ethoxymethyl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopenta[a]noncyclopentadiene, yield 65%.

6-(4-Methoxy-phenyl)-2-pyridin-4-yl-4-(2-trimethyldecane-ethoxymethyl)-4,7-dihydro-1-sulfo- 4,5-Diazino-cyclopenta[a]indolecyclopentadiene (0.49 g, 0.98 mmol) was dissolved in MeOH then EtOAc (EtOAc) The reaction mixture was heated to 100 ° C for 4 hours. The solution was cooled to room temperature, and the obtained residue was filtered, washed with methanol, and then evaporated under reduced pressure to give the corresponding 6-(4-methoxy-phenyl)-2-pyridine-4 as a brown solid. -yl-4,7-dihydro-1-thio-4,5-diaza-cyclopentadienyl[a]indolecyclopentadiene (0.14 g, 0.42 mmol), yield 98%.

MS (ESI) m/z: 346.3 (M+H) ⁺ . ¹ H NMR (DMSO - d ₆ ): 8.80 (d, 2 H), 8.47 (s, 1 H), 8.28 (d, 2 H), 7.71 (d, 2 H), 7.07 (d, 2 H), 4.08 (s, 2 H), 3.81 (s, 3 H).

Example 70

6-(4-methoxy-phenyl)-2-pyridin-3-yl-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]indole Diene

Add NaH (60%, 1.3 g, 33.0 mmol) to 2-bromo-6-(4-methoxy-phenyl)-4,7-dihydro-1-sulfo-4,5 at 0 °C a solution of diaza-cyclopenta[a]indolecyclopentadiene (8.3 g, 24.0 mmol) in THF (40 ml). Further, SEM-Cl (5.6 ml, 28 mmol) was added to the reaction mixture, and the obtained mixture was stirred at 0 ° C for 30 minutes, and then heated to 80 ° C and stirred for 2 hours. The solution was cooled to room temperature and poured into ice water. The resulting mixture was extracted with ethyl acetate. The organic layer was collected and rinsed with saturated aqueous NH ₄ Cl, to MgSO _{4 (s)} sulfate, and concentrated under reduced pressure. The oily residue was purified by gravity column chromatography (20% EtOAc in hexane) to afford 2-bromo-6-(4-methoxy-phenyl)-4-(2-trimethyldecane-ethyl Oxymethyl)-4,7-dihydro-1-thio-4,5-diaza-cyclopenta[a]indolecyclopentadiene (9.0 g, 18 mmol) as a brown solid, yield 75%.

The corresponding intermediate 2-bromo-6-(4-methoxy-phenyl)-4-(2-trimethyldecane-ethoxymethyl)-4,7-dihydro-1-sulfo- 4,5-diaza-cyclopenta[a]indenecyclopentadiene (0.76 g, 1.5 mmol), 3-(4,4,5,5-tetramethyl-[1,3,2] Dioxaborolan-2-yl)-pyridine (0.3 g, 2.3 mmol), Na ₂ CO ₃ (2 M, 3.7 mL) and Pd(PPh ₃ ) ₂ Cl ₂ (14.6 mg, 0.012 mmol) in toluene The mixture in /ethanol (1:1, 10 mL) was heated to 100 ° C for 8 hours. The mixture was cooled to room temperature and extracted with ethyl acetate. The desired product 6-(4-methoxy-phenyl)-2-pyridin-3-yl-4-(2-trimethyl) was obtained as a brown solid. Pyridinium-ethoxymethyl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopenta[a]noncyclopentadiene, yield 65%.

6-(4-Methoxy-phenyl)-2-pyridin-3-yl-4-(2-trimethyldecane-ethoxymethyl)-4,7-dihydro-1-sulfo- 4,5-diaza-cyclopenta[a]noncyclopentadiene (0.49 g, 0.98 mmol) was dissolved in MeOH then EtOAc (EtOAc) The reaction mixture was heated to 100 ° C for 4 hours. The solution was cooled to room temperature, and the obtained precipitate was filtered, washed with methanol, and then evaporated to give the corresponding 6-(4-methoxy-phenyl)-2-pyridine-3 as a brown solid. -yl-4,7-dihydro-1-thio-4,5-diaza-cyclopentadienyl[a]indolecyclopentadiene (0.14 g, 0.42 mmol), yield 98%.

MS (ESI) m / z: . 346.0 (M + H) + 1 H NMR (DMSO- d 6): 9.16 (d, 1 H), 8.67 (t, 1 H), 8.54 (d, 1 H), 8.02 (s, 1 H), 7.83 (q, 1 H), 7.71 (d, 2 H), 7.07 (d, 2 H), 3.99 (s, 2 H), 3.81 (s, 3 H).

Example 71

2-(4-Fluoro-phenyl)-6-(4-methoxy-phenyl)-4,7-dihydro-1-thio-4,5-diaza-cyclopentadienyl hydrazone [a] Cyclopentadiene

Add NaH (60%, 1.3 g, 33.0 mmol) to 2-bromo-6-(4-methoxy-phenyl)-4,7-dihydro-1-sulfo-4,5 at 0 °C a solution of diaza-cyclopenta[a]indolecyclopentadiene (8.3 g, 24.0 mmol) in THF (40 ml). Further, SEM-Cl (5.6 ml, 28 mmol) was added to the reaction mixture, and the obtained mixture was stirred at 0 ° C for 30 minutes, and then heated to 80 ° C and stirred for 2 hours. The solution was cooled to room temperature and poured into ice water. The resulting mixture was extracted with ethyl acetate. The organic layer was collected and rinsed with saturated aqueous NH ₄ Cl, to MgSO _{4 (s)} sulfate, and concentrated under reduced pressure. The oily residue was purified by gravity column chromatography (20% EtOAc in hexane) to afford 2-bromo-6-(4-methoxy-phenyl)-4-(2-trimethyldecane-ethyl Oxymethyl)-4,7-dihydro-1-thio-4,5-diaza-cyclopenta[a]indolecyclopentadiene (9.0 g, 18 mmol) as a brown solid, yield 75%.

The corresponding intermediate 2-bromo-6-(4-methoxy-phenyl)-4-(2-trimethyldecane-ethoxymethyl)-4,7-dihydro-1-sulfo- 4,5-diaza-cyclopenta[a]indolecyclopentadiene (0.87 g, 1.8 mmol), 2-(4-fluoro-phenyl)-4,4,5,5-tetramethyl -[1,3,2]dioxaborolan (0.4 g, 2.7 mmol), Na ₂ CO ₃ (2 M, 4.3 mL) and Pd(PPh ₃ ) ₂ Cl ₂ (170 mg, 0.14 mmol) The mixture in toluene/ethanol (1:1, 10 mL) was heated to 100 °C for 8 hours. The mixture was cooled to room temperature and extracted with ethyl acetate. The desired product 2-(4-fluoro-phenyl)-6-(4-methoxy-phenyl)-4-(2) was obtained as a brown solid. -Trimethyldecane-ethoxymethyl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopenta[a]noncyclopentadiene, yield 66%.

2-(4-Fluoro-phenyl)-6-(4-methoxy-phenyl)-4-(2-trimethyldecane-ethoxymethyl)-4,7-dihydro-1 -Sulpho-4,5-diaza-cyclopenta[a]indolecyclopentadiene (0.62 g, 0.12 mmol) was dissolved in MeOH then EtOAc (EtOAc) The reaction mixture was heated to 100 ° C for 4 hours. The solution was cooled to room temperature, and the obtained precipitate was filtered, washed with methanol, and then concentrated under reduced pressure to give the corresponding 2-(4-fluoro-phenyl)-6- Oxy-phenyl)-4,7-dihydro-1-thio-4,5-diaza-cyclopentadienyl[a]indolecyclopentadiene (0.26 g, 0.09 mmol), yield 75% .

S(ESI) m/z: 363.0 (M+H) ⁺ . ¹ H NMR (DMSO- d ₆ ): 7.77-7.72 (m, 4 H), 7.68 (s, 1 H), 7.27 (t, 2 H) ), 7.07 (d, 2 H), 3.93 (s, 2 H), 3.810 (s, 3 H).

Example 72

2-(3,4-Difluoro-phenyl)-6-(4-methoxy-phenyl)-4,7-dihydro-1-thio-4,5-diaza-cyclopentadienium [a]cyclopentadiene

Add NaH (60%, 1.3 g, 33.0 mmol) to 2-bromo-6-(4-methoxy-phenyl)-4,7-dihydro-1-sulfo-4,5 at 0 °C a solution of diaza-cyclopenta[a]indolecyclopentadiene (8.3 g, 24.0 mmol) in THF (40 ml). Further, SEM-Cl (5.6 ml, 28 mmol) was added to the reaction mixture, and the obtained mixture was stirred at 0 ° C for 30 minutes, and then heated to 80 ° C and stirred for 2 hours. The solution was cooled to room temperature and poured into ice water. The resulting mixture was extracted with ethyl acetate. The organic layer was collected and rinsed with saturated aqueous NH ₄ Cl, to MgSO _{4 (s)} sulfate, and concentrated under reduced pressure. The oily residue was purified by gravity column chromatography (20% EtOAc in hexane) to afford 2-bromo-6-(4-methoxy-phenyl)-4-(2-trimethyldecane-ethyl Oxymethyl)-4,7-dihydro-1-thio-4,5-diaza-cyclopenta[a]indolecyclopentadiene (9.0 g, 18 mmol) as a brown solid, yield 75%.

The corresponding intermediate 2-bromo-6-(4-methoxy-phenyl)-4-(2-trimethyldecane-ethoxymethyl)-4,7-dihydro-1-sulfo- 4,5-diaza-cyclopenta[a]indolecyclopentadiene (0.5 g, 0.1 mmol), 2-(3,4-difluoro-phenyl)-4,4,5,5- Tetramethyl-[1,3,2]dioxaborolane (0.24 g, 0.1 mmol), Na ₂ CO ₃ (2 M, 2.45 mL), and Pd(PPh ₃ ) ₂ Cl ₂ (9.7 mg, 0.084 The mixture of mmol) in toluene/ethanol (1:1, 10 mL) was heated to 100 ° C for 8 hours. The mixture was cooled to room temperature and extracted with ethyl acetate. The desired product, 2-(3,4-difluoro-phenyl)-6-(4-methoxy-phenyl)-, was obtained as an orange solid from EtOAc (EtOAc) 4-(2-trimethyldecane-ethoxymethyl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopenta[a]indolecyclopentadiene The rate is 65%.

2-(3,4-Difluoro-phenyl)-6-(4-methoxy-phenyl)-4-(2-trimethylhydrazine Alkano-ethoxymethyl)-4,7-dihydro-1-thio-4,5-diaza-cyclopenta[a]indolecyclopentadiene (0.11 g, 0.2 mmol) dissolved in methanol It was treated with concentrated hydrochloric acid (0.07 mL, 0.2 mmol). The reaction mixture was heated to 100 ° C for 4 hours. The solution was cooled to room temperature, and the obtained residue was filtered, washed with methanol, and then concentrated under reduced pressure to give the corresponding 2-(3,4-difluoro-phenyl)-6- 4-methoxy-phenyl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]indolecyclopentadiene (0.08 g, 0.2 mmol), produced The rate is 95%.

MS (ESI) m/z: 381.0 (M+H) ⁺ . ¹ H NMR (DMSO- d ₆ ): 7.89-7.85 (m, 1 H), 7.79 (s, 1 H), 7.71 (d, 2 H) ), 7.53 - 7.48 (m, 2 H), 7.07 (d, 2 H), 3.94 (s, 2 H), 3.85 (s, 3 H).

Example 73

2,6-bis-(4-methoxy-phenyl)-4,7-dihydro-1-thio-4,5-diaza-cyclopentadienyl[a]noncyclopentadiene

Add NaH (60%, 1.3 g, 33.0 mmol) to 2-bromo-6-(4-methoxy-phenyl)-4,7-dihydro-1-sulfo-4,5 at 0 °C a solution of diaza-cyclopenta[a]indolecyclopentadiene (8.3 g, 24.0 mmol) in THF (40 ml). Further, SEM-Cl (5.6 ml, 28 mmol) was added to the reaction mixture, and the obtained mixture was stirred at 0 ° C for 30 minutes, and then heated to 80 ° C and stirred for 2 hours. The solution was cooled to room temperature and poured into ice water. The resulting mixture was extracted with ethyl acetate. The organic layer was collected and rinsed with saturated aqueous NH ₄ Cl, to MgSO _{4 (s)} sulfate, and concentrated under reduced pressure. The oily residue was purified by gravity column chromatography (20% EtOAc in hexane) to afford 2-bromo-6-(4-methoxy-phenyl)-4-(2-trimethyldecane-ethyl Oxymethyl)-4,7-dihydro-1-thio-4,5-diaza-cyclopenta[a]indolecyclopentadiene (9.0 g, 18 mmol) as a brown solid, yield 75%.

The corresponding intermediate 2-bromo-6-(4-methoxy-phenyl)-4-(2-trimethyldecane-ethoxymethyl)-4,7-dihydro-1-sulfo- 4,5-diaza-cyclopenta[a]indolecyclopentadiene (0.76 g, 1.5 mmol), 2-(4-methoxy-phenyl)-4,4,5,5-tetra Methyl-[1,3,2]dioxaborolane (0.36 g, 2.3 mmol), Na ₂ CO ₃ (2 M, 3.7 mL), and Pd(PPh ₃ ) ₂ Cl ₂ (150 mg, 0.012 mmol The mixture in toluene/ethanol (1:1, 10 mL) was heated to 100 ° C for 8 hours. The mixture was cooled to room temperature and extracted with ethyl acetate. The desired product 2,6-bis-(4-methoxy-phenyl)-4-(2-trimethyldecane-) was obtained as an orange solid. Ethoxymethyl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopenta[a]indolene, yield 76%.

2,6-bis-(4-methoxy-phenyl)-4-(2-trimethyldecane-ethoxymethyl)-4,7-dihydro-1-sulfo-4,5- Diazo-cyclopenta[a]indolecyclopentadiene (0.11 g, 0.2 mmol) was dissolved in MeOH then EtOAc (EtOAc (EtOAc) The reaction mixture was heated to 100 ° C for 4 hours. The solution was cooled to room temperature, and the obtained precipitate was filtered, washed with methanol, and then concentrated under reduced pressure to give the corresponding 2,6-bis-(4-methoxy-phenyl)- 4,7-Dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]indolecyclopentadiene (0.08 g, 0.19 mmol), yield 95%.

MS (ESI) m/z: 375.0 (M+H) ⁺ . ¹ H NMR ( d- Acetone): 7.71 (d, 2 H), 7.643 (d, 2 H), 7.57 (s, 1 H), 7.07 (d, 2 H), 7.00 (d, 2 H), 3.94 (s, 2 H), 3.82 (s, 3 H), 3.80 (s, 3 H).

Example 74

2-(3,4-dimethoxy-phenyl)-6-(4-methoxy-phenyl)-4,7-dihydro-1- Sulfur-4,5-diaza-cyclopentadienyl[a]indolecyclopentadiene

Add NaH (60%, 1.3 g, 33.0 mmol) to 2-bromo-6-(4-methoxy-phenyl)-4,7-dihydro-1-sulfo-4,5 at 0 °C a solution of diaza-cyclopenta[a]indolecyclopentadiene (8.3 g, 24.0 mmol) in THF (40 ml). Further, SEM-Cl (5.6 ml, 28 mmol) was added to the reaction mixture, and the obtained mixture was stirred at 0 ° C for 30 minutes, and then heated to 80 ° C and stirred for 2 hours. The solution was cooled to room temperature and poured into ice water. The resulting mixture was extracted with ethyl acetate. The organic layer was collected and rinsed with saturated aqueous NH ₄ Cl, to MgSO _{4 (s)} sulfate, and concentrated under reduced pressure. The oily residue was purified by gravity column chromatography (20% EtOAc in hexane) to afford 2-bromo-6-(4-methoxy-phenyl)-4-(2-trimethyldecane-ethyl Oxymethyl)-4,7-dihydro-1-thio-4,5-diaza-cyclopenta[a]indolecyclopentadiene (9.0 g, 18 mmol) as a brown solid, yield 75%.

The corresponding intermediate 2-bromo-6-(4-methoxy-phenyl)-4-(2-trimethyldecane-ethoxymethyl)-4,7-dihydro-1-sulfo- 4,5-diaza-cyclopenta[a]indolecyclopentadiene (0.76 g, 1.5 mmol), 2-(3,4-dimethoxy-phenyl)-4,4,5, 5-Tetramethyl-[1,3,2]dioxaborolan (0.4 g, 2.3 mmol), Na ₂ CO ₃ (2 M, 2.45 mL), and Pd(PPh ₃ ) ₂ Cl ₂ (9.7 mg , 0.084 mmol) The mixture in toluene/ethanol (1:1, 8.0 mL) was heated to 100 ° C for 8 hours. The mixture was cooled to room temperature and extracted with ethyl acetate. The desired product 2-(3,4-dimethoxy-phenyl)-6-(4-methoxy-phenyl) was obtained as an orange solid. )-4-(2-trimethyldecane-ethoxymethyl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopenta[a]indolecyclopentadiene The yield is 65%.

2-(3,4-Dimethoxy-phenyl)-6-(4-methoxy-phenyl)-4-(2-trimethyldecane-ethoxymethyl)-4,7 -Dihydro-1-thio-4,5-diaza-cyclopenta[a]indolecyclopentadiene (0.39 g, 0.7 mmol) dissolved in methanol and then concentrated hydrochloric acid (0.22 mL, 7.3 mmol) deal with. The reaction mixture was heated to 100 ° C for 4 hours. The solution was cooled to room temperature, and the obtained residue was filtered, washed with methanol and then evaporated -(4-methoxy-phenyl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienium[a]indolecyclopentadiene (0.25 g, 0.62 mmol) The yield was 88%.

MS (ESI) m / z: . 405.0 (M + H) + 1 H NMR (DMSO- d 6): 7.71 (d, 2 H), 7.66 (s, 1 H), 7.30 (d, 1 H), 7.20(d,1 H),7.07(d,2 H),6.99(d,1 H),3.91(s,2 H),3.85(s,3 H),3.80(s,3 H),3.78( s, 3 H).

Example 75

2-methoxy-4-[6-(4-methoxy-phenyl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]fluorene ring Pentadien-2-yl]-phenol

Add NaH (60%, 1.3 g, 33.0 mmol) to 2-bromo-6-(4-methoxy-phenyl)-4,7-dihydro-1-sulfo-4,5 at 0 °C a solution of diaza-cyclopenta[a]indolecyclopentadiene (8.3 g, 24.0 mmol) in THF (40 ml). Further, SEM-Cl (5.6 ml, 28 mmol) was added to the reaction mixture, and the obtained mixture was stirred at 0 ° C for 30 minutes, and then heated to 80 ° C and stirred for 2 hours. The solution was cooled to room temperature and poured into ice water. The resulting mixture was extracted with ethyl acetate. The organic layer was collected and rinsed with saturated aqueous NH ₄ Cl, to MgSO _{4 (s)} sulfate, and concentrated under reduced pressure. The oily residue was purified by gravity column chromatography (20% EtOAc in hexane) to afford 2-bromo-6-(4-methoxy-phenyl)-4-(2-trimethyldecane-ethyl Oxymethyl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopenta[a]indolecyclopentadiene (9.0 g, 18 mmol) as a brown solid, yield 75%.

The corresponding intermediate 2-bromo-6-(4-methoxy-phenyl)-4-(2-trimethyldecane-ethoxymethyl)-4,7-dihydro-1-sulfo- 4,5-diaza-cyclopenta[a]indolecyclopentadiene (0.76 g, 1.5 mmol), 2-methoxy-4-(4,4,5,5-tetramethyl-[ 1,3,2]dioxaborolan-2-yl)-phenol (0.6 g, 2.3 mmol), Na ₂ CO ₃ (2 M, 3.7 mL), and Pd(PPh ₃ ) ₂ Cl ₂ (14.5 mg , 0.12 mmol) The mixture in toluene/ethanol (1:1, 8.0 mL) was heated to 100 ° C for 8 hours. The mixture was cooled to room temperature and extracted with ethyl acetate. The desired product, 2-methoxy-4-[6-(4-methoxy-phenyl)-4-(2-tri), was obtained as a brown solid. Methyl decane-ethoxymethyl)-4,7-dihydro-1-thio-4,5-diaza-cyclopenta[a]indolecyclopentadien-2-yl]-phenol, The yield was 60%.

2-methoxy-4-[6-(4-methoxy-phenyl)-4-(2-trimethyldecane-ethoxymethyl)-4,7-dihydro-1-sulfo -4,5-diaza-cyclopenta[a]indolecyclopentadien-2-yl]-phenol (0.47 g, 0.9 mmol) dissolved in methanol and then concentrated hydrochloric acid (0.3 mL, 9. deal with. The reaction mixture was heated to 100 ° C for 4 hours. The solution was cooled to room temperature, and the obtained residue was filtered, washed with methanol, and then evaporated under reduced pressure to give the corresponding 2-methoxy-4-[6-(4-methoxy) -phenyl)-4,7-dihydro-1-thio-4,5-diaza-cyclopentadienyl[a]decenecyclopentadien-2-yl]-phenol (0.35 g, 0.76 mmol) The yield is 85%.

MS (ESI) m / z: . 391.0 (M + H) + 1 H NMR (DMSO- d 6): 7.73 (d, 2 H), 7.57 (s, 1 H), 7.26 (s, 1 H), 7.09-7.07 (m, 3 H), 6.82 (d, 1 H), 4.00 (s, 2 H), 3.93 (s, 3 H), 3.80 (s, 3 H).

Example 76

6-(4-Methoxy-phenyl)-2-(6-methoxy-pyridin-3-yl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentane Iridinium [a]pyrene

Add NaH (60%, 1.3 g, 33.0 mmol) to 2-bromo-6-(4-methoxy-phenyl)-4,7-dihydro-1-sulfo-4,5 at 0 °C a solution of diaza-cyclopenta[a]indolecyclopentadiene (8.3 g, 24.0 mmol) in THF (40 ml). Further, SEM-Cl (5.6 ml, 28 mmol) was added to the reaction mixture, and the obtained mixture was stirred at 0 ° C for 30 minutes, and then heated to 80 ° C and stirred for 2 hours. The solution was cooled to room temperature and poured into ice water. The resulting mixture was extracted with ethyl acetate. The organic layer was collected and rinsed with saturated aqueous NH ₄ Cl, to MgSO _{4 (s)} sulfate, and concentrated under reduced pressure. The oily residue was purified by gravity column chromatography (20% EtOAc in hexane) to afford 2-bromo-6-(4-methoxy-phenyl)-4-(2-trimethyldecane-ethyl Oxymethyl)-4,7-dihydro-1-thio-4,5-diaza-cyclopenta[a]indolecyclopentadiene (9.0 g, 18 mmol) as a brown solid, yield 75%.

The corresponding intermediate 2-bromo-6-(4-methoxy-phenyl)-4-(2-trimethyldecane-ethoxymethyl)-4,7-dihydro-1-sulfo- 4,5-diaza-cyclopenta[a]indolecyclopentadiene (0.76 g, 1.5 mmol), 2-methoxy-5-(4,4,5,5-tetramethyl-[ 1,3,2]dioxaborolan-2-yl)-pyridine (0.33 g, 2.1 mmol), Na ₂ CO ₃ (2 M, 3.3 mL), and Pd(PPh ₃ ) ₂ Cl ₂ (13 mg The mixture of 1.1 mmol) in toluene/ethanol (1:1, 8.0 mL) was heated to 100 ° C for 8 hours. The mixture was cooled to room temperature and extracted with ethyl acetate. The desired product 6-(4-methoxy-phenyl)-2-(6-methoxy-pyridin-3-yl) was obtained as an orange solid. )-4-(2-trimethyldecane-ethoxymethyl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopenta[a]indolecyclopentadiene The yield is 75%.

6-(4-Methoxy-phenyl)-2-(6-methoxy-pyridin-3-yl)-4-(2-trimethyldecane-ethoxymethyl)-4,7 -Dihydro-1-sulfo-4,5-diaza-cyclopenta[a]indolecyclopentadiene (0.35 g, 0.69 mmol) dissolved in methanol and then concentrated hydrochloric acid (0.21 mL, 6.9 mmol) deal with. The reaction mixture was heated to 100 ° C for 4 hours. The solution was cooled to room temperature, and the obtained residue was filtered, washed with methanol, and then concentrated under reduced pressure to give the corresponding 6-(4-methoxy-phenyl)-2- -Methoxy-pyridin-3-yl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienylhydrazide [a]indolecyclopentadiene (0.55 g, 0.6 mmol) The yield was 87%.

MS (ESI) m/z: 376.0 (M+H) ⁺ . ¹ H NMR (DMSO - d ₆ ): 8.54 (d, 1 H), 8.03 (d, 1 H), 7.72-7.68 (m, 3 H ), 7.07 (d, 2 H), 6.90 (d, 1 H), 3.93 (s, 2 H), 3.89 (s, 3 H), 3.80 (s, 3 H).

Example 77

2-furan-3-yl-6-(4-methoxy-phenyl)-4,7-dihydro-1-thio-4,5-diaza-cyclopentadienyl[a]indole Diene

Add NaH (60%, 1.3 g, 33.0 mmol) to 2-bromo-6-(4-methoxy-phenyl)-4,7-dihydro-1-sulfo-4,5 at 0 °C a solution of diaza-cyclopenta[a]indolecyclopentadiene (8.3 g, 24.0 mmol) in THF (40 ml). Further, SEM-Cl (5.6 ml, 28 mmol) was added to the reaction mixture, and the obtained mixture was stirred at 0 ° C for 30 minutes, and then heated to 80 ° C and stirred for 2 hours. The solution was cooled to room temperature and poured into ice water. The resulting mixture was extracted with ethyl acetate. The organic layer was collected and rinsed with saturated aqueous NH ₄ Cl, to MgSO _{4 (s)} sulfate, and concentrated under reduced pressure. The oily residue was purified by gravity column chromatography (20% EtOAc in hexane) to afford 2-bromo-6-(4-methoxy-phenyl)-4-(2-trimethyldecane-ethyl Oxymethyl)-4,7-dihydro-1-thio-4,5-diaza-cyclopenta[a]indolecyclopentadiene (9.0 g, 18 mmol) as a brown solid, yield 75%.

The corresponding intermediate 2-bromo-6-(4-methoxy-phenyl)-4-(2-trimethyldecane-ethoxymethyl)-4,7-dihydro-1-sulfo- 4,5-diaza-cyclopenta[a]indolecyclopentadiene (0.8 g, 1.7 mmol), 2-furan-3-boronic acid (0.28 g, 2.5 mmol), Na ₂ CO ₃ (2 M , 3.9 mL) and a mixture of Pd(PPh ₃ ) ₂ Cl ₂ (15 mg, 0.13 mmol) in toluene/ethanol (1:1, 12 mL) was heated to 100 ° C for 8 hours. The mixture was cooled to room temperature and extracted with ethyl acetate. The desired product, 2-furan-3-yl-6-(4-methoxy-phenyl)-4-(2-tri), was obtained as an orange solid. Methyl decane-ethoxymethyl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopenta[a]noncyclopentadiene, yield 67%.

2-furan-3-yl-6-(4-methoxy-phenyl)-4-(2-trimethyldecane-ethoxymethyl)-4,7-dihydro-1-sulfo- 4,5-Dinitro-cyclopenta[a]indolecyclopentadiene (0.3 g, 0.57 mmol) was dissolved in MeOH then EtOAc (EtOAc) The reaction mixture was heated to 100 ° C for 4 hours. The solution was cooled to room temperature, and the obtained residue was filtered, washed with methanol, and then concentrated under reduced pressure to give the corresponding 2-furan-3-yl-6-(4-methoxy- Phenyl)-4,7-dihydro-1-thio-4,5-diaza-cyclopentadienyl[a]indolecyclopentadiene (0.15 g, 0.4 mmol), yield 78%.

MS (ESI) m/z: 335.0 (M+H) ⁺ . ¹ H NMR (DMSO- d ₆ ): 8.12 (s, 1 H), 7.76- 7.71 (m, 3 H), 7.47 (s, 1 H) ), 7.07 (d, 2 H), 6.92 (s, 1 H), 3.92 (s, 2 H), 3.80 (s, 3 H).

Example 78

5-[6-(4-Methoxy-phenyl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]indolecyclopentadiene-2- Pyridyl-2-ylamine

Add NaH (60%, 1.3 g, 33.0 mmol) to 2-bromo-6-(4-methoxy-phenyl)-4,7-dihydro-1-sulfo-4,5 at 0 °C a solution of diaza-cyclopenta[a]indolecyclopentadiene (8.3 g, 24.0 mmol) in THF (40 ml). Further, SEM-Cl (5.6 ml, 28 mmol) was added to the reaction mixture, and the obtained mixture was stirred at 0 ° C for 30 minutes, and then heated to 80 ° C and stirred for 2 hours. The solution was cooled to room temperature and poured into ice water. The resulting mixture was extracted with ethyl acetate. The organic layer was collected and rinsed with saturated aqueous NH ₄ Cl, to MgSO _{4 (s)} sulfate, and concentrated under reduced pressure. The oily residue was purified by gravity column chromatography (20% EtOAc in hexane) to afford 2-bromo-6-(4-methoxy-phenyl)-4-(2-trimethyldecane-ethyl Oxymethyl)-4,7-dihydro-1-thio-4,5-diaza-cyclopenta[a]indolecyclopentadiene (9.0 g, 18 mmol) as a brown solid, yield 75%.

The corresponding intermediate 2-bromo-6-(4-methoxy-phenyl)-4-(2-trimethyldecane-ethoxymethyl)-4,7-dihydro-1-sulfo- 4,5-diaza-cyclopenta[a]indolene (0.8 g, 1.7 mmol), 5-(4,4,5,5-tetramethyl-[1,3,2] Dioxaborolan-2-yl)-pyridin-2-ylamine (0.4 g, 1.7 mmol), Na ₂ CO ₃ (2 M, 2.7 mL), and Pd(PPh ₃ ) ₂ Cl ₂ (100 mg, A mixture of 0.09 mmol) in toluene/ethanol (1:1, 10 mL) was heated to 100 ° C for 8 hours. The mixture was cooled to room temperature and extracted with ethyl acetate. The desired product 6-(4-methoxy-phenyl)-2-(6-methoxy-pyridin-3-yl) was obtained as an orange solid. )-4-(2-trimethyldecane-ethoxymethyl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopenta[a]indolecyclopentadiene The yield is 60%.

6-(4-Methoxy-phenyl)-2-(6-methoxy-pyridin-3-yl)-4-(2-trimethyldecane-ethoxymethyl)-4,7 -Dihydro-1-thio-4,5-diaza-cyclopenta[a]indolecyclopentadiene (0.2 g, 0.4 mmol) dissolved in methanol and then concentrated hydrochloric acid (0.1 mL, 4.0 mmol) deal with. The reaction mixture was heated to 100 ° C for 4 hours. The solution was cooled to room temperature, and the obtained residue was filtered, washed with methanol, and then concentrated under reduced pressure to give the corresponding 5-[6-(4-methoxy-phenyl)-4 as a brown solid. ,7-Dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]indolecyclopentadien-2-yl]-pyridin-2-ylamine (0.12 g, 0.32 mmol), The yield was 80%.

MS (ESI) m/z: 361.0 (M+H) ⁺ . ¹ H NMR (DMSO - d ₆ ): 8.33 - 8.27 (m, 3 H), 7.73 (t, 2 H), 7.11-7.06 (m, 3 H), 4.33 (brs, 2H), 3.95 (s, 2 H), 3.81 (s, 3 H).

Example 79

5-[6-(4-Methoxy-phenyl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]indolecyclopentadiene-2- Pyrimidine-2-ylamine

Add NaH (60%, 1.3 g, 33.0 mmol) to 2-bromo-6-(4-methoxy-phenyl)-4,7-dihydro-1-sulfo-4,5 at 0 °C a solution of diaza-cyclopenta[a]indolecyclopentadiene (8.3 g, 24.0 mmol) in THF (40 ml). Further, SEM-Cl (5.6 ml, 28 mmol) was added to the reaction mixture, and the obtained mixture was stirred at 0 ° C for 30 minutes, and then heated to 80 ° C and stirred for 2 hours. The solution was cooled to room temperature and poured into ice water. The resulting mixture was extracted with ethyl acetate. The organic layer was collected and rinsed with saturated aqueous NH ₄ Cl, to MgSO _{4 (s)} sulfate, and concentrated under reduced pressure. The oily residue was purified by gravity column chromatography (20% EtOAc in hexane) to afford 2-bromo-6-(4-methoxy-phenyl)-4-(2-trimethyldecane-ethyl Oxymethyl)-4,7-dihydro-1-thio-4,5-diaza-cyclopenta[a]indolecyclopentadiene (9.0 g, 18 mmol) as a brown solid, yield 75%.

The corresponding intermediate 2-bromo-6-(4-methoxy-phenyl)-4-(2-trimethyldecane-ethoxymethyl)-4,7-dihydro-1-sulfo- 4,5-diaza-cyclopenta[a]indenecyclopentadiene (0.68 g, 1.2 mmol), 5-(4,4,5,5-tetramethyl-[1,3,2] Dioxaborolan-2-yl)-pyrimidin-2-ylamine (0.3 g, 1.3 mmol), Na ₂ CO ₃ (2 M, 2.9 mL), and Pd(PPh ₃ ) ₂ Cl ₂ (100 mg, A mixture of 0.09 mmol) in toluene/ethanol (1:1, 10 mL) was heated to 100 ° C for 8 hours. The mixture was cooled to room temperature and extracted with ethyl acetate. The desired product 6-(4-methoxy-phenyl)-2-(2-methoxy-pyrimidin-3-yl) was obtained as an orange solid. )-4-(2-trimethyldecane-ethoxymethyl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopenta[a]indolecyclopentadiene The yield is 60%.

6-(4-Methoxy-phenyl)-2-(2-methoxy-pyrimidin-3-yl)-4-(2-trimethyldecane-ethoxymethyl)-4,7 -Dihydro-1-sulfo-4,5-diaza-cyclopenta[a]indolecyclopentadiene (0.53 g, 1.0 mmol) dissolved in methanol and then concentrated hydrochloric acid (0.3 mL, 10 mmol) deal with. The reaction mixture was heated to 100 ° C for 4 hours. The solution was cooled to room temperature, and the obtained residue was filtered, washed with methanol, and then concentrated under reduced pressure to give the corresponding 5-[6-(4-methoxy-phenyl)-4 as a yellow solid. ,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]fluorene ring Pentadien-2-yl]-pyrimidin-2-ylamine (0.14 g, 0.37 mmol), yield 37%.

MS (ESI) m / z: . 398.0 (M + H) + 1 H NMR (DMSO- d 6): 8.86 (s, 2 H), 7.73 (t, 3 H), 7.06 (d, 2 H), 3.96 (s, 2 H), 3.80 (s, 3 H).

Example 80

6-[4-(4-Methyl-piperazin-1-yl)-phenyl]-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]幷Cyclopentadiene

Add NaH (60%, 0.48 g, 12 mmol) to 6-(4-bromo-phenyl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentane at 0 °C A solution of diene[a]indolecyclopentadiene (3.1 g, 9.7 mmol) in THF (15 ml). Further, SEM-Cl (90% purity, 2.4 ml, 12 mmol) was added to the reaction mixture, and the obtained mixture was stirred at 0 ° C for 30 minutes, and then heated to 80 ° C for further 2 hours. The solution was cooled to room temperature and poured into ice water. The resulting mixture was extracted with ethyl acetate. The organic layer was collected and rinsed with saturated aqueous NH ₄ Cl, to MgSO _{4 (s)} sulfate, and concentrated under reduced pressure. The oily residue was purified by gravity column chromatography (20% EtOAc in hexane) to afford 6-(4-bromo-phenyl)--4-(2-trimethyldecane-ethoxymethyl) -4,7-Dihydro-1-thio-4,5-diaza-cyclopenta[a]indolecyclopentadiene (3.0 g, 6.7 mmol) as a brown solid, yield 69%.

The corresponding intermediate 6-(4-bromo-phenyl)--4-(2-trimethyldecane-ethoxymethyl)-4,7-dihydro-1-sulfo-4,5-di Nitro-cyclopenta[a]indolecyclopentadiene (0.7 g, 1.5 mmol), 1-methyl-piperazine (0.2 g, 3 mmol), Cs ₂ CO ₃ (2 M, 1.5 mL), A mixture of Xantphos (180 mg, 0.06 mmol) and Pd(OAc) ₂ (70 mg, 0.06 mmol) in toluene/ethanol (1:1, 10 mL) was warmed to 100 ° C and maintained for 8 hours. The mixture was cooled to room temperature and extracted with ethyl acetate. The desired product 6-[4-(4-methoxy-piperazin-1-yl)-phenyl]-4-(2) was obtained as a brown solid. -Trimethyldecane-ethoxymethyl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopenta[a]noncyclopentadiene, yield 39%.

6-[4-(4-Methoxy-piperazin-1-yl)-phenyl]-4-(2-trimethyldecane-ethoxymethyl)-4,7-dihydro-1 - Sulfur-4,5-diaza-cyclopenta[a]indolecyclopentadiene (0.22 g, 0.47 mmol) was dissolved in MeOH then EtOAc (EtOAc) The reaction mixture was heated to 100 ° C for 4 hours. The solution was cooled to room temperature, and the obtained residue was filtered, washed with methanol, and then evaporated to dryness to give the corresponding 6-[4-(4-methyl-piperazin-1-yl) as a brown solid. )-Phenyl]-4,7-dihydro-1-thio-4,5-diaza-cyclopentadienyl[a]indolecyclopentadiene (0.1 g, 0.35 mmol), yield 74%.

M MS (ESI) m / z : 373.0 (M + H) + 1 H NMR (DMSO- d 6):. 11.14 (s, 1H), 7.71 (d, 2 H), 7.62 (d, 1 H), 7.28 (d, 1 H), 7.13 (d, 2 H), 3.92 (brs, 4 H), 3.49 (d, 2 H), 3.18 (brs, 4 H), 2.81 (s, 3 H).

Example 81

6-(4-Methoxy-phenyl)-2-[6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-4,7-dihydro-1-sulfo- 4,5-diaza-cyclopentadienyl[a]indolecyclopentadiene

Add NaH (60%, 1.3 g, 33.0 mmol) to 2-bromo-6-(4-methoxy-phenyl)-4,7-dihydro-1-sulfo-4,5 at 0 °C a solution of diaza-cyclopenta[a]indolecyclopentadiene (8.3 g, 24.0 mmol) in THF (40 ml). Further, SEM-Cl (5.6 ml, 28 mmol) was added to the reaction mixture, and the obtained mixture was stirred at 0 ° C for 30 minutes, and then heated to 80 ° C and stirred for 2 hours. The solution was cooled to room temperature and poured into ice water. The resulting mixture was extracted with ethyl acetate. The organic layer was collected and rinsed with saturated aqueous NH ₄ Cl, to MgSO _{4 (s)} sulfate, and concentrated under reduced pressure. The oily residue was purified by gravity column chromatography (20% EtOAc in hexane) to afford 2-bromo-6-(4-methoxy-phenyl)-4-(2-trimethyldecane-ethyl Oxymethyl)-4,7-dihydro-1-thio-4,5-diaza-cyclopenta[a]indolecyclopentadiene (9.0 g, 18 mmol) as a brown solid, yield 75%.

The corresponding intermediate 2-bromo-6-(4-methoxy-phenyl)-4-(2-trimethyldecane-ethoxymethyl)-4,7-dihydro-1-sulfo- 4,5-diaza-cyclopenta[a]indolecyclopentadiene (0.75 g, 1.5 mmol), 1-methyl-4[5-(4,4,5,5-tetramethyl- [1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-piperazine (0.5 g, 17 mmol), Na ₂ CO ₃ (2 M, 3.6 mL) and Pd ( A mixture of PPh ₃ ) ₂ Cl ₂ (110 mg, 0.15 mmol) in toluene/ethanol (1:1, 12 mL) was warmed to 100 ° C and maintained for 8 hours. The mixture was cooled to room temperature and extracted with ethyl acetate. The desired product 6-(4-methoxy-phenyl)-2-[6-(4-methyl-piperazine-) was obtained as an orange solid (m.). 1-yl)-pyridin-3-yl]-4-(2-trimethyldecane-ethoxymethyl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentane Alkeno[a]noncyclopentadiene in a yield of 60%.

6-(4-Methoxy-phenyl)-2-[6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-4-(2-trimethyldecane- Ethoxymethyl)-4,7-dihydro-1-thio-4,5-diaza-cyclopenta[a]indolecyclopentadiene (0.33 g, 5.5 mmol) dissolved in methanol Treat with concentrated hydrochloric acid (0.2 mL, 5.5 mmol). The reaction mixture was heated to 100 ° C for 4 hours. The solution was cooled to room temperature, and the obtained precipitate was filtered, washed with methanol, and then concentrated under reduced pressure to give a white solid. Should be 6-(4-methoxy-phenyl)-2-[6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-4,7-dihydro-1-thio -4,5-diaza-cyclopentadienyl[a]indolecyclopentadiene (0.26 g, 5.2 mmol), yield 95%.

MS (ESI) m / z: . 444.0 (M + H) + 1 H NMR (DMSO- d 6): 11.35 (s, 1 H), 8.47 (d, 1 H), 8.07 (s, 1 H), 7.74 (d, 2 H), 7.67 (s, 1 H), 7.16 (d, 1 H), 7.08 (d, 2 H), 4.47 (d, 2 H), 3.96 (s, 2 H), 3.81 ( s, 3 H), 3.94-3.50 (m, 4 H), 3.11-3.09 (m, 2 H), 2.78 (d, 3 H).

Example 82

N-{5-[6-(4-methoxy-phenyl)-4,7-dihydro-1-thio-4,5-diaza-cyclopentadienyl[a]noncyclopentadiene -2-yl]-pyridin-2-yl}-2-pyrrolidin-1-yl-acetamide

Add NaH (60%, 1.5 g, 3.0 mmol) to 5-[6-(4-methoxy-phenyl)-4,7-dihydro-1-sulfo-4,5- at 0 °C A solution of diaza-cyclopenta[a]indolecyclopentadien-2-yl]-pyridin-2-ylamine (3.1 g, 2.0 mmol) in THF (15 mL). Further, SEM-Cl (90% purity, 0.42 ml, 2 mmol) was added to the reaction mixture, and the obtained mixture was stirred at 0 ° C for 30 minutes, heated to 80 ° C and stirred for additional 2 hours. The solution was cooled to room temperature and poured into ice water. The resulting mixture was extracted with ethyl acetate. The organic layer was collected and rinsed with saturated aqueous NH ₄ Cl, to MgSO _{4 (s)} sulfate, and concentrated under reduced pressure. The oily residue was purified by gravity column chromatography (20% EtOAc in hexane) to afford 5-[6-(4-methoxy-phenyl)-4-(2-trimethyldecane-ethoxy Methyl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopenta[a]indolylcyclopent-2-yl]-pyridin-2-ylamine (0.7 g, 1.44 mmol) of a brown solid, yield 72%.

The corresponding intermediate 5-[6-(4-methoxy-phenyl)-4-(2-trimethyldecane- Ethoxymethyl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopenta[a]indolecyclopentadien-2-yl]-pyridin-2-ylamine (0.5 g, 1.0 mmol), a mixture of chloro-acetamidine chloride (0.17 g, 1.5 mmol) and triethylamine (0.15 mL, 2.0 mmol) in dioxane (5 mL) was stirred at ambient temperature 3 hour. Pyrrolidine was added to the mixture and maintained for 2 hours. The solvent was evaporated under reduced pressure and extracted with ethyl acetate. The desired product N-{5-[6-(4-methoxy-phenyl)-4-(2-trimethyldecane) was obtained as a brown solid. -ethoxymethyl)-4,7-dihydro-1-thio-4,5-diaza-cyclopenta[a]indolecyclopentadienyl-2-yl]-pyridin-2-yl} -2-pyrrolidin-1-yl-acetamide, yield 71%.

N-{5-[6-(4-Methoxy-phenyl)-4-(2-trimethyldecane-ethoxymethyl)-4,7-dihydro-1-sulfo-4, 5-diaza-cyclopenta[a]fluorenecyclopentadien-2-yl]-pyridin-2-yl}-2-pyrrolidin-1-yl-acetamide (0.3 g, 0.5 mmol) Treatment with trifluoroacetic acid (0.57 g, 5 mmol) in MeOH. The reaction mixture was heated to 100 ° C for 2 hours. The solution was cooled to room temperature, and the obtained residue was filtered, washed with methanol, and then concentrated under reduced pressure to give the corresponding N-{5-[6-(4-methoxy-phenyl) as a yellow solid. -4,7-Dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]noncyclopentadien-2-yl]-pyridin-2-yl}-2-pyrrolidine 1-yl-acetamide (0.41 g, 0.44 mmol), yield 88%.

MS (ESI) m/z: 472.0 (M+H) ⁺ . ¹ H NMR (DMSO - d ₆ ): 12.92 (s, 1 H), 10.07 (s, 1 H), 8.70 (s, 1 H), 8.13 (d, 2 H), 7.77 (s, 1 H), 7.71 (d, 2 H), 7.07 (d, 2 H), 3.94 (s, 2 H), 3.81 (s, 3 H), 3.37 ( s, 1 H), 3.33 (s, 1 H), 2.66 (s, 4 H), 1.77 (s, 4 H).

Example 83

2-(3-Fluoro-4-methoxy-phenyl)-6-(4-methoxy-phenyl)-4,7-dihydro-1-thio-4,5-diaza-cyclopentyl Diene oxime [a] quinone cyclopentadiene

Add NaH (60%, 1.3 g, 33.0 mmol) to 2-bromo-6-(4-methoxy-phenyl)-4,7-dihydro-1-sulfo-4,5 at 0 °C a solution of diaza-cyclopenta[a]indolecyclopentadiene (8.3 g, 24.0 mmol) in THF (40 ml). Further, SEM-Cl (90% alcohol, 5.6 ml, 28 mmol) was added to the reaction mixture, and the mixture was stirred at 0 ° C for 30 minutes, and then heated to 80 ° C and stirred for 2 hours. The solution was cooled to room temperature and poured into ice water. The resulting mixture was extracted with ethyl acetate. The organic layer was collected and rinsed with saturated aqueous NH ₄ Cl, to MgSO _{4 (s)} sulfate, and concentrated under reduced pressure. The oily residue was purified by gravity column chromatography (20% EtOAc in hexane) to afford 2-bromo-6-(4-methoxy-phenyl)-4-(2-trimethyldecane-ethyl Oxymethyl)-4,7-dihydro-1-thio-4,5-diaza-cyclopenta[a]indolecyclopentadiene (9.0 g, 18 mmol) as a brown solid, yield 75%.

The corresponding intermediate 2-bromo-6-(4-methoxy-phenyl)-4-(2-trimethyldecane-ethoxymethyl)-4,7-dihydro-1-sulfo- 4,5-diaza-cyclopenta[a]noncyclopentadiene 1.1 g, 2.3 mmol), 2-(3-fluoro-4-methoxy-phenyl)-4,4,5, 5-Tetramethyl-[1,3,2]dioxaborolan (0.59 g, 3.4 mmol), Na ₂ CO ₃ (2 M, 5.4 mL) and Pd(PPh ₃ ) ₂ Cl ₂ (260 mg , 0.23 mmol) The mixture in toluene/ethanol (1:1, 15 mL) was heated to 100 ° C for 8 hours. The mixture was cooled to room temperature and extracted with ethyl acetate. The title product 2-(3-fluoro-4-methoxy-phenyl)-6-(4-methoxy-phenyl) was obtained as a brown solid. )-4-(2-trimethyldecane-ethoxymethyl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopenta[a]indolecyclopentadiene The yield is 60%.

2-(3-Fluoro-4-methoxy-phenyl)-6-(4-methoxy-phenyl)-4-(2-trimethyldecane-ethoxymethyl)-4, 7-Dihydro-1-sulfo-4,5-diaza-cyclopenta[a]indolecyclopentadiene (0.43 g, 0.8 mmol) dissolved in methanol then concentrated hydrochloric acid (0.25 mL, 7 mmol )deal with. The reaction mixture was heated to 100 ° C for 4 hours. The solution was cooled to room temperature, and the obtained residue was filtered, washed with EtOAc EtOAcjjjjj 6-(4-Methoxy-phenyl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]indolecyclopentadiene (0.24 g, 0.61 mmol) ), the yield was 76%.

MS (ESI) m / z: . 393.0 (M + H) + 1 H NMR (DMSO- d 6): 7.67 (d, 2 H), 7.63 (d, 2 H), 7.62 (s, 1 H), 7.46 (d, 1 H), 7.21 (d, 1 H), 7.07 (d, 2 H), 3.92 (s, 2 H), 3.87 (s, 3 H), 3.83 (s, 3 H).

Example 84

6-(4-Pyrrolidin-1-yl-phenyl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]noncyclopentadiene

Add NaH (60%, 0.48 g, 12 mmol) to 6-(4-bromo-phenyl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentane at 0 °C A solution of diene[a]indolecyclopentadiene (3.1 g, 9.7 mmol) in THF (15 ml). Further, SEM-Cl (90% purity, 2.5 ml, 12 mmol) was added to the reaction mixture, and the obtained mixture was stirred at 0 ° C for 30 minutes, and then heated to 80 ° C and stirred for 2 hours. The solution was cooled to room temperature and poured into ice water. The resulting mixture was extracted with ethyl acetate. The organic layer was collected and rinsed with saturated aqueous NH ₄ Cl, to MgSO _{4 (s)} sulfate, and concentrated under reduced pressure. The oily residue was purified by gravity column chromatography (20% EtOAc in hexane) to afford 6-(4-bromo-phenyl)--4-(2-trimethyldecane-ethoxymethyl) -4,7-Dihydro-1-thio-4,5-diaza-cyclopenta[a]indolecyclopentadiene (3.0 g, 6.7 mmol) as a brown solid, yield 69%.

The corresponding intermediate 6-(4-bromo-phenyl)-4-(2-trimethyldecane-ethoxymethyl)-4,7-dihydro-1-sulfo-4,5-diaza -cyclopenta[a]noncyclopentadiene (0.7 g, 1.5 mmol), 1-methyl-piperazine (0.2 g, 3 mmol), Cs ₂ CO ₃ (2 M, 1.5 mL), Xantphos A mixture of (180 mg, 0.06 mmol) and Pd(OAc) ₂ (70 mg, 0.06 mmol) in toluene/ethanol (1:1, 10 mL) was warmed to 100 ° C and maintained for 8 hours. The mixture was cooled to room temperature and extracted with ethyl acetate. The desired product 6-(4-pyrrolidin-1-yl-phenyl)-4-(2-trimethyldecane-ethoxy) was obtained as a brown solid. Methyl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopenta[a]noncyclopentadiene, yield 39%.

6-(4-Pyrrolidin-1-yl-phenyl)-4-(2-trimethyldecane-ethoxymethyl)-4,7-dihydro-1-sulfo-4,5-di Nitro-cyclopenta[a]indolecyclopentadiene (1.7 g, 0.38 mmol) was dissolved in MeOH then EtOAc (EtOAc (EtOAc) The reaction mixture was heated to 100 ° C for 4 hours. The solution was cooled to room temperature, and the obtained precipitate was filtered, washed with methanol, and then obtained to give the corresponding 6-(4-pyrrolidin-1-yl-phenyl)-4 as a brown solid. 7-Dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]indolecyclopentadiene (0.1 g, 0.3 mmol), yield 85%.

MS (ESI) m / z: 308.0 (M + H) +.

Example 85

6-(4-morpholin-4-yl-phenyl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadiene 幷[a]幷cyclopentadiene

Add NaH (60%, 0.6 g, 12 mmol) to 6-(4-bromo-phenyl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentane at 0 °C A solution of diene[a]indolecyclopentadiene (3.1 g, 9.7 mmol) in THF (15 ml). Further, SEM-Cl (90% purity, 2.5 ml, 12 mmol) was added to the reaction mixture, and the obtained mixture was stirred at 0 ° C for 30 minutes, and then heated to 80 ° C and stirred for 2 hours. The solution was cooled to room temperature and poured into ice water. The resulting mixture was extracted with ethyl acetate. The organic layer was collected and rinsed with saturated aqueous NH ₄ Cl, to MgSO _{4 (s)} sulfate, and concentrated under reduced pressure. The oily residue was purified by gravity column chromatography (20% EtOAc in hexane) to afford 6-(4-bromo-phenyl)--4-(2-trimethyldecane-ethoxymethyl) -4,7-Dihydro-1-thio-4,5-diaza-cyclopenta[a]indolecyclopentadiene (3.0 g, 6.7 mmol) as a brown solid, yield 69%.

The corresponding intermediate 6-(4-bromo-phenyl)-4-(2-trimethyldecane-ethoxymethyl)-4,7-dihydro-1-sulfo-4,5-diaza -cyclopenta[a]noncyclopentadiene (0.7 g, 1.5 mmol), 1-methyl-piperazine (0.2 g, 3 mmol), Cs ₂ CO ₃ (2 M, 1.5 mL), Xantphos A mixture of (180 mg, 0.06 mmol) and Pd(OAc) ₂ (70 mg, 0.06 mmol) in toluene/ethanol (1:1, 10 mL) was warmed to 100 ° C and maintained for 8 hours. The mixture was cooled to room temperature and extracted with ethyl acetate. The desired product 6-(4-morpholin-4-yl-phenyl)-4-(2-trimethyldecane-ethoxy) was obtained as a brown solid. Methyl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopenta[a]noncyclopentadiene, yield 45%.

6-(4-morpholin-4-yl-phenyl)-4-(2-trimethyldecane-ethoxymethyl)-4,7-dihydro-1-sulfo-4,5-di Nitrogen-cyclopenta[a]noncyclopentadiene (0.21 g, 0.4 Methyl) was dissolved in methanol and treated with cone. EtOAc (EtOAc (EtOAc) The reaction mixture was heated to 100 ° C for 4 hours. The solution was cooled to room temperature, and the obtained residue was filtered, washed with methanol, and then concentrated under reduced pressure to give the corresponding 6-(4-morpholin-4-yl-phenyl)-4 as a brown solid. , 7-Dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]indolecyclopentadiene (0.1 g, 0.3 mmol), yield 65%.

MS (ESI) m / z: . 324.0 (M + H) + 1 H NMR (DMSO- d 6): 7.72 (d, 2 H), 7.65 (d, 1 H), 7.29 (d, 1 H), 7.18 (d, 2 H), 3.96 (s, 2 H), 3.79 (t, 4 H), 3.25 (t, 4 H).

Example 86

3-[6-(4-Methoxy-phenyl)-4,7-dihydro-1-thio-4,5-diaza-cyclopentadienyl[a]indolecyclopentadiene-2- P-phenylamine

Add NaH (60%, 1.3 g, 33 mmol) to 2-bromo-6-(4-methoxy-phenyl)-4,7-dihydro-1-sulfo-4,5 at 0 °C a solution of diaza-cyclopenta[a]indolecyclopentadiene (8.3 g, 24 mmol) in THF (15 ml). Further, SEM-Cl (5.6 ml, 28 mmol) was added to the reaction mixture, and the obtained mixture was stirred at 0 ° C for 30 minutes, and then heated to 80 ° C and stirred for 2 hours. The solution was cooled to room temperature and poured into ice water. The resulting mixture was extracted with ethyl acetate. The organic layer was collected and rinsed with saturated aqueous NH ₄ Cl, to MgSO _{4 (s)} sulfate, and concentrated under reduced pressure. The oily residue was purified by gravity column chromatography (20% EtOAc in hexane) to afford 2-bromo-6-(4-methoxy-phenyl)-4-(2-trimethyldecane-ethyl Oxymethyl)-4,7-dihydro-1-thio-4,5-diaza-cyclopenta[a]indolecyclopentadiene (9.0 g, 18.0 mmol) as a brown solid, yield 75%.

The corresponding intermediate 2-bromo-6-(4-methoxy-phenyl)-4-(2-trimethyldecane-ethoxymethyl)-4,7-dihydro-1-sulfo- 4,5-diaza-cyclopenta[a]indolecyclopentadiene (0.95 g, 1.9 mmol), 3-(4,4,5,5-tetramethyl-[1,3,2] Dioxaborolan-2-yl)aniline (0.34 g, 1.1 mmol), Na ₂ CO ₃ (2 M, 4.6 mL) and Pd(PPh ₃ ) ₂ Cl ₂ (226 mg, 0.1 mmol) in toluene / The mixture in ethanol (1:1, 16 mL) was heated to 100 ° C for 8 hours. The solution was cooled to room temperature and extracted with ethyl acetate. The desired product, 3-[6-(4-methoxy-phenyl)-4-(2-trimethyldecane-ethoxy), was obtained as a brown solid. Methyl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopenta[a]indolecyclopentadien-2-yl]-phenylamine, yield 67%.

3-[6-(4-Methoxy-phenyl)-4-(2-trimethyldecane-ethoxymethyl)-4,7-dihydro-1-sulfo-4,5-di Nitro-cyclopentadienyl[a]indolecyclopentadien-2-yl]-phenylamine (0.37 g, 0.7 mmol) was dissolved in MeOH then EtOAc (EtOAc) The reaction mixture was heated to 100 ° C for 4 hours. The solution was cooled to room temperature, and the obtained residue was filtered, washed with methanol and then evaporated ,7-Dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]decenecyclopentadien-2-yl]-phenylamine (0.26 g, 0.67 mmol), yield 96 %.

MS (ESI) m/z: 361.0 (M+H) ⁺ . ¹ H NMR (DMSO - d ₆ ): 7.79 - 7.73 (m, 4 H), 7.68 (s, 1 H), 7.54 (t, 1 H) ), 7.30 (d, 1 H), 7.08 (d, 2 H), 3.98 (s, 2 H), 3.81 (s, 3 H).

Example 87

2-(6-Amino-pyridin-3-yl)-6-(4-methoxy-phenyl)-4H-1-thio-4,5-diaza-cyclopentadienyl[a]幷Cyclopentadien-7-one

5-[6-(4-Methoxy-phenyl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienylhydrazone [a] in DMF (10 mL) A mixture of fluorene cyclopentadien-2-yl]-pyridin-2-ylamine (0.18 g, 0.5 mmol) and Cs ₂ CO ₃ (1.6 g, 5.0 mL) was stirred at ambient temperature and in the presence of oxygen molecules. The reaction mixture was stirred for 12 hours. Finally, the mixture is poured into ice water, followed by rinsing with an aqueous solution and volatilizing the solvent to give the corresponding 2-(6-amino-pyridin-3-yl)-6-(4-methoxy- Phenyl)-4H-1-thio-4,5-diaza-cyclopentadienyl[a]indolecyclopentadien-7-one, yield 92%.

MS (ESI) m / z: . 376.0 (M + H) + 1 H NMR (DMSO- d 6): 13.26 (s, 1 H), 8.40 (d, 1 H), 8.11 (d, 2 H), 7.77 (t, 1 H), 7.56 (s, 1 H), 7.12 (d, 2 H), 6.53-6.50 (m, 3 H), 3.83 (s, 3 H).

Example 88

5-[6-(4-morpholin-4-yl-phenyl)-4,7-dihydro-1-thio-4,5-diaza-cyclopentadienyl[a]noncyclopentadiene -2-yl]-pyridin-2-ylamine hydrochloride

The NBS (0.18 g, 1.0 mmol) was added to 6- (4-morpholin-4-yl-phenyl) - in the _{CH 2 Cl 2 (5.0 mL)} -4- (2- trimethyl Silane - ethoxy A solution of methyl)-4,7-dihydro-1-thio-4,5-diaza-cyclopenta[a]indolecyclopentadiene (0.23 g, 0.5 mmol). After 2 hours, the solution was evaporated and washed with EtOAc, filtered and concentrated to give 2-bromo-6-(4-morpholin-4-yl-phenyl)-4-(2-trimethyldecane-ethoxy Methyl)-4,7-dihydro-1-thio-4,5-diaza-cyclopenta[a]indolecyclopentadiene (0.21 g, 0.4 mmol) as a brown solid, yield 80 %.

The corresponding 2-bromo-6-(4-morpholin-4-yl-phenyl)-4-(2-trimethyldecane-ethoxymethyl)-4,7-dihydro-1-sulfide -4,5-diaza-cyclopenta[a]noncyclopentadiene (1.2 g, 2.3 mmol), 5-(4,4,5,5-tetramethyl-[1,3,2 Dioxaborolan-2-yl)-pyridin-2-ylamine (0.75 g, 3.4 mmol), Na ₂ CO ₃ (2 M, 5.4 mL) and Pd(PPh ₃ ) ₂ Cl ₂ (260 mg , 0.23 mmol) The mixture in toluene/ethanol (1:1, 15 mL) was heated to 100 ° C for 8 hours. The solution was cooled to room temperature and extracted with ethyl acetate. Chromatography column chromatography (50% EtOAc in hexanes) afforded the corresponding intermediate 5-[6-(4-morpholin-4-yl-phenyl)-4-(2-trimethyl) as a brown solid.矽-ethoxymethyl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopenta[a]indolylcyclopent-2-yl]-pyridine-2- The amine has a yield of 74%.

5-[6-(4-Morpholin-4-yl-phenyl)-4-(2-trimethyldecane-ethoxymethyl)-4,7-dihydro-1-sulfo-4, 5-Dinitro-cyclopenta[a]fluorenylcyclopentadien-2-yl]-pyridin-2-ylamine (0.44 g, 0.8 mmol) dissolved in methanol and then concentrated hydrochloric acid (0.25 mL, 8 Mm) treatment. The reaction mixture was heated to 100 ° C for 4 hours. The solution was cooled to room temperature, and the obtained residue was filtered, washed with methanol, and then concentrated under reduced pressure to give the corresponding 5-[6-(4-morpholin-4-yl-phenyl) as a yellow solid. -4,7-Dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]indolecyclopentadien-2-yl]-pyridin-2-ylamine hydrochloride (0.24 g, 0.49 mmol), yield 61%.

MS (ESI) m / z: 452.0 (M + H) + 1 H NMR (DMSO- d 6):. 8.42 (d, 1 H), 8.28 (d, 1 H), 7.78-7.74 (m, 2 H ), 7.61 (d, 1 H), 7.28 (t, 2 H), 7.11 (d, 1 H), 3.95 (s, 2 H), 3.60 (s, 4 H), 3.11 (t, 2 H), 2.839 (s, 4 H).

Example 89

5-{6-[4-(4-Methyl-piperazin-1-yl)-phenyl]-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl hydrazine a] indole cyclopentadien-2-yl}-pyridin-2-ylamine hydrochloride

The NBS (0.18 g, 1.0 mmol) was added in CH ₂ Cl ₂ (5.0 mL) of the 6- [4- (4-methyl - piperazin-1-yl) - phenyl] -4- (2- Methyl decane-ethoxymethyl)-4,7-dihydro-1-thio-4,5-diaza-cyclopenta[a]noncyclopentadiene (0.23 g, 0.5 mmol) solution . After 2 hours, the solution was evaporated and washed with EtOAc, filtered and concentrated to afford 2-bromo-6-[4-(4-methyl-piperazin-1-yl)-phenyl]-4-(2- Trimethyldecane-ethoxymethyl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopenta[a]indolecyclopentadiene (0.23 g, 0.42 mmol) The brown solid was obtained in a yield of 85%.

The corresponding 2-bromo-6-[4-(4-methyl-piperazin-1-yl)-phenyl]-4-(2-trimethyldecane-ethoxymethyl)-4,7 -Dihydro-1-sulfo-4,5-diaza-cyclopenta[a]noncyclopentadiene (1.25 g, 2.3 mmol), 5-(4,4,5,5-tetramethyl -[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamine (0.75 g, 3.4 mmol), Na ₂ CO ₃ (2 M, 5.4 mL) and Pd (PPh ₃ The mixture of ₂ Cl ₂ (260 mg, 0.23 mmol) in toluene/ethanol (1:1, 15 mL) was heated to 100 ° C and maintained for 8 hours. The solution was cooled to room temperature and extracted with ethyl acetate. Chromatography column chromatography (50% EtOAc in hexanes) afforded the corresponding intermediate 5-[6-[4-(4-methyl-piperazin-1-yl)-phenyl]-4 as a brown solid. -(2-trimethyldecane-ethoxymethyl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopenta[a]indolecyclopentadiene-2- Base]-pyridin-2-ylamine, yield 75%.

5-[6-[4-(4-Methyl-piperazin-1-yl)-phenyl]-4-(2-trimethyldecane-ethoxymethyl)-4,7-dihydro 1-sulfo-4,5-diaza-cyclopenta[a]noncyclopentadien-2-yl]-pyridin-2-ylamine (0.45 g, 0.8 mmol) dissolved in methanol Treat with concentrated hydrochloric acid (0.25 mL, 8 mmol). The reaction mixture was heated to 100 ° C for 4 hours. The solution was cooled to room temperature, and the obtained precipitate was filtered, washed with methanol, and then concentrated under reduced pressure to give the corresponding 5-{6-[4-(4-methyl-piperazine) as a yellow solid. 1-yl)-phenyl]-4,7-dihydro-1-sulfo-4,5-diaza-ring Pentadiene oxime [a] fluorene cyclopentadien-2-yl}-pyridin-2-ylamine hydrochloride (0.18 g, 0.39 mmol), yield 49%.

MS (ESI) m / z: . 465.0 (M + H) + 1 H NMR (DMSO- d 6): 11.17 (s, 1 H), 8.43 (d, 2 H), 8.33 (s, 1 H), 7.78 (d, 2 H), 7.61 (d, 1 H), 7.29 (t, 2 H), 7.13 (d, 1 H), 3.95 (s, 2 H), 3.34 (d, 2 H), 3.20 ( d, 2 H), 3.10 (s, 4 H), 2.78 (s, 3 H).

Example 90

6-[4-(4-Methyl-piperazin-1-yl)-phenyl]-2-pyridin-3-yl-4,7-dihydro-1-sulfo-4,5-diaza-ring Pentadiene oxime [a] quinone cyclopentadienide hydrochloride

The NBS (0.18 g, 1.0 mmol) was added in CH ₂ Cl ₂ (5.0 mL) of the 6- [4- (4-methyl - piperazin-1-yl) - phenyl] -4- (2- Methyl decane-ethoxymethyl)-4,7-dihydro-1-thio-4,5-diaza-cyclopenta[a]noncyclopentadiene (0.23 g, 0.5 mmol) solution . After 2 hours, the solution was evaporated and washed with EtOAc, filtered and concentrated to afford 2-bromo-6-[4-(4-methyl-piperazin-1-yl)-phenyl]-4-(2- Trimethyldecane-ethoxymethyl)-4,7-dihydro-1-thio-4,5-diaza-cyclopenta[a]indolecyclopentadiene (0.223 g, 0.4 mmol) The brown solid was obtained in a yield of 80%.

The corresponding 2-bromo-6-[4-(4-methyl-piperazin-1-yl)-phenyl]-4-(2-trimethyldecane-ethoxymethyl)-4,7 -Dihydro-1-sulfo-4,5-diaza-cyclopenta[a]indolecyclopentadiene (1.25 g, 2.3 mmol), 3-(4,4,5,5-tetramethyl -[1,3,2]dioxaborolan-2-yl)-pyridine (0.70 g, 3.4 mmol), Na ₂ CO ₃ (2 M, 5.0 mL) and Pd(PPh ₃ ) ₂ Cl ₂ ( A mixture of 260 mg, 0.23 mmol) in toluene/ethanol (1:1, 15 mL) was heated to 100 ° C for 8 hours. The solution was cooled to room temperature and extracted with ethyl acetate. The corresponding intermediate 6-[4-(4-methyl-piperazin-1-yl)-phenyl]-2-pyridine was obtained as a brown solid from EtOAc (EtOAc) 3-yl-4-(2-trimethyldecane-ethoxymethyl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopenta[a]indolyl Diene, yield 67%.

6-[4-(4-Methyl-piperazin-1-yl)-phenyl]-2-pyridin-3-yl-4-(2-trimethyldecane-ethoxymethyl)-4 ,7-Dihydro-1-sulfo-4,5-diaza-cyclopenta[a]indolecyclopentadiene (0.45 g, 0.8 mmol) dissolved in methanol and then concentrated hydrochloric acid (0.25 mL, 8 Mm) treatment. The reaction mixture was heated to 100 ° C for 4 hours. The solution was cooled to room temperature, and the obtained residue was filtered, washed with methanol, and then concentrated under reduced pressure to give the corresponding 6-[4-(4-methyl-piperazin-1-yl) as a yellow solid. )-Phenyl]-2-pyridin-3-yl-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl hydrazide [a] quinolidine hydrochloride (0.2 g, 0.44 mmol), yield 55%.

MS (ESI) m / z: . 450.0 (M + H) + 1 H NMR (DMSO- d 6): 11.21 (s, 1 H), 9.32 (s, 1 H), 9.01 (d, 1 H), 8.94 (d, 1 H), 8.13 (q, 1 H), 7.92 (s, 1 H), 7.88 (t, 1 H), 7.61 (d, 1 H), 7.40 (d, 1 H), 7.29 ( d, 1 H), 3.96 (s, 2 H), 3.30 (d, 2 H), 3.13 (d, 4 H), 3.01 (d, 2 H), 2.75 (s, 3 H).

Example 91

5-[6-(4-Methoxy-phenyl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]indolecyclopentadiene-2- Pyridyl-3-ylamine hydrochloride

Add NaH (60%, 1.3 g, 33 mmol) to 2-bromo-6-(4-methoxy-phenyl)-4,7-dihydro-1-sulfo-4,5 at 0 °C a solution of diaza-cyclopenta[a]indolecyclopentadiene (8.3 g, 24 mmol) in THF (15 ml). Further, SEM-Cl (90% purity, 5.6 ml, 28 mmol) was added to the reaction mixture, and the obtained mixture was stirred at 0 ° C for 30 minutes, and then heated to 80 ° C and stirred for 2 hours. The solution was cooled to room temperature and poured into ice water. The resulting mixture was extracted with ethyl acetate. The organic layer was collected and rinsed with saturated aqueous NH ₄ Cl, to MgSO _{4 (s)} sulfate, and concentrated under reduced pressure. The oily residue was purified by gravity column chromatography (20% EtOAc in hexane) to afford 2-bromo-6-(4-methoxy-phenyl)-4-(2-trimethyldecane-ethyl Oxymethyl)-4,7-dihydro-1-thio-4,5-diaza-cyclopenta[a]indolecyclopentadiene (9.0 g, 18.0 mmol) as a brown solid, yield 79%.

The corresponding intermediate 2-bromo-6-(4-methoxy-phenyl)-4-(2-trimethyldecane-ethoxymethyl)-4,7-dihydro-1-sulfo- 4,5-diaza-cyclopenta[a]indolecyclopentadiene (1.1 g, 2.3 mmol), 5-(4,4,5,5-tetramethyl-[1,3,2] Dioxaborolan-2-yl)-pyridin-3-ylamine (0.75 g, 3.4 mmol), Na ₂ CO ₃ (2 M, 5.4 mL), and Pd(PPh ₃ ) ₂ Cl ₂ (226 mg, A mixture of 0.1 mmol) in toluene/ethanol (1:1, 15 mL) was heated to 100 ° C for 8 hours. The solution was cooled to room temperature and extracted with ethyl acetate. The desired product 5-[6-(4-methoxy-phenyl)-4-(2-trimethyldecane-ethoxy) was obtained as a brown solid. Methyl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopenta[a]noncyclopentadien-2-yl]-pyridin-3-ylamine The rate is 68%.

5-[6-(4-Methoxy-phenyl)-4-(2-trimethyldecane-ethoxymethyl)-4,7-dihydro-1-sulfo-4,5-di Nitro-cyclopentadienyl[a]indolecyclopentadien-2-yl]-pyridin-3-ylamine (0.39 g, 0.8 mmol) was dissolved in MeOH then EtOAc (EtOAc) . The reaction mixture was heated to 100 ° C for 4 hours. The solution was cooled to room temperature, and the obtained precipitate was filtered, washed with methanol, and then concentrated under reduced pressure to give the corresponding 5-[6-(4- Methoxy-phenyl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]indolylcyclopent-2-yl]-pyridin-3-yl Amine hydrochloride (0.21 g, 0.57 mmol), yield 71%.

MS (ESI) m / z: . 397.0 (M + H) + 1 H NMR (DMSO- d 6): 8.49 (s, 1 H), 8.00 (s, 1 H), 7.93 (d, 1 H), 7.82 (s, 1 H), 7.71 (d, 2 H), 7.07 (d, 2 H), 4.03 (s, 2 H), 3.81 (s, 3 H).

Example 92

4-[2-(6-Amino-pyridin-3-yl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]indolecyclopentadiene- 6-yl]-phenol

The medium of _{BBr 3 (1.25 g, 5.0 mmol} ) was added in _{CH 2 Cl 2 (8.0 mL)} 5- [6- (4- methoxy-phenyl) - 4,7-dihydro-1-thio -4 , a solution of 5-diaza-cyclopenta[a]indolecyclopentadien-2-yl]-pyridin-2-ylamine (0.18 g, 0.5 mmol). After 2 hours, the solution was evaporated and washed with EtOAc, filtered and concentrated to afford 4-[2-(6-amino-pyridin-3-yl)-4,7-dihydro-1-thio-4. 5-Dinitro-cyclopentadienyl[a]indolecyclopenta-6-yl]-phenol (0.14 g, 0.42 mmol), m.

MS (ESI) m / z: . 347.0 (M + H) + 1 H NMR (DMSO- d 6): 8.24 (d, 1 H), 7.70 (q, 1 H), 7.58 (d, 2 H), 7.43 (s, 1 H), 6.87 (d, 2 H), 6.52 (d, 1 H), 3.79 (s, 2 H).

Example 93

4-(4,7-Dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]indolecyclopentadienyl-6-yl)-phenol

Add BBr ₃ (1.25 g, 5.0 mmol) to 6-(4-methoxy-phenyl)-4,7-dihydro-1-sulfo-4,5- in CH ₂ Cl ₂ (8.0 mL) A solution of diazo-cyclopenta[a]indolecyclopentadiene (0.13 g, 0.5 mmol). After 2 hours, the solution was evaporated and washed with EtOAc, filtered and concentrated to give the corresponding 4-(4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]fluorene ring. Pentadien-6-yl)-phenol (0.11 g, 0.44 mmol) as a brown solid, yield 88%.

MS (ESI) m / z: . 255.0 (M + H) + 1 H NMR (DMSO- d 6): 7.66 (d, 2 H), 7.64 (s, 1 H), 7.30 (d, 1 H), 6.92 (d, 2 H), 3.96 (s, 2 H).

Example 94: Biological Activity

Characterization of multiple representative compounds of formula (I) against various proteases (eg FLT3, c- The inhibition ability of kit, PDGFR-β and Aurora kinase is described in the following.

1. FTL3 kinase analysis

Inhibition of FLT3 kinase activity by the compounds disclosed herein is quantified by measuring the amount of [ ^33P ] incorporated into the substrate. Briefly, 25 μL of final body containing 5 ng of FLT3 kinase (FLT3 kinase domain, Upstate), 5 μg of substrate [(Poly(Glu-Try, 4:1, Sigma)), kinase reaction Buffer (20 mM MOPS pH 7.0, 1 mM EDTA, 5% glycerol, 0.01% Brij-35, 0.1% β-巯 ethanol, 1 mg/mL BSA, 100 μM ATP, 0.1 μCi per well [ ³³ P]- The reaction mixture of γ-ATP (2,500-3,000 Ci/mmol) and the test compound (diluted to a desired final concentration by 4% DMSO from 9 μM) or DMSO (as a control) was incubated at 30 ° C for 30 minutes. The reaction was stopped by adding 5 μL of 30% phosphoric acid. The resulting solution (30 μL) was collected by UniFilter Plate GF/B (PerkinElmer), followed by addition of 30 μL of scintillation c°C ktail (MicroScint 20, PerkinElmer) to the wells. The radioactivity remaining on the filter was measured by a brightness calculator (PerkinElmer). The results were analyzed by linear regression software (GraphPad Prism 4; GraphPad Software Inc.).

The inhibitory activities of the compounds are listed in Table 1 and are summarized in Table 2. IC ₅₀ values are diagrams concentration of test compound to inhibit by half the amount of the maximum activity of the kinase. ± indicates that the concentration is greater than 1,000 nM; + indicates the concentration is 1,000-500 nM; ++ indicates the concentration is 499-100 nM; and +++ indicates that the concentration is less than 100 nM.

2. PDGFR-β kinase analysis

Inhibition of PDGFR-[beta] kinase activity by the compounds disclosed herein is quantified by measuring the amount of [ ^33P ] incorporated into the host. Briefly, 25 μL of final body containing 55 ng of PDGFR-β kinase (obtained by purification of the recombinant N-terminal 6x His-tag PDGFR-β kinase domain construct from baculovirus), 2.5 μg The receptor [(Poly(Glu-Try, 4:1, Sigma)], kinase reaction buffer (20 mM MOPS pH 7.0, 1 mM EDTA, 5% glycerol, 0.01% Brij-35, 0.1% β-巯 ethanol) , 1 mg/mL BSA, 2 mM MnCl ₂ , 30 μM ATP, 0.1 μCi of [ ³³ P]-γ-ATP (2,500-3,000 Ci/mmol) per well and test compound (by 4% DMSO from 9 μM) The reaction mixture diluted to the desired final concentration) or DMSO (as a control) was incubated for 30 minutes at 30° C. The reaction was stopped by the addition of 5 μL of 30% phosphoric acid. Collected by UniFilter Plate GF/B (PerkinElmer) The resulting solution (30 μL), followed by 30 μL of scintillation cocktail (MicroScint 20, PerkinElmer) was added to the well. The radioactivity remaining on the filter was measured by a brightness calculator (PerkinElmer). analyzing the selection of PDGFR-β kinase IC ₅₀ values of the compounds shown in table 3; by linear regression software (GraphPad Software Inc. GraphPad Prism 4) ..

3. C-kit kinase analysis

Inhibition of C-kit kinase activity by the compounds disclosed herein is quantified by measuring the amount of [ ^33P ] incorporated into the substrate. Briefly, 25 μL of final body containing 5 ng of C-kit kinase (obtained by purification of the recombinant N-terminal 6x His-tag C-kit kinase domain from the baculovirus), 5 μg The substrate [(Poly(Glu-Try, 4:1, Sigma)], kinase reaction buffer (8 mM MOPS/NaOH pH 7.0, 0.2 mM EDTA, 10 mM MnCl ₂ , 0.5% glycerol, 0.001% Brij-35) , 0.1% β-巯 ethanol, 0.1 mg/mL BSA, 100 μM ATP, 0.1 μCi of [ ³³ P]-γ-ATP (2,500-3,000 Ci/mmol) per well and test compound (by 4% DMSO) The reaction mixture was diluted from 9 μM to the desired final concentration) or DMSO (as a control) for 30 minutes at 30 ° C. The reaction was stopped by adding 5 μL of 30% phosphoric acid. By UniFilter Plate GF/B (PerkinElmer) The resulting solution (30 μL) was collected, and then 30 μL of scintillation cocktail (MicroScint 20, PerkinElmer) was added to the well. The radioactivity remaining on the filter was measured by a brightness calculator (PerkinElmer). results based software by linear regression (GraphPad Prism 4; GraphPad Software Inc. ) analysis of the selected C-kit kinase IC ₅₀ values of the compounds shown in table 3.

Claims (13)

a compound of formula (I) or a pharmaceutically acceptable salt thereof, Wherein: R ¹ and R ² independently represent hydrogen, halo, cyano, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, C _{3 - 15} cycloalkyl, C _4-15 cycloalkenyl, -(CH ₂ ) _m OR _a , -(CH ₂ ) _m NR _a R _b , -NR _a R _b , -OR _a , SR _b , -CO ₂ R _a , -NR _a CO-(CH ₂ ) _m NR _a R _b , -CONR _a R _b , -CONR _a -(CH ₂ ) _m NR _a R _b , C ₆ -C ₁₄ aryl, heteroaryl or hetero a cyclic group wherein the C _1-4 alkyl group, C _2-4 alkenyl group, C _2-4 alkynyl group, C _1-4 alkoxy group, C _3-15 cycloalkyl group, C _4-15 cycloalkenyl group, OR _a , SR _b , C ₆ -C ₁₄ aryl, heteroaryl and heterocyclic are unsubstituted or substituted by one, two or three substituents selected from the group consisting of halo, hydroxy, C _{1- 4-} alkyl, halo C _1-4 alkyl, C _1-4 alkoxy, amine, C _3-15 cycloalkyl C _1-4 alkyl, C ₆ -C ₁₄ aryl C _1-4 alkyl , C ₆ -C ₁₄ aryl, heteroaryl, heterocyclic, heterocyclyl-C _1-4 alkyl and -CONH-heteroaryl; X represents C _1-4 alkyl, C _2-4 Alkenyl, C _1-4 alkyl-carbonyl, C _2-4 alkenyl-carbonyl, carbonyl, oxygen, -C=NOR _c ; Y represents a direct bond; ring A represents a C ₆ -C ₁₄ aryl, heteroaryl group Or a heterocyclic group; R ³ and R ⁴ Independently represents a hydroxyl group, a hydrogen, a halogen group, a nitro group, a cyano group, an amine group, an oxo group (oxo), a C _1-4 alkyl group, a halogen C _1-4 alkyl group, a C _1-4 alkoxy group, a halogen C _1-4 alkoxy, C _2-4 alkenyl, C _6-14 aryl, C _1-4 alkyl C ₆ -C ₁₄ aryl, NR _a R _b , -NH-C ₆ -C ₁₄ Aryl, heteroaryl, C _2-4 alkenyl-C ₆ -C ₁₄ aryl, S(O) _n -heterocyclyl, -NH-heterocyclyl or heterocyclyl, wherein C _1-4 Alkyl, halogen C _1-4 alkyl, C _1-4 alkoxy, halo C _1-4 alkoxy, C _2-4 alkenyl, C ₆ -C ₁₄ aryl, C ₆ -C ₁₄ aryl C _1-4 alkyl, -NH-C ₆ -C ₁₄ aryl, C ₆ -C ₁₄ heteroaryl, C _2-4 alkenyl-C ₆ -C ₁₄ aryl, S(O) _n - The cyclo), -NH-heterocyclyl and heterocyclyl are unsubstituted or substituted by one, two or three substituents selected from the group consisting of amino, cyano, halo, halo C _1-4 alkyl , hydroxy, C _1-4 alkyl, C _1-4 alkoxy and halo C _1-4 alkoxy; R _a and R _{b are} independently hydrogen, C _1-4 alkyl, C _2-4 alkenyl , C _2-4 alkynyl, C _1-4 alkoxy, C _3-15 cycloalkyl C _1-4 alkyl, C _4-15 cycloalkenyl C _2-4 alkenyl, C ₆ -C ₁₄ aryl group, aryl, heteroaryl or heterocyclyl, or R _a and oxygen to which they are bonded R _b of Together with the nitrogen or sulfur atom of the heteroaryl or heterocyclyl; R _c represents hydrogen or alkyl, m is 2 or 3, n is 0, 1 or 2, heteroaryl means an aryl group having 5 to 14 a ring-shaped atom and having 1, 2 or 3, independently of a carbon atom, a monocyclic, bicyclic, tricyclic or polycyclic group independently selected from the group consisting of N, O and S, and the heterocyclic group means having 3 a monocyclic, bicyclic or polycyclic structure of up to 14 atoms, wherein 1, 2 or 3 atomic systems are independently selected from the group consisting of N, O and S, the remaining ring constituent atoms are carbon atoms, and the ring structure is saturated or Unsaturated ring, but not aromatic ring. A compound of the formula (I), or a pharmaceutically acceptable salt thereof, according to claim ¹ , wherein: R ¹ and R ² independently represent hydrogen, C _1-4 alkyl, halo, cyano, -NR _a CO- (CH ₂ ) _m NR _a R _b , -CONR _a R _b , -CONR _a -(CH ₂ ) _m NR _a R _b , -(CH ₂ ) _m OR _a , -(CH ₂ )NR _a R _b , C _{a 6-} C ₁₄ aryl, heteroaryl or heterocyclic group wherein the C _1-4 alkyl, heteroaryl, C _6-14 aryl and heterocyclic groups are unsubstituted or one, two or three Substituents selected from the group consisting of halo, hydroxy, C _1-4 alkoxy, amine, heterocyclyl-C _1-4 alkyl and -CONH-heteroaryl; X represents C _1-3 Alkyl or carbonyl; Y represents a direct bond; ring A represents a phenyl, pyridyl, pyrimidinyl or furyl group; R ³ and R ⁴ independently represent an amine group, a halogen group, a hydroxyl group, a nitro group, a pendant oxy group, C _{1 -4} alkyl, C _1-4 alkoxy, halo-C _1-4 alkyl, phenyl, C _1-3 stretch alkenyl-phenyl, NR _a R _b , -NH-phenyl, S ( O) ₂ -piperidinyl, -NH-pyridyl, piperazinyl, pyrrolidinyl or morpholinyl, wherein the C _1-4 alkyl, C _1-4 alkoxy, halo-C _1-4 alkyl, phenyl, C _1-3 alkenylene group - phenyl, -NH- phenyl, S (O) ₂ - Piperidinyl, -NH- pyridyl, piperazinyl, pyrrolidinyl and morpholinyl group based unsubstituted or with 1 to 2 substituents selected from the substituent group: halo, hydroxy, C _1-4 alkyl, C _1-4 alkoxy, amine, cyano, halo-C _1-4 alkyl and halo-C _1-4 alkoxy; R _a and R _{b are} independently hydrogen, C _1-4 alkane , C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, C _3-15 cycloalkyl, C _4-15 cycloalkenyl, C ₆ -C ₁₄ aryl, heteroaryl Or a heterocyclic group, or R _a and R _b together with an oxygen, nitrogen or sulfur atom to which they are bonded form a morpholinyl, piperidinyl, piperazinyl, methylpiperazinyl, thiomorpholinyl or pyrrole group A pyridyl group; m is 0, 1 or 2, and the heteroaryl group and the heterocyclic group have the definitions as defined in claim 1. A compound of the formula (I), or a pharmaceutically acceptable salt thereof, according to claim 1 or 2, wherein X represents a methylene group. A compound of the formula (I), or a pharmaceutically acceptable salt thereof, according to claim 1 or 2, wherein X represents a carbonyl group. A compound of formula (I), or a pharmaceutically acceptable salt thereof, according to claim 1 or 2, wherein ring A is phenyl. A compound of the formula (I), or a pharmaceutically acceptable salt thereof, according to claim 1 or 2, wherein ring A is pyridyl. A compound of the formula (I), or a pharmaceutically acceptable salt thereof, according to claim 1 or 2, wherein the ring A is a furyl group. A compound of the formula (I), or a pharmaceutically acceptable salt thereof, according to claim 1 or 2, wherein R ³ and R ⁴ independently represent an amine group, a halogen group, a hydroxyl group, a nitro group, a pendant oxy group, a methoxy group, Trifluoromethyl, trifluoromethoxy, phenyl, styryl-phenyl, -NH-phenyl, S(O) ₂ -piperidinyl, -NH-pyridyl, piperazinyl, pyrrolidinyl Or morpholinyl, wherein the phenyl, styryl-phenyl, -NH-phenyl, S(O) ₂ -piperidinyl, -NH-pyridyl, piperazinyl, pyrrolidinyl and morpholinyl It is unsubstituted or substituted with 1 to 2 substituents selected from the group consisting of halo, hydroxy, methyl, methoxy, amine, cyano, trifluoromethyl and trifluoromethoxy. A compound of the formula (I), or a pharmaceutically acceptable salt thereof, according to claim 1 or 2, wherein ring A together with R ³ and R ⁴ form a phenyl group, a 2-bromo-phenyl group, a 3-bromo-phenyl group, 4-bromo-phenyl, 2-chloro-phenyl, 3-chloro-phenyl, 4-chloro-phenyl, 2,3-dichloro-phenyl, 2,4-dichloro-phenyl, 3, 4-Dichloro-phenyl, 3,5-dichloro-phenyl, 2-fluoro-phenyl, 3-fluoro-phenyl, 4-fluoro-phenyl, 4-iodo-phenyl, phenylamine, 2-methoxy-phenyl, 3-methoxy-phenyl, 4-methoxy-phenyl, 2,4-dimethoxy-phenyl, 3,4-dimethoxy-phenyl 4-nitro-phenyl, 4-amino-phenyl, 2-trifluoromethyl-phenyl, 3-trifluoromethyl-phenyl, 4-trifluoromethyl-phenyl, 3,5 - bis-trifluoromethyl-phenyl, phenyl-(4-fluoro-phenyl)-amine, phenyl-(4-methoxy-phenyl)-amine, biphenyl-4-phenol, 3- Methoxy-biphenyl-4-phenol, phenylamino-phenol, phenol, 4-styryl-phenyl, phenyl]-benzene-1,4-diamine, 3',4'-dimethyl Oxy-biphenyl-4-yl, biphenyl-4-carbonitrile, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 6-bromo-pyridin-3-yl, phenyl-pyridine 3-yl, phenyl-pyridin-4-yl, 1-oxy-pyridin-3-yl, 1-oxy-pyridine-4- , pyridin-2-ylamine, pyridin-3-ylamine, pyridin-4-ylamine, 4-pyrrolidin-1-yl-phenyl, furan-3-yl, 3',5'-dichloro-linked Benz-4-yl, 4'-trifluoromethyl-biphenyl-4-yl, phenyl-(3-fluoro-phenyl)-amine, 4-(piperidin-1-sulfonyl)-phenyl 4-(4-Methyl-piperazin-1-yl)-phenyl or 4-morpholin-4-yl-phenyl. A compound of the formula (I), or a pharmaceutically acceptable salt thereof, according to claim 1 or 2, which is selected from the group consisting of: 6-(4-bromo-phenyl)-5,7-dihydro-1-thio-4 ,5-diaza-cyclopentadienyl[a]indolecyclopentadiene, 4-(4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]pyrene Cyclopentadienyl-6-yl)-phenylamine hydrochloride, 6-(3-methoxy-phenyl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]noncyclopentadiene, 6-(2, 4-dimethoxy-phenyl)-4,7-dihydro-1-thio-4,5-diaza-cyclopentadienyl[a]noncyclopentadiene, 6-(4-nitro -phenyl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]noncyclopentadiene, 6-phenyl-4,7-dihydro-1 - sulfur-4,5-diaza-cyclopentadienyl[a]indolecyclopentadiene, [4-(4,7-dihydro-1-thio-4,5-diaza-cyclopentadiene)幷[a]幷cyclopentadienyl-6-yl)-phenyl]-(4-fluoro-phenyl)-amine, [4-(4,7-dihydro-1-sulfo-4,5-di Nitrogen-cyclopentadienyl[a]indolecyclopentadienyl-6-yl)-phenyl]-(4-methoxy-phenyl)-amine, 4'-(4,7-dihydro-1 - sulfur-4,5-diaza-cyclopentadienyl[a]noncyclopentadienyl-6-yl)-3-methoxy-biphenyl-4-phenol, 3-[4-(4, 7-Dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]decenecyclopentadienyl-6-yl)-phenylamino]-phenol, 4'-(4,7 -Dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]indolecyclopentadienyl-6-yl)-biphenyl-4-phenol, 6-(4-styryl- Phenyl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]indolecyclopentadiene, N-[4-(4,7-dihydro-1 -sulfur-4,5-diaza-cyclopentadienyl[a]decenecyclopentadienyl-6-yl)-benzene Benzene-1,4-diamine, 6-(3',4'-dimethoxy-biphenyl-4-yl)-4,7-dihydro-1-sulfo-4,5-di Nitrogen-cyclopentadienyl[a]noncyclopentadiene, 4'-(4,7-Dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]indolecyclopentadienyl-6-yl)-biphenyl-4-carbonitrile, 6 -pyridin-3-yl-4,7-dihydro-1-thio-4,5-diaza-cyclopentadienyl[a]noncyclopentadiene, 6-furan-3-yl-4,7 -Dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]noncyclopentadiene, 4,7-dihydro-1-sulfo-4,5-diaza-cyclopentane Iridinium [a]indole cyclopentadiene, 6-(3',5'-dichloro-biphenyl-4-yl)-4,7-dihydro-1-sulfo-4,5-diaza-ring Pentadiene oxime [a] fluorene cyclopentadiene, 6-(4'-trifluoromethyl-biphenyl-4-yl)-4,7-dihydro-1-thio-4,5-diaza- Cyclopentadienyl[a]indolecyclopentadiene, 2-bromo-6-phenyl-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]幷Cyclopentadiene, 6-(1-oxy-pyridin-3-yl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]fluorenecyclopentane Alkene, 2-bromo-6-(4-bromo-phenyl)-4,7-dihydro-1-thio-4,5-diaza-cyclopentadienyl[a]noncyclopentadiene, 2 -Bromo-6-(4-methoxy-phenyl)-4,7-dihydro-1-thio-4,5-diaza-cyclopentadienyl[a]noncyclopentadiene, 6- (3-fluoro-phenyl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl hydrazone [a]indolecyclopentadiene, 6-(3-chloro-phenyl )-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]幷Cyclopentadiene, 6-(4-fluoro-phenyl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl hydrazone [a] Cyclopentadiene, 6-(2-fluoro-phenyl)-4,7-dihydro-1-thio-4,5-diaza-cyclopentadienyl[a]noncyclopentadiene, 6 -(3,5-bis-trifluoromethyl-phenyl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]noncyclopentadiene, 6 -(2-bromo-phenyl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]indolecyclopentadiene,6-(3-bromo-benzene -4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]noncyclopentadiene,6-(3-chloro-phenyl)-4H-1- Sulfur-4,5-diaza-cyclopentadienyl[a]indolecyclopentadien-7-one, 6-(2-methoxy-phenyl)-4,7-dihydro-1-sulfo -4,5-diaza-cyclopentadienyl hydrazone [a] fluorene cyclopentadiene, 6-(4-amino-phenyl)-4H-1-thio-4,5-diaza-cyclopentane Alkene [a] indole cyclopentadien-7-one, 6-(3,5-dichloro-phenyl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentane Alkene [a]pyrene,6-pyridin-2-yl-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]noncyclopentadiene Hydrochloride, 3-(4,7-dihydro-1-thio-4,5-diaza-cyclopentadienyl[a]indolecyclopentadienyl-6-yl)-phenylamine hydrochloride ,6-Pyridin-4-yl-4,7-dihydro-1-thio-4,5-diaza-cyclopentadienyl hydrazide [a] quinolidine hydrochloride, 6-(1-oxo Base-pyridin-4-yl)-4,7-dihydro-1- 4,5-N - cyclopentadiene Alkene [a]indole cyclopentadiene, 6-(6-bromo-pyridin-3-yl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl hydrazone [a幷cyclopentadiene, 6-(4-methoxy-phenyl)-2-phenyl-4,7-dihydro-1-thio-4,5-diaza-cyclopentadienyl hydrazone [a幷cyclopentadiene, 5-(4,7-dihydro-1-thio-4,5-diaza-cyclopentadienyl[a]indolecyclopentadienyl-6-yl)-pyridine-2 -ylamine hydrochloride, 2-bromo-6-(6-bromo-pyridin-3-yl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl hydrazone [a幷cyclopentadiene, 6-(4-amino-phenyl)-4H-1-thio-4,5-diaza-cyclopentadienyl[a]noncyclopentadien-7-one, 6-(6-Bromo-pyridin-3-yl)-4H-1-thio-4,5-diaza-cyclopentadienyl[a]indolecyclopentadien-7-one, 6-(4- Methoxy-phenyl)-2-pyridin-4-yl-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]noncyclopentadiene, 6- (4-methoxy-phenyl)-2-pyridin-3-yl-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]noncyclopentadiene ,2-(4-Fluoro-phenyl)-6-(4-methoxy-phenyl)-4,7-dihydro-1-thio-4,5-diaza-cyclopentadienyl hydrazone [a幷cyclopentadiene, 2-(3,4-difluoro-phenyl)-6-(4-methoxy-phenyl)-4,7-dihydro-1-sulfo-4,5-di Nitrogen-cyclopentadienyl[a]indolecyclopentadiene, 2,6-bis-(4-A Oxy-phenyl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]noncyclopentadiene, 2-(3,4-dimethoxy -phenyl)-6-(4-methoxy-phenyl)-4,7-dihydro-1- Sulfur-4,5-diaza-cyclopentadienyl[a]noncyclopentadiene, 2-methoxy-4-[6-(4-methoxy-phenyl)-4,7-di Hydrogen-1-sulfo-4,5-diaza-cyclopentadienyl[a]decenecyclopentadien-2-yl]-phenol, 6-(4-methoxy-phenyl)-2-( 6-methoxy-pyridin-3-yl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]noncyclopentadiene, 2-furan-3 -yl-6-(4-methoxy-phenyl)-4,7-dihydro-1-thio-4,5-diaza-cyclopentadienyl[a]noncyclopentadiene, 5- [6-(4-Methoxy-phenyl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]indolyl-2-yl] -pyridin-2-ylamine, 5-[6-(4-methoxy-phenyl)-4,7-dihydro-1-thio-4,5-diaza-cyclopentadienyl[a]幷cyclopentadien-2-yl]-pyrimidin-2-ylamine, 6-(4-methoxy-phenyl)-2-pyridin-3-yl-4,7-dihydro-1-sulfo- 4,5-diaza-cyclopentadienyl[a]indolecyclopentadiene,6-[4-(4-methyl-piperazin-1-yl)-phenyl]-4,7-dihydro 1-sulfo-4,5-diaza-cyclopentadienyl[a]indolecyclopentadiene, 5-[6-(4-methoxy-phenyl)-4,7-dihydro-1 - sulfur-4,5-diaza-cyclopentadienyl[a]decenecyclopentadien-2-yl]-pyridin-2-ylamine, 6-(4-methoxy-phenyl)-2 -[6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-4,7-di Hydrogen-1-sulfo-4,5-diaza-cyclopentadienyl[a]indolecyclopentadiene, 5-[6-(4-methoxy-phenyl)-4,7-dihydro- 1-sulfo-4,5-diaza-cyclopentadienyl[a]decenecyclopentadien-2-yl]-pyridin-2-ylamine, N-{5-[6-(4-methoxy -Phenyl)-4,7-dihydro-1-thio-4,5-diaza-cyclopentadienyl[a]indolecyclopentadien-2-yl]-pyridin-2-yl}- 2-pyrrolidin-1-yl-acetamide, 2-(3-Fluoro-4-methoxy-phenyl)-6-(4-methoxy-phenyl)-4,7-dihydro-1-thio-4,5-diaza-cyclopentyl Diene oxime [a] fluorene cyclopentadiene, 6-(4-pyrrolidin-1-yl-phenyl)-4,7-dihydro-1-thio-4,5-diaza-cyclopentadiene幷[a]幷cyclopentadiene, 6-(4-morpholin-4-yl-phenyl)-4,7-dihydro-1-thio-4,5-diaza-cyclopentadienyl hydrazine [ a] indole cyclopentadiene, 3-[6-(4-methoxy-phenyl)-4,7-dihydro-1-thio-4,5-diaza-cyclopentadienyl[a]幷cyclopentadien-2-yl]-phenylamine, 2-(6-amino-pyridin-3-yl)-6-(4-methoxy-phenyl)-4H-1-thio-4 ,5-diaza-cyclopentadienyl[a]indolecyclopentadien-7-one, N-{5-[6-(4-methoxy-phenyl)-4,7-dihydro- 1-sulfo-4,5-diaza-cyclopentadienyl[a]decenecyclopentadien-2-yl]-pyridin-2-yl}-2-pyrrolidin-1-yl-acetamide salt Acid salt, 5-[6-(4-morpholin-4-yl-phenyl)-4,7-dihydro-1-sulfo-4,5-diaza-cyclopentadienyl[a]fluorene ring Pentadien-2-yl]-pyridin-2-ylamine hydrochloride, 5-{6-[4-(4-methyl-piperazin-1-yl)-phenyl]-4,7-di Hydrogen-1-sulfo-4,5-diaza-cyclopentadienyl[a]decenecyclopentadien-2-yl}-pyridin-2-ylamine hydrochloride, 6-[4-(4- Methyl-piperazin-1-yl)-phenyl]-2-pyridin-3-yl-4,7-dihydro-1-sulfo-4, 5-diaza-cyclopentadienyl hydrazone [a] fluorene cyclopentadienyl hydrochloride, 5-[6-(4-methoxy-phenyl)-4,7-dihydro-1-thio-4 ,5-diaza-cyclopentadienyl[a]decenecyclopentadien-2-yl]-pyridin-3-ylamine hydrochloride, 4-[2-(6-amino-pyridine-3- -4,7-dihydro-1-thio-4,5-diaza-cyclopentadienyl[a]indolecyclopentadienyl-6-yl]-phenol, 4-(4,7-di Hydrogen-1-sulfo-4,5-diaza-cyclopentadienyl[a]indolecyclopentadiene-6- -Phenol, [4-(4,7-dihydro-1-thio-4,5-diaza-cyclopentadienyl[a]indolecyclopenta-6-yl)-phenyl]- (3-fluoro-phenyl)-amine, [4-(4,7-dihydro-1-thio-4,5-diaza-cyclopentadienyl[a]indolyl-6-yl) )-Phenyl]-(4-methoxy-phenyl)-amine, and (4,7-dihydro-1-thio-4,5-diaza-cyclopentadienyl[a]indole Diene-6-yl)-(2-methoxy-phenyl)-amine. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 10, and a pharmaceutically acceptable carrier. A use of a compound of the formula (I) according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating an RTK-related disease in an individual. The use of claim 12, wherein the RTK-related disease is selected from the group consisting of a hematopoietic malignant disease, a carcinoma, a melanoma, a bone marrow disorder, an adenoma, a sarcoma, an autoimmune disease, an allergic reaction, an organ transplant rejection syndrome, and combinations thereof. .