WO2003091255A1 - Inhibitors of checkpoint kinases (wee1 and chk1) - Google Patents

Inhibitors of checkpoint kinases (wee1 and chk1) Download PDF

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WO2003091255A1
WO2003091255A1 PCT/IB2003/001417 IB0301417W WO03091255A1 WO 2003091255 A1 WO2003091255 A1 WO 2003091255A1 IB 0301417 W IB0301417 W IB 0301417W WO 03091255 A1 WO03091255 A1 WO 03091255A1
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dione
carbazole
hydroxy
pyrrolo
chloro
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PCT/IB2003/001417
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French (fr)
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Richard John Booth
William Alexander Denny
Ellen Myra Dobrusin
Alan John Kraker
Lorna Helen Mitchell
Jeffrey Bruce Smaill
Andrew Mark Thompson
Ho Huat Lee
Florence Oliver Joseph Mccarthy
Brian Desmond Palmer
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Warner-Lambert Company Llc
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Priority to JP2003587813A priority Critical patent/JP2006504632A/en
Priority to BR0309783-8A priority patent/BR0309783A/en
Priority to MXPA04010617A priority patent/MXPA04010617A/en
Priority to CA002483496A priority patent/CA2483496A1/en
Priority to EP03720766A priority patent/EP1501831A1/en
Priority to AU2003224341A priority patent/AU2003224341A1/en
Publication of WO2003091255A1 publication Critical patent/WO2003091255A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • This invention relates to small chemical molecules that specifically inhibit one or both of the checkpoint kinases Weel and Chkl.
  • kinases are responsible for inhibiting the cell's normal progression through cell division, while others are normally active in promoting the progression of cells through the cell cycle leading to cell division. Increased activity or temporally abnormal activation of these kinases has been shown to result in development of tumors and other proliferative disorders.
  • Weel tyrosine specific kinase
  • Cdc2/cyclinB another kinase complex
  • Weel kinase is a regulatory kinase that has Cdc2/cyclinB as its substrate and when Weel is active, it phosphorylates a specific tyrosine (Tyr 15) on Cdc2 that causes an inactivation of the Cdc2/cyclinB complex which in turn results in a pause or checkpoint in the cell cycle at the G2 and M transition.
  • Cdc2/cyclinB The kinase activity of Cdc2/cyclinB is absolutely required for cells to progress through the G2 stage of the cell division cycle to the M (or mitotic) phase where two daughter cells are formed from the division of the parent cell. Under normal circumstances, as cells are progressing through the cell cycle, the Cdc2/cyclinB complex is assembled in late S phase and through G2-
  • Weel is active and thus phosphorylates the Cdc2/cyclinB complex until the end of G2 when all of the necessary components have been synthesized for the entry of cells into M phase. Weel activity then diminishes, a phosphatase removes the inhibitory phosphorylation from Tyrl5 of Cdc2/cyclinB, the complex becomes activated and cells move into M phase where the replicated DNA is divided and the daughter cells are formed. Inhibition of Weel results in no inhibitory phosphorylation of Tyrl5 on Cdc2/cyclinB and the potentially inappropriate and premature entry of the cell into mitosis.
  • the cell cycle transitions are regulated in response to damage to DNA presumably giving cells opportunities either to repair potentially genotoxic DNA damage before replication using a damaged DNA template or to permanently exit the cell cycle and die.
  • Chkl Another kinase of interest named Chkl participates in this DNA damage dependent signaling pathway by phosphorylating a phosphatase called Cdc25C which when itself is active and co-localized with Cdc2/cyclinB in the nucleus, dephosphorylates Tyrl5 and causes the activation of the Cdc2/cyclinB complex.
  • Cdc25C phosphatase
  • the Chkl mediated phosphorylation of Cdc25C causes Cdc25C to be exported from the nucleus at which point it is no longer able to dephosphorylate and thus activate Cdc2/cyclinB.
  • Chkl is active (in response to DNA damage) it will indirectly contribute to the inactivation of Cdc2/cyclinB (whose activity is required for progression into M phase) through the preservation of the inactivating phosphorylation of Tyr 15 on Cdc2/cyclinB.
  • inhibition of Chkl would result in the dephosphorylation of Cdc2/cyclinB by the phosphatase Cdc25C in the nucleus (not exported to the cytoplasm since it is not phosphorylated by Chkl) and the consequent activation of Cdc2/cyclinB with the accompanying entry of the cells in mitosis.
  • Pyrrolocarbazole derivatives are known to have inhibitory activity against Protein kinase c and anti tumor activity (US Patent No. 4,912,107) but compared to the compounds of the present invention, the compounds disclosed in US Patent No. 4,912,107 have very low checkpoint kinase abrogator activity. Pyrrolocarbazole derivatives are also known to stimulate platelet production (WO96/28447) and to promote thrombopoiesis (WO9809967). EP 0695755 discloses another pyrrolocarbazole derivative having Protein kinase c activity. US Patent No.
  • 5,166,204 discloses antitumor isoindole derivatives having a linkage or lower alkylene group bonded to the 2 and 3 or 3 and 4 of a carbazole skeleton.
  • US Patent No. 5,728,709 discloses pyrrolocarbazole derivatives that stimulate platelet production.
  • WO 01/85686 also discloses pyrrolocarbazole derivatives.
  • R 1 is hydrogen, halogen, d - Cg alkyl, NR 5 R 6 or an aryl or heteroaryl ring optionally substituted with up to five substituents selected from halogen, alkyl, haloalkyl, hydroxyl, nitro, cyano, C(O)R 3 , OR 3 , S(0) m R 3 , NR 3 R 4 ,
  • heterocyclic ring optionally substituted with up to five substituents selected from, halogen, alkyl, haloalkyl, hydroxyl, nitro, cyano, C(0)R 3 , OR 3 , S(O) m R 3 , NR 3 R 4 ,
  • n 0-2;
  • X is hydrogen or halogen
  • Yl is O, S(0)m, or NR 1 ";
  • r is 0-6;
  • R 2 , R 7 , R 8 and R 10 are in each instance independently selected from ((CR 5 R 6 ) n T) a (CR n R 12)b)-Z wherein the sum of n, a and b is in each instance less than 10;
  • T may be absent, or, when present, is in each instance independently selected from O, CONR 3 , CONHSO , S(0) m , NR 3 , NR 3 0, OS(0) ra , S(0) m O, NR 3 S(O) 2 , or S(0) 2 NR 3 ;
  • R 5 , R ⁇ , Rl 1 and Rl2 are in each instance independently selected from hydrogen, hydroxyl, alkyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, halogen, cyano, nitro, CH 2 NR 3 R 4 CH OR 3 , C(0)R 3 , OR 3 , S(0) m R 3 , NR R 4 COOR 3 , CONR 3 R 4 , S0 2 NR R 4 , NHCONR 3 R 4 , NR 3 CONHR 4 ; wherein the alkyl, haloalkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl group may be substituted with up to four groups independently selected from halogen, alkyl, hydroxyl, nitro, cyano, OR 3 , S(0) m R 3 , NR 3 R 4 , OC(0)R 3 , NR 3 (CO)
  • R 5 and R" or R l * and Rl2 together with the carbon atom to which they are attached may form a carbonyl group; or together with the carbon or heteratom to which they are attached may form a cycloalkyl or heterocyclyl group, said carbonyl, cycloalkyl or heterocyclyl group may be substituted with up to four groups independently selected from halogen, hydroxyl, nitro, cyano, alkyl, haloalkyl, halogen, alkyl, nitro, cyano,
  • R 3 , R 4 are independently selected from hydrogen, alkyl, haloalkyl or a substituted or unsubstituted carbocyclic group selected from cycloalkyl, cycloalkenyl, heterocyclyl, aryl, and heteroaryl, wherein the said alkyl, or a substituted carbocyclic group may be substituted with up to 4 groups selected from halogen, hydroxyl, nitro, cyano, alkyl, haloalkyl, alkyloxy, carboxy, COOH, CONH 2 , NHCOCH3, N(CH 3 ) 2 , NHCH3, thiomethyl, thioethyl, SOCH3, SO2CH3;
  • R 3 and R 4 together with the carbon atom or heteroatom to which they are attached may form a cycloalkyl or heterocyclyl group substituted with up to four groups independently selected from halogen, hydroxyl, nitro, cyano, alkyl, haloalkyl, alkyloxy, fo ⁇ nyl, carboxy, acetyl, CH 2 NH 2 , CH 2 OH, COOH, CONH2, NHCOCH3, N(CH3)2, thiomethyl, thioethyl, SOCH3, SO2CH3, alkoxycarbonyl, alkylcarbonyl, alkynylamino, aminoalkyl, aminoalkylcarbonyl, amino, mono- or dialkylamino, or
  • R 3 and R 4 together with the nitrogen to which they are attached may form a heterocyclic ring containing 3-8 members, up to four of which members are optionally carbonyl groups or heteroatoms independently selected from oxygen, sulfur, S(O), S(0)2, and nitrogen, wherein the carbocyclic group is unsubstituted or substituted with up to four groups independently selected from halogen, hydroxy, hydroxyalkyl, alkyl, haloalkyl, alkoxy, alkoxycarbonyl, alkylcarbonyl, alkynylamino, aminoalkyl, aminoalkylcarbonyl, amino, mono- or dialkylamino.
  • Figure 1 represents a Western blot of tumor cells treated in vivo with cisplatin and the Compound of Example 80.
  • Figure 2 represent a Western Blot of cells treated in vitro with Adriamycin and the Compound of Example 80
  • Figure 3 represents a Western blot of tumor cells treated in vivo with cpt-11 and the Compound of Example 362.
  • Figure 4 represents a graph of life span enhancement in animals treated with the Compound of Example 80
  • R 1 is hydrogen, halogen, - C g alkyl; NR 5 R 6 or an aryl or heteroaryl ring optionally substituted with up to five substituents selected from halogen, alkyl, haloalkyl, hydroxyl, nitro, cyano, C(0)R 3 , OR 3 , S(0) m R 3 , NR 3 R 4 ,
  • n 0-2;
  • X is hydrogen or halogen
  • Y 1 is O, S(0)m, or NR 10 ;
  • r is 0-6;
  • R 2 , R 7 , R 8 and R 10 are in each instance independently selected from ((CR 5 R 6 ) n T) a (CR 1 1 Rl2) ⁇ )-Z wherein the sum of n, a and b is in each instance less than 10;
  • T may be absent, or, when present, is in each instance independently selected from O,
  • CONR 3 CONHS0 2> S(0) m , NR 3 , NR 3 -0, 0-S(0) m , S(0) m -0, NR 3 -S(0) 2 , or S(0)2-NR 3 ;
  • Z is selected from hydrogen, halogen, alkyl, haloalkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, cyano, nitro, hydroxy, C(0)R 3 , CONHS0 2 R 3 , OR 3 , S(0)mR 3
  • R 5 , R6, Rl 1 and R 12 are in each instance independently selected from hydrogen, hydroxyl, alkyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, halogen, cyano, nitro, CH 2 NR 3 R 4 CH 2 OR 3 , C(0)R 3 , OR 3 , S(0) m R 3 , NR 3 R 4 COOR 3 , CONR 3 R 4 S0 2 NR 3 R 4 , NHCONR R 4 , NR 3 CONHR 4 ; wherein the alkyl, haloalkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl group may be substituted with up to four groups independently selected from halogen, alkyl, hydroxyl, nitro, cyano, OR 3 ,
  • R 5 and R" or Rl 1 and R* 2 together with the carbon atom to which they are attached may form a carbonyl group; or together with the carbon or heteratom to which they are attached may form a cycloalkyl or heterocyclyl group, said carbonyl, cycloalkyl or heterocyclyl group may be substituted with up to four groups independently selected from halogen, hydroxyl, nitro, cyano, alkyl, haloalkyl, halogen, alkyl, nitro, cyano, OR 3 , S(0) m R 3 , NR 3 R 4 , OC(0)R 3 , NR 3 (CO)OR 4 , C(0)R 3 , COOR 3 , CONR 3 R 4 ,
  • R 3 , R 4 are independently selected from hydrogen, alkyl, haloalkyl or a substituted or unsubstituted carbocyclic group selected from cycloalkyl, cycloalkenyl, heterocyclyl, aryl, and heteroaryl, wherein the said alkyl, or a substituted carbocyclic group may be substituted with up to 4 groups selected from halogen, hydroxyl, nitro, cyano, alkyl, haloalkyl, alkyloxy, carboxy, COOH, CONH2, NHCOCH3, N(CH 3 ) 2 , NHCH3, thiomethyl, thioethyl, SOCH3, SO2CH3;
  • R 3 and R 4 together with the carbon atom or heteroatom to which they are attached may form a cycloalkyl or heterocyclyl group substituted with up to four groups independently selected from halogen, hydroxyl, nitro, cyano, alkyl, haloalkyl, alkyloxy, formyl, carboxy, acetyl, CH 2 NH2 > CH 2 OH, COOH, CONH2, NHCOCH3, N(CH3)2, thiomethyl, thioethyl, SOCH3, SO2CH3, alkoxycarbonyl, alkylcarbonyl, alkynylamino, aminoalkyl, aminoalkylcarbonyl, amino, mono- or dialkylamino, or
  • R 3 and R 4 together with the nitrogen to which they are attached may form a heterocyclic ring containing 3-8 members, up to four of which members are optionally carbonyl groups or heteroatoms independently selected from oxygen, sulfur, S(O), S(0)2, and nitrogen, wherein the carbocyclic group is unsubstituted or substituted .with up to four groups independently selected from halogen, hydroxy, hydroxyalkyl, alkyl, haloalkyl, alkoxy, alkoxycarbonyl, alkylcarbonyl, alkynylamino, aminoalkyl, aminoalkylcarbonyl, amino, mono- or dialkylamino.
  • Rl in compounds according to Formula I is aryl.
  • R ⁇ is selected from an unsubstituted aryl ring or an aryl ring substituted with up to 3 substituents selected from the group consisting of halogen, haloalkyl, alkoxy, hydroxyl, nitro or NR 3 R 4 .
  • Rl is an aryl ring substituted with up to 2 halogens or alkoxy groups.
  • Another preferred embodiment of the present invention comprises compounds according to Formula I in which R ⁇ is selected from Me and I.
  • R 9 in compounds according to Formula I is a hydrogen, hydroxyl, halogen or N ⁇ C ⁇ O group.
  • R 9 in compounds according to Formula I is a hydroxyl group.
  • R 9 in compounds according to Formula I is a fluorine group.
  • R9 is hydroxyl and R 1 is aryl, such as but not limited to:
  • R 9 is Rl is aryl and ⁇ l is NR*0 such as, but not limited to, compounds selected from the group consisting of:
  • Another especially preferred embodiment of the present invention comprises compounds according to Formula I in which R 9 is hydrogen and R 8 is ((CR 5 R ⁇ ) n T) a (CRl 1
  • R 12 b)-Z; wherein T may be absent or O and Z is NR 3 R 4 .
  • Another especially preferred embodiment of the present invention comprises compounds according to Formula I in which R 9 is selected from halogen or hydroxyl and R 8 is ((CR 5 R 6 ) n T) a (CR 1 ! R 12 )b)Z wherein T is absent and Z is hydrogen.
  • halogen and halo refer to fluorine, chlorine, bromine and iodine.
  • unsaturated ring includes partially unsaturated and aromatic rings.
  • alkyl in the present invention means a straight or branched hydrocarbon radical having from 1 to 8 carbon atoms and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec -butyl, isobutyl, tert-butyl, n-pentyl, iso-pentyl, n-hexyl, and the like.
  • aryl means an aromatic carbocyclic group having a single ring (e.g., phenyl), multiple rings (e.g., biphenyl), or multiple condensed rings in which at least one is aromatic, (e.g., 1,2,3,4-tetrahydronaphthyl, naphthyl, anthryl, or phenanthryl).
  • heteroaryl means an aromatic “heterocycle,” “heterocyclic,” “heterocyclyl,” or “heterocyclo” group as defined below that comprises at least one heteroatom.
  • the aryl or heteroaryl ring may be optionally substituted with up to five substituents selected from NH(C ⁇ -Cg alkyl), N(C ⁇ -C ⁇ alkyl)2, thio Ci -Cg alkyl, Ci -Cg alkoxy, hydroxy, carboxy, C ⁇ -C( ) alkoxycarbonyl, halo, nitrile, and cycloalkyl.
  • alkoxy is meant straight or branched chain alkoxy groups having 1 to 10 carbon atoms, such as, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentyloxy, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy.
  • Alkynyl means straight and branched hydrocarbon radicals having from 2 to 8 carbon atoms and one triple bond and includes ethynyl, 3-butyn-l-yl, propynyl, 2-butyn- 1-yl, 3-pentyn-l-yl, and the like.
  • cycloalkyl and “cycloalkenyl” refer to cyclic hydrocarbon groups of 3 to 8 carbon atoms and includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
  • acyl means an alkyl, aryl, cycloalkyl, heterocycle, heterocyclic, heterocyclyl, or heterocyclo group bonded through a carbonyl group, i.e., R-C(O)-.
  • Typical acyl groups include acetyl, benzoyl, and the like having from 1-10 carbon atoms, preferably 1-6 carbon atoms.
  • haloalkyl means an akyl group substituted with 1 to 6 halogen atoms and include trifluoromethyl, trichloromethyl, tribromomethyl, trifluoroethyl, trifluoropropyl, trifluorobutyl , pentafluoroethyl and the like.
  • alkyl, alkenyl, alkoxy, and alkynyl groups described above are optionally substituted, preferably by 1 to 3 groups selected from NH(C ⁇ -Cg alkyl), N(C ⁇ -Cg alkyl)2, phenyl, substituted phenyl, thio Cj-Cg alkyl, C ⁇ -Cg alkoxy, hydroxy, carboxy, Ci -Cg alkoxycarbonyl, halo, nitrile, cycloalkyl, and a 5- or 6-membered carbocyclic ring or heterocyclic ring having 1 or 2 heteroatoms selected from nitrogen, substituted nitrogen, oxygen, and sulfur.
  • "Substituted nitrogen” means nitrogen bearing Ci -C ⁇ alkyl or (CH2)pPh where p is 1, 2, or 3. Perhalo and polyhalo substitution is also included.
  • heteroatom means an oxygen, nitrogen, sulfur, or phosphorous atom.
  • heterocycle refers to fully saturated or unsaturated, including aromatic (heteroaryl) or nonaromatic cyclic groups, for example, 4- to 7-membered monocyclic, 7- to 11 -membered bicyclic, or 10- to 15-membered tricyclic ring systems, which have at least one heteroatom in at least one carbon atom-containing ring.
  • Each ring of the heterocyclic group containing a heteroatom may have 1, 2, 3, or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and/or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized.
  • the heterocyclic group may be attached at any heteroatom or carbon atom of the ring or ring system.
  • Monocyclic heterocyclic groups include, but are not limited to, piperidine, 2,6- dimethylpiperazine, piperazine, n-methylpiperazine, pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, S(0)-imidazoles, S(0)2-imidazoles oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, mo ⁇ holine and dimethylmo ⁇ oline, 2-thiophene, thiophene, 1 -imidazole, 2- imidazole, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-ox
  • Bicyclic heterocyclic groups include , but are not limited to, indolyl, benzothiazolyl, benzoxazolyl, benzodioxolyl, benzothienyl, quinuclidinyl, quinolinyl, tetra-hydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofaryl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl,furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,2-b]pyridinyl or furo[2,3-blpyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such as 3,4- dihydro-4-oxo-quin
  • cancer includes, but is not limited to, the following cancers: cancers of the breast, ovary, cervix, prostate, testis, esophagus, stomach, skin, lung, bone, colon, pancreas, thyroid, biliary passages, buccal cavity and pharynx (oral), lip, tongue, mouth, pharynx, small intestine, colon-rectum, large intestine, rectum, brain and central nervous system, glioblastoma, neuroblastoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, adenocarcinoma, adenoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder carcinoma, liver carcinoma , kidney carcinoma, myeloid disorders, lymphoid disorders, Hodgkin's, hairy cells, and leukemia.
  • salts refers to those carboxylate salts, amino acid addition salts, esters, amides, and prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention.
  • salts refers to the relatively non- toxic, inorganic and organic acid addition salts of compounds of the present invention.
  • salts can be prepared in situ during the final isolation and purification of the compounds or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed.
  • Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate mesylate, glucoheptonate, lactobionate and laurylsulphonate salts, and the like.
  • alkali and alkaline earth metals such as sodium, lithium, potassium, calcium, magnesium and the like
  • non-toxic ammonium, quaternary ammonium, and amine cations including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.
  • ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like See, for example, Berge S.M. et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977;66:1-19 which is inco ⁇ orated herein by reference.)
  • the compounds of Formula I are capable of further forming pharmaceutically acceptable formulations comprising salts, including but not limited to acid addition and/or base salts, solvates and N-oxides of a compound of Formula I.
  • This invention also provides pharmaceutical formulations comprising a compound of Formula I together with a pharmaceutically acceptable carrier, diluent, or excipient therefor. All of these forms are within the present invention.
  • Pharmaceutically acceptable acid addition salts of the compounds of Formula I include salts derived form inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic, phosphorus, and the like, as well as the salts derived from organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc.
  • inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic, phosphorus, and the like
  • organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc.
  • Such salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like.
  • salts of amino acids such as arginate, gluconate, galacturonate, and the like; see, for example, Berge et al., "Pharmaceutical Salts,” J. of Pharmaceutical Science, 1977;66:1-19.
  • the acid addition salts of the basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt in the conventional manner.
  • the free base form may be regenerated by contacting the salt form with a base and isolating the free base in the conventional manner.
  • the free base forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free base for pu ⁇ oses of the present invention.
  • Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metal hydroxides, or of organic amines.
  • metals used as cations are sodium, potassium, magnesium, calcium, and the like.
  • suitable amines are N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine, and procaine; see, for example, Berge et al., supra., 1977.
  • the base addition salts of acidic compounds are prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt in the conventional manner.
  • the free acid form may be regenerated by contacting the salt form with an acid and isolating the free acid in a conventional manner.
  • the free acid forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free acid for pu ⁇ oses of the present invention.
  • esters of the compounds of this invention include Ci -C ⁇ alkyl esters wherein the alkyl group is a straight or branched chain. Acceptable esters also include C5-C7 cycloalkyl esters as well as arylalkyl esters such as, but not limited to benzyl. C1-C4 alkyl esters are preferred. Esters of the compounds of the present invention may be prepared according to conventional methods "March's Advanced
  • Examples of pharmaceutically acceptable, non-toxic amides of the compounds of this invention include amides derived from ammonia, primary Ci -Cg alkyl amines and secondary
  • Ci -C 5 dialkyl amines wherein the alkyl groups are straight or branched chain.
  • the amine may also be in the form of a 5- or 6-membered heterocycle containing one nitrogen atom.
  • Amides derived from ammonia, C1 -C3 alkyl primary amines and Ci -C2 dialkyl secondary amines are preferred. Amides of the compounds of the invention may be prepared according to conventional methods such as "March's Advanced
  • prodrug refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formulae, for example, by hydrolysis in blood.
  • a thorough discussion is provided in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems,” Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are hereby inco ⁇ orated by reference.
  • the present invention also includes isotopically labelled compounds, which are identical to those recited in Formula I, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be inco ⁇ orated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine and chlorine, such as 2 H, 3 H, 13 C, n C, 14 C, 15 N, 18 0, 17 0, 31 P, P, S, F, and Cl, respectively.
  • Compounds of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention.
  • Certain isotopically labelled compounds of the present invention, for example those into which radioactive isotopes such as H and C are inco ⁇ orated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability.
  • Isotopically labelled compounds of Formula I of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples and Preparations below, by substituting a readily available isotopically labelled reagent for a non- isotopically labelled reagent.
  • the compounds of Formula I and their pharmaceutically acceptable salts can be administered to mammals via either the oral, parenteral (such as subcutaneous, intraveneous, intramuscular, intrasternal and infusion techniques), rectal, intranasal or topical routes.
  • these compounds are most desirably administered in doses ranging from about 10 to about 10,000 mg per day, in single or divided doses (i.e., from 1 to 4 doses per day), although variations will necessarily occur depending upon the species, weight and condition of the subject being treated and the particular route of administration chosen.
  • a dosage level that is in the range of about 0.15 mg to about 150 mg per kg of body weight per day is most desirably employed.
  • dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effects, provided that such higher dose levels are first divided into several small doses for administration throughout the day.
  • the compounds of the present invention may be administered alone or in combination with pharmaceutically acceptable carriers or diluents by either of the routes previously indicated, and such administration may be carried out in single or multiple doses. More particularly, the novel therapeutic agents of this invention can be administered in a wide variety of different dosage forms, e., they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, sprays, creams, salves, suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, and the like.
  • Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc.
  • oral pharmaceutical compositions can be suitably sweetened and/or flavored.
  • the therapeutically-effective compounds of this invention are present in such dosage forms at concentration levels ranging from about 5.0% to about 70% by weight.
  • tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine may be employed along with various disintegrants such as starch (and preferably corn, potato or tapioca starch), alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia.
  • disintegrants such as starch (and preferably corn, potato or tapioca starch), alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia.
  • lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting pu ⁇ oses.
  • compositions of a similar type may also be employed as fillers in gelatin capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols.
  • preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols.
  • the active ingredient may be combined with various sweetening or flavoring agents, coloring matter or dyes, and, if so desired, emulsifying and/or suspending agents as well, together with such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.
  • solutions of a compound of the present invention in either sesame or peanut oil or in aqueous propylene glycol may be employed.
  • the aqueous solutions should be suitably buffered (preferably pH from about 3 to about 8) if necessary and the liquid diluent first rendered isotonic.
  • These aqueous solutions are suitable for intravenous injection pu ⁇ oses.
  • the oily solutions are suitable for intra-articular, intramuscular and subcutaneous injection pu ⁇ oses. The preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.
  • the activity of the compounds of the present invention is determined by their ability to act as check point abrogators.
  • Checkpoint abrogators inhibit kinases involved in the regulation of the G2 M checkpoint resulting in the reversal of the imposed checkpoint.
  • Weel or Chkl are examples of such kinases.
  • Utilization in cells either having damaged DNA, for instance, but not limited to, DNA damaged by conventional DNA-directed chemotherapeutic agents or by radiation of cells with undamaged DNA presents an opportunity to utilize cellular regulatory pathways to inappropriately and prematurely cause cells to progress into M phase. Such cells may be less likely to survive and further divide since the commitment to M phase was made in the presence of potentially catastrophically damaged DNA.
  • checkpoint abrogators of the present invention by measuring the activity in the assays described in Examples 483 (Weel) and 484 (Chkl) and 486 (PKC) and selecting those compounds that have at least 10- fold less activity in the PKC assay than they have in the Weel assay or at least 5-fold less activity in the PKC assay than they have in the Chkl assay.
  • the compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms.
  • the solvated forms, including hydrated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention.
  • animal refers to mammals, including rodents, bovine, equine, canine, feline, and human.
  • the compounds of the present invention are useful for treating cancer (for example, leukemia and cancer of the lung, breast, prostate, and skin such as melanoma) and other proliferative diseases including but not limited to psoriasis, HSV, HIV, restenosis, and atherosclerosis in combination with other conventional therapies.
  • cancer for example, leukemia and cancer of the lung, breast, prostate, and skin such as melanoma
  • other proliferative diseases including but not limited to psoriasis, HSV, HIV, restenosis, and atherosclerosis
  • cancer for example, leukemia and cancer of the lung, breast, prostate, and skin such as melanoma
  • other proliferative diseases including but not limited to psoriasis, HSV, HIV, restenosis, and atherosclerosis
  • a patient in need of such treatment such as one having cancer or another cell proliferative diseases is administered an effective amount of the compound of the invention.
  • the compounds of the present invention are useful for treating cancers when combined as adjuvant therapy with other clinical treatment agents and modalities such as, but not limited to, X-irradiation, beam therapy, conventional chemotherapeutic agents such as gemcitabine, paclitaxel, docetaxel, cisplatin, carboplatin, etoposide, adriamycin, topotecan, CPT-11, capecitabine, or ionizing radiation alkylating agents, antimetabolites, antibodies, DNA intercalators, or other such anti-proliferative agents ultimately leading to DNA damage.
  • chemotherapeutic agents such as gemcitabine, paclitaxel, docetaxel, cisplatin, carboplatin, etoposide, adriamycin, topotecan, CPT-11, capecitabine, or ionizing radiation alkylating agents, antimetabolites, antibodies, DNA intercalators, or other such anti-proliferative agents ultimately leading to DNA damage.
  • transformations include, but are not limited to; alkylation, dealkylation, oxidation, reduction, Curtus rearrangement, Suzuki reaction, esterification, Wittig reaction, amide formation, hydrogenation, protection, deprotection, hydrolysis, dihydroxylation., ozonolysis, acetylation, and hydroboration.
  • Benzyl (triphenylphosphoranylidene)acetate (49.2 g, 0.120 mol) was added to a stirred solution of 5-methoxy-lH-indole-2-carbaldehyde (1) (20.0 g, 0.114 mol) in CH 2 C1 2 (500 mL) and the solution was stirred at room temperature for 4 h. The solvent was removed in vacuo and the residue slurried with methanol (200 mL), whereupon crystallisation of the product occurred.
  • Activated manganese dioxide (69 g) was added to a solution of benzyl 9-methoxy- l,3-dioxo-l,2,3,3a,4,5,6,10c-octahydropyrrolo[3,4-c]carbazole-4-carboxylate (13.76 g, 0.034 mol), prepared as in example 2, in p-dioxane (300 mL) and the mixture was refluxed with vigorous stirring for 0.5-2 h. The mixture was filtered while hot through a plug of Celite, which was washed exhaustively with a MeOH/p-dioxane (1:1) mixture until the washings were colorless.
  • Diphenylphosphoryl azide (1.81 mL, 8.38 mmol) was added to a mixture of the 9- methoxy-l,3-dioxo-l,2,3,6-tetrahydropyrrolo[3,4-c]carbazole-4-carboxylic acid (2.55 g, 8.22 mmol), prepared as in example 4 , and Et 3 N (1.17 mL, 8.38 mmol) in anhydrous t-butanol (300 mL) and the mixture was refluxed under an atmosphere of nitrogen for 16 h. The solution was concentrated in vacuo and the residue partitioned between EtOAc and saturated aqueous NaHC0 3 .
  • Powdered 4-Iodo-9-methoxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione (0.50 g, 1.27 mmol) prepared as in example 6 was added in one portion to dry, freshly-prepared pyridine hydrochloride melt at 200 °C under a CaCl 2 drying tube and the mixture was stirred at this temperature for 15 min. Water was added and the mixture was extracted with EtOAc. The EtOAc extracts were dried, the drying agent was removed and the solution was concentrated to dryness to give a solid which was chromatographed on silica.
  • Lithium diisopropyl amide (34.4 mL of a 1.5 N solution, 0.052 mol) was added dropwise under nitrogen to a suspension of benzyl(triphenyl)phosphonium chloride (20.17 g, 0.048 mol) in dry THF (200 mL) and the solution was stirred at room temperature for 15 min.
  • a solution of the 5-methoxy-lH-indole-2-carbaldehyde (1) (6.99 g, 0.040 mol) in THF (30 mL) was added and stirring was continued at room temperature for 15 min and then the reaction mixture was heated at reflux for 6 h.
  • Aromatisation of the Diels-Alder adduct using the procedure described in example 70 gave crude material that was then dissolved in methanol (100 mL) to which 2N potassium hydroxide (2 mL) was added. This solution was stirred at rt for 2h before being diluted with water and acidified by the addition of IN hydrochloric acid to precipitate the product as a yellow solid, which was collected by filtration and washed with water before being dried in vacuo. Chromatography on silica eluting with ethyl acetate followed by trituration with diethyl ether/hexane, gave acid (262) as a yellow powder (0.10 g, 16%), mp 251-254 °C.
  • trans-diene (27) prepared as described in example 37 (1.5 g, 5.25 mmol) in acetonitrile (30 mL) was added acrylonitrile (2.42 mL, 36.8 mmol) and 1,8- diazabicyclo[5.4.0]undec-7-ene (20 drops).
  • acrylonitrile (2.42 mL, 36.8 mmol) 1,8- diazabicyclo[5.4.0]undec-7-ene (20 drops).
  • the resulting solution was stirred at room temperature under nitrogen for 18 h before being diluted with water and extracted with ethyl acetate. The organic layer was dried, the drying agent was removed and the solution was concentrated to dryness.
  • Diene (236) (1.30 g, 3.86 mmol) prepared as described in example 96 was reacted with maleimide (0.49 g) following The procedure described in example 68 and then aromatized according to the procedure described in example 70 to give crude material that was chromatographed on silica eluting with ethyl acetate/hexane (1:1). Trituration from methanol gave nitrile (237) (1.33 g, 80%) as a yellow powder, mp 287-288 °C.
  • the 5-methoxy-lH-indole-2-carbaldehyde (1) was reacted with (2,6- dichlorobenzyl)(triphenyl)phosphonium bromide (511) prepared as described in example 102 using the procedure described in example 37, except that the LDA and aldehyde were (sequentially) added at 0 °C, the ratio of LDA: aldehyde was 1.37:1 and the reaction time was 5 h, to give (after crystallisation from CH 2 Cl 2 /hexane) the diene (512) as a yellow solid (the pure E isomer) (97 %), mp 144-147 °C.
  • the pure E diene (512) prepared as described in example 103 was reacted with maleimide according to the procedure described in example 68 in a foil-covered sealed vial, except that the ratio of diene:maleimide:SnCl 2 was 1:4:0.075 and the reaction time was 3 h, to give a crude solid containing the adduct (513), which was used without further purification.
  • the crude adduct (513) prepared as described in example 104 was aromatised with DDQ (5 equiv.) using the procedure described in example 70, except that the solvent was 1:1 toluene/dioxane and the reaction time was 48 h, to give (after crystallisation from MeOH/CH 2 Cl 2 /hexane) the product (514) (78 %) as a yellow crystalline solid, mp 299-301 °C.
  • the methyl ether (514) prepared as described in example 105 was demethylated with BBr 3 using the procedure described in example 80 to give (after crystallisation from MeOH/CH 2 Cl 2 /hexane) the phenol (515) (98 %) as an orange solid, mp 205-215 °C (dec).
  • the 5-methoxy-lH-indole-2-carbaldehyde (1) was reacted with (2,6- dibromobenzyl)(triphenyl)phosphonium bromide (516) prepared as described in example 107 using the procedure described in example 37, except that the ratio of LDA: aldehyde was 1.37:1 and the reaction time was 5 h, to give (after crystallisation from CH 2 Cl 2 /hexane) the diene (517) as a yellow solid (the pure E isomer) (80 %), mp 140-141 °C.
  • the pure E diene (517) prepared as described in example 108 was reacted with maleimide according to the procedure described in example 68 in a foil-covered sealed vial, except that the ratio of diene:maleimide:SnCl 2 was 1 :5:0.075 and the reaction time was 3.5 h, to give a crude solid containing the adduct (518), which was used without further purification.
  • the crude adduct (518) prepared as described in example 109 was aromatised with DDQ (5 equiv.) using the procedure described in example 70, except that the solvent was 1:1 toluene/dioxane and the reaction time was 24 h, to give (after crystallisation from MeOH/CH 2 Cl 2 /hexane) the product (519) (68 %) as an orange crystalline solid, mp 329-331 °C. !
  • the methyl ether (519) prepared as described in example 110 was demethylated with BBr 3 using the procedure described in example 80, except that the reaction time was 1.5 h, to give (after crystallisation from MeOH/CH 2 Cl 2 /EtOAc/hexane) the phenol (520) (98 %) as a yellow-orange solid, mp 180-190 °C (dec).
  • the 5-methoxy-lH-indole-2-carbaldehyde (1) was reacted with (2,6-dichloro-4- methoxybenzyl)(triphenyl)phosphonium bromide (521), prepared as described in example 112, using the procedure described in example 37, except that the aldehyde was added at 0 °C, the ratio of LDA: aldehyde was 1.37:1 and the reaction time was 5 h, to give (after crystallisation from CH 2 Cl 2 /hexane) the diene (522) as a cream solid (the pure E isomer) (70 %), mp 128-129 °C.
  • the pure E diene (522) prepared as described in example 113 was reacted with maleimide according to the procedure described in example 68 in a foil-covered sealed vial, except that the ratio of diene:maleimide:SnCl 2 was 1:6:0.05 and the reaction time was 1.5 h, to give a crude solid containing the adduct (523), which was used without further purification.
  • the crude adduct (523) prepared as described in example 114 was aromatised with DDQ (6 equiv.) using the procedure described in example 70, except that the solvent was 1:1 toluene/dioxane and the reaction time was 24 h, to give (after crystallisation from MeOH/CH 2 Cl 2 /hexane) the product (524) (74 %) as a yellow-orange crystalline solid, mp 272-274 °C.
  • the methyl ether (524) prepared as described in example 115 was bis-demethylated with BBr 3 using the procedure described in example 80, except that the reaction time was 4 h with 10 equiv. BBr 3 , then a further 9 h with an extra 10 equiv. BBr 3 , to give (after crystallisation from MeOH/CH 2 Cl 2 /hexane) the phenol (525) (95 %) as a yellow-orange solid, mp 300-308 °C.
  • the 5-methoxy-lH-indole-2-carbaldehyde (1) was reacted with (2,6-dichloro-3- methoxybenzy])(triphenyl)phosphonium bromide (526), prepared as described in example 117, using the procedure described in example 37, except that the aldehyde was added at 0 °C, the ratio of LDA: aldehyde was 1.55:1 and the reaction time was 5 h, to give (after crystallisation from CH 2 Cl 2 /hexane) the diene (527) as a cream solid (the pure E isomer) (76 %), mp 138-140 °C.
  • the crude adduct (528) prepared as described in example 119 was aromatised with DDQ (5 equiv.) using the procedure described in example 70, except that the solvent was 1:1 toluene/dioxane and the reaction time was 24 h, to give (after crystallisation from CH 2 Cl 2 /hexane) the product (529) (70 %) as an orange crystalline solid, mp 240-242 °C.
  • the methyl ether (529) prepared as described in example 120 was bis-demethylated with BBr 3 using the procedure described in example 80, except that the reaction time was 6 h with 10 equiv. BBr 3 , to give (after crystallisation from MeOH/CH 2 Cl 2 /hexane) the phenol (530) (91 %) as an orange crystalline solid, mp 313-318 °C.
  • the 5-methoxy-lH-indole-2-carbaldehyde (1) was reacted with (2- bromobenzyl)(triphenyl)phosphonium bromide using the procedure described in example 37, except that the aldehyde was added at 0 °C, the ratio of LDA: aldehyde was 1.46:1 and the reaction time was 5 h, to give (after crystallisation from CT ⁇ Ch/hexane) the diene (531) as a yellow solid (the pure E isomer) (88 %), mp 120-123 °C.
  • the methyl ether (532) prepared as described in example 123 was demethylated with BBr 3 using the procedure described in example 80, except that the reaction time was 4 h. Crystallisation from MeOH/CH 2 Cl 2 /hexane gave the phenol (533) in a yield of 89 % as a yellow-orange solid, mp 244-246 °C.

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Abstract

This invention relates to pyrrolocarbazole derivatives according formula (I) wherein R1, R2, r7, R8 R9, X and Y are as defined in the specification wherein said derivatives specifically inhibit one or both of the checkpoint kinases Wee1 and Chk1.

Description

INHIBITORS OF CHECKPOINT KINASES (Weel and Chkl)
FIELD OF THE INVENTION
This invention relates to small chemical molecules that specifically inhibit one or both of the checkpoint kinases Weel and Chkl.
BACKGROUND OF THE INVENTION
The proper orchestration of the steps required for orderly progression of the cell through the cell cycle requires a number of signaling pathways within cells. Many of these pathways utilize protein kinases to effect the transmission of crucial signals at the appropriate time and intracellular location. Cell cycle kinases are naturally occurring enzymes involved in regulation of the cell cycle which is generally divided into four segments: Gi (gapl), S
(DNA systhesis), G2 (gap 2) and M (mitosis). Some of these kinases are responsible for inhibiting the cell's normal progression through cell division, while others are normally active in promoting the progression of cells through the cell cycle leading to cell division. Increased activity or temporally abnormal activation of these kinases has been shown to result in development of tumors and other proliferative disorders.
One of the protein kinases involved is a tyrosine specific kinase, Weel, that has as its substrate another kinase complex called Cdc2/cyclinB. Weel kinase is a regulatory kinase that has Cdc2/cyclinB as its substrate and when Weel is active, it phosphorylates a specific tyrosine (Tyr 15) on Cdc2 that causes an inactivation of the Cdc2/cyclinB complex which in turn results in a pause or checkpoint in the cell cycle at the G2 and M transition. The kinase activity of Cdc2/cyclinB is absolutely required for cells to progress through the G2 stage of the cell division cycle to the M (or mitotic) phase where two daughter cells are formed from the division of the parent cell. Under normal circumstances, as cells are progressing through the cell cycle, the Cdc2/cyclinB complex is assembled in late S phase and through G2-
Normally, Weel is active and thus phosphorylates the Cdc2/cyclinB complex until the end of G2 when all of the necessary components have been synthesized for the entry of cells into M phase. Weel activity then diminishes, a phosphatase removes the inhibitory phosphorylation from Tyrl5 of Cdc2/cyclinB, the complex becomes activated and cells move into M phase where the replicated DNA is divided and the daughter cells are formed. Inhibition of Weel results in no inhibitory phosphorylation of Tyrl5 on Cdc2/cyclinB and the potentially inappropriate and premature entry of the cell into mitosis.
In addition to regulation of the transition of cells between the different phases of the cell cycle under normal conditions, the cell cycle transitions are regulated in response to damage to DNA presumably giving cells opportunities either to repair potentially genotoxic DNA damage before replication using a damaged DNA template or to permanently exit the cell cycle and die.
Another kinase of interest named Chkl participates in this DNA damage dependent signaling pathway by phosphorylating a phosphatase called Cdc25C which when itself is active and co-localized with Cdc2/cyclinB in the nucleus, dephosphorylates Tyrl5 and causes the activation of the Cdc2/cyclinB complex. The Chkl mediated phosphorylation of Cdc25C causes Cdc25C to be exported from the nucleus at which point it is no longer able to dephosphorylate and thus activate Cdc2/cyclinB. Therefore, if Chkl is active (in response to DNA damage) it will indirectly contribute to the inactivation of Cdc2/cyclinB (whose activity is required for progression into M phase) through the preservation of the inactivating phosphorylation of Tyr 15 on Cdc2/cyclinB. Conversely, inhibition of Chkl would result in the dephosphorylation of Cdc2/cyclinB by the phosphatase Cdc25C in the nucleus (not exported to the cytoplasm since it is not phosphorylated by Chkl) and the consequent activation of Cdc2/cyclinB with the accompanying entry of the cells in mitosis.
Inhibition of Weel or Chkl or both kinases in the presence of DNA damaged by conventional DNA-directed chemotherapeutic agents or by radiation presents an opportunity to utilize cellular regulatory pathways to inappropriately and prematurely cause cells to progress into M phase. Such cells may be less likely to survive and further divide since the commitment to M phase was made in the presence of potentially catastrophically damaged DNA ( Alan J. Kraker and Robert N. Booher, "New Cell Cycle Targets,", Ann. Rep. Med. Chem., 1999;34:247-256).
Small molecule inhibitors of Weel kinase have been reported, WO 0119825 and Cancer Res. (2001), 61(22), 8211-8217. Small molecule inhibitors of Chkl kinase have also been reported W00016781, Cancer Res. (2000), 60(3), 566-572.
Pyrrolocarbazole derivatives are known to have inhibitory activity against Protein kinase c and anti tumor activity (US Patent No. 4,912,107) but compared to the compounds of the present invention, the compounds disclosed in US Patent No. 4,912,107 have very low checkpoint kinase abrogator activity. Pyrrolocarbazole derivatives are also known to stimulate platelet production (WO96/28447) and to promote thrombopoiesis (WO9809967). EP 0695755 discloses another pyrrolocarbazole derivative having Protein kinase c activity. US Patent No. 5,166,204 discloses antitumor isoindole derivatives having a linkage or lower alkylene group bonded to the 2 and 3 or 3 and 4 of a carbazole skeleton. US Patent No. 5,728,709 discloses pyrrolocarbazole derivatives that stimulate platelet production. WO 01/85686 also discloses pyrrolocarbazole derivatives.
However, there are no reports that any type of pyrrolocarbazole inhibits either Weel kinase or Chkl kinase. Nor have there been any reports that any type of pyrrolocarbazole inhibits both Weel kinase and Chkl kinase.
SUMMARY OF THE INVENTION
Compounds claimed are of the general structure described by Formula I
Figure imgf000004_0001
Wherein
Each dashed line represents an optional bond;
R1 is hydrogen, halogen, d - Cg alkyl, NR5R6 or an aryl or heteroaryl ring optionally substituted with up to five substituents selected from halogen, alkyl, haloalkyl, hydroxyl, nitro, cyano, C(O)R3, OR3, S(0)mR3, NR3R4,
OC(0)R3, NR (CO)OR4, CH2NR3R4, CH2OR3, COOR3, CONR3R4, NR3COR4
SO NR3R4 CONHSO2R3, NR S(O)mR4, NHCONR3R4, NR3CONHR4; or a cycloalkyl or cycloalkenyl ring optionally substituted with up to five substituents selected from, halogen, alkyl, haloalkyl, hydroxyl, nitro, cyano, C(O)R3, OR3, S(O)mR3, NR3R4 OC(O)R3, NR3(CO)OR4, CH2NR3R4 CH2OR3, COOR3, CONR R4, NR3COR4, S02NR3R4 CONHSO2R3, NR3S(0)mR4, NHCONR R4, NR3CONHR4; or
a heterocyclic ring optionally substituted with up to five substituents selected from, halogen, alkyl, haloalkyl, hydroxyl, nitro, cyano, C(0)R3, OR3, S(O)mR3, NR3R4,
OC(0)R3, NR3(CO)OR4, CH2NR R4, CH2OR3, COOR3, CONR R4, NR3COR4,
S02NR R4, CONHS02R3, NR S(0)mR4, NHCONR R4, NR3CONHR4;
m is 0-2;
X is hydrogen or halogen;
Yl is O, S(0)m, or NR1";
R9 is hydrogen, hydroxyl, halogen, NR3C(0)R4 NHCONR3R4, (C=NR3)NHR4, NH(C=NR3)NHR4, NH(C=NH)NR R4, NH(C=0)0 R3, NR5R6, (CR5R6)rZ;
r is 0-6;
R2, R7, R8 and R10 are in each instance independently selected from ((CR5 R6)nT)a(CRn R 12)b)-Z wherein the sum of n, a and b is in each instance less than 10;
T may be absent, or, when present, is in each instance independently selected from O, CONR3, CONHSO , S(0)m, NR3, NR30, OS(0)ra, S(0)mO, NR3S(O)2, or S(0)2NR3;
n is in each instance independently 0-6; a is in each instance independently 0-6; b is in each instance independently 0-6; Z is selected from hydrogen, halogen, alkyl, haloalkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, cyano, nitro, hydroxy, C(0)R3, CONHSO2R3, OR3, S(0)mR3, OS0 R3, NR3R4 C02R3, CONR3 R4 NR3COR4, S02NR3R4, OPO(OR3)(OR4), CH=CR R4, CCR3, (C=NR3)NH R4, NH(C=NR3)NHR4, NH(C=NH)NR3R4, wherein the alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl group may be substituted with up to four groups independently selected from halogen, alkyl, hydroxyl, nitro, cyano, OR3, S(0)mR3, NR3R4, OC(0)R3, NR3(CO)OR4, C(0)R3, COOR3, CONR R4, NR3COR4, SO2NR3R4, CONHS02R3, NR3S(0)mR4, CH2NR3R4, CH2OR3 NHC0NR3R4, NR3CONHR4;
R5, R^, Rl 1 and Rl2 are in each instance independently selected from hydrogen, hydroxyl, alkyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, halogen, cyano, nitro, CH2NR3R4 CH OR3, C(0)R3, OR3, S(0)mR3, NR R4 COOR3, CONR3R4, S02NR R4 , NHCONR3R4, NR3CONHR4; wherein the alkyl, haloalkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl group may be substituted with up to four groups independently selected from halogen, alkyl, hydroxyl, nitro, cyano, OR3, S(0)mR3, NR3R4, OC(0)R3, NR3(CO)OR4, C(0)R3, COOR3, CONR3R4 NR COR4 S0 NR R4 CONHS02R3, NR3S(0)mR4, NHCONR3R4, NR3CONHR4;
R5 and R" or Rl * and Rl2 together with the carbon atom to which they are attached may form a carbonyl group; or together with the carbon or heteratom to which they are attached may form a cycloalkyl or heterocyclyl group, said carbonyl, cycloalkyl or heterocyclyl group may be substituted with up to four groups independently selected from halogen, hydroxyl, nitro, cyano, alkyl, haloalkyl, halogen, alkyl, nitro, cyano,
OR3, S(0)mR3, NR3R4, OC(0)R3, NR (CO)OR4, C(0)R3, COOR3, CONR R4, NR COR4, S02NR3R4, CONHSO2R3, NR3S(0)mR4, NHCONR R4, NR CONHR4;
R3, R4 are independently selected from hydrogen, alkyl, haloalkyl or a substituted or unsubstituted carbocyclic group selected from cycloalkyl, cycloalkenyl, heterocyclyl, aryl, and heteroaryl, wherein the said alkyl, or a substituted carbocyclic group may be substituted with up to 4 groups selected from halogen, hydroxyl, nitro, cyano, alkyl, haloalkyl, alkyloxy, carboxy, COOH, CONH2, NHCOCH3, N(CH3)2, NHCH3, thiomethyl, thioethyl, SOCH3, SO2CH3;
R3 and R4 together with the carbon atom or heteroatom to which they are attached may form a cycloalkyl or heterocyclyl group substituted with up to four groups independently selected from halogen, hydroxyl, nitro, cyano, alkyl, haloalkyl, alkyloxy, foπnyl, carboxy, acetyl, CH2NH2, CH2OH, COOH, CONH2, NHCOCH3, N(CH3)2, thiomethyl, thioethyl, SOCH3, SO2CH3, alkoxycarbonyl, alkylcarbonyl, alkynylamino, aminoalkyl, aminoalkylcarbonyl, amino, mono- or dialkylamino, or
R3 and R4 together with the nitrogen to which they are attached may form a heterocyclic ring containing 3-8 members, up to four of which members are optionally carbonyl groups or heteroatoms independently selected from oxygen, sulfur, S(O), S(0)2, and nitrogen, wherein the carbocyclic group is unsubstituted or substituted with up to four groups independently selected from halogen, hydroxy, hydroxyalkyl, alkyl, haloalkyl, alkoxy, alkoxycarbonyl, alkylcarbonyl, alkynylamino, aminoalkyl, aminoalkylcarbonyl, amino, mono- or dialkylamino.
Unless the context clearly requires otherwise, throughout the description and the claims, the words "comprise", "comprising", and the like are to be construed in an inclusive sense as opposed to an exclusive or exhaustive sense; that is to say, in the sense of "including, but not limited to".
DESCRIPTION OF THE FIGURES
Figure 1 represents a Western blot of tumor cells treated in vivo with cisplatin and the Compound of Example 80.
Figure 2 represent a Western Blot of cells treated in vitro with Adriamycin and the Compound of Example 80
Figure 3 represents a Western blot of tumor cells treated in vivo with cpt-11 and the Compound of Example 362. Figure 4 represents a graph of life span enhancement in animals treated with the Compound of Example 80
DETAILED DESCRIPTION OF THE INVENTION Compounds of the present invention are of the general structure described by Formula
Figure imgf000008_0001
Wherein
Each dashed line represents an optional bond;
R1 is hydrogen, halogen, - Cg alkyl; NR5R6 or an aryl or heteroaryl ring optionally substituted with up to five substituents selected from halogen, alkyl, haloalkyl, hydroxyl, nitro, cyano, C(0)R3, OR3, S(0)mR3, NR3R4,
OC(0)R3, NR3(CO)OR4, CH2NR R4, CH2OR3, COOR3, CONR R4, NR3COR4,
S02NR R4, CONHS02R3, NR3S(0)mR4, NHCONR3R4, NR CONHR4; or a cycloalkyl or cycloalkenyl ring optionally substituted with up to five substituents selected from, halogen, alkyl, haloalkyl, hydroxyl, nitro, cyano, C(0)R3, OR3, S(0)mR3,
NR3R4, OC(0)R3, NR (CO)OR4, CH2NR3R4, CH2OR3, COOR3, C0NR3R4, NR COR4,
S02NR3R4, CONHS02R3, NR S(0)mR4, NHCONR3R4, NR3CONHR4; or a heterocyclic ring optionally substituted with up to five substituents selected from, halogen, alkyl, haloalkyl, hydroxyl, nitro, cyano, C(0)R3, OR3, S(0)mR3, NR3R4 OC(0)R3, NR3(CO)OR4, CH2NR3R4, CH2OR3, COOR3, CONR3R4, NR3COR4,
S02NR3R4, CONHS02R3, NR3S(0)mR4 NHCONR3R4, NR3CONHR4;
m is 0-2;
X is hydrogen or halogen;
Y1 is O, S(0)m, or NR10;
R9 is hydrogen, hydroxyl, halogen, NR3C(0)R4, NHCONR3R4, (C=NR )NHR4, NH(C=N R )NH R4 NH(C=NH)N R3 R4, NH(C=0)0 R3, NR R6, (CR5R6)r-Z;
r is 0-6;
R2, R7, R8 and R10 are in each instance independently selected from ((CR5 R6)nT)a(CR1 1 Rl2)^)-Z wherein the sum of n, a and b is in each instance less than 10;
T may be absent, or, when present, is in each instance independently selected from O,
CONR3, CONHS02> S(0)m, NR3, NR3-0, 0-S(0)m, S(0)m-0, NR3-S(0)2, or S(0)2-NR3;
n is in each instance independently 0-6; a is in each instance independently 0-6; b is in each instance independently 0-6;
Z is selected from hydrogen, halogen, alkyl, haloalkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, cyano, nitro, hydroxy, C(0)R3, CONHS02R3, OR3, S(0)mR3
,OS02R3, NR3R4, C02R3, CONR R4, NR3COR4, S02NR3R4 OPO(OR3)(OR4),
CH=CR3R4, CCR3, (C=NR3)NHR4, NH(C=NR3)NHR4, NH(C=NH)NR3R4, wherein the alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl group may be substituted with up to four groups independently selected from halogen, alkyl, hydroxyl, nitro, cyano, OR3, S(0)mR3, NR3R4 OC(0)R3, NR3(CO)OR4 C(0)R3,
COOR3, CONR R4, NR COR4 S02NR3R4, CONHS02R3, NR3S(0)mR4,
CH NR3R4, CH20R3 NHCONR3R4, NR3CONHR4; R5, R6, Rl 1 and R12 are in each instance independently selected from hydrogen, hydroxyl, alkyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, halogen, cyano, nitro, CH2NR3R4 CH2OR3, C(0)R3, OR3, S(0)mR3, NR3R4 COOR3, CONR3R4 S02NR3R4 , NHCONR R4, NR3CONHR4; wherein the alkyl, haloalkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl group may be substituted with up to four groups independently selected from halogen, alkyl, hydroxyl, nitro, cyano, OR3, S(0)mR3, NR3R4, OC(0)R3, NR3(CO)OR4 C(0)R3, COOR3, CONR R4 NR3COR4, S02NR3R4, CONHS02R3, NR3S(0)mR4, NHCONR3R4 NR3CONHR4;
R5 and R" or Rl 1 and R*2 together with the carbon atom to which they are attached may form a carbonyl group; or together with the carbon or heteratom to which they are attached may form a cycloalkyl or heterocyclyl group, said carbonyl, cycloalkyl or heterocyclyl group may be substituted with up to four groups independently selected from halogen, hydroxyl, nitro, cyano, alkyl, haloalkyl, halogen, alkyl, nitro, cyano, OR3, S(0)mR3, NR3R4, OC(0)R3, NR3(CO)OR4, C(0)R3, COOR3, CONR3R4,
NR3COR4, S02NR3R4 CONHS02R3, NR3S(0)mR4, NHCONR3R4,
NR3CONHR4;
R3, R4 are independently selected from hydrogen, alkyl, haloalkyl or a substituted or unsubstituted carbocyclic group selected from cycloalkyl, cycloalkenyl, heterocyclyl, aryl, and heteroaryl, wherein the said alkyl, or a substituted carbocyclic group may be substituted with up to 4 groups selected from halogen, hydroxyl, nitro, cyano, alkyl, haloalkyl, alkyloxy, carboxy, COOH, CONH2, NHCOCH3, N(CH3)2, NHCH3, thiomethyl, thioethyl, SOCH3, SO2CH3;
R3 and R4 together with the carbon atom or heteroatom to which they are attached may form a cycloalkyl or heterocyclyl group substituted with up to four groups independently selected from halogen, hydroxyl, nitro, cyano, alkyl, haloalkyl, alkyloxy, formyl, carboxy, acetyl, CH2NH2> CH2OH, COOH, CONH2, NHCOCH3, N(CH3)2, thiomethyl, thioethyl, SOCH3, SO2CH3, alkoxycarbonyl, alkylcarbonyl, alkynylamino, aminoalkyl, aminoalkylcarbonyl, amino, mono- or dialkylamino, or
R3 and R4 together with the nitrogen to which they are attached may form a heterocyclic ring containing 3-8 members, up to four of which members are optionally carbonyl groups or heteroatoms independently selected from oxygen, sulfur, S(O), S(0)2, and nitrogen, wherein the carbocyclic group is unsubstituted or substituted .with up to four groups independently selected from halogen, hydroxy, hydroxyalkyl, alkyl, haloalkyl, alkoxy, alkoxycarbonyl, alkylcarbonyl, alkynylamino, aminoalkyl, aminoalkylcarbonyl, amino, mono- or dialkylamino.
In one preferred embodiment of the invention the compound of Formula I is selected from the group consisting of:
4-(2-Chlorophenyl)-6-(3-hydroxypropyl)-9-methoxypyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
4-(5-Amino-2-methoxyphenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
9-Hydroxy-4-(2-hydroxyphenyl)-6-(3-hydroxypropyl)pyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
4-(2-Chloro-6-methoxyphenyl)-9-hydroxy-6-[2-(4-mo holinyl)ethyl]pyrrolo[3,4- c]carbazole- 1 ,3(2H,6H)-dione;
6-Benzyl-4-(2-chlorophenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
9-Hydroxy-6-(3-hydroxypropyl)-4-phenylpyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
9-Hydroxy-6-(6-hydroxyhexyl)-4-phenylpyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
9-Hydroxy-6-methyl-4-phenylpyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(5-Amino-2-chlorophenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
3-{ [3-(4-(2-Chlorophenyl)-9-hydroxy-l,3-dioxo-2,3-dihydropyrrolo[3,4-c]carbazol- 6(lH)-yl)propyl]amino}benzoic acid;
2-{ [3-(4-(2-Chlorophenyl)-9-hydroxy-l,3-dioxo-2,3-dihydropyrrolo[3,4-c]carbazol- 6(lH)-yl)propyl]amino}benzoic acid; 4-{ [3-(4-(2-Chlorophenyl)-9-hydroxy-l,3-dioxo-2,3-dihydropyrrolo[3,4-c]carbazol- 6(lH)-yl)propyl]amino}benzoic acid;
4-(2-Chlorophenyl)-6-{3-[(cis)-3,5-dimethylpiperazinyl]propyl}-9- hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2,6-Dichlorophenyl)-6-{3-[(cis)-3,5-dimethylpiperazinyl]propyl }-9- hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
6-(2-aminoethyl)-9-hydroxy-4-phenylpyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
9-hydroxy-6-[2-(methylamino)ethyl]-4-phenylpyrrolo[3,4-c]carbazole-l,3(2H,6H)- dione;
6-(3-aminopropyl)-9-hydroxy-4-phenylpyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
9-hydroxy-4-phenyl-6-[3-(l-pyrrolidinyl)propyl]pyrrolo[3,4-c]carbazole-l,3(2H,6H)- dione;
6-[3-(diethylamino)propyl]-9-hydroxy-4-phenylpyrrolo[3,4-c]carbazole-l,3(2H,6H)- dione;
9-hydroxy-4-phenyl-6-[3-(l-piperidinyl)propyl]pyrrolo[3,4-c]carbazole-l,3(2H,6H)- dione;
9-hydroxy-6-[3-(4-methyl-l-piperazinyl)propyl]-4-phenylpyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
6-[6-(dimethylamino)hexyl]-9-hydroxy-4-phenylpyrrolo[3,4-c]carbazole-l,3(2H,6H)- dione;
9-hydroxy-6-[6-(4-methyl-l-piperazinyl)hexyl]-4-phenylpyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
6-(2-aminoethyl)-4-(2-chlorophenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)- dione;
4-(2-chlorophenyl)-9-hydroxy-6-[3-(dimethylamino)ethyl]pyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
4-(2-chlorophenyl)-9-hydroxy-6-[2-(lH-imidazol-l-yl)ethyl]pyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione; 4-(2-chlorophenyl)-9-hydroxy-6-[2-(4-morpholinyl)ethyl]pyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
4-(2-chlorophenyl)-9-hydroxy-6-[2-(4-methyl-l-piperazinyl)ethyl]pyrrolo[3,4- c]carbazole-l ,3(2H,6H)-dione;
6-(2-anilinoethyl)-4-(2-chlorophenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)- dione;
4-(2,6-dichlorophenyl)-9-hydroxy-6-[3-(dimethylamino)ethyl]pyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
4-(2,6-dichlorophenyl)-9-hydroxy-6-[2-(4-moφholinyl)ethyl]pyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
4-(2,6-dichlorophenyl)-9-hydroxy-6-[2-(4-methyl-l-piperazinyl)ethyl]pyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
6-(2-anilinoethyl)-4-(2,6-dichlorophenyl)-9-hydroxypyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
4-(2-chlorophenyl)-9-hydroxy-6-[3-(methylamino)propyl]pyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
4-(2-chlorophenyl)-6-[3-(dimethylamino)propyl]-9-hydroxypyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
4-(2-chlorophenyl)-9-hydroxy-6-[3-(4-morpholinyl)propyl]pyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
4-(2-chlorophenyl)-9-hydroxy-6-[3-(4-methyl-l-piperazinyl)propyl]pyrrolo[3,4- c]carbazole-l ,3(2H,6H)-dione;
6-(3-anilinopropyl)-4-(2-chlorophenyl)-9-hydroxypyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
4-(2,6-dichlorophenyl)-9-hydroxy-6-[3-(methylamino)propyl]pyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
4-(2,6-dichlorophenyl)-6-[3-(dimethylamino)propyl]-9-hydroxypyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione; 4-(2,6-dichlorophenyl)-9-hydroxy-6-[3-(lH-imidazol-l-yl)propyl]pyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
4-(2,6-dichlorophenyl)-9-hydroxy-6-[3-(4-moφholinyl)propyl]pyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
4-(2,6-dichlorophenyl)-9-hydroxy-6-[3-(4-methyl-l-piperazinyl)propyl]pyrrolo[3,4- c]carbazole- 1 ,3(2H,6H)-dione;
6-(3-anilinopropyl)-4-(2,6-dichlorophenyl)-9-hydroxypyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
9-Hydroxy-6-[3-(4-moφholinyl)propyl]-4-phenylpyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
9-Hydroxy-6-[2-(4-moφholinyl)ethyl]-4-phenylpyrrolo[3,4-c]carbazole-l,3(2H,6H)- dione;
9-Hydroxy-6-[3-(lH-imidazol-l-yl)propyl]-4-phenylpyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
9-Hydroxy-6-[2-(lH-imidazol-l-yl)ethyl]-4-phenylpyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
9-Hydroxy-6-[3-(methylamino)propyl]-4-phenylpyrrolo[3,4-c]carbazole-l,3(2H,6H)- dione;
9-Hydroxy-4-phenyl-6-[3-(l-piperazinyl)propyl]pyrrolo[3,4-c]carbazole-l,3(2H,6H)- dione;
6-[3-(Benzylamino)propyl]-9-hydroxy-4-phenylpyrrolo[3,4-c]carbazole-l,3(2H,6H)- dione;
6-(3-Anilinopropyl)-9-hydroxy-4-phenylpyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-Chloro-6-methoxyphenyl)-6-{3-[cis-3,5-dimethylpiperazinyl]propyl}-9- hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-Chlorophenyl)-9-hydroxy-6-[2-(phenylsulfanyl)ethyl]pyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione; 3-(4-(2-Chlorophenyl)-9-hydroxy-l,3-dioxo-2,3-dihydropyrrolo[3,4-c]carbazol- 6(lH)-yl)-N-[2-(dimethylamino)ethyl]-N-methylpropanamide;
3-(4-(2-Chlorophenyl)-9-hydroxy-l,3-dioxo-2,3-dihydropyrrolo[3,4-c]carbazol- 6(lH)-yl)-N-(2,2,6,6-tetramethyl-4-piperidinyl)propanamide (XIII; Ar=2-chlorophenyl, n=2, R3=H, R4=2,2,6,6-tetramethyl-4-piperidinyl);
4-(2-Chlorophenyl)-6-{ 3-[cis-3,5-dimethylpiperazinyl]-3-oxopropyl}-9- methoxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
3-(4-(2-Chloroρhenyl)-9-hydroxy-l,3-dioxo-2,3-dihydropyrrolo[3,4-c]carbazol- 6(lH)-yl)-N-[2-(lH-imidazol-5-yl)ethyl]propanamide (XIII; Ar=2-chlorophenyl, n=2, R3=H, R4=( 1 H-imidazol-5-yl)ethyl);
3-(4-(2,6-Dichlorophenyl)-9-hydroxy-l,3-dioxo-2,3-dihydropyrrolo[3,4-c]carbazol- 6(lH)-yl)propanoic acid;
N-[2-(Dimethylamino)ethyl]-3-(9-hydroxy-l,3-dioxo-4-phenyl-2,3- dihydropyrrolo[3,4-c]carbazol-6(lH)-yl)propanamide;
N-[2-(Dimethylamino)ethyl]-3-(9-hydroxy-4-(2-methoxyphenyl)-l,3-dioxo-2,3- dihydropyrrolo[3,4-c]carbazol-6(lH)-yl)propanamide;
3,9-dihydroxy-4-phenyl-3,6-dihydropyrrolo[3,4-c]carbazol-l(2H)-one;
4-(2-Chlorophenyl)-l,9-dihydroxy-6-(3-hydroxypropyl)-l,6-dihydropyrrolo[3,4- c]carbazol-3(2H)-one;
4-(2-chlorophenyl)-3,9-dihydroxy-6-(3-hydroxypropyl)-3,6-dihydropyrrolo[3,4- c]carbazol-l(2H)-one;
4-(2-Chlorophenyl)-9-hydroxy-6-(3-hydroxypropyl)-4,5,6,10c-tetrahydropyrrolo[3,4- c]carbazole-l,3(2H,3aH)-dione;
8-Hydroxy-4-phenylcyclopenta[c]carbazole-l,3(2H,6H)-dione;
4-(2-Chlorophenyl)-8-hydroxy-6-methylpyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-Chlorophenyl)-6-[3-(cis-3,5-dimethyl-l-piperazinyl)-2-hydroxypropyl]-9- hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione; 4-(2-Chlorophenyl)-6-[3-(dimethylamino)-2-hydroxypropyl]-9-hydroxypyrrolo[3,4- c]carbazole-l ,3(2H,6H)-dione;
4-(2-chlorophenyl)-9-hydroxy-6-propylpyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-chlorophenyl)-9-hydroxy-6-pentylpyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
6-allyl-4-(2-chlorophenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-chlorophenyl)-9-hydroxy-6-(2-phenylethyl)pyrrolo[3,4-c]carbazole-l,3(2H,6H)- dione;
4-(2-chlorophenyl)-9-hydroxy-6-(2-propynyl)pyrrolo[3,4-c]carbazole-l,3(2H,6H)- dione;
4-(2-chlorophenyl)-9-hydroxy-6-isopentylpyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-chlorophenyl)-9-hydroxy-6-(2,2,2-trifluoroethyl)pyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
4-(2-chlorophenyl)-9-hydroxy-6-(4-pentenyl)pyrrolo[3,4-c]carbazole-l,3(2H,6H)- dione;
2-(4-(2-chlorophenyl)-9-hydroxy-l,3-dioxo-2,3-dihydropyrrolo[3,4-c]carbazol-6(lH)- yl)acetamide;
6-(3-butenyl)-4-(2-chlorophenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)- dione;
4-(2-chlorophenyl)-9-hydroxy-6-isobutylpyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-chlorophenyl)-9-hydroxy-6-(4,4,4-trifluorobutyl)pyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
6-sec-butyl-4-(2-chlorophenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-chlorophenyl)-6-cyclopentyl-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)- dione;
4-(2-Chlorophenyl)-8-[4-(dimethylamino)butyl]-9-hydroxypyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
4-(2-Chlorophenyl)-9-hydroxy-8-[4-(l-pyrrolidinyl)butyl]pyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione; 4-(2-Chlorophenyl)-9-hydroxy-6,8-bis(2-hydroxyethyl)pyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
4-(2-Chlorophenyl)-9-hydroxy-6-(2-hydroxyethyl)-8-[3-(4- moφholinyl)propoxy]pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
9-Hydroxy-8-(3-hydroxypropyl)-6-methyl-4-phenylpyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
8-Ethyl-9-hydroxy-6-methyl-4-phenylpyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
8-(2,3-Dihydroxypropyl)-9-hydroxy-6-methyl-4-phenylpyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
4-(2-Chlorophenyl)-8-ethyl-9-hydroxy-6-methylpyrrolo[3,4-c]carbazole-l,3(2H,6H)- dione;
9-Hydroxy-8-(2-hydroxyethyl)-6-methyl-4-phenylpyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
4-(2-Chlorophenyl)-9-hydroxy-8-(2-hydroxyethyl)-6-methylpyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
8-[3-(Dimethylamino)propyl]-9-hydroxy-6-methyl-4-phenylpyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
8-[2-(Dimethylamino)ethyl]-9-hydroxy-6-methyl-4-phenylpyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
9-Hydroxy-5-methyl-4-phenylpyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
9-Hydroxy-4,5-diphenylpyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-Chlorophenyl)-8-(3-hydroxypropoxy)-9-methoxy-6-methylpyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
4-(2-Chlorophenyl)-8-[3-(dimethylamino)propoxy]-9-methoxy-6-methylpyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
4-(2-Chlorophenyl)-8-[3-(dimethylamino)propoxy]-9-hydroxy-6-methylpyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione; 8-[3-(Dimethylamino)propoxy]-9-hydroxy-6-methyl-4-phenylpyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
4-(2-Chlorophenyl)-9-hydroxy-6-methyl-8-[3-(4-moφholinyl)propoxy]pyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
4-(2-Chlorophenyl)-9-hydroxy-6-methyl-8-[3-(l-pyrrolidinyl)propoxy]pyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
4-(2-Chlorophenyl)-8-(2-hydroxyethyl)-6-methylpyrrolo[3,4-c]carbazole-l,3(2H,6H)- dione;
4-(2-Chlorophenyl)-8-(l,2-dihydroxyethyl)-6-methylpyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
4-(2-Chlorophenyl)-8-(hydroxymethyl)-6-methylpyrrolo[3,4-c]carbazole-l,3(2H,6H)- dione;
4-(2-Chlorophenyl)-8-(3-hydroxypropoxy)-6-methylpyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
4-(2-Chlorophenyl)-8-[3-(dimethylamino)propoxy]-6-methylpyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
4-(2-Chlorophenyl)-6-methyl-8-[3-(methylamino)propoxy]pyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
4-(2-Chlorophenyl)-8-[3-(cis-3,5-dimethyl-l-piperazinyl)propoxy]-6- methylpyιτolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-Chlorophenyl)-8-(2-hydroxyethoxy)-6-methylpyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
4-(2-Chlorophenyl)-8-(2,3-dihydroxypropoxy)-6-methylpyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
9-Hydroxy-4-(2-methoxyphenyl)-6-[2-(4-moφholinyl)ethyl]pyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
1 ,3-Dioxo-4-phenyl-l ,2,3,6-tetrahydropyrrolo[3,4-c]carbazol-9-yl dihydrogen phosphate; 4-(2-Chlorophenyl)-8-(3-dimethylamino-propoxy)-9-hydroxy-6-(3-hydroxy-propyl)- 6H-pyrrolo[3,4-c]carbazole-l,3-dione;
6-(3-Bromo-propyl)-4-(2-chlorophenyl)-8-(3-dimethylamino-propoxy)-9-hydroxy- 6H-pyrrolo[3,4-c]carbazole-l,3-dione;
4-(2-Chlorophenyl)-8-(4-dimethylamino-3-hydroxy-butoxy)-6-methyl-6H- pyrrolo[3,4-c]carbazole-l,3-dione;
4-(2-Chlorophenyl)-8-hydroxy-6-(3-hydroxy-propyl)-6H-pyrrolo[3,4-c]carbazole-l,3- dione;
4-(2-Chlorophenyl)-8-(4-dimethylamino-butyl)-6-methyl-6H-pyrrolo[3,4-c]carbazole- 1,3-dione;
4-(2-Chlorophenyl)-6-methyl-8-(4-pyrrolidin-l-yl-butyl)-6H-pyrrolo[3,4-c]carbazole- 1,3-dione;
4-(2-Chlorophenyl)-6-methyl-8-(4-methylamino-butyl)-6H-pyrrolo[3,4-c]carbazole- 1,3-dione;
4-(2-Chlorophenyl)-9-hydroxy-6-(3-hydroxy-propyl)-8-(3-pyrrolidin-l-yl-propoxy)- 6H-pyrrolo[3,4-c]carbazole-l,3-dione;
4-(2-Chlorophenyl)-9-hydroxy-8-(4-hydroxy-butyl)-6-methyl-6H-pyrrolo[3,4- c]carbazole-l,3-dione;
8-{3-[Bis-(2-hydroxy-ethyl)-amino]-propoxy}-4-(2-chlorophenyl)-9-hydroxy-6- methyl-6H-pyrrolo[3,4-c]carbazole-l,3-dione;
4-(2-Chloro-phenyl)-9-hydroxy-6-(3-hydroxy-propyl)-8-[3-(4-methyl-piperazin-l-yl)- propoxy]-6H-pyrrolo[3,4-c]carbazole-l,3-dione;
9-Amino-4-(2-chloro-phenyl)-6-(3-hydroxy-propyl)-6H-pyrrolo[3,4-c]carbazole-l,3- dione;
3-[4-(2-Chloro-phenyl)-9-nitro-l,3-dioxo-2,3-dihydro-lH-pyrrolo[3,4-c]carbazol-6- yl]-propionic acid;
4-(2-Chloro-phenyl)-9-hydroxy-8-(4-hydroxy-butoxy)-6-methyl-6H-pyrrolo[3,4- c]carbazole-l,3-dione; 4-(2-Chloro-phenyl)-6-(3-hydroxy-propyl)-8-methoxy-6H-pyrrolo[3,4-c]carbazole- 1.3-dione;
4-(2-Chloro-phenyl)-9-fluoro-8-methoxy-6-methyl-6H-pyrrolo[3,4-c]carbazole-l,3- dione;
4-(2-Chloro-phenyl)-9-fluoro-8-hydroxy-6-methyl-6H-pyrrolo[3,4-c]carbazole-l,3- dione;
4-(2-Chloro-phenyl)-8-(3-dimethylamino-propoxy)-6-(3-hydroxy-propyl)-6H- pyrrolo[3,4-c]carbazole-l,3-dione;
4-(2-Chloro-phenyl)-6-(3-hydroxy-propyl)-8-(3-pyrrolidin-l-yl-propoxy)-6H- pyrrolo[3,4-c]carbazole-l,3-dione;
4-(2-Chloro-phenyl)-9-fluoro-8-(3-hydroxy-propoxy)-6-methyl-6H-pyrrolo[3,4- c]carbazole-l,3-dione;
4-(2-Chloro-phenyl)-9-fluoro-6-methyl-8-(3-methylamino-propoxy)-6H-pyrrolo[3,4- c]carbazole-l,3-dione;
4-(2-Chloro-phenyl)-9-hydroxy-6-methyl-8-(4-moφholin-4-yl-butyl)-6H-pyrrolo[3,4- c]carbazole-l,3-dione;
4-(2-Chloro-phenyl)-9-fluoro-6-methyl-8-(3-pyrrolidin-l-yl-propoxy)-6H- pyrrolo[3,4-c]carbazole-l,3-dione;
4-(2-Chloro-phenyl)-9-hydroxy-6-(2-hydroxy-ethyl)-8-[3-(4-methyl-piperazin-l-yl)- propoxy]-6H-pyrrolo[3,4-c]carbazole-l,3-dione;
4-(2-Chloro-phenyl)-8-(3-diethylamino-propoxy)-9-hydroxy-6-(2-hydroxy-ethyl)-6H- pyrrolo[3,4-c]carbazole-l,3-dione;
4-(2-Chloro-phenyl)-8-(3-dimethylamino-propoxy)-9-fluoro-6-methyl-6H- pyrrolo[3,4-c]carbazole-l,3-dione;
N-[4-(2-Chloro-phenyl)-6-(3-hydroxy-propyl)-l,3-dioxo-l,2,3,6-tetrahydro- pyrrolo[3,4-c]carbazol-9-yl]-formamide;
4-(2-Chloro-phenyl)-9-hydroxy-6-(3-hydroxy-propyl)-8-piperidin-4-yl-6H- pyrrolo[3,4-c]carbazole-l,3-dione; 4-(2-Chloro-phenyl)-6-methyl-8-piperidin-4-yl-6H-pyrrolo[3,4-c]carbazole-l,3-dione;
7-(2-Amino-l-hydroxy-ethyl)-4-(2-chlorophenyl)-9-hydroxy-6-oxa-2-aza- cyclopenta[c]fluorene-l,3-dione;
4-(2-Chloro-phenyl)-9-hydroxy-7-(l-hydroxy-2-methylamino-ethyl)-6-oxa-2-aza- cyclopenta[c]fluorene-l,3-dione;
4-(2-Chloro-phenyl)-9-hydroxy-7-(l -hydroxy-2-piperazin- 1 -yl-ethyl)-6-oxa-2-aza- cyclopenta[c]fluorene- 1 ,3-dione;
4-(2-Chloro-phenyl)-9-hydroxy-7-(l-hydroxy-2-moφholin-4-yl-ethyl)-6-oxa-2-aza- cyclopenta[c]fluorene-l,3-dione;
4-(2-Chloro-phenyl)-9-hydroxy-7-[l-hydroxy-2-(2-methoxy-ethoxy)-ethyl]-6-oxa-2- aza-cyclopenta[c]fluorene-l,3-dione;
7-(2-Amino-l-hydroxy-ethyl)-4-(2-Chlorophenyl)-6-oxa-2-aza-cyclopenta [c]fluorene-l,3-dione;
4-(2-Chlorophenyl)-6-methyl-8-piperidin-3-yl-6H-pyrrolo[3,4-c]carbazole-l,3-dione;
4-(2-Chlorophenyl)-6-methyl-8-piperidin-4-yl-6H-pyrrolo[3,4-c]carbazole-l,3-dione;
4-(2-Chlorophenyl)-8-(4-hydroxy-piperidin-3-yl)-6-methyl-6H-pyrrolo[3,4- c]carbazole-l,3-dione;
8-(l-Aminomethyl-2-hydroxy-ethyl)-4-(2-Chlorophenyl)-6-methyl-6H-pyrrolo[3,4- c]carbazole-l,3-dione;
4-(2-Chlorophenyl)-6-(3-hydroxy-propyl)-8-piperidin-3-yl-6H-pyrrolo[3,4- c]carbazole-l,3-dione;
4-(2-Chlorophenyl)-8-(4-hydroxy-piperidin-3-yl)-6-(3-hydroxy-propyl)- 6H- pyrrolo[3,4-c]carbazole-l,3-dione;
4-(2-chlorophenyl)-9-hydroxy-8-[4-(methylamino)butyl]pyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
4-(2-chlorophenyl)-9-hydroxy-8-[3-(methylamino)propoxy]pyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione; 4-(2-chlorophenyl)-8-[3-(dimethylamino)propoxy]-9-hydroxypyrrolo[3,4- c]carbazole-l ,3(2H,6H)-dione;
4-(2-chlorophenyl)-8-[3-(dimethylamino)propoxy]-9-hydroxy-6-(2- hydroxyethyl)pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-chlorophenyl)-9-hydroxy-6-(2-hydroxyethyl)-8-[3- (methylamino)propoxy]pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-chlorophenyl)-9-hydroxy-6-(2-hydroxyethyl)-8-[4- (methylamino)butyl]pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-chlorophenyl)-8-[4-(dimethylamino)butyl]-9-hydroxy-6-(2- hydroxyethyl)pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-chlorophenyl)-8-[4-(dimethylamino)butyl]-9-hydroxy-6-(3- hydroxypropyl)pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-chlorophenyl)-8-[4-(dimethylamino)butyl]-9-hydroxy-6-(3- hydroxypropyl)pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-chlorophenyl)-9-hydroxy-6-(3-hydroxypropyl)-8-[3- (methylamino)propoxy]pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-chlorophenyl)-8-[3-(dimethylamino)propoxy]-9-hydroxy-6-(3- hydroxypropyl)pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-chlorophenyl)-9-hydroxy-6-(3-hydroxypropyl)-8-[3-(l- pyrrolidinyl)propoxy]pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-chlorophenyl)-9-hydroxy-6-methyl-8-[4-(methylamino)butyl]pyrrolo[3,4- c]carbazole-l ,3(2H,6H)-dione;
4-(2-chlorophenyl)-9-hydroxy-6-methyl-8-[3-(methylamino)propoxy]pyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
4-(2-chlorophenyl)-8-[4-(dimethylamino)butyl]-9-hydroxy-6-methylpyrrolo[3,4- c]carbazole- 1 ,3(2H,6H)-dione;
4-(2-chlorophenyl)-8-{3-[(3,5-dimethylpiperazinyl]propoxy}-9-hydroxy-6- methylpyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione; 6-butyl-4-(2-chlorophenyl)-8-[4-(dimethylamino)butyl]-9-hydroxypyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
4-(2-chlorophenyl)-9-hydroxy-8-[4-(methylamino)butyl]-6-propylpyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
6-butyl-4-(2-chlorophenyl)-9-hydroxy-8-[3-(methylamino)propoxy]pyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
6-butyl-4-(2-chlorophenyl)-8-[3-(dimethylamino)propoxy]-9-hydroxypyrrolo[3,4- c]carbazole-l ,3(2H,6H)-dione;
6-butyl-4-(2-chlorophenyl)-9-hydroxy-8-[4-(l-pyrrolidinyl)butyl]pyrrolo[3,4- c]carbazole-l ,3(2H,6H)-dione;
4-(2,6-dichlorophenyl)-9-hydroxy-8-[4-(methylamino)butyl]pyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
4-(2-chloro-6-methoxyphenyl)-9-hydroxy-8-[4-(methylamino)butyl]pyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
4-(2-bromophenyl)-9-hydroxy-8-[4-(methylamino)butyl]pyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
4-(2-bromophenyl)-8-[4-(dimethylamino)butyl]-9-hydroxypyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
4-(2-chloro-6-methoxyphenyl)-8-[4-(dimethylamino)butyl]-9-hydroxypyrrolo[3,4- c]carbazole-l ,3(2H,6H)-dione;
4-(2-chloro-6-methoxyphenyl)-8-[3-(dimethylamino)propoxy]-9-hydroxypyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
4-(2,6-dichlorophenyl)-8-[3-(dimethylamino)propoxy]-9-hydroxypyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
4-(2-bromophenyl)-8-[3-(dimethylamino)propoxy]-9-hydroxypyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
4-(2-bromophenyl)-9-hydroxy-8-[3-(methylamino)propoxy]pyrrolo[3,4-c]carbazole- L3(2H,6H)-dione; 4-(2-chloro-6-methoxyphenyl)-9-hydroxy-8-[3-(methylamino)propoxy]pyrrolo[3,4- c]carbazole- 1 ,3(2H,6H)-dione;
4-(2-chloro-6-methoxyphenyl)-9-hydroxy-6-methyl-8-[3- (methylamino)propoxy]pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2,6-dichlorophenyl)-9-hydroxy-6-methyl-8-[3-(methylamino)propoxy]pyrrolo[3,4- c]carbazole- 1 ,3(2H,6H)-dione;
4-(2-bromophenyl)-9-hydroxy-6-methyl-8-[3-(methylamino)propoxy]pyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
4-(2-bromophenyl)-8-[3-(dimethylamino)propoxy]-9-hydroxy-6-methylpyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
4-(2,6-dichlorophenyl)-8-[4-(dimethylamino)butyl]-9-hydroxy-6-methylpyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
4-(2-chloro-6-methoxyphenyl)-8-[4-(dimethylamino)butyl]-9-hydroxy-6- methylpyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-chloro-6-methoxyphenyl)-8-[3-(dimethylamino)propoxy]-9-hydroxy-6- methylpyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
6-butyl-4-(2-chloro-6-methoxyphenyl)-8-[3-(dimethylamino)propoxy]-9- hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
6-butyl-4-(2-chloro-6-methoxyphenyl)-9-hydroxy-8-[3- (methylamino)propoxy]pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
6-butyl-4-(2-chloro-6-methoxyphenyl)-8-[4-(dimethylamino)butyl]-9- hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
6-butyl-4-(2,6-dichlorophenyl)-8-[4-(dimethylamino)butyl]-9-hydroxypyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
6-butyl-4-(2,6-dichlorophenyl)-8-[3-(dimethylamino)propoxy]-9-hydroxypyrrolo[3,4- c]carbazole- 1 ,3(2H,6H)-dione;
6-butyl-4-(2,6-dichlorophenyl)-9-hydroxy-8-[3-(methylamino)propoxy]pyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione; 6-butyl-4-(2,6-dichlorophenyl)-9-hydroxy-8-[4-(methylamino)butyl]pyrrolo[3,4- arbazole- 1 ,3(2H,6H)-dione;
4-(2-chlorophenyl)-9-hydroxy-8-[4-(l-pyrrolidinyl)butyl]-lH-[l]benzofuro[3,2- e]isoindole- 1 ,3(2H)-dione;
8-(4-aminobutyl)-4-(2-chlorophenyl)-9-hydroxy-lH-[l]benzofuro[3,2-e]isoindole- l,3(2H)-dione;
8-(4-aminobutyl)-4-(2-chlorophenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)- dione;
8-(4-aminobutyl)-4-(2-chlorophenyl)-9-hydroxy-6-methylpyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
4-(2-chlorophenyl)-9-(hydroxymethyl)pyrrolo[3,4-c]carbazole-l,3(2H,6/-T)-dione;
4-(2-chlorophenyl)-9-(trifluoromethyl)pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
9-(2-amino-l-hydroxyethyl)-4-(2-chlorophenyl)pyrrolo[3,4-c]carbazole-l,3(2H,6H)- dione;
4-(2-chlorophenyl)-9-[l-hydroxy-2-(methylamino)ethyl]pyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
4-(2-chlorophenyl)-9-[2-(dimethylamino)-l-hydroxyethyl]pyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
4-(2-chlorophenyl)-9-[l-hydroxy-2-(l-piperidinyl)ethyl]pyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
4-(2-chlorophenyl)-9-[l-hydroxy-2-(4-moφholinyl)ethyl]pyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
4-(2-chlorophenyl)-8-(4-hydroxybutoxy)-6-methylpyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
4-(2-chlorophenyl)-8-(3,4-dihydroxybutoxy)-6-methylpyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
4-(2-chlorophenyl)-6-methyl-8-[4-(methylamino)butoxy]pyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione; 4-(2-chlorophenyl)-8-[4-(dimethylamino)-3-hydroxybutoxy]-6-methylpyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
4-(2-chlorophenyl)-8-[3-hydroxy-4-(methylamino)butoxy]-6-methylpyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
4-(2-chlorophenyl)-8-[3-hydroxy-4-(l-pyrrolidinyl)butoxy]-6-methylpyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
4-(2-chlorophenyl)-8-[(lE)-4-(dimethylamino)-l-butenyl]-6-methylpyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
4-(2-chlorophenyl)-6-methyl-8-[(lE)-4-(methylamino)-l-butenyl]pyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
4-(2-chlorophenyl)-6-methyl-8-[4-(methylamino)butyl]pyrrolo[3,4-c]carbazole- l,3(2H6H)-dione;
4-(2-chlorophenyl)-8-[4-(dimethylamino)butyl]-6-methylpyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
4-(2-chlorophenyl)-8-[(lE)-4-hydroxy-l-butenyl]-6-methylpyrrolo[3,4-c]carbazole- l,3(2H6H)-dione;
4-(2-chlorophenyl)-8-[(lE)-4-hydroxy-l-butenyl]pyrrolo[3,4-c]carbazole- l,3(2H,6H) -dione;
4-(2-chlorophenyl)-8-(4-hydroxybutyl)pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-chlorophenyl)-8-[4-(methylamino)butyl]pyrrolo[3,4-c]carbazole-l,3(2H,6H)- dione;
4-(2-chlorophenyl)-8-[(lϋr)-4-(methylamino)-l-butenyl]pyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
4-(2-chlorophenyl)-6-(3-hydroxypropyl)-8-[3-(methylamino)propoxy]pyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
4-(2-chlorophenyl)-8-f3-(methylamino)propoxy]-6-[3- (methylamino)propyl]pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione; 4-(2-chlorophenyl)-8-(3-hydroxypropoxy)-6-[3-(methylamino)propyl]pyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
4-(2-chlorophenyl)-9-fluoro-8-[3-(methylamino)propoxy]-6-[3- (methylamino)propyl]pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-chlorophenyl)-9-fluoro-8-(3-hydroxyρropoxy)-6-[3- (methylamino)propyl]pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-chlorophenyl)-9-fluoro-6-(3-hydroxypropyl)-8-[4- (methylamino)butyl]pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-chlorophenyl)-9-fluoro-8-(4-hydroxybutoxy)-6-methylpyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
4-(2-chlorophenyl)-9-fluoro-6-methyl-8-[3-(methylamino)propoxy]pyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
4-(2-chlorophenyl)-9-fluoro-8-(3-hydroxypropoxy)-6-methylpyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
4-(2-chloro-3-hydroxyphenyl)-8-[4-(methylamino)butyl]pyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
4-(2-chloro-3-hydroxyphenyl)-9-fluoro-8-[3-(methylamino)propoxy]pyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
4-(2-chloro-3-hydroxyphenyl)-9-fluoro-8-[4-(methylamino)butyl]pyrrolo[3,4- c]carbazole- 1 ,3(2H,6H)-dione;
4-(2-chloro-3-hydroxyphenyl)-9-fluoro-6-(3-hydroxypropyl)-8-[4- (methylamino)butyl]pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(3-amino-2-chlorophenyl)-9-fluoro-6-(3-hydroxypropyl)-8-[4- (methylamino)butyl]pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(3-amino-2-chlorophenyl)-9-fluoro-8-[4-(methylamino)butyl]pyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
4-(3-amino-2-chlorophenyl)-9-fluoro-8-[3-(methylamino)propoxy]pyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione; 4-(2-chlorophenyl)-9-fluoro-6-methylpyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
3-(4-(2-chlorophenyl)-9-(formylamino)-l,3-dioxo-2,3-dihydropyrrolo[3,4-c]carbazol- 6(lH)-yl)-N-[2-(dimethylamino)ethyl]propanamide;
3-(9-amino-4-(2-chlorophenyl)-l,3-dioxo-2,3-dihydropyrrolo[3,4-c]carbazol-6(lH)- yl)-N-[2-(dimethylamino)ethyl]propanamide;
4-(2-chlorophenyl)-6-methyl-9-{ [3-(l-piperidinyl)propyl]amino}pyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
4-(2-chlorophenyl)-9-fluoropyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
9-amino-4-(2-chlorophenyl)-6-(3-hydroxypropyl)pyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
4-(2-chlorophenyl)-6-(3-hydroxypropyl)-l,3-dioxo-l,2,3,6-tetrahydropyrrolo[3,4- c]carbazol-9-ylformamide;
4-(2-chlorophenyl)-9-{ [4-(dimethylamino)butyl]amino}-6-methylpyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
4-(2-chlorophenyl)-6-methyl-9-{ [4-(methylamino)butyl]amino}pyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
4-(2-chlorophenyl)-9-{ [3-(l-piperidinyl)propyl]amino}pyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
4-(2-methoxyphenyl)-6-methyl-l,3-dioxo-l,2,3,6-tetrahydropyrrolo[3,4-c]carbazol-9- ylformamide;
4-(2-methoxyphenyl)-6-methyl-9-(methylamino)pyrrolo[3,4-c]carbazole-l,3(2H,6H)- dione;
4-(2-chlorophenyl)-6-methyl-8-[3-(methylamino)propoxy]-l,3-dioxo-l, 2,3,6- tetrahydropyrrolo[3,4-c]carbazol-9-ylformamide;
4-(2-chlorophenyl)-9-hydroxy-6-methyl-8-[4-(methylamino)butanoyl]pyrrolo[3,4- c]carbazole-l,3(2H,6/- )-dione;
4-(2-chlorophenyl)-8-[4-(dimethylamino)butanoyl]-9-hydroxy-6-methylpyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione; 4-(2-chlorophenyl)-8-[3-(dimethylamino)propoxy]-6-methyl-l,3-dioxo- 1,2,3,6- tetrahydropyrrolo[3,4-c]carbazol-9-ylformamide;
4-(2-chlorophenyl)-8-{ [3-(dimethylamino)propyl]sulfinyl}-9-hydroxy-6- methylpyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione; and
4-(2-chlorophenyl)-9-hydroxy-6-methyl-8-{ [3- (methylamino)propyl]sulfonyl }pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione.
In another preferred embodiment of the present invention, Rl in compounds according to Formula I is aryl.
In one preferred embodiment are compounds according to Formula I wherein R^ is selected from an unsubstituted aryl ring or an aryl ring substituted with up to 3 substituents selected from the group consisting of halogen, haloalkyl, alkoxy, hydroxyl, nitro or NR3R4.
In a more preferred embodiment are compounds according to Formula I wherein Rl is an aryl ring substituted with up to 2 halogens or alkoxy groups.
Another preferred embodiment of the present invention comprises compounds according to Formula I in which R^ is selected from Me and I.
In one preferred embodiment of the present invention, R9 in compounds according to Formula I is a hydrogen, hydroxyl, halogen or NΗCΗO group.
In another embodiment are compounds according to Formula I wherein at least one of X, R7, R8, and R9 is not hydrogen. In another embodiment, when three of X, R7, R8, and R9 are hydrogen and Rl is lower alkyl, then R2 must be hydrogen.
In a more preferred embodiment of the present invention, R9 in compounds according to Formula I is a hydroxyl group.
In a more preferred embodiment of the present invention, R9 in compounds according to Formula I is a fluorine group.
In a more preferred embodiment of the present invention are compounds according to Formula I in which R9 is hydroxyl and R1 is aryl, such as but not limited to:
4-(2-Chloro-3-hydroxyphenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione; 9-Hydroxy-4-(2-iodophenyl)pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-Chloro-6-methoxyphenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2,6-Dichloro-3-hydroxyphenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)- dione;
4-(4-Amino-2-bromophenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione);
4-(3-Amino-2-chlorophenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-Chloro-4-hydroxyphenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-Bromophenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
9-Ηydroxy-4-(2-methoxyphenyl)pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(4-Amino-2-chlorophenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2,6-Dimethoxyphenyl)-9-hydroxyρyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2,6-Dichlorophenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2,3-Dichlorophenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-Chloro-5-hydroxyphenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
9-Ηydroxy-4-[2-(methylsulfanyl)phenyl]pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2,6-Dibromophenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
9-Ηydroxy-4-(3-thienyl)pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-Chloro-6-hydroxyphenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
9-Ηydroxy-4-(2-nitrophenyl)pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2,6-Dichloro-4-hydroxyphenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)- dione;
4-(3-Chlorophenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
9-Ηydroxy-4-(2-hydroxyphenyl)pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
9-Ηydroxy-4-(4-hydroxyphenyl)pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(3-Aminophenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2,6-Dimethylphenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione; 9-Hydroxy-4-(3-hydroxyphenyl)pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(5-Amino-2-methoxyphenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
9-Ηydroxy-4-(3-hydroxy-4-methoxyphenyl)pyrrolo[3,4-c]carbazole-l,3(2H,6H)- dione;
9-Ηydroxy-4-(2-thienyl)pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(4-Aminophenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
2-(9-Ηydroxy-l,3-dioxo-l,2,3,6-tetrahydropyrrolo[3,4-c]carbazol-4-yl)benzonitrile;
4-(2-Aminophenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-Bromo-4-nitrophenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
9-Ηydroxy-4-[2-(methylsulfinyl)phenyl]pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-Ethoxyphenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
9-Ηydroxy-4-(3-nitrophenyl)pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-Ethylphenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
9-Ηydroxy-4-[2-(hydroxymethyl)phenyl]pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-Chloro-4-nitrophenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
9-Ηydroxy-4-(2-trifluoromethylphenyl)pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-[l, -Biphenyl]-2-yl-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(4-Chlorophenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
9-Ηydroxy-4-(4-hydroxymethylphenyl)pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
9-Ηydroxy-4-o-tolyl-6Η-pyrrolo[3,4-c]carbazole-l,3-dione;
3-(9-Hydroxy-l,3-dioxo-l,2,3,6-tetrahydro-pyrrolo[3,4-c]carbazol-4-yl)-benzonitrile;
4-Furan-2-yl-9-hydroxy-6H-pyrrolo[3,4-c]carbazole-l,3-dione;
9-Hydroxy-4-m-tolyl-6H-pyrrolo[3,4-c]carbazole- 1 ,3-dione;
9-Hydroxy-4-(2-methylsulfanyl-phenyl)-6H-pyrrolo[3,4-c]carbazole-l,3-dione;
9-Hydroxy-4-(3-trifluoromethoxy-phenyl)-6H-pyrrolo[3,4-c]carbazole-l,3-dione;
9-Hydroxy-4-(3-hydroxymethyl-phenyl)-6H-pyrrolo[3,4-c]carbazole-l,3-dione; 9-Hydroxy-4-(4-trifluoromethoxy-phenyl)-6H-pyrrolo[3,4-c]carbazole-l,3-dione;
9-Hydroxy-4-(3-hydroxy-phenyl)-6H-pyrrolo[3,4-c]carbazole-l,3-dione; and
4-(2-Acetyl-phenyl)-9-hydroxy-6H-pyrrolo[3,4-c]carbazole-l,3-dione.
In yet another preferred embodiment of the present invention are compounds according to Formula I in which Y1 is oxygen , such as but not limited to:
4-(2-Chlorophenyl)-7-(l,2-dihydroxyethyl)-9-hydroxy-lH-[l]benzofuro[3,2- e]isoindole-l,3(2H)-dione;
4-(2-Chlorophenyl)-9-hydroxy-lH-[l]benzofuro[3,2-e]isoindole-l,3(2H)-dione;
4-(2-Chlorophenyl)-8-ethyl-9-hydroxy-lΗ-[l]benzofuro[3,2-e]isoindole-l,3(2Η)- dione;
4-(2-ChIorophenyl)-7-ethyl-9-hydroxy-lH-[l]benzofuro[3,2-e]isoindole-l,3(2H)- dione;
9-Ηydroxy-4-phenyl-lH-[l]benzofuro[3,2-e]isoindole-l,3(2H)-dione;
4-(2-Chlorophenyl)-8-[3-(dimethylamino)propoxy]-9-hydroxy-lH-[l]benzofuro[3,2- e]isoindole-l,3(2H)-dione; and
4-(2-Chlorophenyl)-9-hydroxy-8-(4-hydroxybutyl)-lH-[l]benzofuro[3,2-e]isoindole- l,3(2H)-dione.
In another preferred embodiment of the present invention are compounds according to Formula I in which Y1 is sulfur, such as but not limited to:
4-(2-Chlorophenyl)-9-hydroxy-lH-[l]benzothieno[3,2-e]isoindole-l,3(2H)-dione.
In another preferred embodiment of the present invention are compounds according to Formula I in which R9 is hydroxyl and γl is NRIO.
In another preferred embodiment of the present invention are compounds according to
Formula I in which R9 is
Figure imgf000032_0001
Rl is aryl and γl is NR*0 such as, but not limited to, compounds selected from the group consisting of:
9-Amino-4-(2-methoxyphenyl)-6-methylpyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
9-Amino-4-(2-chlorophenyl)-6-methylpyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione; 9-(Dimethylamino)-4-(2-methoxyphenyl)-6-methylpyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
9-Amino-4-(2-chlorophenyl)pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-Chlorophenyl)-6-methyl-l,3-dioxo-l,2,3,6-tetrahydropyrrolo[3,4-c]carbazol-9- ylformamide;
4-(2-Chlorophenyl)-l,3-dioxo-l,2,3,6-tetrahydropyrrolo[3,4-c]carbazol-9- ylformamide;
4-(2-Chlorophenyl)-6-methyl-9-(methylamino)pyrrolo[3,4-c]carbazole-l,3(2H,6H)- dione;
N-[4-(2-Chlorophenyl)-6-methyl-l,3-dioxo-l,2,3,6-tetrahydropyrrolo[3,4-c]carbazol- 9-yl]acetamide;
4-(2-Chlorophenyl)-9-(ethylamino)-6-methylpyrrolo[3,4-c]carbazole-l,3(2H,6H)- dione; and
N-[4-(2-Chlorophenyl)-6-methyl-l,3-dioxo-l,2,3,6-tetrahydropyrrolo[3,4-c]carbazol- 9-yl]-3-(l-piperidinyl)propanamide.
In another preferred embodiment of the present invention are compounds according to Formula I in which R9 is hydroxyl and γl is ΝRIO.
In another preferred embodiment of the present invention are compounds according to Formula I in which R9 is hydroxyl and Y^ is ΝR^O, and T may be absent, O, COΝR3, or COΝΗS02- Such compounds are exemplified below:
9-Methoxy-4-(2-methoxy-5-nitrophenyl)-4,5,6,10c-tetrahydropyrrolo[3,4- c]carbazole-l ,3(2H,3aH)-dione;
N-[3-(4-(2-Chlorophenyl)-9-hydroxy-l,3-dioxo-2,3-dihydropyrrolo[3,4-c]carbazol- 6(lH)-yl)propanoyl]benzenesulfonamide;
4-(2,6-Dichlorophenyl)-9-hydroxy-6-(3-hydroxypropyl)pyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
4-(2,6-Dichlorophenyl)-9-hydroxy-6-(2-hydroxyethyl)pyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione; 3-(4-(2-Chlorophenyl)-9-hydroxy-l,3-dioxo-2,3-dihydropyrrolo[3,4-c]carbazol- 6(lH)-yl)-N-(lH-tetraazol-5-yl)propanamide;
4-(2-Chlorophenyl)-9-hydroxy-6-[2-(lH-l,2,4-triazol-5-ylsulfinyl)ethyl]pyrrolo[3,4- c]carbazole- 1 ,3(2H,6H)-dione;
6-(3-Bromopropyl)-4-(2-chlorophenyl)-9-hydroxypyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
3-(4-(2-Chlorophenyl)-9-hydroxy-l,3-dioxo-2,3-dihydropyrrolo[3,4-c]carbazol- 6(lH)-yl)propanoic acid;
N-[3-(4-(2-Chlorophenyl)-9-hydroxy-l,3-dioxo-2,3-dihydropyrrolo[3,4-c]carbazol- 6(lH)-yl)propanoyl]-2-(dimethylamino)ethanesulfonamide;
4-(2-Chlorophenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
N-[3-(4-(2-Chlorophenyl)-9-hydroxy-l,3-dioxo-2,3-dihydropyrrolo[3,4-c]carbazol- 6(lH)-yl)propanoyl]methanesulfonamide;
4-(4-(2-Chlorophenyl)-9-hydroxy-l,3-dioxo-2,3-dihydropyrrolo[3,4-c]carbazol- 6(lH)-yl)butanoic acid;
N-[4-(4-(2-Chlorophenyl)-9-hydroxy-l,3-dioxo-2,3-dihydropyrrolo[3,4-c]carbazol- 6(lH)-yl)butanoyl]methanesulfonamide;
6-Acetyl-4-(2-chlorophenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
3-(4-(2,6-Dichlorophenyl)-9-hydroxy-l,3-dioxo-2,3-dihydropyrrolo[3,4-c]carbazol- 6(lH)-yl)-N-[2-(dimethylamino)ethyl]propanamide;
3-(4-(2-Chlorophenyl)-9-hydroxy-l,3-dioxo-2,3-dihydropyrrolo[3,4-c]carbazol- 6(lH)-yl)propanenitrile;
4-(2-Chlorophenyl)-9-hydroxy-6-[3-(lH-tetraazol-5-yl)propyl]pyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
4-(2-Chlorophenyl)-9-hydroxy-6-[2-(lH-imidazol-2-ylsulfanyl)ethyl]pyrrolo[3,4- c]carbazole- 1 ,3(2H,6H)-dione;
N-[4-(4-(2-Chlorophenyl)-9-hydroxy-l,3-dioxo-2,3-dihydropyrrolo[3,4-c]carbazol- 6(lH)-yl)butanoyl]benzenesulfonamide; 4-(2-Chlorophenyl)-9-hydroxy-6-[2-(lH-l,2,4-triazol-5-ylsulfonyl)ethyl]pyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
4-(2-Chlorophenyl)-9-hydroxy-6-[2-(lH-imidazol-2-ylsulfinyl)ethyl]pyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
4-(2-Chlorophenyl)-9-hydroxy-6-[2-(lH-tetraazol-5-yl)ethyl]pyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
3-(9-Ηydroxy-l,3-dioxo-4-phenyl-2,3-dihydropyrrolo[3,4-c]carbazol-6(lH)- yl)propanamide;
4-(2-Chlorophenyl)-9-hydroxy-6-[2-(lH-imidazol-2-ylsulfonyl)ethyl]pyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
3-(9-Ηydroxy-l,3-dioxo-4-phenyl-2,3-dihydropyrrolo[3,4-c]carbazol-6(lH)- yl)propanoic acid;
4-(2-Chlorophenyl)-6-(2,3-dihydroxypropyl)-9-hydroxypyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
2-(4-(2,6-Dichlorophenyl)-9-hydroxy-l,3-dioxo-2,3-dihydropyrrolo[3,4-c]carbazol- 6(lH)-yl)ethyl methanesulfonate;
4-(2-Chlorophenyl)-9-hydroxy-6-[2-(4H-l,2,4-triazol-3-ylsulfanyl)ethyl]pyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
9-Ηydroxy-6-(2-hydroxyethyl)-4-phenylpyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
6-(3-Bromopropyl)-4-(2,6-dichlorophenyl)-9-hydroxypyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
4-(2-Chlorophenyl)-9-hydroxy-6-(3-methoxypropyl)pyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
4-(2-Chlorophenyl)-9-hydroxy-6-(2-hydroxypropyl)pyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
4-(2-Chlorophenyl)-9-hydroxy-6-[(2S)-3-hydroxy-2-methylpropyl]pyrrolo[3,4- c]carbazole-l ,3(2H,6H)-dione; 3-(4-(2-Chlorophenyl)-9-hydroxy-l,3-dioxo-2,3-dihydropyrrolo[3,4-c]carbazol- 6(lH)-yl)-N-[2-(lH-imidazol-5-yl)ethyl]propanamide;
9-Hydroxy-6-(3-hydroxypropyl)-4-(2-methoxyphenyl)pyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
Methyl 3-(4-(2-chlorophenyl)-9-hydroxy-l,3-dioxo-2,3-dihydropyrrolo[3,4- c]carbazol-6(lH)-yl)propanoate;
3-(4-(2-Chlorophenyl)-9-hydroxy-l,3-dioxo-2,3-dihydropyrrolo[3,4-c]carbazol- 6(lH)-yl)-N-[2-(4-moφholinyl)ethyl]propanamide;
4-(4-(2-Chlorophenyl)-9-hydroxy-l,3-dioxo-2,3-dihydropyrrolo[3,4-c]carbazol- 6( 1 H)-yl)butanenitrile;
4-(2-Chloro-6-methoxyphenyl)-9-hydroxy-6-(2-hydroxyethyl)pyrrolo[3,4- c]carbazole-l ,3(2H,6H)-dione;
3-(4-(2-Chlorophenyl)-9-hydroxy-l,3-dioxo-2,3-dihydropyrrolo[3,4-c]carbazol- 6(lH)-yl)-N-[2-(dimethylamino)ethyl]propanamide;
4-(2-Chlorophenyl)-6-(3,4-dihydroxybutyl)-9-hydroxypyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
3-(4-(2-Chloro-6-methoxyphenyl)-9-hydroxy-l,3-dioxo-2,3-dihydropyrrolo[3,4- c]carbazol-6(lH)-yl)-N-[2-(dimethylamino)ethyl]propanamide;
4-(2-Chlorophenyl)-9-hydroxy-6-[(2R)-3-hydroxy-2-methylpropyl]pyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
2-(4-(2-Chlorophenyl)-9-hydroxy-l,3-dioxo-2,3-dihydropyrrolo[3,4-c]carbazol- 6(lΗ)-yl)ethyl methanesulfonate;
4-(2-Chloro-6-methoxyphenyl)-9-hydroxy-6-(3-hydroxypropyl)pyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
9-Ηydroxy-6-(2-hydroxyethyl)-4-(2-methoxyphenyl)pyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
4-(2-Chlorophenyl)-6-(2-hydroxyethyl)-9-hydroxypyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione; 4-(2-Chlorophenyl)-9-hydroxy-6-[3-(methylsulfanyl)propyl]pyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
4-(2-Chlorophenyl)-6-ethyl-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione (VI; Ar=2-chlorophenyl, R=CΗ CΗ3);
4-(2-Chlorophenyl)-9-hydroxy-6-isopropylpyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-Chlorophenyl)-9-hydroxy-6-[3-(lH-imidazol-l-yl)propyl]pyrrolo[3,4- c]carbazole- 1 ,3(2H,6H)-dione;
4-(2-Chloro-6-methoxyphenyl)-9-hydroxy-6-[3-(4-moφholinyl)propyl]pyrrolo[3,4- c]carbazole-l ,3(2H,6H)-dione;
6-(2-Chloroethyl)-4-(2-chlorophenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)- dione;
6-(3-Bromopropyl)-4-(2-chloro-6-methoxyphenyl)-9-hydroxypyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
4-(2-Chlorophenyl)-9-hydroxy-6-[2-hydroxy-3-(methylamino)propyl]pyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
4-(2-Chlorophenyl)-9-hydroxy-6-methylpyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-Chlorophenyl)-9-hydroxy-6-[2-hydroxy-3-(4-moφholinyl)propyl]pyrrolo[3,4- c]carbazole-l ,3(2H,6H)-dione;
4-(2,6-Dichlorophenyl)-9-hydroxy-6-[3-(lH-imidazol-l-yl)propyl]pyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione; and
6-Butyl-4-(2-chlorophenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione.
In a more preferred embodiment of the present invention are compounds according to Formula I in which R9 is hydroxyl and Y* is NR1^ and the bond represented by the dashed line (C — O) is absent.
In an especially preferred embodiment of the present invention are compounds according to Formula I in which R" is hydroxyl and R° is not hydrogen.
In another preferred embodiment of the present invention are compounds according to Formula I in which R9 is hydroxyl and Y* is NR^υ and Rl is aryl. In another especially preferred embodiment of the present invention are compounds according to Formula I in which R8 is not hydrogen, and R9 is hydrogen.
In another especially preferred embodiment of the present invention are compounds according to Formula I in which R8 is not hydrogen, R9 is hydrogen and γl is NR^υ.
Another especially preferred embodiment of the present invention comprises compounds according to Formula I in which R9 is hydrogen and R8 is ((CR5 R^)nT)a(CRl 1
R12)b)-Z; wherein T may be absent or O and Z is NR3R4.
Another especially preferred embodiment of the present invention comprises compounds according to Formula I in which R9 is selected from halogen or hydroxyl and R8 is ((CR5R6)nT)a(CR1 !R12)b)Z wherein T is absent and Z is hydrogen.
The following are definitions of terms used in this specification. The initial definition provided for a group or term herein applies to that group or term throughout the present specification, individually or as part of another group, unless otherwise indicated.
Where stereoisomers or enantiomers exist all possible combinations are claimed.
The terms "halogen" and "halo" refer to fluorine, chlorine, bromine and iodine.
The term "unsaturated ring" includes partially unsaturated and aromatic rings.
The term "alkyl" in the present invention means a straight or branched hydrocarbon radical having from 1 to 8 carbon atoms and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec -butyl, isobutyl, tert-butyl, n-pentyl, iso-pentyl, n-hexyl, and the like. The term "aryl" means an aromatic carbocyclic group having a single ring (e.g., phenyl), multiple rings (e.g., biphenyl), or multiple condensed rings in which at least one is aromatic, (e.g., 1,2,3,4-tetrahydronaphthyl, naphthyl, anthryl, or phenanthryl).
The term "heteroaryl" means an aromatic "heterocycle," "heterocyclic," "heterocyclyl," or "heterocyclo" group as defined below that comprises at least one heteroatom.
The aryl or heteroaryl ring may be optionally substituted with up to five substituents selected from NH(Cι -Cg alkyl), N(Cι-Cζ alkyl)2, thio Ci -Cg alkyl, Ci -Cg alkoxy, hydroxy, carboxy, C\-C() alkoxycarbonyl, halo, nitrile, and cycloalkyl. By "alkoxy" is meant straight or branched chain alkoxy groups having 1 to 10 carbon atoms, such as, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentyloxy, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy.
"Alkynyl" means straight and branched hydrocarbon radicals having from 2 to 8 carbon atoms and one triple bond and includes ethynyl, 3-butyn-l-yl, propynyl, 2-butyn- 1-yl, 3-pentyn-l-yl, and the like.
The terms "cycloalkyl" and "cycloalkenyl" refer to cyclic hydrocarbon groups of 3 to 8 carbon atoms and includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
"Acyl" means an alkyl, aryl, cycloalkyl, heterocycle, heterocyclic, heterocyclyl, or heterocyclo group bonded through a carbonyl group, i.e., R-C(O)-. Typical acyl groups include acetyl, benzoyl, and the like having from 1-10 carbon atoms, preferably 1-6 carbon atoms.
The term "haloalkyl" means an akyl group substituted with 1 to 6 halogen atoms and include trifluoromethyl, trichloromethyl, tribromomethyl, trifluoroethyl, trifluoropropyl, trifluorobutyl , pentafluoroethyl and the like.
The alkyl, alkenyl, alkoxy, and alkynyl groups described above are optionally substituted, preferably by 1 to 3 groups selected from NH(Cι -Cg alkyl), N(Cι -Cg alkyl)2, phenyl, substituted phenyl, thio Cj-Cg alkyl, C^-Cg alkoxy, hydroxy, carboxy, Ci -Cg alkoxycarbonyl, halo, nitrile, cycloalkyl, and a 5- or 6-membered carbocyclic ring or heterocyclic ring having 1 or 2 heteroatoms selected from nitrogen, substituted nitrogen, oxygen, and sulfur. "Substituted nitrogen" means nitrogen bearing Ci -Cβ alkyl or (CH2)pPh where p is 1, 2, or 3. Perhalo and polyhalo substitution is also included.
The term "heteroatom" means an oxygen, nitrogen, sulfur, or phosphorous atom.
The terms "heterocycle," "heterocyclic," "heterocyclyl," or "heterocyclo" refer to fully saturated or unsaturated, including aromatic (heteroaryl) or nonaromatic cyclic groups, for example, 4- to 7-membered monocyclic, 7- to 11 -membered bicyclic, or 10- to 15-membered tricyclic ring systems, which have at least one heteroatom in at least one carbon atom-containing ring. Each ring of the heterocyclic group containing a heteroatom may have 1, 2, 3, or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and/or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized. The heterocyclic group may be attached at any heteroatom or carbon atom of the ring or ring system.
Monocyclic heterocyclic groups include, but are not limited to, piperidine, 2,6- dimethylpiperazine, piperazine, n-methylpiperazine, pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, S(0)-imidazoles, S(0)2-imidazoles oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, moφholine and dimethylmoφoline, 2-thiophene, thiophene, 1 -imidazole, 2- imidazole, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, 2-azepinyl, 4-piperidonyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, moφholinyl, thiamoφholinyl, thiamoφholinyl sulfoxide, thiamoφholinyl sulfone, 1,3-dioxolane and tetrahydro-l,l-dioxothianyl, tetrazole, SO-triazole, SO2~triazole and the like.
Bicyclic heterocyclic groups include , but are not limited to, indolyl, benzothiazolyl, benzoxazolyl, benzodioxolyl, benzothienyl, quinuclidinyl, quinolinyl, tetra-hydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofaryl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl,furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,2-b]pyridinyl or furo[2,3-blpyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such as 3,4- dihydro-4-oxo-quinazolinyl), tetrahydroquinolinyl and the like, tricyclic heterocyclic groups include , but are not limited to, carbazolyl, benzindolyl, phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl and the like.
The term "cancer" includes, but is not limited to, the following cancers: cancers of the breast, ovary, cervix, prostate, testis, esophagus, stomach, skin, lung, bone, colon, pancreas, thyroid, biliary passages, buccal cavity and pharynx (oral), lip, tongue, mouth, pharynx, small intestine, colon-rectum, large intestine, rectum, brain and central nervous system, glioblastoma, neuroblastoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, adenocarcinoma, adenoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder carcinoma, liver carcinoma , kidney carcinoma, myeloid disorders, lymphoid disorders, Hodgkin's, hairy cells, and leukemia. The term "pharmaceutically acceptable salts, esters, amides, and prodrugs" as used herein refers to those carboxylate salts, amino acid addition salts, esters, amides, and prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention. The term "salts" refers to the relatively non- toxic, inorganic and organic acid addition salts of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate mesylate, glucoheptonate, lactobionate and laurylsulphonate salts, and the like. These may include cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. (See, for example, Berge S.M. et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977;66:1-19 which is incoφorated herein by reference.)
The compounds of Formula I are capable of further forming pharmaceutically acceptable formulations comprising salts, including but not limited to acid addition and/or base salts, solvates and N-oxides of a compound of Formula I. This invention also provides pharmaceutical formulations comprising a compound of Formula I together with a pharmaceutically acceptable carrier, diluent, or excipient therefor. All of these forms are within the present invention.
Pharmaceutically acceptable acid addition salts of the compounds of Formula I include salts derived form inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic, phosphorus, and the like, as well as the salts derived from organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Such salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like. Also contemplated are the salts of amino acids such as arginate, gluconate, galacturonate, and the like; see, for example, Berge et al., "Pharmaceutical Salts," J. of Pharmaceutical Science, 1977;66:1-19.
The acid addition salts of the basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt in the conventional manner. The free base form may be regenerated by contacting the salt form with a base and isolating the free base in the conventional manner. The free base forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free base for puφoses of the present invention.
Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metal hydroxides, or of organic amines. Examples of metals used as cations are sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines are N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine, and procaine; see, for example, Berge et al., supra., 1977.
The base addition salts of acidic compounds are prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt in the conventional manner. The free acid form may be regenerated by contacting the salt form with an acid and isolating the free acid in a conventional manner. The free acid forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free acid for puφoses of the present invention.
Examples of pharmaceutically acceptable, non-toxic esters of the compounds of this invention include Ci -Cβ alkyl esters wherein the alkyl group is a straight or branched chain. Acceptable esters also include C5-C7 cycloalkyl esters as well as arylalkyl esters such as, but not limited to benzyl. C1-C4 alkyl esters are preferred. Esters of the compounds of the present invention may be prepared according to conventional methods "March's Advanced
Organic Chemistry, 5th Edition". M. B. Smith & J. March, John Wiley & Sons, 2001.
Examples of pharmaceutically acceptable, non-toxic amides of the compounds of this invention include amides derived from ammonia, primary Ci -Cg alkyl amines and secondary
Ci -C(5 dialkyl amines wherein the alkyl groups are straight or branched chain. In the case of secondary amines the amine may also be in the form of a 5- or 6-membered heterocycle containing one nitrogen atom. Amides derived from ammonia, C1 -C3 alkyl primary amines and Ci -C2 dialkyl secondary amines are preferred. Amides of the compounds of the invention may be prepared according to conventional methods such as "March's Advanced
Organic Chemistry, 5th Edition". M. B. Smith & J. March, John Wiley & Sons, 2001.
The term "prodrug" refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formulae, for example, by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are hereby incoφorated by reference.
The present invention also includes isotopically labelled compounds, which are identical to those recited in Formula I, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incoφorated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine and chlorine, such as 2H, 3H, 13C, nC, 14C, 15N, 180, 170, 31P, P, S, F, and Cl, respectively. Compounds of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically labelled compounds of the present invention, for example those into which radioactive isotopes such as H and C are incoφorated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3H, and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., 2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labelled compounds of Formula I of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples and Preparations below, by substituting a readily available isotopically labelled reagent for a non- isotopically labelled reagent.
The compounds of Formula I and their pharmaceutically acceptable salts can be administered to mammals via either the oral, parenteral (such as subcutaneous, intraveneous, intramuscular, intrasternal and infusion techniques), rectal, intranasal or topical routes. In general, these compounds are most desirably administered in doses ranging from about 10 to about 10,000 mg per day, in single or divided doses (i.e., from 1 to 4 doses per day), although variations will necessarily occur depending upon the species, weight and condition of the subject being treated and the particular route of administration chosen. However, a dosage level that is in the range of about 0.15 mg to about 150 mg per kg of body weight per day is most desirably employed. Nevertheless, variations may occur depending upon the species of animal being treated and its individual response to said medicament, as well as on the type of pharmaceutical formulation chosen and the time period and interval at which such administration is carried out. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effects, provided that such higher dose levels are first divided into several small doses for administration throughout the day.
The compounds of the present invention may be administered alone or in combination with pharmaceutically acceptable carriers or diluents by either of the routes previously indicated, and such administration may be carried out in single or multiple doses. More particularly, the novel therapeutic agents of this invention can be administered in a wide variety of different dosage forms, e., they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, sprays, creams, salves, suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, and the like. Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc. Moreover, oral pharmaceutical compositions can be suitably sweetened and/or flavored. In general, the therapeutically-effective compounds of this invention are present in such dosage forms at concentration levels ranging from about 5.0% to about 70% by weight.
For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine may be employed along with various disintegrants such as starch (and preferably corn, potato or tapioca starch), alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting puφoses. Solid compositions of a similar type may also be employed as fillers in gelatin capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols. When aqueous suspensions and/or elixirs are desired for oral administration, the active ingredient may be combined with various sweetening or flavoring agents, coloring matter or dyes, and, if so desired, emulsifying and/or suspending agents as well, together with such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.
For parenteral administration, solutions of a compound of the present invention in either sesame or peanut oil or in aqueous propylene glycol may be employed. The aqueous solutions should be suitably buffered (preferably pH from about 3 to about 8) if necessary and the liquid diluent first rendered isotonic. These aqueous solutions are suitable for intravenous injection puφoses. The oily solutions are suitable for intra-articular, intramuscular and subcutaneous injection puφoses. The preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.
Additionally, it is also possible to administer the compounds of the present invention topically when treating proliferative cell conditions of the skin and this may be done by way of creams, jellies, gels, pastes, patches, ointments and the like, in accordance with standard pharmaceutical practice.
The activity of the compounds of the present invention is determined by their ability to act as check point abrogators. Checkpoint abrogators inhibit kinases involved in the regulation of the G2 M checkpoint resulting in the reversal of the imposed checkpoint. Weel or Chkl are examples of such kinases. Utilization in cells either having damaged DNA, for instance, but not limited to, DNA damaged by conventional DNA-directed chemotherapeutic agents or by radiation of cells with undamaged DNA presents an opportunity to utilize cellular regulatory pathways to inappropriately and prematurely cause cells to progress into M phase. Such cells may be less likely to survive and further divide since the commitment to M phase was made in the presence of potentially catastrophically damaged DNA. In the case of undamaged cells having no detectable DNA damage, treatment of these cells with the checkpoint abrogators of the present invention may be forced into M phase prematurely with similar cytotoxic effects. ( Alan J. Kraker and Robert N. Booher, "New Cell Cycle Targets,", Ann. Rep. Med. Chem., 1999;34:247-256).
One can identify the checkpoint abrogators of the present invention by measuring the activity in the assays described in Examples 483 (Weel) and 484 (Chkl) and 486 (PKC) and selecting those compounds that have at least 10- fold less activity in the PKC assay than they have in the Weel assay or at least 5-fold less activity in the PKC assay than they have in the Chkl assay.
The present invention is illustrated by the following examples. It will be understood, however, that the invention is not limited to the specific details of these examples. Melting points are uncorrected. Proton nuclear magnetic resonance spectra (Η NMR) and 13C nuclear magnetic resonance spectra were measured for solutions in deuterochloroform (CDC13) or in CD3OD or CD3SOCD3 and peak positions are expressed in parts per million (ppm) downfield from tetramethylsilane (TMS). The peak shapes are denoted as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; b, broad.
The compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms, including hydrated forms, are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention.
The term "animal" refers to mammals, including rodents, bovine, equine, canine, feline, and human.
The compounds of the present invention are useful for treating cancer (for example, leukemia and cancer of the lung, breast, prostate, and skin such as melanoma) and other proliferative diseases including but not limited to psoriasis, HSV, HIV, restenosis, and atherosclerosis in combination with other conventional therapies. To utilize a compound of the present invention to treat cancer, a patient in need of such treatment, such as one having cancer or another cell proliferative diseases is administered an effective amount of the compound of the invention.
Furthermore, the compounds of the present invention are useful for treating cancers when combined as adjuvant therapy with other clinical treatment agents and modalities such as, but not limited to, X-irradiation, beam therapy, conventional chemotherapeutic agents such as gemcitabine, paclitaxel, docetaxel, cisplatin, carboplatin, etoposide, adriamycin, topotecan, CPT-11, capecitabine, or ionizing radiation alkylating agents, antimetabolites, antibodies, DNA intercalators, or other such anti-proliferative agents ultimately leading to DNA damage. As new antineoplastic agents or modalities are discovered, the use of the Weel and /or Chkl inhibitors in combination with these other therapeutic agents or modalities is contemplated.
While the in vivo tests described herein teach administering the compounds according to Formula I simultaneously with or subsequent to the administration of the conventional agent, it is contemplated that the compound of the present invention may also be administered prior to the conventional chemotherapeutic agent or agents.
The following examples illustrate particular embodiments of the invention and are not intended to limit the specification, including the claims, in any way. Those skilled in the art will appreciate that numerous changes and modifications can be made to the preferred embodiments of the invention and that such changes and modifications can be made without departing from the spirit of the invention. It is, therefore, intended that the cover all such equivalent variations as fall within the true spirit and scope of the invention.
The chemical synthesis schemes provided below exemplify the best mode for preparing the compounds of the present invention. This patent describes a number of synthetic transformations known to those skilled in the art. In each case alternative conditions known to one skilled in the art and described in the literature, for instance in Advanced Organic Chemistry 5th Edition, Author: Jerry March,m. b. smith & J. March, John Wiley & Sons 2001; Comprehensive Organic Transformation, Author: Richard C. Larock, The Journal of Organic chemistry, published by the American Chemical Society and the references cited therein) may also lead to the desired product. Known transformations include, but are not limited to; alkylation, dealkylation, oxidation, reduction, Curtus rearrangement, Suzuki reaction, esterification, Wittig reaction, amide formation, hydrogenation, protection, deprotection, hydrolysis, dihydroxylation., ozonolysis, acetylation, and hydroboration.
Sche e 1 - Preparation of substituted 4-aryl pyrrolo[3,4-c]carbazoles
Figure imgf000049_0001
maleimide neat, 175°C
Figure imgf000049_0002
lux
Figure imgf000049_0003
Figure imgf000049_0004
Figure imgf000049_0005
(6) (7)
Figure imgf000049_0006
(8) (I)
SCHEME 1 EX
AMPLE 1
The preparation of Benzyl (2E)-3-(5-methoxy-lH-indol-2-yl)-2-propenoate (2)
Benzyl (triphenylphosphoranylidene)acetate (49.2 g, 0.120 mol) was added to a stirred solution of 5-methoxy-lH-indole-2-carbaldehyde (1) (20.0 g, 0.114 mol) in CH2C12 (500 mL) and the solution was stirred at room temperature for 4 h. The solvent was removed in vacuo and the residue slurried with methanol (200 mL), whereupon crystallisation of the product occurred. The mixture was filtered, washed with several portions of cold methanol, and dried to give benzyl (2E)-3-(5-methoxy-lH-indol-2-yl)-2-propenoate (2) in a 30.46 g, 87 % yield as pale yellow plates; mp 155-157 °C. Η NMR δ (CDC13) 8.28 (s, IH), 7.69 (d, J=16.1 Hz, IH), 7.43-7.32 (m, 5H), 7.23 (d, J=9.1 Hz, IH), 7.03 (d, J=2.3 Hz, IH), 6.92 (dd, J=9.1, 2.3 Hz, IH), 6.74 (d, J=1.8 Hz, IH), 6.24 (d, J=16.1 Hz, IH), 5.26 (s, 2H), 3.84 (s, 3H).Found: C, 74.45; H, 5.62; N, 4.58. C,9Hι7N03 requires C, 74.25; H, 5.57; N, 4.56.
EXAMPLE 2
The preparation of Benzyl 9-methoxy-1.3-dioxo- 1 ,2.3, 3a,4,5,6,l 0c-octahvdropyrrolor3.4- clcarbazole-4-carboxylate 3
Maleimide (4.82 g, 0.050 mol) was added to a solution of benzyl (2E)-3-(5-methoxy- lH-indol-2-yl)-2-propenoate, (12.71 g, 0.041 mol) prepared as in example 1 in THF (150 mL) in a 250 mL flat-bottomed flask and the mixture was stirred until homogeneous. The THF was removed in vacuo and the residue dried under high vacuum for 30 min. The flask was immersed in a 175 °C oil bath and the mixture was stirred at this temperature for 3 h. The solid melt was cooled to room temperature and ethyl acetate (100 mL) was added. The solid mass was partially broken up with a spatula and the mixture was stirred vigorously overnight, after which time the product (3) was present as a cream precipitate. Filtration followed by washing with diethyl ether gave benzyl 9-methoxy-l,3-dioxo-l,2,3,3a,4,5,6,10c- octahydropyrrolo[3,4-c]carbazole-4-carboxylate (13.76 g, 83%), mp 179-181°C. !H NMR δ [(CD3)2SO] 10.98 (br s, IH), 10.87 (s, IH), 7.45-7.32 (m, 5H), 7.20 (d, J=2.4 Hz, IH), 7.17 (d, J=8.7 Hz, IH), 6.69 (dd, J=8.7, 2.4 Hz, IH), 5.21 (s, IH), 4.22 (br d, J=7.8 Hz, IH), 4.14 (dd, J=7.8, 4.2 Hz, IH), 3.75 (s, 3H), 3.19-3.13 (m, IH), 3.00 (dd, J=16.5, 4.8 Hz, IH), 2.79- 2.70 (m, IH).
EXAMPLE 3
The preparation of Benzyl 9-methoxy- 3-dioxo-l,2,3,6-tetrahvdropyrrolor3,4-c1carbazole-4- carboxylate (4)
Activated manganese dioxide (69 g) was added to a solution of benzyl 9-methoxy- l,3-dioxo-l,2,3,3a,4,5,6,10c-octahydropyrrolo[3,4-c]carbazole-4-carboxylate (13.76 g, 0.034 mol), prepared as in example 2, in p-dioxane (300 mL) and the mixture was refluxed with vigorous stirring for 0.5-2 h. The mixture was filtered while hot through a plug of Celite, which was washed exhaustively with a MeOH/p-dioxane (1:1) mixture until the washings were colorless. The combined washings and filtrate were concentrated to dryness and the residue triturated several times with diethyl ether to give benzyl 9-methoxy-l,3-dioxo- l,2,3,6-tetrahydropyrrolo[3,4-c]carbazole-4-carboxylate (4) as a yellow/orange powder (12.47 g, 91.5 %), mp 245 °C. A small sample was recrystallised from EtOAc to give benzyl 9-methoxy-l,3-dioxo-l,2,3,6-tetrahydropyrrolo[3,4-c]carbazole-4-carboxylate as orange cubes; mp 289-292 °C. Η NMR δ [(CD3)2SO] 12.11 (br s, IH), 11.27 (br s, IH), 8.45 (d, J=2.6 Hz, IH), 7.98 (s, IH), 7.59 (d, J=8.9 Hz, IH), 7.55-7.51 (m, 2H), 7.44-7.34 (m, 3H), 7.27 (dd, J=8.9, 2.6 Hz, IH), 5.41 (s, 2H), 3.88 (s, 3H). Found: C, 68.99; H, 4.09; 6.91. C23H16N205 requires C, 69.00; H, 4.03; N, 6.99.
EXAMPLE 4
The preparation of 9-Methoxy-L3-dioxo-l,2,3,6-tetrahydropyrrolor3,4-c1carbazole-4- carboxylic acid (5)
A solution of benzyl 9-methoxy-l,3-dioxo-l,2,3,6-tetrahydropyrrolo[3,4-c]carbazole- 4-carboxylate (2.00 g), prepared as in example 3, in DMF/MeOH (4:1) (50 mL) containing 5% Pd-C (0.50 g) was hydrogenated at 60 psi for 2 h (Parr apparatus). The solution was filtered through a plug of Celite, which was washed 6 times with neat DMF followed by MeOH (several cycles). The combined filtrate and washings were concentrated to dryness in vacuo and the residue was slurried with diethyl ether to give the 9-methoxy-l,3-dioxo- l,2,3,6-tetrahydropyrrolo[3,4-c]carbazole-4-carboxylic acid (5) as a greenish solid. The reaction was repeated 5 times on this scale to and the products were combined to give 9- methoxy-l,3-dioxo-l,2,3,6-tetrahydropyrrolo[3,4-c]carbazole-4-carboxylic acid, (8.1 g, 84%). A portion of the product was purified by adsoφtion onto silica, followed by chromatography on silica, eluting with EtOAc. The product was triturated with diethyl ether to give 9-methoxy-l,3-dioxo-l,2,3,6-tetrahydropyrrolo[3,4-c]carbazole-4-carboxylic acid as an orange solid; mp >300°C. 1H NMR δ [(CD3)2SO] 12.15 (s, IH), 8.42 (d, J=2.5 Hz, IH), 7.97 (s, IH), 7.57 (d, J=8.8 Hz, 1H0, 7.25 (dd, J=8.8, 2.5 Hz, IH), 3.82 (s, 3H), 3.40 (br, 2H). Found: C, 58.69; H, 3.55; N, 8.40. C16H10N2O5.H2O requires C, 58.54; H, 3.68; N, 8.53. EXAMPLE 5
The preparation of 4-Amino-9-methoxypyrrolor3,4-c1carbazole-L3(2H,6H)-dione (6.
Diphenylphosphoryl azide (1.81 mL, 8.38 mmol) was added to a mixture of the 9- methoxy-l,3-dioxo-l,2,3,6-tetrahydropyrrolo[3,4-c]carbazole-4-carboxylic acid (2.55 g, 8.22 mmol), prepared as in example 4 , and Et3N (1.17 mL, 8.38 mmol) in anhydrous t-butanol (300 mL) and the mixture was refluxed under an atmosphere of nitrogen for 16 h. The solution was concentrated in vacuo and the residue partitioned between EtOAc and saturated aqueous NaHC03. Insoluble material was removed by filtration of the two layers through Celite, washing through with more EtOAc. The organic phase was dried, the drying agent was removed and the solution was concentrated to dryness and gave a yellow solid. This material was dissolved in CH Cl2/trifluoroacetic acid (1:1) (200 mL) and the solution was held at room temperature for 1 h. After concentration in vacuo the residue was partitioned between EtOAc and saturated aqueous NaHC0 solution. The EtOAc solution was dried, the drying agent was removed and the solution was concentrated to dryness to give an orange solid which was adsorbed onto silica and chromatographed. Elution with ethyl acetate/petroleum ether (1:1) followed by ethyl acetate and then methanol/ethyl acetate (1 :9) gave 4-amino-9-methoxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione (6) as an orange powder (2.16 g, 93%), mp 342-345 °C. Η NMR δ [(CD3)2SO] 11.18 (s, IH), 10.78 (br s, IH), 8.18 (d, J=2.5 Hz, IH), 7.29 (d, J=8.7 Hz, IH), 7.01 (dd, J=8.7, 2.5 Hz, IH), 6.83 (s, IH), 6.28 (br s, 2H), 3.82 (s, 3H). Found: C, 63.05; H, 3.99; N, 14.05. Cι5HnN303.l/2H2O requires C, 63.04; H, 4.06; N, 14.7.
EXAMPLE 6
The preparation of 4-Iodo-9-methoxypyrrolor3,4-c"|carbazole-l,3(2H,6H)-dione (7)
Concentrated H2S04 (10 mL) was added at room temperature to powdered 4-amino-9- methoxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione (0.50 g, 1.78 mmol), prepared as in example 5, and the mixture was stirred for 5 min and then cooled in an ice bath. An ice-water slurry (ca 40 mL) was added in one portion with vigorous stirring and the mixture was stirred for a further 15 min to give a tan precipitate. When the internal temperature had reached 3 °C a solution of NaN02 (0.18 g, 2.65 mmol) in cold water (1 mL) was added dropwise over 30 seconds and the mixture was stirred for an additional 3 minutes. Powdered urea (74 mg, 1.23 mmol) was added and the mixture was stirred for another 3 min. Finally a suspension of KI (1.46 g, 8.79 mmol) and Cul (1.46 g, 7.66 mmol) in cold water (10 mL) was added and the mixture was stirred vigourously for 5 min, and then warmed slowly to 70 °C and held at this temperature for 1 h. Ethyl acetate was added and the two-phase mixture was filtered through a plug of Celite, washing through with more EtOAc. The combined organic portions were washed with 0.5 N aqueous sodium sulfite solution and were dried, the drying agent was removed and the solution was concentrated to dryness to give an oil which was chromatographed on silica. Elution with EtOAc, then crystallisation of the product from THF/petroleum ether as a gave the 4-Iodo-9-methoxypyrrolo[3,4-c]carbazole-l,3(2H,6H)- dione (7) (0.32 g, 46 %) as a yellow powder; mp 322-325 °C. 1H NMR δ [(CD3)2SO] 11.89 (s, IH), 11.29 (s, IH), 8.40 (d, J=2.6 Hz, IH), 8.18 (s, IH), 7.54 (d, J=8.9 Hz, IH), 7.24 (dd, J=8.9, 2.6 Hz, IH), 3.87 (s, 3H). Found: C, 45.49; H, 2.36; N, 6.92. Cι5H9IN203.l/4H20 requires C, 45.42; H, 2.41; N, 7.06.
EXAMPLE 7
The preparation of 9-Hvdroxy-4-iodopyrrolor3,4-clcarbazole-l,3(2H,6H)-dione (8)
Powdered 4-Iodo-9-methoxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione (0.50 g, 1.27 mmol) prepared as in example 6 was added in one portion to dry, freshly-prepared pyridine hydrochloride melt at 200 °C under a CaCl2 drying tube and the mixture was stirred at this temperature for 15 min. Water was added and the mixture was extracted with EtOAc. The EtOAc extracts were dried, the drying agent was removed and the solution was concentrated to dryness to give a solid which was chromatographed on silica. Elution with EtOAc gave 9- Hydroxy-4-iodopyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione (8) (0.43 g, 89 %) as an orange powder; mp >350 °C. Η NMR δ [(CD3)2SO] 11.76 (br s, IH), 11.24 (br s, IH), 9.29 (br s, IH), 8.27 (d, J=2.4 Hz, IH), 8.13 (s, IH), 7.44 (d, J=8.7 Hz, IH), 7.08 (dd, J=8.7, 2.4 Hz, IH). Found: C, 44.90; H, 1.79; N, 7.14. C,4H7IN2O3 requires C, 44.47; H, 1.87; N, 7.40.
EXAMPLE 8
The preparation of 4-(2-chlorophenyl)-9-hydroxypyrrolo[3,4-clcarbazole-l,3(2H,6H)-dione (9) (I, Ar=2-chlorophenyl)
A mixture of the 9-Hydroxy-4-iodopyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione (41.8 mg, 0.110 mmol) prepared as in example 7 and 2-chlorobenzeneboronic acid (52 mg, 0.332 mmol) in p-dioxane (3 mL) and 2N Na2C03 (0.5 mL) was purged with nitrogen. Pd(dppf)Cl2 (35 mg, 0.011 mmol) was added and the mixture was refluxed under N2 for 4 h and then partitioned between EtOAc and water. The organic layer was dried, the drying agent was removed and the solution was concentrated to dryness, adsorbed onto silica and chromatographed. Elution with EtOAc/petroleum ether (1:4) followed by EtO Ac/petroleum ether (2:3) gave a solid the carbazole (50) which crystallised from EtOAc/petroleum ether to yield 4-(2-chlorophenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione (9) (I, Ar=2- chlorophenyl) (33.1 mg, 83 %) as a yellow powder, mp 215-220 °C (dec). Η NMR δ [(CD3)2SO] 11.83 (br s, IH), 11.01 (br s, IH), 9.27 (br s, IH), 8.32 (d, J=2.4 Hz, IH), 7.65- 7.40 m, 5H), 7.08 (dd, J=8.7, 2.4 Hz), IH). Found: C, 65.72; H, 3.50, N, 6.97. C20HnClN2O3.l/4EtOAc requires C, 65.54; H, 3.40; N, 7.28.
EXAMPLE 9
The preparation of 9-Hvdroxy-4-(3-hvdroxy-4-methoxyphenyl)pyrrolor3,4-clcarbazole- l,3(2H,6H)-dione (10) (I. Ar=3-hvdroxy-4-methoxyphenyl)
The reaction of 9-hydroxy-4-iodopyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione, prepared as in example 7, with 3-hydroxy-4-methoxybenzeneboronic acid according to the procedure described in example 8 gave 9-hydroxy-4-(3-hydroxy-4- methoxyphenyl)pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione (10) (I, Ar=3-hydroxy-4- methoxyphenyl) (51 %), mp 265 °C (dec). 1H NMR δ [(CD3)2SO] 11.67 (s, IH), 10.96 (s, IH), 9.22 (s, IH), 9.15 (s, IH), 8.33 (d, J=2.4 Hz, IH), 7.57 (s, IH), 7.41 (d, J=8.7 Hz, IH), 7.22 (d, J=2.0 Hz, IH), 7.06-6.99 (m, 2H), 6.85 (d, J=8.1 Hz, IH), 3.81 (s, 3H). EIMS found M+: 374.0900. C2]Hι4N205 requires 374.0903.
EXAMPLE 10
The preparation of 9-Hvdroxy-4-(3-thienyl)pyrrolor3,4-clcarbazole- 3(2H,6H)-dione (12) (I. Ar=3-thienyl)
The reaction of 9-hydroxy-4-iodopyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione, prepared as in example 7,with 3-thienylboronic acid according to the procedure described in example 8 gave 9-hydroxy-4-(3-thienyl)pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione (12) (I, Ar=3-thienyl) in a 74 % yield; mp 247 °C (dec). Η NMR δ [(CD3)2SO] 11.73 (br s, IH), 11.05 (br s, IH), 9.24 (s, IH), 9.15 (s, IH), 8.34 (d, J=2.4 Hz, IH), 7.92 (dd, J=5.0, 2.7 Hz, IH), 7.70 (s, IH), 7.61 (dd, J=5.0, 2.7 Hz, IH), 7.51 (dd, J=5.0, 0.9 Hz, IH), 7.42 (d, J=8.7 Hz, IH), 7.06 (dd, J=8.7, 2.4 Hz, IH). Found: C, 61.05; H, 2.96; N, 7.60. Cι8Hι0N2SO3.H2O requires C, 61.36; H, 3.43; N, 7.95. EXAMPLE 11
The preparation of 4-(3-Aminophenyl)-9-hydroxypyrrolor3,4-clcarbazole-1.3('2H,6H)-dione
(15) (I, Ar=3-aminophenyl)
The reaction of 9-hydroxy-4-iodopyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione, prepared as in example 7, with 3-aminobenzeneboronic acid according to the procedure described in example 8 gave 4-(3-aminophenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione (15) (I, Ar=3-aminophenyl) in a 62 % yield; mp 279-284 °C . ]H NMR δ [(CD3)2SO] 11.70 (s, IH), 10.96 (s, IH), 9.22 (s, IH), 8.33 (d, J=2.4 Hz, IH), 7.50 (s, IH), 7.42 (d, J=8.7 Hz, IH), 7.10-7.03 (m, 2H), 6.77-6.74 (m, IH), 6.72-6.68 (m, IH), 6.61 (dd, J=8.1, 2.3 Hz), IH), 5.11 (br s, 2H). Found: C, 69.41; H, 4.12; N, 10.73. C20H N3O3 requires C, 69.96; H, 3.82; N, 12.24.
EXAMPLE 12
The preparation of 4-(4-Aminophenyl>9-hvdroxypyιτolor3,4-c1carbazole- 3(2H,6H)-dione
(16) (I, Ar-4-aminophenyl,
The reaction of 9-hydroxy-4-iodopyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione prepared as in example 7 with 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenylamine according to the procedure described in example 8 gave 4-(4-Aminophenyl)-9-hydroxypyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione (16) (I, Ar=4-aminophenyl) in a 57 % yield; mp 256-258 °C . Η NMR δ [(CD3)2SO] 11.60 (s, IH), 10.92 (s, IH), 9.19 (s, IH), 8.31 (d, J=2.3 Hz, IH), 7.48 (s, IH), 7.39 (d, J=8.6 Hz, IH), 7.30 (d, J=8.4 Hz, 2H), 7.02 (dd, J=8.6, 2.3 Hz, IH), 6.62 (d, J=8.4 Hz, 2H), 5.29 (br s, 2H). Found: C, 68.09; H, 4.34; N, 11.03. C20Hι3N3O3.l/2H2O requires C, 68.17; H, 4.00; N, 11.92.
EXAMPLE 13
The preparation of 4-(2,6-Dimethylphenyl)-9-hydroxypyrrolor3,4-c1carbazole-l ,3(2H,6H)- dione (17) (I, Ar=-2,6-dimethylphenyl)
The reaction of 9-hydroxy-4-iodopyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione, prepared as in example 7, with 2,6-dimethylbenzeneboronic acid according to the procedure described in example 8 gave 4-(2,6-dimethylphenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)- dione (17) (I, Ar=2,6-dimethylphenyl) in a 62 % yield; mp 230-238 °C (dec). ]H NMR δ [(CD3)2SO] 11.72 (s, IH), 10.95 (s, IH), 9.25 (s, IH), 8.32 (d, J=2.3 Hz, IH), 7.44 (d, J=8.7 Hz, IH), 7.35 (s, IH), 7.20 (t, J=7.5 Hz, IH), 7.12 (d, J=7.5 Hz, 2H), 7.06 ((dd, J=8.7, 2.3 Hz, IH), 1.93 (s, 6H). EIMS found M+: 356.1159. C22Hι6N203 requires 356.1161.
EXAMPLE 14
The preparation of 4-(2 -Dichlorophenyl)-9-hvdroxypyrrolor3.4-c]carbazole- 3(2H.6H)- dione (18) (I, Ar=2,3-dichlorophenyl)
The reaction of 9-hydroxy-4-iodopyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione, prepared as in example 7, with 2,3-dichlorobenzeneboronic acid according to the procedure described in example 8 gave 4-(2,3-dichlorophenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)- dione (18) (I, Ar=2,3-dichlorophenyl) in a yield 27 %; mp 233-235 °C. Η NMR δ [(CD3)2SO] 11.87 (br, IH), 11.05 (br, IH), 9.29 (br, IH), 8.31 (d, J=2.5 Hz, IH), 7.74-7.70 (m, IH), 7.55 (s, IH), 7.48-7.45 (m, 3H), 7.09 (dd, J=8.7, 2.5Hz, IH). Found: C, 59.19; H, 3.04; N, 6.56. C20Hι0Cl2N2O3.l/2H2O requires C, 59.13; H, 2.73; N, 6.89.
EXAMPLE 15
The preparation of 4-(2,6-Dimethoxyphenyl)-9-hvdroxypyrrolor3,4-c"|carbazole-L3(2H,6H)- dione (19) (I, Ar=2,6-dimethoxyphenyl)
The reaction of 9-hydroxy-4-iodopyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione, prepared as in example 7, with 2,6-dimethoxybenzeneboronic acid according to the procedure described in example 8 gave 4-(2,6-dimethoxyphenyl)-9-hydroxypyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione (19) (I, Ar=2,6-dimethoxyphenyl) in a 43 % yield; mp 275-277 °C (dec). !H NMR δ [(CD3)2SO] 11.62 (br s, IH), 10.83 (br s, IH), 9.21 (br s, IH), 8.29 (d, J=2.4 Hz, IH), 7.42 (s, IH), 7.41 (d, J=8.4 Hz, IH), 7.35 (t, J=8.4 Hz, IH), 7.04 (dd, J=8.4, 2.4 Hz, IH), 6.75 (d, J=8.4 Hz, 2H), 3.63 (s, 6H). Found: C, 66.31; H, 4.50, N, 6.70. C22H16N205.1/2H20 requires C, 66.49; H, 4.31; N, 7.04.
EXAMPLE 16
The preparation of 9-Hvdroxy-4-(2-methoxyphenyl)pyrrolor3,4-c1carbazole-l,3(2H.6H,- dione (20) (I, Ar=2-methoxyphenyl)
The reaction of 9-hydroxy-4-iodopyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione, prepared as in example 7, with 2-methoxybenzeneboronic acid according to the procedure described in example 8 gave 9-hydroxy-4-(2-methoxyphenyl)pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione (20) (I, Ar=2-methoxyphenyl) in a 75 % yield, mp 216 °C. JH NMR δ [(CD3)2SO] 11.70 (s. 1H), 10.90 (s, IH), 9.23 (s, IH), 8.31 (d, J=2.4 Hz, IH), 7.50 (s, IH), 7.43 (d, J=8.0 Hz, IH), 7.43-7.38 (m, IH), 7.31 (dd, J--8.0, 2.4 Hz, IH), 7.11-7.01 (m, 3H), 3.68 (s, 3H). Found: C, 69.21; H, 3.80; N, 7.58. C2ιH,4N204.l/4H20 requires C, 69.51; H, 4.03; N, 7.72.
EXAMPLE 17
The preparation of 9-Hvdroxy-4-(4-hvdroxymethylphenyl)pyrrolor3,4-clcarbazole- l,3f2H,6H)-dione (21) ( Ar=4-hvdroxymethylphenyl)
The reaction of 9-hydroxy-4-iodopyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione, prepared as in example 7, with 4-hydroxymethylbenzeneboronic acid according to the procedure described in example 8 gave 9-hydroxy-4-(4-hydroxymethylphenyl)pyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione (21) (I, Ar=4-hydroxymethylphenyl) in a 34 % yield ; mp 266-271 °C. 1H NMR δ [(CD3)2SO] 11.74 (br s, IH), 11.00 (br s, IH), 9.25 (br s, IH), 8.34 (d, J=2.4 Hz, IH), 7.56 (d, J=8.3 Hz, 2H), 7.56 (s, IH), 7.43 (d, J=8.7 Hz, IH), 7.40 (d, J=8.3 Hz, IH), 7.06 (dd, J=8.7, 2.4 Hz, IH), 5.27 (t, J=5.7 Hz, IH), 4.59 (d, J=5.7 Hz, 2H). Found: C, 69.74; H, 4.04; N, 7.57. C2ιH,4N204.l/4H 0 requires C, 69.51; H, 4.02; N, 7.72.
EXAMPLE 18
The preparation of 9-Hvdroxy-4-(2-trifluoromethylphenyl)pyrrolor3,4-c1carbazole- l,3(2H,6H)-dione (22) (I. Ar=2-trifluoromethylphenyl)
The reaction of 9-hydroxy-4-iodopyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione, prepared as in example 7, with 2-trifluoromethylbenzeneboronic acid according to the procedure described in example 8 gave 9-Hydroxy-4-(2-trifluoromethylphenyl)pyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione (22) (I, Ar=2-trifluoromethylphenyl) in a 47 % yield, mp 210 °C (dec). Η NMR δ [(CD3)2SO] 11.81 (br s, IH), 11.01 (br s, IH), 9.30 (br s, IH), 8.31 (d, J=2.4 Hz, IH), 7.86 (br d, J=7.2 Hz, IH), 7.75-7.64 (m, 2H), 7.51 (s, IH), 7.49 (br d, J=7.6 Hz, IH), 7.46 (d, J=8.7 Hz, IH), 7.09 (dd, J=8.7, 2.4 Hz, IH). E S found M÷: 396.0721. C2]HuF3N203 requires 396.0722.
EXAMPLE 19
The preparation of 9-Hvdroxy-4-(4-hydroxy-3-methoxyphenyl,pyrrolor3,4-clcarbazole- 1.3(2H,6H)-dione (23) (I, Ar--4-hvdroxy-3-methoxyphenyl)
The reaction of 9-hydroxy-4-iodopyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione, prepared as in example 7, with 2-methoxy-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenol according to the procedure described in example 8 gave 9-hydroxy-4-(4-hydroxy-3- methoxyphenyl)pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione (23) (I, Ar=4-hydroxy-3- methoxyphenyl) in a 58 % yield; mp 290-295 °C (dec). !H NMR δ [(CD3)2SO] 11.67 (br s, IH), 10.97 (br s, IH), 9.22 (br s, IH), 9.15 (s, IH), 8.33 (d, J=2.4 Hz, IH), 7.57 (s, IH), 7.41 (d, J=8.6 Hz, IH), 7.23 (d, J=2.0 Hz, IH), 7.04 (m, 2H), 6.86 (d, J=8.1 Hz, IH), 3.82 (s, 3H). FABMS found [M+H]+: 375.0973. C2ιHι5N205 requires 375.0981.
EXAMPLE 20
The preparation of 4-(2-Ethylphenyl)-9-hvdroxypyrrolor3.4-c1carbazole-l ,3(2H.6H)-dione (501) (I; Ar=2-ethylphenyl)
The reaction of 9-hydroxy-4-iodopyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione, prepared as in example 7, with 2-ethylbenzeneboronic acid according to the procedure described in example 8 gave 4-(2-Ethylphenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione (501) (I; Ar=2-ethylphenyl) in a 69 % yield; mp (MeOHyCH2Cl2/hexane) 273-275 °C. Η NMR [(CD3)2SO] δ 11.73 (br s, IH), 10.95 (br s, IH), 9.25 (s, IH), 8.32 (d, J-=2.4 Hz, IH), 7.44 (s, IH), 7.44 (d, J=8.6 Hz, IH), 7.36 (td, J=7.2, 1.5 Hz, IH), 7.33 (dd, J=8.1, 2.2 Hz, IH), 7.25 (td, J=7.0, 1.8 Hz, IH), 7.20 (dd, J=7.5, 1.2 Hz, IH), 7.07 (dd, J=8.7, 2.5 Hz, IH), 2.42 (m, 2H), 0.96 (t, J=7.6 Hz, 3H). Found: C, 73.83; H, 4.46; N, 7.82. C22Hι6N203 requires C, 74.15; H, 4.53; N, 7.86.
EXAMPLE 21
The preparation of 9-Hvdroxy-4-r2-(hydroxymethyl)phenyllpyrrolor3,4-c1carbazole- 1.3(2H,6H)-dione (503) (I; Ar=2-(hvdroxymethyl)phenyl)
The reaction of 9-hydroxy-4-iodopyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione, prepared as in example 7, with 2-(hydroxymethyl)benzeneboronic acid cyclic monoester according to the procedure described in example 8 gave 9-Hydroxy-4-[2- (hydroxymethyl)phenyl]pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione (503) (I; Ar=2- (hydroxymethyl)ρhenyl) in a 57 % yield , mp (T-HF/CH2Cl2/hexane) 270-280 °C (dec). ]H NMR [(CD3)2SO] δ 11.76 (br s, IH), 10.96 (br s, IH), 9.25 (br s, IH), 8.32 (d, J=2.4 Hz, IH), 7.57 (d, J=7.6 Hz, IH), 7.47 (s, IH), 7.44 (d, J=8.5 Hz, IH), 7.43 (td, J=7.6, 1.2 Hz, IH), 7.31 (td, J=7.4, 0.9 Hz, IH), 7.23 (dd, J=7.5, 1.0 Hz, IH), 7.06 (dd, J=8.7, 2.5 Hz, IH), 5.00 (t, J=5.4 Hz, IH), 4.33 (dd, J=13.6, 5.2 Hz, IH), 4.24 (dd, J=13.5, 5.3 Hz, IH). Found: C, 68.41; H, 4.29; N, 7.59. C2ιHι4N204.l/2 H20 requires C, 68.66; H, 4.12; N, 7.63. EXAMPLE 22
The preparation of 4-(2-Ethoxyphenyl)-9-hvdroxypyrrolo 3,4-clcarbazole-l ,3(2H.6H)-dione (504) (I; Ar=2-ethoxyphenyl)
The reaction of 9-hydroxy-4-iodopyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione, prepared as in example 7, with 2-ethoxybenzeneboronic acid according to the procedure described in example 8 gave 4-(2-ethoxyphenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione (504) (I; Ar=2-ethoxyphenyl) in a 74 % yield ; mp (THF/CH2Cl2/hexane) 190-193 °C (dec). Η NMR [(CD3)2SO] δ 11.71 (br s, IH), 10.91 (br s, IH), 9.23 (s, IH), 8.31 (d, J=2.4 Hz, IH), 7.51 (s, IH), 7.43 (d, J=8.7 Hz, IH), 7.38 (td, J=7.8, 1.7 Hz, IH), 7.33 (dd, J=7.5, 1.7 Hz, IH), 7.07 (br d, J=6.7 Hz, IH), 7.05 (dd, J=8.7, 2.3 Hz, IH), 7.02 (dd, J=7.3, 6.6 Hz, IH), 3.97 (q, J=6.7 Hz, 2H), 1.11 (t, J=6.9 Hz, 3H). Found: C, 70.63; H, 4.74; N, 6.88. C22Hι6N204.l/4 THF requires C, 70.76; H, 4.65; N, 7.18.
EXAMPLE 23
The preparation of 9-Hydroxy-4-(2-thienyl)pyrrolor3,4-c~lcarbazole-l,3(2H,6H)-dione (505) (I; Ar=2-thienyl)
The reaction of 9-hydroxy-4-iodopyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione prepared as in example 7 with 2-thiopheneboronic acid according to the procedure described in example 8 gave 9-hydroxy-4-(2-thienyl)pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione (505) (I; Ar=2-thienyl) in a 69 % yield; mp (THF/CH2Cl2/hexane) 179-184 °C (dec). 1H NMR [(CD3)2SO] δ 11.75 (br s, IH), 11.11 (br s, IH), 9.26 (br s, IH), 8.34 (d, J=2.4 Hz, IH), 7.75 (s, IH), 7.73 (dd, J=3.6, 1.0 Hz, IH), 7.68 (dd, J=5.1, 1.3 Hz, IH), 7.43 (d, J=8.7 Hz, IH), 7.20 (dd, J=5.1, 3.6 Hz, IH), 7.07 (dd, J=8.7, 2.5 Hz, IH). Found: C, 62.38; H, 3.11; N, 7.74. Cι8H,0N2O3S.3/4 H20 requires C, 62.15; H, 3.33; N, 8.05.
EXAMPLE 24
The preparation of 3-(9-Hvdroxy- 3-dioxo-l,2,3,6-tetrahydropyrrolo[3,4-c1carbazol-4- yPbenzaldehvde (507) (I; Ar=3-formylphenyl)
The reaction of 9-hydroxy-4-iodopyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione, prepared as in example 7, with 3-formylbenzeneboronic acid according to the procedure described in example 8 gave 3-(9-Hydroxy-l,3-dioxo-l,2,3,6-tetrahydropyrrolo[3,4-c]carbazol-4- yl)benzaldehyde (507) (I; Ar=3-formylphenyl) in a 69 % yield; mp (THF/CH2Cl2/pentane) 280-286 °C (dec). Η NMR [(CD3)2SO] δ 11.82 (br s, IH), 11.07 (br s, IH), 10.11 (s, IH), 9.27 (br s, IH), 8.35 (d, J=2.4 Hz, IH), 8.14 (t, J=1.4 Hz, IH), 7.97 (m, 2H), 7.70 (t, J=7.7 Hz, 2H), 7.65 (s, IH), 7.46 (d, J=8.7 Hz, IH), 7.08 (dd, J=8.7, 2.5 Hz, IH). FABMS found [M+H]+: 357.0857. C21Hι3N204 requires 357.0875.
EXAMPLE 25
The preparation of 9-Hvdroxy-4-r2-(methv]sulfanyl)phenyllpyrrolor3.4-c1carbazole- l,3(2H.6H)-dione (508) (I; Ar=2-(methylsulfanyl)phenyl)
The reaction of 9-hydroxy-4-iodopyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione, prepared as in example 7, with 2-(methylthio)benzeneboronic acid according to the procedure described in example 8 gave 9-hydroxy-4-[2-(methylsulfanyl)phenyl]pyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione (508) (I; Ar=2-(methylsulfanyl)phenyl) in a 72 % yield, mp (MeOH/CH2Cl2/hexane) 208-216 °C. Η NMR [(CD3)2SO] δ 11.76 (br s, IH), 10.95 (br s, IH), 9.25 (br s, IH), 8.31 (d, J=2.5 Hz, IH), 7.47 (s, IH), 7.44 (d, J=8.6 Hz, IH), 7.43 (td, J=7.3, 2.2 Hz, IH), 7.38 (br d, J=7.5 Hz, IH), 7.27 (dd, J=7.8, 2.2 Hz, IH), 7.24 (td, J=7.3, 1.3 Hz, IH), 7.07 (dd, J=8.7, 2.5 Hz, IH), 2.32 (s, 3H). Found: C, 66.55; H, 3.88; N, 7.38. C2ιHι4N203S.l/4 H20 requires C, 66.57; H, 3.86; N, 7.39.
EXAMPLE 26
The preparation of 4-(9-Hvdroxy- 3-dioxo- 2,3.6-tetrahvdropyrrolor3,4-c1carbazol-4- yPbenzaldehvde (509) (I; Ar=4-formylphenyl)
The reaction of 9-hydroxy-4-iodopyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione, prepared as in example 7, with 4-formylbenzeneboronic acid according to the procedure described in example 8 gave 4-(9-hydroxy-l,3-dioxo-l,2,3,6-tetrahydropyrrolo[3,4-c]carbazol-4- yl)benzaldehyde (509) (I; Ar=4-formylphenyl) in a 52 % yield; mp (THF/CH2Cl2/pentane) 276-280 °C. Η NMR [(CD3)2SO] δ 11.84 (br s, IH), 11.07 (br s, IH), 10.11 (s, IH), 9.28 (br s, IH), 8.34 (d, J=2.3 Hz, IH), 8.00 (d, J=8.2 Hz, 2H), 7.85 (d, J=8.1 Hz, 2H), 7.65 (s, IH), 7.46 (d, J=8.7 Hz, IH), 7.08 (dd, J=8.7, 2.4 Hz, IH). Found: C, 68.43; H, 4.16; N, 7.26. C2)Hι2N204.3/4 H20 requires C, 68.20; H, 3.68; N, 7.57. FABMS found [M+H]+: 357.0841. C2ιH)3N204 requires 357.0875. EXAMPLE 27
The preparation of 9-Hvdroxy-4-r2-(methylsulfjnyl)phenyl]pyrrolor3,4-clcarbazole- (2H,6H)-dione (510) (I; Ar=2-(methylsulfinyl)phenyl)
A mixture of the 9-hydroxy-4-[2-(methylsulfanyl)phenyl]pyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione (508) (34.5 mg, 0.092 mmol), prepared according to example 25, and 2- phenylsulfonyl-3-phenyloxaziridine (Davis reagent) (26.5 mg, 0.102 mmol) in THF (10 mL) was stirred at 20 °C for 2.5 h, then adsorbed directly onto silica gel and chromatographed. Elution with 0-3% MeOH/CH2Cl2 then 3-4% MeOH/CH2Cl2 gave (after crystallisation from THF/CH2Cl2/pentane) the 9-Hydroxy-4-[2-(methylsulfinyl)phenyl]pyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione (510) (I; Ar=2-(methylsulfinyl)phenyl) in a 86 % yield as a yellow solid; mp 321-323 °C. ]H NMR [(CD3)2SO] δ 11.86, 11.85 (2br s, IH), 11.09 (br s, IH), 9.30 (br s, IH), 8.32 (d, J=2.4 Hz, IH), 8.04, 7.97 (2d, J=7.6 Hz, IH), 7.74 (t, J=7.6 Hz, IH), 7.65, 7.62 (2t, J=7.4 Hz, IH), 7.62, 7.54 (2s, IH), 7.47 (d, J=9.1 Hz, IH), 7.44 (d, J=8.4 Hz, IH), 7.09 (dd, J--8.7, 2.5 Hz, IH), 2.43, 2.31 (2s, 3H). Found: C, 64.60; H, 3.88; N, 6.87. C2]H14N204S requires C, 64.61; H, 3.61; N, 7.18.
EXAMPLE 28
The preparation of 9-Hvdroxy-4-(4-hvdroxyphenyl)pyrrolor3,4-clcarbazole-L3(2H,6H)- dione (24) (I, Ar=4-hydroxyphenyl)
The reaction of 9-hydroxy-4-(4-methoxyphenyl)pyrrolo[3,4-c]carbazole-l,3(2H,6H)- dione prepared as decribed in example 34 with BBr3 using the procedure described in example 80 of Scheme 2 gave 9-Hydroxy-4-(4-hydroxyphenyl)pyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione (24) (I, Ar=4-hydroxyphenyl) in a 92 % yield; mp 230 °C (dec). Η NMR δ [(CD3)2SO] 11.67 (s, IH), 10.96 (s, IH), 9.59 (s, IH), 9.22 (s, IH), 8.32 (d, J=2.4 Hz, IH), 7.51 (s, IH), 7.43 (d, J=8.7 Hz, IH), 7.41 (d, J=8.6 Hz, 2H), 7.04 (dd, J=8.7, 2.4 Hz, IH), 6.84 (d, J=8.6 Hz, 2H). FABMS found [M+H]+: 345.0875. C20Hι3N2O4 requires 345.0875.
EXAMPLE 29
The preparation of 9-Hvdroxy-4-(3-hvdroxyphenyl)pyrrolor3,4-clcarbazole-l,3(2H,6H)- dione (25) (I, Ar=3-hydroxyphenyl)
9-Hydroxy-4-(3-methoxyphenyl)pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione (prepared as decribed in example 35) was reacted with BBr3 using the procedure described in the proceedure described in example 80 of Scheme 2 to give 9-hydroxy-4-(3- hydroxyphenyl)pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione (25) (I, Ar=3-hydroxyphenyl) in a yield of 88 %; p 282-285 °C (dec). *H NMR δ [(CD3)2SO] 11.73 (br s, IH), 11.00 (br s, IH), 9.48 (br s, IH), 9.24 (s, IH), 8.34 (d, J=2.4 Hz, IH), 7.54 (s, IH), 7.43 (d, J=8.7 Hz, IH), 7.24 (dd, J=7.7, 7.7 Hz, IH), 7.05 (dd, J=8.7, 2.4 Hz, IH), 7.01-6.96 (m, 2H), 6.82 (dd, J=8.2, 2.1 Hz, IH). FABMS found [M+H]+: 345.0865. C20Hι3N2O4 requires 345.0875.
EXAMPLE 30
The preparation of 4-(2-Chloro-6-hvdroxyphenv])-9-hvdroxypyrrolor3,4-clcarbazole- l,3(2H,6H)-dione (26) (I, Ar=2-chloro-6-hvdroxyphenyl)
4-(2-Chloro-6-methoxyphenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)- dioneprepared as in example 33 was reacted with BBr3 using the procedure described in example 80 of Scheme 2 to give 4-(2-Chloro-6-hydroxyphenyl)-9-hydroxypyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione (26) (I, Ar=2-chloro-6-hydroxyphenyl) in a yield of 70 %; m.p. 228-235 °C. Η NMR δ [(CD3)2SO] 11.73 (s, IH), 10.94 (s, IH), 9.75 (br s, IH), 9.25 (s, IH), 8.30 (d, J=2.4 Hz, IH), 7.45 (s, IH), 7.44 (d, J=8.7 Hz, IH), 7.23 (dd, J=8.1, 8.1 Hz, IH), 7.07 (dd, J=8.7, 2.4 Hz, IH), 6.99 (d, J=8.1 Hz, IH), 6.90 (d, J=8.1 Hz, IH). FABMS found [M+Hf: 381.0461, 379.0479. C20Hι2ClN2O4 requires 381.0456, 379.0486.
Compounds described in examples 31-35 were prepared in an array manner by reaction of the iodide (8) prepared as described in Example 7 with the appropriate substituted arylboronic acid using the procedure described in Example 8.
EXAMPLE 31
The preparation of 4-(3-Chlorophenyl)-9-hvdroxypyιτolof3,4-c1carbazole-l,3(2H,6H)-dione (I; Ar=3-chlorophenyl) (866) by reaction with 3-chlorobenzeneboronic acid. Found [M+H]+: 363.
EXAMPLE 32
The preparation of 4-(4-Chlorophenyl)-9-hvdroxypyrrolor3,4-c1carbazole- 3(2H,6H)-dione (I; Ar=4-chlorophenyl) (867) by reaction with 4-chlorobenzeneboronic acid. Found [M+H]+: 363. EXAMPLE 33
The preparation of 4-(2-Chloro-6-methoxyphenyl)-9-hydroxypyrrolor3.4-c1carbazole- 3(2H,6H)-dione (I; Ar=2-chloro-6-methoxyphenyl) (868) by reaction with 2-chloro-6- methoxybenzeneboronic acid. Found [M+H]+: 393.
EXAMPLE 34
The preparation of 9-Hvdroxy-4-(4-methoxyphenyl)pyrrolor3,4-clcarbazole-L3(2H,6H)- dione (I; Ar=4-methoxyphenyl) (870) by reaction with 4-methoxybenzeneboronic acid. Found [M+Η]+: 359
EXAMPLE 35
The preparation of 9-Hvdroxy-4-(3-methoxyphenyl)pyrrolor3,4-clcarbazole- 3(2H,6H)- dione (I; Ar=4-methoxyphenyl) by reaction with 4-methoxybenzeneboronic acid. Found [M+Η]+: 359
EXAMPLE 36
The preparation of a series of compounds using multiple parallel synthetic techquires from 9-hydroxy-4-iodopyrrolor3,4-clcarbazole-l,3(2H.6H)-dione prepared as in Example 7
Combichem Procedure 1
In a 8 ml screw cap vial was added a solution of 9-Hydroxy-4-iodo-6H-pyrrolo[3,4- c]carbazole-l,3-dione, ( 0.1 mmol) prepared as in example 7 in dioxane (1 ml), a solution of Reagent 1 (see table) ( 0.1 mmol) in 1: 1 dioxane/2.5 M K2C03 (1 ml) and [l,l'Bis(diphenylphosphino)feιτocene]-dichloropalladium(II) complex with dichloromethane (0.003 g, 0.0037 mmol). The vial was capped and the reaction mixture was shaken for 4 hours at 90 °C. After cooling to room temperature, the solution was was removed under vacuum. Purification was carried out via reverse-phase HPLC (3% n-propanol in acetonitrile and 3% n-propanol in water as the eluent; C-18 column). The products were characterised by mass spectral analysis ( See Table 1).
Combichem Procedure 2
In a 8 ml screw cap vial was added a solution of 9-Hydroxy-4-iodo-6H-pyrrolo[3,4- c]carbazole-l,3-dione, (0.1 mmol) prepared as in example 7 in anhydrous toluene (1 ml), a solution of Reagent 1 (see table) in 1:1 anhydrous toluene/dimethylformamide (1 ml) and a solution of 0.05 M palladium(II) diacetate plus 0.2 M o-dicyclohexylphosphinobiphenyl in anhydrous toluene (20 μl), and 40 mg of K3P0 -2H20 under N2. The vial was capped and the reaction mixture was shaken for 20 hours at 100°C. After cooling to room temperature, the solution was was removed under vacuum. Purification was carried out via reverse-phase HPLC (3% n-propanol in acetonitrile and 3% n-propanol in water as the eluent; C-18 column). The products were characterised by mass spectral analysis ( See Table 1).
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
1. NBS
Me PPhjBr 1. HBr/HOAc
2. PPh 2- PPh3 Ar METHOD 10a A rr
METHOD 10b r' OH
Ar
SCHEME 2
Scheme 2 Procedures
Representative Procedure for Method 2 of Scheme 2
EXAMPLE 37
The preparation of 2-[2-(2-Chlorophenyl)ethenyll-5-methoxy-lH-indole (II; Ar=2- chlorophenyl) (27)
Lithium diisopropyl amide (34.4 mL of a 1.5 N solution, 0.052 mol) was added dropwise under nitrogen to a suspension of benzyl(triphenyl)phosphonium chloride (20.17 g, 0.048 mol) in dry THF (200 mL) and the solution was stirred at room temperature for 15 min. A solution of the 5-methoxy-lH-indole-2-carbaldehyde (1) (6.99 g, 0.040 mol) in THF (30 mL) was added and stirring was continued at room temperature for 15 min and then the reaction mixture was heated at reflux for 6 h. The cooled solution was diluted with water, extracted with EtOAc and the organic phase was dried, the drying agent was removed and the solution was concentrated to dryness to give an oil which was adsorbed onto silica and chromatographed on silica. Elution with ethyl acetate/petroleum ether (1:1) gave 2-[2-(2- Chlorophenyl)ethenyl]-5-methoxy-lH-indole (27) as a mixture of E/Z isomers in a yield of 9.76 g, 87%. Crystallisation of a small samplefrom methanol afforded pure E-isomer, mp 135-137°C. 1H NMR δ (CDC13) 11.39 (s, IH), 7.86 (dd, J=7.8, 1.5 Hz, IH), 7.49 (dd, J=8.0, 1.2 Hz, IH), 7.43 (d, J=16.4 Hz, IH), 7.37 (m, IH), 7.31-7.23 (m, 3H), 7.01 (d, J=2.4 Hz, IH), 6.77 (dd, J=8.7, 2.4 Hz, IH), 6.56 (s, IH), 3.75 (s, 3H). Found: C, 72.01; H, 5.03; N, 4.98. CπHι4ClNO requires C, 71.96; H, 4.79; N, 4.94.
Representative Procedure for Method 3 of Scheme 2
EXAMPLE 38
The preparation of l-(3-{ rtert-Butyl(dimethyl)silyl1oxy)propyl)-2-r2-(2-chlorophenyl)
Figure imgf000068_0001
Sodium hydride (1.05 g of a 50% dispersion in mineral oil, 0.022 mol) was added to a solution of the 2-[2-(2-Chlorophenyl)ethenyl]-5-methoxy-lH-indole prepared according to example 37 (4.13 g, 0.014 mol) in DMF (30 mL) and the solution was stirred at room temperature for 5 min. 3-Bromopropyl tert-butyl(dimethyl)silyl ether (4.04 g, 0.016 mol) was added and stirring was continued for 2 h. The solution was diluted with water, extracted with EtOAc which was washed well with brine and the organic phase was dried, the drying agent was removed and the solution was concentrated to dryness to give l-(3-{ [tert- Butyl(dimethyl)silyl]oxy}propyl)-2-[2-(2-chlorophenyl)ethenyl]-5-methoxy-lH-indole.(28) as an oily solid (4.98 g) (as a mixture of E/Z isomers) which was used without further purification.
EXAMPLE 39
The preparation of 6-(3-( rtert-ButvKdimethvDsilylloxy )propyl)-4-(2-chlorophenyl)-9- methoxypyrrolor3,4-clcarbazole-l ,3(2H,6H)-dione (V; Ar=2-chlorophenyl, R10--:CH CH7CH7OSiMe2t-Bu) (29) l-(3-{[tert-Butyl(dimethyl)silyl]oxy}propyl)-2-[2-(2-chlorophenyl)ethenyl]-5- methoxy-lH-indole prepared according to example 38 was reacted with maleimide according to the procedure described in example 68 except that the reaction time was 16 h. The resultant product was reacted with Mn02 according to the procedure described in example 81 except that the reaction time was 8 h. Following chromatography on silica the product was triturated with diethyl ether to give 6-(3-{ [tert-Butyl(dimethyl)silyl]oxy}propyl)- 4-(2-chlorophenyl)-9-methoxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione (29) in a 4.87 g, 61 % yield, as a yellow solid; mp 199-201 °C. Η NMR δ [(CD3)2SO 11.12 (br, IH), 8.52 (d, J=2.6 Hz, IH), 7.75 (s, IH), 7.66 (d, J=8.9 Hz, IH), 7.57 (dd, J=8.3 Hz, IH), 7.5-7.4 (m, 3H), 7.30 (dd, J=8.9, 2.6 Hz, IH), 4.53 (t, J=6.4 Hz, 2H), 3.90 (s, 3H), 3.55 (t, J=5.8 Hz, 2H), 1.94 (m, 2H), 0.77 (s, 9H), -0.06 (s, 3H). Found: C, 65.72; H, 6.09; N, 5.19. C30H32ClSiN2O4 requires C, 65.74; H, 5.88; N, 5.11.
EXAMPLE 40
The preparation of 4-(2-Chlorophenyl)-6-(3-hvdroxypropyl)-9-methoxypyrrolor3,4- clcarbazole-1.3(2H.6H)-dione (V; Ar=2-chlorophenyl. R10-- CH7CH7θH) (31)
3N HCI (50 mL) was added to a solution of 6-(3-{ [tert-Butyl(dimethyl) silyl]oxy}propyl)-4-(2-chlorophenyl)-9-methoxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione (4.87 g, 8.85 mmol) prepared according to example 39 in 1 :1 THF/methanol (200 mL). After stirring at room temperature for 2 h most of the solvents were removed in vacuo, the residue was extracted with ethyl acetate, washed well with water and the organic portion was concentrated to a volume of 60 mL. Petroleum ether was added to precipitate the product, which was filtered off and triturated several times with diethyl ether. The solid was crystallised from THF/petroleum ether and gave 4-(2-Chlorophenyl)-6-(3-hydroxypropyl)-9- methoxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione (V; Ar=2-chlorophenyl, R10=CH2CH2CH2OH) (31)in a 3.77 g, 88 % yield as a yellow powder; mp 228-230 °C. 1H NMR δ [(CD3)2SO] 11.12 (br s, IH), 8.52 (d, J=2.5 Hz, IH), 7.80 (s, IH), 7.70 (d, J=8.9 Hz, IH), 7.58 (dd, J=8.1, 2 2 Hz, IH), 7.53-7.42 (m, 3H), 7.31 (dd, J=8.9, 2.5 Hz, IH), 4.63 (br, IH), 4.53 (t, J=6.9 Hz, 2H), 3.91 (s, 3H), 3.40 (m, 2H), 1.91 (m, 2H). Found: C, 66.00; H, 4.23; N, 6.55. C24H,9C1N204 requires C, 66.29; H, 4.40; N, 6.44.
EXAMPLE 41
The preparation of 2-{2-r2-(2-Chlorophenyl)ethenyll-5-methoxy-lH-indol-l-yl )ethanol (III;
Figure imgf000069_0001
Alkylation of 2-[2-(2-Chlorophenyl)ethenyl]-5-methoxy-lH-indole (27) prepared according to example 37 with 2-bromoethyl tetrahydro-2H-pyran-2-yl ether using the procedure described in example 38 followed by reaction of the crude product with 2N HCI in methanol gave 2-{2-[2-(2-Chlorophenyl)ethenyl]-5-methoxy-lH-indol-l-yl}ethanol (III; Ar=2-chlorophenyl, R10=CH2CH2OH) (44) in a yield of 86 % as a mixture of E/Z isomers, which was used without further purification.
EXAMPLE 42
The preparation of 4-(2-Chlorophenyl)-6-(2-hydroxyethyl)-9-methoxy-4,5.6,10c- tetrahvdropyrrolor3,4-clcarbazole- 3(2H,3aH)-dione (IV; Ar=2-chlorophenyl,
Figure imgf000070_0001
Reaction of 2-{2-[2-(2-Chlorophenyl)ethenyl]-5-methoxy-lH-indol-l-yl}ethanol (III; Ar=2-chlorophenyl, R10=CH2CH2OH) (44) prepared according to example 41 with maleimide according to the procedure described in example 68 gave 4-(2-Chlorophenyl)-6-(2- hydroxyethyl)-9-methoxy-4,5,6,10c-tetrahydropyrrolo[3,4-c]carbazole-l,3(2H,3aH)-dione (IV; Ar=2-chlorophenyl, R10=CH2CH2OH) (45) in a 79% yield as an oily solid, which was used without further purification.
EXAMPLE 43
The preparation of 4-(2-Chlorophenyl)-6-(2-hvdroxyethyl)-9-methoxypyrrolo[3,4- clcarbazole-1.3(2H.6H)-dione (V: Ar=2-chlorophenyl. R10= CH^CH^OH) (46)
4-(2-Chlorophenyl)-6-(2-hy droxyethyl)-9-methoxy-4,5 ,6, 10c-tetrahydropyrrolo[3,4- c]carbazole-l,3(2H,3aH)-dione (IV; Ar=2-chlorophenyl, R10=CH2CH2OH) (45) prepared according to example 42 was reacted with Mn02 using the procedure described in example 79 except that the reaction time was 18 h gave 4-(2-Chlorophenyl)-6-(2-hydroxyethyl)-9- methoxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione (V; Ar=2-chlorophenyl, R10= CH2CH2OH) (46]_in a 72 % yield as a yellow powder, mp 255-257 °C. 1H NMR δ [(CD3)2SO] 11.10 (br s, IH), 8.52 (d, J=2.6 Hz, IH), 7.80 (s, 1H), 7.71 (d, J=9.0 Hz, IH), 7.59-7.56 (m, IH), 7.52-7.43 (m, 4H), 7.29 (dd, J=9.0, 2.2.6 Hz, IH), 4.84 (t, J=5.0 Hz, IH), 4.53 (t, J=5.2 Hz, 2H), 3.90 (s, 3H), 3.77 (m, 2H). Found: C, 65.50; H, 4.07; N, 6.59. C23HπClN204 requires C, 65.64; H, 4.07; N, 6.66. EXAMPLE 44
The preparation of 4-(2-Chlorophenyl)-6-(2-hvdroxyethyl)-9-hvdroxypyrrolor3,4- clcarbazole-1.3(2H.6H)-dione (VI; Ar=2-chlorophenyl. R10= CH?CH?OH) (47)
The reaction of 4-(2-Chlorophenyl)-6-(2-hydroxyethyl)-9-methoxypyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione (V; Ar=2-chlorophenyl, R10= CH2CH2OH) (46) prepared according to example 43 with BBr3 using the procedure described in example 80 gave the 4- (2-Chlorophenyl)-6-(2-hydroxyethyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione (VI; Ar=2-chlorophenyl, R10= CH2CH2OH) (47) in a yield of 87 % as a yellow/orange powder; mp 265 °C (dec). ]H NMR δ [(CD3)2SO] 11.04 (br s, IH), 9.33 (br s, IH), 8.38 (d, J=2.4 Hz, IH), 7.75 (s, IH), 7.60-7.56 (m, 2H), 7.52-7.43 (m, 4H), 7.12 (dd, J=8.8, 2.4 Hz, IH), 4.83 (t, J=5.5 Hz, IH), 4.49 (t, J=5.2 Hz, 2H), 3.77 (dt, J=5.5, 5.2 Hz, 2H). Found: C, 63.41; H, 4.11; N, 6.32. C 2Hι5ClN204.l/2H20 requires C, 63.54; H, 3.87; N, 6.73.
EXAMPLE 45
The preparation of 5-Methoxy-2-r2-(2-methoxy-5-nitrophenyl)ethenvn-lH-indole (II; Ar=2- methoxy-5-nitrophenyl) (35)
Reaction of 5-methoxy-lH-indole-2-carbaldehyde (1) with 2-methoxy-5- nitrobenzyltriphenylphosphonium chloride using the procedure described in example 37 gave 5- methoxy-2-[2-(2-methoxy-5-nitrophenyl)ethenyl]-lH-indole (II; Ar=2-methoxy-5-nitrophenyl) (35) in a 76% yield as an orange solid (a mixture of E/Z isomers) which was used without further purification.
EXAMPLE 46
The preparation of 5-Methoxy-2-r2-(3,5-dinitrophenyl)ethenvn-lH-indole (II; Ar=3,5- dinitrophenyl) (40)
Reaction of 5-methoxy-lH-indole-2-carbaldehyde(l) with 3,5- dinitrobenzyltriphenylphosphonium bromide using the procedure described in example 37 gave 5-Methoxy-2-[2-(3,5-dinitrophenyl)ethenyl]-lH-indole (II; Ar=3,5-dinitrophenyl) (40) in a 26% yield as an orange solid (a mixture of E/Z isomers) which was used without further purification. EXAMPLE 47
The preparation of 4-(3,5-Dinitrophenyl)-9-methoxy-4,5,6,10c-tetrahydropyrrolor3.4- c1carbazole-1.3(2H.3aH)-dione (IV; Ar=3.5-dinitrophenyl. R10=H) (41)
The reaction of 5-Methoxy-2-[2-(3,5-dinitrophenyl)ethenyl]-lH-indole (II; Ar=3,5- dinitrophenyl) (40) prepared as described in example 46 with maleimide using the procedure described in example 69gave 4-(3,5-Dinitrophenyl)-9-methoxy-4,5,6,10c- tetrahydropyrrolo[3,4-c]carbazole-l,3(2H,3aH)-dione (IV; Ar=3,5-dinitrophenyl, R10=H) (41) in a 89% yield as a glassy solid which was used without further purification.
EXAMPLE 48
The preparation of 4-(3,5-Dinitrophenyl)-9-methoxypyrrolor3,4-c1carbazole-l,3(2H,6H)- dione (V: Ar=3,5-dinitrophenyl R10=H) (42)
The reaction of 4-(3,5-Dinitrophenyl)-9-methoxy-4,5,6, 10c-tetrahydropyrrolo[3,4- c]carbazole-l,3(2H,3aH)-dione (IV; Ar=3,5-dinitrophenyl, R=H) (41) prepared as described in example 47 with DDQ according to the procedure described in example 70 gave 4-(3,5- dinittophenyl)-9-methoxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione (V; Ar=3,5- dinitrophenyl, R1 =H) (42) in a 42% yield as a reddish solid which was used without further purification.
EXAMPLE 49
The preparation of 4-(3,5-Dinitrophenyl)-9-hvdroxypyrrolor3,4-clcarbazole- 3(2H,6H)- dione (V: Ar=3,5-dinitrophenyl R10=H) (43)
The reaction of 4-(3,5-dinitrophenyl)-9-methoxypyrrolo[3,4-c]carbazole-l,3(2H,6H)- dione (V; Ar=3,5-dinitrophenyl, R10=H) (42) prepared as described in example 48 with pyridinium hydrochloride according to the proceedure described in example 81 gave 4-(3,5- Dinιtrophenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione (V; Ar=3,5- dinitrophenyl, R10=H) (43) in a 57% yield as an orange powder, mp >330 °C. Η NMR δ [(CD3)2SO] 11.94 (br s, IH), 11.18 (br s, IH), 9.32 (br s, IH), 8.91 (s, 3H), 8.35 (d, J=2.3 Hz, IH), 7.83 (s, IH), 7.49 (d, J=8.7 Hz, IH), 7.11 (dd, J=8.7, 2.3 Hz, IH). EXAMPLE 50
The preparation of 5-Methoxy-2-r2-(2-methoxyphenyl)ethenvn-lH-indole (II; Ar=2- methoxyphenyl) (97)
The reaction of 5-methoxy-lH-indole-2-carbaldehyde (1) with 2- methoxybenzyltriphenylphosphonium chloride using the procedure described in example 37 gave 5-methoxy-2-[2-(2-methoxyphenyl)ethenyl]-lH-indole (II; Ar=2-methoxyphenyl) (97) in a 98 % yield as a yellow solid (a mixture of E/Z isomers) which was used without further purification.
EXAMPLE 51
The preparation of l-(3-{ rtert-Butyl(dimethv])silylloxy)propyl)-5-methoxy-2-r2-(2-
Figure imgf000073_0001
Bu) (98)
Reaction of 5-Methoxy-2-[2-(2-methoxyphenyl)ethenyl]-lH-indole (II; Ar=2- methoxyphenyl) (97) prepared as in example 50 with 3-bromopropyl tert- butyl(dimethyl)silyl ether using the procedure described in example 38 gave l-(3-{ [tert- Butyl(dimethyl)silyl]oxy}propyl)-5-methoxy-2-[2-(2-methoxyphenyl)ethenyl]-lH-indole (III; Ar=2-methoxyphenyl, R10=CH2CH2CH2OSiMe2t-Bu) (98) in a 97% yield which was used without further purification.
EXAMPLE 52
The preparation of 6-(3-( rtert-Butyl(dimethyl)silvnoxy)propyl)-9-methoxy-4-(2- methoxyphenyl)-4,5,6,10c-tetrahvdropyιτoIor3,4-clcarbazole- 3(2H,3aH)-dione (IV; Ar=2-
Figure imgf000073_0002
The reaction of l-(3-{ [tert-Butyl(dimethyl)silyl]oxy}propyl)-5-methoxy-2-[2-(2- methoxyphenyl)ethenyl]-lH-indole (III; Ar=2-methoxyphenyl, R10=CH2CH2CH2OSiMe2t- Bu) (98) prepared as described in example 51 with maleimide using the procedure described in example 68 gave 6-(3-{ [tert-Butyl(dimethyl)silyl]oxy}propyl)-9-methoxy-4-(2- methoxyphenyl)-4,5,6,10c-tetrahydropyrrolo[3,4-c]carbazole-l,3(2H,3aH)-dione (IV; Ar=2- methoxyphenyl; R10=CH2CH2CH2OSiMe2t-Bu) (99 ) in a 89% yield as a tan powder, which was used without further purification. EX AMPLE 53
The preparation of 6-(3-Hydroxypropyl)-9-methoxy-4-(2-methoxyphenyl)pyrrolor3,4-
Figure imgf000074_0001
The reaction of 6-(3-{ [tert-Butyl(dimethyl)silyl]oxy }propyl)-9-methoxy-4-(2- methoxyphenyl)-4,5,6,10c-tetrahydropyrrolo[3,4-c]carbazole-l,3(2H,3aH)-dione (IV; Ar=2- methoxyphenyl; R10=CH2CH2CH2OSiMe2t-Bu) prepared as described in example 52 with DDQ using the procedure described in example 70 followed reaction with 2N HCI in THF/methanol gave 6-(3-Hydroxypropyl)-9-methoxy-4-(2-methoxyphenyl)pyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione (V; Ar=2-methoxyphenyl, R10=CH2CH2CH2OH) (100) in a 72% yield as an orange powder; mp 223-225 °C. !H NMR δ [(CD3)2SO] 10.99 (br s, IH), 8.53 (d, 2.6 Hz, IH), 7.74 (s, IH), 7.67 (d, J=8.9 Hz, IH), 7.45-7.40 (m, IH), 7.36 (dd, J=7.4, 1.7 Hz, IH), 7.29 (dd, J=8.9, 2.7 Hz, IH), 7.11 (d, J=8.1 Hz, IH), 7.06 (dd, J=7.2, 7.2 Hz, IH), 4.63 (t, J=4.8 Hz, IH), 4.52 (t, J=6.9 Hz, 2H), 3.90 (s, 3H), 3.69 (s, 3H), 3.40 (m, 2H), 1.91 (m, 2H). Found: C, 69.55; H, 5.31; N, 6.30. C25H22N205 requires C69.76; H, 5.15; N, 6.51.
EXAMPLE 54
The preparation of 9-Hvdroxy-4-(2-hvdroxyphenyl)-6-(3-hvdroxypropyl)pyrrolor3,4-
Figure imgf000074_0002
The reaction of 6-(3-Hydroxypropyl)-9-methoxy-4-(2-methoxyphenyl)pyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione (V; Ar=2-methoxyphenyl, R10=CH2CH2CH2OH) (100) prepared as described in example 53 with BBr3 using the procedure described in example 80 gave 9-Hydroxy-4-(2-hydroxyphenyl)-6-(3-hydroxypropyl)pyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione (VI; Ar=2-hydroxyphenyl, R10=CH2CH2CH2OH) (101) in an 82% yield as an orange powder, mp 306-309 °C. Η NMR δ [(CD3)2SO] 10.90 (br, IH), 9.40 (br, IH), 8.38 (d, J=2.4 Hz, IH), 7.67 (s, IH), 7.56 (d, J=8.8 Hz, IH), 7.30-7.23 (m, 2H), 7.13 (dd, J=8.8, 2.4 Hz, IH), 6.94-6.88 (m, 2H), 4.78 (br, 2H), 4.47 (t, J=6.8 Hz, 2H), 3.41 (t, J=6.0 Hz, 2H), 1.91 ( , 2H). Found: C, 66.85; H, 4.61; N, 6.63. C23Hι8N205.l/2H20 requires C, 67.14; H, 4.65; N, 6.80. EXAMPLE 55
The preparation of 2-[2-(2-Chloro-6-methoxyphenyl)ethenvn-5-methoxy-lH-indole (II: Ar=2-chloro-6-methoxyphenyl) (102)
The reaction of 5-methoxy-lH-indole-2-carbaldehyde (1) with 2-chloro-6- methoxybenzyltriphenylphosphonium bromide using the procedure described in example 37 gave 2-[2-(2-Chloro-6-methoxyphenyl)ethenyl]-5-methoxy-lH-indole (II; Ar=2-chloro-6- methoxyphenyl) (102) in a 92% yield as a yellow solid (a mixture of E/Z isomers) which was used without further purification.
EXAMPLE 56
The preparation of l-(3-{ rtert-Butyl(dimethyl)silynoxy|propyl)-2-r2-(2-chloro-6- methoxyphenyl)ethenyl1-5-methoxy-lH-indole (III; Ar=2-chloro-6-methoxyphenyl, R10=CH.CH.CH7QSiMe?t-Bu) (103)
The reaction of 2-[2-(2-Chloro-6-methoxyphenyl)ethenyl]-5-methoxy-lH-indole (II; Ar=2- chloro-6-methoxyphenyl) (102) prepared as described in example 55 with 3-bromopropyl tert-butyl(dimethyl)silyl ether using the procedure described in example 38 gave l-(3-{[tert- Butyl(dimethyl)silyl]oxy}propyl)-2-[2-(2-chloro-6-methoxyphenyl)ethenyl]-5-methoxy-lH- indole (III; Ar=2-chloro-6-methoxyphenyl, R10=CH2CH2CH2OSiMe2t-Bu) (103) in a 91 % yield which was used without further purification.
EXAMPLE 57
The preparation of 6-(3-( ftert-Butyl(dimethyl)silyl1oxy )propyl)-4-(2-chloro-6- methoxyphenyl)-9-methoxy-4,5,6 0c-tetrahvdropyrrolo[3,4-c1carbazole-1.3(2H,3aH)-dione (IV; Ar=2-chloro-6-methoxyphenyl. R10=CH2CH2CH2OSiMe?t-Bu) (104).
The reaction of l-(3-{ [tert-Butyl(dimethyl)silyl]oxy}propyl)-2-[2-(2-chloro-6- methoxyphenyl)ethenyl]-5-methoxy-lH-indole (III; Ar=2-chloro-6-methoxyphenyl, R10=CH2CH2CH2OSiMe2t-Bu) (103)_prepared as described in example 56 with maleimide using the procedure described in example 68 gave 6-(3-{ [tert-
Butyl(dimethyl)silyl]oxy}propyl)-4-(2-chloro-6-methoxyphenyl)-9-methoxy-4,5,6,10c- tetrahydropyrrolo[3,4-c]carbazole-l,3(2H,3aH)-dione (IV; Ar=2-chloro-6-methoxyphenyl, R,0=CH2CH2CH2OSiMe2t-Bu) (104) in a 77% yield as a cream powder, which was used without further purification. EXAMPLE 58
The preparation of 4-(2-Chloro-6-methoxyphenyl)-6-(3-hvdroxypropyl)-9- methoxypyιτolor3,4-clcarbazo1e-l,3(2H,6H)-dione (V; Ar=2-chloro-6-methoxyphenyl.
Figure imgf000076_0001
The reaction of 6-(3-{ [tert-Butyl(dimethyl)silyl]oxy }propyl)-4-(2-chloro-6- methoxyphenyl)-9-methoxy-4,5,6,10c-tetrahydropyrrolo[3,4-c]carbazole-l,3(2H,3aH)-dione (IV; Ar=2-chloro-6-methoxyphenyl, R10=CH2CH2CH2OSiMe2t-Bu) (104) prepared as described in example 57 with DDQ using the procedure described in example 70 followed by reaction with 2N HCI in THF/methanol gave 4-(2-Chloro-6-methoxyphenyl)-6-(3- hydroxypropyl)-9-methoxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione (V; Ar=2-chloro-6- methoxyphenyl, R10=CH2CH2CH2OH) (105) in a 76% yield as an orange powder; mp 224- 227 °C. 1H NMR δ [(CD3)2SO] 11.05 (br, IH), 8.51 (d, J=2.6 Hz, IH), 7.75 (s, IH), 7.69 (d, J=8.9 Hz, IH), 7.44 (dd, J=8.2, 8.2 Hz, IH), 7.31 (dd, J=8.9, 2.6 Hz, IH), 7.18 (d, J=8.2 Hz, IH), 7.13 (d, J-8.2 Hz, IH), 4.63 (t, J=4.9 Hz, IH), 4.51 (t, J=6.8 Hz, 2H), 3.91 (s, 3H), 3.68 (s, 3H), 3.41 (m, 2H), 1.89 (m, 2H). Found: C, 69.71; H, 4.53; N, 6.43. C25H22N205 requires C, 69.76; H, 5.15; N, 6.51.
EXAMPLE 59
The preparation of 4-(2-Chloro-6-methoxyphenyl)-9-hydroxy-6-(3- hydroxypropyl )pyrrolor3,4-c~lcarbazole-l ,3(2H,6H)-dione (VI; Ar=2-chloro-6-
Figure imgf000076_0002
The reaction of 4-(2-Chloro-6-methoxyphenyl)-6-(3-hydroxypropyl)-9- methoxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione (V; Ar=2-chloro-6-methoxyphenyl, R10=CH2CH2CH2OH) (105) prepared as described in example 58 with BBr3 using the procedure described in example 80 and with a reaction time of 90 minutes gave 4-(2-Chloro- 6-methoxyphenyl)-9-hydroxy-6-(3-hydroxypropyl)pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione (VI; Ar=2-chloro-6-methoxyphenyl, R10=CH2CH2CH2OH) (106) in a 64 % yield as an orange powder, mp 270-273 °C. Η NMR δ [(CD3)2SO] 11.01 (br s, IH), 9.35 (br s, IH), 8.37 (d, J=2.4 Hz, IH), 7.70 (s, IH), 7.58 (d, J=8.7 Hz, IH), 7.44 (dd, J=8.3, 8.3 Hz, IH), 7.20-7.11 (m, 3H), 4.61 (br t, IH), 4.47 (t, J=6.9 Hz, 2H), 3.68 (s, 3H), 3.42 (m, 2H), 1.88 (m, 2H). Found: C, 64.16; H, 4.55; N, 6.01. C24H19C1N205 requires C, 63.93; H, 4.25; N, 6.21. EXAMPLE 60
The preparation of 9-Hydroxy-6-(3-hvdroxypropyl)-4-(2-methoxyphenyl)pyrrolo[3.4- clcarbazole-1.3(2H.6H)-dione (VI; Ar=2-methoxyphenyl. R10=CH?CH7CH?OH) (107).
4-(2-Chloro-6-methoxyphenyl)-9-hydroxy-6-(3-hydroxypropyl)pyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione (VI; Ar=2-chloro-6-methoxyphenyl, R10=CH2CH2CH2OH) (106) (0.20 g, 0.44 mmol) prepared as described in example 59, potassium acetate (0.20 g) and 5 % Pd/C in a solution of ethyl acetate (25ml) and methanol 1:1 (25 mL) under a atmosphere of hydrogen at 60 psi was reacted for 7 h. The catalyst was filtered off and the filtrate concentrated to dryness. The residue was partitioned between ethyl acetate and water and the organic solution was dried, the drying agent was removed and the solution was concentrated to dryness and chromatographed on silica. Elution with ethyl acetate/petroleum ether (2: 1) gave 9-Hydroxy-6-(3-hydroxypropyl)-4-(2-methoxyphenyl)pyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione (VI; Ar=2-methoxyphenyl, R10=CH2CH2CH2OH) (107) in a yield of 51 % as an orange powder (from THF/petroleum ether), mp 296-300 °C. !H NMR δ [(CD3)2SO] 10.93 (br s, IH), 9.31 (br s, IH), 8.38 (d, J=2.4 Hz, IH), 7.69 (s, IH), 7.55 (d, J=8.8 Hz, IH), 7.42 (m, IH), 7.35 (dd, J=7.5, 1.7 Hz, IH), 7.13-7.08 (m, 2H), 7.05 (dd, J=7.2, 7.2 Hz, IH), 4.62 (t, J=4.8 Hz, IH), 4.48 (t, J=6.8 Hz, 2H), 3.68 (s, 3H), 3.40 (m, 2H), 1.90 (m, 2H). Found: C, 69.29; H, 4.90; N, 6.54. C2 H2oN205 requires C, 69.22; H, 4.84; N, 6.73.
EXAMPLE 61
The preparation of 2-{2-r2-(2-Chloro-6-methoxyphenyl)ethenyll-5-methoxy-lH-indol-l- yllethanol (III; Ar=2-chloro-6-methoxyphenyl. R10=CH?CH OH) (109)
The reaction of 2-[2-(2-Chloro-6-methoxyphenyl)ethenyl]-5-methoxy-lH-indole (II; Ar=2-chloro-6-methoxyphenyl) (102) prepared as described in example 55 with 2- bromoethyl tetrahydro-2H-pyran-2-yl ether using the procedure described in example 38 followed by reaction of the crude product with 2N HCI in methanol gave 2-{2-[2-(2-Chloro- 6-methoxyphenyl)ethenyl]-5-methoxy-lH-indol-l-yl}ethanol (III; Ar=2-chloro-6- methoxyphenyl, R10=CH2CH2OH) (109) in a 91 % yield as a mixture of E/Z isomers, which was used without further purification. EXAMPLE 62
The preparation of 4-(2-Chloro-6-methoxyphenyl)-6-(2-hydroxyethyl)-9-methoxy-4,5,6,10c- tetrahvdropyrrolo[3.4-c1carbazole-l,3(2H.3aH)-dione (IV; Ar=2-chloro-6-methoxyphenyl. R'°=CH?CH2OH) (110).
Reaction of the 2-{2-[2-(2-Chloro-6-methoxyphenyl)ethenyl]-5-methoxy-lH-indol-l- yl jethanol (III; Ar=2-chloro-6-methoxyphenyl, R=CH2CH2OH) (109) prepared as described in example 61 with maleimide using the procedure described in example 68 gave 4-(2- Chloro-6-methoxyphenyl)-6-(2-hydroxyethyl)-9-methoxy-4,5,6,10c-tetrahydropyrrolo[3,4- c]carbazole-l,3(2H,3aH)-dione (IV; Ar=2-chloro-6-methoxyphenyl, R10=CH2CH2OH) (110) in a 72% yield as a cream powder, which was used without further purification.
EXAMPLE 63
The preparation of 4-(2-Chloro-6-methoxyphenyl)-6-(2-hvdroxyethyl)-9- methoxypyrrolor3.4-c1carbazole-1.3(2H,6H)-dione (V; Ar=2-chloro-6-methoxyphenyl,
Figure imgf000078_0001
The reaction of 4-(2-Chloro-6-methoxyphenyl)-6-(2-hydroxyethyl)-9-methoxy- 4,5,6, 10c-tetrahydropyrrolo[3,4-c]carbazole-l,3(2H,3aH)-dione (IV; Ar=2-chloro-6- methoxyphenyl, R10=CH2CH2OH) (110) prepared as described in example 62 with Mn02 using the procedure described in example 79 except that the reaction time was 8 h 4-(2- Chloro-6-methoxyphenyl)-6-(2-hydroxyethyl)-9-methoxypyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione (V; Ar=2-chloro-6-methoxyphenyl, R10=CH2CH2OH) (111) in a 75 % yield as a yellow/orange powder; mp 264-268 °C. 1H NMR δ [(CD3)2SO] 11.04 (br s, IH), 8.50 (d, J=2.6 Hz, IH), 7.75 (s, IH), 7.69 (d, J=9.0 Hz, IH), 7.44 (dd, J=8.3, 8.3 Hz, IH), 7.28 (dd, J=9.0, 2.6 Hz, IH), 7.18 (d, J=8.3 Hz, IH), 7.13 (d, J=8.3 Hz, IH), 4.83 (t, J=5.5 Hz, IH), 4.51 (t, J=5.3 Hz, 2H), 3.90 )s, 3H), 3.75 (m, 2H), 3.67 (s, 3H). Found: C, 63.84; H, 4.32; N, 5.97. C24H)9C1N205 requires C, 63.93; H, 4.25; N, 6.21.
EXAMPLE 64
The preparation of 4-(2-Chloro-6-methoxyphenyl)-9-hvdroxy-6-(2-hydroxyethyl .pyrrolof 3.4- clcarbazole-1.3(2H.6H)-dione (VI; Ar-2-chloro-6-methoχyphenyl R10=CH2CH.OH) (112)
The reaction of 4-(2-Chloro-6-methoxyphenyl)-6-(2-hydroxyethyl)-9- methoxypyrrolo[3,4-c]carbazole-l ,3(2H,6H)-dione (V; Ar=2-chloro-6-methoxyphenyl, R10=CH2CH2OH) (111) prepared as described in example 63 with BBr3 using the procedure described in example 80 except that the reaction conditions were 2 h at 0 °C gave 4-(2- Chloro-6-methoxyphenyl)-9-hydroxy-6-(2-hydroxyethyl)pyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione (VI; Ar-2-chloro-6-methoxyphenyl, R10=CH2CH2OH) (112) in a 56% yield as a yellow powder (56 %); mp 275-278 °C. ]H NMR δ [(CD3)2SO] 10.98 (br s, IH), 9.30 (br s, IH), 8.36 (d, J=2.4 Hz, IH), 7.70 (s, IH), 7.57 (d, J=8.7 Hz, IH), 7.43 (dd, J=8.3, 8.3 Hz, IH), 7.17 (d, J=7.9 Hz, IH), 7.14-7.09 (m, 2H), 4.81 (t, J=5.5 Hz, IH), 4.46 (t, J=5.3 Hz, 2H), 3.74 (dt, J=5.5, 5.3 Hz, 2H), 3.66 (s, 3H). FABMS found [M+H]+: 439.0882, 437.0889. C23H]8C1N205 requires 439.0875, 437.0904.
EXAMPLE 65
The preparation of 9-Hvdroxy-6-(2-hvdroxyethyl)-4-(2-methoxyphenyl)pyrrolor3.4-
Figure imgf000079_0001
Reaction of 4-(2-Chloro-6-methoxyphenyl)-9-hydroxy-6-(2- hydroxyethyl)pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione (VI; Ar-2-chloro-6-methoxyphenyl, R10=CH2CH2OH) (112) prepared as described in example 64 with hydrogen gas, using a Pd/C catalyst, according to the procedure for example 60 gave 9-Hydroxy-6-(2- hydroxyethyl)-4-(2-methoxyphenyl)pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione (VI; Ar=2- methoxyphenyl, R10=CH2CH2OH) (113) in a 77 % yield as a yellow solid; mp 285-289 °C. Η NMR δ [(CD3)2SO] 10.91 (br s, IH), 9.29 (br s, IH), 8.37 (d, J=2.4 Hz, IH), 7.70 (s, IH), 7.55 (d, J=8.8 Hz, IH), 7.42 (m, IH), 7.33 (dd, J=8.8, 2.4 Hz, IH), 7.12-7.02 (m, 3H), 4.84 (t, J=5.5 Hz, IH), 4.73 (t, J=5.3 Hz, 2H), 3.76 (dt, J=5.5, 5.3 Hz, 2H), 3.68 (s, 3H). Found: C, 67.30; H, 4.47; N, 6.79. C23H,8N205.1/2H20 requires C, 67.15; H, 4.65; N, 6.81.
EXAMPLE 66
The preparation of 2-(4-(2-Chloro-6-methoxyphenyl)-9-hvdroxy-l,3-dioxo-2.3- dihydropyrrolor3.4-clcarbazol-6(lH)-yl)ethyl methanesulfonate (VII; Ar=2-chloro-6- methoxyphenyl, n=2. mesylate) (114).
Reaction of 4-(2-Chloro-6-methoxyphenyl)-6-(2-hydroxyethyl)-9- methoxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione (V; Ar=2-chloro-6-methoxyphenyl, R10=CH2CH2OH) (111) prepared as described in example 63 with methanesulphonyl chloride, followed by reaction with BBr3 using the procedure described in example 170 of Scheme 3 gave 2-(4-(2-Chloro-6-methoxyphenyl)-9-hydroxy-l,3-dioxo-2,3- dihydropyrrolo[3,4-c]carbazol-6(lH)-yl)ethyl methanesulfonate (VII; Ar=2-chloro-6- methoxyphenyl, n=2, mesylate) (114). as a yellow solid, which was used without further purification.
EXAMPLE 67
The preparation of 4-(2-Chloro-6-methoxyphenyl)-9-hvdroxy-6-r2-(4- morpholinyl)ethyllpyrrolor3,4-clcarbazole-1.3(2H.6H)-dione (VIII; Ar=2-chloro-6- methoxyphenyl. n=2. Z=4-morpholinyl) (115).
Reaction of 2-(4-(2-Chloro-6-methoxyphenyl)-9-hydroxy-l,3-dioxo-2,3- dihydropyrrolo[3,4-c]carbazol-6(lH)-yl)ethyl methanesulfonate (VII; Ar=2-chloro-6- methoxyphenyl, n=2, mesylate) (114) prepared as described in example 66 with morpholine using the procedure described in example 179 of Scheme 3 gave 4-(2-Chloro-6- methoxyphenyl)-9-hydroxy-6-[2-(4-morpholinyl)ethyl]pyrrolo[3,4-c]carbazole-l,3(2H,6H)- dione (VIII; Ar=2-chloro-6-methoxyphenyl, n=2, Z=4-morpholinyl) (115) in an 81% yield as a yellow powder; mp 185 °C. Η NMR δ [(CD3)2SO] 10.99 (br s, IH), 9.34 (br s, IH), 8.37 (d, J=2.4 Hz, IH), 7.69 (s, IH), 7.57 (d, J=8.8 Hz, IH), 7.44 (dd, J=8.3, 8.3 Hz, IH), 7.17 (d, J=8.3 Hz, IH), 7.14-7.10 (m, 2H), 4.53 (t, J=6.1 Hz, 2H), 3.66 (s, 3H), 3.41 (t, J=4.5 Hz, 4H), 2.64 (t, J=6.1 Hz, 2H), 2.37 (m, 4H). Found: C, 63.57; H, 4.71; N, 8.06. C27H24C1N305.1/4H20 requires C, 63.53; H, 4.84; N, 8.23.
Representative Procedure for Method 4 of Scheme 2
EXAMPLE 68
The preparation of 4-(2-Chlorophenyl)-9-methoxy-4,5,6 0c-tetrahvdropyrrolor3,4- clcarbazole-1.3(2H.3aH)-dione (IV; Ar=2-chlorophenyl. R10=H) (32)
A solution of 2-[2-(2-Chlorophenyl)ethenyl]-5-methoxy-lH-indole (II; Ar=2- chlorophenyl) (27) (1.5 g, 5.29 mmol) prepared according to example 37, maleimide (0.61 g, 6.34 mmol) and SnCl2 (0.20 g, 1.05 mmol) in toluene (25 mL) was refluxed for 6 h. After dilution with ethyl acetate the solution was washed with water and The organic phase was dried, the drying agent was removed and the solution was concentrated to dryness to give 4- (2-Chlorophenyl)-9-methoxy-4,5,6,10c-tetrahydropyrrolo[3,4-c]carbazole-l,3(2H,3aH)-dione (IV; Ar=2-chloroρhenyl, R10=H) (32) in a yield of 1.98 g , 98% as a yellow solid (as a mixture of diastereomers), which was used without further purification. Representative Procedure for Method 5 of Scheme 2
EXAMPLE 69
The preparation of 9-Methoxy-4-(2-methoxy-5-nitrophenyl)-4.5.6,10c-tetrahydropyrrolor3.4- clcarbazole-1.3(2H.3aH)-dione (IV; Ar=2-methoxy-5-nitrophenyl, R10=H) (185)
A solution of 5-methoxy-2-[2-(2-methoxy-5-nitrophenyl)ethenyl]-lH-indole (II; Ar=2-methoxy-5-nitrophenyl) (0.437 g, 1.35 mmol) prepared as described in example 45 and maleimide (0.156 g, 1.62 mmol) in THF (10 mL) was concentrated to dryness in a 25 mL flask. The resulting solid was placed in an oil bath at 180 °C and the resulting melt was kept at this temperature for 4 h. The residue was cooled and triturated with diethyl ether to give 9- methoxy-4-(2-methoxy-5-nitrophenyl)-4,5,6,10c-tetrahydropyrrolo[3,4-c]carbazole- l,3(2H,3aH)-dione (IV; Ar=2-methoxy-5-nitrophenyl, R10=H) (185) in a yield of 0.51 g, 90% as a tan powder, which was used without further purification in the next step.
Representative Procedure for Method 6 of Scheme 2
EXAMPLE 70
The preparation of 9-Methoxy-4-(2-methoxy-5-nitrophenyl )pyrrolor3,4-clcarbazole- 1.3(2H.6H)-dione (V; Ar=2-methoxy-5-nitrophenyl. R10=H) (36)
A solution of 9-methoxy-4-(2-methoxy-5-nitrophenyl)-4,5, 6,10c - tetrahydropyrrolo[3,4-c]carbazole-l,3(2H,3aH)-dione (IV; Ar=2-methoxy-5-nitrophenyl, R10=H) (185) (0.51 g, 1.21 mmol) prepared according to example 69 and DDQ (0.82 g, 3.63 mmol) in dioxane (30 mL) was refluxed for 2 h. After dilution with water the solution was extracted with dichloromethane. The organic extracts were washed with saturated aqueous NaHC03 solution (3x). The organic phase was dried, the drying agent was removed and the solution was concentrated to dryness to give a solid which was chromatographed on silica. Elution with ethyl acetate/petroleum ether (3:7) followed by ethyl acetate/petroleum ether (1 :1) gave a solid which when triturated with diethyl ether gave 9-Methoxy-4-(2-methoxy-5- nitrophenyl)pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione (V; Ar=2-methoxy-5-nitrophenyl, R10=H) (36) in a 0.42 g, 82% yield; mp 302-304 °C. 1H NMR δ [(CD3)2SO] 11.95 (br s, IH), 11.06 (br s, IH), 8.46 (d, J=2.6 Hz, IH), 8.37 (dd, J=9.2, 3.0 Hz, IH), 8.22 (d, J=3.0 Hz, IH), 7.69 (s, IH), 7.57 (d, J=8.8 Hz, IH), 7.36 (d, J=9.2 Hz, IH), 7.24 (dd, J=8.8, 2.6 Hz, IH), 3.89 (s, 3H), 3.85 (s, 3H). Found: C, 63.90; H, 3.79; N, 9.52. C22Hι5N306 requires C, 63.61 ; H, 3.62; N, 10.07.
EXAMPLE 71
The preparation of 9-Hvdroxy-4-(2-hydroxy-5-nitrophenyl)pyrrolor3.4-c1carbazole- 1.3(2H.6H)-dione (VI; Ar=2-hvdroxy-5-nitrophenyl. R10--H) (37)
9-Methoxy-4-(2-methoxy-5-nitrophenyl)pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione (V; Ar=2-methoxy-5-nitrophenyl, R=H) (36)_prepared according to example 70 was reacted using the procedure described in example 81 by reaction at 210 °C for 30 min, to give 9- hydroxy-4-(2-hydroxy-5-nitrophenyl)pyrrolo[3,4-c]carbazole-l ,3(2H,6H)-dione (VI; Ar=2- hydroxy-5-nitrophenyl, R10=H) (37) in a 82 % yield as a yellow/orange powder; mp >330 °C. ]H NMR δ [(CD3)2SO] 11.78 (s, IH), 10.99 (s, IH), 9.26 (s, IH), 8.32 (d, J=2.4 Hz, IH), 8.21-8.16 (m, 2H), 7.63 (s, IH), 7.45 (d, J=8.7 Hz, IH), 7.08 (m, 2H).
EXAMPLE 72
The preparation of 9-Hvdroxy-4-(2-methoxy-5-nitrophenyl)pyrrolor3,4-clcarbazole- 1.3(2H.6H)-dione (VI; Ar=2-methoxy-5-nitrophenyl R10=H) (38)
9-Methoxy-4-(2-methoxy-5-nitrophenyl)pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione (V; Ar=2-methoxy-5-nitrophenyl, R10=H) (36) prepared according to example 70 was reacted using the procedure described in example 80 to give 9-hydroxy-4-(2-methoxy-5- nitrophenyl)pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione (VI; Ar=2-methoxy-5-nitrophenyl, R10=H) (38) in a 76% yield as a yellow powder; mp 265-273 °C (dec). 1H NMR δ [(CD3)2SO] 11.86 (br, IH), 11.01 (br, IH), 8.38 (dd, J=9.3, 2.8 Hz, IH), 8.31 (d, J=2.4 Hz, IH), 8.20 (d, J=2.8 Hz, IH), 7.65 (s, lh), 7.48 (d, J=8.7 Hz, IH), 7.36 (d, J=9.3 Hz, IH), 7.10 (dd, J=8.7, 2.4 Hz, IH), 3.84 (s, 3H). EIMS found M+: 403.0794. C 1Hι3N306 requires 403.0804.
EXAMPLE 73
The preparation of 4-(5-Amino-2-methoxyphenyl)-9-hvdroxypyrrolor3.4-c1carbazole- 1.3(2H.6H)-dione (VI: Ar--5-amino-2-methoxyphenyl. R10=H) (39)
To a solution of 9-hydroxy-4-(2-methoxy-5-nitrophenyl)pyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione (VI; Ar=2-methoxy-5-nitrophenyl, R10=H) (38) (64 mg, 0.159 mmol) prepared according to example 72 in methanol (10 mL) and THF (1 mL) was added 2N HCI (1 mL) Freshly prepared nickel boride (-0.50 g) was added and the mixture was warmed at 60 °C. After 1 h HCI (1 mL) and Ni B (-0.50 g) were added and the reaction mixture was maintained at 60°C a total of 4 h. The solvents were removed in vacuo and the residue was partitioned between ethyl acetate and 2N HCI. The aqueous layer was basified with cone, ammonia solution and extracted with ethyl acetate. The organic phase was dried, the drying agent was removed and the solvent concentrated to dryness gave a solid which when crystallised from THF/petroleum ether gave 4-(5-Amino-2-methoxyphenyl)-9- hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione (VI; Ar=5-amino-2-methoxyphenyl, R10=H) (39) in a yield of 49.7 mg, 84% as a yellow powder; mp 246-250 °C. ]H NMR δ [(CD3)2SO] 11.67 (s, IH), 10.87 (s, IH), 9.21 (s, IH), 8.30 )d, J=2.4 Hz, IH), 7.44 (s, IH), 7.42 (d, J=8.7 Hz, IH), 7.05 (dd, J=8.6, 2.5 Hz, IH), 6.80 (d, J=8.7 Hz, IH), 6.61 (dd, J=8.6, 2.7 Hz, IH), 6.55 (d, J=2.8 Hz, IH), 4.68 (br, 2H), 3.53 (s, 3H). FABMS found [M+H]+: 373.1056. C2ιHι5N304 requires 373.1062.
EXAMPLE 74
The preparation of 2-r(E)-2-(2-BiOmo-4-nitτophenyl)ethenyl]-5-methoxy-lH-indole (II. Ar=2-bromo-4-nitrophenyI) (49)
Reaction of 5-methoxy-lH-indole-2-carbaldehyde (1) with 2-bromo-4- nitrobenzyltriphenylphosphonium bromide using the procedure described in example 37 gave the diene 2-[(E)-2-(2-Bromo-4-nitrophenyl)ethenyl]-5-methoxy-lH-indole (II, Ar=2- bromo-4-nitrophenyl) (49) in a 98 % yield as a red solid which was used without further purification.
EXAMPLE 75
The preparation of 4-(2-Bromo-4-nitrophenyl)-9-methoxy-4,5.6.10c-tetrahvdropyrrolo[3.4- clcarbazole-1.3(2H.3aH)-dione (IV: Ar=2.bromo-4-nitrophenyl. R10=H) (50)
Reaction of 2-[(E)-2-(2-Bromo-4-nitrophenyl)ethenyl]-5-methoxy-lH-indole (II, Ar=2-bromo-4-nitrophenyl) (49) prepared as described in example 74 with maleimide using the procedure described in example 69 gave 4-(2-Bromo-4-nitrophenyl)-9-methoxy- 4,5,6, 10c-tetrahydropyrrolo[3,4-c]carbazole- 1 ,3(2H,3aH)-dione (IV; Ar=2,bromo-4- nitrophenyl, R1 =H) (50) in a 54% yield as a tan powder; mp 272 °C (dec), which was used without further purification. EXAMPLE 76
The preparation of 4-(2-Bromo-4-nitrophenyl)-9-methoxypyιτolo[3,4-clcarbazole- 1.3(2H.6H)-dione (V; Ar=2-bromo-4-nitrophenyl. R10=H) (51).
Reaction of 4-(2-bromo-4-nitrophenyl)-9-methoxy-4,5,6,10c-tetrahydropyrrolo[3,4- c]carbazole-l,3(2H,3aH)-dione (IV; Ar=2,bromo-4-nitrophenyl, R10=H) (50) prepared as described in example 75 with DDQ using the procedure described in example 70 gave 4-(2- bromo-4-nitrophenyl)-9-methoxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione (V; Ar=2-bromo- 4-nitrophenyl, R10=H) (51). in a 67% yield as a yellow powder, mp 288-292 °C (dec). Η NMR δ [(CD3)2SO] 12.07 (br, IH), 11.18 (br, IH), 8.56 (d, J=2.3 Hz, IH), 8.46 (d, J=2.6 Hz, IH), 8.33 (dd, J=8.5, 2.6 Hz, IH), 7.80 (d, J=8.5 Hz, IH), 7.63 (s, IH), 7.59 (d, J=8.8 Hz, IH), 7.27 (dd, J=8.8, 2.3 Hz, IH), 3.90 (s, 3H). Found: C, 54.06; H, 2.59; N, 8.72. C2ιHι2BrN305 requires C, 54.10; H, 2.59; N, 9.01.
EXAMPLE 77
The preparation of 4-(2-Bromo-4-nitrophenyl)-9-hvdroxypyrrolor3.4-c1carbazole- 1.3(2H.6H)-dione (VI: Ar--2-bromo-4-nitrophenyl. R10=H) (52).
Reaction of 4-(2-bromo-4-nitrophenyl)-9-methoxypyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione (V; Ar=2-bromo-4-nitrophenyl, R10=H) (51) prepared as described in example 76 with pyridinium hydrochloride using the procedure described in the proceedure described in example 81 gave 4-(2-bromo-4-nitrophenyl)-9-hydroxypyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione (VI; Ar=2-bromo-4-nitrophenyl, R10=H) (52) in a 92 % yield as a yellow powder; mp >330 °C. Η NMR δ [(CD3)2SO] 11.94 (s, IH), 11.13 (s, IH), 9.32 (br s, IH), 8.55 (d, J=2.3 Hz, IH), 8.34 (d, J=2.4 Hz, IH), 8.31 (m, 2H), 7.79 (d, J=8.5 Hz, IH), 7.58 (s, IH), 7.48 (d, J=8.7 Hz, IH), 7.11 (dd, J=8.7, 2.4 Hz, IH).
EXAMPLE 78
The preparation of 4-(4-Amino-2-bromophenyl)-9-hydroxypyrrolor3.4-c1carbazole- 1.3(2H.6H)-dione (VI; Ar=4-amino-2-bromophenyl. R10=H) (53).
Freshly prepared nickel boride (5.00 g, 0.039 mol) was added in portions to a solution of 4-(2-Bromo-4-nitrophenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione (VI; Ar=2-bromo-4-nitropheny , R10=H) (52) (0.50 g, 1.10 mmol) prepared as described in example 77 in methanol (80 mL) and 2N HCI (5.0 mL) at 60 °C. After 2 h the mixture was cooled, diluted with water, basified with cone, aqueous ammonia and extracted with ethyl acetate. The extract was worked up to give a solid which was chromatographed on silica. Elution with ethyl acetate gave 4-(4-amino-2-bromophenyl)-9-hydroxypyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione (VI; Ar=4-amino-2-bromophenyl, R10=H) (53) in a 0.47 g, 97 % yield which crystallised from ethyl acetate/petroleum ether as a yellow powder, mp 324- 326 °C. Η NMR δ [(CD3)2SO] 11.71 (br s, IH), 10.93 (br s, IH), 9.23 (br s, IH), 8.30 (d, J=2.4 Hz, IH), 7.43 (d, J=8.6 Hz, IH), 7.42 (s, IH), 7.09-7.03 (m, 2H), 6.89 (d, J=2.1 Hz, IH), 6.61 (dd, J=8.6, 2.4 Hz, IH), 5.48 (br s, 2H). Found: C, 56.79; H, 3.26; N, 8.77. C20H12BrN3O3.l/2EtOAc requires C, 56.67; H, 3.46; N, 9.01.
Representative Procedure for Method 7 of Scheme 2
EXAMPLE 79
The preparation of 4-(2-Chlorophenyl)-9-methoxypyrrolor3.4-c1carbazole- 3(2H.6H)-dione (V: Ar=2-chlorophenyl. R10--H) (33)
Manganese dioxide (12.0 g) was added to a solution of 4-(2-Chlorophenyl)-9- methoxy-4,5,6,10c-tetrahydropyrrolo[3,4-c]carbazole-l,3(2H,3aH)-dione (IV; Ar=2- chlorophenyl, R1 =H) (32) prepared as described in example 68 (2.1 g, 5.51 mmol) in dioxane (100 mL) and the mixture was refluxed with stirring for 16 h. The mixture was filtered hot through a plug of Celite, washing through with more dioxane and then 10% methanol/dioxane. The combined filtrate and washings were concentrated to dryness and the residue was adsorbed onto silica and chromatographed. Elution with ethyl acetate/petroleum ether (3:7) gave 4-(2-Chlorophenyl)-9-methoxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione (V; Ar=2-chlorophenyl, R10=H) (33) in a yield of 1.66 g, 79 % which crystallised from THF/petroleum ether as a yellow powder, mp 170-175 °C (dec). !H NMR δ [(CD3)2SO 11.96 (br s, IH), 11.08 (br s, IH), 8.46 (d, J=2.6 Hz, IH), 7.60-7.55 (m, 3H), 7.51-7.42 (m, 3H), 7.24 (dd, J=8.9, 2.6 Hz, IH), 3.89 (s, 3H). Found: C, 65.64; H, 3.63; N, 7.12. C2ιHι3ClN203.l/2H2O requires C, 65.37; H, 3.66; N, 7.26.
Representative procedure for Method 8 of Scheme 2
EXAMPLE 80
The preparation of 4-(2-Chlorophenyl)-9-hvdroxy-6-(3-hvdroxypropyl)pyrrolor3.4-
Figure imgf000085_0001
A solution of IN BBr3 in CH2C12 (11.5 mL, 0.011 mol) was added to a solution of 4- (2-Chlorophenyl)-6-(3-hydroxypropyl)-9-methoxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione (V; Ar=2-chlorophenyl, R10=CH2CH2CH2OH) (31) prepared as described in example 40 (1.00 g, 2.30 mmol) in CH2C12 under nitrogen and the reaction mixture was stirred at room temperature for 3 h. Saturated aqueous NaHC0 solution was added and the solution was diluted with water and extracted with ethyl acetate. The organic phase was dried, the drying agent was removed and the solution was concentrated to dryness, adsorbed onto silica and chromatographed. Elution with ethyl acetate/petroleum ether (1 :1) followed by ethyl acetate gave 4-(2-Chlorophenyl)-9-hydroxy-6-(3-hydroxypropyl)pyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione (VI; Ar=2-chlorophenyl, R10=CH2CH2CH2OH) (34) in a yield of 0.90 g, 93%, which crystallised from THF/petroleum ether as a yellow/orange powder, mp 291-294 °C. 1H NMR δ [(CD3)2SO 11.05 (br s, IH), 9.36 (s, IH), 8.38 (d, J=2.5 Hz, IH), 7.74 (s, IH), 7.59-7.54 (m, 2H), 7.52-7.42 (m, 3H), 7.14 (dd, J=8.7, 2.5 Hz, IH), 4.62 (br t, IH), 4.49 (t, J=6.8 Hz, 2H), 3.41 (m, 2H), 1.90 (m, 2H). Found: C, 64.99; H, 4.13; N, 6.43. C23H17C1N204.1/4H20 requires C, 64.94; H, 4.15; N, 6.58.
Representative Procedure fof Method 9 of Scheme 2
EXAMPLE 81
The preparation of 4-(2-Chlorophenyl)-9-hydroxypyrrolor3.4-c1carbazole-1.3(2H.6H)-dione (VI; Ar--2-chlorophenvI. R10=H) (9)
4-(2-Chlorophenyl)-9-methoxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione (V; Ar=2- chlorophenyl, RI0=H) (33) prepared as described in example 79 (0.512 g, 1.36 mmol) was added to a pyridinium hydrochloride melt at 200 °C and the mixture was stirred at this temperature for 20 min. Water was added and the resultant precipitate was filtered off, washed well with water, adsorbed onto silica and chromatographed. Elution with ethyl acetate/petroleum ether (1:1) gave 4-(2-Chlorophenyl)-9-hydroxypyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione (VI; Ar=2-chlorophenyl, R10=H) (9) in a 0.42 g, 85% yield; mp 215-220 °C (dec). Η NMR δ [(CD3)2SO] 11.83 (br s, IH), 11.01 (br s, IH), 9.27 (br s, IH), 8.32 (d, J=2.4 Hz, IH), 7.65-7.40 m, 5H), 7.08 (dd, J=8.7, 2.4 Hz), IH). Found: C, 65.72; H, 3.50; N, 6.97. C20H„ClN2O3.l/4CH3COOCH2CH3 requires C, 65.54; H, 3.40; N, 7.28. EXAMPLE 82
The preparation of 6-(2-Hvdroxyethyl)-9-methoxy-4-phenylpyrrolor3.4-clcarbazole-
Figure imgf000087_0001
5-methoxy-2-[(E,Z)-2-phenylethenyl]-lH-indole (II; Ar=phenyl) (1.93 g, 7.74 mmolwas reacted with 2-(2-bromoethoxy)tetrahydro-2H-pyran using the procedure described in example 38. This material was reacted directly with maleimide (0.79 g) using the procedure described in method 4. The product obtained was reacted using the procedure described in example 70 gave crude material that was then dissolved in methanol (100 mL) to which p-toluenesulfonic acid (30 mg) was added before the solution was warmed to 50 °C for 3h. The solution was then diluted with water and extracted with ethyl acetate. The organic phase was dried, the drying agent was removed and the solution was concentrated to dryness before being adsorbed onto silica and chromatographed eluting with ethyl acetate/hexane (1:2 to 1:1) to give 6-(2-Hydroxyethyl)-9-methoxy-4-phenylpyrrolo[3,4-c]carbazole-l,3(2H,6H)- dione (V; Ar=phenyl, R10=(CH2)2OH) (201) in a yield of 0.51 g, 17% as a yellow powder; mp 262-264 °C. Η NMR δ [(CD3)2SO] 11.09 (br s, IH), 8.56 (d, J=2.6 Hz, IH), 7.83 (s, IH), 7.66 (m, 3H), 7.47 (m, 3H), 7.28 (dd, J=9.0, 2.6 Hz, IH), 4.86 (t, J=5.5 Hz, IH), 4.55 (t, J=5.3 Hz, 2H), 3.90 (s, 3H), 3.78 (m, 2H). Found: C, 71.47; H, 4.77; N, 7.32. C23H18N204 requires: C, 71.49; H, 4.70; N, 7.25.
EXAMPLE 83
The preparation of 6-(3-Hvdroxypropyl)-9-methoxy-4-phenylpyrrolor3.4-clcarbazole- 1.3(2H.6H)-dione (V; Ar=phenyl. R10=(CH^OH) (202)
5-Methoxy-2-[(E,Z)-2-phenylethenyl]-lH-indole (II; Ar=phenyl) (6.85 g, 27.5 mmol) was reacted with with 3-bromopropyl tert-butyl(dimethyl)silyl ether using the procedure described in example 38. The product isolated was reacted directly with maleimide (5.2 g) using the procedure described in example 68. Aromatisation of the crude Diels-Alder adduct using the procedure described in example 79 gave crude material that was then dissolved in methanol (300 mL) to which IN hydrochloric acid (50 mL) was added. This solution was stirred at rt for 3h before being diluted with water and extracted with ethyl acetate. The organic layer was dried, the drying agent was removed and the solution was concentrated to dryness. The residue was adsorbed onto silica and chromatographed eluting with dichloromethane to ethyl acetate/dichloromethane (7:3). Trituration with diethyl ether gave alcohol (202) as a yellow powder (2.55 g, 23%), mp 241-243 °C. Η NMR δ [(CD3)2SO] 11.10 (br s, IH), 8.56 (d, J=2.6 Hz, IH), 7.82 (s, IH), 7.67 (m, 3H), 7.47 (m, 3H), 7.30 (dd, J=9.0, 2.6 Hz, IH), 4.66 (t, J=4.9 Hz, IH), 4.55 (t, J=6.9 Hz, 2H), 3.90 (s, 3H), 3.39 (m, 2H), 1.93 (m, 2H). Found: C, 71.95; H, 5.09; N, 6.93. C24H20N2O4 requires: C, 71.99; H, 5.03; N, 6.99.
EXAMPLE 84
The preparation of 6-(6-Hvdroxyhexyl)-9-methoxy-4-phenylpyrrolor3.4-c1carbazole- 1.3(2H.6H)-dione (V Ar=phenyl. R10=(CH2)ftQH) (203)
Alkylation of 5-methoxy-2-[(E,Z)-2-phenylethenyl]-lH-indole (II; Ar=phenyl) (0.30 g, 0.71 mmol) ) with 6-bromohexyl-tert-butyl(dimethyl)silyl ether according to procedure described in example 38 gave crude material that was reacted directly with maleimide (0.14 g) following Method 4a.
Aromatisation of the crude Diels- Alder adduct using the procedure described in example 79 gave crude material that was then dissolved in methanol (100 mL) to which IN hydrochloric acid (15 mL) was added. This solution was stirred at rt for 2h before being diluted with water and extracted with ethyl acetate. The organic layer was dried, the drying agent was removed and the solution was concentrated to dryness. Chromatography on silica eluting with dichloromethane to ethyl acetate/hexane (4:1) followed by trituration with diethyl ether gave alcohol (203) as a yellow powder (0.31 g, 98%), mp 170-173 °C. 1H NMR δ [(CD3)2SO] 11.10 (br s, IH), 8.56 (d, J=2.6 Hz, IH), 7.82 (s, IH), 7.67 (m, 3H), 7.47 (m, 3H), 7.29 (dd, J=8.9, 2.6 Hz, IH), 4.50 (t, J=7.0 Hz, 2H), 4.28 (t, J=5.1 Hz, IH), 3.90 (s, 3H), 3.32 (t, J=6.4 Hz, 2H), 1.76 (m, 2H), 1.36-1.26 (m, 6H). Found: C, 73.57; H, 6.17; N, 6.39. C27H26N2O requires: C, 73.28; H, 5.92; N, 6.33.
EXAMPLE 85
The preparation of 4-(2.6-Dichlorophenyl)-6-(2-hvdroxyethyl)-9-methoxypyrrolo, 3.4- clcarbazole-1.3(2H.6H)-dione (V; Ar=2,6-dichlorophenyl. R10=(CH?)2OID (230)
Alkylation of pure trans-diene (512) (3.0 g, 10.6 mmol) prepared as described in example 103 with 2-(2-bromoethoxy)tetrahydro-2H-pyran according to the procedure described in example 38 gave crude material that was dissolved in methanol/tetrahydrofuran (4:1, 250 mL) to which 2N hydrochloric acid (20 mL) was added before the solution was stirred at room temperature for 2h. The solution was then diluted with saturated sodium bicarbonate and concentrated under reduced pressure to precipitate the crude product which was collected by filtration and dried in vacuo. This solid was reacted directly with maleimide (1.26 g) following The procedure described in example 68. Aromatisation of the chromatographed Diels-Alder adduct using the procedure described in example 70 gave material that was then triturated from methanol to give alcohol (230) as a yellow powder (2.14 g, 44%), mp 229-231 °C. 'H NMR δ [(CD3)2SO] 11.17 (br s, IH), 8.50 (d, J=2.6 Hz, IH), 7.86 (s, IH), 7.72 (d, J=9.0 Hz, IH), 7.62 (m, 2H), 7.51 (dd, J=8.9, 7.4 Hz, IH), 7.31 (dd, J=9.0, 2.6 Hz, IH), 4.83 (t, J=5.3 Hz, IH), 4.54 (t, J=5.2 Hz, 2H), 3.91 (s, 3H), 3.77 (m, 2H). Found: C, 60.61; H, 3.85; N, 5.88. C23H16C12N204 requires: C, 60.66; H, 3.54; N, 6.15.
EXAMPLE 86
The preparation of 4-(2,6-Dichlorophenyl)-6-(3-hvdroxypropyl)-9-methoxypyrrolor3.4-
Figure imgf000089_0001
Alkylation of diene (512) (3.0 g, 9.43 mmol) prepared as described in example 103 with 3-bromopropyl tert-butyl(dimethyl)silyl ether according to the procedure described in example 38 gave crude material that was dissolved in methanol/dichloromethane (3:1, 300 mL) to which IN hydrochloric acid (60 mL) was added. This solution was stirred at rt for 2h before being diluted with saturated sodium bicarbonate and concentrated under reduced pressure to precipitate the crude product which was collected by filtration and dried in vacuo. This solid was reacted with maleimide (1.20 g) following The procedure described in example 68. Aromatisation of the crude Diels-Alder adduct using the procedure described in example 70 gave material that was then chromatographed on silica eluting with methanol/dichloromethane (2:98 to 5:95) to give alcohol (232) (2.4 g, 54%) as a yellow powder, p 254-256 °C. Η NMR δ [(CD3)2SO] 11.18 (br s, IH), 8.51 (d, J=2.6 Hz, IH), 7.86 (s, IH), 7.72 (d, J=9.0 Hz, IH), 7.63 (m, 2H), 7.51 (dd, J=8.8, 7.4 Hz, IH), 7.34 (dd, J=9.0, 2.6 Hz, IH), 4.62 (t, J=5.0 Hz, IH), 4.54 (t, J=6.9 Hz, 2H), 3.91 (s, 3H), 3.42 (m, 2H), 1.90 (m, 2H). FABMS found M+: 468.0630, 470.0628, 472.0626. C 4Hι8Cl2N2O4 requires 468.0644, 470.0614, 472.0585.
EXAMPLE 87
The preparation of 4-(4-(2-Chlorophenyl)-9-methoxy-1.3-dioxo-2.3-dihvdropyrrolor3.4- c1carbazol-6(lH)-yl)butanoic acid (V: Ar=2-chlorophenyl. R10--(CH7) COOH) (262) Alkylation of diene (27) (0.40 g, 1.41 mmol) prepared as described in example 37 with ethyl bromobutyrate according to the procedure described in example 38 gave crude material that was reacted with maleimide (0.27 g) following the procedure described in example 68. Aromatisation of the Diels-Alder adduct using the procedure described in example 70 gave crude material that was then dissolved in methanol (100 mL) to which 2N potassium hydroxide (2 mL) was added. This solution was stirred at rt for 2h before being diluted with water and acidified by the addition of IN hydrochloric acid to precipitate the product as a yellow solid, which was collected by filtration and washed with water before being dried in vacuo. Chromatography on silica eluting with ethyl acetate followed by trituration with diethyl ether/hexane, gave acid (262) as a yellow powder (0.10 g, 16%), mp 251-254 °C. Η NMR δ [(CD3)2SO] 12.12 (br s, IH), 11.12 (br s, IH), 8.53 (d, J=2.6 Hz, IH), 7.85 (s, IH), 7.72 (d, J=9.0 Hz, IH), 7.58 (m, IH), 7.53-7.45 (m, 3H), 7.32 (dd, J=9.0, 2.6 Hz, IH), 4.50 (t, J=7.3 Hz, 2H), 3.91 (s, 3H), 2.30 (m, 2H), 1.97 (m, 2H). FABMS found [M+H]+: 463.1025, 465.1034. C25Hι9ClN205 requires 463.1061, 465.1031.
EXAMPLE 88
The preparation of 4-(4-(2-Chlorophenyl)-9-hydroxy-l ,3-dioxo-2,3-dihydropyrrolor3.4- clcarbazol-6(lH)-yl)butanoic acid (VI; Ar=2-chlorophenyl, R10--(CH2)2COOH) (263)
Demethylation of acid (262) (32 mg, 0.07 mmol) prepared as described in example 87 employing the procedure described in example 80 gave phenol (263) (6 mg, 19%) as an orange powder, mp 274-277 °C. ]H NMR δ [(CD3)2SO] 12 (v br s, IH), 11.06 (br s, IH), 9.38 (br s, IH), 8.38 (d, J=2.4 Hz, IH), 7.80 (s, IH), 7.60 (d, J=8.9 Hz, IH), 7.58 (m, IH), 7.52- 7.43 (m, 3H), 7.14 (dd, J=8.9, 2.4 Hz, IH), 4.45 (t, J=7.5 Hz, 2H), 2.27 (m, 2H), 1.95 (m, 2H). FABMS found [M+H]+: 449.0874, 451.0879. C24Hι7ClN205 requires 449.0904, 451.0875.
EXAMPLE 89
The preparation of 9-Hvdroxy-6-(2-hvdroxyethyl)-4-phenylpyιτoIor3,4-clcarbazole- 1.3(2H.6H)-dione (VI; Ar=phenyl. R' CH. )?OH) (220)
Demethylation of alcohol (201) (135 mg, 0.35 mmol) prepared as described in example 82 employing The procedure described in example 81 gave alcohol (220) (90 mg, 69%) as an orange powder, mp 298-301 °C. 1H NMR δ [(CD3)2SO] 11.04 (br s, IH), 9.31 (br s, IH), 8.40 (d, J=2.5 Hz, IH), 7.79 (s, IH), 7.64 (m, 2H), 7.55 (d, J=8.8 Hz, IH), 7.47 (m, 3H), 7.10 (dd, J=8.8, 2.5 Hz, IH), 4.85 (t, J=5.3 Hz, IH), 4.51 (t, J=5.4 Hz, 2H), 3.77 (m, 2H). Found: C, 68.88; H, 4.43; N, 6.76. C22H16N204.3/4H20 requires: C, 68.48; H, 4.57; N, 7.26.
EXAMPLE 90
The preparation of 9-Hvdroxy-6-(3-hvdroxypropyl)-4-phenylpyrrolor3,4-clcarbazole- 1.3(2H.6H)-dione (VI; Ar=phenyl. R10--(CH2)2OH) (221)
Demethylation of alcohol (202) prepared as described in example 83 (60 mg, 0.15 mmol) employing the procedure described in example 80 gave alcohol (221) (45 mg, 78%) as an orange powder, mp 274-276 °C. ]H NMR δ [(CD3)2SO] 11.05 (br s, IH), 9.33 (s, IH), 8.41 (d, J=2.4 Hz, IH), 7.77 (s, IH), 7.64 (m, 2H), 7.56 (d, J=8.8 Hz, IH), 7.46 (m, 3H), 7.12 (dd, J=8.8, 2.4 Hz, IH), 4.64 (t, J=4.9 Hz, IH), 4.51 (t, J=6.9 Hz, 2H), 3.39 (m, 2H), 1.92 (m, 2H). Found: C, 71.59; H, 4.74; N, 7.57. C23Hι8N204 requires: C, 71.49; H, 4.70; N, 7.25.
EXAMPLE 91
The preparation of 9-Hvdroxy-6-(6-hvdroxyhexyl)-4-phenylpyrrolor3.4-c1carbazole- 1.3(2H.6H)-dione (VI; Ar=phenyl. R10=(CH2V,OH) (222)
Demethylation of alcohol (203) prepared as described in example 84 (55 mg, 0.12 mmol) employing the procedure described in example 80 gave alcohol (222) (12 mg, 23%) as an orange powder, mp 132-140 °C. Η NMR δ [(CD3)2SO] 11.04 (br s, IH), 9.33 (s, IH), 8.41 (d, J=2.5 Hz, IH), 7.77 (s, IH), 7.64 (m, 2H), 7.54 (d, J=8.8 Hz, IH), 7.46 (m, 3H), 7.12 (dd, J=8.8, 2.5 Hz, IH), 4.46 (t, J=7.1 Hz, 2H), 4.29 (t, J=5.1 Hz, IH), 3.31 (m, 2H), 1.75 (m, 2H), 1.36-1.26 (m, 6H). FABMS found M+: 428.1730. C26H24N204 requires 428.1736.
EXAMPLE 92
The preparation of 9-Methoxy-6-methyl-4-phenylpyrrolor3,4-clcarbazole-1.3(2H,6H)-dione (V: Ar=phenyl R10--CH^) (223)
Alkylation of pure trans 5-methoxy-2-[(E)-2-phenylethenyl]-lH-indole (II; Ar=phenyl) (0.20 g, 0.80 mmol) with methyl iodide according to the procedure described in example 38 gave crude material that was reacted with maleimide (92 mg) following Method 4a, except that the reaction time was 24 h. Aromatisation of the crude Diels-Alder adduct using the procedure described in example 79 gave crude material that was chromatographed on silica eluting with ethyl acetate/dichloromethane (1:3). Trituration from methanol gave carbazole (223) (0.20 g, 70%) as a yellow powder, mp 286-291 °C. ]H NMR δ [(CD3)2SO] 11.11 (br s, IH), 8.53 (d, J=2.6 Hz, IH), 7.80 (s, IH), 7.66 (m, 3H), 7.47 (m, 3H), 7.30 (dd, J=9.0, 2.6 Hz, IH), 3.96 (s, 3H), 3.90 (s, 3H). Found: C, 74.29; H, 4.67; N, 7.86. C22Hι6N203 requires: C, 74.15; H, 4.53; N, 7.86.
EXAMPLE 93
The preparation of 9-Hvdroxy-6-methyl-4-phenylpyrrolor3,4-clcarbazole-1.3(2H.6H)-dione (VI; Ar=phenyl, R10=CH (224)
Demethylation of alcohol (223) prepared as described in example 92 (180 mg, 0.51 mmol) employing the procedure described in example 81, was followed by chromatography on silica eluting with ethyl acetate/dichloromethane (1 :2). Trituration from dichloromethane/hexane gave alcohol (224) (155 mg, 90%) as an orange powder, mp 297- 300 °C. 1H NMR δ [(CD3)2SO] 11.05 (br s, IH), 9.34 (s, IH), 8.39 (d, J=2.5 Hz, IH), 7.76 (s, IH), 7.65 (m, 2H), 7.54 (d, J=8.8 Hz, IH), 7.46 (m, 3H), 7.13 (dd, J=8.8, 2.5 Hz, IH), 3.93 (s, 3H). Found: C, 69.96; H, 4.58; N, 7.70. C2ιH14N203.H20 requires: C, 69.99; H, 4.48; N, 7.77.
EXAMPLE 94
The preparation of 4-(2.6-Dichlorophenyl)-9-hvdroxy-6-(2-hvdroxyethyl)pyrrolor3.4- clcarbazole-1.3(2H.6H)-dione (VI; Ar--2.6-dichlorophenyl. R10=(CH. )?OH) (234)
Demethylation of alcohol (230) (0.10 g, 0.22 mmol) prepared as described in example
85 employing the procedure described in example 80 gave phenol (234) (49 mg, 50%) as an orange/yellow powder, mp 254-257 °C. Η NMR δ [(CD3)2SO] 11.10 (br s, IH), 9.35 (s, IH), 8.36 (d, J=2.4 Hz, IH), 7.80 (s, IH), 7.61 (m, 3H), 7.50 (dd, J=8.7, 7.3 Hz, IH), 7.13 (dd, J=8.8, 2.4 Hz, IH), 4.82 (t, J=5.5 Hz, IH), 4.49 (t, J=5.2 Hz, 2H), 3.75 (m, 2H). Found: C, 58.76; H, 3.34; N, 6.25. C22Hι4Cl2N204.l/2H20 requires: C, 58.67; H, 3.36; N, 6.22.
EXAMPLE 95
The preparation of 4-(2.6-Dichlorophenyl)-9-hvdroxy-6-(3-hvdroxypropyl)pyrrolo[3.4- clcarbazole-1.3(2H.6H)-dione (VI; Ar--2.6-dichlorophenyl. R10=(CH )3OH) (235)
Demethylation of alcohol (232) (0.36 g, 0.77 mmol) prepared as described in example
86 employing the procedure described in example 80 gave phenol (235) (0.32 g, 92%) as an orange/yellow powder, mp 215-218 °C. ]H NMR δ [(CD3)2SO] 11.12 (br s, IH), 9.39 (s, IH), 8.37 (d, J=2.5 Hz, IH), 7.80 (s, IH), 7.61 (m, 3H), 7.51 (dd, J=8.7, 7.2 Hz, IH), 7.16 (dd, J=8.8, 2.5 Hz, IH), 4.61 (t, J=5.0 Hz, IH), 4.49 (t, J=6.9 Hz, 2H), 3.42 (m, 2H), 1.88 (m, 2H). Found: C, 60.36; H, 3.47; N, 6.08. C23Hι6Cl2N204 requires: C, 60.66; H, 3.54; N, 6.15.
EXAMPLE 96
The preparation of 3-{2-r(E)-2-(2-Chlorophenyl)ethenyl"l-5-methoxy-lH-indol-l-
Figure imgf000093_0001
To a solution of trans-diene (27) prepared as described in example 37 (1.5 g, 5.25 mmol) in acetonitrile (30 mL) was added acrylonitrile (2.42 mL, 36.8 mmol) and 1,8- diazabicyclo[5.4.0]undec-7-ene (20 drops). The resulting solution was stirred at room temperature under nitrogen for 18 h before being diluted with water and extracted with ethyl acetate. The organic layer was dried, the drying agent was removed and the solution was concentrated to dryness. Chromatography on silica eluting with ethyl acetate/hexane (1:1), followed by trituration from methanol gave the diene (236) (1.36 g, 77%) as an off-white solid, mp 136-138 °C. !H NMR δ [(CD3)2SO] 8.05 (dd, J=7.9, 1.5 Hz, IH), 7.50 (m, 4H), 7.41 (m, IH), 7.33 (m, IH), 7.04 (d, J=2.4 Hz, IH), 6.90 (s, IH), 6.81 (dd, J=9.0, 2.4 Hz, IH), 4.68 (t, J=6.6 Hz, 2H), 3.77 (s, 3H), 2.93 (t, J=6.6 Hz, 2H). Found: C, 71.32; H, 5.14; N, 8.51. C20H17ClN2O requires: C, 71.31; H, 5.09; N, 8.31.
EXAMPLE 97
The preparation of 3-(4-(2-Chlorophenyl)-9-methoxy-1.3-dioxo-2.3-dihydropyrrolor3.4- c1carbazol-6(lH)-yl)ρropanenitrile (V; Ar=2-chlorophenyl. R10=CH?CH2CN) (237)
Diene (236) (1.30 g, 3.86 mmol) prepared as described in example 96 was reacted with maleimide (0.49 g) following The procedure described in example 68 and then aromatized according to the procedure described in example 70 to give crude material that was chromatographed on silica eluting with ethyl acetate/hexane (1:1). Trituration from methanol gave nitrile (237) (1.33 g, 80%) as a yellow powder, mp 287-288 °C. Η NMR δ [(CD3)2SO] 11.16 (br s, IH), 8.53 (d, J=2.6 Hz, IH), 8.02 (s, IH), 7.83 (d, J=9.0 Hz, IH), 7.59 (m, IH), 7.49 (m, 3H), 7.33 (dd, J=9.0, 2.6 Hz, IH), 4.86 (t, J=6.7 Hz, 2H), 3.91 (s, 3H), 3.04 (t, J=6.7 Hz, 2H). Found: C, 65.32; H, 4.15; N, 9.60. C24Hι6ClN303.3/4H2O requires: C, 65.01; H, 3.98; N, 9.47. EXAMPLE 98
The preparation of 3-(4-(2-Chlorophenyl)-9-hydroxy-l ,3-dioxo-2,3-dihvdropyrrolof3.4- clcarbazol-6(lH)-yl)propanenitrile (VI; Ar=2-ch1orophenyl. R10=CH?CH.CN) (238)
Demethylation of nitrile (237) (0.15 g, 0.35 mmol) prepared as described in example 97 employing The procedure described in example 80, followed by trituration from methanol, gave phenol (238) (0.13 g, 89%) as an orange/yellow powder, mp 332-336 °C. ]H NMR δ [(CD3)2SO] 11.10 (br s, IH), 9.42 (br s, IH), 8.39 (d, J=2.4 Hz, IH), 7.96 (s, IH), 7.69 (d, J=8.8 Hz, IH), 7.58 (m, IH), 7.48 (m, 3H), 7.15 (dd, J=8.8, 2.4 Hz, IH), 4.82 (t, J=6.7 Hz, 2H), 3.02 (t, J=6.7 Hz, 2H). Found: C, 66.24; H, 3.66; N, 9.93. C23Hι4ClN303 requires: C, 66.43; H, 3.39; N, 10.10.
EXAMPLE 99
The preparation of 6-Benzyl-4-(2-chlorophenyl)-9-methoxypyrrolor3,4-c1carbazole-
Figure imgf000094_0001
Alkylation of pure trans-diene (27) (0.20 g, 0.70 mmol) prepared as described in example 37 with benzyl bromide according to the procedure described in example 38 gave crude material that was reacted directly with maleimide (103 mg) following the procedure described in example 68, except that the reaction time was 24 h. Aromatisation of the crude Diels-Alder adduct using the procedure described in example 70 gave crude material that was chromatographed on silica eluting with ethyl acetate/hexane (1 :2). Trituration from ethyl acetate/hexane gave carbazole (239) (0.15 g, 46%) as a yellow powder, mp 234-237 °C. Η NMR δ [(CD3)2SO] 11.15 (br s, IH), 8.55 (d, J=2.6 Hz, IH), 7.91 (s, IH), 7.69 (d, J=9.0 Hz, IH), 7.56 (m, IH), 7.46 (m, 3H), 7.25 (m, 4H), 7.16 (m, 2H), 5.79 (s, 2H), 3.90 (s, 3H). Found: C, 71.78; H, 4.39; N, 6.18. C28H]9C1N203 requires: C, 72.02; H, 4.10; N, 6.00.
EXAMPLE 100
The preparation of 6-Benzyl-4-(2-chlorophenyl)-9-hvdroxypyrrolor3.4-c1carbazole- 1.3(2H.6H)-dione (VI: Ar=2-chlorophenyl. R10--:CH.Ph) (240)
Demethylation of carbazole (239) (0.10 g, 0.21 mmol) prepared as described in example 99 employing the procedure described in example 80, followed by chromatography on silica eluting with ethyl acetate/hexane (1:2) and trituration from ethyl acetate/hexane, gave carbazole (240) (87 mg, 91%) as an orange/yellow powder, mp 269-271 °C. Η NMR δ [(CD3)2SO] 11.09 (br s, IH), 9.40 (s, IH), 8.40 (d, J=2.5 Hz, IH), 7.86 (s, IH), 7.56 (m, 2H), 7.45 (m, 3H), 7.25 (m, 3H), 7.16 (m, 2H), 7.11 (dd, J=8.9, 2.5 Hz, IH), 5.75 (s, 2H). Found: C, 72.06; H, 4.18; N, 6.20. C27HπClN203 requires: C, 71.60; H, 3.78; N, 6.18.
EXAMPLE 101
The preparation of Methyl 3-(4-(2-chlorophenyl)-9-hvdroxy-1.3-dioxo-2.3- dihvdropyrrolor3.4-clcarbazol-6(lH)-yl)propanoate (VI. Ar=2-chlorophenyl. R10=(CH?)ZCOOCH (264)
Gaseous hydrochloric acid was bubbled through a stirred solution of acid (117) (35 mg, 0.08 mmol) prepared as described in example 230 in methanol (10 mL) for 30 seconds. The resulting solution was stirred for 30 minutes at room temperature before being diluted with water and extracted with ethyl acetate. The organic layer was dried, the drying agent was removed and the solution was concentrated to dryness. Chromatography on silica eluting with ethyl acetate/hexane (1:1) followed by crystallisation from ethyl acetate/hexane gave ester (264) (25 mg, 70%) as an orange powder, mp 218-220 °C. !H NMR δ [(CD3)2SO] 11.07 (br s, IH), 9.39 (br s, IH), 8.38 (d, J=2.5 Hz, IH), 7.79 (s, IH), 7.57 (m, 2H), 7.51-7.44 (m, 3H), 7.14 (dd, J=8.8, 2.5 Hz, IH), 4.71 (t, J=6.8 Hz, 2H), 3.48 (s, 3H), 2.83 (t, J=6.8 Hz, 2H). Found: C, 62.18; H, 4.04; N, 5.99. C24H17C1N205.3/4H20 requires: C, 62.34; H, 4.03; N, 6.06.
Representative Procedure for Method 10a of Scheme 2
EXAMPLE 102
The preparation of (2,6-Dichlorobenzyl)(triphenyl)phosphonium bromide (511)
A mixture of 2,6-dichlorotoluene (20.1 g, 0.125 mol), N-bromosuccinimide (24.6 g, 0.138 mol) and 2,2'-azobisisobutyronitrile (0.41 g, 2.50 mmol) in dry benzene (300 mL) under N2 was stirred at reflux for 6 h with continuous irradiation from a 100W lamp. The resulting reaction mixture was concentrated under vacuum (to 50 mL), cooled and filtered, washing with dry benzene. The filtrate (containing the crude benzyl bromide) was treated directly with triphenylphosphine (49.3 g, 0.188 mol), stirring at reflux for 17 h. After cooling, the precipitate was collected by filtration, washing thoroughly with dry benzene, then pentane, and dried under vacuum at 50 °C to give the phosphonium salt (511) as a cream powder (62.1 g, 99 %), mp (benzene) 247-250 °C. 1H NMR (CDC13) δ 7.76 (m, 9H), 7.64 (m, 6H), 7.18 (s, 3H), 5.50 (d, J=14.3 Hz, 2H). Found: C, 60.03; H, 3.76. C^HsoBrClzP requires C, 59.79; H, 4.01.
EXAMPLE 103
The preparation of 2- (E)-2-(2.6-Dichlorophenyl)ethenyll-5-methoxy-lH-indole (512) (II. Ar=2,6-dichlorophenyl)
The 5-methoxy-lH-indole-2-carbaldehyde (1) was reacted with (2,6- dichlorobenzyl)(triphenyl)phosphonium bromide (511) prepared as described in example 102 using the procedure described in example 37, except that the LDA and aldehyde were (sequentially) added at 0 °C, the ratio of LDA: aldehyde was 1.37:1 and the reaction time was 5 h, to give (after crystallisation from CH2Cl2/hexane) the diene (512) as a yellow solid (the pure E isomer) (97 %), mp 144-147 °C. ]H NMR (CDC13) δ 8.20 (br s, IH), 7.36 (d, J=8.1 Hz, IH), 7.27 (m, IH), 7.25 (d, J=16.8 Hz, IH), 7.11 (t, J=8.0 Hz, IH), 7.03 (d, J=2.4 Hz, IH), 6.93 (d, J=16.8 Hz, IH), 6.88 (dd, J=8.7, 2.5 Hz, IH), 6.61 (d, J=1.8 Hz, IH), 3.86 (s, 3H). Found: C, 64.04; H, 4.13; N, 4.39. CπHι3Cl2NO requires C, 64.17; H, 4.12; N, 4.40.
EXAMPLE 104
The preparation of 4-(2.6-Dichlorophenyl)-9-methoxy-4,5.6.10c-tetrahydropyιτolor3.4- clcarbazole-1.3(2H.3aH)-dione (513) (IV. R10=H. Ar=2.6-dichlorophenyl)
The pure E diene (512) prepared as described in example 103 was reacted with maleimide according to the procedure described in example 68 in a foil-covered sealed vial, except that the ratio of diene:maleimide:SnCl2 was 1:4:0.075 and the reaction time was 3 h, to give a crude solid containing the adduct (513), which was used without further purification.
EXAMPLE 105
The preparation of 4-(2.6-Dichlorophenyl)-9-methoxypyrrolor3.4-c1carbazole-L3(2H.6H)- dione (514) (V. R10=H. Ar=2,6-dichlorophenyl)
The crude adduct (513) prepared as described in example 104 was aromatised with DDQ (5 equiv.) using the procedure described in example 70, except that the solvent was 1:1 toluene/dioxane and the reaction time was 48 h, to give (after crystallisation from MeOH/CH2Cl2/hexane) the product (514) (78 %) as a yellow crystalline solid, mp 299-301 °C. Η NMR [(CD3)2SO] δ 12.02 (br s, IH), 11.15 (br s, IH), 8.45 (d, J=2.6 Hz, IH), 7.61 (d, J=7.7 Hz, 2H), 7.61 (s, IH), 7.59 (d, J=8.9 Hz, IH), 7.50 (dd, J=8.8, 7.4 Hz, IH), 7.26 (dd, J=8.9, 2.7 Hz, IH), 3.90 (s, 3H). Found: C, 61.26; H, 2.92; N, 6.65. C2ιHι2Cl2N203 requires C, 61.33; H, 2.94; N, 6.81.
EXAMPLE 106
The preparation of 4-(2,6-Dichlorophenyl)-9-hvdroxypyrrolo[3.4-clcarbazole-1.3(2H.6H)- dione (515) (VI. R10=H. Ar=2.6-dichlorophenyl)
The methyl ether (514) prepared as described in example 105 was demethylated with BBr3 using the procedure described in example 80 to give (after crystallisation from MeOH/CH2Cl2/hexane) the phenol (515) (98 %) as an orange solid, mp 205-215 °C (dec). Η NMR [(CD3)2SO] δ 11.89 (br s, IH), 11.08 (br s, IH), 9.32 (br s, IH), 8.30 (d, J=2.4 Hz, IH), 7.61 (d, J=7.9 Hz, 2H), 7.55 (s, IH), 7.50 (dd, J=8.7, 7.4 Hz, IH), 7.47 (d, J=8.7 Hz, IH), 7.10 (dd, J=8.7, 2.4 Hz, IH). Found: C, 58.98; H, 2.99; N, 6.68. C20Hι0Cl2N2O3.l/2 H20 requires C, 59.13; H, 2.73; N, 6.90.
EXAMPLE 107
(2,6-Dibromobenzyl)(triphenyl)phosphonium bromide (516)
Bromination of 2,6-dibromotoluene with NBS/AIBN, followed by reaction of the crude bromide with triphenylphosphine, using the procedure described in example 102, except that the reaction time for the bromination was 3 h, gave the phosphonium salt (516) (95 %) as a cream powder, mp (CH2Cl2/benzene) 241-243 °C. Η NMR (CDC13) δ 7.78 (m, 9H), 7.64 (m, 6H), 7.40 (br d, J=7.9 Hz, 2H), 6.99 (td, J=8.0, 2.5 Hz, IH), 5.58 (d, J=14.1 Hz, 2H). Found: C, 47.06; H, 3.37. C25H20Br3P.3/4 CH2C12 requires C, 47.23; H, 3.31.
EXAMPLE 108
The preparation of 2-r(E)-2-(2.6-Dibromophenyl)ethenvn-5-methoxy-lH-indole (517) (II. Ar=2.6-dibromophenyl)
The 5-methoxy-lH-indole-2-carbaldehyde (1) was reacted with (2,6- dibromobenzyl)(triphenyl)phosphonium bromide (516) prepared as described in example 107 using the procedure described in example 37, except that the ratio of LDA: aldehyde was 1.37:1 and the reaction time was 5 h, to give (after crystallisation from CH2Cl2/hexane) the diene (517) as a yellow solid (the pure E isomer) (80 %), mp 140-141 °C. Η NMR (CDC13) δ 8.20 (br s, IH), 7.60 (d, J=8.1 Hz, IH), 7.27 (d, J=8.2 Hz, IH), 7.05 (br s, IH), 7.03 (d, J=16.7 Hz, IH), 6.96 (t, J=8.0 Hz, IH), 6.88 (dd, J=8.7, 2.5 Hz, IH), 6.82 (d, J=16.7 Hz, IH), 6.61 (d, J=1.9 Hz, IH), 3.86 (s, 3H). Found: C, 50.37; H, 3.24; N, 3.37. C]7Hι3Br2NO requires C, 50.16; H, 3.22; N, 3.44.
EXAMPLE 109
The preparation of 4-(2.6-Dibromophenyl)-9-methoxy-4.5.6.10c-tetrahydropyrrolof3.4- clcarbazoIe-1.3(2H.3aH)-dione (518) (IV. R10=H. Ar=2.6-dibromophenyl)
The pure E diene (517) prepared as described in example 108 was reacted with maleimide according to the procedure described in example 68 in a foil-covered sealed vial, except that the ratio of diene:maleimide:SnCl2 was 1 :5:0.075 and the reaction time was 3.5 h, to give a crude solid containing the adduct (518), which was used without further purification.
EXAMPLE 110
The preparation of 4-(2.6-Dibromophenyl)-9-methoxypyrrolor3,4-clcarbazole-1.3(2H.6H)- dione (519) (V. R10=H. Ar--2,6-dibromophenyl)
The crude adduct (518) prepared as described in example 109 was aromatised with DDQ (5 equiv.) using the procedure described in example 70, except that the solvent was 1:1 toluene/dioxane and the reaction time was 24 h, to give (after crystallisation from MeOH/CH2Cl2/hexane) the product (519) (68 %) as an orange crystalline solid, mp 329-331 °C. !H NMR [(CD3)2SO] δ 12.02 (br s, IH), 11.13 (br s, IH), 8.45 (d, J=2.6 Hz, IH), 7.80 (d, J=8.1 Hz, 2H), 7.59 (d, J=8.3 Hz, IH), 7.54 (s, IH), 7.33 (t, J=8.0 Hz, IH), 7.26 (dd, J=8.8, 2.6 Hz, IH), 3.90 (s, 3H). Found: C, 50.29; H, 2.32; N, 5.69. C21H12Br2N203 requires C, 50.43; H, 2.42; N, 5.60.
EXAMPLE 111
The preparation of 4-(2.6-Dibromophenyl)-9-hvdroxypyrrolor3.4-c1carbazole- 3(2H.6H)- dione (520) (VI, R10=H. Ar=2,6-dibromophenyl)
The methyl ether (519) prepared as described in example 110 was demethylated with BBr3 using the procedure described in example 80, except that the reaction time was 1.5 h, to give (after crystallisation from MeOH/CH2Cl2/EtOAc/hexane) the phenol (520) (98 %) as a yellow-orange solid, mp 180-190 °C (dec). Η NMR [(CD3)2SO] δ 11.90 (br s, IH), 11.08 (br s, IH), 9.35 (br s, IH), 8.30 (d, J=2.3 Hz, IH), 7.80 (d, J=8.1 Hz, 2H), 7.49 (s, IH), 7.48 (d, J=8.9 Hz, IH), 7.33 (t, J=8.1 Hz, IH), 7.11 (dd, J=8.7, 2.5 Hz, IH). Found: C, 49.13; H, 2.29; N, 6.05. C20Hι0Br2N2O3 requires C, 49.42; H, 2.07; N, 5.76.
Representative Procedure for Method 10b of Scheme 2
EXAMPLE 112
The preparation of (2.6-Dichloro-4-methoxybenzyl)(triphenyl)phosphonium bromide (521)
A solution of (2,6-dichloro-4-methoxyphenyl)methanol (3.00 g, 14.5 mmol) in 30% HBr in acetic acid (45 mL) was stirred at 20 °C for 3 h, then poured onto ice-water (120 mL) and extracted with pentane (6 x 100 mL). The extracts were washed with water (3 x 200 mL), backextracting with pentane (100 mL). Removal of the solvent gave the crude bromide as white crystals, which was immediately redissolved in benzene (80 mL) and treated with triphenylphosphine (5.70 g, 21.7 mmol), stirring at reflux for 15 h. After cooling, the precipitate was collected by filtration, washing thoroughly with dry benzene, then pentane, and dried under vacuum at 50 °C to give the phosphonium salt (521) as a white solid (7.75 g, 100 %), mp (CH2Cl2/benzene) 188-190 °C. ]HNMR (CDC13) δ 7.83-7.60 (m, 15H), 6.74 (s, 2H), 5.37 (d, J=13.5 Hz, 2H), 3.76 (s, 3H). Found: C, 58.40; H, 4.35. C26H22BrCl2OP requires C, 58.67; H, 4.17.
EXAMPLE 113
The preparation of 2-r(E)-2-(2,6-Dichloro-4-methoxyphenyl)ethenvH-5-methoxy-lH-indole (522) (II. Ar=2.6-dichloro-4-methoxyphenyl)
The 5-methoxy-lH-indole-2-carbaldehyde (1) was reacted with (2,6-dichloro-4- methoxybenzyl)(triphenyl)phosphonium bromide (521), prepared as described in example 112, using the procedure described in example 37, except that the aldehyde was added at 0 °C, the ratio of LDA: aldehyde was 1.37:1 and the reaction time was 5 h, to give (after crystallisation from CH2Cl2/hexane) the diene (522) as a cream solid (the pure E isomer) (70 %), mp 128-129 °C. ]H NMR (CDC13) δ 8.17 (br s, IH), 7.25 (d, J=8.7 Hz, IH), 7.17 (d, J=16.8 Hz, IH), 7.04 (d, J=2.4 Hz, IH), 6.93 (s, 2H), 6.88 (d, J=16.8 Hz, IH), 6.86 (dd, J=8.7, 2.5 Hz, IH), 6.57 (br d, J=1.7 Hz, IH), 3.85 (s, 3H), 3.82 (s, 3H). Found: C, 62.01; H, 4.23; N, 4.21. Cι8Hι5Cl2N02 requires C, 62.09; H, 4.34; N, 4.02. EXAMPLE 114
The preparation of 4-(2,6-Dichloro-4-methoxyphenyl)-9-methoxy-4,5,6,10c- tetrahvdropyrrolor3.4-c1carbazole-1.3(2H.3aH)-dione (523) (IV. R10=H. Ar=2.6-dichloro-4- methoxyphenyl)
The pure E diene (522) prepared as described in example 113 was reacted with maleimide according to the procedure described in example 68 in a foil-covered sealed vial, except that the ratio of diene:maleimide:SnCl2 was 1:6:0.05 and the reaction time was 1.5 h, to give a crude solid containing the adduct (523), which was used without further purification.
EXAMPLE 115
The preparation of 4-(2.6-Dichloro-4-methoxyphenyl)-9-methoxypyrrolor3.4-clcarbazole- 1.3(2H.6H)-dione (524) (V. R10=H. Ar=2,6-dichloro-4-methoχyphenyl)
The crude adduct (523) prepared as described in example 114 was aromatised with DDQ (6 equiv.) using the procedure described in example 70, except that the solvent was 1:1 toluene/dioxane and the reaction time was 24 h, to give (after crystallisation from MeOH/CH2Cl2/hexane) the product (524) (74 %) as a yellow-orange crystalline solid, mp 272-274 °C. ]H NMR [(CD3)2SO] δ 11.98 (br s, IH), 11.12 (br s, IH), 8.44 (d, J=2.6 Hz, IH), 7.58 (d, J=8.7 Hz, IH), 7.57 (s, IH), 7.26 (dd, J=8.8, 2.6 Hz, IH), 7.23 (s, 2H), 3.89 (2s, 2x3H). Found: C, 56.89; H, 3.18; N, 5.94. C22Hι4Cl2N204.5/4 H20 requires C, 56.97; H, 3.59; N, 6.04.
EXAMPLE 116
The preparation of 4-(2.6-Dichloro-4-hvdroxyphenyl)-9-hvdroxypyrrolor3,4-clcarbazole- 1.3(2H.6H)-dione (525) (VI. R10=H. Ar=2.6-dichloro-4-hydroxyphenyl)
The methyl ether (524) prepared as described in example 115 was bis-demethylated with BBr3 using the procedure described in example 80, except that the reaction time was 4 h with 10 equiv. BBr3, then a further 9 h with an extra 10 equiv. BBr3, to give (after crystallisation from MeOH/CH2Cl2/hexane) the phenol (525) (95 %) as a yellow-orange solid, mp 300-308 °C. JH NMR [(CD3)2SO] δ 11.82 (br s, IH), 11.03 (br s, IH), 10.47 (br s, IH), 9.28 (br s, IH), 8.29 (d, J=2.4 Hz, IH), 7.50 (s, IH), 7.46 (d, J=8.7 Hz, IH), 7.08 (dd, J=8.7, 2.5 Hz, IH), 6.96 (s, 2H). Found: C, 56.28; H, 2.94; N, 6.16. C20Hι0Cl2N2O4.3/4 H2O requires C, 56.29; H, 2.72; N, 6.56. EXAMPLE 117
The preparation of (2,6-Dichloro-3-methoxybenzyl)(triphenyl)phosphonium bromide (526)
Bromination of (2,6-dichloro-3-methoxyphenyl)methanol with 30% HBr in acetic acid, followed by reaction of the crude bromide with triphenylphosphine, using the procedure described in example 112, except that the reaction time for the displacement was 36 h, gave the phosphonium salt (526) (97 %) as a white solid, mp (CH2Cl2/benzene) 242-244 °C. Η NMR (CDC13) δ 7.83-7.60 (m, 15H), 7.15 (dd, J=9.1, 0.8 Hz, IH), 6.88 (dd, J=9.0, 2.4 Hz, IH), 5.41 (d, J=14.3 Hz, 2H), 3.84 (s, 3H). Found: C, 58.68; H, 4.16. C26H22BrCl2OP requires C, 58.67; H, 4.17.
EXAMPLE 118
The preparation of 2-F(E)-2-(2,6-Dichloro-3-methoxyphenyl)ethenyl'l-5-methoxy-lH-indole (527) (II. Ar=2.6-dichloro-3-methoxyphenyl)
The 5-methoxy-lH-indole-2-carbaldehyde (1) was reacted with (2,6-dichloro-3- methoxybenzy])(triphenyl)phosphonium bromide (526), prepared as described in example 117, using the procedure described in example 37, except that the aldehyde was added at 0 °C, the ratio of LDA: aldehyde was 1.55:1 and the reaction time was 5 h, to give (after crystallisation from CH2Cl2/hexane) the diene (527) as a cream solid (the pure E isomer) (76 %), mp 138-140 °C. Η NMR (CDC13) δ 8.21 (br s, IH), 7.32 (d, J=8.9 Hz, IH), 7.26 (d, J=8.7 Hz, IH), 7.22 (d, J=16.8 Hz, IH), 7.04 (d, J=2.4 Hz, IH), 6.92 (d, J=16.8 Hz, IH), 6.87 (dd, J=8.8, 2.5 Hz, IH), 6.80 (d, J=8.9 Hz, IH), 6.61 (d, J=1.7 Hz, IH), 3.92 (s, 3H), 3.85 (s, 3H). Found: C, 61.92; H, 4.52; N, 3.91. Cι8H15Cl2N02 requires C, 62.09; H, 4.34; N, 4.02.
EXAMPLE 119
The preparation of 4-(2,6-Dichloro-3-methoxyphenyl)-9-methoxy-4.5.6,10c- tetrahvdropyrrolor3.4-c1carbazole-1.3(2H.3aH)-dione (528) (IV. R10=H. Ar=2.6-dichloro-3- methoxyphenyl)
The pure E diene (527) prepared as described in example 118 was reacted with maleimide according to the procedure described in example 68 in a foil-covered sealed vial, except that the ratio of diene:maleimide:SnCl2 was 1 :5:0.03 and the reaction time was 2.5 h, to give a crude solid containing the adduct (528), which was used without further purification. EXAMPLE 120
The preparation of 4-(2.6-Dichloro-3-methoxyphenyl)-9-methoxypyrrolor3.4-c1carbazole- 1.3(2H.6H)-dione (529) (V. R10=H. Ar=2.6-dichloro-3-methoxyphenyl)
The crude adduct (528) prepared as described in example 119 was aromatised with DDQ (5 equiv.) using the procedure described in example 70, except that the solvent was 1:1 toluene/dioxane and the reaction time was 24 h, to give (after crystallisation from CH2Cl2/hexane) the product (529) (70 %) as an orange crystalline solid, mp 240-242 °C. Η NMR [(CD3)2SO] δ 12.00 (br s, IH), 11.13 (br s, IH), 8.45 (d, J=2.6 Hz, IH), 7.58 (d, J=8.2 Hz, IH), 7.56 (s, IH), 7.56 (d, J=8.7 Hz, IH), 7.28 (d, J=9.3 Hz, IH), 7.26 (dd, J=9.0, 2.4 Hz, IH), 3.94 (s, 3H), 3.90 (s, 3H). Found: C, 60.11; H, 3.16; N, 6.30. C22H]4C12N204 requires C, 59.88; H, 3.20; N, 6.35.
EXAMPLE 121
The preparation of 4-(2.6-Dichloro-3-hvdroxyphenyl)-9-hydroxypyrrolor3.4-c1carbazole- 1.3(2H.6H)-dione (530) (VI. R10=H. Ar=2.6-dichloro-3-hvdroxyphenyl)
The methyl ether (529) prepared as described in example 120 was bis-demethylated with BBr3 using the procedure described in example 80, except that the reaction time was 6 h with 10 equiv. BBr3, to give (after crystallisation from MeOH/CH2Cl2/hexane) the phenol (530) (91 %) as an orange crystalline solid, mp 313-318 °C. 'H NMR [(CD3)2SO] δ 11.84 (br s, IH), 11.05 (br s, IH), 10.56 (br s, IH), 9.29 (br s, IH), 8.30 (d, J=2.4 Hz, IH), 7.48 (s, IH), 7.46 (d, J=8.7 Hz, IH), 7.36 (d, J=8.8 Hz, IH), 7.09 (dd, J=8.8, 2.6 Hz, IH), 7.06 (d, J=8.9 Hz, IH). Found: C, 57.21; H, 2.65; N, 6.58. C20HioCl2N204.l/2 MeOH requires C, 57.36; H, 2.82; N, 6.53.
EXAMPLE 122
The preparation of 2-[(E)-2-(2-Bromophenyl)ethenyll-5-methoxy-lH-indole (531) (II. Ar=2- bromophenyl)
The 5-methoxy-lH-indole-2-carbaldehyde (1) was reacted with (2- bromobenzyl)(triphenyl)phosphonium bromide using the procedure described in example 37, except that the aldehyde was added at 0 °C, the ratio of LDA: aldehyde was 1.46:1 and the reaction time was 5 h, to give (after crystallisation from CT^Ch/hexane) the diene (531) as a yellow solid (the pure E isomer) (88 %), mp 120-123 °C. ]H NMR (CDC13) δ 8.21 (br s, IH), 7.66 (dd, J=7.9, 1.5 Hz, IH), 7.59 (dd, J=8.1, 1.0 Hz, IH), 7.32 (br t, J=7.1 Hz, IH), 7.27 (d, J=8.3 Hz, IH), 7.22 (d, J=16.4 Hz, IH), 7.12 (td, J=7.6, 1.5 Hz, IH), 7.05 (d, J=16.4 Hz, IH), 7.04 (d, J=2.4 Hz, IH), 6.88 (dd, J=8.8, 2.4 Hz, IH), 6.59 (d, J=1.7 Hz, IH), 3.86 (s, 3H). Found: C, 61.97; H, 4.30; N, 4.17. CπH]4BrNO requires C, 62.21; H, 4.30; N, 4.27.
Representative Procedure for Combining Method 4a and Method 6 of Scheme 2
EXAMPLE 123
The preparation of 4-(2-bromophenyl)-9-methoxypyrrolo[3.4-clcarbazole-l,3(2H.6H)-dione
(532) (V. R10=H. Ar=2-bromophenyl)
A foil -covered mixture of the pure E diene (531) (1.00 g, 3.05 mmol) prepared as described in example 122 and maleimide (1.48 g, 15.2 mmol) in dry toluene (10 mL) was stirred in a sealed vial at reflux for 24 h. The resulting thick suspension was transferred to a flask using further toluene (30 mL) and dioxane (40 mL), then treated with DDQ (3.49 g, 15.4 mmol), stirring under reflux for 24 h. The resulting mixture was treated with saturated aqueous NaHC03 solution (250 mL) and the product extracted with 15% MeOH/CH2Cl2. These extracts were washed with aqueous NaHC03 solution and water. The aqueous NaHC03 solution and water was extracting several times with 15% MeOH/CH2Cl2, then the combined extracts were concentrated to dryness. The residue was adsorbed onto silica gel and chromatographed. Elution with 0-0.75% MeOH/CH2Cl2, then with 0.75% MeOH/CH Cl2 gave the crude product (532) which crystallised pure from MeOH/Q^C^/hexane as an orange crystalline solid (1.23 g, 96 %), mp 273-275 °C. ]H NMR [(CD3)2SO] δ 11.96 (br s, IH), 11.08 (br s, IH), 8.46 (d, J=2.6 Hz, IH), 7.74 (d, J=7.8 Hz, IH), 7.58 (d, J=8.9 Hz, IH), 7.55 (s, IH), 7.48 (m, 2H), 7.39 (m, IH), 7.25 (dd, J=8.9, 2.7 Hz, IH), 3.89 (s, 3H). Found: C, 60.08; H, 3.02; N, 6.68. C2ιHι3BrN203 requires C, 59.88; H, 3.11; N, 6.65.
EXAMPLE 124
The preparation of 4-(2-Bromophenyl)-9-hvdroxypyιτolo[3,4-c1carbazole- 3(2H,6H)-dione
(533) (VI. R10=H, Ar=2-bromophenyl)
The methyl ether (532) prepared as described in example 123 was demethylated with BBr3 using the procedure described in example 80, except that the reaction time was 4 h. Crystallisation from MeOH/CH2Cl2/hexane gave the phenol (533) in a yield of 89 % as a yellow-orange solid, mp 244-246 °C. *H NMR [(CD3)2SO] δ 11.83 (br s, IH), 11.01 (br s, IH), 9.29 (br s, IH), 8.31 (d, J=2.4 Hz, IH), 7.73 (br d, J=7.9 Hz, IH), 7.47 (m, 4H), 7.38 (m, IH), 7.08 (dd, J=8.7, 2.5 Hz, IH). Found: C, 57.82; H, 2.90; N, 6.72. C20HιιBrN2O3.l/2 H20 requires C, 57.71; H, 2.91; N, 6.73.
EXAMPLE 125
The preparation of 4-π. r-Biphenvn-2-yl-9-methoxypyrrolor3,4-clcarbazole-1.3(2H.6H)- dione (534) (V. R10=H. Ar=2-biphenyl)
A mixture of the bromo derivative (532) (85.5 mg, 0.203 mmol) prepared as described in example 123, [l, -bis(diphenylphosphino)ferrocene]dichloropalladium(II).CH2Cl2 (85 mg, 0.104 mmol) and tetraphenyltin (0.451, 1.06 mmol) in dry DMF (2.5 mL) was stirred in a sealed vial at 130 °C for 4 d. The resulting mixture was added to aqueous NaHC03 (100 mL) then extracted with 2:1 CH2Cl2/EtOAc (5 x 80 mL). The extracts were washed with water. The water was extracting with 2:1 CH2Cl2/EtOAc, then the combined organic extracts were concentrated to dryness. The residue was chromatographed several times on silica gel (eluting with CH2C12) to give the crude product (44.5 mg, 54%). This was combined with material from similar reactions and purified by preparative reversed phase C-18 HPLC (using a gradient of 65-99% CH3CN/aqueous HC02NHι buffer, pH 3.45) to give (after crystallisation from MeOH/CH Cl2/hexane) the pure product (534) (21 % overall) as a yellow solid, mp 220-223 °C. Η NMR [(CD3)2SO] δ 11.76 (br s, IH), 10.87 (br s, IH), 8.39 (d, J=2.6 Hz, IH), 7.50 (m, 5H), 7.38 (s, IH), 7.20 (dd, J=8.9, 2.6 Hz, IH), 7.10 (m, 5H), 3.86 (s, 3H). Found: C, 77.37; H, 4.21; N, 6.88. C27Hι8N203 requires C, 77.50; H, 4.34; N, 6.69.
EXAMPLE 126
The preparation of 4-π, -Biphenvn-2-yl-9-hydroxypyrrolor3.4-clcarbazole-1.3(2H.6H)- dione (535) (VI. Ri0=H. Ar=2-biphenyl)
The methyl ether (534) prepared as described in example 125 was demethylated with BBr3 using the procedure described in example 80, except that the reaction time was 4 h, to give (after crystallisation from Me0H/CH2Cl2 hexane) the phenol (535) (98 %) as a yellow solid, mp 198-203 °C (dec). Η NMR [(CD3)2SO] δ 11.61 (br s, IH), 10.82 (br s, IH), 9.22 (br s, IH), 8.24 (d, J=2.4 Hz, IH), 7.52 (m, IH), 7.45 (m, 3H), 7.37 (d, J=8.7 Hz, IH), 7.31 (s, IH), 7.11 (m, 5H), 7.03 (dd, J=8.7, 2.5 Hz, IH). Found: C, 76.38; H, 3.94; N, 6.99. C26Hι6N203.l/4 H20 requires C, 76.37; H, 4.07; N, 6.85. EXAMPLE 127
The preparation of 5-Methoxy-2-r(E)-2-(2-nitrophenyl)ethenyll-lH-indole (536) (II. Ar=2- nitrophenyl)
The 5-methoxy-lH-indole-2-carbaldehyde (1) was reacted with (2- nitrobenzyl)(triphenyl)phosphonium chloride using the procedure described in example 37, except that the ratio of LDA: aldehyde was 1.37:1 and the reaction time was 5 h, to give (after crystallisation from CH2Cl2/hexane) the diene (536) as red-orange crystals (the pure E isomer) (47 %), mp 136-138 °C. Η NMR (CDC13) δ 8.25 (br s, IH), 7.98 (dd, J=8.2, 1.2 Hz, IH), 7.78 (dd, J=7.9, 1.0 Hz, IH), 7.61 (td, J=7.6, 0.9 Hz, IH), 7.41 (d, J=16.3 Hz, IH), 7.39 (td, J=7.8, 1.3 Hz, IH), 7.27 (m, IH), 7.13 (d, J=16.3 Hz, IH), 7.04 (d, J=2.4 Hz, IH), 6.90 (dd, J=8.8, 2.5 Hz, IH), 6.62 (d, J=1.8 Hz, IH), 3.86 (s, 3H). Found: C, 69.44; H, 4.49; N, 9.70. Cι7Hι N203 requires C, 69.38; H, 4.79; N, 9.52.
EXAMPLE 128
The preparation of 9-Methoxy-4-(2-nitrophenyl)pyrrolor3,4-clcarbazole-l,3(2H,6H)-dione
(537) (V. R10=H. Ar=2-nitrophenyl)
The pure E diene (536) prepared as described in example 127 was subjected to successive reactions with maleimide and then DDQ according to the above representative procedure described in example 123 , to give (after crystallisation from MeOH/EtOAc/CH2Cl2/hexane) the product (537) (97 %) as a yellow-orange solid, mp 294- 298 °C. lH NMR [(CD3)2SO] δ 12.01 (br s, IH), 11.10 (br s, IH), 8.44 (d, J=2.5 Hz, IH), 8.21 (dd, 1=8-1, 1.0 Hz, IH), 7.86 (td, J=7.5, 1.4 Hz, IH), 7.74 (td, J=7.8, 1.3 Hz, IH), 7.67 (s, IH), 7.65 (dd, J=7.6, 1.4 Hz, IH), 7.59 (d, J=8.9 Hz, IH), 7.25 (dd, J=8.7, 2.6 Hz, IH), 3.90 (s, 3H). Found: C, 64.99; H, 3.42; N, 10.79. C2ιH13N305 requires C, 65.12; H, 3.38; N, 10.85.
EXAMPLE 129
The preparation of 9-Hvdroxy-4-(2-nitrophenyl)pyrrolor3.4-c1carbazole-l,3(2H.6H)-dione
(538) (VI. R10=H. Ar=2-nitrophenyl)
The methyl ether (537) prepared as described in example 128 was demethylated with BBr3 using the procedure described in example 80, except that the reaction time was 5 h with 5 equiv. BBr3, then a further 21 h with an extra 5 equiv. BBr3, to give (after crystallisation from MeOH/CH2Cl2/hexane) the phenol (538) (53 %) as an orange solid, mp 322-330 °C. H NMR [(CD3)2SO] δ 11.88 (br s, IH), 11.05 (br s, IH), 9.29 (br s, IH), 8.30 (d, J=2.4 Hz, IH), 8.20 (dd, J=8.2, 1.1 Hz, IH), 7.85 (td, J=7.5, 1.2 Hz, IH), 7.73 (td, J=7.9, 1.4 Hz, IH), 7.63 (dd, J=7.6, 1.4 Hz, IH), 7.61 (s, IH), 7.47 (d, J=8.7 Hz, IH), 7.09 (dd, J=8.7, 2.5 Hz, IH). Found: C, 63.03; H, 3.27; N, 10.59. C2oHnN305.l/2 MeOH requires C, 63.24; H, 3.37; N, 10.79.
EXAMPLE 130
The preparation of 4-(2-Aminophenyl)-9-methoxypyrrolor3.4-c1carbazole-l,3(2H,6H)-dione
(539) (V, R10=H, Ar=2-aminophenyl)
A solution of the nitro derivative (537) (71 mg, 0.183 mmol) prepared as described in example 128 in 2:1 THF/MeOH (45 mL) containing wet 10% Pd-C (71 mg) was hydrogenated at 60 psi for 7 h. The solution was filtered throught celite, the celite and catalyst were washed thoroughly with MeOH and THF, then the filtrate was concentrated to dryness. Crystallisation of the residue from MeOH/CH2Cl2/hexane gave the amine (539) (67 mg, 97%) as a yellow solid, mp >320 °C. *H NMR [(CD3)2SO] δ 11.80 (br s, IH), 10.94 (br s, IH), 8.47 (d, J=2.6 Hz, IH), 7.54 (d, J=8.8 Hz, IH), 7.51 (s, IH), 7.21 (dd, J=8.8, 2.6 Hz, IH), 7.08 (td, J=7,7, L5 Hz,JH), 7.01 (dd, J=7.6, 1.5 Hz, IH), 6.73 (dd, J=8.1, 0.6 Hz, IH), 6.61 (td, J=7.4, 0.9 Hz, IH), 4.70 (s, 2H), 3.89 (s, 3H). Found: C, 67.22; H, 4.50; N, 11.03. C2ιHι5N303.H20 requires C, 67.19; H, 4.56; N, 11.19.
EXAMPLE 131
The preparation of 4-(2-Aminophenyl)-9-hvdroxypyrrolor3.4-c1carbazole-1.3(2H,6H)-dione
(540) (VI. R10=H. Ar=2-aminophenyl)
A solution of the nitro derivative (538) (81 mg, 0.217 mmol) prepared as described in example 129 in 2:1 THF/MeOH (60 mL) containing wet 10% Pd-C (81 mg) was hydrogenated at 60 psi for 12 h. The solution was filtered throught celite, the celite and catalyst were washed thoroughly with MeOH and THF, then the filtrate was concentrated to dryness. Crystallisation of the residue from MeOH/CH2Cl2/hexane gave the amine (540) (60 mg, 81%) as a brown solid, mp >330 °C. !H NMR [(CD3)2SO] δ 11.67 (br s, IH), 10.88 (br s, IH), 9.21 (s, IH), 8.32 (d, J=2.4 Hz, IH), 7.46 (s, IH), 7.42 (d, J=8.6 Hz, IH), 7.08 (td, J=7.9, 1.5 Hz, IH), 7.05 (dd, J=8.7, 2.4 Hz, IH), 7.00 (dd, J=7.6, 1.4 Hz, IH), 6.72 (br d, J=8.1 Hz, IH), 6.60 (td, J=7.4, 0.9 Hz, IH), 4.69 (s, 2H). Found: C, 66.35; H, 4.06; N, 11.76. C20Hι3N3O3.H2O requires C, 66.48; H, 4.18; N, 11.63. EXAMPLE 132
The preparation of 4-(2-Hvdroxyphenyl)-9-methoxypyrrolor3,4-clcarbazole-l,3(2H.6H)- dione (541) (V. R10=H, Ar=2-hvdroxyphenyl)
A solution of the amine (539) (129 mg, 0.361 mmol) prepared as described in example 130 in 90% H2S0 (7.5 mL) was cooled to -10 °C and diluted with ice-water (20 mL). After stirring at -10 °C for 10 min, the resulting suspension was treated dropwise with a solution of NaN02 (38 mg, 0.551 mmol) in cold water (2x 1 mL), and stirred at -10 to -5 °C for 30 mm. A solution of urea (13 mg, 0.216 mmol) in cold water (2x 0.75 mL) was added and the mixture was stirred at -5 °C for 5 min. Finally, a suspension of Kl (400 mg, 2.41 mmol) and Cul (402 mg, 2.11 mmol) in cold water (2x 2.5 mL) was added, then the cooling bath was removed and the mixture was stirred for 10 min, then at 60-65 °C for 2 h. An aqueous solution of sodium metabisulfite (100 mL of 5%) was added, then the pH was adjusted to pH = 3 with NaHC03 and the mixture extracted with EtOAc (5x 100 mL). The extracts were washed with water (200 mL), the water was extracting with EtOAc, the combined organic extracts were concentrated to dryness. The residue was adsorbed onto silica gel and chromatographed. Elution with 0-0.5% MeOH/CH2Cl2 followed but 0.5% MeOH/CH2Cl2 gave a mixture of crude iodides (543,544) (24 mg, see experiment below for analytical data). Elution with 1% MeOH/CH2Cl2 gave (after crystallisation from THF/CH2Cl2/pentane) the phenol (541) (31 mg, 24 %) as a bright yellow solid, mp 264-267 °C. Η NMR [(CD3)2SO] δ 11.82 (br s, IH), 10.95 (br s, IH), 9.41 (br s, IH), 8.47 (d, J=2.6 Hz, IH), 7.56 (s, IH), 7.54 (d, J=8.9 Hz, IH), 7.25 (dd, J=7.4, 1.6 Hz, IH), 7.23 (td, J=7.9, 1.7 Hz, IH), 7.22 (dd, J=8.7, 2.6 Hz, IH), 6.91 (br d, J=7.5 Hz, IH), 6.87 (td, J=7.4, 0.9 Hz, IH), 3.89 (s, 3H). Found: C, 70.40; H, 4.06; N, 7.95. C2ιH14N204 requires C, 70.39; H, 3.94; N, 7.82.
EXAMPLE 133
The preparation of 9-Hydroxy-4-(2-hvdroxyphenyl)pyrrolor3,4-c1carbazole-1.3(2H.6H)- dione (542) (VI. R10=H, Ar=2-hvdroxyphenyl)
The methyl ether (541) prepared as described in example 132 was demethylated with BBr3 using the procedure described in example 80, except that the reaction time was 4 h, to give (after crystallisation from MeOH/THF/CH2Cl2/hexane) the phenol (542) (73 %) as a yellow-orange solid, mp 291-296 °C. Η NMR [(CD3)2SO] δ 11.67 (br s, IH), 10.88 (br s, IH), 9.37 (br s, IH), 9.22 (br s, IH), 8.31 (d, J=2.4 Hz, IH), 7.51 (s, IH), 7.42 (d, J=8.7 Hz, IH), 7.24 (dd, J=7.5, 1.5 Hz, IH), 7.22 (td, J=7.7, 1.8 Hz, IH), 7.05 (dd, J=8.7, 2.5 Hz, IH), 6.91 (br d, J=8.0 Hz, IH), 6.86 (td, J=7.4, 0.9 Hz, IH). Found: C, 66.61; H, 3.67; N, 7.70. C20H12N2O4.H2O requires C, 66.30; H, 3.89; N, 7.73.
EXAMPLE 134
The preparation of 4-(2-Iodophenyl)-9-methoxypyrrolor3,4-clcarbazole-1.3(2H,6H)-dione (543) (V. R10=H. Ar=2-iodophenyl)
A solution of the amine (539) (46 mg, 0.129 mmol) prepared as described in example 130 in 90% H2SO4 (2.5 mL) was cooled to -5 °C, diluted with ice-water (2.5 mL), then allowed to warm to 7 °C. The resulting suspension was treated dropwise with a solution of NaN02 (13.6 mg, 0.197 mmol) in cold water (2x 0.5 mL), and stiired at 7 °C for 8 min. A solution of urea (5 mg, 0.083 mmol) in cold water (2x 0.4 mL) was added and the mixture was stirred at 7 °C for 4 min. Finally, a suspension of KI (140 mg, 0.843 mmol) and Cul (140 mg, 0.735 mmol) in cold water (2x 1 mL) was added, then the cooling bath was removed and the mixture was stirred for 10 min, then at 60-65 °C for 2 h. An aqueous solution of sodium metabisulfite (100 mL of 0.5%) was added, then the mixture was extracted with 20% THF/EtOAc (5x 100 mL). The extracts were washed with water (200 mL), the water was extracting with EtOAc, the the combined organic extracts were concentrated to dryness. The residue was adsorbed onto silica gel and chromatographed. Elution with 0-0.5% MeOH/CH2Cl2 followed by 0.5% MeOH/CH2Cl2 gave the crude product (22 mg). This was purified by further chromatography on silica gel (eluting with 1% EtOH/CHCl3) to yield the crude major iodide (543) (18 mg, 30%), which was combined with material from similar reactions, rechromatographed (eluting with 20% EtOAc/petroleum ether) and crystallised from MeOH/T-HF/CH2Cl2/hexane as yellow-orange crystals, mp 311-315 °C. Η NMR [(CD3)2SO] δ 11.95 (br s, IH), 11.07 (br s, IH), 8.46 (d, J=2.6 Hz, IH), 7.97 (dd, J=7.7, 0.9 Hz, IH), 7.58 (d, J=8.8 Hz, IH), 7.50 (td, J=7.6, 0.9 Hz, IH), 7.48 (s, IH), 7.44 (dd, J=7.6, 1.8 Hz, IH), 7.25 (dd, J=8.9, 2.7 Hz, IH), 7.19 (td, J=7.6, 1.8 Hz, IH), 3.89 (s, 3H). Found: C, 53.87; H, 2.76; N, 5.98. C2,Hι3IN203 requires C, 53.87; H, 2.80; N, 5.98. FABMS found [M+H]+: 469.0046. C2ιH]4IN203 requires 469.0049.
EXAMPLE 135
The preparation of 9-Hvdroxy-4-(2-iodophenyl)pyrrolor3,4-c1carbazole-l,3(2H,6H)-dione (545) (VI. R10=H. Ar=2-iodophenyl) The methyl ether (543) prepared as described in example 134 was demethylated with BBr3 using the procedure described in example 80, to give (after crystallisation from MeOH/CH2Cl2/hexane) the phenol (545) (88 %) as a yellow-orange solid, mp 217-223 °C. Η NMR [(CD3)2SO] δ 11.82 (br s, IH), 11.01 (br s, IH), 9.28 (br s, IH), 8.32 (d, J=2.4 Hz, IH), 7.96 (br d, J=7.8 Hz, IH), 7.49 (br t, J=7.7 Hz, IH), 7.46 (d, J=8.9 Hz, IH), 7.42 (s, IH), 7.42 (dd, J=7.4, 1.7 Hz, IH), 7.19 (td, J=7.6, 1.7 Hz, IH), 7.08 (dd, J=8.7, 2.5 Hz, IH). Found: C, 52.93; H, 2.55; N, 6.07. C20HπIN2O3 requires C, 52.89; H, 2.44; N, 6.17. FABMS found [M+H]+: 454.9889. C20Hι2IN2O3 requires 454.9893.
EXAMPLE 136
The preparation of (2-Cyanobenzyl)(triphenyl)phosphonium bromide (547)
Bromination of o-tolunitrile with NBS/AIBN, followed by reaction of the crude bromide with triphenylphosphine (1.2 equiv.), using the procedure described in example 102, except that the reaction time for the bromination was 2 h, gave the phosphonium salt (547) (70 %) as a light brown powder, mp (CH2Cl2/benzene) 237-241 °C. Η NMR (CDC13) δ 7.90 (dd, J=7.8, 2.3 Hz, IH), 7.85-7.63 (m, 15H), 7.52 (br t, J=7.7 Hz, IH), 7.44 (br d, J=7.5 Hz, IH), 7.38 (tdd, J=7.6, 2.1, 1.0 Hz, IH), 5.86 (d, J=14.7 Hz, 2H). Found: C, 67.88; H, 4.42; N, 3.09. C26H2]BrNP requires C, 68.13; H, 4.62; N, 3.06.
EXAMPLE 137
The preparation of 2-r(E)-2-(5-Methoxy-lH-indol-2-yl)ethenyllbenzonitrile (548) (II. Ar=2- cvanophenyl)
The 5-methoxy-lH-indole-2-carbaldehyde (1) was reacted with (2- cyanobenzyl)(triphenyl)phosphonium bromide (547) prepared as described in example 136 using the procedure described in example 37, except that the LDA and aldehyde were (sequentially) added at 0 °C, the ratio of LDA: aldehyde was 1.55:1 and the reaction time was 5 h, to give (after crystallisation from CH2Cl2/hexane) the diene (548) as a yellow solid (the pure E isomer) (60 %), mp 192-196 °C. Η NMR (CDC13) δ 8.40 (br s, IH), 7.79 (d, J=8.1 Hz, IH), 7.66 (dd, 1=8.1-, 0.9 Hz, IH), 7.58 (td, J=7.9, 1.3 Hz, IH), 7.32 (td, J=8.0, 0.9 Hz, IH), 7.29 (d, J=8.5 Hz, IH), 7.28 (d, J=16.9 Hz, IH), 7.18 (d, J=16.4 Hz, IH), 7.04 (d, J=2.4 Hz, IH), 6.91 (dd, J=8.9, 2.4 Hz, IH), 6.64 (d, J=1.8 Hz, IH), 3.86 (s, 3H). Found: C, 79.05; H, 5.16; N, 10.31. Cι8Hι4N20 requires C, 78.81; H, 5.14; N, 10.21. EXAMPLE 138
The preparation of 2-(9-Methoxy-1.3-dioxo-L2,3.6-tetrahvdropyrrolo[3.4-clcarbazol-4- vDbenzonitrile (549) (V. R10=H. Ar=2-cvanophenyl)
The E diene (548) prepared as described in example 137 was subjected to successive reactions with maleimide and then DDQ according to the above representative procedure described in example 123 , except that most of the poorly soluble final product was obtained by filtration of the diluted product solution, then washing thoroughly with aqueous NaHC03 solution, 15% MeOH/CH2Cl2 and water, with the reminder being obtained by the extraction of the water phase with ethyl acetate. The organic layer was dried, the drying agent was removed and the solution was concentrated to dryness. Crystallization from THF/CH2Cl2/hexane, to give the product (549) (96 %) as a yellow solid, mp 348-350 °C. Η NMR [(CD3)2SO] δ 12.06 (br s, IH), 11.19 (br s, IH), 8.48 (d, J=2.6 Hz, IH), 7.96 (dd, J=7.7,
1.0 Hz, IH), 7.82 (td, J=7.7, 1.4 Hz, IH), 7.71 (br d, J=7.4 Hz, IH), 7.71 (s, IH), 7.66 (td, J=7.6,
1.1 Hz, IH), 7.60 (d, J=8.9 Hz, IH), 7.27 (dd, J-=8.8, 2.6 Hz, IH), 3.90 (s, 3H). EIMS found M+: 367.0956. C22Hι3N303 requires 367.0957.
EXAMPLE 139
The preparation of 2-(9-Hvdroxy-l,3-dioxo-l,2,3,6-tetrahydropyιτolor3,4-c1carbazol-4- vDbenzonitrile (550) (VI. R10=H. Ar=2-cvanophenyl)
The methyl ether (549) prepared as described in example 138 was demethylated with BBr3 using the procedure described in example 80, except that the reaction time was 5 h with 5 equiv. BBr3, then a further 4 h with an extra 5 equiv. BBr3, to give (after crystallisation from THF/CH2Cl2/hexane) the phenol (550) (83 %) as a yellow solid, mp 199-204 °C (dec). Η NMR [(CD3)2SO] δ 11.93 (br s, IH), 11.13 (br s, IH), 9.31 (br s, IH), 8.34 (d, J=2.4 Hz, IH), 7.96 (dd, J=7.6, 0.9 Hz, IH), 7.82 (td, J=7.7, 1.4 Hz, IH), 7.70 (br d, J=7.5 Hz, IH), 7.65 (s, IH), 7.65 (td, J=7.7, 1.0 Hz, IH), 7.48 (d, J=8.7 Hz, IH), 7.10 (dd, J=8.7, 2.5 Hz, IH). Found: C, 70.17; H, 3.46; N, 11.49. C21HπN303.l/4 H20 requires C, 70.49; H, 3.24; N, 11.74.
EXAMPLE 140
The preparation of 5-Methoxy-2-r(E)-2-(3-nitrophenyl)ethenyll-lH-indole (551) (II, Ar=3- nitrophenyl) The 5-methoxy-lH-indole-2-carbaldehyde (1) was reacted with (3- nitrobenzyl)(triphenyl)phosphonium bromide using the procedure described in example 37, except that the LDA and aldehyde were sequentially added at 0 °C, the ratio of LDA:aldehyde was 1.5:1 and the reaction time was 5 h, to give (after crystallisation from MeOH/CH2Cl2/hexane) the diene (551) as an orange-red solid (the pure E isomer) (51 %), mp 178-182 °C. Η NMR [(CD3)2SO] δ 11.27 (br s, IH), 8.34 (t, J=1.9 Hz, IH), 8.09 (dd, J=8.1, 1.8 Hz, IH), 7.99 (d, J=7.9 Hz, IH), 7.67 (t, J=8.0 Hz, IH), 7.47 (d, J=16.5 Hz, IH), 7.26 (d, J=8.6 Hz, IH), 7.25 (d, J=16.6 Hz, IH), 7.03 (d, J=2.4 Hz, IH), 6.77 (dd, J=8.8, 2.5 Hz, IH), 6.61 (d, J=1.6 Hz, IH), 3.76 (s, 3H). Found: C, 69.36; H, 4.77; N, 9.78. Cι7Hi4N203 requires C, 69.38; H, 4.79; N, 9.52.
EXAMPLE 141
The preparation of 9-Methoxy-4-(3-nitrophenyl)pyrro1or3,4-clcarbazole-l,3(2H,6H)-dione
(552) (V. R10=H. Ar=3-nitrophenyl)
The pure E diene (551) prepared as described in example 140 was subjected to successive reactions with maleimide and then DDQ according to the above representative procedure described in example 123, except that the poorly soluble final product was obtained by filtration of the diluted product solution, then washing thoroughly with aqueous NaHC03 solution, 15% MeOH/CH2Cl2 and water, followed by crystallization from MeOH/THF, to give the product (552) (81 %) as a brown solid, mp >340 °C. Η NMR [(CD3)2SO] δ 11.99 (br s, IH), 11.18 (br s, IH), 8.50 (d, J=2.5 Hz, IH), 8.48 (t, J=1.9 Hz, IH), 8.31 (dd, J=8.1, 1.7 Hz, IH), 8.11 (br d, J=7.8 Hz, IH), 7.78 (t, J=8.0 Hz, IH), 7.75 (s, IH), 7.58 (d, J=8.8 Hz, IH), 7.25 (dd, J=8.8, 2.6 Hz, IH), 3.90 (s, 3H). Found: C, 62.17; H, 3.52; N, 10.33. C2ιHι3N305.H20 requires C, 62.22; H, 3.73; N, 10.37.
Example 142
The preparation of 9-Hydroxy-4-(3-nitrophenyl)pyιτolor3,4-c'|carbazole-l,3(2H,6H)-dione
(553) (VI. R10=H, Ar=3-nitrophenyl)
The methyl ether (552) prepared as described in example 142 was demethylated with pyridinium hydrochloride using the procedure described in example 81, to give (after crystallisation from THF/hexane) the phenol (553) (74 %) as an orange-brown solid, mp 300- 310 °C (dec). !H NMR [(CD3)2SO] δ 11.86 (br s, IH), 11.11 (br s, IH), 9.29 (br s, IH), 8.46 (t, J=1.9 Hz, IH), 8.35 (d, J=2.4 Hz, IH), 8.30 (ddd, J=8.2, 2.5, 0.8 Hz, IH), 8.10 (dt, J=7.8, 1.2 Hz, IH), 7.77 (t, J=8.0 Hz, IH), 7.70 (s, IH), 7.47 (d, J=8.7 Hz, IH), 7.09 (dd, J=8.7, 2.5 Hz, IH). FABMS found M+: 373.0692. C20HnN3O5 requires 373.0699.
EXAMPLE 143
The preparation of (2-Chloro-3-nitrobenzyl)(triphenyl)phosphonium bromide (554)
Bromination of 2-chloro-3-nitrotoluene with NBS/AIBN, followed by reaction of the crude bromide with triphenylphosphine, using the procedure described in example 102, except that the reaction time for the bromination was 2 h and the displacement reaction was performed at 70 °C for 1 d, gave the phosphonium salt (554) (44 %) as a light brown solid, mp (CH2Cl2/benzene) 224-228 °C. !H NMR (CDC13) δ 8.09 (br d, J=8.3 Hz, IH), 7.86-7.63 (m, 16H), 7.34 (t, J=8.1 Hz, IH), 5.95 (d, J=14.6 Hz, 2H). Found: C, 58.68; H, 4.12; N, 2.79. C25H20BrClNO2P requires C, 58.56; H, 3.93; N, 2.73.
EXAMPLE 144
The preparation of 2-r(E)-2-(2-Chloro-3-nitrophenyl)ethenyl1-5-methoxy-lH-indole (555) (II, Ar=2-chloro-3-nitrophenyl)
The 5-methoxy-lH-indole-2-carbaldehyde (1) was reacted with (2-chloro-3- nitrobenzyl)(triphenyl)phosphonium bromide (554) preared as described in example 143 using the procedure described in example 37, except that the LDA and aldehyde were (sequentially) added at 0 °C, the ratio of LDA: aldehyde was 1.5:1 and the reaction time was 5 h, to give (after crystallisation from CH2Cl2/pentane) the diene (555) as an orange crystalline solid (the pure E isomer) (50 %), mp 131-133 °C. Η NMR (CDC13) δ 8.24 (br s, IH), 7.86 (dd, j=8.0, 1.4 Hz, IH), 7.63 (dd, J=7.9, 1.4 Hz, IH), 7.40 (t, J=8.0 Hz, IH), 7.28 (d, J=8.5 Hz, IH), 7.25 (d, J=15.8 Hz, IH), 7.15 (d, J=16.4 Hz, IH), 7.05 (d, J=2.4 Hz, IH), 6.91 (dd, J=8.9, 2.4 Hz, IH), 6.65 (d, J=1.7 Hz, IH), 3.86 (s, 3H). Found: C, 61.97; H, 3.92; N, 8.50. CπHι3ClN203 requires C, 62.11; H, 3.99; N, 8.52.
EXAMPLE 145
The preparation of 4-(2-Chloro-3-nitrophenyl)-9-methoxypyrrolo[3,4-c1carbazole- 1.3(2H.6H)-dione (556) (V. R10=H. Ar=2-chloro-3-nitrophenyl)
The pure E diene (555) prepared as described in example 144 was subjected to successive reactions with maleimide and then DDQ according to the procedure described in example 123 , to give (after crystallisation from THF/pentane) the product (556) (93 %) as a yellow-brown solid, mp 315-320 °C (dec). Η NMR [(CD3)2SO] δ 12.07 (br s, IH), 11.16 (br s, IH), 8.46 (d, J=2.6 Hz, IH), 8.11 (dd, J=8.1, 1.5 Hz, IH), 7.82 (dd, J=7.7, 1.6 Hz, IH), 7.69 (t, J=7.9 Hz, IH), 7.69 (s, IH), 7.59 (d, J=8.9 Hz, IH), 7.26 (dd, J=8.8, 2.6 Hz, IH), 3.90 (s, 3H). Found: C, 60.47; H, 3.17; N, 9.78. C21Hι2ClN305.l/4 THF requires C, 60.08; H, 3.21; N, 9.55.
EXAMPLE 146
The preparation of 4-(2-Ch]oro-3-nitrophenyl)-9-hvdroxypyrrolor3,4-c1carbazole- l,3(2H,6H)-dione (557) (VI. R10=H. Ar=2-chloro-3-nitrophenvI)
The methyl ether (556) prepared as described in example 145 was demethylated with BBr3 using the procedure described in example 80, except that the reaction time was 5 h with 10 equiv. BBr3, to give (after crystallisation from THF/CH2Cl2/pentane) the phenol (557) (84 %) as a yellow solid, mp 304-308 °C. Η NMR [(CD3)2SO] δ 11.92 (br s, IH), 11.11 (br s, IH), 9.30 (s, IH), 8.31 (d, J=2.4 Hz, IH), 8.11 (dd, J=8.2, 1.5 Hz, IH), 7.81 (dd, J=7.6, 1.5 Hz, IH), 7.68 (t, J=7.9 Hz, IH), 7.63 (s, IH), 7.47 (d, J=8.7 Hz, IH), 7.10 (dd, J=8.7, 2.5 Hz, IH). Found: C, 58.70; H, 2.72; N, 10.10. C20HιoClN305 requires C, 58.91; H, 2.47; N, 10.30.
EXAMPLE 147
The preparation of 4-(3-Amino-2-chlorophenyl)-9-hvdroxypyrrolor3,4-clcarbazole- 1.3(2H,6H)-dione (558) (VI. R10= H. Ar=3-amino-2-chlorophenyl)
A mixture of the nitro derivative (557) (66 mg, 0.162 mmol) prepared as described in example 146 and freshly prepared (wet) nickel boride (202 mg) in MeOH (4.8 mL) and IM HCI (1.2 mL) was stirred at reflux for 100 min. Cone, aqueous ammonia and aqueous NaHC03 (100 mL) were added and the mixture extracted with EtOAc (8x 100 mL). The extracts were concentrated, adsorbed onto silica gel and chromatographed. Elution with 0-1% MeOH/CH2Cl2 then 1.5% MeOH/CH2Cl2 and THF gave (after crystallisation from THF/CH2Cl2/pentane) the amine (558) (83 %) as a yellow-orange solid, mp 348-352 °C. Η NMR [(CD3)2SO] δ 11.76 (br s, IH), 10.96 (br s, IH), 9.25 (br s, IH), 8.31 (d, J=2.4 Hz, IH), 7.45 (s, IH), 7.44 (d, J=8.7 Hz, IH), 7.08 (t, J=7.8 Hz, IH), 7.07 (dd, J=8.7, 2.5 Hz, IH), 6.86 (dd, J=8.1, 1.5 Hz, IH), 6.60 (dd, J=7.4, 1.3 Hz, IH), 5.39 (s, 2H). Found: C, 63.79; H, 3.47; N, 10.37. C20Hι2ClN3O3.l/2 THF requires C, 63.85; H, 3.90; N, 10.15.
EXAMPLE 148
The preparation of (2-Chloro-4-nitrobenzyl)(triphenyl .phosphonium bromide (559) Bromination of 2-chloro-4-nitrotoluene with NBS/AIBN, followed by reaction of the crude bromide with triphenylphosphine, using the procedure described in example 102, except that the reaction time for the bromination was 24 h and the displacement reaction was performed at 20 °C for 7 d, gave the crude phosphonium salt (559) (34 %) as a light brown solid, mp (benzene) 70-75 °C (dec). ]H NMR [(CD3)2SO] δ 8.21 (d, J=2.5 Hz, IH), 8.13 (dd, J=8.7, 2.5 Hz, IH), 7.94 (td, J=7.5, 1.6 Hz, 3H), 7.80-7.66 (m, 12H), 7.43 (dd, J=8.5, 2.6 Hz, IH), 5.33 (d, J=15.7 Hz, 2H). FABMS found M+=432.0916, 434.0904. C25H20ClNO2P requires 432.0921, 434.0891.
EXAMPLE 149
The preparation of 2-r(E)-2-(2-Chloro-4-nitrophenyl)ethenyll-5-methoxy-lH-indole (560) (II. Ar=2-chloro-4-nitrophenyl)
The 5 -methoxy- lH-indole-2-carbaldehyde (1) was reacted with (2-chloro-4- nitrobenzyl)(triphenyl)phosphonium bromide (559) prepared as described in example 148 using the procedure described in example 37, except that the LDA and aldehyde were (sequentially) added at 0 °C, the ratio of LDA: aldehyde was 1.5:1 and the reaction time was 5 h, to give (after crystallisation from CH2Cl2/hexane) the diene (560) as a dark red-brown solid (the pure E isomer) (46 %), mp 239-241 °C. Η NMR [(CD3)2SO] δ 11.57 (br s, IH), 8.32 (d, J=2.0 Hz, IH), 8.18 (dd, J=8.8, 2.1 Hz, IH), 8.15 (d, J=8.9 Hz, IH), 7.59 (d, J=16.3 Hz, IH), 7.47 (d, J=16.3 Hz, IH), 7.29 (d, J=8.9 Hz, IH), 7.05 (d, J=2.4 Hz, IH), 6.82 (dd, J=8.7, 2.5 Hz, IH), 6.70 (s, IH), 3.76 (s, 3H). Found: C, 62.14; H, 3.91; N, 8.52. C17Hι3ClN203 requires C, 62.11; H, 3.99; N, 8.52.
Example 150
The preparation of 4-(2-Chloro-4-nitrophenyl)-9-methoxypyrrolor3,4-clcarbazole- 1.3(2H.6H)-dione (561) (V, R10=H. Ar=2-chloro-4-nitrophenyl)
The pure E diene (560) prepared as described in example 149 was subjected to successive reactions with maleimide and then DDQ according to the procedure described in example 123 , to give (after crystallisation from THF/hexane) the product (561) (98 %) as an orange solid, mp 279-282 °C. Η NMR [(CD3)2SO] δ 12.06 (br s, IH), 11.20 (br s, IH), 8.46 (d, J=2.6 Hz, IH), 8.43 (d, J=2.2 Hz, IH), 8.29 (dd, J=8.4, 2.4 Hz, IH), 7.83 (d, J=8.4 Hz, IH), 7.66 (s, IH), 7.59 (d, J=8.9 Hz, IH), 7.27 (dd, J=8.8, 2.6 Hz, IH), 3.90 (s, 3H). Found: C, 59.83; H, 3.61; N, 9.57. C2ιH12ClN305.l/4 THF requires C, 60.08; H, 3.21; N, 9.55. EXAMPLE 151
The preparation of 4-(2-Chloro-4-nitrophenyl)-9-hvdroxypyrrolor3,4-clcarbazole- l,3(2H.6H)-dione (562) (VI, R10=H, Ar=2-chloro-4-nitrophenyl)
The methyl ether (561) prepared as described in example 150 was demethylated with BBr3 using the procedure described in example 80, except that the reaction time was 5 h with 5 equiv. BBr , then a further 5 h with an extra 5 equiv. BBr3, to give (after crystallisation from THF/CH2Cl2/pentane) the phenol (562) (85 %) as a red-orange solid, mp 301-305 °C. Η NMR [(CD3)2SO] δ 11.94 (br s, IH), 11.13 (br s, IH), 9.32 (br s, IH), 8.43 (d, J=2.3 Hz, IH), 8.32 (d, J=2.4 Hz, IH), 8.29 (dd, J=8.5, 2.3 Hz, IH), 7.82 (d, J=8.4 Hz, IH), 7.61 (s, IH), 7.48 (d, J=8.7 Hz, IH), 7.10 (dd, J=8.7, 2.5 Hz, IH). Found: C, 58.81; H, 2.35; N, 10.05. C20Hι0ClN3O5 requires C, 58.91; H, 2.47; N, 10.30.
EXAMPLE 152
The preparation of 4-(4-Amino-2-chlorophenyl)-9-hydroxypyrrolor3.4-clcarbazole- 1.3(2H.6H)-dione (563) (VI. R10= H. Ar=4-amino-2-chlorophenyl)
A mixture of the nitro derivative (562) (90 mg, 0.221 mmol) prepared as described in example 151 and freshly prepared (wet) nickel boride (277 mg) in MeOH (7.2 mL) and IM HCI (1.8 mL) was stirred at reflux for 1 h. Cone, aqueous ammonia and aqueous NaHC03 (120 mL) were added and the mixture extracted with EtOAc (6 x 80 mL). The extracts were concentrated, adsorbed onto silica gel and chromatographed. Elution with 0-2% MeOH/CH2Cl2 then elution with THF gave (after crystallisation from THF/CH2Cl2/pentane) the amine (563) (100 %) as an orange solid, mp 293-303 °C (dec). 1H NMR [(CD^SO] δ 11.70 (br s, IH), 10.92 (br s, IH), 9.23 (br s, IH), 8.30 (d, J=2.4 Hz, IH), 7.44 (s, IH), 7.43 (d, J---8.7 Hz, IH), 7.09 (d, J=8.2 Hz, IH), 7.05 (dd, J=8.7, 2.5 Hz, IH), 6.71 (d, J=2.2 Hz, IH), 6.58 (dd, J=8.1, 2.2 Hz, IH), 5.51 (s, 2H). Found: C, 60.42; H, 3.64; N, 10.05. C20Hι2ClN3O3.5/4 H20 requires C, 60.01; H, 3.65; N, 10.50.
EXAMPLE 153
The preparation of (2-Chloro-5-nitrobenzyl)(tripheny1)phosphonium bromide (564)
Bromination of (2-chloro-5-nitrophenyl)methanol with 30% HBr in acetic acid, followed by reaction of the crude bromide with triphenylphosphine, using the procedure described in example 112, gave the phosphonium salt (564) (63 %) as a white solid, mp (CH2Cl2/benzene) 239-243 °C. ]H NMR (CDC13) δ 8.22 (br s, IH), 8.07 (br d, J=8.7 Hz, IH), 7.87-7.65 (m, 15H), 7.41 (d, J=8.9 Hz, IH), 5.80 (d, J=14.8 Hz, 2H). Found: C, 58.56; H, 3.93; N, 2.73. C25H2oBrClN02P requires C, 58.47; H, 3.98; N, 2.66.
EXAMPLE 154
The preparation of 2-[(E)-2-(2-Chloro-5-nitrophenyl)ethenyll-5-methoxy-lH-indole (565) (II. Ar=2-chloro-5-nitrophenyl)
The 5-methoxy-lH-indole-2-carbaldehyde (1) was reacted with (2-chloro-5- nitrobenzyl)(triphenyl)phosphonium bromide (564) prepared as described in example 153 using the procedure described in example 37, except that the LDA and aldehyde were sequentially added at 0 °C, the ratio of LDAfaldehyde was 1.5:1 and the reaction time was 5 h, to give (after crystallisation from CH2Cl2/pentane) the diene (565) as an orange solid (the pure E isomer) (57 %), mp 191-193 °C. ]H NMR (CDC13) δ 8.54 (d, J=2.6 Hz, IH), 8.25 (br s, IH), 8.02 (dd, J=8.8, 2.6 Hz, IH), 7.56 (d, J=8.9 Hz, IH), 7.28 (d, J=8.7 Hz, IH), 7.26 (d, J=16.4 Hz, IH), 7.20 (d, J=16.5 Hz, IH), 7.06 (d, J=2.4 Hz, IH), 6.91 (dd, J=8.8, 2.5 Hz, IH), 6.70 (br s, IH), 3.86 (s, 3H). Found: C, 61.44; H, 3.92; N, 8.55. CπHι3ClN203.l/4 H20 requires C, 61.27; H, 4.08; N, 8.41.
EXAMPLE 155
The preparation of 4-(2-Chloro-5-nitrophenv1)-9-methoxypyrrolor3,4-c1carbazole- 1.3(2H.6H)-dione (566) (V. R10=H. Ar=2-chloro-5-nitrophenyl)
The pure E diene (565) prepared as described in example 154 was subjected to successive reactions with maleimide and then DDQ according to the above representative procedure described in example 123, to give (after crystallisation from THF/CH2Cl2/pentane) the product (566) (95 %) as a yellow-orange solid, mp 285-287 °C. Η NMR t(CD3)2SO] δ 12.06 (br s, IH), 11.16 (br s, IH), 8.46 (d, J=2.6 Hz, IH), 8.36 (d, J=2.8 Hz, IH), 8.33 (dd, J=8.7, 2.7 Hz, IH), 7.91 (d, J=8.7 Hz, IH), 7.71 (s, IH), 7.60 (d, J=8.9 Hz, IH), 7.27 (dd, J=8.9, 2.6 Hz, IH), 3.90 (s, 3H). Found: C, 57.34; H, 2.68; N, 9.38. C2]Hι2ClN305.l/4 CH2C12 requires C, 57.61; H, 2.84; N, 9.48.
EXAMPLE 156
The preparation of 4-(2-Chloro-5-nitrophenyl)-9-hvdroxypyrrolor3,4-c1carbazole- 1.3(2H,6H)-dione (567) (VI. R10=H. Ar=2-chloro-5-nitrophenyl) The methyl ether (566) prepared as described in example 155 was demethylated with BBr3 using the procedure described in example 80, except that the reaction time was 6 h with 10 equiv. BBr3, then a further 4 h with an extra 10 equiv. BBr , to give (after crystallisation from THF/CH2Cl2/pentane) the phenol (567) (88 %) as a yellow-orange solid, mp 268 °C (dec). ]H NMR [(CD3)2S0] δ 11.94 (br s, IH), 11.11 (br s, IH), 9.31 (br s, IH), 8.35 (d, J=2.6 Hz, IH), 8.32 (dd, J=8.6, 2.9 Hz, IH), 8.32 (d, J=2.4 Hz, IH), 7.91 (d, J=8.7 Hz, IH), 7.66 (s, IH), 7.48 (d, J=8.7 Hz, IH), 7.10 (dd, J=8.7, 2.5 Hz, IH). Found: C, 58.31; H, 2.45; N, 9.98. C20H10ClN3O5.l/4H2O requires C, 58.27; H, 2.57; N, 10.19.
EXAMPLE 157
The preparation of 4-(5-Amino-2-chlorophenyl)-9-hvdroxypyrrolor3,4-clcarbazole- 1.3(2H.6H)-dione (568) (VI. R10=H. Ar=5-amino-2-chlorophenyl)
A mixture of the nitro derivative (567) (70 mg, 0.172 mmol) prepared as described in example 156 and freshly prepared (wet) nickel boride (266 mg) in MeOH (5.6 mL) and IM HCI (1.4 mL) was stirred at reflux for 3 h. Cone, aqueous ammonia and aqueous NaHC03 (100 mL) were added and the mixture extracted with EtOAc (5x 70 mL). The extracts were washed with water, concentrated, adsorbed onto silica gel and chromatographed. Elution with 0-2% MeOH/CH2Cl2 then 3% MeOH/CH2Cl2 gave (after crystallisation from THF/CH2Cl2/pentane) the amine (568) (97 %) as an orange solid, mp 301-306 °C (dec). 1H NMR [(CD3)2SO] δ 11.78 (br s, IH), 10.97 (br s, IH), 9.26 (br s, IH), 8.31 (d, J=2.4 Hz, IH), 7.45 (s, IH), 7.45 (d, J=8.7 Hz, IH), 7.13 (d, J=8.3 Hz, IH), 7.07 (dd, J=8.7, 2.5 Hz, IH), 6.62 (dd, J=8.2, 2.8 Hz, IH), 6.60 (d, J=2.3 Hz, IH), 5.29 (s, 2H). Found: C, 63.09; H, 3.17; N, 10.91. C20H12ClN3O3.l/4H2O requires C, 62.84; H, 3.30; N, 10.99.
EXAMPLE 158
The preparation of (2-Chloro-3-methoxybenzyl)(triphenyl)phosphonium bromide (569)
Bromination of 2-chloro-l-methoxy-3-methylbenzene with NBS/AIBN, followed by reaction of the crude bromide with triphenylphosphine, using the procedure described in example 102, except that the reaction time for the bromination was 5 h, gave a mixture of phosphonium salts containing (569) (20 %) as a light brown solid which was used without further purification. A small amount of the pure salt (569) was obtained by crystallisation of the mother liquors as white needles, mp (CH2Cl2/benzene) 228-231 °C. Η NMR (CDC13) δ 7.81-7.60 (m, 15H), 7.17 (dt, J=7.8, 2.0 Hz, IH), 7.11 (t, J=8.0 Hz, IH), 6.87 (dt, J=8.2, 1.8 Hz, 1H), 5.65 (d, J=14.4 Hz, 2H), 3.81 (s, 3H). Found: C, 62.88; H, 4.64. C26H23BrC10P requires C, 62.73; H, 4.66.
EXAMPLE 159
The preparation of 2-r(E)-2-(2-Chloro-3-methoxyphenyl)ethenyll-5-methoxy-lH-indole (570) (II. Ar=2-chloro-3-methoxyphenyl) and 2-chloro-3-[YE)-2-(5-methoxy-lH-indol-2- vDethenyllphenol (571) (II. Ar=2-chloro-3-hvdroxyphenyl)
The 5-methoxy-lH-indole-2-carbaldehyde (1) was reacted with very crude (2-chloro- 3-methoxybenzyl)(triphenyl)phosphonium bromide (569) prepared as described in example 158 using the procedure described in example 37, except that the LDA and aldehyde were sequentially added at 0 °C,"the ratio of LDA.aldehyde was 1.5:1 and the reaction time was 5 h, to give a^rude mixture of dienes, Which were chromatographed on silica gel. Elution with 0-50% CH2Cl2/petroleum ether then elution with 60% CH2Cl2/petroleum ether gave (after crystallisation from CH2Cl2/pentane) the major product diene (570) as a pale yellow solid (the pure E isomer) (31 %), mp 179-183 °C. !H NMR (CDC13) δ 8.22 (br s, IH), 7.32 (d, J=16.4 Hz, IH), 7.31 (dd, J=8.2, 1.4 Hz, IH), 7.26 (d, J=8.7 Hz, IH), 7.23 (t, J=8.0 Hz, IH), 7.09 (d, J=16.5 Hz, IH), 7.04 (d, J=2.4 Hz, IH), 6.87 (dd, J=8.7, 2.5 Hz, IH), 6.85 (dd, J=7.8, 1.3 Hz, IH), 6.58 (d, J=1.6 Hz, IH), 3.93 (s, 3H), 3.85 (s, 3H). Found: C, 68.79; H, 5.22; N, 4.51. C]8Hι6ClN02 requires C, 68.90; H, 5.14; N, 4.46. Further elution of the column with 60% CH2Cl2/petroleum ether and CH2C12 gave (after crystallisation from CH2Cl /pentane) the minor product diene (571) as a pale yellow solid (the pure E isomer) (25 %), mp 172-175 °C. Η NMR (CDC13) δ 8.20 (br s, IH), 7.27 (m, IH), 7.26 (d, J=8.7 Hz, IH), 7.19 (t, J--7.9 Hz, IH), 7.18 (d, J=16.4 Hz, IH), 7.10 (d, J=16.4 Hz, IH), 7.04 (d, J=2.4 Hz, IH), 6.95 (dd, J=8.1, 1.5 Hz, IH), 6.88 (dd, J=8.8, 2.5 Hz, IH), 6.60 (d, J=1.7 Hz, IH), 5.65 (s, IH), 3.86 (s, 3H). Found: C, 67.23; H, 4.72; N, 4.72. CπHι4ClN02.l/4 H20 requires C, 67.11; H, 4.80; N, 4.60.
EXAMPLE 160
The preparation of 4-(2-Chloro-3-hvdroxyphenyl)-9-methoxypyιτolor3,4-clcarbazole- 1.3(2H.6H)-dione (572) (V. R10=H, Ar=2-chloro-3-hvdroxyphenyl)
A foil-covered mixture of the pure E diene (571) (110 mg, 0.367 mmol) prepared as described in example 159 and maleimide (180 mg, 1.85 mmol) in dry toluene (2 mL) was stirred in a sealed vial at reflux for 24 h (Method 4a). The resulting thick suspension was transferred to a flask using dioxane (5 mL), then treated with manganese dioxide (738 mg, 8.49 mmol), stirring at reflux under N2 for 22 h (as decribed in the procedure for example 79), after addition of water and extraction with ethyl acetate. The organic phase was dried, the drying agent was removed and the solvent concentrated to dryness. Chromatography and crystallisation from THF/CH2Cl2/pentane the product (572) (34 %) as an orange-brown solid, mp 280-290 °C (dec). Η NMR [(CD3)2SO] δ 11.92 (br s, IH), 11.04 (br s, IH), 10.23 (br s, IH), 8.46 (d, J=2.6 Hz, IH), 7.57 (d, J=8.8 Hz, IH), 7.52 (s, IH), 7.24 (dd, J=8.9, 2.6 Hz, IH), 7.21 (t, J=7.8 Hz, IH), 7.05 (dd, J=8.2, 1.5 Hz, IH), 6.88 (dd, J=7.5, 1.4 Hz, IH), 3.89 (s, 3H). Found: C, 64.09; H, 3.48; N, 7.25. C2!Hι3ClN204 requires C, 64.21; H, 3.34; N, 7.13.
EXAMPLE 161
The preparation of 4-(2-Chloro-3-hvdroxyphenyl)-9-hvdroxypyrrolor3.4-clcarbazole- 1.3(2H,6H)-dione (573) (VI. R10=H. Ar=2-chloro-3-hvdroxyphenyl)
The methyl ether (572) prepared as described in example 160 was demethylated with BBr3 using the procedure described in example 80, to give (after crystallisation from THF/CH2Cl2/pentane) the phenol (573) (91 %) as a yellow-orange solid, mp 197-203 °C (dec). Η NMR [(CD3)2SO] δ 11.78 (br s, IH), 10.98 (br s, IH), 10.17 (br s, IH), 9.26 (s, IH), 8.31 (d, J=2.4 Hz, IH), 7.47 (s, IH), 7.45 (d, J=8.7 Hz, IH), 7.20 (t, J=7.8 Hz, IH), 7.07 (dd, J=8.7, 2.5 Hz, IH), 7.04 (dd, J=8.3, 1.5 Hz, IH), 6.87 (dd, J=7.5, 1.4 Hz, IH). Found: C, 62.06; H, 3.29; N, 7.36. C20HnClN2O .l/2 H20 requires C, 61.95; H, 3.12; N, 7.22.
EXAMPLE 162
The preparation of (2-Chloro-4-methoxybenzyl)(triphenyl)phosphonium bromide (574)
Bromination of (2-chloro-4-methoxyphenyl)methanol with 30% HBr in acetic acid, followed by reaction of the crude bromide with triphenylphosphine, using the procedure described in example 112, except that the reaction time for the bromination was 4 h and the reaction time for the displacement was 28 h, gave the phosphonium salt (574) (100 %) as a white solid, mp (CH2Cl2/benzene) 223-226 °C. ]HNMR (CDC13) δ 7.82-7.61 (m, 15H), 7.53 (dd, J=8.4, 2.7 Hz, IH), 6.72 (d, J=2.8 Hz, IH), 6.70 (dd, J=8.9, 2.5 Hz, IH), 5.57 (d, J=13.6 Hz, 2H), 3.74 (s, 3H). Found: C, 63.05; H, 4.74. C26H23BrC10P requires C, 62.73; H, 4.66.
EXAMPLE 163
The preparation of 2-r(E)-2-(2-Chloro-4-methoxyphenyl)ethenyll-5-methoxy-lH-indole (575) (II, Ar=2-chloro-4-methoxyphenyl) The 5-methoxy-lH-indole-2-carbaldehyde (1) was reacted with (2-chloro-4- methoxybenzyl)(triphenyl)phosphonium bromide (574) prepared as described in example 162 using the procedure described in example 37, except that the LDA and aldehyde were sequentially added at 0 °C, the ratio of LDA:aldehyde was 1.5:1 and the reaction time was 5 h, to give (after crystallisation from CH2Cl2/pentane) the diene (575) as a pale yellow solid (the pure E isomer) (64 %), mp 129-132 °C. Η NMR (CDC13) δ 8.17 (br s, IH), 7.60 (d, J=8.8 Hz, IH), 7.25 (d, J=8.3 Hz, IH), 7.19 (d, J=16.5 Hz, IH), 7.03 (d, J=2.4 Hz, IH), 6.96 (d, J=17.3 Hz, IH), 6.94 (d, J=2.4 Hz, IH), 6.86 (dd, J=8.7, 2.6 Hz, IH), 6.85 (dd, J=8.7, 2.8 Hz, IH), 6.54 (d, J=1.7 Hz, IH), 3.85 (s, 3H), 3.83 (s, 3H). Found: C, 69.05; H, 5.41; N, 4.68. d8H16ClN02 requires C, 68.90; H, 5.14; N, 4.46.
EXAMPLE 164
The preparation of 4-(2-Chloro-4-methoxyphenyl)-9-methoxypyrrolor3,4-c1carbazole- 1.3(2H.6H)-dione (576) (V. R10=H. Ar=2-chloro-4-methoxyphenyl)
The pure E diene (575) prepared as described in example 163 was subjected to successive reactions with maleimide and then DDQ according to the above representative procedure described in example 123 , to give (after crystallisation from THF/pentane) the product (576) (86 %) as a yellow-orange solid, mp 284-286 °C. *H NMR [(CD3)2SO] δ 11.93 (br s, IH), 11.06 (br s, IH), 8.46 (d, J=2.6 Hz, IH), 7.56 (d, J=8.9 Hz, IH), 7.54 (s, IH), 7.41 (d, J=8.5 Hz, IH), 7.24 (dd, J=8.9, 2.6 Hz, IH), 7.15 (d, J=2.6 Hz, IH), 7.01 (dd, J=8.5, 2.6 Hz, IH), 3.89 (s, 3H), 3.86 (s, 3H). Found: C, 65.30; H, 4.79; N, 5.82. C22Hi5ClN204.THF requires C, 65.20; H, 4.84; N, 5.85.
EXAMPLE 165
The preparation of 4-(2-Chloro-4-hvdroxyphenyl)-9-hvdroxypyrrolor3,4-c lcarbazole- 1.3(2H.6H)-dione (577) (VI. R10=H. Ar=2-chloro-4-hvdroxyphenyl)
The methyl ether (576) prepared as described in example 164 was bis-demethylated with BBr3 using the procedure described in example 80, except that the reaction time was 5 h with 10 equiv. BBr3, to give (after crystallisation from THF/CH2Cl2/pentane) the phenol (577) (90 %) as a yellow-orange solid, mp 330-340 °C (dec). lH NMR [(CD^SO] δ 11.75 (br s, IH), 10.97 (br s, IH), 10.00 (br s, IH), 9.25 (s, IH), 8.31 (d, J=2.4 Hz, IH), 7.47 (s, IH), 7.44 (d, J=8.7 Hz, IH), 7.27 (d, J=8.4 Hz, IH), 7.06 (dd, J=8.7, 2.5 Hz, IH), 6.93 (d, J=2.5 Hz, IH), 6.82 (dd, J=8.3, 2.4 Hz, IH). Found: C, 62.63; H, 3.44; N, 7.10. C2oHι,ClN204.l/4 H20 requires C, 62.68; H, 3.02; N, 7.31.
EXAMPLE 166
The preparation of (2-Chloro-5-methoxybenzyl)(triphenyl)phosphonium bromide (578)
Bromination of l-chloro-4-methoxy-2-methylbenzene with NBS/AIBN, followed by reaction of the crude bromide with triphenylphosphine, using the procedure described in example 102, except that the reaction time for the bromination was 4 h, gave the phosphonium salt (578) (76 %) as a light brown solid, mp (CH2Cl2/benzene) 189-190.5 °C. Η NMR (CDC13) δ 7.82-7.61 (m, 15H), 7.21 (t, J=2.8 Hz, IH), 7.04 (dd, J=8.8, 0.8 Hz, IH), 6.76 (dt, J=8.9, 2.7 Hz, IH), 5.59 (d, J=14.4 Hz, 2H), 3.58 (s, 3H). Found: C, 62.75; H, 4.70. C26H23BrC10P requires C, 62.73; H, 4.66.
EXAMPLE 167
-The preparation of 2-r(E)-2-(2-Chloro-5-methoxyphenyl)ethenvI"l-5-methoxy-lH-indole (579) (II. Ar=2-chloro-5-methoxyphenyl)
The 5-methoxy-lH-indole-2-carbaldehyde (1) was reacted with (2-chloro-5- methoxybenzyl)(triphenyl)phosphonium bromide (578) prepared as described in example 166 using the procedure described in example 37, except that the LDA and aldehyde were (sequentially) added at 0 °C, the ratio of LDA: aldehyde was 1.5: 1 and the reaction time was 5 h, to give (after crystallisation from CH2Cl2/hexane) the diene (579) as a pale yellow solid (the pure E isomer) (85 %), mp 119-121 °C. Η NMR (CDC13) δ 8.22 (br s, IH), 7.29 (d, J=8.9 Hz, IH), 7.26 (br d, J=8.7 Hz, IH), 7.22 (d, J=16.5 Hz, IH), 7.18 (d, J=3.0 Hz, IH), 7.06 (d, J=16.7 Hz, IH), 7.04 (br s, 1 H), 6.88 (dd, J=8.7, 2.5 Hz, IH), 6.77 (dd, J=8.8, 3.0 Hz, IH), 6.59 (d, J=1.8 Hz, IH), 3.86 (s, 3H), 3.85 (s, 3H). Found: C, 68.70; H, 5.11; N, 4.37. d8Hι6ClN02 requires C, 68.90; H, 5.14; N, 4.46.
EXAMPLE 168
The preparation of 4-(2-Chloro-5-methoxyphenyl)-9-methoxypyrrolor3,4-clcarbazole- 1.3(2H,6H)-dione (580) (V, R10=H. Ar=2-chloro-5-methoχyphenyl)
The pure E diene (579) prepared as described in example 167 was subjected to successive reactions with maleimide and then DDQ according to the above representative procedure described in example 123 , to give (after crystallisation from MeOH/CH2Cl2/hexane) the product (580) (84 %) as a bright orange solid, mp 284-286 °C. Η NMR [(CD3)2SO] δ 11.96 (br s, IH), 11.08 (br s, IH), 8.46 (d, J=2.6 Hz, IH), 7.58 (s, IH), 7.57 (m, IH), 7.46 (d, J=8.7 Hz, IH), 7.25 (dd, J=8.8, 2.6 Hz, IH), 7.07 (d, J=2.9 Hz, IH), 7.04 (dd, J=8.7, 3.1 Hz, IH), 3.89 (s, 3H), 3.80 (s, 3H). Found: C, 62.50; H, 3.77; N, 6.54. C22Hι5ClN20 .H20 requires C, 62.20; H, 4.03; N, 6.59.
EXAMPLE 169
The preparation of 4-(2-Ch1oro-5-hvdroxyphenyl)-9-hvdroxypyrrolor3,4-c]carbazole- 1.3(2H.6H)-dione (581) (VI, R10=H, Ar=2-chloro-5-hvdroxyphenyl)
The methyl ether (580) prepared as described in example 168 was bis-demethylated with BBr3 using the procedure described in example 80, except that the reaction time was 6.5 h with 10 equiv. BBr3, to give (after crystallisation from MeOH/CH2Cl2/hexane) the phenol (581) (90 %) as an orange-red crystalline solid, mp 335-340 °C. !H NMR [(CD3)2SO] δ 11.80 (br s, IH), 11.00 (br s, IH), 9.78 (br s, IH), 9.27 (br s, IH), 8.31 (d, J=2.4 Hz, IH), 7.49 (s, IH), 7.45 (d, J=8.7 Hz, IH), 7.32 (d, J=8.5 Hz, IH), 7.07 (dd, J=8.7, 2.5 Hz, IH), 6.84 (dd, J=8.5, 2.9 Hz, IH), 6.82 (d, J=2.8 Hz, IH). Found: C, 63.25; H, 3.63; N, 6.73. C20HπClN2O4.l/2 H2O.l/4 Hexane requires C, 63.09; H, 3.82; N, 6.84.
Figure imgf000122_0001
(V); Rlυ=(CH2)nOH (VII) (VII)
Figure imgf000122_0002
(VIII)
SCHEME 3 Scheme 3 Procedures
Representative Procedure for Method 11 of Scheme 3
EXAMPLE 170
Phe preparation of 2-(4-(2-Chlorophenyl)-9-methoxy-1.3-dioxo-2,3-dihvdropyrrolor3,4-
Figure imgf000123_0001
(228)
Alcohol (46) prepared as described in example 43 (1.10 g, 2.61 mmol) was dissolved in dry tetrahydrofuran (80 mL) under nitrogen. The resulting solution was cooled to 0 °C and triethylamine (2.0 mL) was added followed by methanesulfonyl chloride (263 mL, 3.40 mmol) dropwise. After 30 minutes a further portion of methanesulfonyl chloride (50 mL) was added and then after another 30 minutes the reaction was diluted with saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was dried, the drying agent was removed and the solution was concentrated to drynessCrystallisation from ethyl acetate/hexane gave mesylate (228) (0.96 g, 74%) as a yellow solid, mp 254 °C (dec). Η NMR δ [(CD3)2SO] 11.15 (s, IH), 8.53 (d, J=2.6 Hz, IH), 7.90 (s, IH), 7.74 (d, J=9.0 Hz, IH), 7.58 (m, IH), 7.48 (m, 3H), 7.33 (dd, J=9.0, 2.6 Hz, IH), 4.89 (t, J=5.0 Hz, 2H), 4.56 (m, 2H), 3.91 (s, 3H), 2.94 (s, 3H). FABMS found [M+H]+: 499.0694, 501.0696. C2 H19C1N206S requires 499.0731, 501.0701.
EXAMPLE 171
The preparation of 2-(4-(2-Chlorophenyl)-9-hvdroxy-1.3-dioxo-2,3-dihydropyrrolor3.4- clcarbazol-6(lH)-yl)ethyl methanesulfonate (VII; Ar-=2-chlorophenyl, n=2, mesylate) (229)
Mesylate (228) (1.23 g, 2.48 mmol) prepared as described in example 170 was reacted according to the procedure described in example 80, except that the reaction time was 7 hours, after which chromatography on silica eluting with ethyl acetate/hexane (1:1 to 3:1) and trituration from ethyl acetate/hexane gave phenol (229) (1.05 g, 87%) as a yellow solid, mp 266 °C (dec). Η NMR δ [(CD3)2SO] 11.09 (br s, IH), 9.40 (s, IH), 8.39 (d, J=2.5 Hz, IH), 7.84 (s, IH), 7.62 (d, J=8.9 Hz, IH), 7.58 (m, IH), 7.48 (m, 3H), 7.14 (dd, J=8.9, 2.5 Hz, IH), 4.85 (t, J=5.0 Hz, 2H), 4.54 (m, 2H), 2.93 (s, 3H). Found: C, 58.13; H, 3.74; N, 5.72. C23H,17ClN206S.l/4hexane requires C, 58.10; H, 4.08; N. 5.53. EXAMPLE 172
The preparation of 6-(3-Bromopropyl)-4-(2-chlorophenyl)-9-hvdroxypyrrolor3.4- c1carbazole-1.3(2H.6H)-dione (VII . Ar=2-chlorophenyl. n=3, bromide) (58)
Reaction of alcohol (31) prepared as described in example 40 with methanesulfonyl chloride, followed by demethylation with BBr3 following the proceedure described in example 170 gave the bromide (58) (81%), orange powder, mp 278 ° C (dec). Η NMR δ [(CD3)2SO] 11.08 (s, IH), 9.39 (s, IH), 8.39 (d, J=2.4 Hz, IH), 7.81 (s, IH), 7.60 (d, J=8.7 Hz, IH), 7.60-7.58 (m, IH), 7.53-7.43 (m, 3H), 7.16 (dd, J=8.7, 2.4 Hz, IH), 4.55 (t, J=6.9 Hz, 2H), 3.56-3.49 (m, 2H), 2.34-2.24 (m, 2H). Found: C, 56.94; H, 3.45, N, 5.69. C23Hi6BrClN203 requires C, 57.10; H, 3.33; N, 5.79.
Example 173
The preparation of 6-(3-Bromopropyl)-9-hvdroxy-4-phenylpyrrolor3,4-c1carbazole- 1.3(2H.6H)-dione (VII: Ar=phenyl. n=3. bromide) (204)
Alcohol (202) prepared as described in example 83 (0.50 g, 1.25 mmol) was reacted according to the proceedure described in example 170 followed by the procedure described in example 80. Chromatography on silica eluting with ethyl acetate/hexane (1:1 to 4:1) followed by crystallisation from ethyl acetate/hexane gave bromide (204) (0.54 g, 97%) as an orange powder, mp 280-282 °C. Η NMR δ [(CD3)2SO] 11.07 (s, IH), 9.36 (s, IH), 8.41 (d, J=2.2 Hz, IH), 7.83 (s, IH), 7.66 (m, 2H), 7.58 (d, J=8.8 Hz, IH), 7.47 (m, 3H), 7.14 (dd, J=8.8, 2.2 Hz, IH), 4.57 (t, J=6.9 Hz, 2H), 3.53 (t, J=6.5 Hz, 2H), 2.32 (m, 2H). Found: C, 61.87; H, 3.69; N, 6.59. C23HπBrN203 requires: C, 61.48; H, 3.81; N, 6.23.
EXAMPLE 174
The preparation of 2-(9-Hvdroxy-l,3-dioxo-4-phenyl-2,3-dihydropyrrolor3,4-clcarbazol- 6(lH)-yl)ethyl methanesulfonate (VII; Ar=phenyl, n=2, mesylate) (205)
Alcohol (201) (0.21 g, 0.53 mmol) prepared as described in example 82 was reacted according to the proceedure described in example 170 followed by the procedure described in example 80. Chromatography on silica eluting with ethyl acetate/hexane (1: 1 to 4: 1) followed by crystallisation from ethyl acetate/hexane gave mesylate (205) (0.19 g, 80%) as a yellow solid, mp 271-276 °C. 1H NMR δ [(CD3)2SO] 11.08 (s, IH), 9.37 (br s, IH), 8.40 (d, J=2.4 Hz, IH), 7.86 (s, IH), 7.67 (m, 2H), 7.60 (d, J=8.8 Hz, IH), 7.46 (m, 3H), 7.13 (dd, J=8.8, 2.4 Hz, IH), 4.86 (t, J=4.8 Hz, 2H), 4.57 (t, J=4.8 Hz, 2H), 2.97 (s, 3H). FABMS found [M+H]+: 451.0958. C23H]8N206S requires 451.0964.
EXAMPLE 175
The preparation of 6-(6-Bromohexyl)-9-hvdroxy-4-phenylpyrrolof3,4-c1carbazole- 1.3(2H.6H)-dione (VII; Ar=phenyl. n=6. bromide) (206)
Alcohol (203) (0.30 g, 0.67 mmol) prepared as described in example 84 was reacted according to the proceedure described in example 170 followed using the procedure described in example 80. Chromatography on silica eluting with ethyl acetate/hexane (1:1 to 4:1) followed by crystallisation from ethyl acetate/hexane gave bromide (206) (0.29 g, 88%) as a orange solid, mp 214-216 °C. 1H NMR δ [(CD3)2SO] 11.04 (s, IH), 9.33 (s, IH), 8.41 (d, J=2.4 Hz, IH), 7.78 (s, IH), 7.65 (m, 2H), 7.56 (d, J=8.8 Hz, IH), 7.46 (m, 3H), 7.13 (dd, J=8.8, 2.4 Hz, IH), 4.46 (t, J=7.1 Hz, 2H), 3.46 (t, J=6.7 Hz, 2H), 1.74 (m, 4H), 1.41-1.29 (m, 4H). Found: C, 63.75; H, 4.72; N, 5.94. C26H23BrN203 requires: C, 63.66; H, 4.73; N, 5.71.
EXAMPLE 176
The preparation of 6-(3-Bromopropyl)-4-(2-chloro-6-methoxyphenyl)-9-hvdroxypyrrolor3.4- clcarbazole-l,3(2H,6H)-dione (VII; Ar=2-chloro-6-methoxyphenyl, n=3, bromide) (207)
Alcohol (105) (0.20 g, 0.43 mmol) prepared as described in example 58 was reacted according to the proceedure described in example 170 followed using the procedure described in example 80, except that the boron tribromide reaction was performed at 0 °C for 2 h and the subsequent worked-up crude was then dissolved in ethyl acetate (100 mL) to which lithium bromide (1.0 g) was added. This solution was warmed to 50 °C for 2 h before being absorbed onto silica and chromatographed eluting with ethyl acetate/hexane (1:3 to 1:1) to give bromide (207) (132 mg, 60%) as a yellow solid, mp 286-288 °C. Η NMR δ [(CD3)2SO] 11.03 (s, IH), 9.38 (s, IH), 8.38 (d, J=2.4 Hz, IH), 7.77 (s, IH), 7.58 (d, J=8.8 Hz, IH), 7.44 (t, J=8.8 Hz, IH), 7.18 (d, J=8.8 Hz, IH), 7.14 (m, 2H), 4.54 (t, J=7.0 Hz, 2H), 3.52 (t, J=6.8 Hz, 2H), 2.27 (m, 2H). FABMS found [M+H]+: 513.0182, 515.0192, 517.0169. C2 H]8BrClN204 requires 513.0217, 515.0196, 515.0187, 517.0167. EXAMPLE 177
The preparation of 2-(4-(2,6-Dichlorophenyl)-9-hvdroxy-l,3-dioxo-2,3-dihvdropyrrolor3.4- clcarbazol-6(lH)-yl)ethyl methanesulfonate (VII; Ar=2.6-dichlorophenyl, n=2, mesylate) (231)
Alcohol (230) (1.0 g, 2.2 mmol) prepared as described in example 85 was reacted according to the proceedure described in example 170 followed by the procedure described in example 80, except that the reaction time with boron tribromide was 30 h. Chromatography on silica eluting with ethyl acetate/hexane (1:1 to 4:1) followed by crystallisation from ethyl acetate/hexane gave mesylate (231) (0.95 g, 83%) as a yellow solid, mp 255-260 °C. ]H NMR δ [(CD3)2S0] 11.16 (br s, IH), 9.43 (br s, IH), 8.38 (d, J=2.5 Hz, IH), 7.91 (s, IH), 7.63 (m, 3H), 7.51 (dd, J=8.7, 7.3 Hz, IH), 7.16 (dd, J=8.9, 2.5 Hz, IH), 4.85 (t, J=4.9 Hz, 2H), 4.53 (t, J=4.9 Hz, 2H), 2.88 (s, 3H). Found: C, 53.48; H, 3.22; N, 5.23. C23H16C12N206S requires: C, 53.18; H, 3.10; N, 5.39.
EXAMPLE 178
The preparation of 6-(3-Bromopropyl)-4-(2,6-dichlorophenyl)-9-hvdroxypyrrolor3.4- clcarbazole-l ,3(2H,6H)-dione (VII; Ar=2,6-dichlorophenyI, n=3. bromide) (233)
Alcohol (232) (0.77 g, 1.68 mmol) prepared as described in example 86 was reacted according to the proceedure described in example 170 followed by the procedure described in example 80, except that the reaction time with boron tribromide was 18 h. Chromatography on silica eluting with ethyl acetate/hexane (1:1 to 4:1) followed by crystallisation from ethyl acetate/hexane gave bromide (233) (0.70 g, 80%) as an orange solid, mp 273-276 °C. Η NMR δ [(CD3)2SO] 11.15 (br s, IH), 9.42 (s, IH), 8.38 (d, J=2.4 Hz, IH), 7.87 (s, IH), 7.62 (m, 3H), 7.51 (dd, J=8.9, 7.6 Hz, IH), 7.18 (dd, J=8.8, 2.4 Hz, IH), 4.56 (t, J=6.9 Hz, 2H), 3.51 (t, J=6.7 Hz, 2H), 2.27 (m, 2H). Found: C, 53.44; H, 2.96; N, 5.23. C23H15BrCl2N203 requires: C, 53.30; H, 2.92; N, 5.40.
Representative Procedure for Method 12 of Scheme 3
EXAMPLE 179
The preparation of 6-r3-(Dimethylamino)propyll-9-hvdroxy-4-phenylpyrrolor3.4- clcarbazole-1.3(2H.6H)-dione (VIII; Ar=phenyl. n=3. Z=NMe7) (208) To a solution of bromide (204) prepared as described in example 173 (0.12 g, 0.27 mmol) in dimethylacetamide (4 mL) was added the amine , dimethylamine (25 mol eq., 0.85 mL in this case as an 40% aqueous solution). The reaction vessel was sealed and heated at 80 °C with stirring for 18 h, before being diluted with water. The resulting solution was then acidified by the dropwise addition of concentrated hydrochloric acid and the pH was then adjusted to approximately pH=9 by the addition of solid potassium carbonate. The precipitated product was either collected by filtration and washed with water and diisopropyl ether before being dried or extracted with ethyl acetate. The organic layer was dried, the drying agent was removed and the solution was concentrated to dryness. Chromatography on silica eluting with methanol/dichloromethane (1:9 to 1:4), followed by trituration in ethyl acetate/hexane gave amine (208) (52 mg, 47%) as a yellow powder, mp 185-189 °C. *H NMR δ [(CD3)2SO] 11.05 (s, IH), 9.34 (s, IH), 8.41 (d, J=2.4 Hz, IH), 7.78 (s, IH), 7.64 (m, 2H), 7.56 (d, J=8.9 Hz, IH), 7.47 (m, 3H), 7.14 (dd, J=8.9, 2.4 Hz, IH), 4.48 (t, J=6.6 Hz, 2H), 2.16 (t, J=6.5 Hz, 2H), 2.08 (s, 6H), 1.90 (m, 2H). Found: C, 71.98; H, 5.67; N, 10.14. C25H23N303.1/4H20 requires: C, 71.84; H, 5.67; N, 10.05.
EXAMPLE 180
The preparation of 6-f2-(Dimethylamino)ethyl1-9-hvdroxy-4-phenylpyrrolor3,4-c1carbazole- 1.3(2H,6H)-dione (VIII; Ar=phenyl, n=2. Z=NMe2) (209)
Mesylate (205) prepared as described in example 174 (70 mg, 0.16 mmol) was reacted with aqueous dimethylamine solution according to the procedure described in example 179 to give amine (209) (30 mg, 48%) as a yellow powder, mp 283-286 °C. Η NMR δ [(CD3)2SO] 11.05 (br s, IH), 9.33 (s, IH), 8.41 (d, J=2.4 Hz, IH), 7.77 (s, IH), 7.65 (m, 2H), 7.54 (d, J=8.8 Hz, IH), 7.46 (m, 3H), 7.12 (dd, J=8.8, 2.4 Hz, IH), 4.55 (t, J=6.5 Hz, 2H), 2.62 (t, J=6.5 Hz, 2H), 2.19 (s, 6H). Found: C, 71.92; H, 5.16; N, 10.55. C24H21N303 requires: C, 72.17; H, 5.30; N, 10.52.
EXAMPLE 181
The preparation of 9-Hvdroxy-6-r3-(4-moφholinyl)propyl1-4-phenylpyrrolor3,4-clcarbazole- 1.3(2H.6H)-dione (VIII: Ar=phenyl. n=3. Z=4-morpholinyl) (210)
Bromide (204) (0.10 g, 0.22 mmol) prepared as described in example 173 was reacted with morpholine according to the procedure described in example 179to give amine (210) (73 mg, 72%) as a yellow powder, mp 252-255 °C. Η NMR δ [(CD3)2SO] 11.04 (br s, IH), 9.33 (s, IH), 8.41 (d, J=2.5 Hz, IH), 7.81 (s, IH), 7.62 (m, 2H), 7.57 (d, J=8.9 Hz, IH), 7.47 (m, 3H), 7.12 (dd, J=8.9, 2.5 Hz, IH), 4.51 (t, J=6.3 Hz, 2H), 3.38 (t, J=4.0 Hz, 4H), 2.18 (br s, 4H), 2.14 (t, J=6.3 Hz, 2H), 1.93 (m, 2H). Found: C, 71.11; H, 5.46; N, 9.29. C27H25N304 requires: C, 71.19; H, 5.53; N, 9.22.
EXAMPLE 182
The preparation of 9-Hydroxy-6-r2-(4-morpholinyl)ethyll-4-phenylpyrrolor3,4-c1carbazole- 1.3(2H.6H)-dione (VIII; Ar=phenyl. n=2. Z=4-morpholinyl) (211)
Mesylate (205) (70 mg, 0.16 mmol) prepared as described in example 174 was reacted with morpholine according to the procedure described in example 179 to give amine (211) (53 mg, 75%) as a yellow powder, mp 260-262 °C. 1H NMR D [(CD3)2SO] JH NMR δ [(CD3)2SO] 11.04 (br s, IH), 9.33 (s, IH), 8.40 (d, J=2.5 Hz, IH), 7.78 (s, IH), 7.64 (m, 2H), 7.54 (d, J=8.9 Hz, IH), 7.47 (m, 3H), 7.12 (dd, J=8.9, 2.5 Hz, IH), 4.57 (t, J=6.4 Hz, 2H), 3.45 (t, J=4.5 Hz, 4H), 2.67 (t, J=6.4 Hz, 2H), 2.18 (br t, J=4 Hz, 4H). Found: C, 70.55; H, 5.25; N, 9.22. C26H23N304 requires: C, 70.74; H, 5.25; N, 9.51.
-EXAMPLE 183 -
The preparation of 9-Hydroxy-6-r3-(lH-imidazol-l-yl)propyll-4-phenylpyrrolor3.4- c1carbazo1e-1.3(2H.6H)-dione (VIII; Ar=phenyl. n=3. Z=l -imidazolyl) (212)
Bromide (204) (80 mg, 0.18 mmol) prepared as described in example 173 was reacted with imidazole according to the procedure described in example 179to give amine (212) (41 mg, 53%) as a yellow powder, mp 309-311 °C. ]H NMR δ [(CD3)2SO] 11.06 (s, IH), 9.36 (s, IH), 8.40 (d, J=2.3 Hz, IH), 7.69 (s, IH), 7.64 (m, 3H), 7.47 (m, 4H), 7.22 (s, IH), 7.14 (dd, J=8.8, 2.3 Hz, IH), 6.89 (s, IH), 4.44 (t, J=7.4 Hz, 2H), 4.07 (t, J=7.3 Hz, 2H), 2.24 (m, 2H). Found: C, 70.31; H, 4.78; N, 12.43. C26H20N4O3.l/2H2O requires: C, 70.10; H, 4.75; N, 12.57.
EXAMPLE 184
The preparation of 9-Hvdroxy-6-r2-(lH-imidazol-l-yl)ethyll-4-phenylpyrrolor3.4- clcarbazole-l,3(2H,6H)-dione (VIII: Ar=phenyl. n=2. Z=l -imidazolyl) (213)
Mesylate (205) (70 mg, 0.16 mmol) prepared as described in example 174 was reacted with imidazole according to the procedure described in example 179 to give amine (213) (34 mg, 50%) as a yellow powder, mp > 345 °C. Η NMR δ [(CD3)2SO] 11.05 (br s, 1H), 9.34 (s, IH), 8.39 (d, J=2.4 Hz, IH), 7.59 (m, 2H), 7.45 (m, 5H), 7.27 (s, IH), 7.06 (dd, J=8.8, 2.4 Hz, IH), 7.02 (s, IH), 6.75 (s, IH), 4.80 (t, J=5.7 Hz, 2H), 4.41 (t, J=5.7 Hz, 2H). Found: C, 70.36; H, 4.38; N, 12.68. C25Hι8N403.l/4H20 requires: C, 70.33; H, 4.37; N, 13.12.
EXAMPLE 185
The preparation of 9-Hydroxy-6-F3-(methv1amino)propyll-4-phenylpyιτolor3,4-c"lcarbazole- 1.3(2H.6H)-dione (VIII: Ar=phenyl. n=3, Z=NHMe) (214)
Bromide (204) (40 mg, 0.09 mmol) prepared as described in example 173 was reacted with aqueous methylamine solution (10 mol equiv.) according to the procedure described in example 179 except that the reaction was performed in dimethylsulfoxide at room temperature for 3 h, to give amine (214) (22 mg, 61%) as an orange/yellow powder, mp 265- 268 °C. Η NMR δ [(CD3)2SO] 9.33 (br s, IH), 8.41 (d, J=2.5 Hz, IH), 7.80 (s, IH), 7.64 (m, 2H), 7.57 (d, J=8.8 Hz, IH), 7.47 (m, 3H), 7.14 (dd, J=8.8, 2.5 Hz, IH), 4.51 (t, J=6.8 Hz, 2H), 2.40 (t, J=6.5 Hz, 2H), 2.20 (s, 3H), 1.88 (m, 2H). FABMS found [M+H]+: 400.1659. C24H22N303 requires 400.1661.
EXAMPLE 186
The preparation of 9-Hvdroxy-4-phenyl-6-r3-(l-piperazinyl)propyl1pyrrolor3.4-c1carbazole- 1.3(2H.6H)-dione (VIII; Ar=phenyl. n=3. Z=l-piperazinyl) (215)
Bromide (204) (70 mg, 0.16 mmol) prepared as described in example 173 was reacted with piperazine according to The procedure described in example 179except that the reaction was performed at room temperature for 20 h, to give amine (215) (40 mg, 55%) as a yellow powder, mp 178-183 °C. 1H NMR δ [(CD3)2SO] 11.0 (br s, IH), 9.35 (br s, IH), 8.40 (d, J=2.4 Hz, IH), 7.78 (s, IH), 7.62 (m, 2H), 7.56 (d, J=8.8 Hz, IH), 7.45 (m, 3H), 7.14 (dd, J=8.8, 2.4 Hz, IH), 4.49 (t, J=6.3 Hz, 2H), 2.52 (m, 4H), 2.12 (m, 6H), 1.91 (m, 2H). Found: C, 69.31; H, 5.97; N, 11.49. C27H26N403.4/5H20 requires: C, 69.16; H, 5.93; N, 11.94.
EXAMPLE 187
The preparation of 6-r3-(Benzylamino)propy11-9-hydroxy-4-phenylpyrrolor3,4-clcarbazole- 1.3(2H.6H)-dione (VIII; Ar=phenyl. n=3. Z=NHBn) (216)
Bromide (204) (75 mg, 0.17 mmol) prepared as described in example 173 was reacted with benzylamine according to the procedure described in example 179 except that the reaction was performed at room temperature for 20 h, to give amine (216) (36 mg, 45%) as a yellow powder, mp 139-144 °C. Η NMR δ [(CD3)2SO] 11.04 (br s, IH), 9.33 (br s, IH), 8.41 (d, J=2.4 Hz, IH), 7.80 (s, IH), 7.62 (m, 2H), 7.57 (d, J=8.8 Hz, IH), 7.44 (m, 3H), 7.24-7.19 (m, 5H), 7.11 (dd, J=8.8, 2.4 Hz, IH), 4.53 (t, J=6.7 Hz, 2H), 3.57 (s, 2H), 2.46 (t, J=6.4 Hz, 2H), 1.92 (m, 2H). Found: C, 74.84; H, 5.39; N, 8.80. C3oH25N3θ3.1/4H20 requires: C, 75.06; H, 5.35; N, 8.75.
EXAMPLE 188
The preparation of 6-(3-Anilinopropyl)-9-hvdroxy-4-phenylpyrrolor3,4-c1carbazoIe- l,3(2H,6H)-dione (VIII; Ar=phenyl, n=3. Z=NHPh) (217)
Bromide (204) (75 mg, 0.17 mmol) prepared as described in example 173 was reacted with aniline according to the procedure described in example 179 except that the reaction was performed at room temperature for 20 h, to give aniline (217) (30 mg, 38%) as a yellow powder, mp 240 °C (dec). 1H NMR δ [(CD3)2S0] 11.04 (br s, IH), 9.33 (s, IH), 8.40 (d, J=2.4 Hz, IH), 7.78 (s, IH), 7.59 (d, J=8.9 Hz, IH), 7.48 (m, 2H), 7.42 (m, 3H), 7.10 (dd, J=8.8, 2.4 Hz, IH), 7.05 (m, 2H), 6.52 (m, 3H), 5.70 (t, J=5.3 Hz, IH), 4.59 (t, J=6.8 Hz, 2H), 2.98 (t, J=6.3 Hz, 2H), 2.07 (m, 2H). Found: C, 74.00; H, 5.22; N, 8.76. C29H23N303.1/2H20 requires: C, 74.03; H, 5.14; N, 8.93.
EXAMPLE 189
The preparation of 4-(2-Chloro-6-methoxyphenyl)-6-{ 3-rcis-3,5- dimethylpiperazinyllpropyl |-9-hvdroxypyrro1or3,4-clcarbazole-l,3(2H.6H)-dione (VIII; Ar=2-chloro-6-methoxyphenyl, n=3, Z=l-(cis-3,5-dimethylpiperazinyl)) (218)
Bromide (207) (60 mg, 0.12 mmol), prepared as described in example 176, was reacted with cis-2,6-dimethylpiperazine according to the procedure described in example 179 except that the reaction was performed at room temperature for 20 h, to give amine (218) (63 mg, 98%) as a yellow powder, mp 199-202 °C. 1H NMR δ [(CD3)2SO] 10.99 (br s, IH), 9.37 (br s, IH), 8.36 (d, J=2.4 Hz, IH), 7.75 (s, IH), 7.57 (d, J=8.8 Hz, IH), 7.43 (t, J=8.2 Hz, IH), 7.15 (m, 3H), 4.45 (t, J=6.1 Hz, 2H), 3.67 (s, 3H), 2.49 (m, 4H), 2.11 (m, 2H), 1.90 (m, 2H), 1.27 (m, 2H), 0.79 (m, 6H). Found: C, 61.35; H, 5.68; N, 9.14.
Figure imgf000130_0001
requires: C, 61.32; H, 6.09; N, 9.54. EXAMPLE 190
The preparation of 4-(2-Chloro-6-methoxyphenyl)-9-hvdroxy-6-r3-(4- moφholinyl)propyllpyrrolor3,4-clcarbazole-l,3(2H,6H)-dione (VIII; Ar=2-chloro-6- methoxyphenyl. n=3, Z=4-moφholinyl) (219)
Bromide (207) (60 mg, 0.12 mmol), prepared as described in example 176, was reacted with moφholine according to the procedure described in example 179 except that the reaction was performed at 50 °C for 6 h, to give amine (219) (40 mg, 66%) as a yellow powder, mp 169-174 °C. Η NMR δ [(CD3)2SO] 10.99 (br s, IH), 9.34 (br s, IH), 8.36 (d, J=2.4 Hz, IH), 7.77 (s, IH), 7.58 (d, J=8.8 Hz, IH), 7.44 (t, J=8.2 Hz, IH), 7.18 (d, J=8.2 Hz, IH), 7.12 (m, 2H), 4.47 (t, 1=6.1 Hz, 2H), 3.66 (s, 3H), 3.35 (t, J=4.4 Hz, 4H), 2.22-2.11 (m, 6H), 1.91 (m, 2H). Found: C, 63.09; H, 5.26; N, 7.97. C28H26C1N305.3/4H20 requires: C, 63.04; H, 5.20; N, 7.88.
EXAMPLE 191
The preparation of 4-(4-(2-Ch1orophenyl)-9-hvdroxy-l ,3-dioxo-2,3-dihvdropyrrolor3,4- clcarbazol-6(lH)-yl)butanenitrile (VIII; Ar=2-chlorophenyl, n=3, Z=CN) (241)
To a solution of bromide 0 (0.13 g, 0.27 mmol) prepared as described in example 172 in dimethylsulfoxide (2 mL) was added a solution of sodium cyanide (15 mg, 0.30 mmol) in dimethylsulfoxide (2 mL) dropwise over 15 minutes. After 30 minutes the reaction was diluted with water and extracted with ethyl acetate. The organic layer was dried, the drying agent was removed and the solution was concentrated to dryness. Chromatography on silica eluting with ethyl acetate/hexane (1:4 to 1:1), followed by crystallization from ethyl acetate/hexane gave nitrile (241) (68 mg, 59%) as an orange powder, mp 262-266 °C. 1H NMR δ [(CD3)2SO] 11.08 (br s, IH), 9.39 (s, IH), 8.39 (d, J=2.4 Hz, IH), 7.83 (s, IH), 7.59 (m, 2H), 7.49 (m, 3H), 7.15 (dd, J=8.8, 2.4 Hz, IH), 4.50 (t, J=7.3 Hz, 2H), 2.57 (m, 2H), 2.07 (m, 2H). FABMS found [M+H]+: 430.0927, 432.0916. C24H16C1N303 requires 430.0958, 432.0929.
EXAMPLE 192
The preparation of 4-(2-Chlorophenyl)-9-hvdroxy-6-r2-(phenylsulfanyl)ethvπpyrrolo.3.4- c1carbazole-1.3(2H.6H)-dione (VII; Ar-=2-chlorophenyl, n=2, Z=SPh) (242) Mesylate (229) (55 mg, 0.11 mmol) prepared as decribed in example 171 was reacted with excess thiophenol (0.10 mL) according to the procedure described in example 179 , except that triethylamine (2.0 mL) was added and the reaction was heated at 110 °C for 4 days. Addition of water was followed by extracted of the compound with with ethyl acetate. The organic layer was dried, the drying agent was removed and the solution was concentrated to dryness. The organic layer was dried, the drying agent was removed and the solution was concentrated to dryness followed by chromatography on silica eluting with ethyl acetate/hexane (1 :4 to 1:1) to give carbazole (242) (16 mg, 27%) as an orange powder, mp 262-264 °C. Η NMR δ [(CD3)2SO] 11.04 (br s, IH), 9.37 (br s, IH), 8.34 (d, J=2.5 Hz, IH), 7.58 (m, IH), 7.46 (m, 5H), 7.19 (m, 2H), 7.12 (m, 3H), 7.05 (m, IH), 4.66 (t, J=6.4 Hz, 2H), 3.46 (t, J=6.4 Hz, 2H). Found: C, 63.64; H, 4.09; N, 4.98. C28H19C1N203S.13/4H20 requires: C, 63.39; H, 4.28; N, 5.28.
EXAMPLE 193
The preparation of 2-{ r3-(4-(2-Chlorophenyl)-9-hvdroxy-l,3-dioxo-2,3-dihvdropyrrolor3,4- clcarbazol-6(lH)-yl)propynamino|benzoic acid (VIII; Ar=2-chlorophenyl, n=3, Z=2- carboxyanilino) (60).
Reaction of the bromide (58) prepared as described in example 172 with o-anthranilic acid using the procedure described in example 179 gave the aniline (60) (88%), mp 261-263 °C Η NMR δ [(CD3)2SO] 11.05 (s, IH), 9.38 (s, IH), 8.39 (d, J=2.4 Hz, IH), 7.76 (m, IH), 7.75 (s, IH), 7.59 (d, J=8.7 Hz, IH), 7.55 (m, IH), 7.46 (m, IH), 7.40 (m, IH), 7.33 (m, IH), 7.27 (m, IH), 7.12 (dd, J=8.7, 2.4 Hz, IH), 6.59-6.50 (m, 2H), 4.57 (t, J=6.7 Hz, 2H), 3.22- 3.10 (m, 2H), 2.15-2.05 (m, 2H). FABMS found M+: 541.1230, 539.1234. C3oH22ClN3O5 requires 541.1218, 539.1248.
EXAMPLE 194
The preparation of 3-{ r3-(4-(2-Chlorophenyl)-9-hvdroxy-l,3-dioxo-2,3-dihydropyrrolor3.4- clcarbazol-6(lH)-yl)propyllamino)benzoic acid (VIII; Ar=2-chlorophenyl, n=3, Z=3- carboxyanilino) (61).
Reaction of the bromide (58) prepared as described in example 172 with m-anthranilic acid using the procedure described in example 179 gave the aniline (61) (82%), mp 160-166 °C (dec). Η NMR δ f(CD3)2SO] 11.04 (s, IH), 9.38 (s, IH), 8.39 (d, J=2.4 Hz, IH), 7.77 (s, IH), 7.61 (d, J=8.7 Hz, IH), 7.54 (m, IH), 7.45 (m, IH), 7.27 (m, IH), 7.14-7.08 (m, 4H), 6.67 (m, IH), 5.92 (br s, IH), 4.58 (m, 2H), 3.09-2.92 (m, 2H), 2.12-2.02 (m, 2H). FABMS found M+: 541.1223, 539.1237. C30H22ClN3O5 requires 541.1218, 539.1248.
EXAMPLE 195
The preparation of 4-{ r3-(4-(2-Chlorophenyl)-9-hvdroxy-l,3-dioxo-2,3-dihvdropyrro1or3.4- clcarbazol-6(lH)-yl)propyllamino)benzoic acid (VIII; Ar=2-chlorophenyl, n=3, Z=4- carboxyanilino) (62).
Reaction of the bromide (58) prepared as described in example 172 with p-anthranilic acid using the procedure described in example 179 gave the aniline (62) (77 %), mp 160- 165 °C (dec). !H NMR δ [(CD3)2SO] 11.06 (br s, IH), 9.43 (br s, IH), 8.39 (d, J=2.4 Hz, IH), 7.75 (s, IH), 7.65-7.59 (m, 3H), 7.54 (m, IH), 7.45 (m, IH), 7.37 (m, IH), 7.26 (m, IH), 7.13 (dd, J=8.7, 2.4 Hz, IH), 6.49 (d, J=8.7 Hz, 2H), 4.58 (m, 2H), 3.11-2.99 (m, 2H), 2.12- 2.04 (m, 2H). Found: C, 63.24; H, 4.66; N, 7.95. C3oH22ClN305.H20 requires C, 63.55; H, 4.23; N, 7.41.
EXAMPLE 196
The preparation of'4-(2-ChloroprienyI)-6-{ "3-r.cis)-3",5-dimethylpiperazinyllpropyl 1-9- hydroxypyrrolor3,4-clcarbazole-l,3(2H,6H)-dione (VIII; Ar=2-chlorophenyl. n=3, Z=cis- 3.5-dimethylpiperazinyl) (63).
Reaction of the bromide (58) prepared as described in example 172 with cis-1,3- dimethylpiperazine using the procedure described in example 179 gave (63) (65 %), mp 165-172 °C. Η NMR δ [(CD3)2SO] 11.04 (br s, IH), 9.36 (br s, IH), 8.38 (d, J=2.4 Hz, IH), 7.80 (s, IH), 7.59-7.54 (m, 2H), 7.51-7.42 (m, 3H), 7.13 (dd, J=8.7, 2.4 Hz, IH), 4.47 (m, 2H), 2.58-2.38 (m), 2.09 (t, J=6.2 Hz, 2H), 1.96-1.87 (m, 2H), 1.32-1.23 (m, 2H), 0.81 (d, J=6.1 Hz, 3H), 0.77 (d, J=6.1 Hz, 3H). Found: C, 64.09; H, 5.43; N, 10.08. C29H28C1N403.1.5H20 requires C, 64.14; H, 5.75; N, 10.31.
EXAMPLE 197
The preparation of 4-(2,6-Dichlorophenyl)-6-{ 3-r(cis)-3,5-dimethylpiperazinyllpropyl)-9- hydroxypyrrolor3,4-c1carbazole-l,3(2H,6H)-dione (VIII; Ar=2,6-dichlorophenyl, n=3. Z=cis- 3.5-dimethylpiperazinyl) (64).
Reaction of the bromide (233) prepared as described in example 178 with cis-1,3- dimethylpiperazine using the procedure described in example 179 gave (64) (68 %), mp 160-165 °C. ]H NMR δ [(CD3)2SO] 11.11 (br, IH), 9.39 (br s, IH), 8.37 (d, J=2.4 Hz, IH), 7.85 (s, IH), 7.62 (d, J=8.1 Hz, 2H), 7.59 (d, J=8.7 Hz, IH), 7.51 (m, IH), 7.16 (dd, J=8.7, 2.4 Hz, IH), 4.46 (t, J=5.7 Hz, 2H), 2.55-2.42 (m), 2.10 (t, J=6.4 Hz, 2H), 1.96-1.89 (m, 2H),1.27 (t, J=10 Hz, 2H), 0.80 (d, J=6.2 Hz, 6H). Found: C, 61.34; H, 5.53; N, 9.56. C29H27C12N403.H20 requires C, 61.27; H, 5.14; N, 9.85.
EXAMPLE 198
The following amino-compounds of general structure VIII were prepared in an array manner by reaction of the appropriate mesylate or bromide with the appropriate amine using the procedure described in example 179:
The preparation of 6-(2-aminoethyl)-9-hvdroxy-4-phenylpyrrolor3,4-c lcarbazole- 1.3(2H,6H)-dione (VIII; Ar=phenyl, n=2, Z=NH2) (65) by reaction of (205) prepared as described in example 174 with aqueous ammonia. Found: M+H=372
The preparation of 9-hvdroxy-6-r2-(methylamino)ethyl1-4-phenylpyrrolor3,4-c"lcarbazole- 1.3(2H.6H)-dione (VIII; Ar=phenyl, n=2, Z=NHCH3) (66) by reaction of (205) prepared as described in example 174 with aqueous methylamine. Found: M+H=386
The preparation of 6-(3-aminopropyl)-9-hvdroxy-4-phenylpyrrolor3,4-c1carbazole- 1.3(2H.6H)-dione (VIII, Ar=phenyl, n=3, Z=NH2) (67) by reaction of (204) prepared as described in example 173 with aqueous ammonia . Found: M+H=386
The preparation of 9-hvdroxy-4-phenyl-6-r3-(l-pyrrolidinyl)propyllpyrrolor3.4-c1carbazole- 1.3(2H,6H)-dione (VIII; Ar=phenyl, n=3, Z=l -pyrrolidinyl) (68) by reaction of (204) prepared as described in example 173 with pyrrolidine. Found: M+H=440
The preparation of 6-r3-(diethylamino)propyn-9-hvdroxy-4-phenylpyrrolor3,4-c1carbazole- 1.3(2H,6H)-dione (VIII; Ar=phenyl, n=3, Z=N(CH2CH3)2) (69) by reaction of (204) prepared as described in example 173 with diethylamine. Found: M+H=442.
The preparation of 9-hvdroxy-4-phenyl-6-r3-(l-piperidinyl)propyllpyrrolor3,4-c1carbazole- 1.3(2H,6H)-dione (VIII; Ar=phenyl, n=3, Z=l -piperidinyl) (70) by reaction of (204) prepared as described in example 173 with piperidine. Found: M+H=454.
The preparation of 9-hvdroxy-6-r3-(4-methyl-l-piperazinyl)propyll-4-phenylpyιτolor3.4- c .carbazole-l,3(2H,6H)-dione (VIII; Ar=phenyl, n=3, Z=4-methyl-l -piperazinyl) (71) by reaction of (204) prepared as described in example 173 with 1-methylpiperazine. Found: M+H=469
The preparation of 6-r6-(dimethylamino)hexyl1-9-hvdroxy-4-phenylpyrrolor3,4-c"lcarbazole- l ,3(2H,6H)-dione (VIII; Ar=phenyl, n=6, Z=N(CH3)2) (72) by reaction of (206) prepared as described in example 175 with aqueous dimethylamine. Found: M+H=456
The preparation of 9-hvdroxy-6-r6-(4-methyl-l-piperazinvI)hexyl1-4-phenylpyrrolor3.4- clcarbazole-1.3(2H,6H)-dione (VIII; Ar=phenyl, n=6, Z=4-methyl-l -piperazinyl) (73) by reaction of (206) prepared as described in example 175 with 1-methylpiperazine. Found: M+H=512.
The preparation of 6-(2-aminoethyl)-4-(2-chlorophenyl)-9-hydroxypyrrolor3.4-c1carbazole- 1.3(2H.6H)-dione (VHI; Ar=2-chlorophenyl, n=2, R=NH2) (74) by reaction of (229) prepared as decribed in example 171 with aqueous ammonia. Found: M-H=404
The preparation of 4-(2-ch]orophenyl)-9-hvdroxy-6-r3-(dimethylamino)ethyllpyrrolor3,4- clcarbazole-1.3(2H,6H)-dione (VIII, Ar=2-chlorophenyl, n=2, Z=N(CH3)2) (75) by reaction of (229 prepared as decribed in example 171 with aqueous dimethylamine. Found: M+H=434.
The preparation of 4-(2-chlorophenyl)-9-hvdroxy-6-r2-(lH-imidazol-l-yl)ethvI1pyrroloF3.4- clcarbazole-1.3(2H.6H)-dione (VIII, Ar=2-chlorophenyl, n=2, Z=lH-imidazol-l-yl) (76) by reaction of (229) prepared as decribed in example 171 with imidazole. Found: M+H=457.
The preparation of 4-(2-chlorophenyl)-9-hvdroxy-6-r2-(4-moφholinyl)ethyl1pyrrolor3.4- clcarbazole- 1 ,3(2H,6H)-dione (VIII, Ar=2-chlorophenyl, n=2, Z=4-moφholinyl) (77) by reaction of (229) prepared as decribed in example 171 with moφholine. Found: M+H=476.
The preparation of 4-(2-chlorophenyl)-9-hvdroxy-6-r2-(4-methyl-l- piperazinyl)ethyllpyrrolor3.4-c1carbazole-l,3(2H.6H)-dione (VIII, Ar=2-chlorophenyl, n=2, Z=4-methyl-l -piperazinyl) (78) by reaction of (229 prepared as decribed in example 171 with 1-methylpiperazine. Found: M+H=489.
The preparation of 6-(2-amlinoethyl)-4-(2-chlorophenyl)-9-hvdroxypyrrolor3,4-c1carbazole- 1.3(2H,6H)-dione (VIII, Ar=2-chlorophenyl, n=2, Z=anilino) (79) by reaction of (229) prepared as decribed in example 171 with aniline. Found: M+H=481 The preparation of 4-(2,6-dich1orophenyl)-9-hydroxy-6-r3- (dimethylamino)ethyl1pyrrolor3.4-clcarbazole-1.3(2H.6H)-dione (VIII, Ar=2,6- dichlorophenyl, n=2, Z=N(CH3)2) (80) by reaction of (231) prepared as decribed in example 177 with aqueous dimethylamine. Found: M+H=468.
The preparation of 4-(2,6-dichlorophenyl)-9-hydroxy-6-r2-(lH-imidazol-l- yl)ethyl .pyrrolor3,4-c"lcarbazole-l,3(2H,6H)-dione (VIII, Ar=2,6-dichlorophenyl, n=2, Z=lH-imidazol-l-yl) (81) by reaction of (231) prepared as decribed in example 177 with imidazole. Found: M+H=491.
The preparation of 4-(2,6-dichlorophenyl)-9-hvdroxy-6-r2-(4-moφholinyl)ethyllpyrroloF3.4- clcarbazole-1 ,3(2H,6H)-dione (VIII, Ar=2,6-dichlorophenyl, n=2, Z=4-moφholinyl) (82) by -reaction of (231) prepared as decribed in example 177 with moφholine. Found: M+H=510.
The preparation of 4-(2.6-dichlorophenyl)-9-hvdroxy-6-F2-(4-methyl-l- piperazinyl)ethyllpyrroloF3,4-clcarbazole-l,3(2H,6H)-dione (VIII, Ar=2,6-dichlorophenyl, n=2, Z=4-methyl-l -piperazinyl) (83) by reaction of (231) prepared as decribed in example 177 with 1-methylpiperazine. Found: M+H=523.
The preparation of 6-(2-anilinoethyl)-4-(2,6-dichlorophenyl)-9-hvdroxypyιτolor3.4- clcarbazole-1 ,3(2H,6H)-dione (VIII, Ar=2,6-dichlorophenyl, n=2, Z=anilino) (84) by reaction of (231) prepared as decribed in example 177 with aniline. Found: M+H=516
The preparation of 4-(2-chIorophenyl)-9-hvdroxy-6-r3-(methylamino)propyl1pyrrolor3,4- clcarbazole-l,3(2H,6H)-dione (VIII, Ar=2-chlorophenyl, n=3, Z=NHMe) (85) by reaction of (58) prepared as described in example 172 with aqueous methylamine. Found: M+H=434.
The preparation of 4-(2-chlorophenyl)-6-r3-(dimethylamino)propyI1-9-hvdroxypyrrolor3,4- clcarbazole-1 ,3(2H,6H)-dione (VIII, Ar=2-chlorophenyl, n=3, Z=N(CH3) ) (86) by reaction of (58) prepared as described in example 172 with aqueous dimethylamine. Found: M+H=448.
The preparation of 4-(2-chlorophenyl)-9-hvdroxy-6-r3-(lH-imidazol-l- yl)propyllpyrrolor3,4-clcarbazole-1.3(2H.6H)-dione (VIII, Ar=2-chlorophenyl, n=3, Z=1H- imidazol-1-yl) (87) by reaction of bromo prepared as described in example 172 with imidazole. Found: M+H=471. The preparation of 4-(2-chlorophenyl)-9-hvdroxy-6-r3-(4-morpholinyl)propyl1pyrrolor3.4- clcarbazole-1.3(2H,6H)-dione (VIII, Ar=2-chlorophenyl, n=3, Z=4-moφholinyl) (88) by reaction of (58) prepared as described in example 172 with moφholine. Found: M+H=490.
The preparation of 4-(2-ch1orophenyl)-9-hvdroxy-6-r3-(4-methyl-l- piperazinyl)propynpyrrolor3,4-clcarbazole-l,3(2H,6H)-dione (VIII, Ar=2-chlorophenyl, n=3, Z=4-methyl-l -piperazinyl) (89) by reaction of (58) prepared as described in example 172 with 1-methylpiperazine. Found M+H=503.
The preparation of 6-(3-anilinopropyl)-4-(2-chlorophenyl)-9-hvdroxypyrrolor3,4- clcarbazole-1.3(2H,6H)-dione (VIII, Ar=2-chlorophenyl, n=3, Z=anilino) (90) by reaction of (58) prepared as described in example 172 with aniline. Found: M+H=495.
The preparation of 4-(2,6-dichlorophenyl)-9-hydroxy-6-r3- (methv1amino)propyl1pyrrolor3,4-clcarbazole-l,3(2H,6H)-dione (VIII, Ar=2,6- dichlorophenyl, n=3, Z=NHMe) (91) by reaction of (233) prepared as decribed in example 178 with aqueous methylamine. Found: M+H=468.
The preparation of 4-(2,6-dichlorophenyl)-6-r3-(dimethylamino)propyl1-9- hvdroxypyrrolor3,4-c]carbazole-l,3(2H,6H)-dione (VIII, Ar=2,6-dichlorophenyl, n=3, Z=N(CH3)2) (92) by reaction of (233) prepared as decribed in example 178 with aqueous dimethylamine. Found: M+H=482.
The preparation of 4-(2,6-dichlorophenyl)-9-hydroxy-6-r3-(lH-imidazol-l- yl)propynpyrrolor3,4-clcarbazole-l,3(2H,6H)-dione (VIII, Ar=2,6-dichlorophenyl, n=3, Z=lH-imidazol-l-yl) (93) by reaction of (233) prepared as decribed in example 178 with imidazole. Found: M+H=505.
The preparation of 4-(2.6-dichlorophenyl)-9-hydroxy-6-r3-(4- morpholinyl)propynpyrrolor3,4-c1carbazole-l,3(2H,6H)-dione (VIII, Ar=2,6-dichlorophenyl, n=3, Z=4-moφholinyl) (94) by reaction of (233) prepared as decribed in example 178 with moφholine. Found: M+H=524.
The preparation of 4-(2,6-dichlorophenvI)-9-hvdroxy-6-r3-(4-methyl-l- piperazinyl)propyl1pyrrolor3,4-clcarbazole-1.3(2H,6H)-dione (VIII, Ar=2,6-dichlorophenyl, n=3, Z=4-methyl-l -piperazinyl) (95) by reaction of (233) prepared as decribed in example 178 with 1-methylpiperazine. Found M+H=537. The preparation of 6-(3-ani1inopropyl)-4-(2.6-dichlorophenyl)-9-hvdroxypyrrolor3.4- clcarbazole-1 ,3(2H,6H)-dione (VIII, Ar=2,6-chlorophenyl, n=3, Z=anilino) (96) by reaction of (233) prepared as decribed in example 178 with aniline. Found: M+H=530.
EXAMPLE 199
Combinatorial Procedure for Aniline Displacements of Br and OMs
To a 8 ml screw cap vial was added a solution of 6-(3-Bromopropyl)-4-(chloro- phenyl)-9-hydroxy-6H-pyrrolo[3,4-c]carbazole-l,3-dione (reagent A), (0.048 g, 0.1 mmol) prepared as described in example 83 or 2-(9-Hydroxy-l,3-dioxo-4-phenyl-2,3- dihydropyrrolo[3,4-c]carbazol-6(lH)-yl)ethyl methanesulfonate (205) prepared as described in example 174 (reagent B) (See table 2) in anhydrous dimethylacetamide (1 ml), a solution of the appropriate aniline (0.012 g, 0.1 mmol) in anhydrous dimethylacetamide (0.150 ml). The vial was capped and the reaction mixture was shaken for 18 hours at 100°C. After cooling to room temperature, the solvent was removed under vacuum. Purification was carried out via reverse-phase HPLC (3% n-propanol in acetonitrile and 3% n-propanol in water as the eluent; C-18 column). The compounds were analysed by mass spectral analysis.
Table 2 Compounds made combinatorially bv reaction of the appropariate commercial anilines
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000140_0001
Figure imgf000141_0001
Figure imgf000142_0001
Figure imgf000143_0001
EXAMPLE 200
The preparation of 4-(2-Chlorophenyl)-9-hydroxy-6-r3-(methylsulfanyl)propyl1pyrrolor3.4- c1carbazole-1.3(2H,6H)-dione (Viπ; Ar=2-chlorophenyl, n=3. Z=SCHV) (130)
A mixture of the bromide (58) (60.0 mg, 0.124 mmol) prepared as described in example 172 and lithium thiomercaptide (13 mg, 0.2481 mmol) in p-dioxane (5 mL) was refluxed for 16 h. A further 10 mg of LiSMe was added and refluxing was continued for a further 9 h. The mixture was diluted with water, extracted with ethyl acetate. The organic layer was dried, the drying agent was removed and the solution was concentrated to drynessto give the sulfide (130 directly (47.1 mg, 84%) which crystallised from ethyl acetate/petroleum ether as an orange powder, mp 218-220 °C. Η NMR δ [(CD3)2SO] 11.07 (br s, IH), 9.39 (br s, IH), 8.39 (d, J=2.4 Hz, IH), 7.80 (s, IH), 7.61-7.56 (m, 2H), 7.53-7.43 (m, 3H), 7.15 (dd, J=8.8, 2.4 Hz, IH), 4.52 (t, J=6.9 Hz, 2H), 2.45 (t, J=7.0 Hz, 2H), 2.01 (m, 2H), 2.00 (s, 3H). FABMS found [M+H]+: 453.0840, 451.0859. C24H20ClN2O3S requires 453.0854, 451.0883.
EXAMPLE 201
The preparation of 4-(2-Chlorophenyl)-9-hvdroxy-6-r3-(phenylsu]fanyl)propyl1pyrrolor3,4- clcarbazole-1.3(2H.6H)-dione (VIII: Ar=2-chlorophenyl, n=3, Z=SPh) (131).
A solution of the bromide (58) (41 mg, 0.085 mmol) prepared as described in example 172, thiophenol (9.5 μL, 0.093 mmol) and triethylamine (0.25 mL, 3.40 mmol) in p-dioxane (1.5 mL) was refluxed for 16 h. Water was added and the mixture was extracted with ethyl acetate. The organic layer was dried, the drying agent was removed and the solution was concentrated to dryness the sulfide (131) directly (37.2 mg, 85 %), which crystallised from ethyl acetate/petroleum ether as an orange powder, mp 229-231 °C. H NMR δ [(CD3)2SO] 11.06 (br s, IH), 9.37 (s, IH), 8.37 (d, J=2.4 Hz, IH), 7.76 (s, IH), 7.60-7.42 (m, 5H), 7.25- 7.19 (m, 4H), 7.16-7.10 m, 2H), 4.57 (t, J=6.8 Hz, 2H), 2.98 (m, 2H), 2.01 (m, 2H). Found: C, 67.36; H, 4.29; N, 5.36. C29H2ιClN2S03.l/4H20 requires C, 67.31; H, 4.19; N, 5.41.
EXAMPLE 202
The preparation of 4-(2-Chlorophenyl)-9-hvdroxy-6-(3-methoxypropyl)pyrrolor3.4- clcarbazole-1.3(2H,6H)-dione (VIII; Ar=2-chlorophenyl, n=3, Z=OCH^) (132).
A solution of the bromide (58) (50 mg, 0.103 mmol) prepared as described in example 172 and sodium methoxide (35.2 mg, 0.65 mmol) in methanol (0.5 mL) and p-dioxane (8 mL) was refluxed for 3 h. The solution was acidified with 2N HCI, extracted with ethyl acetate and the organic layer was dried, the drying agent was removed and the solution was concentrated to dryness and chromatographed on silica. Elution with ethyl acetate gave the anhydride, 4-(2-chlorophenyl)-9-hydroxy-6-(3-methoxypropyl)-lH-furo[3,4-c]carbazole- l,3(6H)-dione as an orange powder. Η NMR δ [(CD3)2SO] 9.57 (br, IH), 8.24 (d, J=2.3 Hz, IH), 8.00 (s, IH), 7.66-7.61 (m, 2H), 7.58-7.48 (m, 3H), 7.22 (dd, J=9.0, 2.3 Hz, IH), 4.56 (t, J=6.7 Hz, 2H), 3.22 (t, J=6.0 Hz, 2H), 3.13 (s, 3H), 2.02 (m, 2H). The product was added to molten ammonium acetate (10 g) at 140 °C and the mixture was warmed at this temperature for 3 h. Water was added and the resultant precipitate was filtered off, adsorbed onto silica from a THF solution, and chromatographed. Elution with ethyl acetate/petroleum ether (1:1) gave (132) (32 mg, 71 %) an orange powder, mp 260-262 °C. Η NMR δ [(CD3)2SO] 11.07 (br s, IH), 9.42 (br s, IH), 8.39 (d, J=2.4 Hz, IH), 7.69 (s, IH), 7.60-7.44 (m, 5H), 7.15 (dd, J=8.8, 2.4 Hz, IH), 4.49 (t, J=6.6 Hz, 2H), 3.22 (t, J=6.0 Hz, 2H), 3.13 (s, 3H), 1.99 (m, 2H). FABMS found [M+H]+: 437.1088, 435.1090. C2 H20ClN2O4 requires 437.1082, 435.1112.
Figure imgf000145_0001
SCHEME 4
Scheme 4 Procedures
Representative Procedure for Method 13 of Scheme 4
EXAMPLE 203
The preparation of 3-(9-Methoxy-l,3-dioxo-4-phenyl-2,3-dihvdropyrrolo[3,4-clcarbazol- 6(lH)-yl)propanoic acid (IX; Ar=phenyl, n=2) (243)
Dess-Martin periodinane (1.91 g, 4.5 mmol) was added to a stirred solution of alcohol (202) (1.20 g, 3.0 mmol) prepared as decribed in example 83 in dry tetrahydrofuran (80 mL) under nitrogen. After 1 hour at room temperature a solution of saturated sodium thiosulphate and saturated sodium bicarbonate (1:1, 100 mL) was added and the reaction mixture was stirred vigorously for 15 minutes before being given extracted with ethyl acetate. The organic layer was dried, the drying agent was removed and the solution was concentrated to dryness. The resulting crude aldehyde was then dissolved in tert-butanol/tetrahydrofuran (9:1, 230 mL) and 2-methyl-2-butene was added (12.0 mmol, 6.0 mL of a 2M solution in tetrahydrofuran). To this solution was added a solution of sodium chlorite (1.09 g, 12.0 mmol) and sodium dihydrogen phosphate (2.5 g, 18.0 mmol) in water (100 mL) containing tert-butanol (4 mL). The resulting solution was stirred at room temperature for 18 hours before being diluted with brine and extracted with ethyl acetate. The organic layer was dried, the drying agent was removed and the solution was concentrated to dryness. Chromatography on silica eluting with ethyl acetate/methanol (1:0 to 9:1), followed by crystallisation from ethyl acetate/hexane gave acid (243) (0.86 g, 69%) as a yellow powder, mp 252-255 °C. Η NMR δ [(CD3)2SO] 12.2 (v br s, IH), 11.13 (br s, IH), 8.55 (d, J=2.6 Hz, IH), 7.89 (s, IH), 7.68 (m, 3H), 7.47 (m, 3H), 7.28 (dd, J=9.0, 2.6 Hz, IH), 4.73 (t, J=6.6 Hz, 2H), 3.90 (s, 3H), 2.76 (t, J=6.6 Hz, 2H). Found: C, 67.95; H, 4.37; N, 6.47. C24H18N205.1/2H2) requires C, 68.08; H, 4.52; N, 6.62.
EXAMPLE 204
The preparation of 3-(4-(2,6-Dichlorophenyl)-9-methoxy-l,3-dioxo-2.3-dihydropyrrolor3.4- c1carbazol-6(lH)-yl)propanoic acid (IX; Ar=2,6-dichlorophenyl, n=2) (244)
Oxidation of alcohol (232) prepared as decribed in example 86 (0.50 g, 1.1 mmol) according to the procedure decrsibed in example 203 , followed by chromatography on silica eluting with methanol/dichloromethane (3:97 to 1:9) and trituration from ethyl acetate/hexane gave acid (244) (0.35 g, 66%) as a yellow powder, mp 203-209 °C. !H NMR δ [(CD3)2SO] 12.3 (v br s, IH), 11.19 (br s, IH), 8.50 (d, J=2.6 Hz, IH), 7.94 (s, IH), 7.74 (d, J=9.0 Hz, IH), 7.62 (m, 2H), 7.51 (dd, J=13.3, 6.1 Hz, IH), 7.33 (dd, J=9.0, 2.6 Hz, IH), 4.71 (t, J=6.9 Hz, 2H), 3.91 (s, 3H), 2.75 (t, J=6.9 Hz, 2H). Found: C, 59.74; H, 3.62; N, 5.65. C24Hι6Cl2N205 requires: C, 59.63; H, 3.34; N, 5.79. EXAMPLE 205
The preparation of 3-(4-(2-Ch1oro-6-methoxyphenyl)-9-methoxy-l,3-dioxo-2.3- dihvdropyrrolof3clcarbazol-6(lH)-yl)propanoic acid (IX; Ar=2-chloro-6-methoxyρhenyl. n=2) (245)
Oxidation of alcohol (105) (2.1 g, 4.5 mmol) prepared as described in example 58 according to the procedure decrsibed in example 203 gave acid (245) (0.81 g, 38%) as a yellow powder, mp 241-243 °C. Η NMR δ [(CD3)2SO] 12.5 (v br s, IH), 11.07 (br s, IH), 8.50 (d, J=2.6 Hz, IH), 7.82 (s, IH), 7.70 (d, J=9.0 Hz, IH), 7.44 (t, J=8.3 Hz, IH), 7.30 (dd, J=9.0, 2.6 Hz, IH), 7.18 (d, J=8.3 Hz, IH), 7.12 (d, J=8.3 Hz, IH), 4.68 (t, J=6.8 Hz, 2H), 3.90 (s, 3H), 3.68 (s, 3H), 2.71 (t, J=6.8 Hz, 2H). Found: C, 62.71; H, 4.09; N, 5.62. C25Hι9ClN206 requires C, 62.70; H, 4.00; N, 5.85.
EXAMPLE 206
The preparation of 3-(4-(2,6-Dichlorophenyl)-9-hvdroxy-l,3-dioxo-2,3-dihydropyrrolor3,4- clcarbazol-6(lH)-yl .propanoic acid (X; Ar=2,6-dichIorophenyl, n=2) (246)
Demethylation of acid (244) (90 mg, 0.19 mmol) prepared as described in example 204 employing the procedure described in example 80 gave phenol (246) (63 mg, 71%) as an orange/yellow powder, mp 245-253 °C (dec). Η NMR δ [(CD3)2S0] 12.2 (v br s, IH), 11.13 (br s, IH), 9.40 (br s, IH), 8.36 (d, J=2.5 Hz, IH), 7.88 (s, IH), 7.62 (m, 3H), 7.50 (dd, J=8.7, 7.3 Hz, IH), 7.15 (dd, J=8.9, 2.5 Hz, IH), 4.66 (t, J=6.9 Hz, IH), 2.73 (t, J=6.9 Hz, 2H). Found: C, 58.98; H, 3.31; N, 5.81. C23Hι4Cl2N205 requires: C, 58.85; H, 3.01; N, 5.97.
Representative Procedure for Method 14 of Scheme 4
EXAMPLE 207
The preparation of N-r2-(Dimethylamino)ethyl1-3-(9-methoxy-l,3-dioxo-4-phenyl-2,3- dihvdropyrrolor3,4-c1carbazoI-6(lH)-yl)propanamide (XI; Ar=phenyl, n=2, R =H, R4=CH?CH,N(CH ?) (247)
To a solution of acid (243) (100 mg, 0.24 mmol) prepared as described in example 203 in dry tetrahydrofuran (20 mL) under nitrogen was added 1 drop of dimethylformamide, followed by oxalyl chloride (84 uL, 0.96 mmol) dropwise. The resulting solution was stirred at room temperature for 2 hours before being reduced to dryness in vacuo. Dry benzene (20 mL) was added to the residue and the suspension was again reduced to dryness in vacuo, before being dissolved in dry tetrahydrofuran (20 uL) and flushed with nitrogen. To this solution was added dimethylethylenediamine (105mL, 0.96 mmol) via syringe. The reaction mixture was stirred at room temperature for 2 hours and then diluted with water, basified by the addition of solid potassium carbonate and extracted with ethyl acetate. The organic layer was dried, the drying agent was removed and the solution was concentrated to dryness. Chromatography on silica eluting with ethyl acetate/methanol/triethylamine (1:0:0 to 3:l :trace) followed by crystallization from ethyl acetate/hexane, gave amide (247) (85 mg, 73%) as a yellow powder, mp 206-210 °C. Η NMR δ [(CD3)2SO] 11.11 (br s, IH), 8.54 (d, J=2.6 Hz, IH), 7.81 (s, IH), 7.73 (t, J=5.6 Hz, IH), 7.67 (m, 3H), 7.48 (m, 3H), 7.29 (dd, J=8.9, 2.6 Hz, IH), 4.73 (t, J=6.3 Hz, 2H), 3.89 (s, 3H), 2.93 (dd, J=6.8, 5.6 Hz, 2H), 2.59 (t, J=6.3 Hz, 2H), 1.90 (s, 6H), 1.84 (t, J=6.8 Hz, 2H). Found: C, 67.02; H, 5.80; N, 11.17. C28H28N404.H20 requires: C, 66.92; H, 6.02; N, 11.14.
EXAMPLE 208
The— preparation of 3-(9-Methoxy-l,3-dioxo-4-phenyl-2.3-dihvdropyrrolor3.4-c1carbazol- 6(lH)-yl)propanamide (XI; Ar=phenyl. n=2. R3=H, R4=H) (248)
Reaction of acid (243) (100 mg, 0.24 mmol) prepared as described in example 203 according to the procedure described in example 207 , except that a saturated solution of ammonia gas in tetrahydrofuran (20 mL) was added as the amine, gave amide (248) (61 mg, 62%) as a yellow powder, mp 266-270 °C. Η NMR δ [(CD3)2SO] 11.11 (br s, IH), 8.55 (d, J=2.6 Hz, IH), 7.87 (s, IH), 7.68 (m, 3H), 7.48 (m, 3H), 7.33 (br s, IH), 7.29 (dd, J=9.0, 2.6 Hz, IH), 6.85 (br s, IH), 4.71 (t, J=6.5 Hz, 2H), 3.90 (s, 3H), 2.60 (t, J=6.5 Hz, 2H). Found: C, 68.36; H, 4.70; N, 9.99. C24H19N304.1/2H20 requires: C, 68.24; H, 4.78; N, 9.94.
EXAMPLE 209
The preparation of 3-(4-(2-Ch1orophenyl)-9-methoxy-l,3-dioxo-2,3-dihydropyrroIor3.4- c1carbazol-6(lH)-yl)-N-r2-(dimethylamino)ethvnpropanamide (XI; Ar=2-chlorophenyl, n=2, R3=H. R4=CH,CH?N(CH.)?) (249)
Reaction of acid (116) (95 mg, 0.21 mmol) prepared as described in example 229 according to the procedure described in example 207 , followed by trituration in diethyl ether, gave amide (249) (76 mg, 70%) as a yellow powder, mp 250-252 °C. Η NMR δ [(CD3)2SO] 11.12 (br s, IH), 8.51 (d, J=2.6 Hz, IH), 7.77 (s, IH), 7.76 (partially obscured t, J=5.9 Hz, IH), 7.68 (d, J=9.0 Hz, IH), 7.58 (m, 2H), 7.48 (m, 3H), 7.32 (dd, J=9.0, 2.6 Hz, IH), 4.71 (t, J=6.4 Hz, 2H), 3.90 (s, 3H), 2.95 (m, 2H), 2.58 (t, J=6.4 Hz, 2H),1.94 (s, 6H), 1.93 (partially obscured t, J=6.8 Hz, 2H). Found: C, 64.88; H, 5.56; N, 10.70. C28H27C1N404 requires: C, 64.79; H, 5.24; N, 10.79.
EXAMPLE 210
The preparation of 3-(4-(2,6-Dichlorophenyl)-9-methoxy-l,3-dioxo-2,3-dihvdropyrrolor3.4- clcarbazol-6(lH)-yl)propanamide (XI; Ar=2,6-dichlorophenyl. n=2. R3=H. R4=H) (250)
Reaction of acid (244) (0.23 g, 0.48 mmol) prepared as described in example 204 according to the procedure described in example 207 , except that concentrated ammonia (-30%, 20 mL) was added as the amine, gave amide (250) (0.17 g, 73%) as a yellow powder, mp 261-264 °C. Η NMR δ [(CD3)2SO] 11.19 (br s, IH), 8.50 (d, J=2.6 Hz, IH), 7.87 (s, IH), 7.73 (d, J=9.0 Hz, IH), 7.63 (m, 2H), 7.52 (dd, J=8.8, 7.3 Hz, IH), 7.38 (br s, IH), 7.33 (dd, J=9.0, 2.6 Hz, IH), 6.87 (br s, IH), 4.69 (t, J=6.7 Hz, 2H), 3.91 (s, 3H), 2.57 (t, J=6.7 Hz, 2H). Found: C, 59.55; H, 3.79; N, 8.73. C24HπCl2N304 requires: C, 59.75; H, 3.55; N, 8.71.
EXAMPLE 211
The preparation of 3-(4-(2,6-DichlorophenvI)-9-methoxy-l,3-dioxo-2,3-dihvdropyrrolor3.4- c1carbazo1-6(lH)-yl)-N-r2-(dimethylamino)ethyllpropanamide (XI; Ar=2.6-dichlorophenyl. n=2, R3=H, R =CH?CH7N(CHO?) (251)
Reaction of acid (244) (150 mg, 0.30 mmol) prepared as described in example 204 according to the procedure described in example 207 , gave amide (251) (91 mg, 55%) as a yellow powder, mp 141-146 °C. 1H NMR δ [(CD3)2SO] 11.19 (br s, IH), 8.50 (d, J=2.6 Hz, IH), 7.82 (s, IH), 7.81 (partially obscured t, J=5.6 Hz, IH), 7.69 (d, J=9.0 Hz, IH), 7.62 (m, 2H), 7.52 (dd, J=8.8, 7.4 Hz, IH), 7.34 (dd, J=9.0, 2.6 Hz, IH), 4.71 (t, J=6.4 Hz, 2H), 3.90 (s, 3H), 2.95 (q, J=6.2 Hz, 2H), 2.58 (t, J=6.4 Hz, 2H), 2.07 (m, 2H), 2.02 (s, 6H). Found: C, 59.13; H, 4.73; N, 9.87. C28H26C12N404.H20 requires C, 58.85; H, 4.94; N, 9.80.
EXAMPLE 212
The preparation of 3-(4-(2-Chloro-6-methoxyphenyl)-9-methoxy-l,3-dioxo-2,3- dihvdropyrrolor3,4-clcarbazol-6(lH)-yl)-N-r2-(dimethylamino)ethyllpropanamide (XI; Ar=2-chloro-6-methoxyphenyl. n=2. R3=H, R4=CH7CH7N(CHτb) (252)
Reaction of acid (245) prepared as described in example 205 (160 mg, 0.33 mmol) according to the procedure described in example 207 , gave amide (252) (93 mg, 51%) as a yellow powder, mp 164-169 °C. Η NMR δ [(CD3)2SO] 11.06 (br s, IH), 8.50 (d, J=2.6 Hz, IH), 7.80 (t, J=5.6 Hz, IH), 7.72 (s, IH), 7.66 (d, J=9.0 Hz, IH), 7.45 (t, J=8.3 Hz, IH), 7.30 (dd, J=9.0, 2.6 Hz, IH), 7.18 (d, J=8.3 Hz, IH), 7.13 (d, J=8.3 Hz, IH), 4.68 (t, J=6.4 Hz, 2H), 3.90 (s, 3H), 3.68 (s, 3H), 2.98 (dd, J=6.6, 5.6 Hz, 2H), 2.56 (t, J=6.4 Hz, 2H), 2.05 (t, J=6.6 Hz, 2H), 1.90 (s, 6H). Found: C, 61.32; H, 5.28; N, 9.91. C29H29C1N405.H20 requires: C, 61.43; H, 5.51; N, 9.88.
EXAMPLE 213
The preparation of 3-(4-(2-Chlorophenyl)-9-methoxy-1.3-dioxo-2,3-dihvdropyrrolor3,4- clcarbazol-6(lH)-yl)-N-(lH-tetraazol-5-yl)propanamide (XI; Ar=2-chlorophenyl. n=2, R3=H. R4=5-tetrazolyl) (253)
Reaction of acid (116) (70 mg, 0.16 mmol) prepared as described in example 229 according to the procedure described in example 207 , except that solid 5-aminotetrazole (27 mg, 0.31 mmol) was added as the amine and the reaction was heated at reflux for 2 hours before work-up, gave amide (253) (52 mg, 63%) as a yellow powder, mp 232 °C (dec). 1H NMR δ [(CD3)2SO] 15.8 (v br s, IH), 11.90 (br s, IH), 11.13 (br s, IH), 8.52 (d, J=2.6 Hz, IH), 7.84 (s, IH), 7.75 (d, J=9.0 Hz, IH), 7.57 (d, J=7.4 Hz, IH), 7.50-7.40 (m, 3H), 7.30 (dd, J=9.0, 2.6 Hz, IH), 4.83 (t, J=6.8 Hz, 2H), 3.90 (s, 3H), 2.97 (t, J=6.8 Hz, 2H). FABMS found [M=H]+=516.1174, 518.1154. C25H,8C1N704 requires 516.1187, 518.1158.
EXAMPLE 214
The preparation of N-r2-(Dimethv1amino)ethyl1-3-(9-hvdroxy-l,3-dioxo-4-phenyl-2.3- dihvdropyrrolor3,4-c1carbazol-6(lH)-yl)propanamide (XIII; Ar=phenyl, n=2, R3=H, R4=CH.CH.N(CHO?) (254)
Reaction of methyl ether (247) (70 mg, 0.14 mmol) ) prepared as described in example 207 according to the procedure described in example 81, except that the reaction mixture was diluted with water, basified by the addition of concentrated ammonia and extracted with ethyl acetate. The organic layer was dried, the drying agent was removed and the solution was concentrated to dryness. Chromatography on silica eluting with ethyl acetate/methanol/triethylamine (1:0:0 to 3: l :trace). Crystallization from ethyl acetate/hexane then gave amide (254) (35 mg, 53%) as an orange powder, mp 176-180 °C. Η NMR δ [(CD3)2SO] 11.06 (br s, IH), 9.35 (br s, IH), 8.39 (d, J=2.5 Hz, IH), 7.77 (s, IH), 7.74 (t, J=5.6 Hz, IH), 7.66 (m, 2H), 7.53 (d, J=8.8 Hz, IH), 7.48 (m, 3H), 7.12 (dd, J=8.8, 2.5 Hz, 1H), 4.69 (t, J=6.4 Hz, 2H), 2.94 (m, 2H), 2.58 (t, J=6.4 Hz, 2H), 1.91 (s, 6H), 1.87 (m, 2H). Found: C, 66.87; H, 5.83; N, 11.47. C27H26N404.3/4H20 requires: C, 67.00; H, 5.73; N, 11.57.
EXAMPLE 215
The preparation of 3-(9-Hvdroxy-l,3-dioxo-4-pheny1-2,3-dihvdropyrrolor3,4-c1carbazol- 6(lH)-yl)propanamide (XIII; Ar=phenyl. n=2, R,-=H. R,=H) (255) and 3-(9-hvdroxy-1.3- dioxo-4-phenyl-2,3-dihydropyrrolof3,4-clcarbazol-6(lH)-yl)propanoic acid (X; Ar=phenyl. n=2) (256)
Reaction of methyl ether (248) (56 mg, 0.14 mmol) ) prepared as described in example 208 according to the procedure described in example 81, followed by chromatography on silica eluting with ethyl acetate/hexane (4:1) to ethyl acetate/methanol (9:1) gave initially, amide (255) (11 mg, 20%) as an orange powder, mp 284-288 °C. 1H NMR δ [(CD3)2SO] 11.05 (br s, IH), 9.33 (br s, IH), 8.40 (d, J=2.5 Hz, IH), 7.82 (s, IH), 7.67 (m, 2H), 7.56 (d, J=8.8 Hz, IH), 7.47 (m, 3H), 7.34 (br s, IH), 7.12 (dd, J=8.8, 2.5 Hz, IH), 6.86 (br s, IH), 4.67 (t, J=6.5 Hz, 2H), 2.58 (t, J=6.5 Hz, 2H). FABMS found [M+H]+: 400.1307. C23H17N304 requires 400.1297. This was followed at lower Rf by the acid (256) (34 mg, 63%) as an orange powder, mp 300-310 °C (dec). ]H NMR δ [(CD3)2SO] 12.1 (v br s, IH), 11.06 (br s, IH), 9.34 (br s, IH), 8.40 (d, J=2.4 Hz, IH), 7.84 (s, IH), 7.67 (m, 2H), 7.57 (d, J=8.8 Hz, IH), 7.46 (m, 3H), 7.12 (dd, J=8.8, 2.4 Hz, IH), 4.69 (t, J=6.7 Hz, 2H), 2.75 (t, J=6.7 Hz, 2H). Found: C, 67.64; H, 4.29; N, 6.65. C23Hι6N205.l/2H20 requires: C, 67.48; H, 4.19; N, 6.84.
EXAMPLE 216
The preparation of 3-(4-(2-Chlorophenyl)-9-hvdroxy-l,3-dioxo-2,3-dihvdropyrrolo[3.4- c1carbazol-6(lH)-yl)-N-[2-(dimethylamino)ethyllpropanamide (XIII; Ar=2-chlorophenyl. n=2. R3=H. R4=CH7CH,N(CH2)2) (257)
Reaction of methyl ether (249) (65 mg, 0.13 mmol) prepared as described in example 209 according to the proceedure described in example 81, except that the reaction mixture was diluted with water, basified by the addition of concentrated ammonia and extracted with ethyl acetate, The organic layer was dried, the drying agent was removed and the solution was concentrated to dryness. Chromatography on silica eluting with ethyl acetate/methanol/triethylamine (1:0:0 to 3:l :trace). Crystallization from ethyl acetate/hexane then gave amide (257) (28 mg, 44%) as an orange powder, mp 205-215 °C. Η NMR δ [(CD3)2SO] 11.06 (br s, IH), 9.35 (s, IH), 8.37 (d, J=2.3 Hz, IH), 7.81 (br s, IH), 7.72 (s, IH), 7.57 (m, 2H), 7.48 ( , 3H), 7.14 (dd, J=8.9, 2.3 Hz, IH), 4.67 (t, J=6.4 Hz, 2H), 2.99 (m, 2H), 2.57 (t, J=6.4 Hz, 2H), 2.03 (m, 8H). Found: C, 61.32; H, 5.49; N, 10.72. C27H25C-.N4O4.1V4H2O requires: C, 61.47; H, 5.26; N, 10.62.
EXAMPLE 217
The preparation of 3-(4-(2,6-Dichlorophenyl)-9-hvdroxy-l,3-dioxo-2,3-dihvdropyrrolor3,4- c]carbazol-6(lH)-yl .propanamide (XIII; Ar=2,6-dichlorophenyl, n=2, R3=H, R4=H) (258)
Reaction of methyl ether (250) (80 mg, 0.17 mmol) ) prepared as described in example 210 according to The procedure described in example 80, followed by chromatography on silica eluting with ethyl acetate then tetrahydrofuran and trituration from ethyl acetate, gave amide (258) (47 mg, 59%) as an orange powder, mp 327-329 °C. Η NMR δ [(CD3)2SO] 11.12 (br s, IH), 9.39 (s, IH), 8.36 (d, J=2.4 Hz, IH), 7.82 (s, IH), 7.61 (m, 3H), 7.51 (dd, J=8.8, 7.4 Hz, IH), 7.38 (br s, IH), 7.15 (dd, J=8.9, 2.4 Hz, IH), 6.87 (br s, IH), 4.65 (t, J=6.7 Hz, 2H), 2.55 (t, J=6.7 Hz, 2H). Found: C, 57.75; H, 3.83; N, 8.50. C23Hι5Cl2N304.3/4H20 requires: C, 57.33; H, 3.45; N, 8.72.
EXAMPLE 218
The preparation of 3-(4-(2,6-Dichlorophenyl)-9-hvdroxy-l,3-dioxo-2,3-dihvdropyrrolof3,4- clcarbazol-6(lH)-yl)-N-r2-(dimethylamino)ethvnpropanamide (XIII; Ar=2,6-dichlorophenyl,
Figure imgf000152_0001
Reaction of methyl ether (251) (70 mg, 0.13 mmol) ) prepared as described in example 211 according to The procedure described in example 80, except that the reaction time was 6 hours and chromatography was performed eluting with ethyl acetate/methanol triethylamine (1 :0:0 to 3:l :trace), gave amide (259) (31 mg, 45%) as a yellow powder, mp 220-226 °C. Η NMR δ [(CD3)2SO] 11.13 (br s, IH), 9.39 (s, IH), 8.36 (d, J=2.5 Hz, IH), 7.84 (t, J=5.4 Hz, IH), 7.76 (s, IH), 7.62 (m, 2H), 7.58 (d, J=8.9 Hz, IH), 7.51 (dd, J=8.9, 7.4 Hz, IH), 7.16 (dd, J=8.9, 2.5 Hz, IH), 4.67 (t, J=6.5 Hz, 2H), 3.03 (m, 2H), 2.57 (t, J=6.5 Hz, 2H), 2.16 (br s, 2H), 2.08 (m, 6H). Found: C, 58.09; H, 4.44; N, 9.72. C27H24C12N404.H20 requires: C, 58.18; H, 4.70; N, 10.05. EXAMPLE 219
The preparation of 3-(4-(2-Chloro-6-methoxyphenyl)-9-hvdroxy-1.3-dioxo-2,3- dihydropyrrolor3.4-c1carbazol-6(lH)-yl)-N-r2-(dimethylamino)ethyllpropanamide (XIII: Ar--2-chloro-6-methoχyphenyl. n=2. R3=H. R4=CH7CH,N(CHO?) (260)
Reaction of methyl ether (252) prepared as described in example 212 (80 mg, 0.15 mmol) according to The procedure described in example 80, except that the reaction was performed at 0 °C for 2 hours and chromatography was performed eluting with ethyl acetate/methanol/triethylamine (1:0:0 to 3:l:trace), gave amide (260) (65 mg, 83%) as a yellow/orange powder, mp 200-205 °C. 1H NMR δ [(CD3)2SO] 11.00 (br s, IH), 9.34 (s, IH), 8.36 (d, J=2.4 Hz, IH), 7.87 (br s, IH), 7.66 (s, IH), 7.54 (d, J=8.9 Hz, IH), 7.44 (t, J=8.2 Hz, IH), 7.18 (dd, J=8.2, 0.7 Hz, IH), 7.12 (m, 2H), 4.64 (t, J=6.6 Hz, 2H), 3.68 (s, 3H), 3.05 (m, 2H), 2.56 (t, J=6.6 Hz, 2H), 2.23 (v br s, 2H), 2.15 (br s, 6H). Found: C, 58.98; H, 5.12; N, 9.59. C28H27C1N405.2H20 requires: C, 58.90; H, 5.47; N, 9.81.
EXAMPLE 220
The preparation of N-r2-(Dimethylamino)ethvH-3-(9-hvdroxy-4-(2-methoxyphenyl)-l,3- dioxo-2,3-dihvdropyrrolor3.4-clcarbazol-6(lH)-yl)propanamide (XIII; Ar=2-methoxyphenyl, n=2. R3=H. R4=CH?CH,N(CHV)2) (330)
To a solution of amide (260) (40 mg, 0.07 mmol) ) prepared as described in example 219 in ethyl acetate/methanol (1:1, 80 mL) was added 5% Pd-C (catalytic). The resulting suspension was hydrogenated at 60 psi with stirring for 4 days, with additional portions of Pd-C being added every 24 hours. The reaction mixture was then filtered through celite and concentrated under reduced pressure before being chromatographed on silica eluting with methanol ethyl acetate/triethylamine (l:4:trace), to give amide (330) (6 mg, 16%) as a yellow powder, mp 232-238 °C. Η NMR δ [(CD3)2SO] 10.95 (br s, IH), 9.33 (br s, IH), 8.37 (d, J=2.4 Hz, IH), 8.01 (br s, IH), 7.69 (s, IH), 7.54 (d, J=8.9 Hz, IH), 7.43 (m, IH), 7.34 (dd, J=7.5, 1.8 Hz, IH), 7.13-7.05 (m, 3H), 4.67 (t, J=6.2 Hz, 2H), 3.69 (s, 3H), -3.2 (obscured m, 2H), 2.60 (t, J=6.2 Hz, 2H), 2.54-2.49 (obscured m, 8H). FABMS found [M+H]+: 501.2142. C28H28N405 requires 501.2138. EX AMPLE 221
The preparation of 3-(4-(2-Chlorophenyl)-9-hvdroxy-l .3-dioxo-2.3-dihydropyrrolor3.4- clcarbazol-6(lH)-yl)-N-(IH-tetraazol-5-yl)propanamide (XIII; Ar=2-chlorophenyl, n=2. R3=H, R4=5-tetrazolyl) (261)
Reaction of methyl ether (253) (40 mg, 0.08 mmol) ) prepared as described in example 213 according to the procedure described in example 80, except that the chromatography was performed eluting with ethyl acetate/methanol (1 :0 to 9:1), gave amide (261) (11 mg, 27%) as an orange powder, mp 283 °C (dec). Η NMR δ [(CD3)2SO] 15.82 (br s, IH), 12.03 (br s, IH), 11.08 (s, IH), 9.38 (s, IH), 8.37 (d, J=2.3 Hz, IH), 7.79 (s, IH), 7.62 (d, J=8.8 Hz, IH), 7.56 (d, J=7.6 Hz, IH), 7.49-7.38 (m, 3H), 7.13 (dd, J=8.8, 2.3 Hz, IH), 4.80 (t, J=6.7 Hz, 2H), 2.96 (t, J=6.7 Hz, 2H). FABMS found M+: 501.0955, 503.0956. C24Hι6ClN704 requires 501.0952, 503.0923.
Representative Procedure for Method 15 of Scheme 4
EXAMPLE 222
The preparation of N-r3-(4-(2-Chlorophenyl)-9-methoxy-l,3-dioxo-2,3-dihydropyrrolor3,4- c1carbazol-6(lH)-yl)propanoyllmethanesulfonamide (XII; Ar=2-chlorophenyl, n=2, R3-=CHV) (265)
To a stirred solution of acid (116) (0.20 g, 0.45 mmol) prepared as described in example 229, 4-dimethylaminopyridine (DMAP) (165 mg, 1.35 mmol) and methanesulfonamide (86 mg, 0.90 mmol) in dimethylformamide (10 mL) under nitrogen was added l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI.HC1) (259 mg, 1.35 mmol). The resulting mixture was stirred at room temperature for 18 hours and then diluted with water, acidified by the addition of IN hydrochloric acid and extracted with ethyl acetate. The organic phase was dried, the drying agent was removed and the solution was concentrated to dryness. Chromatography on silica eluting with ethyl acetate/hexane (4:1) to ethyl acetate/methanol (1 :0 to 9:1), gave acylsulfonamide (265) (151 mg, 64%) as a yellow powder, mp 293-295 °C. Η NMR δ [(CD3)2SO] 11.76 (br s, IH), 11.14 (br s, IH), 8.52 (d, J=2.6 Hz, IH), 7.87 (s, IH), 7.73 (d, J=9.0 Hz, IH), 7.58 (m, IH), 7.53-7.46 (m, 3H), 7.32 (dd, J=9.0, 2.6 Hz, IH), 4.74 (t, J=6.9 Hz, 2H), 3.91 (s, 3H), 3.08 (s, 3H), 2.81 (t, J=6.9 Hz, 2H). Found: C, 57.30; H, 3.87; N, 7.72. C25H20ClN3O6S requires: C, 57.08; H, 3.83; N, 7.99. EXAMPLE 223
The preparation of N-r3-(4-(2-Chlorophenyl)-9-hydroxy-l,3-dioxo-2,3-dihvdropyrrolor3.4- c1carbazol-6(lH)-yl)propanoyllbenzenesulfonamide (XIV; Ar=2-chlorophenyl, n=2. R3=Ph) (266)
Reaction of acid (116) (70 mg, 0.16 mmol) prepared as described in example 229 with benzenesulfonamide according to the procedure described in example 222 followed by demethylation employing the procedure described in example 80 and chromatography on silica eluting with ethyl acetate/hexane (1:1 to 3:1), gave acylsulfonamide (266) (63 mg, 70%) as an orange powder, mp 291-293 °C. Η NMR δ [(CD3)2SO] 12.15 (br s, IH), 11.07 (br s, IH), 9.36 (s, IH), 8.35 (d, J=2.4 Hz, IH), 7.81 (m, 2H), 7.76 (s, IH), 7.65 (m, IH), 7.57-7.46 (m, 7H), 7.06 (dd, J=8.9, 2.4 Hz, IH), 4.59 (m, 2H), 2.75 (t, J=7.1 Hz, 2H). Found: C, 60.62; H, 3.80; N, 7.20. C29H20ClN3O6S requires: C, 60.68; H, 3.51; N, 7.32.
EXAMPLE 224
The preparation of N-r3-(4-(2-chlorophenyl)-9-methoxy-l,3-dioxo-2.3-dihvdropyrrolor3.4- c1carbazol-6(-lH)-yl)propanoyl-l-2-(dimethylamino)ethanesulfonamide (XII; Ar=2- chlorophenyl. n=2, R3=CH7CH7N(CH?)2) (267)
Reaction of acid (116) (70 mg, 0.16 mmol) prepared as described in example 229 with 2-(dimethylamino)ethanesulfonamide according to the procedure described in example 222, except that the reaction mixture was diluted with brine before being extracted with ethyl acetate. The organic phase was dried, the drying agent was removed and the solution was concentrated to dryness. and the chromatography was performed eluting with ethyl acetate/methanol (1:0 to 4:l),gave acylsulfonamide (267) (43 mg, 47%) as a yellow powder, mp 208-213 °C. Η NMR δ [(CD3)2SO] 11.11 (br s, IH), 8.52 (d, J=2.6 Hz, IH), 7.80 (s, IH), 7.72 (d, J=9.0 Hz, IH), 7.57 (m, 2H), 7.47 (m, 2H), 7.31 (dd, J=9.0, 2.6 Hz, IH), 4.68 (m, 2H), 3.90 (s, 3H), 3.23 (partially obscured m, 2H), 2.87 (t, J=6.9 Hz, 2H), 2.62 (t, J=6.8 Hz, 2H), 2.43 (s, 6H). Found: C, 59.44; H, 5.57; N, 8.52. C28H27C1N406S.1/20^,4 requires: C, 59.47; H, 5.47; N, 8.95. EXAMPLE 225
The preparation of N-r4-(4-(2-Chlorophenyl)-9-hvdroxy-l,3-dioxo-2,3-dihvdropyrrolor3.4- c1carbazol-6(lH)-yl)butanovnmethanesulfonamide (XTV; Ar=2-chlorophenyl, n=3, R3=CΗV) (268}
Reaction of acid (262) (50 mg, 0.11 mmol) prepared as described in example 87 according to The procedure described in example 222 followed by demethylation employing the procedure described in example 80 and chromatography on silica eluting with ethyl acetate/hexane (1 :1 to 3: 1), gave acylsulfonamide (268) (29 mg, 51%) as an orange powder, mp 257-260 °C. Η NMR δ [(CD3)2SO] 11.66 (br s, IH), 11.06 (br s, IH), 9.37 (s, IH), 8.38 (d, J=2.4 Hz, IH), 7.79 (s, IH), 7.61-7.45 (m, 5H), 7.15 (dd, J=8.8, 2.4 Hz, IH), 4.45 (t, J=7.2 Hz, 2H), 3.10 (s, 3H), 2.32 (m, 2H), 1.97 (m, 2H). Found: C, 57.40; H, 3.94; N, 7.73. C25H20ClN3O6S requires: C, 57.09; H, 3.83; N, 7.99.
EXAMPLE 226
The preparation of N-r4-(4-(2-Chlorophenyl)-9-hvdroxy-l,3-dioxo-2,3-dihvdropyrrolor3,4- clcarbazol-6(lH)-yl)butanoyllbenzenesulfonamide (XIV; Ar=2-chlorophenyl, n=3, R3=Ph) (269)
Reaction of acid (262) (45 mg, 0.10 mmol) prepared as described in example 87 with benzenesulfonamide according to the procedure described in example 222 followed by demethylation employing the procedure described in example 80 and chromatography on silica eluting with ethyl acetate/hexane (1:1 to 3:1), gave acylsulfonamide (269) (39 mg, 68%) as an orange powder, mp 224-230 °C. Η NMR δ [(CD3)2SO] 12.09 (br s, IH), 11.05 (br s, IH), 9.36 (s, IH), 8.36 (d, J=2.4 Hz, IH), 7.88 (m, 2H), 7.73 (s, IH), 7.67 (m, IH), 7.57 (m, 3H), 7.52-7.43 (m, 4H), 7.09 (dd, J=8.8, 2.4 Hz, IH), 4.33 (t, J=7.3 Hz, 2H), 2.29 (t, J=7.2 Hz, 2H), 1.86 (m, 2H). Found: C, 61.10; H, 3.81; N, 6.91. C30H22ClN3O6S requires: C, 61.28; H, 3.77; N, 7.15.
EXAMPLE 227
The preparation of N-r3-(4-(2-Chlorophenyl)-9-hvdroxy-1.3-dioxo-2,3-dihvdropyrrolor3,4- clcarbazol-6(lH)-yl)propanoyllmethanesulfonamide (XTV; Ar=2-chlorophenyI, n=2. R3=CH (270) Reaction of methyl ether (265) (130 mg, 0.25 mmol) prepared according to example 222 according to the procedure described in example 80, except that the chromatography was performed eluting with methanol/dichloromethane (5:95 to 1:9), gave acylsulfonamide (270) (83 mg, 66%) as an orange powder, mp 290-296 °C. Η NMR δ [(CD3)2SO] 11.75 (br s, IH), 11.08 (br s, IH), 9.38 (s, IH), 8.38 (d, J=2.4 Hz, IH), 7.80 (s, IH), 7.59 (m, 2H), 7.53- 7.46 (m, 3H), 7.14 (dd, J=8.9, 2.4 Hz, IH), 4.69 (t, J=6.9 Hz, 2H), 3.04 (s, 3H), 2.76 (t, J=6.9 Hz, 2H). Found: C, 54.70; H, 3.81; N, 7.67. C24Hι8ClN306S.3/4H20 requires: C, 54.85; H, 3.74; N, 7.99.
EXAMPLE 228
The preparation of N-r3-(4-(2-Chlorophenyl)-9-hydroxy-l ,3-dioxo-2,3-dihvdropyrrolor3.4- clcarbazol-6(lH)-yl)propanoyll-2-(dimethylamino)ethanesulfonamide (XIV; Ar=2- chlorophenyl, n=2, R3=CH?CH..N(CH3)7) (271)
Reaction of methyl ether (267) (35 mg, 0.06 mmol) prepared as described in example 224 according to the proceedure described in example 81, except that the reaction mixture was diluted with saturated sodium bicarbonate and extracted with ethyl acetate. The organic phase was dried, the drying agent was removed and the solution was concentrated to dryness. Chromatography on silica eluting with methanol/dichloromethane (1:9 to 1:3), gave acylsulfonamide (271) (8 mg, 23%) as an orange powder, mp 229-233 °C. 1H NMR δ [(CD3)2SO] 11.05 (br s, IH), 9.37 (br s, IH), 8.37 (d, J=2.5 Hz, IH), 7.74 (s, IH), 7.61-7.52 (m, 3H), 7.50-7.43 (m, 2H), 7.14 (dd, J=8.7, 2.5 Hz, IH), 4.63 (m, 2H), 3.21 (partially obscured m, 2H), 2.81 (m, 2H), 2.59 (t, J=6.8 Hz, 2H), 2.38 (s, 6H). FABMS found [M+H]+: 569.1255, 571.1204. C27H25C1N406S requires 569.1262, 571.1232.
EXAMPLE 229
The preparation of 3-(4-(2-Chlorophenyl)-9-methoxy-1.3-dioxo-2,3-dihydropyrrolor3.4- clcarbazol-6(lH)-yl)propanoic acid (IX; Ar=2-chlorophenyl, n=2) (116)
Oxidation of the alcohol (31) prepared as described in example 40 using the procedure described in example 203 gave the acid (116) (62 %) as a yellow solid, mp 277 °C. Η NMR δ [(CD3)2SO] 12.61 (br, IH), 11.12 (s, IH), 8.52 (d, J=2.6 Hz, IH), 7.86 (s, IH), 7.73 (d, J=9.0 Hz, IH), 7.58 (m, IH), 7.54-7.44 (m, 3H), 7.31 (dd, J=9.0, 2.6 Hz, IH), 4.71 (t, J=6.8 Hz, 2H), 3.93 (s, 3H), 2.80 (t, J=6.8 Hz, 2H). Found: C, 62.90; H, 3.79; N, 5.93. C24Hι7ClN205.l/2H2O requires C, 62.96; H, 3.96; N, 6.12. EXAMPLE 230
The preparation of 3-(4-(2-Chlorophenyl)-9-hvdroxy-l ,3-dioxo-2.3-dihydropyrrolof3.4- c1carbazol-6(lH)-yl)propanoic acid (X; Ar=2-chlorophenvI. n=2) (117)
Demethylation of (116) prepared as described in example 229 with pyridinium hydrochloride using the procedure described in example 81 gave (117) (50 %) as a yellow powder, mp 286 °C. ]H NMR δ [(CD3)2SO] 12.40 (br, IH), 11.06 (br s, IH), 9.37 (br s, IH), 8.37 (d, J=2.4 Hz, IH), 7.81 (s, IH), 7.59 (d, J=8.7 Hz, IH), 7.57 (m, IH), 7.53-7.43 (m, 3H), 7.13 (dd, J=8.7, 2.4 Hz, IH), 4.67 (t, J=6.8 Hz, 2H), 2.74 (t, J=6.8 Hz, 2H). Found: C, 60.00; H, 3.65; N, 5.52. C23H,5C1N205.1.5H20 requires C, 59.81; H, 3.92; N, 6.06.
EXAMPLE 231
The preparation of 3-(4-(2-Chlorophenyl)-9-methoxy-l,3-dioxo-2,3-dihvdropyrrolor3.4- clcarbazol-6(lH)-yl)propanamide (XI; Ar=2-chlorophenyl. n=2, R3=R4=H) (118)
Reaction of acid (117) prepared as described in example 230 with oxalyl chloride followed by ammonia using the procedure described in example 207 gave the amide (118) (78 %) as a yellow powder, mp 283-286 °C. 1H NMR δ [(CD3)2SO] 11.12 (br s, IH), 8.52 (d, J=2.6 Hz, IH), 7.82 (s, IH), 7.71 (d, J=9.0 Hz, IH), 7.58 (m, IH), 7.54-7.44 (m, 3H), 7.35 (br, IH), 7.31 (dd, J=9.0, 2.6 Hz, IH), 6.86 (br, IH), 4.69 (t, J=6.6 Hz, 2H), 3.90 (s, 3H), 2.58 (t, J=6.6 Hz, 2H). Found: C, 63.52; H, 4.22; N, 9.04. C24H18C1N304.1/4H20 requires C, 63.72; H, 4.12; N, 9.29.
EXAMPLE 232
The preparation of 3-(4-(2-Chlorophenyl)-9-hydroxy-1.3-dioxo-2,3-dihydropyrrolor3,4- clcarbazol-6(lH)-yl)propanamide (XIII; Ar=2-chlorophenvI. n=2. R3=R4=H) (119).
Demethylation of (118) prepared as described in example 231 with BBr3 using the procedure described in example 80 gave (119) as a yellow/orange powder (77 %), mp 319- 322 °C. 1H NMR δ [(CD3)2SO] 11.06 (br s, IH), 9.36 (br s, IH), 8.37 (d, J=2.4 Hz, IH), 7.77 (s, IH), 7.60-7.55 (m, 2H), 7.52-7.43 (m, 3H), 7.35 (br, IH), 7.13 (dd, J=8.8, 2.4 Hz, IH), 6.87 (br, IH), 4.65 (t, J=6.7 Hz, 2H), 2.57 (t, J=6.7 Hz, 2H). FABMS found M+: 435.0833, 433.0828. C23Hι6ClN304 requires 435.0800, 433.0829. EXAMPLE 233
The preparation of 3-(4-(2-Chlorophenyl)-9-methoxy-l,3-dioxo-2,3-dihvdropyrrolor3.4- c1carbazol-6(lH)-yl)-N-r2-(4-morpholinyl)ethvHpropanamide (XI; Ar=2-chlorophenyl. n=2. R3=H. R4=CH. CH?N(CH,CH?)20) (120)
Reaction of acid (117) prepared as described in example 230 with oxalyl chloride followed by N-(2-aminoethyl)morpholine using the procedure described in example 207 gave the amide (120) (73 %) as a yellow powder, mp 174-176 °C. ]H NMR δ [(CD3)2S0] 11.12 (br s, IH), 8.51 (d, J=2.6 Hz, IH), 7.77 (s, IH), 7.74 (t, J=5.6 Hz, IH), 7.68 (d, J=9.0 Hz, IH), 7.58 (m, IH), 7.53-7.44 (m, 3H), 7.31 (dd, J=9.0, 2.6 Hz, IH), 4.71 (t, J=6.3 Hz, 2H), 3.90 (s, 3H), 3.40 (t, J=4.6Ηz,"4H)72.97 (m, IH), 2.58 (t; J=6.3 Hz 2H), 2.11 (br t, J=4.6 Hz, 4H), 2.00 (t, J=6.7 Hz,-2H). Found: C, 60.46; H, 5.26; N, 9.27. C30H29ClN4O5.2H2O requires C, 60.35; H, 5.94; N, 9.38.
EXAMPLE 234
The preparation of 3-(4-(2-Chlorophenyl)-9-hydroxy-l ,3-dioxo-2,3-dihvdropyrrolor3.4- clcarbazol-6(lH)-yl)-N-r2-(4-morpholinyl)ethyllpropanamide (XIII: Ar=2-chlorophenyl, n=2. R3=H. R^CH.CH.WCH.CH.^O) (121)
Demethylation of (120) prepared as described in example 233 with BBr3 using the procedure described in example 80 except that the reaction time was 16 h gave (121) as a yellow powder (64 %), mp 143-148 °C (dec). Η NMR δ [(CD3)2SO] 11.05 (s, IH), 9.35 (s, IH), 8.36 (d, J=2.4 Hz, IH), 7.74 (t, J=5.6 Hz, IH), 7.71 (s, IH), 7.60-7.55 (m, 2H), 7.52- 7.43 (m, 3H), 7.13 (dd, J=8.8, 2.4 Hz, IH), 4.67 (t, J=6.3 Hz, 2H), 3.40 (t, J=4.7 Hz, 4H), 2.98 (m, 2H), 2.57 (t, J=6.3 Hz, 2H), 2.12 (t, J=4.7 Hz, 4H), 2.02 (t, J=6.7 Hz, IH). Found: C, 62.37; H, 4.99; N, 9.82. C29H27C1N405.1/2H20 requires C, 62.64; H, 5.08; N, 10.08.
EXAMPLE 235
The preparation of 3-(4-(2-Chlorophenyl)-9-methoxy-1.3-dioxo-2,3-dihvdropyιτolor3.4- c .carbazol-6(lH)-yl)-N-F2-(dimethylamino)ethvH-N-methylpropanamide (XI; Ar-=2- chlorophenyl. n=2, R3=CH^, R4=CH2CHzN(CHV (122)
Reaction of acid (117) prepared as described in example 230 with oxalyl chloride followed by N,N,N'-trimethylethylenediamine using the procedure described in example 207 gave the amide (122) (77 %) as a yellow powder, mp 146-152 °C (dec). Η NMR δ [(CD3)2SO] 11.10 (br, IH), 8.51 (d, J=2.6 Hz, IH), 7.83 (s, 0.5H), 7.79 (s, 0.5H), 7.72 (m, IH), 7.58 (m, IH), 7.54-7.43 (m, 3H), 7.31 (m, IH), 4.72 (m, 2H), 3.90 (s, IH), 3.25 (m, IH), 3.09 (m, IH), 2.83 (m, 2H), 2.72 (s, 1.5H), 2.71 (s, 1.5H), 2.13 (t, J=4.8 Hz, IH), 2.05 (s, 3H), 2.00 (t, J=4.8 Hz, IH), 1.88 (s, 3H). Found: C, 63.42; H, 5.46; N, 10.15. C29H29ClN O4.H20 requires C, 63.21; H, 5.67; N, 10.17.
EXAMPLE 236
The preparation of 3-(4-(2-Chlorophenyl)-9-hvdroxy-l ,3-dioxo-2,3-dihvdropyrrolor3,4- c1carbazol-6(lH)-yl)-N-r2-(dimethylamino)ethvH-N-methylpropanamide (XIII; Ar=2- chlorophenyl. n=2. R3=CHZ, R4=CH?CHzN(CH b (123)
Demethylation of (122) prepared as described in example 236 with BBr3 using the procedure described in example 80 except that the reaction time was 48 h gave (123) as a yellow powder (58 %), mp 184-188 °C. ]H NMR δ [(CD3)2SO] 11.06 (br s, IH), 9.36 (br s, IH), 8.37 (d, J=2.4 Hz, IH), 7.78 (s, 0.5H), 7.74 (s, 0.5H), 7.62-7.54 (m, 2H), 7.53-7.42 (m, 3H), 7.14 (dd, J=8.8, 2.4 Hz, IH), 4.69 (m, 2H), 3.22 (m, IH), 3.09 (m, IH), 2.82 (m, 2H), 2.72 (s, 1.5 H), 2.71 (s, 1.5H), 2.14 (t, J=4.8 Hz, IH), 2.06 (s, 3H), 2.00 (t, J=4.8 Hz, IH), 1.88 (s, 3H). Found: C, 62.23; H, 5.23; N, 10.24. C28H27C1N404.1.25H20 requires C, 62.10; H, 5.49; N, 10.35.
EXAMPLE 237
The preparation of 3-(4-(2-Chlorophenyl)-9-methoxy-l,3-dioxo-2,3-dihvdropyrrolor3,4- c1carbazol-6(lH)-yl)-N-(2,2,6,6-tetramethyl-4-piperidinyl)propanamide (XI; Ar=2- chlorophenyl. n=2, R3=H, R4=2,2,6,6-tetramethyl-4-piperidinyl) (124)
Reaction of acid (117) prepared as described in example 230 with oxalyl chloride followed by 4-amino-(2,2,6,6-tetramethyl)piperidine using the procedure described in example 207 gave the amide (124) (72 %) as a yellow powder, mp 155-160 °C (dec). Η NMR δ [(CD3)2SO] 11.12 (br, IH), 8.51 (d, J=2.6 Hz, IH), 7.78 (s, IH), 7.67 (d, J=9.0 Hz, IH), 7.59-7.44 (m, 6H), 7.31 (dd, J=9.0, 2.6 Hz, IH), 4.71 (m, 2H), 3.90 (s, 3H), 3.82 (m, IH), 2.52 (t, J=6.2 Hz, 2H), 1.26 (m, IH), 1.10 (m, IH), 1.03 (s, 3H), 1.02 (s, 3H), 0.91 (s, 3H), 0.96 (s, 3H), 0.64 (t, J=12.3 Hz, IH), 0.53 (t, J=12.3 Hz, IH). Found: C, 64.37; H, 5.97; N, 9.20. C33H35C1N404.1.5H20 requires C, 64.54; H, 6.24; N, 9.12. EXAMPLE 238
The preparation of 3-(4-(2-Chlorophenyl)-9-hvdroxy-1.3-dioxo-2,3-dihvdropyrrolor314- clcarbazo1-6(lH)-yl)-N-(2,2,6,6-tetramethyl-4-piperidinyl)propanamide (XIII; Ar=2- chlorophenyl. n=2, R3=H, R4=2,2,6,6-tetramethyl-4-piperidinyl) (125)
Demethylation of (124) prepared as described in example 237 with BBr3 using the procedure described in example 80 except that the reaction time was 48 h gave (125) as a yellow powder (47 %), mp 293-299 °C (dec). Η NMR δ [(CD3)2SO] 11.08 (br s, IH), 9.38 (br s, IH), 8.72 (br, IH), 8.37 (d, J=2.4 Hz, IH), 7.83 (d, J=7.1 Hz,lH), 7.75 (s, IH), 7.60- 7.44 (m, 5H), 7.14 (dd, J=8.8, 2.4 Hz, IH), 4.70 (t, J=5.8 Hz, 2H), 3.90 (m, IH), 2.54 (t, J=5.8 Hz, 2H), 1.45-1.31 (m 2H), 1.30 (s, 3H), 1.29 (s, 3H), 1.25 (s, 3H), 1.22 (s, 3H), 1.09- 9.93 (m, 2H). Found: C, 58.67; H, 5.37; N, 8.41. C32H33C1N404.1.25CH2C12 requires C, 58.79; H, 5.27; N, 8.25.
EXAMPLE 239
The preparation of 4-(2-Chlorophenyl)-6-( 3-rcis-3,5-dimethylpiperazinvπ-3-oxopropyπ-9- -methoxypyιτolor3.4-c1carbazole--lτ3(2H.6H:)-dione-(XL Ar=2-chlorophenyl, n=2, R3 R4=cis- 3,5-dimethylpiperazinyl) (126)
Reaction of acid (117) prepared as described in example 230 with oxalyl chloride followed by cis-2,6-dimethylpiperazine using the procedure described in example 207 gave the amide (126) (76 %) as a yellow powder, mp 168-173 °C (dec). Η NMR δ [(CD3)2SO] 11.13 (br, IH), 8.52 (d, J=2.6 Hz, IH), 7.80 (s, 0.5H), 7.76 (s, 0.5H), 7.71 (m, IH), 7.58 (m, IH), 7.54-7.43 (m, 3H), 7.31 (dd, J=9.0, 2.6 Hz, IH), 4.71 (m, 2H), 4.17 (m, IH), 3.89 (s, 3H), 2.94 (m, IH), 2.75 (m, IH), 2.23 (m, IH), 2.08 (m, IH), 1.87 (m, 2H), 0.88, 0.86 (2d, J=5.9 Hz, 3H), 0.67 (d, J=6.1 Hz, 3H). Found: C, 64.03; H, 5.47, N, 9.72. C30H29ClN4O4.H2O requires C, 64.00; H, 5.55; N, 9.95.
EXAMPLE 240
The preparation of 4-(2-Chlorophenyl)-6-{ 3-r(3R,5S)-3.5-dimethylpiperazinyl1-3- oxopropyll-9-hvdroxypyrro1or3,4-clcarbazole-l,3(2H,6H)-dione (XIII; Ar=2-chlorophenyl. n=2, R3JR4=cis-3,5-dimethylpiperazinyl) (127)
Demethylation of (126) prepared as described in example 239 (with BBr3 using the procedure described in example 80 except that the reaction time was 48 h gave (127) as a yellow powder (38 %), mp 220-224 °C (dec). Η NMR δ [(CD3)2SO] 11.07 (br s, IH), 9.36 (br s, IH), 8.72 (br, IH), 8.34 br, IH), 7.72 (s, 0.5H), 7.71 (s, 0.5H), 7.60-7.54 (m, 2H), 7.52- 7.43 (m, 3H), 7.13 (dd, J=8.8, 2.4 Hz, IH), 4.68 (m, 3H), 4.15, 4.12 (2s, 2H), 2.94 (m, IH), 2.72 (m, IH), 2.19 (m, IH), 2.00 (m, IH), 1.84 (m, IH), 0.86, 0.84 (2d, J=5.8 Hz, 3H), 0.64 (2d, J=6.1 Hz, 3H). Found: C, 63.38; H, 5.38; N, 9.96. C29H27C1N404.H20 requires C, 63.44; H, 5.32; N, 10.20.
EXAMPLE 241
The preparation of 3-(4-(2-Chlorophenyl)-9-methoxy-l ,3-dioxo-2,3-dihvdropyrrolor3,4- clcarbazol-6(lH)-yl)-N-r2-(lH-imidazol-5-yl)ethvnpropanamide (XI; Ar=2-chlorophenyl, n=2. R3=H. R4=(lH-imidazol-5-yl)ethyl) (128)
Reaction of acid (117) prepared as described in example 230 with oxalyl chloride followed by histamine using the procedure described in example 207 gave the amide (128) (81 %) as a yellow powder, mp 144-149 °C (dec). 1H NMR δ [(CD3)2SO] 11.12 (br, IH), 8.52 (d, J=2.6 Hz, IH), 7.91 (t, J=5.5 Hz, IH), 7.76 (s, IH), 7.69 (d, J=9.0 Hz, IH), 7.58 (m, IH), 7.52-7.42 (m, 4H), 7.32 (dd, J=9.0, 2.6 Hz, IH), 6.56 (s, IH), 4.69 (t, J=6.4 Hz, 2H), 3.90 (s, 3H), 3.12 (m, 2H), 2.58 (t, J=6.4 Hz, 2H), 2.39 (t, J=7.4 Hz, 2H). Found: C, 60.73; H, 4.49; N, 11.49. C29H24C1N504.1/2CH2C12 requires C, 60.62; H, 4.31; N, 11.98.
EXAMPLE 242
The preparation of 3-(4-(2-Chlorophenyl)-9-hydroxy-l,3-dioxo-2,3-dihydropyrrolor3,4- c1carbazol-6(lH)-yl)-N-r2-(lH-imidazol-5-yl)ethvnpropanamide (XIII; Ar=2-chlorophenyl. n=2. R3=H. R4=(lH-imidazol-5-yl)ethyl) (129)
Demethylation of (128) prepared as described in example 241 with BBr3 using the procedure described in example 80 except that the reaction time was 48 h gave (129) as a yellow powder (46 %), mp 158-162 °C (dec). Η NMR δ [(CD3)2SO] 11.75 (br, IH), 11.05 (br s, IH), 9.36 (br s, IH), 8.37 (d, J=2.4 Hz, IH), 7.91 (t, J=5.3 Hz, IH), 7.71 (s, IH), 7.59- 7.54 (m, 2H), 7.50-7.42 (m, 4H), 7.14 (dd, J=8.8, 2.4 Hz, IH), 6.57 (br, IH), 4.65 (t, J=6.5 Hz, 2H), 3.13 (m, 2H), 2.55 (t, J=6.5 Hz, IH), 2.40 (t, J=6.5 Hz, IH). FABMS found [M+H]+: 530.1431, 528.1440. C28H23C1N504 requires 530.1409, 528.1439.
Figure imgf000163_0001
SCHEME 5
Scheme 5 Procedures
Representative Procedure for Method 16 of Scheme 5
EXAMPLE 243
The preparation of l,9-Dihydroxy-4-phenyl-l,6-dihvdropyrrolor3,4-c1carbazol-3(2H)-one (XV: Ar=phenyl, R10=H) (133) and 3.9-dihydroxy-4-phenyl-3,6-dihvdropyrrolor3.4- clcarbazol-l(2H)-one (XVI: Ar=phenyl. R10=H) (134).
Sodium borohydride (4 portions of 0.24 g, 0.025 mol total) was added over 5 h to a solution of 9-hydroxy-4-phenylpyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione (I; Ar=phenyl) (0.50 g, 0.015 mmol) in ethanol (80 mL) and the solution was left overnight. A further four portions of sodium borohydride were added at 1 h intervals and the solution was diluted with water, extracted with ethyl acetate. The organic phase was dried, the drying agent was removed and the solution was concentrated to dryness, which was chromatographed on silica. Ethyl acetate/petroleum ether (2:1) eluted starting material (12 mg), followed by the 3- hydroxy compound (134) (0.07 g, 14 %) as a cream powder, mp 300-310 °C (dec). Η NMR δ [(CD3)2SO] 11.26 (br s, IH), 8.98 (s, IH), 8.83 (s, IH), 8.50 (d, J=2.3 Hz, IH), 7.70 (br d, J==7.0 Hz, 2H), 7.53 (s, IH), 7.49-7.31 (m, 4H), 6.96 (dd, J=8.7, 2.3 Hz, IH), 6.25 (d, J=9.7 Hz, IH), 5.87 (d, J=9.7 Hz, IH). Found: C, 71.77; H, 4.47; N, 8.14. C20Hι3N2O3.l/4H2O requires C, 71.95; H, 4.08; N, 8.39.
Elution with ethyl acetate gave a mixed fraction of (134) and (133) (0.014 g), followed by pure 1-hydroxy compound (133) (0.32 g, 64 %) as a white powder, mp 300-310 °C (dec). 1H NMR δ [(CD3)2SO] 11.38 (br s, IH), 9.06 (s, IH), 8.55 (br s, IH), 7.72 (d, J=2.2 Hz, IH), 7.55 (dd, J=7.8, 2.1 Hz, 2H), 7.47-7.35 (m, 4H), 7.32 (s, IH), 6.98 (dd, J=8.6, 2.2 Hz, IH), 6.38 (d, J=10.3 Hz, IH), 6.20 (d, J=10.3 Hz, IH). Found: C, 68.77; H, 4.66; N, 7.87. C20Hι3N2O3.H2O requires C, 69.15; H, 4.35; N, 8.06.
EXAMPLE 244
The preparation of 9-Hvdroxy-l-methoxy-4-phenyl-l,6-dihvdropyrrolor3,4-clcarbazol- 3(2H)-one (XVII: Ar=phenyl, R10=H) (135).
A solution of (133) prepared as described in example 243 (0.050 g, 0.16 mmol) and p-toluenesulphonic acid (15 mg) on methanol (5 mL) was stirred at room temperature for 30 min, then poured into saturated aqueous NaHC03 solution. The mixture was extracted with ethyl acetate. The organic phase was dried, the drying agent was removed and the solution was concentrated to dryness to give (135), which crystallised from ethyl acetate/petroleum ether as a white solid (0.041 g, 74 %), mp 290-300 °C (dec). ]H NMR δ [(CD3)2SO] 11.47 (br s, IH), 9.15 (br s, IH), 8.75 (s, IH), 7.57-7.53 (m, 3H), 7.44-7.37 (m, 4H), 7.36 (s, IH), 7.09 (dd, J=8.7, 2.4 Hz, IH), 6.26 (s, IH), 3.25 (s, 3H). Found: C, 71.34; H, 4.79, N, 7.84. C2)Hι5N203.l/2H20 requires C, 71.58; H, 4.57; N, 7.95.
EXAMPLE 245
The preparation of 9-Hvdroxy-4-phenyl-l ,6-dihvdropyrrolor3,4-clcarbazol-3(2H)-one (XVIII. Ar=phenyl. R10=H) (136).
To a solution of (133) prepared as described in example 243 (0.20 g, 0.605 mmol) in tetrahydrofuran (30 mL) was added p-toluenesulfonic acid (23 mg, 0.121 mmol), followed be PhSeH (1.48 mL, 4.24 mmol) and the solution was stirred at room temperature for 1 h. After diluting with water the mixture was extracted with ethyl acetate and the extract was washed with aqueous NaHC03 solution. The organic phase was dried, the drying agent was removed and the solution was concentrated to dryness and chromatographed on silica. Elution with ethyl acetate/petroleum ether (1:1) then ethyl acetate followed by ethyl acetate/methanol (95:5) gave (136) as a white powder (0.174 g, 91 %), mp 270-280 °C (dec). ]H NMR δ [(CD3)2S0] 11.41 (br s, IH), 9.13 (br s, IH), 8.27 (br s, IH), 7.60-7.52 (m, 2H), 7.47-7.36 (m, 4H), 7.34-7.31 (m, IH), 7.30 (s, IH), 6.99 (dd, J=8.6, 2,2 Hz, IH), 4.78 (br s, 2H). Found: C, 75.19; H, 4.88, N, 8.37. C20Hι N2θ2.1/4H2O requires C, 75.34; H, 4.58; N, 8.78.
EXAMPLE 246
The preparation of 4-(2-Chlorophenyl)-l ,9-dihydroxy-6-(3-hvdroxypropyl)-l,6-
Figure imgf000165_0001
(137) and 4-(2-chlorophenyl)-3,9-dihvdroxy-6-(3-hvdroxypropyl)-3.6-dihydropyrrolor3.4-
Figure imgf000165_0002
Reduction of alcohol (34) prepared as described in example 243 with sodium borohydride using the procedure described in the procedure described in example 243 of Scheme 5, followed by chromatography of the product on silica gave firstly the 3-hydroxy compound (138) (11 %) as a cream powder, mp 160-164 °C (dec). Η NMR δ [(CD3)2SO] 9.08 (br s, IH), 8.84 (s, IH), 8.54 (d, J=2.5 Hz, IH), 7.62-7.36 (m, 6H), 7.03 (dd, J=8.7, 2.5 Hz, IH), 5.92 (br, IH), 5.81 (br, IH), 4.58 (t, J=5.0 Hz, IH), 4.44 (t, J=6.8 Hz, 2H), 3.38 (m, 2H), 1.88 (m, 2H). Found: C, 64.60; H, 4.82; N, 6.32. C23Hι9ClN204.l/4H20 requires C, 64.64; H, 4.60; N, 6.55; followed by (137) (67 %) as a cream powder, mp 240 °C (dec). 1H NMR δ [(CD3)2SO] 9.18 (br s, IH), 8.53 (br s, IH), 7.76 (m, IH), 7.50 (m, 2H), 7.43-7.35 (m, 3H), 7.40 (s, IH), 7.04 (dd, J-8.7, 2.3 Hz, IH), 6.52 (d, J=10.0 Hz, 0.5H), 6.40 (d, J=10.0 Hz, 0.5H), 6.25 (d, J=10.0 Hz, 0.5H), 6.21 (d, J=10.0 Hz, 0.5H), 4.61 (t, J=4.7 Hz, IH), 4.44 (t, J=6.8 Hz, 2H), 3.39 (m, 2H), 1.88 (m, 2H). Found: C, 65.17; H, 4.80; N, 6.46. C23H,9C1N204 requires C, 65.33; H, 4.53; N, 6.62.
MeO. N3CHgCOOMe M-O.-^-^^-^ OOMe heat MeO
NaOMe
BnO X' X xylene '.r II v J —c c ΞccOOMe BnO
(54) (55) (56)
Figure imgf000166_0001
SCHEME 6
Scheme 6 Procedures
EXAMPLE 247
The preparation of Methyl-2-azido-3-r4'-(benzyloxy)-3'-methoxyphenyl1prop-2-enoate (55)
A solution of the 4-Benzyloxy-3-methoxy-benzaldehyde (12.0 g, 49.6 mmol) and methyl azidoacetate (23 g, 0.200 mol) in methanol (50 mL) was added over 30 min to a cooled (ice-salt bath) solution of sodium methoxide which had been prepared from addition of methanol (80 mL) to sodium (3.4 g, 0.149 mol). The reaction mixture was stirred at 0° C for 45 min, during this time a thick cream precipitate formed, and then stood in the freezer overnight. Ice-cold water was added and the precipitate was removed by filtration and dried to give methyl-2-azido-3-[4'-(benzyloxy)-3'-methoxyphenyl]prop-2-enoate (55) (12.2 g, 73%) which was used in the next step without purification. EXAMPLE 248
The preparation of methyl-6-(benzyloxy)-5-methoxyindole-2-carboxylate (56)
A solution of the azidocinnamate (55) (12.2 g, 36.0 mmol) prepared as described in example 247 in xylene (300 mL) was added dropwise to refluxing xylene (100 mL) over 1.5 h, the reaction mixture was heated at reflux for a further 15 min and then most of the xylene was removed by distillation. The residue, on cooling to room temperature, formed a fine cream precipitate of methyl-6-(benzyloxy)-5-methoxyindole-2-carboxylate which was collected by filtration. The remaining xylene was removed from the mother liquor azeotropically with ethanol, the residue was recrystallized from ethanol to give further methyl-6-(benzyloxy)-5-methoxyindole-2-carboxylate. The mother liquor was again concentrated and the residue recrystallized. The methyl-6-(benzyloxy)-5-methoxyindole-2- carboxylate (56) (9.9 g total, 88%) was used in the next step without purification. Found: C, 69.38; H, 5.54; N, 4.55. CI8HπN04 requires: C, 69.44; H, 5.50; N, 4.50.
EXAMPLE 249
The preparation of 6-(Benzyloxy)-5-methoxy-lH-indole-2-carbaldehyde (57)
To a solution of the ester (56) (1.0 g, 3.22 mmol) prepared as described in example 248 in tetrahydrofuran (10 mL) was added a suspension of lithium aluminum hydride (0.150 g, 3.86 mmol) in tetrahydrofuran (10 mL) dropwise, the reaction mixture was stirred at room temperature for 20 min. Water (1 mL) was added dropwise and then dilute sodium hydroxide (1 mL) was added, the solution was stirred for 10 min and then filtered through Celite and concentrated. The resulting yellow oil was dissolved in chloroform (20 mL) and then manganese dioxide (2.2 g, 26.0 mmol) was added, the reaction mixture was heated at 50° C for 1 h and then filtered through Celite and concentrated. The residue was recrystallized from dichloromethane to give 6-(benzyloxy)-5-methoxy-lH-indole-2- carbaldehyde (57) (0.74 g, 82%) as pale yellow needles. Found: C, 72.53; H, 5.42; N, 4.92. Cι7Hι5N03 requires: C, 72.58; H, 5.37; N, 4.98.
Representative Procedure for Method 16 of Scheme 6
EXAMPLE 250
The preparation of 6-(Benzyloxy)-5-methoxy-2-r(E)-2-phenylethenyll-lH-indole (XX; Ar=phenyl) (150) To a solution of (57) (0.60 g, 2.14 mmol) prepared as described in example 249 and benzyltriphenylphosphonium bromide (1.0 g, 2.35 mmol) in dichloromethane (10 mL) was added a 17 M solution of sodium hydroxide (1.1 mL, 18 mmol) dropwise. The reaction mixture was stirred at room temperature until all the starting material was consumed (30 min), and then it was diluted with water and extracted with dichloromethane (2 x 40 mL). The combined extracts were dried and concentrated to give an approximately 1 :1 mixture of 6-(benzyloxy)-5-methoxy-2-[(E)-2-phenylethenyl]-lH-indole and 6-(benzyloxy)-5-methoxy- 2-[(Z)-2-phenylethenyl]-lH-indole (0.75 g, 99%). Recrystallization from dichloromethane cleanly gave the E-isomer (150), mp 140-145°C (softens), 158-162 °C (melts). 1H NMR δ [(CD3)2SO] 11.08 (s, IH), 7.52-7.47 (m, 4H), 7.42-7.31 (m, 5H), 7.25-7.15 (m, 2H), 7.05-7.01 (m, 2H), 6.91 (s, IH), 6.45 (s, IH), 5.12 (s, 2H), 3.78 (s, 3H). Found: C, 80.84; H, 6.11; N, 3.94. C2 H2ιN02 requires: C, 81.10; H, 5.96; N, 3.94.
EXAMPLE 251
The preparation of 6-(Benzyloxy)-5-methoxy-l-methyl-2-r(E)-2-phenylethenyl1-lH-indole (XXI; Ar=phenyl, R10=Me) (151)
Reaction of (150) prepared as described in example 250 with sodium hydride followed by iodomethane using the procedure described in method 3 gave (151) (100%), mp
142-145°C. !H NMR δ [(CD3)2SO] 7.51-7.46 (m, 4H), 7.40-7.34 (m, 6H), 7.31-7.23 (m,
2H), 7.09-7.05 (m, 2H), 7.30 (s, IH), 5.21 (s, 2H), 3.93 (s, 3H), 3.70 (s, 3H). Found: C,
81.01; H, 6.31; N, 3.79. C25H23Nθ2 requires: C, 81.27; H, 6.27; N, 3.79.
EXAMPLE 252
The preparation of 8-(Benzyloxy)-9-methoxy-6-methyl-4-phenyl-4,5,6,10c- tetrahvdropyrro1or3,4-clcarbazole-l,3(2H.3aH)-dione (XXII; Ar=phenyl. R10=Me) (152)
Reaction of (151) prepared as described in example 251 with maleimide using the procedure described in example 69 gave the adduct (152) as a yellow solid, which was used without further purification. EXAMPLE 253
The preparation of 8-(Benzyloxy)-9-methoxy-6-methyl-4-phenv1pyrrolor3,4-c1carbazole- l ,3(2H,6H)-dione (XXIII; Ar=phenyl. R10=Me) (153)
Aromatisation of crude (152) prepared as described in example 252 with manganese dioxide using the procedure described in example 79 gave (153) as a yellow solid (69% overall from (151), mp 263-265°C. 1H NMR δ [(CD3)2SO] 11.04 (br s, IH), 8.48 (s, IH), 7.73 (s, IH), 7.66-7.63 (m, 2H), 7.57-7.55 (m, 2H), 7.49-7.36 (m, 7H), 5.28 (s, 2H), 3.95 (s, 3H), 3.90 (s, 3H). Found: C, 74.99; H, 4.67; N, 5.95. C29H22N2O requires: C, 75.31; H, 4.79; N, 6.06.
Representative Procedure for Method 17 of Scheme 6
EXAMPLE 254
The preparation of 8-Hvdroxy-9-methoxy-6-methyl-4-phenylpyrrolor3,4-clcarbazole- 1.3(2H.6H)-dione (XXV; Ar=phenyl. R10=Me) (154)
To a solution of (153) (1.0 g, 2.16 mmol) prepared as described in example 253 in a 1:1 mixture of tetrahydrofuran and methanol (100 mL) was added 5% Pd/C (200 mg) and then ammonium formate (1.71 g, 22.0 mmol). The reaction mixture was stirred at room temperature for 2 hr and then filtered through Celite, washing well with tetrahydrofuran. The filtrate was concentrated and then water was added; the resulting yellow precipitate was collected by filtration and dried to give (154) (0.71 g, 88%), mp 298-301°C. 1H NMR δ [(CD3)2SO] 11.01 (s, IH), 9.70 (s, IH), 8.46 (s, IH), 7.71 (s, IH), 7.65-7.63 (m, 2H), 7.49- 7.41 (m, 3H), 3.92 (s, 3H), 3.87 (s, 3H). Found: C, 69.85; H, 4.35; N, 7.15. C2 H]6N204.l/3 H20 requires: C, 69.83; H, 4.44; N, 7.40.
EXAMPLE 255
The preparation of 6-(Benzv]oxy)-2-r2-(2-chlorophenyl)ethenyl1-5-methoxy-lH-indole (XX: Ar=2-ch1orophenyl) (155)
Reaction of the aldehyde (57) prepared as described in example 249 with 2'- chlorobenzyltriphenylphosphonium chloride using the procedure described in the procedure described in example 243 gave the diene (155) as an E/Z mixture of isomers (78 %), green solid, mp 192-194 °C. Η NMR δ [(CD3)2SO] 11.25 (s, IH), 10.70 (s, minor isomer), 7.83
(dd, J=8.0, 1.4 Hz, IH), 7.68-7.20 (m), 7.05 (s, IH), 6.91 (s, IH), 6.88 (d, J=2.9 Hz, minor isomer), 6.64 (d, J=12.1 Hz, minor isomer), 6.51 (d, J=1..4 Hz, IH), 6.46 (d, J=12.1 Hz, minor isomer), 5.89 (br s, minor isomer), 5.13 (s, 2H), 5.06 (s, minor isomer), 3.78 (s, 3H), 3.71 (s, minor isomer). Found: C, 73.92; H, 5.23; N, 3.63. C24H]9C1N02 requires C, 74.13; H, 4.92; N, 3.60.
EXAMPLE 256
The preparation of 6-(Benzyloxy)-2-r2-(2-chloropheny1)ethenyll-5-methoxy-l-methyl-lH- indole (XXI: Ar=2-chlorophenyl. Rl0=Cft) (156).
Alkylation of (155) prepared as described in example 255 with sodium hydride and iodomethane using the procedure described in method 3 gave (156) (100 %) (mixture of E/Z isomers) as a yellow solid, mp 143-145 °C. Η NMR δ [(CD3)2SO] 7.98 (dd, J=7.9, 1.5 Hz, IH), 7.55-7.22 (m), 7.19 (s), 7.12 (s), 6.89 (s), 6.85 (d, J=12.2 Hz), 6.80 (s), 6.63 (d, J=12.2 Hz), 5.14 (s), 5.11 (s), 3.81 (s), 3.78 (s), 3.70 (s), 3.64 (s). Found: C, 74.04; H, 5.71; N, 3.49. C25H22C1N02 requires C, 74.34; H, 5.49; N, 3.47.
EXAMPLE 257
The preparation of 8-(Benzyloxy)-4-(2 :hlorophenyl)-9-methoxy-6-methyl-4,5,6,10c- tetrahvdropyrrolor3,4-clcarbazole-1.3(2H,3aH)-dione (XXII; Ar=2-chlorophenyl. R10=CH.) (1571
Reaction of the diene (156) prepared as described in example 256 with maleimide using the procedure described in example 69 gave the adduct (157) (98 %) as a cream powder, mp 174 °C (dec), which was used without further purification. Found: C, 68.32; H, 4.94; N, 5.51. C29H24C1N204.1/2H20 requires C, 68.43; H, 4.95; N, 5.50.
EXAMPLE 258
The preparation of 8-(Benzyloxy)-4-(2-chlorophenyl)-9-methoxy-6-methylpyrrolo[3,4- clcarbazole-1.3(2H.6H)-dione (XXIII) (158).
Aromatisation of (157) prepared as described in example 257 with manganese dioxide using the procedure described in example 79 gave the carbazole (158) (75 %) as a yellow powder, mp 282-285 °C. ]H NMR δ [(CD3)2SO] 11.05 (s, IH), 8.48 (s, IH), 7.74 (s, IH), 7.59-7.54 (m, 3H), 7.52-7.36 (m, 7H), 5.30 (s, 2H), 3.96 (s, 3H), 3.91 (s, 3H). Found: C, 69.89; H, 4.44; N, 5.61. C29H2ιClN204 requires C, 70.09; H, 4.26; N, 5.64. EXAMPLE 259
The preparation of 4-(2-Chlorophenyl)-8,9-dihvdroxy-6-methylpyrrolor3.4-clcarbazole- 1.3(2H.6H)-dione (XXIV: Ar=2-chlorophenyl, R10=CH (159).
Reaction of (158) prepared as described in example 258 with pyridinium hydrochloride at 220 °C using the procedure described in example 81 gave (159) (76 %) as a yellow powder, mp 310-313 °C. ]H NMR δ [(CD3)2SO] 10.95 (s, IH), 9.57 (br, IH), 9.18 (br, IH), 8.32 (s, IH), 7.64 (s, IH), 7.56 (dd, J=8.1, 2.2 Hz, IH), 7.50-7.41 (m, 4H), 7.02 (s, IH), 3.84 (s, 3H). Found: C, 64.11; H, 3.96; N, 6.54. C21Hι3ClN204.l/4CH3OH requires C, 63.67; H, 3.52; N, 6.98.
Representative Procedure for Method 18 of Scheme 6
EXAMPLE 260
The preparation of 4-(2-Chlorophenyl)-8-hvdroxy-9-methoxy-6-methylpyrrolor3.4- clcarbazole-1.3(2H,6H)-dione (XXV; Ar=2-chlorophenyl. R10=CH^) (160).
A mixture of (158) (1.30 g, 2.62 mmol) prepared as described in example 258, cone. HCI (40 mL) and acetic acid (65 mL) was warmed at 100 °C for 2 h. Water was added and the precipitated product was filtered off and dried. The solid was adsorbed onto silica from a tetrahydrofuran solution and chromatographed. Elution with ethyl acetate/petroleum ether (3:2) gave (160) (1.07 g, 85 %), which crystallised from terahydrofuran/petroleum ether as a green solid, mp 280-285 °C (dec). 1H NMR δ [(CD3)2SO] 11.01 (s, IH), 9.73 (s, IH), 8.44 (s, IH), 7.69 (s, IH), 7.57 (dd, J=8.0, 2.2 Hz, IH), 7.51-7.41 (m, 4H), 7.09 (s, IH), 3.93 (s, 3H), 3.87 (s, 3H). Found: C, 64.53; H, 3.66; N, 6.27. C22Hι5ClN204.l/4H20 requires C, 64.24; H, 3.80; N, 6.81.
EXAMPLE 261
The preparation of 8-(Benzyloxy)-4-(2-chlorophenyl)-9-methoxy-4,5,6,10c- tetrahvdropyrrolor3,4-c1carbazole-l,3(2H,3aH)-dione (XXII. Ar=2-chlorophenyl. R10=H) (161).
Reaction of the diene (155) prepared as described in example 255 with maleimide using the procedure described in example 69 gave the adduct (161) as a tan powder (87 %), which was used without further purification. EXAMPLE 262
The preparation of 8-(BenzvIoxy)-4-(2-chlorophenyl)-9-methoxypyrrolor3,4-c lcarbazole- l,3(2H,6H)-dione (XXIII; Ar=2-chlorophenyl. R10=H) (162).
Aromatisation of (161) prepared as described in example 261 with manganese dioxide using the procedure described in example 79 gave the carbazole (162) (93 %) as an orange powder, mp 260-264 °C. Η NMR δ [(CD3)2SO] 11.86 (s, IH), 11.01 (s, IH), 8.43 (s, IH), 7.58-7.34 (m, 10H), 7.26 (s, IH), 5.26 (s, 2H), 3.91 (s, 3H). Found: C, 69.65; H, 3.84; N, 5.61. C28Hι9ClN204 requires C, 69.64; H, 3.97; N, 5.80.
EXAMPLE 263
The preparation of 4-(2-Chlorophenyl)-8-hvdroxy-9-methoxypyrrolor3,4-c1carbazole- 1.3(2H.6H)-dione (XXV; Ar=2-chlorophenyl. R10--H) (163).
Debenzylation of (162) prepared as described in example 262 with HCI in acetic acid using the procedure described in example 260 have (163) (77 %) as a yellow powder, mp 194-196 °C. Η NMR δ [(CD3)2SO] 11.71 (s, IH), 10.97 (br s, IH), 9.68 (br s, IH), 8.38 (s, IH), 7.56 (dd, J=8.0, 2.2 Hz, IH), 7.49-7.39 (m, 4H), 7.02 (s, IH), 3.90 (s, 3H). Found: C, 63.38; H, 3.38; N, 6.20. C2ιHι3ClN204.l/4 H20 requires C, 63.49; H, 3.42; N, 7.05.
EXAMPLE 264
The preparation of 6-(Benzyloxy)-2-r2-(2-chlorophenyl )ethenyll-5-methoxy-l-(2-
Figure imgf000172_0001
Alkylation of diene (155) prepared as described in example 255 with sodium hydride and l-bromo2-methoxyethane using the procedure described in method3 gave (164) (91 %) (E/Z mixture of isomers) as an orange solid, which was used without further purification.
EXAMPLE 265
The preparation of 8-(Benzyloxy)-4-(2-chlorophenyl)-9-methoxy-6-(2-methoxyethyl)- 4.5.6.10c-tetrahvdropyrrolor3.4-c1carbazole-1.3(2H.3aH)-dione (XXII; Ar=2-chlorophenyl. R10--CH.CH,OCH (165) Reaction of diene (164) prepared as described in example 264 with maleimide using the procedure described in example 69 gave the adduct (165) as a tan solid (74 %), which was used without further purification.
EXAMPLE 266
The preparation of 8-(Benzyloxy)-4-(2-chlorophenyl)-9-methoxy-6-(2- methoxyethyl)pyrrolor3,4-c1carbazole-l,3(2H,6H)-dione (XXIII; Ar-=2-chlorophenyl.
Figure imgf000173_0001
Aromatisation of (165) prepared as described in example 265 with manganese dioxide using the procedure described in example 79 gave the carbazole (166) (89 %) as an orange powder, mp 252-254 °C. 'H NMR δ [(CD3)2SO] 11.04 (br s, IH), 8.49 (s, IH), 7.75 (s, IH), 7.59-7.35 (m, 10H), 5.29 (s, 2H), 4.66 (t, J=5.0 Hz, 2H), 3.91 (s, 3H), 3.68 (t, J=5.0 Hz, 2H), 3.14 (s, 3H). Found: C, 68.72; H, 4.73; N, 5.28. C3ιH25ClN 05 requires C, 68.82; H, 4.66; N, 5.18.
Representative Procedure for Method 19 of Scheme 6
EXAMPLE 267
The preparation of 4-(2-Chlorophenyl)-8-hvdroxy-9-methoxy-6-(2- methoxyethyl )pyrrolor3.4-clcarbazole-l ,3(2H,6H)-dione (XXV; Ar=2-chlorophenyl,
R10=CHoCH?OCHO (167).
Ethane thiol (5 mL) and boron trifluoride etherate (2.5 mL) were added to a solution of the benzyl ether (155) (0.840 g, 1.55 mmol) prepared as described in example 255 in dichloromethane (100 mL) and the solution was stirred at room temperature for 16 h. Petroleum ether (500 mL) was added and the mixture was chilled at -20 °C for 3 h. The solid was isolated by decantation of the liquid layer and partitioned between ethyl acetate and saturated aqueous NaHC03. The organic phase was dried, the drying agent was removed and the solution was concentrated to dryness gave an oily solid which was chromatographed on silica. Elution with ethyl acetate/petroleum ether (1:2) gave foreruns, while ethyl acetate/petroleum ether (1:1) eluted (167) (80 5) which crystallised from ethyl acetate/petroleum ether as a yellow powder, mp 249-252 °C. ]H NMR δ [(CD3)2SO] 10.98 (br, IH), 9.70 (br, IH), 8.44 (s, IH), 7.70 (s, IH), 7.57 (dd, J=8.0, 2.2 Hz, IH), 7.50-7.41 (m, 3H), 7.12 (s, IH), 4.56 (t, J=5.1 Hz, 2H), 3.92 (s, 3H), 3.68 (t, J=5.1 Hz, 2H), 3.16 (s, 3H). Found: C, 64.19; H, 4.43; N, 5.92. C24H19C1N205 requires C, 63.93; H, 4.25; N, 6.21.
Figure imgf000174_0001
SCHEME 7
Scheme 7 Procedures
EXAMPLE 268
The preparation of 4-(2-Chlorophenyl)-9-hvdroxy-6-(3-hydroxypropyl)-4,5,6,10c- tetrahvdropyrrolor3,4-clcarbazole-l,3(2H,3aH)-dione (XIX; Ar=2-chlorophenyl, R10=CH- 2CH2CH2OH) (139).
Demethylation of 4-(2-Chlorophenyl)-6-(3-hydroxypropyl)-9-methoxy-4,5,6,10c- tetrahydropyrrolo[3,4-c]carbazole-l,3(2H,3aH)-dione (IV; Ar=2-chlorophenyl, R10=CH- 2CH2CH2OH) (30) prepared by the first step in the procedure described in example 39 with BBr3 using the procedure described in example 80 followed by an acidic workup gave (139) (77%) as a pink powder, mp 190-196 °C (dec). Η NMR δ [(CD3)2SO] 10.82 (br s, IH), 8.72 (br s, IH), 7.71 (dd, J=7.7, 1.0 Hz, IH), 7.46 (dd, J=8.0, 1.4 Hz, IH), 7.39 (m, IH), 7.31 (m, IH), 7.21 (d, J=8.5 Hz, IH), 7.15 (d, J=2.3 Hz, IH), 6.62 (dd, J=8.5, 2.3 Hz, IH), 4.57 (t, J=4.7 Hz, IH), 4.25 (d, J=7.5 Hz, IH), 4.11 (t, J=6.9 Hz, 2H), 3.94 (dd, J=7.5, 3.6 Hz, IH), 3.53 (dt, J=12.6, 3.7 Hz, IH), 3.22 (m, 2H), 3.03 (dd, J=15.6, 3.6 Hz, IH), 1.77 (m, 2H). Found: C, 63.57; H, 5.13; N, 6.31. C23H2ιClN204.l/2H20 requires C, 63.66; H, 5.11; N, 6.45.
Figure imgf000175_0001
Figure imgf000175_0002
SCHEME 8
Procedures for Scheme 8
EXAMPLE 269
The preparation of 4-Methoxy-2-r2-phenylethenyll-lH-indole (XXVI; Ar=phenyl) (141).
Reaction of 4-methoxyindole-2-carboxaldehyde with benzyltriphenylphosphonium bromide using the procedure described in example 37 gave (141) (89%) as a fluorescent oil, (mixture of E/Z isomers) which was used without further purification.
EXAMPLE 270
The preparation of 10-Methoxy-4-phenyl-4,5,6,10c-tetrahydrocvclopentarc1carbazole- 1.3(2H.3aH)-dione (XXVIII; Ar=phenyl. R10=H) (142). Reaction of the diene (141) prepared by the procedure described in example 269 with maleimide using the procedure described in method4 gave the adduct (142) as a yellow solid (86 %), which was used without further purification.
EXAMPLE 271
The preparation of 10-Methoxy-4-phenylcvclopenta[c1carbazole-1.3(2H,6H)-dione (XXVIX: Ar=phenyl. R10=H) (143).
Aromatisation of (142) prepared by the procedure described in example 270 with DDQ using the procedure described in example 70 gave the carbazole (143) (78%) as yellow needles, mp 273-276 °C. Η NMR δ [(CD3)2SO] 12.10 (s, IH), 10.78 (s, IH), 7.59 (s, IH), 7.57 (dd, J=8.0, 1.8 Hz, 2H), 7.49 (t, J=7.9 Hz, IH), 7.47-7.39 (m, 3H), 7.16 (d, J=7.9 Hz, IH), 6.80 (d, J=7.9 Hz, IH), 3.99 (s, 3H). Found: C, 73.55; H, 4.16; N, 7.93. C2ιH14N203 requires C, 73.67; H, 4.12; N, 8.18.
EXAMPLE 272
The preparation of 10-Hvdroxy-4-phenylcvclopentarc1carbazole-l,3(2H,6H)-dione (XXX;
Figure imgf000176_0001
Demethylation of (143) prepared by the procedure described in example 271 with BBr3 using the procedure described in example 80 gave (144) as a yellow/orange solid (92 %), mp >300 °C. ]H NMR δ [(CD3)2SO] 12.33 (s, IH), 12.16 (s, IH), 11.65 (br, IH), 7.62 (s, IH), 7.60 (dd, J=7.9, 1.8 Hz, 2H), 7.51-7.45 (m, 3H), 7.40 (dd, J=7.6 Hz, IH), 7.03 (d, J=7.6 Hz, IH), 6.63 (d, J=7.6 Hz, IH). Found: C, 72.87; H, 3.76; N, 8.44. C2oHi2N203 requires C, 73.16; H, 3.68; N, 8.53.
EXAMPLE 273
The preparation of 6-Methoxy-2-f2-phenylethenyll-lH-indole (XXXI; Ar=phenyl) (146).
Reaction of 6-methoxyindole-2-carboxaldehyde (145) with benzyltriphenylphosphonium bromide using the procedure described in example 37 gave (146) (94%) as a white solid (mixture of E/Z isomers) which was used without further purification.
EXAMPLE 274 The preparation of 8-Methoxy-4-phenyl-4,5.6,10c-tetrahvdrocvclopentarc1carbazole- 1.3(2H.3aH)-dione (XXXIII; Ar=phenyl, R10=H) (147).
Reaction of the diene (146) prepared by the procedure described in example 273 with maleimide using the procedure described in method4 gave the adduct (147) as a tan solid (61 %), which was used without further purification.
EXAMPLE 275
The preparation of 8-Methoxy-4-phenylcyclopentarclcarbazole-l,3(2H,6H)-dione (XXXIV; Ar=phenyl. R10=H) (148).
Aromatisation of (147) prepared by the procedure described in example 274 with DDQ using the procedure described in example 70 gave the carbazole (148) (65 %) as a yellow powder, mp 154-156 °C. 1H NMR δ [(CD3)2SO] 11.87 (br, IH), 11.02 (br, IH), 8.75 (d, J=8.8 Hz, IH), 7.61 (dd, J=8.0, 1.8 Hz, 2H), 7.60 (s, IH), 7.49-7.40 (m, 3H), 7.10 (d, J=2.2 Hz, IH), 6.94 (dd, J=8.8, 2.2 Hz, IH), 3.90 (s, 3H). Found: C, 72.49; H, 4.14; N, 8.22. C2iHι4N2θ3.1/4H20 requires C, 72.71; H, 4.21; N, 8.07.
EXAMPLE 276
The preparation of 8-Hydroxy-4-phenylcyclopentarclcarbazole-l,3(2H,6H)-dione (XXXV; Ar=phenyl. R10=H) (149)
Demethylation of (148) prepared by the procedure described in example 276 with BBr3 using the procedure described in example 80 gave (149) as a yellow powder (74 %), mp >330 °C. Η NMR δ [(CD3)2SO] 11.75 (br, IH), 10.96 (br, IH), 10.56 (br, IH), 8.66 (d, J=8.6 Hz, IH), 7.60 (dd, J=8.0, 1.8 Hz, 2H), 7.53 (s, IH), 7.49-7.39 (m, 3H), 6.93 (d, J=2.1 Hz, IH), 6.79 (dd, J=8.6, 2.1 Hz, IH). Anal. Found: C, 72.36; H, 3.82; N, 8.18. C20Hι2N2O3.l/4H2O requires C, 72.17; H, 3.78; N, 8.41.
EXAMPLE 277
The preparation of 2-r(E,Z)-2-(2-Chlorophenyl)ethenvH-6-methoxy-lH-indole (XXXI; Ar=2- chlorophenyl) (841)
Reaction of 6-methoxyindole-2-carboxaldehyde (145) with 2- chlorobenzyltriphenylphosphonium chloride using the procedure described in example 37 gave (841) as a mixture of E/Z isomers as a yellow solid (93 %), which was used without further purification. EXAMPLE 278
The preparation of 2-r(E,Z)-2-(2-Chlorophenyl)ethenyl1-6-methoxy-l-methyl-lH-indole (XXXII: Ar=2-chlorophenyl, R10=CHQ (842)
Alkylation of (841) with iodomethane using the procedure described in method3 gave (842) as a yellow solid (77 %), which was used without further purification.
EXAMPLE 279
The preparation of 4-(2-Chlorophenyl)-8-methoxy-6-methylpyrrolor3,4-clcarbazole- l ,3(2H,6H)-dione (XXXIV; Ar=2-chlorophenyl. R10=CH.) (844)
Reaction of (842) prepared as described in example 278 with maleimide using the procedure described in method4 example 68 gave the adduct (XXXIII; Ar=2-chlorophenyl, RI0=CH3) (843) as a tan powder, which was used without further purification. Aromatisation of (843) with Mnθ2 using the procedure described in example 79 gave (844) as a yellow powder (78 % overall), mp >300 °C. !H NMR δ [(CD3)2SO] 11.07 (br s, IH), 8.77 (d, J=8.7 Hz, IH), 7.76 (s, IH), 7.59 (dd, J=8.0, 2.2 Hz, IH), 7.52-7.43 (m, 3H), 7.27 (d, J=2.2 Hz, IH), 7.00 (dd, J=8.7, 2.2 Hz, IH), 3.95 (s, 3H), 3.94 (s, 3H). Found: C, 66.86; H, 4.04; N, 6.90; Cl, 9.26. C22H15C1N203 .0.2H2O requires: C, 66.99; H, 3.94; N, 7.10; Cl, 8.99 .
EXAMPLE 280
The preparation of 4-(2-Chlorophenyl)-8-hvdroxy-6-methylpyrrolor3,4-c1carbazole- 1.3(2H.6H)-dione (XXXV; Ar=2-chlorophenyl. R10=CH^) (845)
Demethylation of (844) prepared as described in example 279 with BBr3 using the procedure described in example 80 gave (845) (54 %) as a yellow solid, mp 304-306 °C. Η NMR δ [(CD3)2SO] 11.02 (br, IH), 10.08 (br, IH), 8.69 (d, J=8.6 Hz, IH), 7.71 (s, IH), 7.58 (m, IH), 7.51-7.42 (m, 3H), 6.99 (d, J=2.0 Hz, IH), 6.88 (dd, J=8.6, 2.0 Hz, IH), 3.87 (s, 3H). Found: C, 63.93; H, 3.95; N, 7.08; Cl, 9.12. C2ιHι3ClN203 .H20 requires: C, 63.89; H, 3.83; N, 7.10; Cl, 8.98.
Figure imgf000179_0001
(XXXVIII) (XXXIX)
SCHEME 9
Scheme 9 Procedures
EXAMPLE 281
The preparation of 4-(2-Chlorophenyl)-9-hvdroxy-6-r2-(lH-tetraazol-5-yl)ethyllpyrroloF3,4- c1carbazole-1.3(2H,6H)-dione (XXXVI; Ar=2-chlorophenyl. n=2) (272)
To a solution of nitrile (238) (0.68 g, 1.63 mmol) prepared as described in example 98 in toluene/dimethylformamide (5:1, 120 mL) was added azidotrimethyl tin (0.67 g, 3.26 mmol). The resulting solution was heated at reflux for 24 hours before a further portion of azidotrimethyl tin (0.34 g, 1.63 mmol) was added. After a further 24 hours at reflux the reaction was diluted with water and extraction with ethyl acetate. The organic phase was dried, the drying agent was removed and the solution was concentrated to dryness. Chromatography on silica eluting with ethyl acetate/hexane (3:1) to ethyl acetate/methanol (9: 1), followed by crystallization from ethyl acetate/hexane, gave tetrazole (272) (0.54 g, 72%) as an orange powder, mp 230-234 °C (dec). Η NMR δ [(CD3)2SO] 11.06 (br s, IH), 9.37 (br s, IH), 8.36 (d, J=2.4 Hz, IH), 7.61 (s, IH), 7.56 (m, IH), 7.48 (m, 4H), 7.10 (dd, J=8.8, 2.4 Hz, IH), 4.82 (t, J=6.9 Hz, 2H), 3.32 (obscured t, J=6.9 Hz, 2H). Found: C, 52.69; H, 4.05; N, 15.91.
Figure imgf000180_0001
requires: C, 52.93; H, 4.25; N, 16.09.
EXAMPLE 282
The preparation of 4-(2-Chlorophenyl)-9-hvdroxy-6-r3-(lH-tetraazol-5- yl)propyllpyrrolor3,4-clcarbazole-l,3(2H,6H)-dione (XXXVI: Ar=2-chlorophenyl. n=3) (273)
To a solution of nitrile (241) (60 mg, 0.14 mmol) prepared as described in example 191 in toluene/dimethylformamide (5:1, 35 mL) was added azidotrimethyl tin (57 mg, 0.28 mmol). The resulting solution was heated at reflux for 72 hours before being diluted with water and extraction with ethyl acetate. The organic phase was dried, the drying agent was removed and the solution was concentrated to dryness. Chromatography on silica eluting with ethyl acetate/hexane (3:1) to ethyl acetate/methanol (9:1), followed by crystallization from tetrahydrofuran/hexane, gave tetrazole (273) (29 mg, 44%) as an orange powder, mp 269-272 °C. Η NMR δ [(CD3)2SO] -16 (v br s, IH), 11.07 (s, IH), 9.38 (br s, IH), 8.39 (d, J=2.5 Hz, IH), 7.84 (s, IH), 7.61 (d, J=8.9 Hz, IH), 7.57 (m, IH), 7.53-7.43 (m, 3H), 7.16 (dd, J=8.9, 2.5 Hz, IH), 4.59 (t, J=7.1 Hz, 2H), 2.93 (m, 2H), 2.20 (m, 2H). Found: C, 59.71; H, 4.27; N, 16.72. C24Hι7ClN603.3/4H20 requires: C, 59.26; H, 3.83; N, 17.27. EXAMPLE 283
The preparation of 4-(2-Chlorophenyl)-9-methoxy-6-r2-(lH-1.2,4-triazol-5- ylsulfanyl)ethvnpyrrolor3.4-clcarbazole-l ,3(2H.6H)-dione (XXXVII: Ar=2-chlorophenyl. R3=5-lH-1.2.4-triazolyl) (274)
A solution of mesylate (228) (0.25 g, 0.50 mmol) prepared as described in example 170 , lH-l,2,4-triazole-5-thiol (76 mg, 0.75 mmol) and triethylamine (2.0 mL) in p-dioxane (50 mL) under nitrogen was heated at reflux for 48 hours, before being diluted with water and extraction with ethyl acetate. The organic phase was dried, the drying agent was removed and the solution was concentrated to dryness. Chromatography on silica eluting with ethyl acetate/hexane (1:1 to 1:0), followed by crystallization from ethyl acetate/hexane, gave carbazole (274) (0.24 g, 95%) as a yellow powder, mp 211-213 °C. 1H NMR δ [(CD3)2S0] 14.09 (br s, IH), 11.13 (br s, IH), 8.52 (d, J=2.6 Hz, IH), 8.43 (v br s, IH), 7.88 (s, IH), 7.80 (d, J=9.0 Hz, IH), 7.57 (m, IH), 7.48 (m, 3H), 7.31 (dd, J=9.0, 2.6 Hz, IH), 4.83 (t, J=7.4 Hz, 2H), 3.91 (s, 3H), 3.52 (t, J=7.4 Hz, 2H). Found: C, 59.29; H, 3.77; N, 13.63. C25H18C1N503S.1/4H20 requires: C, 59.29; H, 3.68; N, 13.82.
EXAMPLE 284
The preparation of 4-(2-Chlorophenyl)-6-r2-(lH-imidazol-2-ylsulfanyl)ethyll-9- methoxypyrrolor3.4-c1carbazole-1.3(2H.6H)-dione (XXXVII; Ar=2-chlorophenyl, R3=2- imidazolyl) (275)
A solution of mesylate (228) (0.30 g, 0.60 mmol) prepared as described in example 170 , 2-mercaptoimidazole (0.12 g, 1.20 mmol) and triethylamine (2.0 mL) in p-dioxane (25 mL) under nitrogen was heated at reflux for 24 hours, before being diluted with water to precipitate the crude product, which was collected by filtration, washed with water and dried in vacuo. Chromatography on silica eluting with ethyl acetate/hexane (1:1), followed by trituration from ethyl acetate, gave carbazole (275) (0.29 g, 96%) as a yellow powder, mp 245-247 °C. Η NMR δ [(CD3)2SO] 12.24 (br s, IH), 11.13 (br s, IH), 8.51 (d, J=2.6 Hz, IH), 7.92 (s, IH), 7.75 (d, J=9.0 Hz, IH), 7.58 (m, IH), 7.48 (m, 3H), 7.29 (dd, J=9.0, 2.6 Hz, IH), 7.00 (v br s, 2H), 4.78 (t, J=7.5 Hz, 2H), 3.91 (s, 3H), 3.44 (t, J=7.5 Hz, 2H). Found: C, 61.57; H, 4.14; N, 10.85. C26H19ClN4O3S.l/4H20 requires: C, 61.53; H, 3.87; N, 11.03. EXAMPLE 285
The preparation of 4-(2-Chlorophenyl)-9-hvdroxy-6-r2-(4H-l,2,4-triazol-3- ylsulfanyl)ethyllpyrro1or3,4-clcarbazole-l ,3(2H.6H)-dione (XXXVIII; Ar=2-chlorophenyl. R3=5-lH-1.2.4-triazolyl) (276)
Reaction of methyl ether (274) (0.25 g, 0.50 mmol) prepared as described in example 283 according to the procedure described in example 80, followed by chromatography on silica eluting with ethyl acetate/tetrahydrofuran (1:0 to 9: 1 to 1: 1) and trituration from methanol, gave phenol (276) (0.22 g, 90%) as an orange powder, mp 314-319 °C. !H NMR δ [(CD3)2SO] 14.10 (br s, IH), 11.07 (br s, IH), 9.39 (s, IH), 8.42 (v br s, IH), 8.38 (d, J=2.3 Hz, IH), 7.83 (s, IH), 7.68 (d, J=8.8 Hz, IH), 7.57 (m, IH), 7.48 (m, 3H), 7.13 (dd, J=8.8, 2.3 Hz, IH), 4.79 (t, J=7.4 Hz, 2H), 3.50 (t, J=7.4 Hz, 2H). Found: C, 58.56; H, 3.82; N, 13.58. H16C1N503S.2/5CH40 requires: C, 58.29; H, 3.53; N, 13.93.
EXAMPLE 286
The preparation of 4-(2-Chlorophenyl)-9-hvdroxy-6-r2-(lH-imidazol-2- ylsulfanyl)ethyllpyrrolor3,4-clcarbazole-1.3(2H.6H)-dione (XXXVIII; Ar=2-chlorophenyl. R3=2-imidazolyl) (277)
Reaction of methyl ether (275) (130 mg, 0.24 mmol) prepared as described in example 284 according to The procedure described in example 80, except that the reaction time was 7 hours and the chromatography was performed eluting with ethyl acetate/hexane (1:1 to 3: 1), gave phenol (277) (97 mg, 83%) as an orange powder, mp 270-275 °C. Η NMR δ [(CD3)2SO] 12.23 (br s, IH), 11.07 (br s, IH), 9.39 (br s, IH), 8.37 (d, J=2.4 Hz, IH), 7.86 (s, IH), 7.61 (d, J=8.9 Hz, IH), 7.57 (m, IH), 7.48 (m, 3H), 7.12 (dd, J=8.9, 2.4 Hz, IH), 6.98 (v br s, 2H), 4.74 (t, J=7.7 Hz, 2H), 3.42 (partially obscured t, J=7.7 Hz, 2H). Found: C, 60.87; H, 3.72; N, 11.00. C25Hι7ClN403S.l/4H20 requires: C, 60.85; H, 3.57; N, 11.35.
EXAMPLE 287
The preparation of 4-(2-Chlorophenyl)-9-hvdroxy-6-r2-(lH-l,2,4-triazoI-5- ylsulfinyl)ethvπpyrrolor3 ,4-clcarbazole-l ,3(2H,6H)-dione (XXXIX; Ar=2-chlorophenyl, m=l. R3=5-lH-l,2.4-triazolyl) (278)
To a solution of carbazole (276) (70 mg, 0.14 mmol) prepared as described in example 285 in tetrahydrofuran (30 mL) containing glacial acetic acid (8 mL), was added 35% hydrogen peroxide (2 mL). The resulting solution was stirred at room temperature for 10 hours before being poured onto solid sodium bicarbonate, diluted with water and extraction with ethyl acetate. The organic phase was dried, the drying agent was removed and the solution was concentrated to dryness. The combined organic layers were partially concentrated under reduced pressure, then adsorbed directly onto silica and chromatographed eluting with methanol/dichloromethane (5:95 to 1:9). Trituration from diethyl ether gave sulfoxide (278) (29 mg, 41%) as an orange powder, mp 237-242 °C. Η NMR δ [(CD3)2SO] 14.7 (v br s, IH), 11.09 (br s, IH), 9.41 (br s, IH), 8.69 (br s, IH), 8.38 (d, J=2.3 Hz, IH), 7.79 (d, J=9.6 Hz, IH), 7.60-7.46 (m, 5H), 7.15 (dd, J=8.8, 2.3 Hz, IH), 4.89 (m, 2H), 3.71 (m, 2H). Found: C, 56.85; H, 3.79; N, 13.74. C24Hι6ClN5O4S.l/5C4H10O requires: C, 57.20; H, 3.48; N, 13.45.
EXAMPLE 288
The preparation of 4-(2-Chlorophenyl)-9-hvdroxy-6-r2-(lH-l,2,4-triazol-5- ylsulfonyl)ethyllpyrrolor3,4-c1carbazole-1.3(2H,6H)-dione (XXXIX; Ar=2-chlorophenyl. m=2. R3=5-lH-1.2.4-triazolyl) (279)
To a solution of carbazole (276) (60 mg, 0.12 mmol) prepared as described in example 285 in tetrahydrofuran (30 mL) containing glacial acetic acid (10 mL), was added 35% hydrogen peroxide (2 mL). The resulting solution was stirred at room temperature for 30 hours before additional 35% hydrogen peroxide (2 mL) was added and the temperature was increased to 50 °C for 18 hours. The reaction was then poured onto solid sodium bicarbonate, diluted with water and extracted with ethyl acetate. The combined organic layers were partially concentrated under reduced pressure, then adsorbed directly onto silica and chromatographed eluting with ethyl acetate/hexane (1: 1 to 1:0). Crystallisation from ethyl acetate/hexane gave sulfone (279) (45 mg, 72%) as an orange powder, mp 301-304 °C. 1H NMR δ [(CD3)2SO] 14.9 (v br s, IH), 11.07 (br s, IH), 9.38 (br s, IH), 8.60 (s, IH), 8.34 (d, J=2.4 Hz, IH), 7.71 (s, IH), 7.56 (m, 2H), 7.48 (m, 3H), 7.12 (dd, J=8.8, 2.4 Hz, IH), 4.89 (m, 2H), 4.03 (m, 2H). Found: C, 55.12; H, 3.52; N, 12.87. C24Hi6ClN505S.l/4C4H802 requires: C, 55.20; H, 3.34; N, 12.88. EXAMPLE 289
The preparation of 4-(2-Chlorophenyl)-9-hvdroxy-6-r2-(lH-imidazol-2- ylsulfonyl)ethyllpyrrolor3,4-clcarbazole-1.3(2H.6H)-dione (XXXIX: Ar=2-chlorophenyl. m=2. R3-=2-imidazolyl) (280) and 4-(2-chlorophenyl)-9-hvdroxy-6-r2-(lH-imidazol-2- ylsulfinyl)ethvnpyrrolor3,4-clcarbazole-l ,3(2H,6H)-dione (XXXIX; Ar=2-chlorophenyl. m=l. R3=2-imidazolyl) (281)
To a solution of carbazole (277) (66 mg, 0.14 mmol) prepared as described in example 286 in tetrahydrofuran (30 mL) containing glacial acetic acid (10 mL), was added 35% hydrogen peroxide (2 mL). The resulting solution was stirred at room temperature for 20 hours before being poured onto solid sodium bicarbonate, diluted with water and extracted with ethyl acetate. The combined organic layers were partially concentrated under reduced pressure, then adsorbed directly onto silica and chromatographed eluting with ethyl acetate/hexane (1:1 to 4:1) to ethyl acetate/methanol (99:1) to give at highest Rf, sulfone (280) (36 mg, 51%) as an orange powder, mp 263-265 °C. ]H NMR δ [(CD3)2SO] 11.09 (br s, JH), 9,44_(br s, H),.8.35iα\ J=2.4 Hz, IH), 7.63 (s, IH), 7.58 (m, IH), 7.52-7.45 (m, 4H), 7.19 (br s, 2H), 7.12 (dd, J=8.8, 2.4 Hz, IH), 4.85 (t, J=6.6 Hz, 2H), 3.96 (m, 2H). Found: C, 57.44; H, 3.87; N, 9.80. C25H17C1N405S.1/2C4H802 requires: C, 57.40; H, 3.75; N, 9.92. This was followed at lower Rf by the sulfoxide (281) (16 mg, 23%) as an orange powder, mp 254- 259 °C. Η NMR δ [(CD3)2SO] 13.35 (br s, IH), 11.10 (br s, IH), 9.42 (s, IH), 8.39 (d, J=2.4 Hz, IH), 7.77 (d, J=12.7 Hz, IH), 7.58 (m, 2H), 7.53-7.44 (m, 3H), 7.24 (br s, 2H), 7.15 (dd, J=8.8, 2.4 Hz, IH), 4.85 (m, 2H), 3.69 (m, 2H). FABMS found [M+H]+: 505.0725, 507.0666. C25Hι7ClN404S requires 505.0737, 507.0708.
Figure imgf000185_0001
μ Maleimide/SnClj Δ METHOD 4 METHOD 8
2) DDQ/Δ Py.HCI/200-220 °C METHOD 6 METHOD 9
Figure imgf000185_0002
(XLIII)
SCHEME 10
Scheme 10 Procedures
EXAMPLE 290
The preparation of 6-(2-Hvdroxy-3-methoxypropyl)-9-methoxy-4-phenylpyrrolo|"3,4- c1carbazole-l,3(2H,6H)-dione (XLII; Ar=phenyl. Z=OCH (225)
Alkylation of 5-methoxy-2-[(E)-2-phenylethenyl]-lH-indole (II; Ar=phenyl) (0.20 g, 0.80 mmol) with epibromohydrin according to the procedure described in example 38 example 38 gave crude epoxide (XL; Ar=phenyl), which was used without further purification. The epoxide was dissolved in methanol (100 mL) to which 35% perchloric acid (10 mL) was added. The resulting solution was heated at reflux for 3 h before being diluted with water and extraction with ethyl acetate. The organic phase was dried, the drying agent was removed and the solution was concentrated to dryness to give diene (XLI; Ar=phenyl, Z=OCH3). This crude material was reacted directly with maleimide (92 mg) following Method 4a, except that the reaction time was 18 h. Aromatisation of the crude Diels-Alder adduct using the procedure described in example 79 gave material that was chromatographed on silica eluting with ethyl acetate/hexane (1:1). Crystallisation from ethyl acetate/hexane gave carbazole (225) (0.10 g, 30%) as a yellow powder, mp 128-136 °C. Η NMR δ [(CD3)2SO] 11.10 (br s, IH), 8.55 (d, J=2.6 Hz, IH), 7.81 (s, IH), 7.64 (m, 3H), 7.47 (m, 3H), 7.29 (dd, J=9.1, 2.6 Hz, IH), 5.17 (d, J=5.5 Hz, IH), 4.52 (dd, J=4.2, 15.0 Hz, IH), 4.43 (dd, J=7.1, 15.0 Hz, IH), 4.04 (m, IH), 3.90 (s, 3H), 3.32 (m, 2H), 3.26 (s, 3H). Found: C, 69.94; H, 5.45; N, 6.36. C25H22N205 requires: C, 69.76; H, 5.15; N, 6.51.
EXAMPLE 291
The preparation of 6-(2,3-Dihvdroxypropyl)-9-hvdroxy-4-phenylpyrrolor3,4-c1carbazole- 1.3(2H.6H)-dione (XLIII; Ar=phenyl, Z=OH) (226)
Demethylation of alcohol (225) (96 mg, 0.22 mmol) prepared as described in example 290 employing the procedure described in example 80 was followed by chromatography on silica eluting with ethyl acetate/hexane (4:1). Crystallisation from ethyl acetate/hexane gave phenol (226) (28 mg, 31%) as an orange/yellow powder, mp 290-295 °C. ]H NMR δ [(CD3)2SO] 11.04 (br s, IH), 9.30 (s, IH), 8.40 (d, J=2.4 Hz, IH), 7.79 (s, IH), 7.63 (m, 2H), 7.55 (d, J=8.8 Hz, IH), 7.47 (m, 3H), 7.11 (dd, J=8.8, 2.4 Hz, IH), 5.00 (d, J=5.4 Hz, IH), 4.86 (t, J=5.4 Hz, IH), 4.51 (dd, J=3.8, 14.9 Hz, IH), 4.35 (dd, J=7.5, 14.9 Hz, IH), 3.89 (m, IH), 3.41 (m, 2H). Found: C, 67.94; H, 4.69; N, 6.50. C23H,8N205.1/4H20 requires: C, 67.89; H, 4.58; N, 6.88.
EXAMPLE 292
The preparation of 4-(2-Chlorophenyl)-9-hydroxy-6-r2-hvdroxy-3-(4- morpholinyl)propyHpyrrolor3,4-clcarbazole-l ,3(2H,6H)-dione (XLIII; Ar=2-chlorophenyl, Z=4-morpholinyl) (282)
Alkylation of pure trans-diene (27) (0.25 g, 0.88 mmol) prepared as described in example 37 with epibromohydrin according to the procedure described in example 38 gave crude epoxide (XL; Ar=2-chlorophenyl), which was used without further purification. The epoxide was dissolved in tetrahydrofuran (2 mL) to which moφholine (0.5 mL) was added. The resulting solution was heated at 60 °C for 48 hours before being diluted with water and extraction with ethyl acetate. The organic phase was dried, the drying agent was removed and the solution was concentrated to dryness to give diene (XLI; Ar=2-chlorophenyl, Z=4- morpholinyl). This crude material was triturated in diethyl ether/hexane and then reacted directly with maleimide (128 mg) following The procedure described in example 68, except that the reaction time was 18 h and p-dioxane was added as a co-solvent. Aromatisation of the crude Diels-Alder adduct using the procedure described in example 70 gave carbazole (XLII; Ar=2-chlorophenyl, Z=4-morpholinyl) which was demethylated employing the procedure described in example 81, to give crude material that was chromatographed on silica eluting with ethyl acetate. Crystallisation from diethyl ether/hexane gave carbazole (282) (0.10 g, 22%) as a yellow powder, mp 275-278 °C. ]H NMR δ [(CD3)2SO] 11.05 (br s, IH), 9.34 (br s, IH), 8.37 (d, J=2.4 Hz, IH), 7.79 (s, IH), 7.63-7.56 (m, 2H), 7.47 (m, 3H), 7.12 (m, IH), 5.01 (t, J=5.7 Hz, IH), 4.53 (m, IH), 4.37 (m, IH), 4.04 (br s, IH), 3.38 (m, 4H), 2.39-2.24 (m, 6H). Found: C, 63.90; H, 4.85; N, 8.55. C27H24C1N305 requires: C, 64.10; H, 4.78; N, 8.31.
EXAMPLE 293
The preparation of 4-(2-Chlorophenyl)-6-r3-(cis-3,5-dimethyl-l-piperazinyl)-2- hydroxypropyll-9-hvdroxypyrrolof3,4-clcarbazole-l,3(2H,6H)-dione (XLIII; Ar=2- chlorophenyl, Z= cis-3,5-dimethyl-l-piperazinyl) (283)
Alkylation of pure trans-diene (27) (0.25 g, 0.88 mmol) prepared as described in example 37 with epibromohydrin according to the procedure described in example 38 gave crude epoxide (XL; Ar=2-chlorophenyl), which was used without further purification. The epoxide was dissolved in tetrahydrofuran (2 mL) to which cis-2,6-dimethylpiperazine (0.50 g, 4.4 mmol) was added. The resulting solution was heated at 60 °C for 48 hours before being diluted with water and extraction with ethyl acetate. The organic phase was dried, the drying agent was removed and the solution was concentrated to dryness to give diene (XLI; Ar=2- chlorophenyl, Z=cis-3,5-dimethyl-l-piperazinyl). This crude material was triturated in diethyl ether/hexane and then reacted directly with maleimide (0.13 g, 1.5 mmol) following The procedure described in example 68, except that the reaction time was 18 h and p-dioxane was added as a co-solvent. Aromatisation of the crude Diels-Alder adduct using the procedure described in example 70 gave carbazole (XLII; Ar=2-chlorophenyl, Z=cis-3,5-dimethyl-l- piperazinyl) which was demethylated employing The procedure described in example 81 to give crude material that was chromatographed on silica eluting with ethyl acetate/methanol triethylamine (4:l:trace). Crystallisation from ethyl acetate/hexane gave carbazole (283) (65 mg, 14%) as a yellow powder, mp 206-210 °C. Η NMR δ [(CD3)2SO] 11.02 (br s, IH), 9.33 (br s, IH), 8.37 (d, J=2.5 Hz, IH), 7.76 (d, J=9.1, IH), 7.58 (m, 2H), 7.47 (m, 3H), 7.11 (m, IH), 4.95 (br s, IH), 4.52 (m, IH), 4.34 (m, IH), 4.04 (m, IH), 2.71- 2.53 (m, 4H), 2.33 (m, IH), 2.20 (m, IH), 1.46 (m, 2H), 0.81 (m, 6H). Found: C, 63.76; H, 5.30; N, 10.02. C29H29C1N404.3/4H20 requires: C, 63.73; H, 5.63; N, 10.25. EXAMPLE 294
The preparation of 4-(2-Chlorophenyl)-9-hydroxy-6-r2-hydroxy-3-
(methylamino)propyllpyrro1or3,4-c]carbazole-l,3(2H,6H)-dione (XLIII; Ar=2-chlorophenyl. Z=NHCH (284)
Alkylation of pure trans-diene (27) (0.25 g, 0.88 mmol) prepared as described in example 37 with epibromohydrin according to proceedure described in example 38 gave crude epoxide (XL; Ar=2-chlorophenyl), which was used without further purification. The epoxide was dissolved in tetrahydrofuran (2 mL) to which aqueous methylamine (0.5 mL, 40% solution) was added. The resulting solution was heated at 60 °C for 6 hours before being diluted with water and extraction with ethyl acetate. The organic phase was dried, the drying agent was removed and the solution was concentrated to dryness to give diene (XLI; Ar=2- chlorophenyl, Z=NHCH3). This crude material was triturated in diethyl ether/hexane and then reacted directly with maleimide (0.13 g, 1.5 mmol) following The procedure described in example 68, except that the reaction time was 18 h and p-dioxane was added as a co-solvent. Aromatisation of the crude Diels-Alder adduct using the procedure described in example 70 gave carbazole (XLII; Ar=2-chlorophenyl, Z=NHCH3) which was demethylated employing The procedure described in example 81 to give crude material that was chromatographed on silica eluting with ethyl acetate/methanol/triethylamine (4:l :trace). Crystallisation from ethyl acetate/hexane gave carbazole (284) (61 mg, 15%) as a yellow powder, mp 188-191 °C. 1H NMR δ [(CD3)2SO] 10.9 (v br s, IH), 9.36 (br s, IH), 8.37 (d, J=2.4 Hz, IH), 7.77 (s, IH), 7.58 (m, 2H), 7.47 (m, 3H), 7.13 (dd, J=8.8, 2.4 Hz, IH), 5.09 (br s, IH), 4.50 (m, IH), 4.34 (m, IH), 3.97 (m, IH), 2.77-2.63 (m, 2H), 2.28 (d, J=2.1Hz, 3H). Found: C, 62.66; H, 4.64; N, 8.69. C24H20ClN3O4.2/3H2O requires: C, 62.40; H, 4.66; N, 9.09.
EXAMPLE 295
The preparation of 4-(2-ChlorophenvI)-6-r3-(dimethylamino)-2-hydroxypropyl"l-9- hvdroxypyrrolor3,4-clcarbazole-l,3(2H.6H)-dione (XLIII; Ar=2-chlorophenyl, Z=N(CH?V) (285)
Alkylation of pure trans-diene (27) (0.25 g, 0.88 mmol) prepared as described in example 37 with epibromohydrin according to proceedure described in example 38 gave crude epoxide (XL; Ar=2-chlorophenyl), which was used without further purification. The epoxide was dissolved in tetrahydrofuran (2 mL) to which aqueous dimethylamine (0.5 mL, 40% solution) was added. The resulting solution was heated at 60 °C for 6 hours before being diluted with water and extraction with ethyl acetate. The organic phase was dried, the drying agent was removed and the solution was concentrated to dryness to give diene (XLI; Ar=2- chlorophenyl, Z=N(CH3)2). This crude material was triturated in diethyl ether/hexane and then reacted directly with maleimide (0.13 g, 1.5 mmol) following the procedure described in example 68, except that the reaction time was 18 h and p-dioxane was added as a co-solvent. Aromatisation of the crude Diels-Alder adduct using the procedure described in example 70 gave carbazole (XLII; Ar=2-chlorophenyl, Z=N(CH3)2) which was demethylated employing the procedure described in example 81 to give crude material that was chromatographed on silica eluting with ethyl acetate/methanol/triethylamine (4:l:trace). Crystallisation from ethyl acetate/hexane gave carbazole (285) (165 mg, 40%) as a yellow powder, mp 225-228 °C. Η NMR δ [(CD3)2SO] 11.04 (br s, IH), 9.34 (br s, IH), 8.38 (d, J=2.4 Hz, IH), 7.75 (s, IH), 7.57 (m, 2H), 7.47 (m, 3H), 7.13 (dd, J=8.8, 2.4 Hz, IH), 4.91 (br s, IH), 4.50 (m, IH), 4.34 (m, IH), 4.00 (m, IH), 2.35 (m, IH), 2.24 (m, IH), 2.17 (s, 6H). Found: C, 63.54; H, 4.60; N, 8.83. C25H22C1N304.1/2H20 requires: C, 63.49; H, 4.90; N, 8.88.
Figure imgf000190_0001
(XLVII)
1) TFA/anisole/90 °C
2) BBr3 (METHOD 8)
METHOD 22
Figure imgf000190_0002
(XLVIII)
Figure imgf000190_0003
SCHEME 11
Scheme 11 Procedures
EXAMPLE 296
The preparation of 4-(2-Chlorophenyl)-9-methoxy-4,5,6,10c-tetrahydro-lH-furor3,4- clcarbazole-1.3(3aH)-dione (XLIV: Ar=2-chlorophenyl) (286) A solution of trans-diene (27) (0.30 g, 1.06 mmol) prepared as described in example 37 and maleic anhydride (0.16 g, 1.59 mmol) in xylene (30 mL) were heated at reflux for 18 hours, before being concentrated in vacuo and chromatographed on silica eluting with ethyl acetate/hexane (1:2). Crystallisation from ethyl acetate/hexane then gave anhydride (286) (0.29 g, 72%) as a pale brown powder, mp 189-191 °C. Η NMR δ [(CD3)2SO] 11.16 (br s, IH), 7.69 (dd, J=7.7, 1.4 Hz, IH), 7.51 (dd, J=7.7, 1.4 Hz, IH), 7.43 (ddd, J=7.7, 7.7, 1.4 Hz, IH), 7.36 (ddd, J=7.7, 7.7, 1.4 Hz, IH), 7.25 (d, J=8.6 Hz, IH), 7.15 (d, J=2.4 Hz, IH), 6.77 (dd, J=8.6, 2.4 Hz, IH), 4.70 (d, J=7.7 Hz, IH), 4.47 (dd, J=7.7, 3.5 Hz, IH), 3.78 (s, 3H), 3.71-3.66 (m, IH), 3.36 (dd, J=15.9, 13.0 Hz, IH), 2.99 (dd, J=15.9, 4.1 Hz, IH). Found: C, 65.85; H, 3.95; N, 3.70. C2]H16C1N04 requires: C, 66.06; H, 4.22; N, 3.67.
EXAMPLE 297
The preparation of 4-(2-Chlorophenyl)-2-(2.4-dimethoxybenzyl)-9-methoxypyrrolor3.4- clcarbazole-l,3(2H,6H)-dione (XLV: Ar=2-chlorophenyl) (287)
To a solution of anhydride (286) (2.80 g, 7.42 mmol) prepared as described in example 296 in glacial acetic acid (70 mL) was added 2,4-dimethoxybenzylamine (1.67 mL, 11.1 mmol). The resulting solution was heated at reflux for 6 hours before being partially concentrated under reduced pressure and diluted with water to precipitate an orange solid, which was collected by filtration, washed with water and dried in vacuo. This crude material was then dissolved in p-dioxane and aromatized according to the procedure for example 79, before being chromatographed on silica eluting with ethyl acetate/hexane (1:1). Crystallisation from methanol then gave carbazole (287) (1.46 g, 37%) as a yellow powder, mp 224-226 °C. Η NMR δ [(CD3)2SO] 12.02 (br s, IH), 8.45 (d, J=2.6 Hz, IH), 7.62 (s, IH), 7.58 (m, 2H), 7.53-7.42 (m, 3H), 7.25 (dd, J=8.8, 2.6 Hz, IH), 6.95 (d, J=8.4 Hz, IH), 6.57 (d, J=2.3 Hz, IH), 6.45 (dd, J=8.4, 2.3 Hz, IH), 4.68 (s, 2H), 3.88 (s, 3H), 3.80 (s, 3H), 3.72 (s, 3H). Found: C, 68.22; H, 4.37; N, 5.29. C3oH23ClN2θ5 requires: C, 68.38; H, 4.40; N, 5.32.
Representative Procedure for Method 20 of Scheme 11
EXAMPLE 298
The preparation of 6-Allyl-4-(2-chlorophenyl)-2-(2,4-dimethoxybenzyl)-9- methoxypyrrolor3,4-clcarbazole-l,3(2H,6H)-dione (XLVI; Ar=2-chlorophenyl, n=l) (288) To a solution of carbazole (287) (150 mg, 0.28 mmol) prepared as described in example 297 in dimethylformamide (10 mL) under nitrogen was added potassium carbonate (0.39 g, 2.80 mmol) and allyl bromide (72 DL, 0.84 mmol). The resulting suspension was warmed to 90 °C with stirring for 3 hours before being diluted with water and extraction with ethyl acetate. The organic phase was dried, the drying agent was removed and the solution was concentrated to dryness. Chromatography on silica eluting with ethyl acetate/hexane (1:2), followed by crystallization from diethyl ether/hexane gave carbazole (288) (90 mg, 57%) as a yellow powder, mp 171-173 °C. ]H NMR δ [(CD3)2SO] 8.51 (d, J=2.6 Hz, IH), 7.84 (s, IH), 7.67 (d, J=8.9 Hz, IH), 7.58 (m, IH), 7.53-7.46 (m, 3H), 7.32 (dd, J=8.9, 2.6 Hz, IH), 6.97 (d, J=8.4 Hz, IH), 6.57 (d, J=2.4 Hz, IH), 6.45 (dd, J=8.4, 2.4 Hz, IH), 5.99 (m, IH), 5.18 (d, J=4.9 Hz, 2H), 5.14 (dd, J=10.3, 1.3 Hz, IH), 4.99 (dd, J=17.2, 1.3 Hz, IH), 4.69 (s, 2H), 3.90 (s, 3H), 3.80 (s, 3H), 3.72 (s, 3H). Found: C, 69.97; H, 4.75; N, 5.12. C33H27C1N205 requires: C, 69.90; H, 4.80; N, 4.94.
EXAMPLE 299
The preparation of 6-(3-Butenyl)-4-(2-chlorophenyl)-2-(2,4-dimethoxybenzyl)-9- methoxypyrrolor3,4-c1carbazole-l,3(2H,6H)-dione (XLVI; Ar=2-chlorophenyl, n=2) (289)
Reaction of carbazole (287) (260 mg, 0.51 mmol) prepared as described in example
297 with 4-bromo-l-butene (155 DL, 1.53 mmol) according to procedure described in example 298 gave carbazole (289) (173 mg, 58%) as a yellow powder, mp 161-164 °C. Η NMR δ [(CD3)2SO] 8.50 (d, J=2.6 Hz, IH), 7.89 (s, IH), 7.73 (d, J=9.0 Hz, IH), 7.60-7.46 (m, 4H), 7.31 (dd, J=9.0, 2.6 Hz, IH), 6.96 (d, J=8.5 Hz, IH), 6.57 (d, J=2.3 Hz, IH), 6.44 (dd, J=8.4, 2.3 Hz, IH), 5.84 (m, IH), 4.96-4.86 (m, 2H), 4.68 (s, 2H), 4.60 (t, J=6.9 Hz, 2H), 3.89 (s, 3H), 3.80 (s, 3H), 3.72 (s, 3H), 2.54 (partially obscured m, 2H). Found: C, 70.23; H, 5.15; N, 4.91. C34H29C1N205 requires: C, 70.28; H, 5.03; N, 4.82.
Representative Procedure for Method 21 of Scheme 11
EXAMPLE 300
The preparation of 4-(2-Chlorophenyl)-6-(2,3-dihydroxypropyl)-2-(2,4-dimethoxybenzyl)-9- methoxypyiTOlor3,4-clcarbazole-l,3(2H,6H)-dione (XLVII; Ar=2-chlorophenyl, n=l) (290)
To a solution of carbazole (288) (80 mg, 0.14 mmol) procedure described in example
298 in acetone/water (4: 1, 20 mL) was added N-methylmorpholine N-oxide (33 mg, 0.28 mmol) and osmium tetroxide (176 uL, 4% solution in water, -0.028 mmol). The reaction mixture was stirred at room temperature for 18 hours before being diluted with IN hydrochloric acid and extraction with ethyl acetate. The organic phase was dried, the drying agent was removed and the solution was concentrated to dryness. Chromatography on silica eluting with ethyl acetate/hexane (2:1), followed by crystallization from diethyl ether/hexane gave diol (290) (80 mg, 94%) as a yellow powder, mp 151-156 °C. !H NMR D [(CD3)2SO] 8.50 (d, J=2.6 Hz, IH), 7.82 (s, IH), 7.69 (br d, J=9.0 Hz, IH), 7.58 (m, IH), 7.52-7.46 (m, 3H), 7.30 (dd, J=9.0, 2.6 Hz, IH), 6.95 (d, J=8.4 Hz, IH), 6.57 (d, J=2.4 Hz, IH), 6.44 (dd, J=8.4, 2.4 Hz, IH), 5.02 (d, J=5.0 Hz, IH), 4.87 (br s, IH), 4.69 (s, 2H), 4.55 (m, IH), 4.38 (m, IH), 3.89 (m, 4H), 3.80 (s, 3H), 3.72 (s, 3H), 3.41 (partially obscured m, 2H). Found: C, 65.32; H, 5.00; N, 4.83. C33H29C1N207.1/4H20 requires: C, 65.45; H, 4.91; N, 4.63.
EXAMPLE 301
The preparation of 4-(2-Chlorophenyl)-6-(3,4-dihvdroxybutyl)-2-(2,4-dimethoxybenzyl)-9- methoxypyrrolor3.4-c1carbazoIe-1.3(2H,6-H)-dione (XLVII; Ar=2-chlorophenyl, n=2) (291)
Reaction of carbazole (289) (100 mg, 0.17 mmol) procedure described in example 299 according to the procedure described in example 300, except that the reaction time was 48 hours, gave diol (291) (74 mg, 71%) as a yellow powder, mp 126-131 °C. Η NMR δ [(CD3)2SO] 8.51 (d, J=2.5 Hz, IH), 7.83 (s, IH), 7.72 (d, J=9.0 Hz, IH), 7.56 (m, 2H), 7.48 (m, 2H), 7.33 (dd, J=9.0, 2.5 Hz, IH), 6.94 (d, J=8.4 Hz, IH), 6.57 (d, J=2.3 Hz, IH), 6.44 (dd, J=8.4, 2.3 Hz, IH), 4.76 (t, J=5.0 Hz, IH), 4.69 (s, 2H), 4.60-4.52 (m, 3H), 3.90 (s, 3H), 3.80 (s, 3H), 3.72 (s, 3H), 3.45-3.20 (partially obscured m, 3H), 1.99 (m, IH), 1.69 (m, IH). Found: C, 66.39; H, 5.02; N, 4.44. C34H3ιClN207 requires: C, 66.39; H, 5.08; N, 4.55.
Representative Procedure for Method 22 of Scheme 11
EXAMPLE 302
The preparation of 4-(2-Chlorophenyl)-6-(2,3-dihydroxypropyl)-9-hvdroxypyrrolof3,4- c . carbazole- 1.3(2H.6H)-dione (XLVIIP. Ar-=2-chlorophenyl, n=l) (292)
To a solution of diol (290) (75 mg, 0.13 mmol) prepared as described in example 300 in anisole (0.5 mL) was added trifluoroacetic acid (2.0 mL). The reaction vessel was sealed and heated to 90 °C in an oil bath for 18 h before the trifluoroacetic acid was removed under reduced pressure. The residue was then diluted with water and extracted with diethyl ether (3 times). The combined organic extracts were washed thoroughly with IN potassium hydroxide and then brine before being dried over anhydrous sodium sulphate and concentrated in vacuo. The aqueous layer was then acidified by the addition of concentrated hydrochloric acid, extracted with diethyl ether and worked-up as above. The combined crude material was triturated with diethyl ether/hexane and then dissolved in dichloromethane (20 mL) and demethylated according to The procedure described in example 80 to give, after chromatography on silica eluting with ethyl acetate/hexane (1:1 to 1 :0), phenol (292) (31 mg, 57%) as an orange powder, mp 305-309 °C. ]H NMR δ [(CD3)2SO] 11.04 (br s, IH), 9.33 (s, IH), 8.38 (d, J=2.4 Hz, IH), 7.73 (s, IH), 7.57 (m, 2H), 7.47 (m, 3H), 7.13 (dd, J=8.8, 2.4 Hz, IH), 4.99 (d, J=5.5 Hz, IH), 4.83 (t, J=5.4 Hz, IH), 4.50 (m, IH), 4.32 (m, IH), 3.87 (br s, IH), 3.45-3.36 (m, 2H). Found: C, 63.17; H, 3.94; N, 6.18. C23H17C1N205 requires: C, 63.24; H, 3.92; N, 6.41.
EXAMPLE 303
The preparation of 4-(2-Chlorophenyl)-6-(3,4-dihvdroxybutyl)-9-hydroxypyrrolor3,4- clcarbazole-1.3(2H,6H)-dione (XLVIII: Ar=2-chlorophenvI, n=2) (293)
Reaction of diol (291) (35 mg, 0.06 mmol) prepared as described in example 301 according to the procedure described in example 302 gave phenol (293) (25 mg, 92%) as an orange powder, mp 263-267 °C. Η NMR δ [(CD3)2SO] 11.05 (br s, IH), 9.35 (s, IH), 8.38 (d, J=2.4 Hz, IH), 7.73 (s, IH), 7.58 (m, 2H), 7.49 (m, 3H), 7.15 (dd, J=8.8, 2.4 Hz, IH), 4.73 (t, J=4.9 Hz, IH), 4.52 (m, 3H), 3.48-3.20 (m, 3H), 1.98 (br s, IH), 1.67 (br s, IH). FABMS found [M+H]+=451.1024, 453.1021. C24H19C1N205 requires 451.1061, 453.1031.
EXAMPLE 304
Reaction of carbazole (287) (50 mg, 0.09 mmol per reaction) prepared as described in example 297 with iodomethane, iodoethane, 1-bromopropane, 1-bromobutane, 1- bromopentane, allyl bromide, (2-bromoethyl)benzene, 3-bromopropyne, l-bromo-3- methylbutane, 2-bromopropane, 2-iodo-l,l,l-trifluoroethane, 5-bromo-l-pentene, iodoacetamide, 4-bromo-l-butene, l-bromo-2-methylpropane and l-bromo-4,4,4- trifluorobutane in an array manner according to the procedure described in example 298 , except that the reaction time wasl8 hours, followed by deprotection according to the procedure described in example 302, except that ethyl acetate was used as the work-up solvent and the IN potassium hydroxide wash was omitted, gave respectively: 4-(2-chlorophenyl)-9-hvdroxy-6-methylpyrrolof3,4-c1carbazole-l,3(2H,6H)-dione (VI: Ar=2-chlorophenyl, R10=CH3) (294). Found: M+H=377.
4-(2-chlorophenyl)-6-ethyl-9-hvdroxypyrrolor3,4-c1carbazole-1.3(2H,6H)-dione (VI; Ar=2- chlorophenyl, R!0=CH2CH3) (295). Found: M+H=391.
4-(2-chlorophenyl)-9-hvdroxy-6-propy]pyrrolor3,4-c1carbazole-1.3(2H.6H)-dione (VI; Ar=2- chlorophenyl, R10=(CH2)2CH3) (296). Found: M+H=405.
6-butyl-4-(2-chlorophenyl)-9-hvdroxypyrrolo[3,4-c1carbazole-l,3(2H,6H)-dione (VI; Ar=2- chlorophenyl, R,0=(CH2)3CH3) (297). Found: M+H=419.
4-(2-chlorophenyl)-9-hvdroxy-6-pentylpyrrolor3,4-clcarbazole-l,3(2H,6H)-dione (VI; Ar=2- chlorophenyl, R10=(CH2)4CH3) (298). Found: M+H=433.
6-allyl-4-(2-chlorophenyl)-9-hvdroxypyrrolor3,4-c1carbazole-l,3(2H,6H)-dione (VI; Ar=2- chlorophenyl, R10=CH2CH=CH2) (299). Found: M+H=403.
4-(2-chlorophenyl)-9-hvdroxy-6-(2-phenylethyl)pyrrolor3,4-c1carbazole-l,3(2H,6H)-dione (VI; Ar=2-chlorophenyl, R10--:CH2CH2Ph) (300). Found: M+H=467.
4-(2-chlorophenyl)-9-hvdroxy-6-(2-propynyl)pyrrolor3,4-c1carbazole-1.3(2H,6H)-dione (VI: Ar=2-chlorophenyl, R'^C^C≡CH) (301). Found: M+H=401.
4-(2-chlorophenyl)-9-hvdroxy-6-isopentylpyrrolor3.4-c1carbazole-l,3(2H.6H)-dione (VI: Ar=2-chlorophenyl, R10=CH2CH2CH(CH3)2) (302). Found: M+H=433.
4-(2-chlorophenyl)-9-hvdroxy-6-isopropylpyrrolor3,4-c1carbazole-l,3(2H,6H)-dione (VI; Ar=2-chlorophenyl, R10=CH(CH3)2) (303). Found: M+H=405.
4-(2-chlorophenyl)-9-hvdroxy-6-(2,2,2-trifluoroethyl)pyrrolor3,4-clcarbazole-l,3(2H,6H)- dione (VI; Ar=2-chlorophenyl, R10-=CH2CF3) (304). Found: M+H=445.
4-(2-chlorophenyl)-9-hvdroxy-6-(4-pentenyl)pyrrolor3,4-c1carbazole-l,3(2H,6H)-dione (VI; Ar=2-chlorophenyl, R10=(CH2)3CH=CH2) (305). Found: M+H=431.
2-(4-(2-chlorophenyl)-9-hvdroxy-l,3-dioxo-2,3-dihvdropyrrolor3,4-c1carbazol-6(lH)- vDacetamide (VI; Ar=2-chlorophenyl, R10=CH2CONH2) (306). Found: M+H=420.
6-(3-butenyl)-4-(2-chlorophenyl)-9-hvdroxypyrrolor3,4-clcarbazole-l,3(2H,6H)-dione (VI; Ar=2-chlorophenyl, R10=(CH2)2CH=CH2) (307). Found: M+H=417. 4-(2-chlorophenyl)-9-hvdroxy-6-isobutylpyrrolor3,4-clcarbazole-l,3(2H,6H)-dione (VI: Ar=2-chlorophenyl, R10=CH2CH(CH3)2) (308). Found: M+H=419.
4-(2-chlorophenyl)-9-hvdroxy-6-(4,4,4-trifluorobutyl)pyrrolor3.4-c1carbazole-l,3(2H.6H)- dione (VI; Ar=2-chlorophenyl, R10=(CH2)3CF3) (309). Found: M+H=473.
EXAMPLE 305
Reaction of carbazole (287) (50 mg, 0.09 mmol per reaction) prepared as described in example 297 with 2-iodobutane and cyclopentyl bromide in an array manner according to the procedure described in example 298 , except that the reaction time was 48 hours, followed by deprotection according to the procedure described in example 302, except that ethyl acetate was used as the work-up solvent and the IN potassium hydroxide wash was omitted, gave respectively:
6-sec-butyl-4-(2-chlorophenyl)-9-hvdroxypyrrolor3,4-clcarbazole-l,3(2H,6H)-dione (VI; Ar=2-chlorophenyl, R10=CH(CH3)CH2CH3) (310). Found: M+H=419.
4-(2-chlorophenyl)-6-cvclopentyl-9-hvdroxypyrrolor3,4-clcarbazole-l,3(2H,6H)-dione (VI; Ar=2-chlorophenyl, R10=cyclopentyl) (311). Found: M+H=431.
EXAMPLE 306
Reaction of carbazole (287) (50 mg, 0.09 mmol) prepared as described in example 297 with 2-bromoethyl methyl ether in an array manner according to the procedure described in example 298 , except that the reaction time was 18 hours, followed by deprotection according tothe procedure described in example 302 , except that ethyl acetate was used as the work-up solvent, the IN potassium hydroxide wash was omitted and the demethylation was according to the proceedure described in example 81, gave:
6-(2-chloroethyl)-4-(2-chlorophenyl)-9-hvdroxypyrrolor3,4-c1carbazole-l,3(2H,6H)-dione (VI; Ar=2-chlorophenyl, R10=CH2CH2C1) (312). Found: M+H=425.
Reaction of carbazole (287) (50 mg, 0.09 mmol per reaction) prepared as described in example 297 with l-chloro-2-propanol, (S)-3-bromo-2-methylpropanol and (R)-3-bromo-2- methylpropanol in an array manner according to the procedure described in example 298 , except that the reaction time was 18 hours, followed by deprotection according to the procedure described in example 302 gave: 4-(2-chlorophenyl)-9-hydroxy-6-(2-hvdroxypropyl)pyrrolor3,4-c1carbazole-l,3(2H,6H)- dione (VI; Ar=2-chlorophenyl, R10=CH2CH(OH)CH3) (313). Found: M+H=421.
4-(2-chlorophenyl)-9-hydroxy-6-r(2S)-3-hvdroxy-2-methylpropyllpyrrolor3,4-c1carbazole- l,3(2H.6H)-dione (VI; Ar=2-chlorophenyl, R,0=CH2CH(CH3)CH2OH) (314). Found: M+H=435.
4-(2-chlorophenyl)-9-hydroxy-6-r(2R)-3-hvdroxy-2-methylpropyllpyrrolor3,4-clcarbazole- 1.3(2H.6H)-dione (VI; Ar=2-chlorophenyl, R10=CH2CH(CH3)CH2OH) (315). Found: M+H=435.
Figure imgf000197_0001
SCHEME 12 Procedures for Scheme 12
Representative Procedure for Method 24 of Scheme 12
EXAMPLE 307
The preparation of 4-(2-Chlorophenyl)-9-methoxy-6-(2-methoxyethyl)-l,3-dioxo-1.2.3.6- tetrahydropyrrolor3,4-clcarbazol-8-yl trifluoromethanesulfonate (XLIX; Ar=2-chlorophenyl.
Figure imgf000198_0001
Trifluoromethanesulfonic anhydride (1.30 mL, 7.77 mmol) was added dropwise at 0 °C to a solution of the phenol (167) (0.50 g, 1.11. mmol) prepared as described in example 267 and pyridine (6.29 mL, 0.077 mol) in tetrahydrofuran (50 mL). The solution was allowed to warm to room temperature over lh before dilution with IN HCI and extraction with ethyl acetate. The extraction was dried, the drying agent was removed and the solution was concentrated to dryness to give a solid which was adsorbed onto silica and chromatographed. Elution with ethyl acetate/petroleum ether (1:1) gave the triflate (168) (0.53 g, 82 %) as a pale yellow powder, mp 229-231 °C. 1H NMR δ [(CD3)2SO] 11.23 (br s, IH), 8.78 (s, IH), 8.01 (s, IH), 7.93 (s, IH), 7.59 (dd, J=8.0, 2.2 Hz, IH), 7.54-7.44 (m, 3H), 4.73 (t, J=4.8 Hz, 2H), 4.04 (s, 3H), 3.68 (t, J=4.8 Hz, 2H), 3.14 (s, 3H). Found: C, 49.26; H, 2.91 ; N, 4.39. C25Hι8ClF3SN207.l/2CH2Cl2 requires C, 48.97 ; H, 3.06; N, 4.48.
EXAMPLE 308
The preparation of 4-(2-Chlorophenyl)-9-methoxy-l,3-dioxo-l,2.3.6-tetrahvdropyrrolor3.4- clcarbazol-8-yl trifluoromethanesulfonate (XLIX; Ar=2-chIorophenyl, R10=H) (169)
Reaction of (163) with trifluoromethanesulfonic anhydride using the procedure described in example 307 gave the triflate (169) (87 %) as a yellow solid, mp 248-252 °C. Η NMR δ [(CD3)2SO] 12.16 (br, IH), 11.21 (br, IH), 8.73 (s, IH), 7.80 (s, IH), 7.71 (s, IH), 7.58 (dd, J=8.0, 2.2 Hz, IH), 7.52-7.43 (m, 3H), 4.03 (s, 3H). Found: C, 52.32; H, 2.87; N, 4.87. C22Hi2ClF3N2S06.THF requires C, 52.31; H, 3.38; N, 4.69.
Representative Procedure for Method 25 of Scheme 12
RXAMPLE 309
The preparation of 4-(2-Chlorophenyl)-8-r(lE)-4-hvdroxy-l-butenyl1-9-methoxypyrrolor3.4- c.carbazole-1.3(2H.6H)-dione (L: Ar=2-chlorophenyl. R10=H. Z=CHZCH2OH) (170). A solution of the triflate (169) (0.20 g, 0.35 mmol) prepared as described in example 308 , (3E)-4-(tributylstannyl)-3-buten-l-ol (0.19 g, 0.53 mmol) and lithium chloride (29 mg, 0.70 mmol) in DMF (10 mL) was purged by bubbling nitrogen through the liquid for 10 min. Bis(triphenylphosphine)palladium dichloride (12 mg, 0.017 mmol) was added last and the solution was flushed with nitrogen for 2 min more, then warmed under an atmosphere of nitrogen for 3 h. The mixture was diluted with brine, extracted with ethyl acetate and worked up to give an oil which was chromatographed on silica. Elution with ethyl acetate/petroleum ether (1 :5) gave foreruns, while ethyl acetate/petroleum ether (1:1) increasing to pure ethyl acetate gave (170) as a yellow solid (0.15 g, 95 %), mp 271-275 °C. ]H NMR δ [(CD3)2SO] 11.86 (br s, IH), 11.07 (br s, IH), 8.45 (s, IH), 7.70 (s, IH), 7.58 (dd, J=8.1, 2.2 Hz, IH), 7.55 (s, IH), 7.51-7.41 (m, 3H), 6.87 (d, J=16.0 Hz, IH), 6.44 (dt, J=16.0, 7.1 Hz, IH), 4.62 (t, J=5.3 Hz, IH), 3.94 (s, 3H), 3.58 (m, 2H), 2.42 (m, 2H). Found: C, 67.09; H, 4.36; N, 5.98. C25Hι9ClN204 requires C, 67.19; H, 4.28; N, 6.27.
Representative Procedure for Method 26 of Scheme 12
EXAMPLE 310
The preparation of 4-(2-Chlorophenyl)-8-(4-hvdroxybutyl)-9-methoxypyrrolo[3,4- clcarbazole-l,3(2H,6H)-dione (LI; Ar=2-chlorophenyl, R10=H. Z=CH?CH.OH) (171)
A mixture of (170) (0.15 g, 0.33 mmol) prepared as described in example 309 and Pt02 (20 mg) in 1 : 1 tetrahydrofuran methanol (30 mL) was shaken under an atmosphere of hydrogen gas at 40 psi pressure for 30 min. The catalyst was removed by filtration through Celite, washing through with more solvent. The combined filtrates were worked up and chromatographed on silica. Elution with ethyl acetate/petroleum ether (1:1) gave (171) as an orange solid (0.20 g, 100 %), mp 256-260 °C (dec). 1H NMR δ [(CD3)2SO] 11.90 (br, IH), 11.10 (br, IH), 8.34 (s, IH), 7.64-7.40 (m, 6H), 4.37 (br, IH), 3.93 (s, 3H), 3.43 (t, J=6.3 Hz, 2H), 2.76 (t, J=7.6 Hz, 2H), 1.66 (m, IH), 1.50 (m, 2H).
EXAMPLE 311
The preparation of 4-[4-(2-Chlorophenyl)-9-methoxy-l,3-dioxo-l,2.3.6- tetrahvdropyrrolor3.4-clcarbazol-8-yllbutyl trifluoromethanesulfonate (LIII; Ar=2- chlorophenyl. R10=H. n=4. Z=OMs) (172). Mesylation of (171) prepared as described in example 310 with methanesulfonyl chloride and triethylamine using the procedure described in example 170 of Scheme 3 gave the mesylate (172) as a yellow solid (98 %), which was used without further purification.
Representative Procedure for Method 27 of Scheme 12
EXAMPLE 312
The preparation of 4-(2-Chlorophenyl)-8-(4-iodobutyl)-9-methoxypyrroIor3,4-c1carbazole- 1.3(2H.6H)-dione (LIII; Ar=2-chlorophenyl. R10=H. n=4. Z-=I) (173).
A mixture of the mesylate (172) 0.12 g, 0.21 mmol) prepared as described in example 311 and sodium iodide (1 g) in ethyl acetate (50 mL) was refluxed for 4 h. The cooled solution was washed with water and worked up to give the iodide (173) which crystallised from tetrahydrofuran/petroleum ether as an orange powder (0.10 g, 85 %), mp 142-144 °C. 'H NMR δ [(CD3)2SO] 11.86 (s, IH), 11.05 (s, IH), 8.43 (s, IH), 7.58 (m, IH), 7.55 (s, IH), 7.52-7.43 (m, 3H), 7.42 (s, IH), 3.94 (s, 3H). EIMS found M+ =558.0212, 560.0178. C25H20ClIN2O3 requires 558.0207, 560.0178.
EXAMPLE 313
The preparation of 4-(2-Chlorophenyl)-8-r4-(dimethylamino)butyl1-9-methoxypyrrolor3.4- clcarbazole-l,3(2H,6H)-dione (LIV; Ar=2-chlorophenyl, R10=H, n=4. Z=N(CH.),) (174)
Reaction of the iodide (173) prepared as described in example 312 with aqueous dimethylamine using the procedure described in example 179 of Scheme 3 except that the reaction conditions were 6 h at room temperature gave (174) (64 %) as an orange powder, mp 162-164 °C. Η NMR δ [(CD3)2SO] 11.85 (s, IH), 11.04 (br s, IH), 8.42 (s, IH), 7.57 (dd, J=8.0, 2.2 Hz, IH), 7.55 (s, IH), 7.51-7.43 (m, 3H), 7.42 (s, IH), 3.93 (s, 3H), 2.77 (t, J=7.4 Hz, 2H), 2.24 (t, J=7.3 Hz, 2H), 2.11 (s, 6H), 1.63 (m, 2H), 1.47 (m, 2H). EIMS found M+=475.1657, 477.1650. C27H26C1N303 requires 475.1663, 477.1633.
EXAMPLE 314
The preparation of 4-(2-Chlorophenyl)-8-r4-(dimethylamino)butyl1-9-hvdroxypyrrolor3,4- clcarbazole-1.3(2H.6H)-dione (LV; Ar=2-chlorophenyl, R10=H, n=4, Z=N(CHQ2) (175)
Demethylation of (174 ???) prepared as described in example 313 with pyridine hydrochloride using the procedure described in example 81 gave (176) (67 %) as a yellow powder, mp 220-226 °C (dec). Η NMR δ [(CD3)2SO] 11.72 (s, IH), 10.98 (s, IH), 9.33 (br, IH), 8.32 (s, IH), 7.56 (dd, J=8.0, 2.2 Hz, IH), 7.49 (s, IH), 7.49-7.40 (m, 3H), 7.33 (s, IH), 2.74 (t, J=7.33 Hz, 2H), 2.54 (m, 2H), 2.34 (br s, 6H), 1.64 (m, 2H), 1.54 (m, 2H). FABMS found [M+H]+: 464.1569, 462.1578. C26H25C1N303 requires 464.1555, 462.1584.
EXAMPLE 315
The preparation of 4-(2-Chlorophenyl)-9-methoxy-8-r4-(l-pyrrolidinyl)butyllpyrrolor3,4- ccllccaarrbbazole-l,3(2H,6H)-dione (LIV; Ar=2-chlorophenyl, R10=H, n=4, Z=l -pyrrolidinyl)
(176)
Reaction of the iodide (173) prepared as described in example 312 with pyrrolidine using the procedure described in example 179 except that the reaction conditions were 2 h at room temperature gave (176) (75 %) as an orange powder, which was used without further purification, mp 173-178 °C. Η NMR δ [(CD3)2SO] 11.85 (s, IH), 11.04 (br s, IH), 8.42 (s, IH), 7.57 (dd, J=8.0, 2.2 Hz, IH), 7.55 (s, IH), 7.51-7.43 (m, 3H), 7.42 (s, IH), 3.93 (s, 3H), 2.77 (t, J=7.4 Hz, 2H), 2.24 (t, J=7.3 Hz, 2H), 2.11 (s, 6H), 1.63 (m, 2H), 1.47 (m, 2H).
EXAMPLE 316
The preparation of 4-(2-Chlorophenyl)-9-hvdroxy-8-[4-(l-pyrrolidinyl)butyl1pyrrolor3,4- ccl1ccaarrbb;azole-1.3(2H,6H)-dione (LV; Ar=2-chlorophenyl, R10=H, n=4. Z=l -pyrrolidinyl)
(177).
Demethylation of (173) prepared as described in example 312 with pyridine hydrochloride using the procedure described in example 81 gave (177) (72 %). Η NMR δ [(CD3)2SO] 11.70 (s, IH), 10.98 (br s, IH), 9.30 (br, IH), 8.31 (s, IH), 7.57 (dd, J=8.0, 2.2 Hz, IH), 7.49 (s, IH), 7.49-7.40 (m, 3H), 7.32 (s, IH), 2.73 (t, J=7.5 Hz, 2H), 2.44-2.36 (m, 6H), 1.69-1.61 (m, 6H), 1.51 (m, 2H). The hydrochloride salt had a mp of 173-178 °C (dec). Found: C, 62.27; H, 5.22; N, 7.74. C28H26C1N303.HC1.H20 requires C, 62.00; H, 5.39; N, 7.75.
EXAMPLE 317
The preparation of 4-(2-Chlorophenyl)-9-methoxy-6-(2-methoxyethyl)-8-vinylpyrrolor3.4- c1carbazoIe-1.3(2H,6H)-dione (L; Ar=2-chlorophenyl. R10=CH7CH.OCH,. Z=H) (178)
Reaction of the triflate (168) prepared as described in example 307 with tetravinyl tin using the procedure described in example 309 gave the vinyl compound (178) (64 %) as a yellow solid, which was used without further purification. Η NMR δ [(CD3)2SO] 11.11 (s, IH), 8.53 (s, IH), 7.95 (s, IH), 7.80 (s, IH), 7.58 (dd, J=8.1, 2.2 Hz, IH), 7.52-7.43 (m, 3H), 7.18 (dd, J=17.6, 11.2 Hz, IH), 6.06 (dd, J=17.6, 1.3 Hz, IH), 5.42 (dd, J=11.2, 1.3 Hz, IH), 4.71 (t, J=5.0 Hz, 2H), 3.97 (s, 3H), 3.71 (t, J=5.0 Hz, 2H), 3.16 (s, 3H).
EXAMPLE 318
The preparation of 4-(2-Chlorophenyl)-8-(2-hvdroxyethyl)-9-methoxy-6-(2- methoxyethyl)pyrrolor3.4-clcarbazole-l,3(2H.6H)-dione (LI; Ar=2-chlorophenyl, R10=H, Z=OH) (179).
Hydroboration of (178) prepared as described in example 317 with 9-BBN using the procedure described in example 344 gave (179) (86 %) as a yellow solid, mp 271-273 °C. !H NMR δ [(CD3)2SO] 11.08 (br, IH), 8.49 (s, IH), 7.78 (s, IH), 7.60 (s, IH), 7.57 (dd, J=8.0, 2.2 Hz, IH), 7.52-7.42 (m, 3H), 4.68 (t, J=5.2 Hz, IH), 4.65 (t, J=5.1 Hz, 2H), 3.94 (s, 3H), 3.70 (m, 4H), 3.15 (s, 3H), 2.96 (t, J=7.2 Hz, 2H).
EXAMPLE 319
The preparation of 4-(2-Chlorophenyl)-9-hydroxy-6,8-bis(2-hydroxyethyl)pyrrolor3,4-
Figure imgf000202_0001
Demethylation of (179) prepared as described in example 318 with BBr3 using the procedure described in example 80 except that the reaction conditions were 12 equiv. of reagent at 0 °C for 6 h gave (180) as a yellow powder (35 %), mp 278-280 °C. !H NMR δ [(CD3)2SO] 11.00 (br s, IH), 9.39 (br, IH), 8.37 (s, IH), 7.72 (s, IH), 7.56 (dd, J=8.0, 2.2 Hz, IH), 7.51-7.42 (m, 4H), 4.82 (t, J=5.5 Hz, IH), 4.72 (br, IH), 4.47 (t, J=5.4 Hz, 2H), 3.76 (dt, J=5.5, 5.4 Hz, 2H), 3.69 (t, J=7.2 Hz, 2H), 2.93 (t, J=7.2 Hz, 2H). FABMS found M+: 452.0993, 450.0984. C24H19C1N205 requires 452.0953, 450.0982.
EXAMPLE 320
The preparation of 9-Methoxy-6-methyl-l,3-dioxo-4-phenvI-l,2,3,6- tetrahvdropyrrolor3,4-clcarbazol-8-yl trifluoromethanesulfonate (XLIX; Ar=phenyl, R10=CHV) (185)
Reaction of (154) prepared as described in example 254 with trifluoromethanesulfonic anhydride using the procedure described in example 307 gave 9-methoxy-6-methyl-l,3- dioxo-4-phenyl-l,2,3,6-tetrahydropyrrolo[3,4-c]carbazol-8-yl trifluoromethanesulfonate as a yellow solid (85%), m.p. 244-246°C; ]H NMR δ [(CD3)2SO] 11.22 (br s, IH), 8.76 (s, IH), 7.96 (s, IH), 7.90 (s, IH), 7.68-7.66 (m, 2H), 7.52-7.46 (m, 3H), 4.02 (s, 3H), 3.99 (s, 3H).
EXAMPLE 321
The preparation of 4-(2-Chlorophenyl)-9-methoxy-6-methyl-l,3-dioxo-l, 2.3.6- tetrahydropyrrolo[3,4-clcarbazol-8-yl trifluoromethanesulfonate (XLIX; Ar=2-chlorophenyl, R10=Me) (700).
Reaction of (160) prepared as described in example 260 with trifluoromethanesulfonic anhydride using the procedure described in example 307 gave the triflate (700) (89%) as a yellow solid, mp 251-253 °C. Η NMR δ [(CD3)2SO] 11.26 (br s, IH), 8.80 (s, IH), 8.02 (s, IH), 7.87 (s, IH), 7.61-7.44 (m, 4H). Found: C, 52.51; H, 3.14; N, 4.97. C23H14N2ClF306S.l/4 Hexane requires: C, 52.51; H, 3.15; N, 5.00. FABMS found [M+H]+: 539.0262, 541.0240. C23Hι5N2ClF306S requires 539.0292, 541.0262.
EXAMPLE 322
The preparation of 2.8-Diallyl-4-(phenyl)-9-methoxy-6-methylpyrrolor3.4-clcarbazole- 1.3(2H.6H)-dione (LVI; Ar=phenyl. R=Me)(186) and 8-allyl-4-(phenyl)-9-methoxy-6- methylpyrrolor3,4-clcarbazole-l,3(2H.6H)-dione (LVII; Ar=phenyl, R10--:Me) (187).
Reaction of triflate (185) prepared as decribed in example 320 and allyltri-n-butyltin at 100 °C for 1 h using the procedure described in example 309 gave a crude product which was chromatographed on silica gel (ethyl acetate/petroleum ether (1:4) to afford (i) pure bis- allyl compound (186) (12%) as an orange solid, mp 188-189 °C. Η NMR δ [(CD3)2SO] 8.52 (s, IH), 7.81 (s, IH), 7.66 (dd, J=8.0, 1.7 Hz, 2H), 7.53-7.43 (m, 4H), 6.10 (m, IH), 5.91(m, IH), 5.21-5.06 (m, 4H), 4.22 (d, J=5.1 Hz, 2H), 3.95 (s, 6H), 3.56 (d, J=6.6 Hz, 2H). Found: C, 76.43; H, 5.59; N, 6.48. C28H24N203 .1/10 H20 requires: C, 76.73; H, 5.56; N, 6.39; followed by (ii) pure mono-allyl compound (187) (42%) mp 204-208 °C. 1H NMR δ (CDC13) 11.08 (s, IH), 8.52 (s, IH), 7.78 (s, IH), 7.67-7.64 (m, 2H), 7.50 (s, IH), 7.49-7.43 (m, 3H), 6.09 (ddt, J = 6.6 Hz, IH), 5.15-5.07 (m, 2H), 3.94 (s, 6H), 3.56 (d, J = 6.6 Hz, 2H); Found: C, 73.75; H, 5.39; N, 6.76. C25H20N2O3.3/2 H20 requires C, 73.51; H, 5.26; N, 6.86.
EXAMPLE 323
The preparation of 4-(Phenyl)-9-methoxy-6-methyl-8-vinylpyrrolor3,4-c1carbazole- 1.3(2H.6H)-dione (L; Ar=phenyl. R10=Me, Z=H) (701). Reaction of triflate (185) prepared as decribed in example 320 and tetravinyltin at 100 °C for 1 h using the procedure described in example 309gave a crude product which was chromatographed on silica gel (ethyl acetate/petroleum ether (1:2) to afford pure 8-vinyl compound (701) (68%) as an orange solid, mp 220 °C (dec). ]H NMR δ [(CD3)2SO] 11.12 (br, IH), 8.57 (s, IH), 7.92 (s, IH), 7.79 (s, IH), 7.69-7.64 (m, 2H), 7.52-7.43 (m, 3H), 7.20 (dd, J=17.7, 11.2 Hz, IH), 6.09 (dd, J=17.7, 1.2 Hz, IH), 5.42 (dd, J=11.2, 1.2 Hz, IH), 4.00 (s, 3H), 3.96 (s, 3H). Found: C, 74.45; H, 4.78; N, 6.94. C24H,8N203 .1/4 H20 requires C, 74.50; H, 4.82; N, 7.24.
EXAMPLE 324
EXAMPLE 325
The preparation of 2,8-Diallyl-4-(2-chlorophenyl)-9-methoxy-6-methylpyrrolor3,4- c1carbazole-1.3(2H.6H)-dione (LVI Ar=2-chlorophenyl, R=Me) (702) and 8-allyl-4-(2- chlorophenyl)-9-methoxy-6-methylpyrrolor3,4-clcarbazole-l,3(2H,6H)-dione (LVH; Ar=2- chlorophenyl. R10=Me) (703).
Reaction of triflate (700) prepared as in example 321 and allyltri-n-butyltin at 100 °C for 1 h using the procedure described in example 309 gave a crude product which was chromatographed on silica gel (ethyl acetate/petroleum ether (1:3) to afford (i) pure bis-allyl compound (702) (49%) as an orange solid, mp 183-185 °C. ]H NMR δ [(CD3)2SO] 8.51 (s, IH), 7.82 (s, IH), 7.61-7.44 (m, 5H), 6.16-6.05 (m, IH), 5.95-5.85 (m, IH), 5.17-5.07 (m, 4H), 4.21 (br d, J=5.0 Hz, 2H), 3.96 (s, 6H), 3.57 (d, J=6.5 Hz, 2H). Found: C, 71.53; H, 5.14; N, 6.20. C28H23N2C103 requires: C, 71.41; H, 4.92; N, 5.95; followed by (ii) mono- allyl compound (703) (31%) as a yellow solid, mp 269-272 °C. 1H NMR δ [(CD3)2SO] 11.10 (br, IH), 8.52 (s, IH), 7.77 (s, IH), 7.58-7.43 (m, 4H), 6.16-6.07 (m, IH), 5.17-5.07 (m, 2H), 3.95 (s, 6H), 3.57 (d, J=6.5 Hz, 2H). Found: C, 69.58; H, 4.55; N, 6.46. C25Hι9N2C103 requires C, 69.69; H, 4.44; N, 6.50.
EXAMPLE 326
The preparation of 4-(2-Chlorophenyl)-9-methoxy-6-methyl-8-vinylpyrrolo[3,4-c1carbazole- 1.3(2H.6H)-dione (L; Ar=2-chlorophenyl. R10=Me. Z=H) (704).
Reaction of triflate (700) prepared as in example 321 and tetravinyltin at 100 °C for 1 h using the procedure described in example 309 followed by treatment with excess ammonium acetate at 100 °C for another lh gave a crude product which was chromatographed on silica gel (ethyl acetate/petroleum ether) (1:2) to afford pure 8-vinyl compound (704) (78%) as an orange solid, mp 330 °C (dec). Η NMR δ [(CD3)2SO] 11.12 (br, IH), 8.53 (s, IH), 7.94 (s, IH), 7.78 (s, IH), 7.60-7.43 (m, 4H), 7.20 (dd, J=17.7, 11.2 Hz, IH), 6.10 (dd, J=17.7, 1.2 Hz, IH), 5.43 (dd, J=11.2, 1.2 Hz, IH), 3.99 (s, 3H), 3.97 (s, 3H). ). Found: C, 58.54; H, 4.08; N, 6.65. C24Hι7N2C103.CH2Cl2.l/2 NH3 requires C, 58.84; H, 4.05; N, 6.86. FABMS found [M+Hf: 417.0982, 419.0955. C24Hι7N2C103 requires 417.1006, 419.0977.
EXAMPLE 327
The preparation of 4-(2-Chlorophenyl)-8-r(lE)-3-hydroxy-l-propenyl1-9-methoxy-6- methylpyrrolor3,4-clcarbazole-l,3(2H,6H)-dione (L; Ar=2-chlorophenyl, R10=Me, Z=CH.OH) (710).
Reaction of triflate (700) prepared as in example 321 and 3-hydroxyallyltri-n-butyltin using the procedure described in example 309 at 100 °C for 1 h_to gave a crude product which was chromatographed on silica gel (ethyl acetate/petroleum ether) (1:1) to afford pure (710) (42%) as an orange solid, mp 283-285 °C. Η NMR δ [(CD3)2SO] ] 11.11 (s, IH), 8.51 (s, IH), 7.89 (s, IH), 7.76 (s, IH), 7.59-7.43 (m, 4H), 7.05 (br d, J=16.0 Hz, IH), 6.67 (dt, J=16.0, 5.0 Hz, IH), 4.94 (t, J=5.4 Hz, IH), 4.22 (br t, J=5.0 Hz, 2H), 3.99 (s, 3H), 3.97 (s, 3H). FABMS found M+ : 446.1031, 448.1037. C2 H17N2C103 requires 446.1033, 448.1004.
Representative Procedure for Method 28 of Scheme 12
EXAMPLE 328
The preparation of De-alkylation of bisallyl compound (LVP. Ar=2-chlorophenyl, R=Me) (702) to give monoallyl compound (LVII; Ar=2-chlorophenyl, R10=Me) (703).
Bisallyl compound (702) (72 mg, 0.153 mmol) prepared as described in example 325 was dissolved in a mixture of acetonitrile (10 mL) and water (1 mL). To this homogeneous solution was added 5M KOH (1 mL) and the mixture was stirred at room temperature for 64 h. Most of the acetonitrile was evaporated in vacuo and the residue was diluted with water (3 mL). After acidification with IN HCI to pH< 1 the acidic solution was stirred at 50-60 °C (bath) for 3 h. After partitioning between ethyl acetate and water the ethyl acetate solution was evaporated and co-evaporated with toluene to give an orange solid which was treated with a large excess of molten ammonium acetate at 140-145 oC (bath) for 3 h. After cooling to room temperature and partitioning between ethyl acetate and water the ethyl acetate solution was evaporated to give a crude product which was chromatographed on silica gel (ethyl acetate-petroleum ether) (1:3) to give pure monoallyl compound (703) (52 mg, 79%). The Rf, mp and Η NMR spectrum were identical with the authentic sample described earlier.
EXAMPLE 329
The preparation of De-alkylation of Bisallyl compound (LVI; Ar=phenyl, R=Me) (186) to give monoallyl compound (LVTP, Ar=phenyl, R10=Me) (187).
Using the procedure described in example 328 bisallyl compound (186) prepared as described in example 322 was converted into monoallyl compound (187) (84%). The Rf, mp and Η NMR spectrum were identical with an authentic sample described earlier.
EXAMPLE 330
The preparation of 8-(2,3-Dihydroxypropyl)-9-methoxy-6-methyl-4-phenylpyrrolor3.4- c1carbazole-l,3(2H,6H)-dione (LIX; n=l, Ar=phenyl, R10=Me) (705).
Reaction of (187) prepared in example 329, N-methylmorpholine N-oxide and osmium tetroxide (at room temperature for 5 h) using the procedure described in example 300 followed by chromatography on silica gel (ethyl acetate) gave (705) (81%) as an orange solid, mp 243-245 °C. }H NMR δ [(CD3)2SO] 11.06 (br, IH), 8.51 (s, IH), 7.78 (s, IH), 7.68-7.63(m, 2H), 7.55 (s, IH), 7.50-7.42 (m, 3H), 4.58-4.52 (m, 2H), 3.95 (s, 3H), 3.93 (s, 3H), 3.40 (d, J=5.3 Hz, 2H), 3.30 (dd, J=13.5, 5.2 Hz, IH), 2.77 (dd, J=13.5, 7.8 Hz, IH). Found: C, 69.02; H, 5.48; N, 6.44. C25H22N205.l/5 H20 requires: C, 69.18; H, 5.20; N, 6.45.
EXAMPLE 331
The preparation of 8-(l,2-Dihydroxyethyl)-9-methoxy-6-methyl-4-phenylpyrrolor3,4- c1carbazole-l,3(2H,6H)-dione (LIX; n=0. Ar=phenyl, R10=Me) (706).
Reaction of (701) prepared as described in example 321, N-methylmorpholine N- oxide and osmium tetroxide (at room temperature for 5 h) using the procedure described in example 300 followed by chromatography on silica gel (chloroform methanol) (10:1) gave (706) (65%) as a yellow solid, mp 242-245 °C. ]H NMR δ [(CD3)2SO] 11.09 (s, IH), 8.53 (s, IH), 7.81 (s, IH), 7.74(s, IH), 7.68-7.64 (m, 2H), 7.50-7.41(m, 3H), 5.35(d, J=4.4 Hz, IH), 5.12-5.06 (m, IH), 4.75 (t, J=5.3 Hz, IH), 3.97 (s, 3H), 3.95 (s, 3H), 3.66-3.60 (m, IH), 3.39-3.33 (m, IH). Found: C, 69.25; H, 5.14; N, 6.43. C24H20N2O5 requires: C, 69.22; H, 4.84; N, 6.73.
EXAMPLE 332
The preparation of 8-(2,3-Dihvdroxypropyl)-9-hydroxy-6-methyl-4-phenylpyιτolor3.4- clcarbazole-l ,3(2H,6H)-dione (LX; n=l, Ar=phenyl, R10=Me) (707).
Reaction of (705) prepared as described in example 330 and BBr3 (at 0 °C for 4 h) using the procedure described in example 80 gave the phenol (707) (53%) as an orange solid, .mp 283-285 °C. ]H NMR δ [(CD3)2SO] 11.01 (br, IH), 9.41 (br, IH), 8.38 (s, IH), 7.74 (s, IH), 7.67-7.62 (m, 2H), 7.50-7.40 (m, 4H), 3.92 (s, 3H), 3.90-3.84 (m, IH), 3.36 (d, J=5.2 Hz, 2H), 2.98 (dd, J=13.5, 5.0 Hz, IH), 2.74 (dd, J=13.5, 7.7 Hz, IH). FABMS found M+: 416.1365. C24H20N2O5 requires 416.1372.
EXAMPLE 333
The preparation of 9-Hydroxy-8-(2-hvdroxyethyl)-6-methyl-4-phenylpyrrolor3.4- c1carbazole-l,3(2H,6H)-dione (LII; Ar=phenyl. R10=Me, Z=OH) (714).
Reaction of (712) prepared as described in example 340 and BBr3 (at 0 °C for 3 h) using the procedure described in example 80 followed by chromatography on silica gel (chloroform methanol) (20:1) gave the phenol (714) (31%) as a yellow solid, mp 233-235 °C. Η NMR δ [(CD3)2SO] 11.01 (br, IH), 9.39 (br, IH), 8.39 (s, IH), 7.74 (s, IH), 7.64 (dd, J=7.6, 1.6 Hz, 2H), 7.50-7.42 (m, 4H), 4.73 (br,lH), 3.92 (s, 3H), 3.70 (t, J=7.1 Hz, 2H), 2.94 (t, J=7.1 Hz, 2H). FABMS found M+: 386.1263. C23H,8N204 requires 386.1267.
EXAMPLE 334
The preparation of 4-(2-Chlorophenyl)-9-hvdroxy-8-(2-hydroxyethyl)-6-methylpyrrolor3.4- c1carbazole-1.3(2H,6H)-dione (LII; Ar=2-chlorophenyl. R10=Me. Z=OH) (715).
Reaction of (713) prepared as described in example 341 and BBr3 (at 0 °C for 3 h) using the procedure described in example 80 followed by chromatography on silica gel (chloroform/methanol) (20:1) gave the phenol (715) (81%) as an orange solid, mp 304-306 °C !H NMR δ [(CD3)2SO] 11.00 (br, IH), 9.30 (br, IH), 8.37 (s, IH), 7.71 (s, IH), 7.57 (dd, J=7.0, 2.0 Hz, IH), 7.52-7.42 (m, 4H), 4.74 (br, IH), 3.91 (s, 3H), 3.71 (t, J=7.0 Hz, 2H), 2.94 (t, J=7.0 Hz, 2H). FABMS found M+: 420.0866, 422.0875. C23H]7C1N204 requires 420.0877, 422.0847. EXAMPLE 335
The preparation of 4-(2-Chlorophenyl)-8-ethyl-9-methoxy-6-methylpyrrolor3,4-c1carbazole- (l,3(2H,6H)-dione (LI; Ar=2-chlorophenyl. R10=Me. Z=H) (708).
Hydrogenation of alkene (704) prepared as in example 326 over Pt02 (45 min reaction time) using the procedure described in example 310 gave 8-ethyl derivative (708) (97%) as an orange solid, mp 262-264 °C. 1H NMR δ [(CD3)2SO] 11.08 (br, IH), 8.48 (s, IH), 7.77 (s, IH), 7.60-7.42 (m, 5H), 3.95 (s, 6H), 3.90-3.84 (m, IH), 2.82 (q, J=7.5 Hz, 2H), 1.28 (t, J=7.5 Hz, 3H). Found: C, 68.21; H, 4.38; N, 6.48. C2 H,9N2C103 .1/10 H20 requires C, 68.52; H, 4.60; N, 6.66.
EXAMPLE 336
The preparation of 4-(2-Chlorophenyl)-8-(3-hvdroxypropyl)-9-methoxy-6-methylpyrrolor3,4- clcarbazole-1.3(2H,6H)-dione (LI; Ar=2-chlorophenyl. R10=Me. Z-=CH7OH) (711).
Hydrogenation of alkene (710) prepared as in example 321 over Pt02 using the procedure described in method26 followed by chromatography on silica gel (ethyl acetate/petroleum ether) (1:1) gave pure 8-(3-hydroxypropyl) compound (711) (44 %) as an orange solid, mp 260-263 °C. Η NMR δ [(CD3)2SO] 11.08 (s, IH), 8.48 (s, IH), 7.77 (s, IH), 7.59-7.43 (m, 5H), 4.50 (t, J=5.2 Hz, IH), 3.95 (s, 6H), 3.49 (m, 2H), 2.83 (t, J=7.7 Hz, 2H), 1.82 (m, 2H). FABMS found M+: 448.1194, 450.1200. C25H2ιClN204 requires 448.1190, 450.1160.
EXAMPLE 337
The preparation of 4-(2-Chlorophenyl)-8-ethyl-9-hvdroxy-6-methylpyrrolor3,4-clcarbazole- 1.3(2H.6H)-dione (LII; Ar=2-chlorophenyl, R10=Me, Z=H) (709).
Reaction of (708) prepared as in example 335 with pyridinium hydrochloride using the procedure described in example 81 followed by chromatography on silica gel (ethyl acetate/petroleum ether) (1:2) gave phenol (709) (78 %) as an orange solid, mp 265-268 °C. 1H NMR δ [(CD3)2SO] 11.01 (s, IH), 9.39 (s, IH), 8.37 (s, IH), 7.71 (s, IH), 7.59-7.55 (m, IH), 7.52-7.42 (m, 4H), 3.93 (s, 3H), 2.79 (q, J=7.5 Hz, 2H), 1.27 (t, J=7.5 Hz, 3H). EIMS found M+: 404.0925, 406.0905. C23HπClN203 requires 404.0928, 406.0898. EXAMPLE 338
The preparation of 8-r3-(Dimethylamino)propyl1-9-hvdroxy-6-methyl-4-phenylpyrrolor3.4- clcarbazole-1.3(2H.6H)-dione (LV; n=3. Ar=phenyl. R10=Me. Z=NMe?) (720).
Reaction of (717) prepared as described in example 342 with pyridinium hydrochloride using the procedure described in example 81 gave phenol (720) (83%) as an orange solid, mp 315 °C. ]H NMR δ[(CD3)2SO] 11.01 (br, IH), 9.79 (br, IH), 8.38 (s, IH), 7.72 (s, IH), 7.64 (dd, J=7.9, 1.4 Hz, 2H), 7.50-7.41 (m, 4H), 3.92 (s, 3H), 2.77 (t, J=7.3 Hz, 2H), 2.25 (t, J=7.0 Hz, 2H) 2.18 (s, 6H), 1.81 (m, 2H). FABMS found [M+Hf: 428.1972. C26H26N3O3 requires 428.1974.
EXAMPLE 339
The preparation of 8-r2-(Dimethylamino)ethyl1-9-hvdroxy-6-methyl-4-phenylpy-rτolor3,4- clcarbazole-1.3(2H,6H)-dione (LV; n=2, Ar=phenyl. R10=Me, Z=NMe?) (721).
Reaction of (719) prepared as described in example 343 with pyridinium hydrochloride using the procedure described in example 81 followed by chromatography on silica gel (chloroform/methanol) (10:1) gave phenol (721) (97%) as an orange solid, mp 278 °C (dec). Η NMR δ[(CD3)2SO] 11.01 (br, 2H), 8.36 (s, IH), 7.73 (s, IH), 7.64 (dd, J=7.9, 1.4 Hz, 2H), 7.50-7.41 (m, 4H), 3.92 (s, 3H), 2.94 (t, J=6.9 Hz, 2H), 2.64 (t, J=6.9 Hz, 2H) 2.31 (s, 6H). FABMS found [M+H]+: 414.1821. C25H2 N303 requires 414.1818.
EXAMPLE 340
The preparation of 8-(2-Hvdroxyethv1)-9-methoxy-6-methyl-4-phenylpyrrolor3,4- clcarbazole-1.3(2H,6H)-dione (LI; Ar=phenyl. R10=Me. Z=OH) (712).
Reaction of alkene (701) prepared as decribed in example 321 with 9-BBN using the procedure described in method29 gave after chromatography on silica gel (chloroform/methanol) (10:1), the 8-(2-hydroxyethyl) compound (712) (51 %) as a yellow solid, mp 284-286 °C. Η NMR δ [(CD3)2SO] 11.09 (s, IH), 8.52 (s, IH), 7.79 (s, IH), 7.66 (br d, J=6.4 Hz, 2H), 7.56 (s, IH), 7.51-7.41 (m, 3H), 4.68 (t, J=5.2 Hz, IH), 3.96 (s, 3H), 3.94 (s, 3H), 3.69 (m, 2H), 2.98 (t, J=7.2 Hz, 2H). ). Found: C, 71.77; H, 5.24; N, 6.81. C2 H20N2O4 requires C, 71.99; H, 5.03; N, 7.00. EXAMPLE 341
The preparation of 4-(2-Chlorophenyl)-8-(2-hydroxyethyl)-9-methoxy-6-methylpyrrolor3.4- clcarbazole-1.3(2H.6H)-dione (LI; Ar=2-ch1orophenyl. R10=Me, Z=OH) (713).
Reaction of alkene (704) prepared as in example 326 with 9-BBN using the procedure described in method29 gave after chromatography on silica gel (ethyl acetate/petroleum ether) (2:1), the 8-(2-hydroxyethyl) compound (713) (50 %) as an orange solid, mp 270-272 °C. Η NMR δ [(CD3)2SO] 11.08 (s, IH), 8.49 (s, IH), 7.77 (s, IH), 7.59-7.55 (m, 2H), 7.53- 7.43 (m, 3H), 4.69 (t, J=5.3 Hz, IH), 3.94 (s, 6H), 3.69 (td, J=7.1, 5.3 Hz, 2H), 2.98 (t, J=7.1 Hz, 2H). Found: C, 66.14; H, 4.69; N, 6.51. C2 Hι9N2C104 requires: C, 66.29; H, 4.40; N, 6.44.
EXAMPLE 342
The preparation of 8-r3-(Dimethylamino)propyl1-9-methoxy-6-methyl-4-phenylpyrrolor3.4- clcarbazole-1.3(2H.6H)-dione (LIV; n=3τ-Ar=phenyl. R10=Me, Z=NMe?) (717).
Reaction of (188) prepared as described in example 344 with methanesulfonyl chloride using the procedure described in example 170 gave intermediate LIII (n=3, Ar=phenyl, R10=Me, Z=OS02CH3) which was further reacted with aq. 40% dimethylamine (using the procedure described in example 179 ) at room temperature for 5 h. Usual workup gave a crude product which was refluxed in toluene in the presence of excess ammonium acetate for 23h. After chromatography on silica gel (chloroform/methanol) (10:1) pure dimethylaminopropyl compound (717) (60 %) was obtained, mp 175-178 °C. Η NMR δ[(CD3)2SO] 11.07 (s, IH), 8.51 (s, IH), 7.78 (s, IH), 7.68-7.63 (m, 2H), 7.55 (s, IH), 7.51- 7.42 (m, 3H), 3.96(s, 3H), 3.94 (s, 3H), 2.80 (t, J=7.8 Hz, 2H), 2.34 (t, J=7.8 Hz, 2H) 2.20 (s, 6H), 1.80 (m, 2H). Found: C, 69.28; H, 6.64; N, 9.05. C27H27N303 3/2 H20 requires C, 69.21; H, 6.45; N, 8.97.
EXAMPLE 343
The preparation of 8-r2-(Dimethylamino)ethyll-9-methoxy-6-methyl-4-phenylpyrrolor3.4- clcarbazole-l,3(2H,6H)-dione (LIV; Ar=phenyl, R10=Me, Z=NMe?, n=2) (719).
Reaction of (712) prepared as described in example 340 with methanesulfonyl chloride using the procedure described in example 170 gave intermediate LIII (Ar=phenyl, n=2, R10=Me, Z=OS02CH3) which was further reacted with aq. 40% dimethylamine (using the procedure described in example 179 ) at room temperature for 25 h. Usual work up gave a crude product which was refluxed in toluene in the presence of excess ammonium acetate for 18 h. After chromatography on silica gel (chloroform/methanol) (10:1) pure di ethylaminoethyl compound (719) (15 %) was obtained, mp 233-236 °C. !H NMR δ[(CD3)2SO] 11.08 (s, IH), 8.51 (s, IH), 7.78 (s, IH), 7.68-7.63 (m, 2H), 7.58 (s, IH), 7.50- 7.41 (m, 3H), 3.96 (s, 3H), 3.94 (s, 3H), 2.93 (t, J=8.0 Hz, 2H), 2.54 (t, J=8.0 Hz, 2H) 2.23 (s, 6H). E S found M+: 427.1890. C26H25N303 requires 427.1896.
Representative Procedure for Method 29 of Scheme 12
EXAMPLE 344
The preparation of 8-(3-HvdroxypropyI)-9-rnethoxy-6-methyl-4-phenylpyrrolor3,4- c1carbazole-l,3(2H,6H)-dione (LVIII: Ar=phenyl, R10=CH (188).
A solution of 9-borabicyclo[3.3.1]nonane (1 mL of a 0.5 M solution in tetrahydrofuran, 0.49 mmol) was added to a solution of (187) (65 mg, 0.16 mmol) prepared as descrined in example 329 in tetrahydrofuran (5 mL). The reaction mixture was stirred at room temperature for 2 hr 20 min and then 3 M sodium acetate (1.5 mL) and 35% hydrogen peroxide (1.0 mL) were added. The mixture was stirred at room temperature for 1 hr 30 min and then diluted with brine and extracted with ethyl acetate (3 x 30 mL). The combined extracts were dried and concentrated. The residue was purified by column chromatography on silica eluting with ethyl acetate/ dichloromethane 1:5 to give 8-(3-hydroxypropyl)-9- methoxy-6-methyl-4-phenylpyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione (58 mg, 85%), mp 105-110 °C softens, 130-134 °C melts. 1H NMR δ [(CD3)2SO] 11.06 (s, IH), 8.51 (s, IH), 7.78 (s, IH), 7.66-7.64 (m, 2H), 7.53 (s, IH), 7.50-7.44 (m, 3H), 4.52 (t, J = 5.1 Hz, IH), 3.96 (s, 3H), 3.94 (s, 3H), 3.52-3.45 (m, 2H), 2.82 (br t, 7.8 Hz, 2H), 1.82 (br dt, J = 7.8 Hz, 2H). Found: C, 70.93; H, 5.40; N, 6.54. C25H22N204.l/2 H20 requires: C, 70.91; H, 5.47; N, 6.62.
EXAMPLE 345
The preparation of 9-Hvdroxy-8-(3-hvdroxypropyl)-6-methyl-4-phenylpyrrolor3.4- clcarbazole-1.3(2H.6H)-dione (LII; Ar=phenyl. R10=CH^, Z=CH,OH) (189)
Demethylation of (188) prepared as described in example 344 with BBr3 using the procedure described in example 80 gave (189) as a yellow solid. !H NMR δ [(CD3)2SO] 11.00 (br s, IH), 9.46 (br s, IH), 8.39 (s, IH), 7.73 (s, IH), 7.46-7.63 (m, 2H), 7.49-7.42 (m, 4H), 4.50 (br s, IH), 3.92 (s, 3H), 3.49-3.44 (m, 2H), 2.78 (br t, J = 7.9 Hz, 2H), 1.82 (br dt, J = 7.8 Hz, 2H).
EXAMPLE 346
The preparation of 8-Ethyl-9-methoxy-6-methyl-4-phenylpyrrolor3,4-c1carbazole- l,3(2H,6H)-dione (LI: Ar=phenyl, R10=CH^, Z=H) (190)
Reaction of the triflate (185) prepared as decribed in example 320 with tetraethyl tin using the procedure described in example 309 gave (190) as a yellow solid (83%), mp 251-253 °C. Η NMR δ [(CD3)2SO] 11.07 (s, IH), 8.53 (s, IH), 7.77 (s, IH), 7.67-7.64 (m, 2H), 7.53 (s, IH), 7.50-7.42 (m, 3H),3.95 (s, 3H), 3.94 (s, 3H), 2.81 (q, J = 7.5 Hz, 2H), 1.27 (t, J = 7.5 Hz, 3H). Found: C, 74.48; H, 5.20; N, 7.24. C24H20N2O3.l/6 H20 requires: C, 74.40; H, 5.29; N, 7.23.
EXAMPLE 347
-The preparation of-8-Ethyl-9-hydroxy-6-methyl-4-phenylpyrrolor3.4-c1carbazole- 1.3(2H.6H)-dione (LII: Ar=phenyl. R10=CTh, Z=H) (191)
Demethylation of (190) prepared as decried in example 346 with BBr3 using the procedure described in example 80 gave (191) as a yellow solid (92%), mp 278-283 °C. Η NMR δ [(CD3)2SO] 11.00 (br s, IH), 9.36 (s, IH), 8.40 (s, IH), 7.73 (s, IH), 7.66-7.63 (m, 2H), 7.49-7.41 (m, 4H), 3.93 (s, 3H), 2.78 (q, J = 7.5 Hz, 2H), 1.27 (t, J = 7.5 Hz, 3H). Found: C, 74.36; H, 5.10; N, 7.45. C23Hι8N203 requires: C, 74.58; H, 4.90; N, 7.56.
Figure imgf000213_0001
SCHEME 13
Procedures for Scheme 13
EXAMPLE 348
The preparation of 4-(2-Chlorophenyl)-8-(3-hvdroxypropoxy)-2-(3-hvdroxypropyl)-9- methoxy-6-(2-methoxyethyl)pyrrolor3,4-c1carbazo1e-l,3(2H,6H)-dione (LXV; Ar=2- chlorophenyl. R10=CH.CH.OCH.. n=3) (181)
Alkylation of (167) prepared as described in example 267 with 3-bromopropanol using the procedure described in example 298 gave (181) (92 %) as a yellow oil, which was used without further purification. EXAMPLE 349
The preparation of 4-(2-Chlorophenyl)-8-(3-hvdroxypropoxy)-9-methoxy-6-(2- methoxyethyl )pyrrolor3,4-clcarbazole-l ,3(2H,6H)-dione (LXVI; Ar=2-chlorophenyl.
Figure imgf000214_0001
Treatment of (182) with the sequence of reactions outlined in the procedure described in example 328 gave (182) (58 %) as an orange powder, mp 251-257 °C. *H NMR δ [(CD3)2SO] 11.03 (br s, IH), 8.46 (s, IH), 7.74 (s, IH), 7.57 (dd, J=8.0, 2.1 Hz, IH), 7.51- 7.42 (m, 3H), 7.36 (s, IH), 4.67 (t, J=4.9 Hz, 2H), 4.61 (br, IH), 4.23 (t, J=6.3 Hz, 2H), 3.90 (s, 3H), 3.70 (t, J=4.9 Hz, 2H), 3.64 (m, 2H), 3.16 (s, 3H), 1.98 (m, 2H). EIMS found: M+=508.1398, 510.1358. C27H25C1N206 requires 508.1401, 510.1371.
EXAMPLE 350
The preparation of 4-(2-Chlorophenyl)-9-methoxy-6-(2-methoxyethyl)-8-r3-(4- ~moφholinyl)ρropox-v1pyrrolo[3.4-c1carbazole-l .3(2H,6H)-dione (LXIII; Ar=2-chlorophenyl, R10=CH9CH,OCH^, Z=4-morpholinyl) (183)
Conversion of (182) prepared as described in example 349 to the corresponding mesylate by reaction with methanesulfonyl chloride using the procedure described in example 170 followed by reaction with morpholine using the procedure described in example 179 gave (183) (71 %) as a yellow powder, mp 271-275 °C, which was immediately demethylated.
EXAMPLE 351
The preparation of 4-(2-Chlorophenyl)-9-hvdroxy-6-(2-hvdroxyethyl)-8-r3-(4- morpholinyl )propoxylpyrrolor3,4-c1carbazole-l ,3(2H,6H)-dione (LXIV; Ar=2-chlorophenyl,
R10=CH.CH.OCH^, Z=4-morpholinyl) (184)
Demethylation of (183) prepared as decribed in example 350 with BBr3 using the procedure described in example 80 except that the reaction conditions were 0 °C for 2 h gave (184) (36 %) as a yellow solid, mp 253-255 °C. Η NMR δ [(CD3)2SO] 10.97 (br s, IH), 8.94 (br s, IH), 8.34 (s, IH), 7.69 (s, IH), 7.56 (dd, J=8.1, 2.2 Hz, IH), 7.49-7.42 (m, 3H), 7.29 (s, IH), 4.83 (br, IH), 4.49 (t, J=5.2 Hz, 2H), 4.18 (t, J=6.2 Hz, 2H), 3.76 (m, 2H), 3.60 (t, J=4.9 Hz, 4H), 2.52 (t, J=7.1 Hz, 2H), 2.41 (m, 4H), 1.99 (m, 2H). FABMS found [M+H]+: 552.1732, 550.1740. C29H29C1N306 requires 552.1715, 550.1745. EXAMPLE 352
The preparation of 8-(3-Bromopropoxy)-2-(3-bromopropyl)-9-methoxy-6-methyl-4- phenylpyrrolor3,4-clcarbazole-1.3(2H,6H)-dione (LXI; Ar=phenyl, R10=Me, n=3) (722).
Alkylation of (154) prepared as described in example 254 with 1,3-dibromopropane (3.0 equiv.) using the procedure described in example 298 (at room temperature for 4 d) and after chromatography on silica gel (dichloromethane/petroleum ether) (3: 1) gave (722) (47 %) as an orange solid, mp 158-160 °C. Η NMR δ [(CD3)2SO] 8.50 (s, IH), 7.76 (s, IH), 7.69-7.64 (m, 2H), 7.51-7.43 (m, 3H), 7.39 (s, IH), 4.3 l(t, J=6.0 Hz, 2H), 3.98 (s, 3H), 3.92 (s, 3H), 3.77-3.71(m, 4H), 3.59 (t, J=6.5 Hz, 2H), 2.41-2.34 (m, 2H), 2.23-2.15 (m, 2H). Found: C, 57.16; H, 4.58; N, 4.73. C28H26N2Br204. 1/2 hexane requires: C, 56.64; H, 5.06; N, 4.26. FABMS found M+: 612.0255, 614.0249, 616.0252. C28H26Br2N204 requires 612.0259. 614.0239, 616.0218.
EXAMPLE 353
The preparation of 8-(3-Bromopropoxy)-2-(3-bromopropyl)-4-(2-chIorophenyl)-9-methoxy-
6 6--mmeetthhylpyrrolor3,4-c1carbazole-l,3(2H,6H)-dione (LXI; Ar=2-chlorophenyl, R10=Me, n=3)
(723).
Alkylation of (160) prepared as described in example 260 with 1,3-dibromopropane (15 equiv.) using the procedure described in example 298 (at room temperature for 5 d) and after chromatography on silica gel (dichloromethane/petroleum ether) (3:1) gave (723) (65 %) as an orange solid, mp 165-167 °C. Η NMR δ [(CD3)2SO] 8.47 (s, IH), 7.76 (s, IH), 7.60-7.57 (m, IH), 7.53-7.43 (m, 3H), 7.41 (s, IH), 4.3 l(t, J=6.0 Hz, 2H), 3.97(s, 3H), 3.93 (s, 3H), 3.77-3.68 (m, 4H), 3.56 (t, J=6.5 Hz, 2H), 2.42-2.34 (m, 2H), 2.20-2.12 (m, 2H). Found: C, 53.54; H, 4.28; N, 4.20. C28H25N2ClBr204. 1/2 hexane requires: C, 53.82; H, 4.66; N, 4.05. FABMS found M+: 645.9866, 647.9868, 649.9834. C28H25N2ClBr204 requires 645.9870, 647.9849, 647.9840, 649.9829, 649.9820.
EXAMPLE 354
The preparation of 4-(2-Chlorophenyl)-8-(3-hvdroxypropoxy)-2-(3-hvdroxypropyl)-9- methoxy-6-methylpyrrolor3,4-clcarbazole-l,3(2H,6H)-dione (LXV; Ar=2-chlorophenyl. R10=Me. n=3) (724). Alkylation of (160) prepared as described in example 260 with 3-bromopropanol (2.2 equiv.) using the procedure described in example 298 (at room temperature for 31 h) and after chromatography on silica gel (chloroform/methanol) (20:1) gave (724) (98 %) as an orange solid, mp 180-183 °C. ]H NMR δ [(CD3)2SO] 8.47 (s, IH), 7.74 (s, IH), 7.60-7.57 (m, IH), 7.53-7.43 (m, 3H), 7.36 (s, IH), 4.60 (t, J=5.1 Hz, IH), 4.50(t, J=5.0 Hz, IH), 4.25 (t, J=6.3 Hz, 2H), 3.96 (s, 3H), 3.92 (s, 3H), 3.67-3.60 (m, 4H), 3.47-3.41 (m, IH), 2.02-1.95 (m, 2H), 1.79-1.71 (m, 2H). Found: C, 64.03; H, 5.21; N, 5.25. C28H27N2C106 requires C, 64.31; H, 5.20; N, 5.36.
EXAMPLE 355
The preparation of 4-(2-Chlorophenyl)-8-(3-hvdroxypropoxy)-9-methoxy-6- methylpyrrolor3.4-clcarbazole-1.3(2H,6H)-dione (LXVI; Ar=2-chlorophenyl, R10=Me. n=3) (725),
Treatment of (724) prepared as described in example 354 with the sequence of reactions (5M KOH/MeOH/reflux/3h; IN HCl/100 °C/3 h; NJLOAc/150 °C/20 min) as described in The procedure described in example 328 gave (725) (85%) as an orange solid, mp 285-287 °C. IH NMR δ [(CD3)2SO] 11.02 (br, IH), 8.46 (s, IH), 7.72 (s, IH), 7.59-7.55 (m, IH), 7.51-7.42 (m, 3H), 7.34 (s, IH), 4.60 (t, J=5.1 Hz, IH), 4.25 (t, J=6.3 Hz, 2H), 3.95(s, 3H), 3.91 (s, 3H), 3.67-3.61 (m, 2H), 2.02-1.95 (m, 2H). Found: C, 64.69; H, 4.60; N, 6.11. C 5H2ιN2C105 requires: C, 64.31; H, 5.20; N, 5.36.
EXAMPLE 356
The preparation of 8-r3-(Dimethylamino)propoxy1-2-r3-(dimethylamino)propyl"|-9-methoxy- 6-methyl-4-phenylpyrrolor3,4-clcarbazole-1.3(2H,6H)-dione (LXII; Ar=phenyl. R1Q=Me. Z=NMe.. n=3) (726).
Reaction of (722) prepared as described in example 352 with excess dimethylamine.HCl in DMF in the presence of triethylamine and 4A molecular sieves at room temperature (Method 30 ?? ) for 66 h gave (726) (35%) as the dihydrochloride salt, mp 278-281 °C (dec). *H NMR δ [(CD3)2SO] ] 9.95 (br, 2H), 8.51 (s, IH), 7.81 (s, IH), 7.70-7.65 (m. 2H), 7.52-7.43 (m, 3H), 7.40 (s, IH), 4.28 (t, J=6.1 Hz, 2H), 3.99 (s, 3H), 3.93 (s, 3H), 3.67 (t, J=6.4 Hz, 2H), 3.28 (t, J=7.6 Hz, 2H), 3.10 (t, J=7.6 Hz, 2H), 2.83 (s, 6H), 2.73 (s, 6H), 2.29-2.20 (m, 2H), 2.26-1.97 (m, 2H). Found: C, 59.07; H, 6.68; N, 8.44. C32H,0N4Cl2O4 requires: C, 58.98; H. 6.81; N, 8.60. EXAMPLE 357
The preparation of 4-(2-Chlorophenyl)-8-r3-(dimethylamino)propoxy1-2-r3- (dimethylamino)propyn-9-methoxy-6-methylpyrrolor3,4-c1carbazole-1.3(2H.6H)-dione (LXII; Ar=2-chlorophenyl. R10=Me, Z=NMe.. n=3) (727).
Reaction of (723) prepared as described in example 353 with excess dimethylamine.HCl in DMF in the presence of triethylamine and 4A molecular sieves at room temperature (Method 30 ??) for 6 d followed by chromatograpy on silica gel (chloroform/methanol triethylamine) (10:1:0.1) gave (727) (63 %) as the dihydrochloride salt, mp 207-210 °C. ]H NMR δ [(CD3)2SO] 9.89 (br, 2H), 8.48 (s, IH), 7.79 (s, IH), 7.61- 7.56 (m, IH), 7.53-7.44 (m, 3H), 7.41 (s, IH), 4.28 (t, J=6.0 Hz, 2H), 3.97 (s, 3H), 3.94 (s, 3H), 3.65(t, J=6.6 Hz, 2H), 3.23 (br, 2H), 3.34 (br, 2H), 2.80 (s, 6H), 2.69 (s, 6H), 2.28-2.19 (m, 2H), 2.03-1.92 (m, 2H). Found: C, 58.09; H, 6.13; N, 8.44. C32H37N4C104 .2.2 HCI requires: C, 58.47; H, 6.01; N, 8.52. Found: C, 59.07; H, 6.68; N, 8.44. C32H oN Cl204 requires: C, 58.98; H, 6.81; N, 8.60.
EXAMPLE 358 ..
The preparation of 4-(2-Chlorophenyl)-8-r3-(dimethylamino)propoxy1-2-r3- (dimethylamino)propyll-9-methoxy-6-methylpyrrolof3,4-c1carbazole-l,3(2H,6H)-dione (LXII; Ar=2-chlorophenyl, R10=Me, Z=NMe. , n=3) (727).
On a larger scale (727)was best prepared from (160) prepared as described in example 260 by reaction with 3-dimethylaminopropylchloride hydrochloride (7.3 equiv.) in the presence of excess anhydrous potassium carbonate and 4A molecular sieves at 60-70 °C (bath temperature) for 3 h. The yield of crude product was 96 %, which was used for the next step without further purification.
EXAMPLE 359
The preparation of 4-(2-Chlorophenyl)-8-r3-(dimethylamino)propoxyl-9-methoxy-6- methylpyrrolor3.4-c1carbazole-1.3(2H.6H)-dione (LXIII; Ar=2-chlorophenyl, R10=Me. Z=NMe.. n=3) (728).
Treatment of (727) prepared as described in example 358 with the sequence of reactions (5M KOH/MeOH/reflux/3 h; IN HCl/100 °C/3 h; NHtOAc/HO °C/10 h) as described in Example 328 , with the modification that after acidic treatment the reaction mixture was evaporated to dryness and fused with NFLtOAc, followed by chromatography on silica (dichloromethane/MeOH=5:l) gave (728) (97 %) as an orange solid, mp 288-290 °C. Η NMR δ [(CD3)2SO] 11.04 (br, IH), 8.46 (s, IH), 7.72 (s, IH), 7.59-7.55 (m, IH), 7.51- 7.42 (m, 3H), 7.33 (s, IH), 4.21(t, J=6.5 Hz, 2H), 3.95(s, 3H), 3.91(s, 3H), 2.43(t, J=7.0 Hz, 2H), 2.18 (s, 6H), 2.01-1.93 (m, 2H). ). Found: C, 68.22; H, 6.57; N, 7.43. C27H26N3C104. hexane requires: C, 68.58; H, 6.97; N, 7.27. FABMS found [M+H]+: 492.1689, 494.1675. C27H27N3C104 requires 492.1690, 494.1661.
EXAMPLE 360
The preparation of 4-(2-Chlorophenyl)-9-methoxy-6-methyl-8-r3-(4- moφhθlinyl)propoxy1pyrrolor3.4-clcarbazole- 1 ,3(2H,6H)-dione (LXIII; Ar=2-chlorophenyl, R10=Me. Z=4-morpholinyl, n=3) (729).
Conversion of (725) prepared as described in example 355 to the corresponding mesylate by reaction with methanesulfonyl chloride using the procedure described in example 170 example 170 followed by reaction with morpholine using the procedure described in example 179, and treatment of the crude product with NHiOAc at 160-170 °C for 2 h, gave (after a silica column; chloroform/MeOH=10: l) (729) (76 %) as an orange powder, mp 293-295 °C. 1H NMR δ [(CD3)2SO] 11.04 (br, IH), 8.47 (s, IH), 7.72 (s, IH), 7.59-7.55 (m, IH), 7.52-7.42 (m, 3H), 7.34 (s, IH), 4.22 (t, J=6.4 Hz, 2H), 3.96 (s, 3H), 3.91 (s, 3H), 3.59 (br t, J=4.6 Hz, 4H), 2.60-2.36 (m, 6H), 2.03-1.95 (m, 2H). FABMS found [M+H]+: 534.1792, 536.1769. C29H29N3C105 requires 534.1796, 536.1766.
EXAMPLE 361
The preparation of 4-(2-Ch1orophenyl)-9-methoxy-6-methyl-8-r3-(l- pyrrolidiny1)propoxy1pyrrolor3,4-c1carbazole-l,3(2H.6H)-dione (LXIII; Ar=2-chlorophenyl. R10=Me. Z=l -pyrrolidinyl. n=3) (730).
Conversion of (725) prepared as described in example 355 to the corresponding mesylate by reaction with methanesulfonyl chloride using the procedure described in example 170 followed by reaction with pyrrolidine using the procedure described in example 179 of Scheme 3, and treatment of the crude product with NILtOAc at 160-170 °C for 4 h, gave (after a silica column; chloroform/MeOH=10:l) (730) (78 %) as an orange solid, 273- 275 °C. 'H NMR δ [(CD3)2SO] 11.03 (br, IH), 8.45 (s, IH), 7.73 (s, IH), 7.59-7.55 (m, IH), 7.52-7.42 (m, 3H), 7.34 (s, IH), 4.22(t, J=6.4 Hz, 2H), 3.95(s, 3H), 3.90 (s, 3H), 2.60 (t, J=7.0 Hz, 2H), 2.42 (m, 4H), 2.03-1.96 (m, 2H), 1.73-1.67 (m, 4H). Found: C, 66.40; H, 5.47; N, 7.85. C29H28N3C104.l/2H2O requires C, 66.09; H, 5.55; N, 7.97.
EXAMPLE 362
The preparation of 8-[3-(Dimethylamino)propoxy1-9-methoxy-6-methyl-4- phenylpyrrolor3,4-clcarbazole-l,3(2H,6H)-dione (LXIII; Ar=2-phenyl, R10=Me, Z=NMe?. n=3) (731).
Treatment of (726) prepared as described in example 356 with the sequence of reactions (5M KOH/MeOH/reflux/3 h; IN HCl/100 °C/3 h; NHUOAc/170 °C/10 h) in the proceedure described example 328 with the modification that after acidic treatment the reaction mixture was evaporated to dryness and fused with NHjOAc, gave (731) (37%), after a silica column (dichloromethane/MeOH=5:l) as a hygroscopic solid, Η NMR δ [(CD3)2SO] 11.04 (br, IH), 8.48 (s, IH), 7.75 (s, IH), 7.68-7.62 (m, 2H), 7.51-7.42 (m, 3H), 7.33 (s, IH), 4.21(t, J=6.9 Hz, 2H), 3.97 (s, 3H), 3.90 (s, 3H), 2.43 (t, J=7.1 Hz, 2H), 2.19 (s, 6H), 2.01- 1.93 (m, 2H). LCMS(APCI) m/z: 458.101 [M+H]+.
EXAMPLE 363
The preparation of 4-(2-Chlorophenyl)-8-r3-(dimethylamino)propoxy1-9-hydroxy-6- methylpyrrolof3,4-clcarbazole-l,3(2H,6H)-dione (LXIV; Ar=2-chlorophenyl, R10=Me. Z=NMe?. n=3) (732).
Demethylation of (728) prepared as described in example 359 with BBr3 using the procedure described in example 80 except that the reaction conditions were 0 °C for 2 h gave
(732) (83%) as an orange solid, mp 259-262 °C. Η NMR δ [(CD3)2SO] 10.99 (s, IH), 9.22 (br, IH), 8.35 (s, IH), 7.70 (s, IH), 7.58-7.54 (m, IH), 7.51-7.42 (m, 3H), 7.29 (s, IH), 4.22 (t, J=6.0 Hz, 2H), 3.92 (s, 3H), 2.89 (br, 2H), 2.50 (br, 6H), 2.13-2.03 (m, 2H). FABMS found [M+H]+: 478.1532, 480.1519. C26H25N3C104 requires 478.1534, 480.1504.
EXAMPLE 364
The preparation of 8-f 3-(Dimethylamino)propoxy1-9-hydroxy-6-methyl-4-phenylpyrrolor3,4- cicarbazole-1.3(2H.6H)-dione (LXIV; Ar=phenyl. R10=Me. Z=NMe2. n=3) (733).
Demethylation of (731) prepared as described in example 362 with BBr3 using the procedure described in example 80 except that the reaction conditions were 0 °C for 2 h gave
(733) (56 %), mp 303-304 °C . Η NMR δ [(CD3)2SO] 11.00 (s, IH), 9.00 (br, 2H), 8.39 (s, 1H), 7.73 (s, IH), 7.66-7.61 (m, 2H), 7.50-7.41 (m, 3H), 7.29 (s, IH), 4.26 (t, J=5.7 Hz, 2H), 3.94 (s, 3H), 3.24 (t, 3=1.1 Hz, 2H), 2.80 (s, 6H), 2.23-2.14 (m, 2H). Found: C, 60.61; H, 5.05; N, 7.82. C26H25N304 requires: C, 60.48; H, 5.06; N, 8.14.
EXAMPLE 365
The preparation of 4-(2-Chlorophenyl)-9-hvdroxy-6-methyl-8-r3-(4- moφholinyl)propoxylpyrrolor3.4-c1carbazole-1.3(2H.6H)-dione (LXIV; Ar=2-chlorophenyl, R10=Me, Z=4-morpholinyl. n=3) (734).
Demethylation of (729) prepared as described in example 360 with BBr3 using the procedure described in example 80 except that the reaction conditions were 0 °C for 2 h gave "(734) (60"%) as an orange solid,~mp 235-237 °C . Η NMR δ [(CD3)2SO] 10.98 (s, IH), 8.97 (br, IH), 8!33 (s, IH), 7.69 (s, IH), 7.59-7.54 (m, IH), 7.51-7.42 (m, 3H), 7.28 (s, IH), 4.21 (t, J=6.1 Hz, 2H), 3.92 (s, 3H), 3.61 (br, 4H), 2.58-2.37 (m, 6H), 2.05-1.95 (m, 2H). FABMS found [M+H]+: 520.1648, 522.1635. C28H27N3C105 requires 520.1639, 522.1610.
EXAMPLE 366
The preparation of 4-(2-Chlorophenyl)-9-hvdroxy-6-methyl-8-r3-(l- pyrrolidinyl)propoxy1pyrrolor3,4-clcarbazole-l,3(2H,6H)-dione (LXIV; Ar=2-chlorophenyl, R10=Me. Z=l -pyrrolidinyl, n=3) (735).
Demethylation of (730) prepared as described in example 361 with BBr3 using the procedure described in example 80 except that the reaction conditions were 0 °C for 2 h gave (735) (60%) as an orange solid, mp 234-236 °C. ]H NMR δ [(CD3)2SO] 10.98 (br, IH), 9.27 (br, IH), 8.33 (s, IH), 7.68 (s, IH), 7.58-7.55 (m, IH), 7.51-7.42 (m, 3H), 7.30 (s, IH), 4.20 (t, J=6.2 Hz, 2H), 3.92 (s, 3H), 2.66 (t, J=6.8 Hz, 2H), 2.54-2.35 (m, 4H), 2.04-1.96 (m, 2H), 1.75-1.68 (m, 4H). FABMS found [M+H]+: 504.1687, 506.1661. C28H27N3C104 requires 504.1690, 506.1661.
Figure imgf000221_0001
SCHEME 14
Procedures for Scheme 14
Representative Procedure for Method 31 of Scheme 14
EXAMPLE 367
The preparation of 5-Methoxy-2-[(E,Z)-2-phenylethenyll-l-benzofuran (LXVIII; Ar=phenyl, R8=H. Y'=Q) (828)
To a suspension of benzyltriphenylphosphonium bromide (1.85 g, 4.26 mmol) in tetrahydrofuran (30 mL) was added a solution of lithium bis(timethylsilyl)amide (4 mL of a 1 M solution in tetrahydrofuran, 3.98 mmol), the solution turned a bright orange/red color. The reaction mixture was stirred at room temperature for 30 min and then a solution of 5- methoxy-l-benzofuran-2-carbaldehyde (827) (0.50 g, 2.84 mmol) in tetrahydrofuran (10 mL) was added. After 20 min water was then added and the tetrahydrofuran removed at reduced pressure. The residue was extracted with ethyl acetate (2 x 50 mL), the combined extracts were dried and concentrated. The residue was purified by column chromatography on silica eluting with dichloromethane to give (828) as a 1 :2 mixture of Z- and E-isomers, (0.63 g, 89%), m.p. 124-128°C. Found: C, 81.60; H, 5.61. C]7H]402 requires: C, 81.58, H, 5.64. EXAMPLE 368
The preparation of 9-Methoxy-4-phenyl-lH-ri1benzofuror3.2-e1isoindole-1.3(2H)-dione (LXX; Ar=phenyl, R8=H, Y'=Q) (830)
The diene mixture (828) prepared as described in example 367 was reacted with maleimide using the procedure described in example 69 to give the adduct (LXIX; Ar=phenyl, R8=H, Y'=0) (829), which was used without further purification. The crude Diels-Alder adduct was aromatised with Mn02 using the procedure described in example 79 of Scheme 2 to give the dibenzofuran (830) as a yellow solid (53%), mp 271-275°C. Η NMR δ [(CD3)2SO] 11.41 (br s, IH), 8.24 (d, J = 2.7 Hz, IH), 7.98 (s, IH), 7.77 (d, J = 9.0 Hz, IH), 7.67-7.65 (m, 2H), 7.51-7.45 (m, 3H), 7.30 (dd, J = 9.0, 2.7 Hz, IH), 3.91 (s, 3H). Found: C, 72.09; H, 3.84; N, 4.04. C2]H13N04.l/3 H20 requires: C, 72.20; H, 3.94; N, 4.01.
EXAMPLE 369
The preparation of 9-Hvdroxy-4-phenyl-lH-ri1benzofuror3,2-e1isoindole-l,3(2H)-dione (LXXI; Ar=phenyl, R8=H. Y'=Q) (831)
Demethylation of (830) prepared as described in example 368 with BBr3 using the procedure described in example 80 gave (831) as a yellow solid (100%), mp 288-290°C. Η NMR δ [(CD3)2SO] 11.37 (br s, IH), 9.74 (s, IH), 8.13 (d, J = 2.6 Hz, IH), 7.94 (s, IH), 7.66-7.63 (m, 3H), 7.51-7.44 (m, 3H), 7.11 (dd, J = 8.9, 2.6 Hz, IH). Found: C, 71.17; H, 3.48; N, 4.07. C20HnNO4.l/2 H20 requires: C, 71.00; H, 3.58; N, 4.14.
EXAMPLE 370
The preparation of 2-[(E,Z)-2-(2-Ch1orophenyl)ethenyl]-5-methoxy-l-benzofuran (LXVIII; Ar=2-chlorophenyl, R8=H, Y^O) (832)
Reaction of 5-methoxy-l-benzofuran-2-carbaldehyde (827) prepared as described in example with 2-chlorobenzyltriphenylphosphonium bromide using the procedure described in method gave (832) as a 1:2 mixture of Z:E isomers (24%), mp 90-92 °C, which was used without further purification. EX AMPLE 371
The preparation of 4-(2-Chlorophenyl)-9-methoxy-lH-rnbenzofuror3.2-e1isoindole-1.3(2H)- dione (LXX: Ar=2-chlorophenyl. R8=H. Y'=Q) (834)
The diene mixture (832) prepared as described in example 370 was reacted with maleimide using the procedure described in example 69 to give the adduct (LXIX; Ar=2- chlorophenyl, R =H, Y =0) (833), which was used without further purification. The crude Diels-Alder adduct was aromatised with Mn02 using the procedure described in example 79 of Scheme 2 to give the dibenzofuran (834) as a yellow solid (49 %), mp 246-248°C. !H NMR δ [(CD3)2SO] 11.46 (br s, IH), 8.22 (d, J = 2.7 Hz, IH), 7.99 (s, IH), 7.80 (d, J = 9.0 Hz, IH), 7.61-7.58 (m, IH), 7.53-7.44 (m, 3H), 7.33 (dd, J = 9.0, 2.7 Hz, IH), 3.92 (s, 3H). Found: C, 66.53; H, 3.41; N, 3.54. C2ιH12ClN04 requires: C, 66.77; H, 3.20; N, 3.71.
EXAMPLE 372
The preparation of 4-(2-Chlorophenyl)-9-hydroxy-lH-rπbenzofuro.3.2-e1isoindole-1.3(2H)- dione (LXXI: Ar=2-chlorophenyl. R8=H. Y*=Q) (835)
Demethylation of (834) prepared as described in example 371 with BBr3 using the procedure described in example 80 gave (835) as a yellow solid (89%), mp 140-145°C. ]H NMR δ [(CD3)2SO] 11.39 (br s, IH), 9.78 (s, IH), 8.12 (d, J = 2.6 Hz, IH), 7.93 (s, IH), 7.66 (d, J = 8.9 Hz, IH), 7.60-7.58 (m, IH), 7.52-7.43 (m, 3H), 7.13 (dd, J = 8.9, 2.6 Hz, IH); EIMS found M+: 363.0294, 365.0269. C20Hι0ClNO4 requires: 363.0298, 365.0289.
EXAMPLE 373
The preparation of 2-f(E.Z)-2-(2-Chlorophenyl)ethenyl1-5-methoxy-l-benzothiophene (LXVIII; Ar=2-chlorophenyl. R8=H. Y'=S) (837)
Reaction of 5-methoxy-l-benzothiophene-2-carbaldehyde (836) with 2- chlorobenzyltriphenylphosphonium chloride using the procedure described in example 37 gave the diene (837) as an E/Z mixture (63 %). Η NMR δ (CDC13) Minor isomer: 7.6 (d, IH), 7.4 (m, 5H), 7.15 (s, IH), 7.05 (s, IH), 6.9 (d, IH), 6.75 (m, 2H), 3.85 (s, 3H). Major isomer: 7.75 (d, J=9 Hz, IH), 7.55 (m, 2H), 7.25-7.4 (m, 3H), 7.18 (m, 2H), 7.05 (s, IH), 6.95 (m, 2H). EXAMPLE 374
The preparation of 4-(2-Chlorophenyl)-9-methoxy-lH-rilbenzothienor3,2-e1isoindole- l,3(2H)-dione (LXX; Ar=2-chlorophenyl, R8=H. Y'=S) (839)
Reaction of (837) prepared as described in example 373 with maleimide using the procedure described in method4 except that the reaction time was 6 days gave the adduct (LXIX; Ar=2-chlorophenyl, R8=H, Y'=S) (838) which was used without further purification. Aromatisation of (838) with DDQ using the procedure described in example 70 of Scheme 2 except that the solvent was chloroform, and the reaction conditions were 5 days at 40 °C gave (839) as a yellow solid (44 %). Η NMR δ [(CD3)2SO] 11.46 (s, IH), 9.37 (d, J= 2.5 Hz, IH), 8.38 (s, IH), 8.2 (d, J=9 Hz, IH), 7.62 (m, 2H), 7.48 (m, 3H), 7.31 (dd, J= 2.5, 9.0 Hz, IH), 3.94 (s, 3H).
EXAMPLE 375
The preparation of 4-(2-Chlorophenyl)-9-hydroxy-lH-ri1benzothienor3,2-e1isoindole- 1.3(2H)-dione (LXXI; Ar=2-chlorophenyl. R8=H. Y*=S) (840).
Demethylation of (839) prepared as described in example 374 with BBr3 using the procedure described in example 80 except that the reaction time was 48 h gave (840) (65 %) as a yellow solid, mp 311-313 °C. 'H NMR δ [(CD3)2SO] 11.42 (s, IH), 9.85 (s, IH), 9.17 (d, .1= 2.5 Hz, IH), 8.32 (s, IH), 7.9 (d, J= 9 Hz, IH), 7.62 (m, 2H), 7.5 (m, 3H), 7.17 (dd, J=2.5, 9 Hz, IH). MH+ 346. Found C, 68.75; H, 3.43; N, 3.89; S, 9.35. C20HnNO3S.0.2 H20 requires: C, 68.83; H, 3.29; N, 4.01; S, 9.19.
EXAMPLE 376
The preparation of 6-(Benzyloxy)-2-r(E,Z)-2-(chlorophenyl)ethenyl1-5-methoxy-l- benzofuran (LXVIII; R8 =OCH?Ph. Y^O. Ar = 2-chlorophenyl) (601)
Reaction of 6-(benzyloxy)-5-methoxy-l-benzofuran-2-carbaldehyde (LXVIII; Y]=0, R8=OCH2Ph) with 2-chlorobenzyltriphenylphosphonium chloride using the procedure described in method 2 with a reaction time of 4 hours gave (601) as a pale yellow solid (83%), mp 130-135 °C. !H NMR δ [(CD3)2SO] 7.88 (d, J= 6.4 Hz, IH), 7.51-7.31 (m, 12H), 7.18 (s, IH), 6.93 (s, IH), 5.17 (s, 2H), 3.78 (s, 3H). EIMS found: M+=390.1021. C24Hι9C103 requires 390.1023. EXAMPLE 377
The preparation of 8-(Benzyloxy)-4-(2-chlorophenyl)-9-methoxy-lH-rilbenzofuror3.2- elisoindo1e-1.3(2H)-dione (LXX R8 = OO Ph. Y'=Q. Ar = 2-chlorophenyl) (603)
Compound (602) (LXIX; R8=OCH2Ph, Y]=0, Ar=2-chlorophenyl) was prepared from (601) using the procedure described in method 4a using xylene as the solvent to give a brown solid which was used without further purification. The crude Diels-Alder adduct was aromatised with Mnθ2 using the procedure described in example 79, to give (603) as a bright yellow solid (24%), mp 296-300 °C. *H NMR δ [(CD3)2SO] 11.38 (s, IH), 8.17 (s, IH), 7.94 (s, IH), 7.67 (s, IH), 7.58-7.36 (m, 13H), 5.28 (s, 2H), 3.93 (s, 3H). EIMS found: M+=483.0871. C28H18C1 05 requires 483.0873.
Figure imgf000225_0001
Figure imgf000225_0002
(LXXIV)
Figure imgf000225_0003
Figure imgf000225_0004
(LXXXI)
(LXXIX) (LXXX) (LXXXII)
SCHEME 15 Sche e 15 Procedures
EXAMPLE 378
The preparation of 4-(2-Chlorophenyl)-8-hvdroxy-9-methoxy-lH-rπbenzofuro.3,- elisoindole-1.3(H)-dione (LXXII: Ar = 2-chlorophenyl) (604)
Removal of the benzyl ether group of (603) prepared as described in example 377 using the procedure described in example 260 gave (604) as a yellow solid (86%), mp 294- 298 °C. 'H NMR δ [(CD3)2SO] 11.34 (s, IH), 10.40 (s, IH), 8.12 (s, IH), 7.87 (s, IH), 7.59- 7.30 (m, 4H), 7.23 (s, IH), 3.96 (s, 3H). EIMS found: M+ =393.0400. C2,Hι2ClN05 requires 393.0404.
EXAMPLE 379
The preparation of 4-(2-Ch]orophenvI)-9-hvdroxy-l,3-dioxo-2,3-dihydro-lH- πibenzofuror3,2-e1isoindol-8-yl trifluoromethanesulfonate (LXXIII; Ar = 2-chlorophenyl) (605)
Compound (605) was prepared from (604) using the procedure described in example 307 as a pale brown solid (88%), mp 237-240 °C. Η NMR δ [(CD3)2SO] 11.55 (s, IH), 8.47 (s, IH), 8.29 (s, IH), 8.11 (s, IH), 7.62-7.45 (m, 4H), 4.07 (s, 3H). FABMS found: [M+H]+=525.9958, 527.9940. C22H12C1F3NS07 requires 525.9975, 527.9946.
EXAMPLE 380
The preparation of 4-(2-Chlorophenyl)-8-ethyl-9-methoxy-lH-rilbenzofuror3,2-elisoindole- 1.3(2H)-dione (LXXV; Z=H. Ar = 2-chlorophenyl) (606)
Compound 606 was prepared from (605) prepared as described in example 379 using the procedure described in example 309 and tetraethyl tin as the stannane, as a yellow solid (87%), mp 252-257 °C. Η NMR δ [(CD3)2SO] 11.45-11.15 (br, IH), 8.16 (s, IH), 7.91 (s, IH), 7.60-7.56 (m, IH), 7.54 (s, IH), 7.52-7.41 (m, 3H), 4.23 (s, 3H), 3.92 (m, 2H), 2.16-2.09 (m, 3H). EIMS found: M+=405.0766. C23Hι6ClN04 requires 405.0768.
EXAMPLE 381
The preparation of 4-(2-Chlorophenyl)-8-ethyl-9-hvdroxy-lH-π .benzofuro[3,2-e~lisoindole- 1.3(2H)-dione (LXXVIII n = 2. Z=H. Ar = 2-chlorophenyl) (607) Demethylation of (606) prepared as described in example 380 via The procedure described in example 80 gave (607) as a yellow solid (32%), mp 265-268 °C. Η NMR δ [(CD3)2SO] 8.13 (s, IH), 7.68 (s, IH), 7.57-7.52 (m, 3H), 7.44-7.31 (m, 4H), 2.85 (q, J=7.6 Hz, 2H), 1.35 (t, J=7.6 Hz, 3H). EIMS found: M+=391.0612. C22Hι4ClN04 requires 391.0611.
EXAMPLE 382
The preparation of 4-(2-Chlorophenyl)-8-r(lE)-4-hvdroxy-l-butenyl1-9-methoxy-lH- ri1benzofuror3,2-e1isoindole-1.3(2H)-dione (LXXIV; Z = CH7CH7OH, Ar = 2-chlorophenyl) (608)
Compound 608 was prepared from triflate (605) prepared as described in example 379 using the procedure described in example 309 and (3E)-4-(tributylstannyl)-3-buten-l-ol as the stannane as a yellow solid (84%), mp 247-250 °C. ]H NMR δ [(CD3)2SO] 11.43 (s, IH), 8.23 (s IH), 7.92 (s, IH), 7.86 (s, IH), 7.58 (d, J=6.5 Hz, IH), 7.48-7.42 (m, 3H), 6.85 (d, J=16.0 Hz, IH), 6.53 (m, IH), 4.35 (br, IH), 3.97 (s, 3H), 3.57 (t, J=6.6 Hz, 2H), 2.41 (m, 2H). EIMS found: M+=447.0886. C25H18C1N05 requires 447.0873.
EXAMPLE 383
The preparation of 4-,2-Chlorophenyl)-8-(4-hvdroxybutyl)-9-methoxy-lH-π~lbenzofuro.3,2- e1isoindole-1.3(2H)-dione (LXXV; Z = CH9CH7OH. Ar = 2-chlorophenyl) (609)
Hydrogenation of (608) prepared as described in example 382 using the procedure described in example 310gave (609) as a yellow solid (96%), mp 158-162 °C. 1H NMR δ [(CD3)2SO] 11.40 (s, IH), 8.29 (s, IH), 7.71 (s, IH), 7.60 (s, IH), 7.56-7.39 (m, 4H), 4.36 (br, IH), 3.95 (s, 3H), 3.39 (m, 2H), 2.75 (t, J=7.6 Hz, 2H), 1.65 (m, 2H), 1.51 (m, 2H). FABMS found: [M+H]+=450.1083, 452.1078. C25H2ιClN05 requires 450.1108, 452.1079.
EXAMPLE 384
The preparation of 4-(2-Chlorophenyl)-9-hvdroxy-8-(4-hydroxybutyl)-lH-ri1benzofuror3.2- elisoindole-l,3(2H)-dione (LXXVIII: n = 4. Z = OH. Ar =2-chlorophenyl (610)
Demethylation of (609) prepared as described in example 383 using the procedure described in example 80 gave (610) as a yellow solid (38%), mp 256-259 °C. Η NMR δ [(CD3)2SO] 11.40 (br, IH), 9.80 (s, IH), 8.13 (s, IH), 7.90 (s, IH), 7.60-7.56 (m, IH), 7.54 (s, IH), 7.52-7.42 (m, 3H), 4.38 (s, IH), 3.44 (m, 2H), 2.72 (t, J=7.4 Hz, 2H), 1.66 (m, 2H), 1.50 (m, 2H). FABMS found: [M+H]+=436.0942, 483.0922. C24Hι9ClN05 requires 436.0952, 438.0915.
EXAMPLE 385
The preparation of 8-(3-Bromopropoxy)-2-(3-bromopropyl)-4-(2-chlorophenyl)-9-methoxy- lH-rilbenzofuror3.2-elisoindole-l,3(2H)-dione (LXXIX; Ar=2-chlorophenyl. n=3) (331)
Reaction of phenol (604) (245 mg, 0.62 mmol) prepared as described in example 378 with 1,3-dibromopropane (excess, 3.0 mL) according to the procedure described in example 298, except that the reaction was performed in refluxing acetone (80 mL), gave dibromide (331) (300 mg, 76%) as a yellow powder, mp 180-182 °C. Η NMR δ [(CD3)2SO] 8.16 (s, IH), 7.96 (s, IH), 7.60 (m, 2H), 7.53-7.44 (m, 3H), 4.26 (t, J=6.0 Hz, 2H), 3.95 (s, 3H), 3.72 (t, J=6.4 Hz, 4H), 3.57 (t, J=6.6 Hz, 2H), 2.35 (m, 2H), 2.17 (m, 2H). Found: C, 51.25; H, 3.52; N, 2.37. C27H22Br2ClN05 requires: C, 51.01; H, 3.49; N, 2.20.
EXAMPLE 386
The preparation of 4-(2-Chlorophenyl)-8-[3-(dimethylamino)propoxyl-9-methoxy-lH- rnbenzofuror3.2-elisoindole-1.3(2H)-dione (LXXXI: Ar=2-chlorophenyl. n=3, Z=N(CH ?) (332)
Reaction of dibromide (331) (100 mg, 0.16 mmol) prepared as described in example 385 with aqueous dimethylamine solution (40%, 5.0 mL) according to The procedure described in example 179, except that the reaction was performed in tetrahydrofuran (50 mL) at room temperature for 30 hours, gave the crude diamine (LXXX; Ar=2-chlorophenyl, n=3, Z=N(CH3)2), which was used without further purification as a tetrahydrofuran solution. To this solution was added 5N potassium hydroxide (2.5 mL), then the procedure outlined in example 328 was followed except that the HCI treatment was for 24 hours and the chromatography was performed eluting with methanol/dichloromethane/concentrated ammonia (15:85:trace). Trituration from ethyl acetate gave amine (332) (64 mg, 84%) as a yellow powder, mp 251-253 °C. 1H NMR δ [(CD3)2SO] 11.37 (br s, IH), 8.15 (s, IH), 7.93 (s, IH), 7.59 (m, IH), 7.55 (s, IH), 7.52-7.43 (m, 3H), 4.18 (t, J=6.4 Hz, 2H), 3.93 (s, 3H), -2.5 (obscured m, 2H), 2.23 (br s, 6H), 1.96 (m, 2H). Found: C, 65.03; H, 4.79; N, 6.00. C26H23C1N205 requires: C, 65.21; H, 4.84; N, 5.85. EXAMPLE 387
The preparation of 4-(2-Chlorophenyl)-9-methoxy-8-r3-(l-pyrrolidinyl)propoxy1-lH- πibenzofuror3.2-e1isoindole-1.3(2H)-dione (LXXXI; Ar=2-chlorophenyl. n=3. Z-=l- pyrrolidinyl) (333)
Reaction of dibromide (331) (110 mg, 0.17 mmol) prepared as described in example
385 with pyrrolidine (361 uL, 4.33 mmol) according to The procedure described in example 179 , except that the reaction was performed in tetrahydrofuran (50 mL) at room temperature for 3 days, gave the crude diamine (LXXX; Ar=2-chlorophenyl, n=3, Z=l -pyrrolidinyl), which was used without further purification as a tetrahydrofuran solution. To this solution was added 5N potassium hydroxide (2.5 mL), then the procedure outlined in example 328 was followed except that the HCI treatment was for 24 hours and the chromatography was performed eluting with methanol/dichloromethane/concentrated ammonia (15:85:trace). Crystallisation from ethyl acetate/hexane, gave amine (333) (51 mg, 59%) as a yellow powder, mp 252-255 °C. Η NMR δ [(CD3)2SO] 11.35 (br s, IH), 8.15 (s, IH), 7.91 (s, IH), 7.58 (m, IH), 7.54 (s, IH), 7.52-7.43 (m, 3H), 4.19 (t, J=6.4 Hz, 2H), 3.93 (s, 3H), 2.57 (t, J=7.1 Hz, 2H), 2.46 (m, 4H), 1.97 (m, 2H), 1.69 (m, 4H). Found: C, 66.46; H, 5.15; N, 5.43.
-C28H25C1N205 requires C, 66.60; H, 4.99; N, 5.55.
EXAMPLE 388
The preparation of 4-(2-Chlorophenyl)-8-r3-(dimethylamino)propoxyl-9-hydroxy-lH- f nbenzofurol"3,2-elisoindole-l,3(2H)-dione (LXXXII; Ar=2-chlorophenyl, n=3. Z=N(CH1)2)
(334)
Demethylation of amine (332) (70 mg, 0.15 mmol) prepared as described in example
386 according to the procedure described in example 80, except that the reaction was performed at 0 °C for 8 hours and the chromatography was performed eluting with methanol dichloromethane/triethylamine (15:85:trace), gave amine (334) (48 mg, 71%) as a yellow powder, which was converted to the hydrochloride salt, mp 255-258 °C. Η NMR δ [(CD3)2SO] 11.34 (br s, IH), 9.96 (br s, IH), 9.44 (br s, IH), 8.10 (s, IH), 7.91 (s, IH), 7.58 (m, IH), 7.51-7.43 (m, 4H), 4.23 (t, J=5.9 Hz, 2H), -3.3 (obscured m, 2H), 2.81 (s, 6H), 2.21 (m, 2H). Found: C, 58.86; H, 4.68; N, 5.35. C25H2]C1N205.HC1.1/2H20 requires: C, 58.84; H, 4.54; N, 5.49. EXAMPLE 389
The preparation of 4-(2-Chlorophenyl)-9-hvdroxy-8-r3-(l-pyrrolidinyl)propoxyl-lH- rnbenzofuro.3,2-e1isoindole-l,3(2H)-dione (LXXXII; Ar=2-chlorophenyl, n=3, Z=l- pyrrolidinyl) (335)
Demethylation of amine (333) (50 mg, 0.10 mmol) prepared as described in example 387 according to the procedure described in example 80, except that the reaction was performed at 0 °C for 6 hours and the chromatography was performed eluting with methanol/dichloromethane/triethylamine (15:85:trace), gave amine (335) ( mg, %) as a yellow powder, which was converted to the hydrochloride salt, mp 302-304 °C. Η NMR δ [(CD3)2SO] 11.34 (s, IH), 9.99 (br, IH), 9.47 (br, IH), 8.10 (s, IH), 7.90 (s, IH), 7.58 (m, IH), 7.51 (s, IH), 7.52-7.42 (m, 3H), 4.24 (t, J=5.7 Hz, 2H), 3.6 (br, 2H), 3.03 (br, 2H), 2.22 (m, 2H), 2.08-1.81 (m, 6H). Found: C, 61.18; H, 4.56; N, 5.16. C27H23C1N205.HC1 requires C, 61.49; H, 4.59; N, 5.31.
Figure imgf000231_0001
Scheme 16 Procedures
EXAMPLE 390
The preparation of 4-(2-Ch1orophenyl)-6-methyl-l,3-dioxo-l,2,3,6-tetrahvdropyrτolof3.4- clcarbazol-8-yl trifluoromethanesulfonate (LXXXIII; Ar--2-chlorophenyl, R10=CH ) (316)
Reaction of phenol (845) (0.25 g, 0.66 mmol) prepared as described in example 280 according to the procedure described in example 307 gave triflate (316) (323 mg, 96%) as a pale yellow solid, mp 230-233 °C. 1H NMR δ [(CD3)2SO] 11.26 (br s, IH), 9.04 (d, J=8.7 Hz, IH), 8.03 (d, J=2.3 Hz, IH), 7.94 (s, IH), 7.59 (m, IH), 7.50 (m, 4H), 4.04 (s, 3H). Found: C, 51.98; H, 2.29; N, 5.41. C22Hι2ClF3N2S05 requires C, 51.93; H, 2.38; N, 5.51.
EXAMPLE 391
The preparation of 4-(2-Chlorophenyl)-6-methyl-8-vinylpyrrolor3,4-clcarbazole-l,3(2H,6H)- dione (LXXXIV; Ar=2-chlorophenyl, R10=CH3) (317)
Reaction of triflate (316) (0.32 g, 0.63 mmol) prepared as described in example 390 with tetravinyltin (172 DL, 0.94 mmol) according to the procedure described in example 309 gave alkene (317) (193 mg, 79%) as a pale yellow solid, mp 276-282 °C. 1H NMR δ [(CD3)2SO] 11.13 (br s, IH), 8.86 (d, J=8.2 Hz, IH), 7.84 (m, 2H), 7.60-7.46 (m, 5H), 6.98 (dd, J=17.6, 10.9 Hz, IH), 6.09 (d, J=17.6 Hz, IH), 5.42 (d, J=10.9 Hz, IH), 4.00 (s, 3H). Found: C, 69.64; H, 4.03; N, 6.88. C23H15ClN2θ2.1/2H2θ requires: C, 69.79; H, 4.07; N, 7.08.
EXAMPLE 392
The preparation of 4-(2-Chlorophenyl)-8-(2-hvdroxyethyl)-6-methylpyιτolor3,4-c1carbazole- 1.3(2H.6H)-dione (LXXXV; Ar=2-chlorophenyl. R1Q=CH (318)
Reaction of alkene (317) (60 mg, 0.16 mmol) prepared as described in example 391 according to to the procedure described in example 344 gave alcohol (318) (36 mg, 57%) as a pale yellow solid, mp 289-292 °C. 1H NMR δ [(CD3)2SO] 11.10 (br s, IH), 8.81 (d, J=8.1 Hz, IH), 7.82 (s, IH), 7.58 (m, 2H), 7.49 (m, 3H), 7.27 (d, J=8.1 Hz, IH), 4.73 (t, J=5.2 Hz, IH), 3.97 (s, 3H), 3.75 (m, 2H), 2.99 (t, J=7.0 Hz, 2H). Found: C, 67.47; H, 4.37; N, 6.51. C23Hι7ClN203.l/4H20 requires: C, 67.49; H, 4.31; N, 6.84. EXAMPLE 393
The preparation of 4-(2-Chlorophenyl)-8-(l ,2-dihydroxyethyl)-6-methylpyrrolor3,4- clcarbazole-1.3(2H,6H)-dione (LXXXVI; Ar=2-chlorophenyl. R10=CH ) (319)
Reaction of alkene (317) (50 mg, 0.13 mmol) prepared as described in example 391 according to the procedure described in example 300 gave diol (319) (40 mg, 74%) as a pale yellow solid, mp 252-255 °C. Η NMR δ [(CD3)2SO] 11.11 (br s, IH), 8.84 (d, J=8.2 Hz, IH), 7.84 (s, IH), 7.71 (br s, IH), 7.58 (m, IH), 7.49 (m, 3H), 7.39 (br d, J=8.2 Hz, IH), 5.46 (d, J=4.2 Hz, IH), 4.79 (m, 2H), 3.98 (s, 3H), 3.57 (m, 2H). Found: C, 65.72; H, 4.50; N, 6.32. C23HπClN204 requires: C, 65.64; H, 4.07; N, 6.66.
EXAMPLE 394
The preparation of 4-(2-Chlorophenyl)-8-(hydroxymethyl)-6-methylpyrrolor3,4-clcarbazole- 1.3(2H.6H)-dione (LXXXVIP. Ar=2-chlorophenyl. R10=CH^) (320)
Ozone was bubbled through a solution of alkene (317) (60 mg, 0.16 mmol) prepared as described in example 391 in methanol/dichloromethane (1 :1, 40 mL) at -78 °C for 10 minutes, by which time the solution had gone from yellow to yellow/green. Excess ozone was purged from the solution by bubbling nitrogen through it for 2 minutes and then a solution of sodium borohydride (180 mg, 4.76 mmol) in methanol (20 mL) was added. The resulting solution was allowed to warm to room temperature over 20 minutes and then it was diluted with water and extraction with ethyl acetate. The organic phase was dried, the drying agent was removed and the solution was concentrated to dryness. Chromatography on silica eluting with ethyl acetate/hexane (3:1 to 1:0), followed by crystallization from ethyl acetate/hexane, gave alcohol (320) (39 mg, 62%) as a pale yellow solid, mp 291-294 °C. lH NMR δ [(CD3)2SO] 11.11 (br s, IH), 8.85 (d, J=8.1 Hz, IH), 7.84 (s, IH), 7.70 (br s, IH), 7.58 (m, IH), 7.49 (m, 3H), 7.35 (br d, J=8.1 Hz, IH), 5.42 (t, J=5.6 Hz, IH), 4.77 (d, J=5.6 Hz, 2H), 3.98 (s, 3H). Found: C, 67.74; H, 4.11; N, 7.13. C22H]5C1N203 requires: C, 67.61; H, 3.87; N, 7.17. EXAMPLE 395
The preparation of 4-(2-Chlorophenyl)-8-(3-hvdroxypropoxy)-2-(3-hvdroxypropyl)-6- methylpyrrolor3,4-clcarbazole-l,3(2H,6H)-dione (LXXXVIII; Ar=2-ch1orophenyl. R10=CH-.) (321)
Reaction of phenol (845) (0.53 g, 1.41 mmol) prepared as described in example 280 with 3-bromopropan-l-ol (280 DL, 3.10 mmol) according to the procedure described in example 298 gave diol (321) (0.29 g, 42%) as a yellow powder, mp 136-140 °C. Η NMR δ [(CD3)2SO] 8.77 (d, J=8.7 Hz, IH), 7.76 (s, IH), 7.58 (m, IH), 7.49 (m, 3H), 7.28 (d, J=2.0 Hz, IH), 7.00 (dd, J=8.7, 2.0 Hz, IH), 4.61 (t, J=5.1 Hz, IH), 4.49 (t, J=5.0 Hz, IH), 4.24 (t, J=6.3 Hz, 2H), 3.94 (s, 3H), 3.63 (m, 4H), 3.43 (m, 2H), 1.96 (m, 2H), 1.75 (m, 2H). Found: C, 64.91; H, 5.13; N, 5.63. C27H25C1N204.1/4H20 requires C, 65.19; H, 5.17; N, 5.63.
EXAMPLE 396
The preparation of 4-(2-Chlorophenyl)-8-(3-hvdroxypropoxy)-6-methylpyrrolor3,4- clcarbazole-l,3(2H,6H)-dione (LXXXIX: Ar=2-chlorophenyl. R10=CH (322)
Reaction of diol (321) (270 mg, 0.55 mmol) prepared as described in example 395 according to the proceedure described example 328 , except that ethanol was used instead of acetonitrile and the HCI treatment was for 18 hours, gave crude material that was dissolved in methanol dichloromethane (4:1, 80 mL), to which IM potassium carbonate (2.0 mL) was added (to hydrolyse a small amount of acetate present by tic). The resulting solution was stirred at room temperature for 2 hours before being diluted with water and extraction with ethyl acetate. The organic phase was dried, the drying agent was removed and the solution was concentrated to dryness. Chromatography on silica eluting with ethyl acetate/hexane (2:1), followed by crystallization from ethyl acetate/hexane, gave alcohol (322) (136 mg, 57%) as a yellow solid, mp 274-276 °C. ]H NMR δ [(CD3)2SO] 11.06 (br s, IH), 8.75 (d, T=8.7 Hz, IH), 7.75 (s, IH), 7.57 (m, IH), 7.48 (m, 3H), 7.27 (d, J=2.1 Hz, IH), 7.00 (dd, J=8.7, 2.1 Hz, IH), 4.61 (t, J=4.9 Hz, IH), 4.24 (t, J=6.3 Hz, 2H), 3.94 (s, 3H), 3.63 (m, 2H), 1.96 (m, 2H). Found: C, 66.01; H, 4.41; N, 6.41. C24Hι9ClN204 requires: C, 66.29; H, 4.40; N, 6.44. EXAMPLE 397
The preparation of 4-(2-Chlorophenyl)-8-(3-iodopropoxy)-6-methylpyrrolor3,4-c1carbazole- 1.3(2H.6H)-dione (XC; Ar=2-chlorophenyl. R10=CH (323)
Reaction of alcohol (322) (82 mg, 0.19 mmol) prepared as described in example 396 according to the proceedure described in example 170followed using the procedure described in method27, gave after chromatography on silica eluting with ethyl acetate/hexane (2:1), iodide (323) (92 mg, 89%) as a yellow solid, mp 264-266 °C. !H NMR δ [(CD3)2SO] 11.07 (br s, IH), 8.77 (d, J=8.7 Hz, IH), 7.76 (s, IH), 7.58 (m, IH), 7.47 (m, 3H), 7.31 (d, J=2.1 Hz, IH), 7.02 (dd, J=8.7, 2.1 Hz, IH), 4.23 (t, J=6.0 Hz, 2H), 3.95 (s, 3H), 3.46 (t, J=6.7 Hz, 2H), 2.30 (m, 2H). Found: C, 53:30; H, 3.27; N, 5.08. C24HιgCHN203 requires: C, 52.91; H, 3.33; N, 5.14.
EXAMPLE 398
The preparation of 4-(2 Ch]orophenyl)-8-r3-(dimethylamino)propoxyl-6-methylpyrrolor3.4- clcarbazole-1.3(2H,6H)-dione (XCI; Ar=2-chlorophenyl. R10=-CH,. Z=N(CH .) (324)
Reaction of iodide (323) (50 mg, 0.09 mmol) prepared as described in example 397 with dimethylamine according to the procedure described in example 179 , except that the reaction was performed at room temperature for 2 hours and the chromatography was performed on alumina (grade II-III) eluting with ethyl acetate/methanol (1:0 to 9:1) gave amine (324) as a yellow powder, which was crystallized as the hydrochloride salt (43 mg, 96%) from methanol/diethyl ether/hexane, mp 262-265 °C. !H NMR D [(CD3)2SO] 11.08 (br s, IH), 10.0 (br s, IH), 8.78 (d, J=8.7 Hz, IH), 7.78 (s, IH), 7.58 (m, IH), 7.48 (m, 3H), 7.29 (d, J=2.1 Hz, IH), 7.02 (dd, J=8.7, 2.1 Hz, IH), 4.26 (t, J=6.0 Hz, 2H), 3.96 (s, 3H), 3.28 (partially obscured m, 2H), 2.82 (s, 6H), 2.22 (m, 2H). Found: C, 59.62; H, 5.01; N, 8.02. C26H24C1N303.HC1.1.5H20 requires: C, 59.43; H, 5.37; N, 8.00.
EXAMPLE 399
The preparation of 4-(2-Chlorophenyl)-6-methyl-8-r3-(methvIamino)propoxy1pyrrolor3,4- clcarbazo1e-1.3(2H,6H)-dione (XCI: Ar=2-chlorophenyl, R10=CH3, Z=NHCH.) (325)
Reaction of iodide (323) (17 mg, 0.03 mmol) prepared as described in example 397 with aqueous methylamine solution (40%, 54 uL) according to The procedure described in example 179 , except that the reaction was performed at room temperature in tetrahydrofuran for 20 hours, gave amine (325) (6 mg, 43%) as a yellow powder, mp 269-271 °C. Η NMR δ [(CD3)2S0] 8.75 (d, J=8.7 Hz, IH), 7.76 (s, IH), 7.57 (m, IH), 7.47 (m, 3H), 7.27 (d, J=2.1 Hz, IH), 8.99 (dd, J=8.7, 2.1 Hz, IH), 4.22 (t, J=6.4 Hz, 2H), 3.94 (s, 3H), 2.67 (t, J=6.7 Hz, 2H), 2.32 (s, 3H), 1.94 (m, 2H). FABMS found: [M+H]+=448.1447, 450.1428. C25H2 C1N303 requires 448.1428, 450.1398.
EXAMPLE 400
The preparation of 4-(2-Chlorophenyl)-8-r3-(cis-3,5-dimethyl-l-piperazinyl )propoxy1-6- methylpyrrolor3,4-clcarbazole-l ,3(2H,6H)-dione (XCI; Ar=2-chlorophenyl, R10=CH^, Z=cis- 3,5-dimethyl-l-piperazinyl) (326)
Reaction of iodide (323) (17 mg, 0.03 mmol) prepared as described in example 397 with cis-2,6-dimethylpiperazine (71 mg, 0.62 mmol) according to The procedure described in example 179 , except that the reaction was performed at room temperature in tetrahydrofuran for 20 hours and the chromatography was performed on alumina (grade II-III) eluting with ethyl acetate/methanol (1:0 to 9:1), gave amine (326) (15 mg, 91%) as a yellow powder, mp 225-227 °C. ]H NMR δ [(CD3)2SO] 11.06 (br s, IH), 8.75 (d, J=8.7 Hz, IH), 7.76 (s, IH), 7.57 (m, IH), 7.47 (m, 3H), 7.25 (d, J=2.1 Hz, IH), 8.99 (dd, J=8.7, 2.1 Hz, IH), 4.19 (t, J=6.3 Hz, 2H), 3.94 (s, 3H), 2.73 (m, 4H), 2.44 (t, J=7.1 Hz, 2H), 1.96 (m, 2H), 1.46 (t, J=10.6 Hz, 2H), 0.92 (d, J=6.2 Hz, 6H). FABMS found: [M+H]+=531.2166, 533.2162. C30H31ClN4O3 requires 531.2163, 533.2133.
EXAMPLE 401
The preparation of 8-(Allyloxy)-4-(2-chlorophenyl)-6-methylpyrrolor3,4-clcarbazole- 1.3(2H,6H)-dione (XCIII; Ar=2-chlorophenyl, R10=CHQ (327)
Reaction of phenol (845) (250 mg, 0.66 mmol) prepared as described in example 280 with allyl bromide according to the procedure described in example 298 gave the bis-allyl derivative (XCII; Ar=2-chlorophenyl, R=CH3), which was used without further purification. Reaction of the crude material according to the proceedure described example 328 gave alkene (327) (216 mg, 79%) as a yellow powder, mp 253-256 °C. Η NMR D [(CD3)2SO] 11.07 (br s, IH), 8.77 (d, J=8.7 Hz, IH), 7.76 (s, IH), 7.57 ( , IH), 7.47 (m, 3H), 7.30 (d, J=2.2 Hz, IH), 7.03 (dd, J=8.7, 2.2 Hz, IH), 6.20-6.11 (m, IH), 5.51 (m, IH), 5.33 (m, IH), 4.77 (m, 2H), 3.92 (s, 3H). Found: C, 69.42; H, 4.27; N, 6.50. C24H17C1N203 requires: C, 69.15; H, 4.11; N, 6.72. EXAMPLE 402
The preparation of 4-(2-Chlorophenyl)-8-(2-hvdroxyethoxy)-6-methylpyrτolof3,4- clcarbazole-1.3(2H,6H)-dione (XCIV; Ar=2-chlorophenyl. R10=CH (328)
Ozone was bubbled through a solution of alkene (327) (50 mg, 0.12 mmol) prepared as described in example 401 in methanol/dichloromethane (1 :1, 40 mL) at -78 °C for 10 minutes, by which time the solution had gone from yellow to yellow/green. Excess ozone was purged from the solution by bubbling nitrogen through it for 2 minutes and then a solution of sodium borohydride (136 mg, 3.60 mmol) in methanol (20 mL) was added. The resulting solution was allowed to warm to room temperature over 45 minutes and then it was diluted with water and extraction with ethyl acetate. The organic phase was dried, the drying agent was removed and the solution was concentrated to dryness. Chromatography on silica eluting with ethyl acetate/hexane (1:1 to 3:1), followed by trituration from diethyl ether, gave alcohol (328) (11 mg, 22%) as a yellow solid, mp 309-312 °C. Η NMR δ [(CD3)2SO] 11.06 (br s, IH), 8.77 (d, J=8.7 Hz, 1H)T7.75 (s, l'H), 7.57 ~(m, IH), 7.47 (m, 3H), 7.28 (d, J=2.0 Hz, IH), 7.01 (dd, J=8.7, 2.0 Hz, IH), 4.94 (t, J=5.4 Hz, IH), 4.19 (t, J=5.1 Hz, 2H), 3.95 (s, 3H), 3.81 (m, 2H). FABMS found [M+H]+: 421.0932, 423.0912. C23H ClN204 requires 421.0955, 423.0926.
EXAMPLE 403
The preparation of 4-(2-Chlorophenyl)-8-(2,3-dihvdroxypropoxy)-6-methylpyrrolo[3.4- clcarbazole-1.3(2H.6H)-dione (XCV; Ar=2-chlorophenyl. R10=CH (329)
Reaction of alkene (327) (30 mg, 0.07 mmol) prepared as described in example 401 according to the procedure described in example 300 gave diol (329) (19 mg, 60%) as a yellow solid, mp 287-290 °C. Η NMR δ [(CD3)2SO] 11.06 (br s, IH), 8.77 (d, J=8.7 Hz, IH), 7.76 (s, IH), 7.57 (m, IH), 7.47 (m, 3H), 7.27 (d, J=2.2 Hz, IH), 7.00 (dd, J=8.7, 2.2 Hz, IH), 5.04 (d, J=5.1 Hz, IH), 4.73 (t, J=5.6 Hz, IH), 4.20 (dd, J=8.8, 4.5 Hz, IH), 4.07 (dd, J=9.9, 6.1 Hz, IH), 3.95 (s, 3H), 3.89 (m, 2H), 3.52 (t, J=5.6 Hz, 2H). FABMS found [M+H]+: 451.1052, 453.1039. C24H19C1N205 requires 451.1061, 453.1031.
Figure imgf000238_0001
Maleimide BBrJDCM rteSrtBϋ*C
Figure imgf000238_0004
*■
METHOD 8
METHOD 5 METHOD 7
Figure imgf000238_0003
Figure imgf000238_0002
(XCVIII) (XCIX)
Figure imgf000238_0005
SCHEME 17
Procedures for Scheme 17
Representative Procedure for Method 32 of Scheme 17
EXAMPLE 404
The preparation of l-(5-Methoxy-lH-indol-2-yl)ethanone (XCVI; R2=CH (800 )
To a solution of the 5-methoxy-lH-indole-2-carbaldehyde (1) (2.0 g, 11.0 mmol) in tetrahydrofuran (30 mL) at 0°C was added a solution of methyl magnesium bromide (11 mL of a 3 M solution in ether, 34.0 mmol) dropwise. The cold-bath was removed and the reaction mixture allowed to warm to room temperature over 50 min. Saturated ammonium chloride was added and then the tetrahydrofuran was removed at reduced pressure. The residue was extracted with ethyl acetate (2 x 60 mL), the combined extracts were washed, dried, and concentrated. The crude alcohol was dissolved in chloroform (40 mL) and manganese dioxide (15 g, 0.171 mol) was added, the reaction mixture was heated at reflux for 40 min. The mixture was filtered through Celite and then concentrated to give an off-white solid. The solid was purified by recrystallization from dichloromethane to give (800) (1.80 g, 83%), mp 170-172 °C. Η NMR δ [(CD3)2SO] 11.58 (br s, IH), 7.34 (d, J = 9.0 Hz, IH), 7.23 (s, IH), 7.12 (d, J = 2.4 Hz, IH), 6.94 (dd, J = 9.0, 2.4 Hz, IH), 3.77 (s, 3H), 2.52 (s, 3H). Found: C, 69.77; H, 5.95; N, 7.54. CnHιιN02 requires: C, 69.83; H, 5.86; N, 7.40. Representative Procedure for Method 33 of Scheme 17
EXAMPLE 405
The preparation of Methyl 2-r(E,Z)-l -methyl-2-phenylethenyl1-lH-indol-5-yl ether (XCVII:
Figure imgf000239_0001
To a suspension of benzyltriphenylphosphonium bromide (3.4 g, 7.9 mmol) in tetrahydrofuran (30 mL) was added a solution of LDA (4.9 mL of a 1.5 M solution in cyclohexane, 7.4 mmol). The red orange reaction mixture was stirred for 10 min and then a solution of the ketone (1.0 g, 5.3 mmol) in tetrahydrofuran (15 mL) was added. The mixture was heated at reflux overnight and then water was added and the solvent was removed at reduced pressure. The organic material was extracted with ethyl acetate (3 x 50 mL). The combined extracts were dried and concentrated. The residue was purified by column chromatography on silica eluting with dichloromethane to give methyl (801) (0.26 g, 19%) as a mixture of E- and Z-isomers, which was used without further purification.
EXAMPLE 406
The preparation of 9-Methoxy-5-methyl-4-phenylpyrrolor3,4-c1carbazole-l,3(2H,6H)-dione (XCIX: R2=CH3, R'=phenyl) (803).
Reaction of (801) prepared as described in example 405 with maleimide at 180 °C for 40 min using the procedure described in example 69 gave the adduct (XCVHI; R2=CH3, R!=phenyl) (802), which was used without further purification. The crude Diels-Alder adduct was aromatised with Mnθ2 using the procedure described in example 79 of Scheme 2 to give (803) (69%).
EXAMPLE 407
The preparation of 9-Hvdroxy-5-methyl-4-phenylpyrrolor3,4-c1carbazole-l,3(2H,6H)-dione (C: R2=CH.. R'=phenyl) (804)
Demethylation of (803) prepared as described in example 406 with BBr3 using the procedure described in example 69 gave (804) (90%), mp 270-280°C. 1H NMR δ [(CD3)2SO] 11.60 (s, IH), 10.82 (s, IH), 9.22 (s, IH), 8.31 (d, J = 2.0 Hz, IH), 7.47-7.42 (m, 4H), 7.36-7.23 (m, 2H), 7.06 (dd, J = 8.7, 2.0 Hz, IH), 2.32 (s, 3H). EIMS found M+: 342.1005. C2ιHι4N203 requires: 342.1004.
EXAMPLE 408 The preparation of (5-Methoxy-lH-indol-2-yl)(pheny1)methanone (XCVI; R2=phenyl) (805)
Reaction of 5-methoxy-lH-indole-2-carbaldehyde with phenylmagnesium bromide using the procedure described in example 404 gave (805) (91%), mp 159-161°C. Η NMR δ [(CD3)2SO] 11.86 (s, IH), 7.94-7.91 (m, 2H), 7.71-7.66 (m, IH), 7.61-7.57 (m, 2H), 7.42 (d, J = 8.9 Hz, IH), 7.16 (d, J = 2.4 Hz, IH), 7.03 (s, IH), 6.99 (dd, J = 8.9, 2.4 Hz, IH), 3.77 (s, 3H). Found: C, 76.28; H, 5.21; N, 5.42. Cι6H]3N02 requires: C, 76.48; H, 5.21; N, 5.57.
EXAMPLE 409
The preparation of 2-r(E)-l,2-Diphenylethenyll-5-methoxy-lH-indole (XCVII;
Figure imgf000240_0001
To freshly washed magnesium turnings (0.29 g, 12 mmol) and an iodine crystal in ether (20 mL) was added benzyl chloride (1.4 mL, 12 mmol) at such a rate as to maintain the reaction mixture at reflux. After addition of the benzyl chloride was complete the reaction mixture was heated at reflux for a further 3 h, it was then added to a solution of the ketone (1.0 g, 3.98 mmol) in tetrahydrofuran (20 mL). The reaction mixture was stirred at room temperature for 1 h and then 2 M hydrochloric acid (2 mL) was added. The mixture was filtered and then the solvent was removed at reduced pressure. The crude oily yellow alcohol was dissolved in ethanol/tetrahydrofuran/2 M HCI (2:2:1) and stirred at room temperature for 15 min, water was added and the organic solvents removed at reduced pressure. The organic material was extracted with ethyl acetate (3 x 50 mL), the combined extracts were dried and concentrated. The residue was purified by recrystallization from dichloromethane (0.95 g, 73%), mp 144-147°C. 1H NMR δ [(CD3)2SO] 11.24 (s, IH), 7.49-7.42 (m, 3H), 7.29-7.26 (m, 4H), 7.17-7.08 (m, 3H), 6.97-6.95 (m, 2H), 6.92 (d, J = 2.4 Hz, IH), 6.75 (dd, J = 8.7, 2.4 Hz, IH), 5.81 (s, IH), 3.70 (s, 3H). Found: C, 84.30; H, 5.85; N, 4.36. C23H19NO.l/10 H20 requires: C, 84.43; H, 5.91; N, 4.28.
EXAMPLE 410
The preparation of 9-Methoxy-4,5-diphenylpyrrolor3,4-c1carbazole-l,3(2H,6H)-dione fXCIX: R'=R2=phenyl) (808).
Reaction of (806) prepared as described in example 409 with maleimide at 180 °C using the procedure described in example 69 gave the adduct (XCVIII; R^R^phenyl) (807), which was used without further purification. The crude Diels-Alder adduct was aromatised with Mn02 using the procedure described in example 79 of Scheme 2 to give (808) (77%). ]H NMR IH NMR δ [(CD3)2SO] 11.08 (s, IH), 11.02 (br s, IH), 8.52 (d, J = 2.6 Hz, IH), 7.50 (d, J = 8.9 Hz, IH), 7.36-7.28 (m, 3H), 7.21-7.11 (m, 8H), 3.89 (s, 3H).
EXAMPLE 411
The preparation of 9-Hvdroxy-4,5-diphenylpyrrolor3,4-clcarbazole-l,3(2H,6H)-dione (C:
Figure imgf000241_0001
Demethylation of (807) prepared as described in example 410 with BBr3 using the procedure described in example 80 gave (809) as a yellow powder (87%), mp >300°C. !H NMR δ [(CD3)2SO] 10.96 (s, IH), 10.94 (s, IH), 9.23 (s, IH), 8.37 (d, J = 2.4 Hz, IH), 7.39 (d, J = 8.7 Hz, IH), 7.35-7.29 (m, 3H), 7.22-7.10 (m, 7H), 7.03 (dd, J = 8.7, 2.4 Hz, IH). Found: C, 77.16; H, 4.00; N, 6.83. C26H16N203 requires: C, 77.22; H, 3.99; N, 6.93.
EXAMPLE 412
The preparation of 5-Methoxy-2-r(lE)-l-phenyl-l-propenyl1-lH-indole (XCVII; R2=phenyl, R'=CH.) (810)
Reaction of (805) prepared as described in example 408 with ethyltriphenylphosphonium bromide using the procedure described in example 405 gave (810) (72%), mp 128-130°C. ]H NMR δ [(CD3)2SO] 10.97 (s, IH), 7.47-7.39 (m, 3H), 7.28-7.19 ( , 3H), 6.88 (d, J = 2.4 Hz, IH), 6.69 (dd, J = 8.7, 2.4 Hz, IH), 6.38 (q, J = 6.9 Hz, IH), 5.69 (s, IH), 3.69 (s, 3H), 1.67 (d, J = 6.9 Hz, 3H) Found: C, 81.78; H, 6.26; N, 5.33. CigHπNO requires: C, 82.10; H, 6.51; N, 5.32.
EXAMPLE 413
The preparation of 9-Methoxy-4-methyl-5-pheny1pyrrolor3,4-c1carbazole-l,3(2H,6H)-dione (XCVIII: R2=phenyl. R^CH.) (812)
Reaction of (810) prepared as described in example 412 with maleimide at 180 °C using the procedure described in example 69 gave the adduct (XCIN; R2=phenyl, R^C ) (811), which was used without further purification. The crude Diels-Alder adduct was aromatised with Mn02 using the procedure described in example 79 of Scheme 2 to give (812) (74%), mp 284-286°C. Η NMR δ [(CD3)2SO] 11.06 (br s, IH), 10.93 (s, IH), 8.43 (d, J = 2.6 Hz, IH), 7.64-7.54 (m, 3H), 7.45-7.42 (m, 3H), 7.14 (dd, J = 8.9, 2.6 Hz, IH), 3.32 (s, 3H), 2.48 (s, 3H). Found: C, 73.13; H, 4.32; N, 7.72. C22H16N203.l/3 H20 requires: C, 72.92; H, 4.64; N, 7.73. EXAMPLE 414
The preparation of 9-Hydroxy-4-methyl-5-phenylpyrrolor3.4-clcarbazole-l,3(2H,6H)-dione (C; R2=phenyl. R'=CH
Demethylation of (812) prepared as described in example 413 with BBr using the procedure described in example 80 gave (813) (85%), mp >300°C. 1H NMR δ [(CD3)2SO] 11.01 (s, IH), 10.79 (s, IH), 9.17 (s, IH), 8.28 (d, J = 2.4 Hz, IH), 7.34-7.60 (m, 2H), 7.57-7.52 (m, IH), 7.43-7.41 (m, 2H), 7.34 (d, J = 8.7 Hz, IH), 6.98 (dd, J = 8.7, 2.4 Hz, IH), 2.26 (s, 3H). EIMS found M+: 342.1003. C21Hι4N 03 requires: 342.1004.
EXAMPLE 415
The preparation of 5-Methoxy-2-vinyl-lH-indole (XCVII; R1=R2=H) (814)
Reaction of 5-methoxy-lH-indole-2-carbaldehyde with methyltriphenylphosphonium bromide using the procedure described in method33 gave (814) (87%), mp 80-81°C. Η NMR δ [(CD3)2SO] 11.09 (s, IH), 7.21 (d, J = 8.7 Hz, IH), 6.97 (d, J = 2.3 Hz, IH), 6.75-6.66 (m, 2H), 6.37 (s, IH), 5.76 (d, J = 17.3 Hz, IH), 5.21 (d, J = 11.6, IH), 3.73 (s, 3H). Found: C, 76.34; H, 6.24; N, 8.11. CnHnNO requires: C, 76.28; H, 6.40; N, 8.09.
EXAMPLE 416
The preparation of 9-Methoxypyrrolor3,4-c1carbazole-l,3(2H,6H)-dione (XC ; R'=R2=H) £816)
Reaction of (814) prepared as described in example 415 with maleimide at 180 °C using the procedure described in example 69 gave the adduct (XCVIII; R=R'=H) (814), which was used without further purification. The crude Diels-Alder adduct was aromatised with Mn02 using the procedure described in example 79 to give (815 ?? ) (76%), mp 260-270°C. Η NMR δ [(CD3)2SO] 11.91 (s, IH), 11.10 (s, IH), 8.38 (d, J = 2.6 Hz, IH), 7.81 (d, J = 8.2 Hz, IH), 7.76 (d, J = 8.2 Hz, IH), 7.54 (d, J = 8.8 Hz, IH), 7.22 (dd, J = 8.8, 2.6 Hz, IH), 3.88 (s, 3H). Found: C, 65.44; H, 3.96; N, 10.30. C]5Hι0N2O3.l/2 H20 requires: C, 65.45; H, 4.03; N, 10.18. EX AMPLE 417
The preparation of 9-Hvdroxypyrrolor3.4-clcarbazole-1.3(2H.6H)-dione (C: R]=R2=H) (817)
Demethylation of (816) prepared as described in example 416 with BBr3 using the procedure described in example 80 gave (817) (79%), mp 335-345°C. Η NMR δ [(CD3)2SO]
11.77 (s, IH), 11.04 (s, IH), 9.23 (s, IH), 8.24 (d, J = 2.3 Hz, IH), 7.75 (2d, J = 8.2 Hz, 2H),
7.43 (d, J = 8.7 Hz, IH), 7.05 (dd, J = 8.7, 2.3 Hz, IH). Found: C, 64.44; H, 3.45; N, 10.41.
C]4H8N203.l/2 H20 requires: C, 64.37; H, 3.47; N, 10.72.
EXAMPLE 418
The preparation of Methyl 2-(l-phenylvinyl)-lH-indol-5-yl ether (XCVII; R2=phenyl. R'=H) (818)
Reaction of (805) prepared as described in example 408 with methyltriphenylphosphonium bromide using the procedure described in example 405 gave (818) (95%), mp 119-1210C. 'H NMR δ [(CD3)2SO] 11.13 (s, IH), 7.47-7.39 (m, 5H), 7.26 (d, J = 8.8 Hz, IH), 6.97 (d, J = 2.4 Hz, IH), 6.76 (dd, J = 8.8, 2.4 Hz, IH), 6.12 (s, IH), 5.77 (s, IH), 5.30 (s, IH), 3.72 (s, 3H). Found: C, 81.83; H, 6.22; N, 5.59. CπHι5NO requires: C, 81.90; H, 6.06; N, 5.62.
EXAMPLE 419
The preparation of 9-Methoxy-5-phenylpyrrolor3.4-clcarbazole-l,3(2H,6H)-dione (XCIX: R2=phenyl, R'=H) (820)
Reaction of (818) prepared as described in example 418 with maleimide at 180 °C using the procedure described in example 69 gave the adduct (XCVIII; R=phenyl, R'=H) (819), which was used without further purification. The crude Diels-Alder adduct was aromatised with Mn02 using the procedure described in example 79 to give (820) (73%), mp 281-285°C. 1H NMR δ [(CD3)2SO] 11.63 (br s, IH), 11.15 (br s, IH), 8.45 (d, J = 2.5 Hz, IH), 7.78-7.76 (m, 2H), 7.68 (s, IH), 7.65-7.62 (m, 2H), 7.57-7.53 (m, 2H), 7.22 (dd, J = 8.8, 2.5 Hz, IH), 3.89 (s, 3H). Found: C, 72.06; H, 4.57; N, 7.69. C2,H)4N203.l/3 H20 requires: C, 72.41; H, 4.24; N, 8.04. EXAMPLE 420
The preparation of 9-Hvdroxy-5-phenylpyrrolor3,4-c1carbazole-l,3(2H,6H)-dione (C; R2=phenyl. R*=H) (821)
Demethylation of 820 prepared as described in example 419 with BBr3 using the procedure described in example 80 gave (821) (89%), mp 335-345°C. Η NMR δ [(CD3)2SO] 11.50 (s, IH), 11.10 (s, IH), 9.26 (d, J = 2.4 Hz, IH), 8.30 (d, J = 2.4 Hz, IH), 7.77-7.75 (m, 2H), 7.65-7.61 (m, 3H), 7.56-7.52 (m, IH), 7.46 (d, J = 8.7 Hz, IH), 7.06 (dd, J = 8.7, 2.4 Hz, IH). Found: C, 72.71; H, 3.55; N, 8.16. C20Hι2N2O3 requires: C, 73.16; H, 3.68; N, 8.53.
EXAMPLE 421
The preparation of l-(5-Methoxy-lH-indol-2-yl)-l-propanone (XCVI: R2=CH.CH.) (822)
Reaction of 5-methoxy-lH-indole-2-carbaldehyde with ethylmagnesium bromide using the procedure described in example 404 gave (822) (82%), mp 170-171.5°C. Η NMR δ [(CD3)2SO] 11.56 (s, IH), 7.34 (d, J = 9.1 Hz, IH), 7.22 (d, J = 1.7 Hz, IH), 7.11 (d, J = 2.4 Hz, IH), 6.93 (d, J = 9.1, 2.4 Hz, IH), 3.77 (s, 3H), 2.96 (q, J = 7.3 Hz, 2H), 1.13 (t, J = 7.3 Hz, 3H). Found: C, 71.15; H, 6.45; N, 7.07. C12H13N02 requires: C, 70.92; H, 6.45; N, 6.89.
EXAMPLE 422
The preparation of 2-f(E,Z)-l-Ethyl-2-phenylethenyll-5-methoxy-lH-indole (XCVII; R2=CH?CH^, R'=phenyl) (823)
Reaction of (822) prepared as described in example 421 with benzyltriphenylphosphonium bromide using the procedure described in example 404 gave (823) (38%), mp 95-97°C. Found: C, 82.28; H, 6.98; N, 5.07. 9H19NO requires: C, 82.28; H, 6.90; N, 5.05.
EXAMPLE 423
The preparation of 5-Ethyl-9-methoxy-4-phenylpyrrolor3,4-clcarbazole-l,3(2H,6H)-dione (XCIX: R2=CH.CH,. R'-zphenyl) (825)
Reaction of (823) prepared as described in example 422 with maleimide at 180 °C using the procedure described in example 69 gave the adduct (XCVIII; R=CH2CH3, R'=phenyl) (824), which was used without further purification. The crude Diels-Alder adduct was aromatised with Mnθ2 using the procedure described in example 79 to give (825) (68%), mp 301-303°C. 1H NMR δ [(CD3)2SO] 11.78 (s, IH), 10.87 (s, IH), 8.47 (d, J = 2.6 Hz, IH), 7.56 (d, J = 8.8 Hz, IH), 7.48-7.41 (m, 3H), 7.32-7.30 (m, 2H), 7.23 (dd, J = 8.8, 2.6 Hz, IH), 3.89 (s, 3H), 2.76 (q, J = 7.4 Hz, 2H), 1.07 (t, J = 7.4 Hz, 3H).
EXAMPLE 424
The preparation of 5-Ethv1-9-hvdroxy-4-phenylpyrrolor3,4-c1carbazole-l,3(2H,6H)-dione (C: R2=CH2CH3. R'=phenyl) (826)
Demethylation of (825) prepared as described in example 423 with BBr3 using the procedure described in example 80 gave (826) (97%), mp 190-196°C. 1H NMR δ [(CD3)2SO] 11.63 (s, IH), 10.81 (s, IH), 9.21 (s, IH), 8.31 (d, J = 2.4 Hz, IH), 7.48-7.40 (m, 4H), 7.31-7.29 (m, 2H), 7.06 (dd, J = 8.7, 2.4 Hz, IH), 2.74 (q, J = 7.4 Hz, 2H), 1.06 (t, J = 7.4 Hz, 3H). Found: C, 72.43; H, 4.54; N, 7.54. C22H16N203.l/2 H20 requires: C, 72.32; H, 4.69; N, 7.67.
Figure imgf000245_0001
SCHEME 18
Procedures for Scheme 18
EXAMPLE 425
The preparation of 5-(Benzyloxy)-2-r(E,Z)-2-(2-methoxyphenyl)ethenyll-lH-indole (CI; Ar=2-methoxyphenyl) (847) Reaction of 5-(benzyloxy)-lH-indole-2-carbaldehyde (846) with 2- methoxybenzyltriphenylphosphonium bromide using the procedure described in example 37 gave (847) as a cream-colored solid (mixture of E/Z isomers) (89 %), which was used without further purification. Η NMR δ [(CD3)2SO] (major isomer) 11.26 (s, IH), 7.62 (d, J=6.8 Hz, IH), 7.48 (m), 7.41-7.15 (m), 7.08-7.02 (m), 6.97 (m, IH), 6.81 (dd, J=8.7, 2.4 Hz, IH), 6.45 (s,lH), 5.08 (s, 2H), 3.87 (s, 3H).
EXAMPLE 426
The preparation of 5-(Benzyloxy)-2-r(E,Z)-2-(2-methoxyphenyl)ethenyl1-l-r2-(4- morpholinvDethyll-lH-indole (CII; Ar=2-methoχyphenyl. R10=CH,CH.N(CH?CH. ).Q) (848)
Alkylation of (847) prepared as described in example 425_with 4-(2- chloroethyl)morpholine using the procedure described in method 3 gave (848) (87 %) as a pale yellow solid, which was used without further purification.
EXAMPLE 427
The preparation of 9-(Benzyloxy)-4-(2-methoxyphenyl)-6-r2-(4- mo holinyl)ethyllpyrrolor3,4-clcarbazole-l,3(2H,6H)-dione (CIV; Ar=2-methoxyphenyl.
Figure imgf000246_0001
Reaction of (848) prepared as described in example 426 with maleimide using the procedure described in method 4a gave the adduct (CIII; Ar=2-methoxyphenyl, R10=CH2CH2N(CH2CH2)2O) (849), which was used without further purification. Aromatisation of (849) with Mn02 using the procedure described in example 79 gave (850) (36%) as a yellow solid, mp 170-172 °C.
EXAMPLE 428
The preparation of 9-Hvdroxy-4-(2-methoxyphenyl)-6-r2-(4-morpholinyl)ethyl1pyrrolor3.4- clcarbazole-l,3(2H.6H)-dione (VI; Ar=2-methoxyphenyl. R10-=CH,CHrN(CH.CH.).O (851)
Removal of the benzyl ether group of (850) prepared as described in example 427 by hydrogenolysis using the procedure described in example 254 gave (851) (66%) as a yellow powder, mp 262-264 °C. !H NMR δ [(CD3)2SO] 10.92 (br s, IH), 9.31 (br s, IH), 8.37 (d, J=2.5 Hz, IH), 7.69 (s, IH), 7.54 (d, J=8.8 Hz, IH), 7.42 (m, IH), 7.33 (dd, J=7.4, 1.7 Hz, IH), 7.12-7.08 (m, 2H), 7.05 (m, IH), 4.54 (t, J=6.3 Hz, 2H), 3.68 (s, 3H), 3.45 (t, J=4.4 Hz, 4H), 2..65 (t, J=6.3 Hz, 2H), 2.41 (br t, 4H). Found EMS M+: 471.1789. C27H25N305 requires 471.1794.
EXAMPLE 429
The preparation of 5-(Benzyloxy)-2-((E)-2-r2-(2-methoxyethoxy)phenyllethenvπ-lH-indole (CI; Ar=2-(2-methoxyethoxy)phenyl) (852)
Reaction of 5-(benzyloxy)-lH-indole-2-carbaldehyde (846) with 2-(2- methoxyethoxy)benzyltriphenylphosphonium bromide using the procedure described in example 37 gave (847) as a cream-colored solid (mixture of E/Z isomers) (86 %), which was used without further purification.
EXAMPLE 430
The preparation of 9-(Benzyloxy)-4-r2-(2-methoxyethoxy)phenyllpyrrolor3,4-c1carbazole- l ,3(2H.6H)-dione (CIV: Ar=2-(2-methoxyethoxy)phenyl. R10=H) (854)
Reaction of (852) with maleimide using the procedure described in method 4a gave the adduct (CIII; Ar=2-(2-methoxyethoxy)phenyl, R10=H) (853), which was used without further purification. Aromatisation of (853) with Mn02 using the procedure described in example 79 gave (854) (46%) as an orange solid, mp 157-159 °C, which was used without further purification.
EXAMPLE 431
The preparation of 9-Hvdroxy-4-r2-(2-methoxyethoxy)phenyllpyrrolo[3,4-c1carbazole- 1.3(2H.6H)-dione (VI: Ar=2-(2-methoxyethoxy)phenyl, R10=H) (855).
Removal of the benzyl ether group of (854) prepared as described in example 430 by hydrogenolysis using the procedure described in example 254 gave (855) (53 %) as a yellow powder, mp 275-279 °C. Η NMR δ [(CD3)2SO] 11.71 (br s, IH), 10.89 (br s, IH), 9.22 (br s, IH), 8.31 (d, J=2.2 Hz, IH), 7.51 (s, IH), 7.43 (d, J=8.5 Hz, IH), 7.39 (m, IH), 7.34 (dd, J=7.5 Hz, IH), 1.7 Hz, IH), 7.10 (d, J=7.7 Hz, IH), 7.05 (m, 2H), 4.04 (m, 2H), 3.45 (t, J=4.7 Hz, 2H), 3.10 (s, 3H). EIMS Found M+: 402.1213. C23Hι8N205 requires 402.1215. EXAMPLE 432
The preparation of (2-Methoxy-4-nitrobenzyl)(triphenyl)phosphonium bromide (582)
Bromination of (2-methoxy-4-nitrophenyl)methanol with 30% HBr in acetic acid, followed by reaction of the crude bromide with triphenylphosphine, using the procedure described in example 112, except that the conditions for the displacement were 3 days at 20 °C followed by 1 day at 55 °C, gave the phosphonium salt (582) (84 %) as a yellow solid, mp (CH2Cl2 benzene) 194-196 °C. ]H NMR (CDC13) δ 7.83-7.63 (m, 17H), 7.45 (br s, IH), 5.52 (d, J=15.0 Hz, 2H). Found: C, 61.10; H, 4.73; N, 3.05. C26H23BrN03P requires C, 61.43; H, 4.56; N, 2.76.
EXAMPLE 433
The preparation of 5-(BenzvIoxy)-2-r(E)-2-(2-methoxy-4-nitrophenvI)ethenyl1-lH-indole (583) (CI, Ar=2-methoxy-4-nitrophenyl)
The aldehyde (846) was reacted with (2-methoxy-4-nitrobenzyl) (triphenyl)phosphonium bromide (582) prepared as described in example 432 using the procedure described in method 2, except that the LDA and aldehyde were (sequentially) added at 0 °C, the ratio of LDA:aldehyde was 1.5:1 and the reaction time was 5 h, to give (after crystallisation from C^CVpentane) the diene (583) as an orange solid (the pure E isomer) (63 %), mp 156-159 °C. Η NMR (CDC13) δ 8.23 (br s, IH), 7.87 (dd, J=8.5, 2.1 Hz, IH), 7.76 (d, J=2.2 Hz, IH), 7.68 (d, J=8.6 Hz, IH), 7.48 (d, J=7.3 Hz, 2H), 7.39 (t, J=7.3 Hz, 2H), 7.32 (t, J=7.2 Hz, IH), 7.28 (d, J=17.1 Hz, IH), 7.26 (d, J=8.7 Hz, IH), 7.20 (d, J=16.7 Hz, IH), 7.12 (d, J=2.4 Hz, IH), 6.97 (dd, J=8.7, 2.5 Hz, IH), 6.63 (br s, IH), 5.11 (s, 2H), 4.01 (s, 3H). Found: C, 71.69; H, 4.94; N, 7.11. C24H20N2O4 requires C, 71.99; H, 5.03; N, 7.00.
EXAMPLE 434
The preparation of 9-(Benzyloxy)-4-(2-methoxy-4-nitrophenyl)-4,5,6.10c- tetrahvdropyrrolor3.4-c1carbazole-1.3(2H,3aH)-dione (584) (CIII. R10=H. Ar=2-methoxy-4- nitrophenyl) and 9-benzyloxy-4-(2-methoxy-4-nitrophenyl)pyrrolo[3,4-c1carbazole- 1.3(2H.6H)-dione (585) (CIV, R10=H, Ar=2-methoxy-4-nitrophenyl)
A foil-covered mixture of the pure E diene (583) (185 mg, 0.463 mmol) prepared as described in example 433 and maleimide (260 mg, 2.68 mmol) in dry toluene (3 mL) was stirred in a sealed vial at reflux for 22 h (Method 4a). The resulting thick suspension was transferred to a flask using dioxane (7 mL), then treated with manganese dioxide (900 mg, 10.4 mmol), stirring at reflux for 24 h ( according to the procedure for example 79), to give (after workup) a mixture, which was adsorbed onto silica gel and chromatographed. Elution with 0-0.25% MeOH/CH2Cl2 gave foreruns, then further elution with 0.25-33% MeOH/CH2Cl2 gave (after crystallisation from THF/CH2Cl2/pentane) the crude product (585) (64 mg). This was further purified by chromatography on silica gel (eluting with 20% EtOAc/petroleum ether) to give (after crystallisation from THF/CH2Cl2/ρentane) the pure material (585) (58 mg, 25%) as a yellow solid, mp 301-303 °C. Η NMR [(CD3)2SO] δ 11.97 (br s, IH), 11.08 (br s, IH), 8.54 (d, J=2.5 Hz, IH), 7.94 (dd, J=8.3, 2.2 Hz, IH), 7.88 (d, J=2.2 Hz, IH), 7.64 (d, J=8.2 Hz, IH), 7.63 (s, IH), 7.58 (d, J=8.8 Hz, IH), 7.56 (br d, J=7.1 Hz, 2H), 7.42 (t, J=7.4 Hz, 2H), 7.35 (t, J=7.4 Hz, IH), 7.32 (dd, J=8.9, 2.7 Hz, IH), 5.23 (s, 2H), 3.83 (s, 3H). Found: C, 68.14; H, 3.89; N, 8.41. C28Hι9N3θ6 requires C, 68.15; H, 3.88; N, 8.52.
Further elution with 1% MeOH/CH2Cl2 gave (after crystallisation from MeOH/CH2Cl2/petroleum ether) recovered adduct (584) (72 mg, 31%) as a pale yellow solid (which was aromatised directly with 5 equiv. DDQ using the procedure described in example 70 to give further product in 79% yield), Η NMR [(CD3)2SO] δ 10.96 (br s, IH), 10.86 (br s, IH), 7.90 (dd, J=8.5, 2.3 Hz, IH), 7.78 (d, J=2.2 Hz, IH), 7.72 (d, J=8.6 Hz, IH), 7.50 (d, J=7.1 Hz, 2H), 7.40 (t, J=7.3 Hz, 2H), 7.34 (d, J=2.4 Hz, IH), 7.33 (t, J=7.4 Hz, IH), 7.21 (d, J=8.7 Hz, IH), 6.80 (dd, J=8.7, 2.5 Hz, IH), 5.09 (s, 2H), 4.27 (d, J=7.6 Hz, IH), 3.98 (dd, J=7.6, 3.6 Hz, IH), 3.97 (s, 3H), 3.54 (dt, J=12.9, 3.8 Hz, IH), 3.24 (br dd, J=15.7, 13.5 Hz, IH), 2.89 (dd, J=15.4, 3.6 Hz, IH). FABMS found: M+=497.1601. C28H23N3θ6 requires 497.1587.
EXAMPLE 435
The preparation of 9-Hydroxy-4-(2-methoxy-4-nitrophenyl)pyιτolor3,4-c1carbazole- 1.3(2H,6H)-dione (586) (VI, R10=H. Ar=2-methoxy-4-nitrophenyl)
A suspension of the benzyl ether (585) (55 mg, 0.112 mmol) prepared as described in example 434 in glacial AcOH (11.2 mL) was treated with concentrated HCI (6.7 mL of 36%), stirring at 100 °C for 50 min (Using the procedure described in example 260 of Scheme 18). The cooled solution was added slowly to ice/aqueous NaHC03 (150 mL), then extracted with EtOAc (5x 100 mL). The extracts were washed with water, then adsorbed onto silica gel and chromatographed. Elution with 0-1% MeOH/CH2θ2 gave foreruns, then elution with 1.5% MeOH/CH2Cl2 gave (after crystallisation from THF/CH2Cl2/pentane) the phenol (586) (86 %) as an orange solid, mp 242-244 °C. Η NMR [(CD3)2SO] δ 11.84 (br s, IH), 11.02 (br s, IH), 9.28 (br s, IH), 8.31 (d, J=2.4 Hz, IH), 7.93 (dd, J=8.2, 2.1 Hz, IH), 7.87 (d, J=2.1 Hz, IH), 7.63 (d, J=8.2 Hz, IH), 7.58 (s, IH), 7.45 (d, J=8.7 Hz, IH), 7.08 (dd, J=8.7, 2.4 Hz, IH), 3.83 (s, 3H). Found: C, 62.55; H, 3.22; N, 10.13. C21H13N306 requires C, 62.53; H, 3.25; N, 10.42.
EXAMPLE 436
The preparation of 4-(4-Amino-2-methoxyphenyl)-9-hvdroxypyrrolor3,4-clcarbazole- 1.3(2H.6H)-dione (587) (VI. R10=H. Ar=4-amino-2-methoχyphenyl)
A mixture of the nitro derivative (586) (31 mg, 0.0769 mmol) prepared as described in example 435 and freshly prepared (wet) nickel boride (242 mg) in MeOH (2.4 mL) and IM HCI (0.6 mL) was stirred at reflux for 1 h. Six drops of cone. HCI were added, then the mixture was stirred at reflux for a further 1 h. Cone, aqueous ammonia and aqueous NaHC03 (100 mL) were added and the mixture extracted with EtOAc (8x 100 mL). The extracts were concentrated, adsorbed onto silica gel and chromatographed. Elution with 0-2% MeOH/CH2Cl2 gave foreruns, then further elution with 2-3% MeOH/CH2Cl2 gave (after crystallisation from MeOH/THF/CH2Cl2/pentane) the amine (587) (77 %) as a yellow-orange solid, mp 308-316 °C. ]H NMR [(CD3)2SO] δ 11.57 (br s, IH), 10.79 (br s, IH), 9.17 (br s, IH), 8.29 (d, J=2.4 Hz, IH), 7.43 (s, IH), 7.39 (d, J=8.7 Hz, IH), 7.02 (dd, J=8.7, 2.5 Hz, IH), 6.95 (d, J=7.9 Hz, IH), 6.30 (d, J=2.0 Hz, IH), 6.22 (dd, J=8.0, 1.9 Hz, IH), 5.26 (br s, 2H), 3.59 (s, 3H). Found: C, 67.65; H, 4.06; N, 11.01. C21H]5N304 requires C, 67.56; H, 4.05; N, 11.25.
Figure imgf000251_0001
Maleimide xylene/SnC-2 METHOD 4
Figure imgf000251_0003
Figure imgf000251_0002
(CVI) (CVII)
Figure imgf000251_0004
SCHEME 19
Scheme 19 Procedures
EXAMPLE 437
The preparation of Methyl 7-bromo-5-methoxy-l-benzofuran-2-carboxylate (856)
To a solution containing 3-Bromo-2-hydroxy-5-methoxy-benzaldehyde (94.7 g, 0.410 mol) and dimethyl bromomalonate (103 g, 0.492 mol) in toluene (1.2 L) was added freshly powdered potassium carbonate (85 g, 0.615 mol) and tetra-n-butylammonium bromide (13.2 g, 0.041 mol). The reaction was heated at reflux under a Dean-Stark trap for 48 h. The reaction was concentrated and the residue dissolved with dichloromethane (-0.5 L) and filtered through Celite, washing with dichloromethane (-0.5 L). The filtrate was washed with 1 L of IM sodium hydroxide and water (2 x 1 L). The organic phase was then passed through a 400 g pad of silica gel washing with dichloromethane (-1 L) and the filtrate was concentrated to give the desired benzofuran (64 g, 56%) as an orange solid, mp 107-111 °C. Η NMR δ (CDC13) 7.50 (s, IH), 7.23 (d, IH), 7.03 (d, IH), 3.98 (s, 3H), 3.82 (s, 3H).
EXAMPLE 438
The preparation of 7-Bromo-2-hydroxymethyl-5-methoxybenzofuran and 7-bromo-5- methoxybenzofuran-2-carbaldehyde (858).
A solution containing ester (857) (69 g, 242 mmol) prepared as described in example 856 in anhydrous tetrahydrofuran (2.5 L) was chilled to -78 °C. A IM lithium aluminum hydride solution in tetrahydrofuran (242 mL, 242 mmol) was added over a 30 min period. The reaction was stirred at -78 °C for 1.25 h and was carefully quenched with 50 mL of water. The mixture was poured into 1 L of an ice-cold IM hydrochloric acid solution and extracted with ethyl acetate (4 x 500 mL). The combined organic phases were dried (Na2S04) and concentrated in vacuo to give 67 g of an orange solid. This residue was adsorbed onto 200 g of silica gel and added to a column of silica gel (1 kg, 70-230 mesh) and eluted with 1:9, 1:4, and 1:3 ethyl acetate-heptanes. This gave firstly 25 g (41%) of the final aldehyde (858) as a pale yellow solid, mp 119-121 °C. *H NMR δ (CDC13) 9.90 (s, IH), 7.55 (s, IH), 7.38 (d, IH), 7.10 (s, IH), 3.85 (s, 3H). Found: C, 47.06; H, 2.66; Br, 31.41. Cι0H7BrO3 requires C, 47.09; H, 2.77; N, 31.33; followed by 20 g (33%) of the expected alcohol. 'H NMR δ (CDC13) 7.08(m,lH), 6.9(m,lH), 6.68(s,lH), 4.78(s, 2H), 3.85(s, 3H).
EXAMPLE 439
The preparation of 7-Bromo-5-methoxybenzofuran-2-carbaldehyde (858)
A solution of the alcohol isolated above (560 mg, 2.18 mmol) prepared as described in example 858, tetrahydrofuran (20 mL) and ether (60 mL) was added manganese dioxide (1.9 g, 21.8 mmol). The reaction was stirred for 2 days and filtered through Celite. The filtrate was concentrated in vacuo and chromatographed on silica give 200 mg (-50%) of the desired aldehyde (858) (spectra as above). Representative Procedure for Method 34 of Scheme 19
EXAMPLE 440
The preparation of 7-Bromo-2-r(E)-2-(2-chlorophenyl)ethenvH-5-methoxy-l-benzofuran (CV; Ar=2-chlorophenyl) (859)
To a solution of diethyl 2-chlorobenzylphosphonate (4.91 g, 0.018 mol) and 7-bromo- 5-methoxybenzofuran-2-carbaldehyde (11.27 g, 0.016 mol) in tetrahydrofuran (80 mL) was added sodium hydride (60% dispersion in mineral oil, 0.74 g, 0.0185 mol). After 5 min. the reaction mixture was warmed to 60 °C for 1 h. The reaction mixture was cooled to room temperature, water (10 mL) was carefully added and the tetrahydrofuran was removed. Water (50 mL) was added and the mixture was extracted with ethyl acetate (3 x lOOmL). The combined ethyl acetate extracts were washed with brine (50 mL), dried over magnesium sulphate, filtered and concentrated to dryness. Trituration with diethyl ether (20 mL) gave solid material which was further washed with diethyl ether (20ml). The liquors were concentrated and triturated with diethyl ether (10 mL), the solid being collected. The combined solids gave (859) (4.89 g, 84 %). 1H NMR δ (CDC13) 7.70 (d, J= 16 Hz, IH), 7.65 (dd, J= 7.7,1.5 Hz, IH), 7.4(dd, J= 6.0, 1 Hz, IH), 7.23 (m, 2H), 7.05 (d, J= 2.3 Hz, IH), 6.94 (d, J= 16 Hz, IH), 6.92 (d, J= 2.3 Hz, IH), 6.72 (s, IH), 3.82 (s, 3H); MH+: 364.9, 362.9 MH": 362.9, 360.9.
EXAMPLE 441
The preparation of 7-Bromo-4-(2-chlorophenyl)-9-methoxy-3a,4,5,10c-tetrahvdro-lH- rilbenzofuror3,2-elisoindole-1.3(2H)-dione (CVI; Ar=2-chlorophenyl) (860)
A solution of (859) (4.89 g, 0.0185 mol) prepared as described in example 441, maleimide (1.44 g, 0.02 mol) and tin(II) chloride (2.8 g, 0.02 mol) in xylenes (40 mL) was heated to 150 °C overnight. After the addition of more maleimide (1.44 g, 0.02 mol) and tin(II) chloride (1.44 g, 0.01 mol) the reaction was again heated to 150 °C overnight. The solid which formed was collected and washed with xylenes (20 mL) before dissolving in ethyl acetate (200 mL). Water (50 mL) was added and the mixture was filtered through a pad of Celite. The resulting layers were separated, the organic phase was washed with brine (50 mL) dried over magnesium sulphate, filtered and concentrated to dryness. The product (860) (6.1g, 71 %) was used without further purification. Η NMR δ (CDC13) 7.60 (d, J=6.5 Hz, 1H), 7.40 (m, 2H), 7.25 (m, IH), 7.1 (m, 2H), 4.36 (dd, J=7,3, 1 Hz, IH), 4.0 (m, IH), 3.86 (s, 3H), 3.81 (m, IH), 3.45 (m, IH), 3.10 (dd, J= 4.7, 17 Hz, IH); MH+: 462,460.
EXAMPLE 442
The preparation of 7-Bromo-4-(2-chlorophenyl)-9-methoxy-lH-rilbenzofuror3.2- e1isoindole-1.3(2H)-dione (CVII: Ar=2-chlorophenyl) (861).
Aromatisation of (860) prepared as described in example442 with Mn02 using the procedure described in example 79 gave the dibenzofuran (861) as a yellow solid (67%). Η NMR δ [(CD3)2SO] 8.22 (d, J=2.6 Hz, IH), 8.14 (s,lH), 7.62 (m, 2H), 7.48 (m, 3H), 3.98 (s, 3H). MH": 458,457,456,454.
EXAMPLE 443
The preparation of 7-Bromo-4-(2-chlorophenyl)-9-hydroxy-lH-ri1benzofurof3,2-e1isoindole- 1.3(2H)-dione (CVIII; Ar=2-chlorophenyl) (862)
Demethylation of (861) prepared as described in example 442 with BBr3 using the procedure described in example 80 gave (862) (98 %) which was used without further purification. 1H NMR δ [(CD3)2SO] 8.04 (d, J=2.3 Hz, IH), 7.91 (s, IH), 7.56 (d, J=8 Hz, IH), 7.45 (m, 3H), 7.2 (d, J=2.5 Hz, IH). MH-: 443.9, 441.9, 439.9.
EXAMPLE 444
The preparation of 4-(2-Chlorophenyl)-9-hvdroxy-7-vinyl-lH-ri1benzofuror3,2-elisoindole- 1.3(2H)-dione (CIX: Ar=2-chlorophenyl, Z=H) (863).
Reaction of (862) prepared as described in example 443 with tributylvinyltin using the procedure described in example 309 gave (863) (79 %). Η NMR δ [(CD3)2SO] 9.80 (s, IH), 8.04 (d, J=2.7 Hz, 1H), 7.91(s,lH), 7.56 (d, J= 8Hz, IH), 7.45 (m, 3H), 7.2 (d, J=2.5 Hz, IH), 6.96 (dd, J=18,l l Hz, IH), 6.25 (d, J=18 Hz, IH), 5.52 (d, J=l l Hz, IH). MH: 390, 388.
EXAMPLE 445
The preparation of 4-(2-Chlorophenyl)-7-ethyl-9-hydroxy-lH-[llbenzofuror3,2-elisoindole- 1.3(2H)-dione (CX; Ar=2-chlorophenyl. Z=H) (864).
A solution of (863) (0.054 g, 0. 167 mmol) prepared as described in example 444 in a methanol:tetrahydrofuran mixture (1:1, 4 mL) was hydrogenated over Raney nickel (100 mg) and hydrogen. The product was purified by column chromatography using a gradient of 0- 100 % ethyl acetate in dichloromethane to give (864) (0.032 g, 59%). !H NMR δ [(CD3)2SO] 9.65 (s, IH), 7.92 (m, IH), 7.56 (d, J=3.0 Hz, IH), 7.43 (m, 3H), 6.96 (d, J=2.5 Hz, IH), 2.90 (q, 2H), 1.5 (t, 3H). MH": 392, 390.
EXAMPLE 446
The preparation of 4-(2-Chlorophenyl)-7-(l,2-dihvdroxyethyl)-9-hydroxy-lH- πibenzofuror3,2-e1isoindole-1.3(2H)-dione (CXI; Ar=2-chlorophenyl, Z=H) (865).
Reaction of (863) prepared as described in example 444 with Os04 using the procedure described in example 300 gave (865) (35 %). Η NMR δ [(CD3)2SO] 9.68 (s, IH), 7.96 (d, J=2.5 Hz, IH), 7.9 (s,lH), 7.55 (d, J=7.8 Hz, IH), 7.45, m, 3H), 7.17 (d, J=2.5 Hz, IH), 5.55 (d, J=4.6 Hz, IH), 5.06 (m,lH), 4.87 (t, J=5.7 Hz, IH), 3.65 (m,lH), 3.55 (m,lH). MH": 424, 422.
H - HmOO-
Figure imgf000255_0002
Ac2OHCIO„
MeO METHOD 8
Figure imgf000255_0003
Figure imgf000255_0004
Figure imgf000255_0001
(V) (CXIV) (CXV)
SCHEME 20 Scheme 20 Procedures
EXAMPLE 447
The preparation of Dibenzyl l,3-dioxo-4-phenyl-l,2,3,6-tetrahvdropyrrolo[3,4-c1carbazol-9- yl phosphate (CXII; Ar=phenyl) (336)
To a solution of 9-hydroxy-4-phenylpyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione (I; Ar=phenyl) (0.50 g, 1.52 mmol) in pyridine (30 mL) under nitrogen was added phosphorous oxychloride (140 DL, 1.52 mmol) dropwise. After 40 minutes stirring at room temperature a further portion of phosphorous oxychloride (40 DL) was added and then after another 20 minutes, benzyl alcohol (0.66 mL, 6.38 mmol) was added. After 3 hours the reaction mixture was diluted with IN hydrochloric acid and extraction with ethyl acetate. The organic phase was dried, the drying agent was removed and the solution was concentrated to dryness, before being chromatographed on silica eluting with methanol/dichloromethane (3:97) to give the dibenzyl phosphate (336) (284 mg, 32%) as a pale yellow powder, mp 193-194 °C. Η NMR δ [(CD3)2SO] 12.12 (br s, IH), 11.15 (br s, IH), 8.81 (br s, IH), 7.69 (s, IH), 7.63 (m, 3H), 7.48-7.34 (m, 14H), 5.22 (d, JH.F= 8.3 Hz, 4H). Found: C, 69.65; H, 4.37; N, 4.88; P, 5.26. C34H25N2O6P requires: C, 69.38; H, 4.28; N, 4.76; P, 5.26.
EXAMPLE 448
The preparation of 1.3-Dioxo-4-phenyl-l ,2,3,6-tetrahydropyrrolor3,4-c1carbazol-9-yl dihydrogen phosphate (CXIII; Ar=phenyl) (337)
A solution of the dibenzyl phosphate (336) (100 mg, 0.17 mmol) prepared as described in example 447 in methanol/tetrahydrofuran (3:1, 70 mL) was hydrogenated at 60 psi over Pd-C (5%, catalytic) with stirring for 3 hours. The reaction mixture was then filtered through celite and concentrated in vacuo. Trituration from ethyl acetate/hexane gave the phosphate (337) (49 mg, 71%) as a yellow solid, mp 285-295 °C. 1H NMR δ [(CD3)2SO] 12.01 (br s, IH), 11.09 (br s, IH), 8.66 (br s, IH), 7.63 (m, 3H), 7.57 (br d, J=8.6 Hz, IH), 7.50-7.44 (m, 4H). Found: C, 55.19; H, 3.29; N, 6.34; P, 6.84. oH^OeP.l ^O requires: C, 55.18; H, 3.71; N, 6.43; P, 7.12. EXAMPLE 449
The preparation of 6-Acetyl-4-(2-chlorophenyl)-9-methoxypyrroloF3,4-clcarbazole- 1.3(2H.6H)-dione (CXIV; Ar=2-chlorophenyl) (338)
To a solution of carbazole (33) (45 mg, 0.12 mmol) prepared as described in example 79 in acetic anhydride (4.0 mL) was added 35% perchloric acid (2 drops). The resulting solution was stirred at room temperature for 30 minutes before being poured onto ice water, basified by the addition of solid potassium bicarbonate and extraction with ethyl acetate. The organic phase was dried, the drying agent was removed and the solution was concentrated to dryness. Chromatography on silica eluting with ethyl acetate/hexane (2:3), followed by trituration from ethyl acetate gave acetamide (338) (40 mg, 80%) as a pale yellow powder, mp 277-280 °C. 1H NMR δ [(CD3)2SO] 11.46 (br s, IH), 8.74 (d, J=2.8 Hz, IH), 8.53 (s, IH), 8.17 (d, J=9.2 Hz, IH), 7.60 (m, IH), 7.54-7.47 (m, 3H), 7.32 (dd, J=9.2, 2.8 Hz, IH), 3.93 (s, 3H), 2.91 (s, 3H). Found: C, 65.50; H, 3.49; N, 6.61. C23Hι5ClN204.l/4H20 requires: C, 65.26; H, 3.69; N, 6.62.
EXAMPLE 450
The preparation of 6-Acetyl-4-(2-chlorophenyl)-9-hvdroxypyrrolor3,4-c1carbazole- l,3(2H,6H)-dione (CXV: Ar=2-chlorophenyl) (339)
Demethylation of acetamide (338) (35 mg, 0.08 mmol) prepared as described in example 449 according to the procedure described in example 80, except that the reaction time was 24 hours and the chromatography was performed eluting with ethyl acetate/hexane (1 :2 to 2:1), gave phenol (339) (22 mg, 65%) as a pale yellow powder, mp 258-261 °C. !H NMR δ [(CD3)2SO] 11.41 (br s, IH), 9.80 (br s, IH), 8.59 (d, J=2.6 Hz, IH), 8.53 (s, IH), 8.07 (d, J=9.1 Hz, IH), 7.59 (m, IH), 7.53-7.46 (m, 3H), 7.15 (dd, J=9.1, 2.6 Hz, IH), 2.89 (s, 3H). Found: C, 65.03; H, 3.14; N, 6.68. C22H,3C1N204 requires: C, 65.28; H, 3.24; N, 6.92.
Figure imgf000258_0001
maleimide MnO, -i6aι/ι«u »u P,N
METHOD 6 2
METHOD 5
Figure imgf000258_0003
Figure imgf000258_0002
Figure imgf000258_0004
Figure imgf000258_0005
SCHEME 21
Procedures for Scheme 21
EXAMPLE 451
The preparation of Ethyl (2E)-2-r(4-nitrophenyl)hvdrazono1propanoate (901)
A mixture of para-nitroaniline (900) (10.0 g, 72.0 mmol), ice (72 g), and 15% hydrochloric acid (72 mL) was treated with a solution of sodium nitrite (5.4 g, 78.0 mmol) in water (15 mL) at such a rate that the temperature did not exceed 7° C. The reaction mixture was stirred for a further 5 min and then filtered through Celite to give a clear pale yellow/brown solution which was added rapidly to a slurry of sodium acetate (59.0 g, 0.72 mol), ethanol (72 mL), ethyl 2-methylacetoacetate (11.4 mL, 80.0 mmol), and ice (72 g). The resulting red mixture was stirred for 2.5 h and then it was extracted with dichloromethane (3 x 100 mL). The combined extracts were dried and concentrated to give a red oil (18 g). The red oil was dissolved in ethanol (40 mL) and concentrated hydrochloric acid (15 mL) was added, a fine orange/yellow precipitate formed instantly. The reaction mixture was heated at reflux for 15 min and then it was poured onto ice. The orange/yellow precipitate was collected by filtration and dried to give ethyl (2E)-2-[(4- nitrophenyl)hydrazono]propanoate (901) (15.2 g, 84%). Η NMR δ [(CD3)2SO] 10.50 (s, IH), 8.20 (m, 2H), 7.40 (m, 2H), 4.23 (q, J=7.2 Hz, 2H), 2.13 (s, 3H), 1.29 (t, J=7 Hz, 3H).
EXAMPLE 452
Ethyl 5-nitro-lH-indole-2-carboxylate (902)
Ethyl (2E)-2-[(4-nitrophenyl)hydrazono]propanoate (901) (10.6 g, 42 mmol) prepared as described in example 451 was heated in polyphosphoric acid (70 g) at 110° C until no starting material remained by tic (40 min). Ice (500 g) was added with vigorous stirring, a thick brown precipitate formed which was removed by filtration and dried to give ethyl 5- nitro-lH-indole-2-carboxylate (902) (6.04 g, 61%). This material was used without purification in the next step. Η NMR δ [(CD3)2SO] 12.59 (br, IH), 8.73 (d, J=2.4 Hz, IH), 8.13 (dd, J=9.2, 2.4 Hz, IH), 7.61 (d, J=9.2 Hz, IH), 7.44 (s, IH), 4.38 (q, J=7.0 Hz, 2H), 1.36 (t, J=7.0 Hz, 3H).
EXAMPLE 453
The preparation of (5-Nitro-lH-indol-2-yl)methanol (903)
To a solution of ethyl 5-nitro-lH-indole-2-carboxylate (9.8 g, 42.0 mmol) in methanol (300 mL) was added a solution of 2 M potassium hydroxide (31 mL, 63.0 mmol). The reaction mixture was heated at reflux for 2 h and then the hot solution was filtered, poured onto ice, and acidified. The resultant fine pale brown precipitate was collected by filtration and dried. The crude acid was dissolved in tetrahydrofuran (250 mL) and stirred with 1,1'- carbonyldiimidazole (10.2 g, 63.0 mmol) with gentle warming for 2 h. Water (100 mL) was added and then solid sodium borohydride (7.9 g, 0.21 mol) was added portionwise over 30 min, the reaction mixture was stirred for a further 40 min and then it was quenched with 1 M hydrochloric acid. The tetrahydrofuran was removed at reduced pressure and the residue was dissolved in ethyl acetate, washed, dried, and concentrated to give (5-nitro-lH-indol-2- yl)methanol (903). This material was used without purification in the next step.
EXAMPLE 454
The preparation of 5-Nitro-lH-indole-2-carbaldehyde (904)
A solution of crude (5-nitro-lH-indol-2-yl)methanol (3.60 g, 18.7 mmol) in chloroform (200 mL) was heated at 50° C with manganese dioxide (20 g, 0.23 mol) for 3 h. The reaction mixture was then filtered through Celite and concentrated to give 5-nitro-lH- indole-2-carbaldehyde (904) (2.04 g, 57% through two steps). 1H NMR δ [(CD3)2SO] 12.64 (br, IH), 9.96 (s, IH), 8.83 (d, J=2.3 HZ, IH), 8.18 (dd, J=9.0 Hz, 2.3 Hz, IH), 7.69 (d, J=0.7 Hz, IH), 7.62 (d, J=9.0 Hz, IH).
EXAMPLE 455
The preparation of 2-f2-(2-Chlorophenyl)ethenyll-5-nitro-lH-indole (CXVI; Ar=2- chlorophenyl) (905)
Reaction of the aldehyde (904) prepared as described in example 454 with 2- chlorobenzyltriphenylphosphonium chloride using the procedure described in example 37(at room temperature) gave the diene (905) as a mixture of E/Z isomers as a yellow solid (95%). Crystallisation from aqueous methanol yielded the pure E-isomer as yellow needles (80%), mp 230-232 °C. Η NMR δ [(CD3)2SO] 12.28 (br s, IH), 8.55 (d, J=2.3 Hz, IH), 8.03 (dd, J=9.1, 2.3 Hz, IH), 7.91 (dd, J=7.8, 1.5 Hz, IH), 7.32-7.61 (m, 6H), 6.92 (s, IH). Found: C, 64.59; H, 5.68; N, 9.49. C16HιιClN2θ2 requires C, 64.33; H, 5.68; N, 9.49.
EXAMPLE 456
The preparation of Methyl 2-r2-(5-nitro-lH-indol-2-v1)ethenyl1phenyl ether (CXVI; Ar=2- methoxyphenyl) (906)
Reaction of the aldehyde (904) prepared as described in example 454 with 2- methoxybenzyltriphenylphosphonium bromide using the procedure described in example 37 gave the diene (905) as a mixture of E/Z isomers as a yellow solid (95%) which was used without further purification. EXAMPLE 457
The preparation of Methyl 2-r2-(l-methyl-5-nitro-lH-indol-2-yl)ethenyllphenyl ether (CXVII; Ar=2-methoxyphenyl. R10=Me) (907)
Alkylation of diene (906) prepared as described in example 456 with methyl iodide using the procedure described in method3 gave the corresponding diene (908) (94%) as a yellow solid (a mixture of E/Z isomers), which was used without further purification.
EXAMPLE 458
The preparation of 2-r2-(2-Chlorophenyl)ethenyll-l -methyl-5-nitro-lH-indole (CXVII; Ar=2-chloropher-yl. R10=Me) (908)
Alkylation of diene (905) prepared as described in example 455 with methyl iodide using the procedure described in example 38 gave the corresponding diene (908) (99%) as a yellow solid. A sample was crystallised from methanol as orange needles, mp 161-163 °C. 1H NMR δ [(CD3)2SO] 8.53 (d, J=2.3 Hz, IH), 8.05 (dd, J=7.7, 1.6 Hz, IH), 8.02 (dd, J=9.1, 2.3 Hz, IH), 7.67 (d, J=9.1 Hz, IH), 7.46-7.64 (m, 3H), 7.43 (dt, J=7.7, 1.6 Hz, IH), 7.36 (dt, J=7.7, 1.6 Hz, IH), 7.22 (s, IH), 3.95 (s, 3H). Found: C, 65.55; H, 4.19; N, 8.90. Cι7Hι3ClN202 requires C, 65.28; H, 4.19; N, 8.96.
EXAMPLE 459
The preparation of 4-(2-Methoxyphenyl)-6-methyl-9-nitro-4,5,6,10c-tetrahydropyrrolor3.4- clcarbazole-1.3(2H.3aH)-dione (CXVIII; Ar=2-methoxyphenyl. R1Q=Me) (909)
Reaction of the diene (907) prepared as described in example 457 with maleimide using the procedure described in example 68 gave the adduct (909) (84%) as a glassy solid which was immediately aromatised.
EXAMPLE 460
The preparation of 4-(2-ChIorophenyl)-6-methyl-9-nitro-4,5,6,10c-tefrahvdropyπOlo.3,4- clcarbazole-1.3(2H.3aH)-dione (CXVIII; Ar=2-chlorophenyl. R10=Me) (910)
Reaction of the diene (908) prepared as described in example 458 with maleimide using the procedure described in example 68 gave the adduct (910) (88%) as a glassy dark solid which was immediately aromatised. EX AMPLE 461
The preparation of 4-(2-Ch]orophenyl)-9-nitro-4,5,6,10c-tetrahvdropyrrolor3,4-c1carbazole- 1.3(2H,3aH)-dione (CXVIH: Ar=2-chlorophenyl. R10=H) (917)
Reaction of the diene (905) prepared as described in example 455 with maleimide using the procedure described in example 68 gave the adduct (917) (74%) as a dark solid which was immediately aromatised.
EXAMPLE 462
The preparation of 4-(2-Methoxyphenyl)-6-methyl-9-nitropyrrolor3,4-c1carbazole- 1.3(2H,6H)-dione (CXIX; Ar=2-methoxyphenyl, R10=Me) (911)
Aromatisation of the adduct (909) prepared as described in example 459 with manganese dioxide using the procedure described in example 79 except that the reaction time was only 4 h gave the nitrocarbazole (911) (50%) as a brown solid mp 320-330 °C (dec). Η NMR δ [(CD3)2SO] 11.24 (s, IH), 9.76 (d, J=2 Hz, IH), 8.50 (dd, J=9.1, 2.2 Hz, IH), 7.93 (s, IH), 7.91 (d, J=9.1 Hz, IH), 7.46 (t, J=7.3 Hz, IH), 7.38 (d, J=7.3 Hz, IH), 7.13 (d, J=7.3 Hz, IH), 7.08 (t, J=7.3 Hz, IH), 4.05 (s, 3H), 3.70 (s, 3H). Found: C, 65.76; H, 3.83; N, 9.30. C22Hι5N305 requires: C, 65.83; H, 3.77; N, 10.47.
EXAMPLE 463
The preparation of 4-(2-Chlorophenyl)-6-methyl-9-nitropyrrolo[3,4-clcarbazole-l,3(2H,6H)- dione (CXIX: Ar=2-chlorophenyl. R10=Me) (912)
Aromatisation of the adduct (910) prepared as described in example 460 with manganese dioxide using the procedure described in example 79 except that the reaction time was only 4 h gave the nitrocarbazole (912) (78%) as an orange solid, mp >320 °C. Η NMR δ [(CD3)2SO] 11.35 (s, IH) 9.68 (d, J=2.3 Hz, IH), 8.46 (dd, J=9.1, 2.3 Hz, IH), 8.00 (s, IH), 7.88 (d, J=9.1 Hz, IH) 7.47-7.62 (m, 4H) 4.04 (s, 3H). Found: C, 58.90; H, 3.28; N, 10.30. C2ιH]2Cl N304.H20 requires: C, 59.57; H, 3.30; N, 9.93. EXAMPLE 464
The preparation of 4-(2-Chlorophenyl)-9-nitropyrrolor3,4-c1carbazole-l,3(2H,6H)-dione (CXIX; Ar=2-chlorophenyl, R10=H) (918)
Aromatisation of the adduct (917) prepared as described in example 463 with manganese dioxide using the procedure described in example 79 except that the reaction time was only 4 h gave the nitrocarbazole (918) (84%) as a yellow solid, mp 253-258 °C. ]H NMR δ [(CD3)2SO] 12.78 (s, IH) 11.33 (s, IH), 9.74 (d, J=2.5 Hz, IH), 8.45 (dd, J=9.1, 2.5 Hz, IH), 7.80 (d, J=9.1 Hz, IH), 7.77 (s, IH), 7.60 (dd, J=7.2, 1.5 Hz, IH), 7.45-7.54 (m, 3H). Found: C, 62.39; H, 3.03; N, 10.10. C20Hι0Cl N304.l/6 hexane requires: C, 62.22; H, 3.04; N, 10.37
Representative Procedure for Method 34 of Scheme 21
EXAMPLE 465
The preparation of 9-Amino-4-(2-chlorophenyl)-6-methylpyrrolor3,4-c1carbazole- 1.3(2H,6H)-dione (CXX; Ar=2-chlorophenyl. R10=Me) (914)
The nitrocarbazole (912) (0.055 g, 0.14 mmol) prepared as described in example 463 was suspended in a mixture of ethanol: water (4:1, 20 mL) and set at reflux. After 15 min iron powder (0.076 g, 1.4 mmol) was added, followed by acetic acid (0.041 g, 0.70 mmol). The red solution was refluxed for 1 hour, turning a dark colour. The cooled solution was filtered through Celite, washing with ethyl acetate (2 x 100 mL). The solvent was evaporated under reduced pressure, leaving a brown residue, which was dissolved in ethyl acetate (200 mL). The solution was washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, then dried and worked up to give the amine (914) as a red solid, mp 208- 216 °C. Η NMR δ [(CD3)2SO] 11.00 (s, IH), 8.15 (d, J=2.2 Hz, IH), 7.68 (s, IH), 7.56 (dd, J=7.0, 1.9 Hz, IH), 7.43-7.49 (m, 4H), 7.02 (dd, J=8.7, 2.2 Hz, IH), 5.03 (br s, 2H, exchanges with D20), 3.88 (s, 3H). Found: C, 64.48; H, 3.82; N, 10.32. C2IH]4C1 N302.H20 requires: C, 64.12; H, 4.07; N, 10.68. EXAMPLE 466
The preparation of 9-Amino-4-(2-methoxyphenyl)-6-methylpyrrolor3,4-clcarbazole- l,3(2H.6H)-dione (CXX: Ar=2-methoxyphenyl, R10=Me) (913)
The nitrocarbazole (911) prepared as described in example 462 was reduced with iron powder using the procedure described in method 34, to give the amine (913) as a brown solid (74%), mp 188-192 °C. Η NMR δ [(CD3)2SO] 10.87 (s, IH), 8.14 (d, J=1.7 Hz, IH), 7.61 (s, IH), 7.40-7.42 (m, 2H), 7.33 (dd, J=7.3, 1.6 Hz, IH), 6.98-7.10 (m, 3H), 5.00 (broad s, 2H, exchanges with D20), 3.86 (s, 3H), 3.68 (s, 3H). Found: C, 69.61; H, 4.66; N, 9.32. C22H17N303.1/2C4H80 requires: C, 69.40; H, 5.06; N, 10.12.
EXAMPLE 467
The preparation of 9-Amino-4-(2-chlorophenyl)pyrrolor3.4-c1carbazole-l,3(2H,6H)-dione (CXX: Ar=2-chlorophenyl. R10=H) (919)
The nitrocarbazole (918) prepared as described in example 464was reduced with iron powder using the procedure described in example 465 with a reaction time of 45 min. and the product was precipitated from THF: petroleum ether to give amine (919) as a brown solid (91%), mp 216-222 °C. Η NMR δ [(CD3)2SO] 11.66 (s, IH), 10.96 (s, IH), 8.09 (d, J=2.3 Hz, IH), 7.57 (dd, J=8.1, 1.8 Hz, IH), 7.40-7.50 (m, 4H), 7.35 (d, J=8.6 Hz, IH), 6.95 (dd, J=8.6, 2.3 Hz, IH) 4.95 (br s, 2H). EMS found: M+=361.0611, 363.0587. C2oHι2ClN3θ2 requires 361.0818, 363.0589.
Representative Procedure for Method 35 of Scheme 21
EXAMPLE 468
The preparation of N-r4-(2-Methoxyphenyl)-6-methyl-1.3-dioxo-1.2.3.6- tetrahvdropyrrolor3,4-c1carbazol-9-vnacetamide (CXXI; Ar=2-methoxyphenyl, R10=Me. R4=Me) (916)
Acetic acid (1 mL) and acetic anhydride (1 mL) were mixed under nitrogen at 0 °C and the solution was stirred at 0 °C for 1 hour. A solution of the amine (913) (0.06 g, 0.16 mmol) prepared as described in example 466 in dry dichloromethane was added and the mixture was allowed to warm to room temperature over 2 h and then the solvent evaporated under reduced pressure. The resulting yellow solid was purified by column chromatography on silica gel eluting with petroleum etheπethyl acetate (100:0 to 0:100). The product (916) was then precipitated from tetrahydrofuran with petroleum ether as a yellow powder (0.044 g, 67%), mp 300-304 °C. Η NMR δ [(CD3)2SO] 10.98 (s, IH), 10.12 (s, IH), 8.99 (d, J=2.0 Hz, IH), 7.97 (dd, J=8.8, 2.0 Hz, IH) 7.74 (s, IH), 7.66 (d, J=8.8 Hz, IH), 7.43 (dt, J=7.4, 1.7 Hz, IH), 7.34 (dd, J=7.4, 1.7 Hz, IH), 7.12 (d, J=8.1 Hz, IH), 7.05 (t, J=8.1 Hz, IH), 3.95 (s, 3H), 3.68 (s, 3H), 2.10 (s, 3H). Found: C, 66.10; H, 4.60; N, 9.44. C24H19N304.H20 requires: C, 66.82; H, 4.41; N, 9.74.
EXAMPLE 469
The preparation of 4-(2-Chlorophenyl)-6-methyl-l,3-dioxo-l,2,3,6-tetrahvdropyrrolof3,4- clcarbazol-9-ylformamide (CXXI; Ar=2-chlorophenyl. R10=Me. R4=H) (920)
Amine (914) prepared as described in example 465 and formic acid were reacted using the procedure described in method35 with a reaction time of 16 h to give the formamide (920) (92%) as a yellow powder, mp 345-348 °C. !H NMR δ [(CD3)2SO] 11.16 (s, 0.5H), 11.12 (s, IH), 10.36 (m, 1.5H), 9.08 (d, J=2.0 Hz, IH), 8.72 (m, 0.5H), 8.32 (d, J=1.8 Hz~ IH), 7.99 (dd, J=8.8, 2.0 Hz, IH), 7.85 (s, 0.5H), 7.83 (s, IH), 7.70-7.73 (m, 1.5H), 7.46- 7.60 (m, 7H), 3.98 (s, 1.5H), 3.98 (s, 3H). FABMS found: [M+H]+=404.0790, 406.0779. C22Hι5ClN3θ3 requires 404.0802, 406.0772.
EXAMPLE 470
The preparation of 4-(2-Chlorophenyl)-l ,3-dioxo-l,2.3,6-tetrahydropyrrolor3,4-c1carbazol-9- ylformamide (CXXI; Ar=2-chlorophenyl, R10=H, R4=H) (921)
Amine (919) prepared as described in example 467 and formic acid were reacted using the procedure described in example 468 with a reaction time of 4 h to give the formamide (921) (54%) as a yellow powder, mp 293-297 °C. Η NMR δ [(CD3)2SO] 12.11 (s, 0.5H), 12.08 (s, IH), 11.12 (s, 0.5 H), 11.08 (s, IH), 10.34 (s, IH), 10.30 (s, 0.5H), 9.03 (d, J=1.9 Hz, IH), 8.69 (m, 0.5H), 8.31 (d, J=1.8 Hz, 1.5H) 7.92 (dd, J=8.8, 1.9 Hz, IH) 7.42- 7.65 (m, 9.5H). Found: C, 64.78; H, 3.53; N, 9.96. C2iHι2ClN303. V4 THF requires: C, 64.86; H, 3.44; N, 10.32. EXAMPLE 471
The preparation of N-r4-(2-Chlorophenyl)-6-methyl-1.3-dioxo-l,2,3,6-tetrahvdropyrrolor3.4- clcarbazol-9-vnacetamide (CXXI; Ar=2-chlorophenyl, R10=Me, R4=Me) (923)
Amine (914) prepared as described in example 465 and acetic acid were reacted using the procedure described in example 468 with a reaction time of 14 h to give the acetamide (923) (85%) as a yellow powder, mp 338-340 °C. Η NMR δ [(CD3)2SO] 11.10 (br s, exchanges with D20, IH), 10.14 (s, exchanges with D20, IH), 9.01 (d, J=2.0 Hz, IH), 7.99 (dd, J=8.9, 2.0 Hz, IH), 7.82 (s, IH), 7.68 (d, J=8.9 Hz, IH), 7.57 (dd, J=7.2, 1.9 Hz, IH), 7.44-7.53 (m, 3H), 3.93 (s, 3H), 2.10 (s, 3H). Found: C, 64.44; H, 4.08; N, 8.98. C23H16CIN3O3.I/2CH3COOH requires C, 64.43; H, 4.03; N, 9.39.
EXAMPLE 472
The preparation of N-r4-(2-Chlorophenyl)-1.3-dioxo-l,2,3,6-tetrahydropyrrolor3,4- clcarbazoI-9-yllacetamide (CXXI; Ar=2-chlorophenyl. R10=H. R4=Me) (926)
Amine (919) prepared as described in example 467 and acetic acid were reacted using the procedure described in example 468 with a reaction time of 4 h to give the acetamide (926) (43%) as a yellow powder, mp 240-245 °C. !H NMR δ [(CD3)2SO] 12.04 (br s, IH), 11.07 (br s, IH), 10.10 (s, IH), 8.95 (d, J=2.1 Hz, IH), 7.90 (dd, J=8.8, 2.1 Hz, IH), 7.58 (m, 2H), 7.42-7.51 (m, 4H), 2.10 (s, 3H). FABMS found: [M+H]+ =404.0787, 406.0776. C22H15C1N303 requires 404.0802, 406.0772.
Representative Procedure for Method 36 of Scheme 21
EXAMPLE 473
The preparation of N-[4-(2-Chlorophenyl)-6-methyl-1.3-dioxo-l,2,3,6-tetrahvdropyιτolor3.4- clcarbazol-9-yll-3-(l-piperidinyl)propanamide (CXXI; Ar=2-chlorophenyl, R10=Me. R4=3- (l-piperidinyl)propyl) (925)
3-Piperidinylpropanoic acid (0.036 g, 0.23 mmol) and l-[3-(dimethylamino)propyl]- 3-ethylcarbodiimide hydrochloride (0.044g, 0.23 mmol) were combined in dry dimethylformamide (2 mL) at 0 °C under an atmosphere of nitrogen and left to stir for 1 h. A solution of the amine (914) (0.085 g, 0.23 mmol) in dry dimethylformamide (3 mL) was added to the reaction mixture. The solution was allowed to warm to room temperature over 16 h. The solvent was removed under reduced pressure and the residue adsorbed onto silica. Purification by column chromatography eluting with ethyl acetate:methanol:triethylamine (100:0:0 to 75:24: 1) yielded (925) as a yellow solid (0.036 g, 30%), mp 241-246 °C. 1H NMR δ [(CD3)2SO] 11.12 (s, IH), 10.46 (s, IH), 9.92 (broad s, IH), 9.09 (d, J=2.0 Hz, IH), 7.98 (dd, J=8.9, 2.0 Hz, IH) 7.83 (s, IH), 7.71 (d, J=8.9 Hz, IH), 7.45-7.60 (m, 4 H), 3.98 (s, 3H), 3.38 (m, 2H), 3.10 (m, 2H), 2.95 (m, 2H), 1.80 (m, 4H), 1.42 (m, 2H). FABMS found: [M+H]+=515.1842, 517.1833. C29H28C1N403 requires 515.1850, 517.1820.
EXAMPLE 474
The preparation of N-r4-(2-Ch]orophenyl)-6-methyl-l,3-dioxo-l,2,3,6-tetrahvdropyrrolof3,4- clcarbazol-9-yll-4-(dimethylamino)butanamide hydrochloride (CXXI; Ar=2-chlorophenyl, R10=Me. R4=4-dimethylaminobutyl) (928)
Amine (914) prepared as described in example 465 was reacted with EDCI and 4- dimethylaminobutyric acid hydrochloride using the procedure described in example 473 to give the amide (928) (44%) as an orange powder, mp 331-333 °C. Η NMR δ [(CD3)2SO] 11.11 (s, IH), 10.25 (s, IH), 9.82 (br s, IH), 9.07 (d, J=2.0 Hz, IH), 7.98 (dd, J=9.0, 2.0 Hz, IH), 7.83 (s, IH), 7.70 (d, J=9.0 Hz, IH), 7.58 (m, IH), 7.44-7.52 (m, 3H), 3.97 (s, 3H), 2.99- 3.11 (m, 4H), 2.77 (s, 6H), 2.00 (m, 2H). FABMS found: [M+H]+=489.1689, 491.1681. C27H26C1N403 requires 489.1693, 491.1664.
Representative Procedure for Method 37 of Scheme 21
EXAMPLE 475
The preparation of 4-(2-Chlorophenyl)-6-methyl-9-(methylamino)pyrrolor3.4-clcarbazole- 1.3(2H.6H)-dione (CXXII; Ar=chlorophenyl. R10=Me. R4=H) (922)
Borane methylsulphide complex (0.074 mL, 0.78 mmol) and trimethylborate (0.089 mL, 0.78 mmol) were added at 0 °C under an atmosphere of nitrogen to a solution of amide (920) (0.105 g, 0.26 mmol) prepared as described in example 469 dry tetrahydrofuran (10 mL) After stirring at 0 °C for 30 min. the solution was allowed to warm to room temperature over 16 h. Methanol (200 mL) was added and the reaction mixture was stirred for 12 h. The solvent was removed under reduced pressure and the yellow residue was purificatied by column chromatography on silica, eluting with petroleum etheπethyl acetate (100:0 to 0:100) to give (922) as a red solid (0.053 g, 45%), mp 293-296 °C. :H NMR δ [(CD3)2SO] 11.01 (br s, IH), 8.10 (d, J=2.3 Hz, IH), 7.69 (s, IH), 7.57 (dd, J=7.1, 2.0 Hz, IH), 7.42-7.52 (m, 4H), 7.02 (dd, J=8.8, 2.3 Hz, IH), 5.61 (q, J=5.2 Hz, IH), 3.90 (s, 3H), 2.81 (d, J=5.2 Hz, 3H). EIMS found: M+=389.0929, 391.0905. C22H16C1N302 requires 389.0931, 391.0902.
EXAMPLE 476
The preparation of 4-(2-Chlorophenyl)-9-(ethylamino)-6-methylpyrrolor3,4-clcarbazole- 1.3(2H,6H)-dione (CXXII: Ar=chlorophenyl, R10=Me, R4=Me) (924)
Amide (923) prepared as described in example 471 was reduced with borane methylsulphide complex using the procedure described in method37 to give amine (924) as a red powder, mp 232-236 °C. ]H NMR δ [(CD3)2SO] 11.00 (s, exchanges with D20, IH), 8.13 (d, J=2.2 Hz, IH), 7.69 (s, IH), 7.57 (dd, J=7.0, 2.0 Hz, IH), 7.42-7.51 (m, 4H), 7.05 (dd, J=8.8, 2.2 Hz, IH), 5.51 (t, J=5.4 Hz, exchanges with D20, IH), 3.15 (m, 2H), 1.27 (t, J=7.1 Hz, 3H). EIMS found: M+=403.1080, 405.1061. C23Hι8ClN302 requires 403.1087, 405.1058.
EXAMPLE 477
The preparation of 4-(2-chlorophenyl)-9-(methylamino)pyrrolor3,4-c1carbazole-l,3(2H,6H)- dione (CXXII: Ar=chlorophenyl, R'°=H, R4=H) (927)
Amide (921) (0.051 g, 0.13 mmol) prepared as described in example 470 was reacted with borane methylsulphide complex using the procedure described in method 37 to give amine (927) (0.021 g, 43%) as an orange powder; m.p. 182-184°C. Η NMR δ [(CD3)2SO] 11.69 (broad s, IH), 10.97 (broad s, IH), 8.05 (d, J=2.1 Hz, IH), 7.40-7.57 (m, 5H), 6.97 (dd, J=8.7, 2.4 Hz, IH), 5.55 (q, J=4.9 Hz, IH), 2.80 (d, J=5.2 Hz, 3H). EIMS found: M+=375.0768, 377.0749. C2ιHι4ClN302 requires 375.0774, 377.0745.
Representative Procedure for Method 38 of Scheme 21
EXAMPLE 478
The preparation of 9-(Dimethylamino)-4-(2-methoxyphenyl)-6-methylpyrrolor3,4- c .carbazole-1.3(2H.6H)-dione (CXXIII; Ar=methoxyphenyl, R10=Me. R3=H) (915)
Amine (913) (0.049 g, 0.13 mmol) prepared as described in example 466 was suspended in methanol (15 mL) and stirred at 0 °C. Formaldehyde (0.01 mL of a 37 % aqueous solution, 0.13 mmol) was added followed immediately by sodium cyanoborohydride (0.022 g, 3.5 mmol) portionwise and the mixture was stirred at room temperature for 14 h. The solvent was removed under reduced pressure and the residue dissolved in ethyl acetate (100 mL). The solution was washed with water (2 x 100 mL), sat. aq. sodium chloride (2 x 100 mL), then dried over anhydrous sodium sulphate and the solvent evaporated. The residue was chromatographed on silica, eluting with petroleum etheπdiethyl ether (100:0 to 0:100) to give (915) as a red solid (0.017 g, 33%), mp 246-251 °C. Η NMR δ [(CD3)2SO] 10.92 (s, IH), 8.39 (d, J=2.5Hz, IH), 7.67 (s, IH), 7.58 (d, J=9.0 Hz, IH), 7.41 (dt, J=7.4, 1.7 Hz, IH), 7.37 (dd, J=7.4, 1.7 Hz, IH), 7.25 (dd, J=9.0, 2.5 Hz, IH), 7.10 (d, J=7.4 Hz, IH), 7.04 (t, J=7.4 Hz, IH) 3.91 (s, 3H), 3.68 (s, 3H), 2.99 (s, 6H). EIMS found M+: 399.1580. C2 H2iN303 requires 399.1583.
Figure imgf000269_0001
(CXXVII)
SCHEME 22
Scheme 22 Procedures
EXAMPLE 479
The preparation of 4-(2-Chlorophenyl)-l ,3-dioxo-l ,2,3,6-tetrahvdropyrrolor3,4-c1carbazol-9- yl trifluoromethanesulfonate (CXXIV; Ar = 2-chlorophenyl) (615)
Compound (615) was prepared from (9) (I; (Ar =2-chlorophenyl) prepared as described in example 8 using the procedure described in example 307 to give a yellow oil. 1H NMR δ [(CD3)2SO] 11.83 (s, IH), 11.03 (s, IH), 8.28 (s, IH), 8.32 (.« IH), 7.6-7.4 (m, 5H), 7.07 (s, IH). EIMS found: M+=493.9946. C2ιHι0ClF3N2SO5 requires^93.9951.
EXAMPLE 480
The preparation of 4-(2-Chlorophenyl)-9-vinylpyrrolo[3,4-clcarbazole-l,3(2H,6H)-dione (CXXV; Ar =2-chlorophenyl) (616)
Compound (616) was prepared from (615) prepared as described in example 479 (using the procedure described in example 309 , with tetraethyl tin as the stannane to give a yellow oil. 1H NMR δ [(CD3)2SO] 11.71 (s, IH), 11.48 (br, IH), 8.23 (s, IH), 8.78, (s, IH), 7.99 (s, IH), 7.62-7.43 (m, 5H), 7.2-7.1 (m, IH), 6.10 (d, J= 17.6 Hz, IH), 5.46 (d, J=11.3 Hz, IH). EIMS found: M+=372.0661. C22Hι3ClN202 requires 372.0666.
EXAMPLE 481
The preparation of 4-(2-Chlorophenyl)-9-(l ,2-dihvdroxyethyl)pyrrolor3,4-c1carbazole- 1.3(2H.6H)-dione (CXXVI: Ar"=2-chlorophenyl) (617) " - - -
The diol (617) was prepared from (616) prepared as described in example 480 using the procedure described in example 300 to give a yellow solid, mp 265-268 °C. Η NMR δ [(CD3) SO] 12.06 (br, IH), 11.08 (br, IH), 8.87 (s, IH), 7.60-7.40 (m, 7H), 5.32 (d, J=3.8 Hz, IH), 4.74 (m, 2H), 3.55 (m, 2H). EMS found: M+=406.0718. C22Hι5ClN204 requires 406.0720.
EXAMPLE 482
The preparation of 4-(2-Chlorophenyl)-9-(2-hydroxyethyl)pyrrolor3,4-clcarbazole- 1.3(2H,6H)-dione (CXXVII; Ar =2-chlorophenyl) (618)
Compound (618) was prepared from (616) prepared as described in example 480 using the procedure described in example 344 to give a yellow solid, mp 253-257 °C. 1H NMR δ [(CD3)2S0] 12.03 (br, IH), 11.08 (br, IH), 8.73 (s, IH), 7.60-740 (m, 6H), 4.69 (t, J=5.2 Hz, IH), 3.71 (m, 2H), 2.93 (t, J=7.2 Hz, 2H). EMS found: M+=390.0769. C22Hι5ClN203 requires 390.0771. EXAMPLE 483
Other novel checkpoint inhibitors
Listed below are other checkpoint inhibitors of the present invention which may be prepared by process known in the art, processes described herein-above, or a combination of said processes. One of skill in the art will understand how each compound is prepared by reference to the disclosure herein.
Figure imgf000272_0001
Figure imgf000273_0001
Figure imgf000274_0001
COMPOUND NAME MP (deg C) APCI (pos)Found Mass
4-(2-Chloro-ρhenyl)-9-fluoro-8-methoxy-6-methyl-
347-351 6H-pyrrolo[3,4-c]carbazole- 1 ,3-dione
4-(2-Chloro-phenyl)-9-fluoro-8-hydroxy-6-methyl-
305-310 6H-pyrrolo[3,4-c]carbazole- 1 ,3-dione
4-(2-Chloro-phenyl)-8-(3-dimethylamino- propoxy)-6-(3-hydroxy-propyl)-6H-pyrrolo[3,4- 208-211 c]carbazole- 1 ,3-dione
4-(2-Chloro-phenyl)-6-(3-hydroxy-propyl)-8-(3- pyrrolidin- 1 -yl-propoxy)-6H-pyrrolo[3,4- 208-210 c]carbazole- 1 ,3-dione
4-(2-Chloro-phenyl)-9-fluoro-8-(3-hydroxy- propoxy)-6-methyl-6H-pyrrolo[3,4-c]carbazole- 311-315
1,3-dione
4-(2-Chloro-phenyl)-9-fluoro-6-methyl-8-(3- methylamino-propoxy)-6H-pyrrolo[3,4- 317-321 c]carbazole- 1 ,3-dione
4-(2-Chloro-phenyl)-9-hydroxy-6-methyl-8-(4- morpholin-4-yl-butyl)-6H-pyrrolo[3,4-c]carbazole- 257-260
1,3-dione
4-(2-Chloro-phenyl)-9-fluoro-6-methyl-8-(3- pyrrolidin- 1 -yl-ρropoxy)-6H-pyrrolo[3,4- 270-273 c]carbazole- 1 ,3-dione
4-(2-Chloro-phenyl)-9-hydroxy-6-(2-hydroxy- sthyl)-8-[3-(4-methyl-piperazin-l-yl)-propoxy]-6H 177-183 (dec) pyrrolo[3,4-c]carbazole- 1 ,3-dione
4-(2-Chloro-phenyl)-8-(3-diethylamino-propoxy)- 9-hydroxy-6-(2-hydroxy-ethyl)-6H-pyrrolo[3,4- 165-167 (dec) c]carbazole- 1 ,3-dione
4-(2-Chloro-phenyl)-8-(3-dimethylamino- proρoxy)-9-fluoro-6- ethyl-6H-pyrrolo[3,4- 272-275 c]carbazole- 1 ,3-dione
N-[4-(2-Chloro-phenyl)-6-(3-hydroxy-propyl)-l- methylene-3-oxo-l,2,3,6-tetrahydro-pyrrolo[3,4- 193-196 c] carbazol-9-yl] -formamide
(2-Chloro-phenyl)-6-methyl-8-pyridin-4-yl-6H-
438.1 pyrrolo[3,4-c]carbazole- 1 ,3-dione
Figure imgf000276_0001
Figure imgf000277_0001
Figure imgf000278_0001
COMPOUND NAME MP (deg C) APCI (pos)Found Mass
4-(2-Chloro-phenyl)-9-hydroxy-6-methyl-8-(4- morpholin-4-yl-butoxy)-6H-pyrrolo[3,4- 212 c]carbazole- 1 ,3-dione
N-[4-(2-Ch]oro-phenyl)-6-(2-hydroxy-ethyl)-l,3- dioxo- 1 ,2,3,6-tetrahydro-pyrrolo[3,4-c]carbazol-9- 273-275 yl]-formamide
4-(2-Fluoro-6-methoxy-phenyl)-9-hydroxy-6H-
377 pyrrolo[3,4-c]carbazole-l,3-dione
N-[4-(2-Chloro-phenyl)-6-(3-hydroxy-propyl)-8- methoxy- 1 ,3-dioxo- 1 ,2,3,6-tetrahydro-pyrrolo[3,4- 492/494 c]carbazol-9-yl]-acetamide
N-[4-(2-Chloro-phenyl)-6-(3-hydroxy-propyl)-8- methoxy- 1 ,3-dioxo- 1 ,2,3,6-tetrahydro-pyrτolo[3,4- 478/480 c]carbazol-9-yl]-formamide
N-[4-(2-Chloro-phenyl)-8-hydroxy-6-(3-hydroxy- propyl)- 1 ,3-dioxo- 1 ,2,3,6-tetrahydro-pyrrolo[3,4- 464/466 c]carbazol-9-yl]-formamide
6-Butyl-4-(2-chloro-phenyl)-9-hydroxy-8-(3- pyrrolidin- 1 -yl-ρropoxy)-6H-pyrrolo[3,4- 222-225 cjcarbazole- 1 ,3-dione
8-(3-(S)-Amino-pyrrolidine-l-carbonyl)-4-(2- chloro-phenyl)-6-(3-hydroxy-propyl)-6H- 517 pyrrolo[3,4-c]carbazole- 1 ,3-dione
4-(2-Chloro-phenyl)-6-methyl-8-pyττolidin-2-yl-
430/432 6H-pyrrolo[3,4-c]carbazole- 1 ,3-dione
8-(4-Amino-butyl)-4-(2-chloro-phenyl)-6-methyl-
432/434 6H-pyrrolo[3,4-c]carbazole-l,3-dione
2-Dimethylamino-ethanesulfonic acid {3-[9-amino-
4-(2-chloro-phenyl)-l,3-dioxo-2,3-dihydro-lH- >350 pyrrolo[3,4-c]carbazol-6-yl]-propionyl}-amide
2-Dimethylamino-ethanesulfonic acid {3-[4-(2- chloro-phenyl)-9-formylamino- 1 ,3-dioxo-2,3-
>370 dihydro-lH-pyrrolo[3,4-c]carbazol-6-yl]- propionyl} -amide
Figure imgf000280_0001
COMPOUND NAME MP (deg C) APCI (pos)Found Mass
4-(2-Chloro-phenyl)-8-[3-(ethyl-propyl-amino)- propylsulfanyl]-9-hydroxy-6-methyl-6H- 520/522 pyrrolo[3,4-c]carbazole- 1 ,3-dione
9-Hydroxy-6-methyl-4-phenyl-8-(3-pyrrolidin-l-yl
248-250 propoxy)-6H-pyrrolo[3,4-c]carbazole-l,3-dione
9-Amino-4-(2-chloro-phenyl)-6-methyl-7-vinyl-
>350 6H-pyrrolo[3,4-c]carbazole-l,3-dione
4-(2-Chloro-phenyl)-8-(3-(R)dimethylamino- pyrrolidine- 1 -carbon yl)-6-(2-hydroxy-ethyl)-6H- 530.2 pyrrolo[3,4-c]carbazole- 1 ,3-dione
N-[4-(2-Chloro-phenyl)-6-methyl- 1 ,3-dioxo-7- vinyl- 1,2,3, 6-tetrahydro-pyrrolo[3,4-c]carbazol-9- 248-254 yl] -formamide
N-[4-(2-Chloro-phenyl)-7-(l,2-dihydroxy-ethyl)-6- methyl- 1 ,3-dioxo- 1 ,2,3,6-tetrahydro-pyrrolo[3,4- >340 c] carbazol-9-yl] -formamide
N- [4-(2-Chloro-phenyl)-9-hydroxy-6-methyl- 1 ,3- dioxo- 1 ,2,3,6-tetrahydro-pyrrolo[3,4-c]carbazole-8 310-315 carbonyl] -methanesulfona ide
2-Dimethylamino-ethanesulfonic acid [4-(2-chloro- phenyl)-9-hydroxy-6- methyl- 1 ,3-dioxo- 1 ,2,3,6-
285-293 tetrahydro-pyrrolo[3,4-c]carbazole-8-carbonyl]- amide
4-(2-Chloro-phenyl)-9-hydroxy-6-methyl-l,3- dioxo-l,2,3,6-tetrahydro-pyrrolo[3,4-c]carbazole-8 448/450 carboxylic acid dimethylamide
4-(2-Chloro-phenyl)-9-hydroxy-8-(3-morpholin-4-
178-184 yl-propoxy)-6H-pyrrolo[3,4-c]carbazole-l,3-dione
4-(2-Chloro-phenyl)-9-hydroxy-6-methyl-8-(2- pyrrolidin- 1 -yl-ethoxy)-6H-pyrrolo[3,4- 242-244 c]carbazole- 1 ,3-dione
8-(3-Amino-propoxy)-4-(2-chloro-phenyl)-9- hydroxy-6-methyl-6H-pyrrolo[3,4-c]carbazole- 1 ,3- 293-296 dione; hydrochloride salt
Figure imgf000282_0001
Figure imgf000283_0001
Figure imgf000284_0001
Figure imgf000285_0001
Figure imgf000286_0001
COMPOUND NAME MP (deg C) APCI (pos)Found Mass
4-(2-Chloro-phenyl)-8-(3-cyclohexylamino- propoxy)-9-hydroxy-6-methyl-6H-pyrrolo[3,4- 532/534 c]carbazole- 1 ,3-dione
4-(2-Chloro-phenyl)-9-hydroxy-6-methyl-8-(3- pyrrolidin- 1 -yl-propane- 1 -sulfinyl)-6H-pyrrolo[3,4- 305-312 (dec) c]carbazole- 1 ,3-dione
4-(2-Chloro-phenyl)-9-hydroxy-6-methy]-8-(3- pyrrolidin- 1 -yl-propane- 1 -sulfonyl)-6H- 252-258 (dec) pyrτolo[3,4-c]carbazole-l,3-dione
4-(2-Chloro-phenyl)-9-hydroxy-6-(2-hydroxy- ethyl)-8-(4-pyrrolidin-l-yl-butyl)-6H-pyrrolo[3,4- 198-203 c]carbazole- 1 ,3-dione
4-(2-Chloro-phenyl)-9-hydroxy-6-(2-hydroxy- ethyl)-8-(4-morpholin-4-yl-butyl)-6H-pyrrolo[3,4- 269-272 c]carbazole- 1 ,3-dione
4-(2-Chloro-phenyl)-9-hydroxy-6-(2-hydroxy- ethyl)-8-[4-(4-methyl-piperazin-l-yl)-butyl]-6H- 196-201 pyrrolo[3,4-c]carbazole- 1 ,3-dione
4-(2-Chloro-phenyl)-8-[3-(ethyl-propyl-amino)- butoxy]-9-hydroxy-6-methyl-6H-pyrrolo[3,4- 238-240 c]carbazole- 1 ,3-dione
4-(2-Chloro-phenyl)-9-hydroxy-6-methyl-8-(l- methyl-3-pyrrolidin- 1 -yl-propoxy)-6H-pyrrolo[3,4- 225-227 cjcarbazole- 1 ,3-dione
9-Amino-4-(2-chloro-phenyl)-8-(4-hydroxy-butyl)-
224-227 6-methyl-pyrrolo[3,4-c]carbazole- 1 ,3-dione
N-[4-(2-Chloro-phenyl)-6-methyl- 1 ,3-dioxo-8-(4- pyrrolidin- 1 -yl-butyl)- 1 ,2,3,6-tetrahydro- 252-257 pyrrolo[3,4-c]carbazol-9-yl]-formamide
N- { 4-(2-Chloro-phenyl)-6-methyl-8-[4-(4-methyl- piperazin-l-yl)-butyl]-l,3-dioxo-l,2,3,6-tetrahydro- 270-273 pyrroIo[3,4-c]carbazol-9-yl}-formamide
N-[4-(2-Chloro-phenyl)-6-methyl-8-(4-morpholin- 4-yl-butyl)- 1 ,3-dioxo- 1 ,2,3,6-tetrahydro- 205-209 pyπ-olo[3,4-c]carbazol-9-yl]-formamide COMPOUND NAME MP (deg C) APCI (pos)Found Mass
9-Amino-4-(2-chloro-phenyl)-7-(4-hydroxy-butyl)-
202-208 6-methyl-6H-pyrrolo[3,4-c]carbazole- 1 ,3-dione
N-[4-(2-Chloro-phenyl)-7-(4-hydroxy-butyl)-6- ethyl- 1 ,3-dioxo- 1 ,2,3,6-tetrahydro-pyrrolo[3,4- 230-243 c]carbazoI-9-yl]-formamide
N-[4-(2-Chloro-ρhenyl)-6-methyl-7-(4-morpholin- 4-yl-butyl)- 1 ,3-dioxo- 1 ,2,3,6-tetrahydro- 256-260 pyrrolo[3,4-c]carbazol-9-yl]-formamide
N- { 4-(2-Chloro-ρhenyl)-6-methyl-7-[4-(4-methyl- piperazin-l-yl)-butyl]-l,3-dioxo-l,2,3,6-tetrahydro 205-209 pyrrolot3,4-c]carbazol-9-yl } -formamide
N-[4-(2-Chloro-phenyl)-7-(4-dimethylamino- butyl)-6-methyl- 1 ,3-dioxo- 1 ,2,3,6-tetrahydro- 257-259 pyrrolo[3,4-c]carbazol-9-yl]-formamide
N-[4-(2-Chloro-phenyl)-6-methyl- 1 ,3-dioxo-7-(4- pyrrolidin-l-yl-butyl)-l,2,3,6-tetrahydro- 238-240 pyrrolo[3,4-c]carbazol-9-yl]-formamide
9-Amino-4-(2-chloro-phenyl)-6-methyl-7-(4- morpholin-4-yl-butyl)-6H-pyrrolo[3,4-c]carbazole- 158-162 (dec)
1,3-dione
9-Amino-4-(2-chloro-phenyl)-6-methyl-7-[4-(4- methyl-piperazin-l-yl)-butyl]-6H-pyrrolo[3,4- 162-166 (dec) c]carbazole-l,3-dione
9-Amino-4-(2-chloro-phenyl)-7-(4-dimethylamino- butyl)-6-methyl-6H-pyrrolo[3,4-c]carbazole-l,3- 211-215 dione
9-Amino-4-(2-chloro-phenyl)-6-methyl-7-(4- pyrrolidin-l-yl-butyl)-6H-pyrrolo[3,4-c]carbazole- 204-206
1,3-dione
EXAMPLE 484
Weel inhibition filter binding assay (OY) to test for Weel inhibition activity
This assay provides a measure of inhibitory ability of the test compounds against isolated Weel kinase. The Weel kinase assay measures enzyme mediated phosphorylation of tyrosine on a synthetic peptide substrate in the presence of compounds being tested. The assay was carried out in 96-well filter microtiter plates (Millipore #MADP NOB 10). Compounds were dissolved and diluted in DMSO. 10 μl 3 x EDB buffer (150 mM Tris, pH 8.0, 30 mM NaCl, 30 mM MgCl2, 3 mM DTT), 18 μl water, and 2 μl of drug dilution were added to the test wells and mixed thoroughly. 10 μl of enzyme-substrate mixture was added to the wells. The Weel enzyme (human Weel kinase aa215-647, Onyx Pharmaceuticals, expressed in and purified from a baculovirus protein expression system) concentration was 0.01 μg/μl and the substrate (Poly Ornithine-Tyrosine (4:1), Sigma Chemical Co.) was 0.6 μg/μl in 1 x EDB buffer. The plates were mixed thoroughly for 5 minutes at room temperature. The reaction was started by adding 10 μl of 1 x EDB buffer containing 47.5 μM ATP (Sigma) and 0.026 μCi/μl γ-32p-ATP (ICN Biomedicals, Inc.) The plates were mixed at room temperature for 20 minutes. The reaction was stopped by adding 50 μl of ice cold 20% TCA with 0.1 M tetrasodium pyro-phosphate. Plates were incubated on ice or refrigerated at 4°C for 1 hour. Liquid reaction mixture was removed on a vacuum manifold, and the precipitated phosphorylated substrate was rinsed 5 times with 200 μl ice cold 10% TCA with 0.1 M tetrasodium pyrophosphate. 25 μl liquid scintillation cocktail were added to the membrane bound substrate and the plate read in a Microbeta (Perkin-Elmer) plate reader. Activity of compounds was calculated in comparison to uninhibited control determinations in each assay.
The data shown in Table 3 demonstrates activities (IC50) of Weel less than 0.1 μM ranging up to 1.65 μM. However, Compound X with the highest Weel activity on this table is a representative compound from US Patent No. 4,912,107. Compound X does not fall within the ambit of this invention either structurally or as a checkpoint abrogator of the present invention. The activity of Compound X against Weel kinase in this assay is less potent than the upper limit for the preferred compounds. The data in Table 3 shows that the modification of the core structure leads to unexpected potency in the inhibition of Weel kinase and a selectivity of at least 10-fold over the inhibition of the PKC enzyme.
The compounds of the present invention are considered to be suitable for use in an animal to treat cell proliferative diseases either alone or in conjunction with one or more other antineoplastic modalities if the Weel activity has an IC50of less than 1 μM in the assay described above. Preferably the compounds have an IC50 of less than 0.5 μM and most preferably an IC50of less than 0.1 μM
TABLE 3. Weel , Chkl and PKC Activity
WEElOY CHK1A PKC
IC50(μM) IC50 (μM) IC50 (μM)
Compound X 1.65 0.297 3.6
Compound of Example 94 0.263 0.056 1.8
Compound of Example 80 0.006 0.167 1.49
Compound of Example 68 0.011 0.435 0.48
Compound of Example 369 0.428 >10 >4
Compound of Example 230 0.009 4.46 1.5
EXAMPLE 485
Chkl Enzyme Inhibition Assay
In order to determine the inhibitory activity of the compounds of the present invention against Chkl, the following assay was performed to measure the inhibition of isolated Chkl enzyme.
The assay was carried out in round bottom polypropylene 96-well plates (Costar). Compounds were tested in serial dilutions beginning with a high concentration of 50 μM followed by up to nine 3-fold dilutions. Compounds were dissolved and diluted in DMSO. 2 μl of drug were spotted on the bottom of the assay plates, then diluted with 58 μl of Chkl buffer (20 mM Tris, pH 8.0, 50 mM NaCl, 10% Glycerol, 10 mM MgCl2, 5 mM dithiothreitol), and mixed at room temperature for 1 minute. 20 μl of buffer containing 250 ηg/well Chkl enzyme (Onyx Pharmaceuticals) and 1 μg/well GST-Cdc25 substrate (Onyx) were added. Contents of the wells were mixed for 1 minute and incubated at room temperature for 10 minutes. 20 μl of buffer containing 20 μM ATP and 0.4 μCi ATP [γ-33p] were added. The contents were mixed for 1 minute and incubated at 30°C for 30 minutes. The reaction was stopped by adding 50 μl of 120 mM EDTA to each well, except the control wells already containing EDTA. 140 μl of the contents of the wells were transferred to the wells of Reacti-Bind Glutathione Coated White 96- Well Plates (Pierce). Contents were mixed for 1 minute and incubated at room temperature for 1 hour. All of the wells were rinsed three times each with 300 μl PBS and air dried. 200 μl MicroScint 20 (Packard) was put in the wells. Plates were sealed with an adhesive cover and counted in a Top Count Microplate Scintillation counter (Packard). Activity of compounds was calculated in comparison to uninhibited control determinations in each assay.
The data shown in Table 4 demonstrates activities (IC50) of Chkl less than 0.002 μM ranging up to 0.297 μM. However, Compound X with the highest Chkl activity on this table is a representative compound from US Patent No. 4,912,107. Compound X does not fall within the ambit of this invention either structurally or as a checkpoint abrogator of the present invention. The activity of Compound X against Chkl kinase in this assay is less ^potent than the upper limit for the preferred compounds. The data in Table 4 shows that the modification of the core structure leads to unexpected potency in the inhibition of Chkl kinase and a selectivity of at least 10-fold over the inhibition of the PKC enzyme.
The compounds of the present invention are considered to be suitable for use in an animal to treat cell proliferative diseases in conjunction with another antineoplastic modality if the Chkl activity has an IC50 of less than 0.275 μM in the assay described above. Preferably the compounds have an IC50 of less than 0.2 μM and most preferably an IC50 of less than 0.1 μM
TABLE 4. Weel, Chkl and PKC Activity
WEElOY CHK1A PKC
IC50(μM) IC50 (μM) ICso (μM)
Compound X 1.65 0.297 3.6
Compound of
0.193 0.013 0.132 Example 198
Compound of
0.295 0.002 0.171 Example 214
Some of the compounds of the present invention are dual inhibitors, being selective for inhibiting both Weel and Chkl activity. These compounds may be equal in efficacy to the compounds that selectively inhibit either Weel or Chkl even if the activity against either enzyme is higher than that desired for the single inhibitors. Preferably the dual inhibitors have an IC 50 of less than 1 μM, more preferably less than 500 nM and most preferably less than 100 nM. TABLE 5. Dual Inhibitors
WEE10Y CHK1A
IC50(μM) IC50 (μM)
Compound of Example 363 0.057 0.02
Compound of Example 366 0.075 0.014
EXAMPLE 486
Myt-1 Inhibition Scintillation Proximity Assay to Test for Myt-1 Inhibition Activity
This assay provides a measure of inhibitory activity of the test compounds against isolated Myt-1 kinase.
The assay was carried out in 96-well SPA (Scintillation Proximity Assay) plates from Wallac. The compounds were tested at 50 μM followed by up to nine 3-fold dilutions (i.e., 50, 16.67, 5.56, 1.85, 0.617, etc.). Drugs were dissolved and diluted in DMSO. 2 μl of drug were spotted on the bottom surface of the wells of the SPA plates. 30 μl of MB buffer (50 mM Tris, pH 8.0, 100 mM NAC1, 0.1% Tween 20, 1 mM MgCl^ 100 μM DTT) containing 27 μM cold ATP were added to each well and then 9 μl of MB buffer with 177.8 ηM Myt-1 enzyme (MW = 54.6 kDa). Plates were mixed at room temperature for 1 minute, then incubated at room temperature for 5-15 minutes. 9 μl MHKB buffer (50 mM Tris, pH 8.0, 1 mM MgCl2, 100 μM DTT, 0.1 mM Na3V04) with 88-9 ηM Cdc2/B (MW = 84.5 kDa) were added, mixed at room temperature for 1 minute. The plates were centrifuged up to 2400 RPM, and incubated for 30 minutes at 30°C. 30 μl MHKB buffer containing 1 μM biotinylated histone HI (Amersham) peptide substrate (stock: 1 mM) and 10 μCi/μl ATP [γ-^^P]) were added. The plates were mixed at room temperature for 1 minute, centrifuged up to 2400 RPM, and incubated for 30 minutes at 30°C. The reaction was stopped with 200 μl stop buffer, 5 mM EDTA and 0.1% Triton X-100 (from 10X stock of 50 mM EDTA and 1.0% Triton X-100 diluted with PBS) with at least 20 μg/ml Streptavidin SPA beads (Amersham) and 50 μM ATP. Plates were sealed with an adhesive cover, mixed by inverting 10 times, and incubated for 10 minutes at room temperature. The plates were centrifuged at 2400 RPM for 15 minutes at room temperature and counted in Wallac Microbeta Trilux counter. Activity of compounds was calculated in comparison to uninhibited control determinations in each assay.
None of the compounds of the present invention had IC 50 for Myt-1 activity in this assay of less than 10 μM. Since phosphorylation of thr 14 on cdc2 (catalyzed by Myt-1 kinase) is also a checkpoint establishing event, a compound that inhibits both Weel kinase and Myt-1 kinase may be a checkpoint abrogator due to its dual inhibitory activity. Lack of Myt-1 inhibition, therefore, rules out the contribnution of Myt-1 to check point abrogation. The absence of significant Myt-1 inhibitory activity of the compounds of the present invention demonstrates the selectivity of theses compounds as Weel kinase and Chkl kinase inhibitors. . . .
-EXAMPLE 487- - - -
Protein Kinase C (PKC) Assay
The PKC assay provides a measure of inhibitory activity of the test compounds against PKC contained in a rat brain preparation.
Enzyme was prepared from a preparation of rat brain (Promega) 0.5 μg diluted with 1.6 ml of 10 mM Hepes buffer pH 7.5. Reaction buffer was comprised of 150 mM Hepes buffer, 4 mM CaCl2, 15 mM MgCl2, 3 mM EDTA, 3.75 mM EGTA at pH 7.5. Histone substrate was made by dissolving histone HI (Sigma) in water at 1.5 mg/ml. Phosphatidylserine/diolein liposomes were made by mixing 75 μl of 10 mg/ml phosphatidylserine (Sigma) in CHCI3 with 60 μl of 2.5 mg/ml diolein in CHCI3 (Sigma) in a glass vial and evaporating the CHCI3 under N2. The film was suspended in 1 ml water and sonicated 6 x 15 sec with a microtip probe at room temperature.
To cany out the assay, 50 μl buffer, 20 μl histone, 20 μl liposomes, and inhibitor or solvent control were added to wells of a 96-well filter plate (Millipore) with enough water, if necessary, to make the final volume 110 μl. 20 μl of enzyme preparation solution were added and incubated for 10 minutes at room temperature. This was followed by the addition of 20 μl of 32P ATP (75 μM ATP in water, labeled ATP at 25 μCi/ml) which was incubated for 15 minutes at room temperature. The reaction was terminated by the addition of 50 μl of 40% (w/v) trichloroacetic acid. The filters were washed by vacuum filtration with 5 x 125 μl of ice cold 10% (w/v) trichloroacetic acid. The filters were placed in scintillation fluor and counted to determine precipitated labeled phosphate incorporated into substrate. The per cent inhibition was calculated in comparison to the uninhibited controls.
EXAMPLE 488
Cell-Based 96- Well Cdc2 Histone HI Kinase Assay for G2 Checkpoint Abrogation
This cellular assay is a measure of the effect of the test compounds on the activity of the Cdc2/cyclin B complex on one of its physiological substrates, Histone HI.
HT-29 cells 20,000 per well (NUNCLON™ cat no. 163320 96-well plate) were plated in 171 μl media [Dulbecco's Modified Eagle's Medium 4500 mg/L Glucose (DME High Glucose), 1% penicillin and streptomycin, 2% L-Glutamate, 10%FBS]. The plate was incubated at 37°C for 24 hours. 9 μl of a 5 μM Adriamycin solution was added to each well (250-nM final concentration) and incubated at 37°C for an additional 16 hours. Next, 20 μl of 500 ng/mL nocodazole was added per well immediately followed by addition of 5 μl test compound. The plate was incubated at 37°C for 4 hrs. The plate was removed from the incubator and spun in a Beckman GS-6R Centrifuge for 10 minutes, 800 rpm, 4°C. The media was removed and the plate surface dried by blotting. 100 μL of PBS was added to each well. The plate was spun as above. The PBS was removed from plate and the plate surface was dried. 20 μl of lysis buffer (50 mM Hepes pH 7.5, 250 mM NaCl, 0.1% NP 40, 10 mM β-Glycerophosphate,l mM NaF.l mM EDTA,1 mM Pefabloc,l mM DTT, 0.1 mM sodium orthovanadate,10 μg/ml Aprotinin, 20 μM Leupeptin) was then added to each well followed by medium-speed rocking at 4°C for 45 minutes. After lysis, 30 μL of kinase assay buffer (50 mM Hepes, 22 mM MgCl2, 1 mM DTT, 166.7 ng/μl Histone HI, 83 μM ATP,
0.033 μCi/μl [γ-33p]ATP) was added. The plate was incubated on a 32°C plate warmer for 25 minutes. The kinase reaction was stopped by adding 80 μl of 100 mM EDTA pH 7.8 to each well. The lysate was harvested onto a pre- wetted Wallac P-30 filtermat (Wallac 1450-523, glass fiber filter with negatively charged P30 active groups size 90 x 120 mm) using 75 mM H3PO4 for 10 seconds, followed by a 10 second aspiration step. The filtermat was placed in a 75 mM H3PO4 bath and shaken gently for 10 minutes at room temperature, then placed within the fold of a single sheet of paper towel, and subjected to microwaves on high power for 2 to 3 minutes, or until filtermat is dry. The filtermat was placed in a sample bag (Wallac 1450-432), 5-ml nonaqueous scintillation fluid was added to the sample bag and the bag was sealed. The samples were read in a Wallac 1450 MicroBeta Liquid Scintilation Counter. The data shown in Table 6 demonstrate the cellular effect of a Weel and/or Chkl inhibitor on a physiological substrate of cdc2/cyclinB which complex is itself a substrate of Weel kinase.
TABLE 6. Histone Kinase Assay
WEEIOY CHK1A Histone Kinase
IC50(μM) IC50 (μM) 1C50 (μM)
Compound of
0.006 0.166 0.646 Example 80
Compound of Example 198 0.1933 0.013 0.798
Compound of Example 363 0.057 0.023 0.505
EXAMPLE 489
Procedure for Clonogenic Assays in HT-29 Cells + Adriamycin
This cellular assay is a measure of the toxicity of the test compounds in the absence and presence of DNA damage induced by a conventional chemotherapeutic agent.
HT-29 cells were grown in Dulbecco's Modified Eagle Medium with high glucose, supplemented with 1 mM sodium pyruvate, 2 mM L-glutamine, 16 mM HEPES, 8 mM MOPS, and 10% fetal bovine serum. The cells were incubated at 37°C in an atmosphere of 5% C02 and 100% relative humidity.
Two or three T-75 tissue culture flasks were seeded at about 50% confluency in 30 ml media and incubated for approximately 24 hours. Adriamycin (ADR) (dissolved at 5 mM in distilled water (dH20)) was added to the flasks to a final concentration of 1 uM or 500 nM.
One flask received no ADR. The cells were allowed to incubate with the ADR for 1 hour. All flasks were then washed twice with 20 ml media allowed to incubate a further 16 hours in 30 ml media.
The stock agar (3.2% Seaplaque GTG Agarose (BioWhittaker Molecular Applications)) was suspended in distilled water and autoclaved for 20 minutes. The agar was melted prior to use in a microwave oven. The bottom agar was a 1:4 dilution of the stock agar in media with enough fetal bovine serum added to bring the solution to 10%. One microliter was plated in each well of 6-well tissue culture plates and the plates allowed to harden. The cloning agar (a 1:8 dilution of stock agar in media with fetal bovine serum added to 10%) was prepared and held at 40°C until used.
The cells were trypsinized using Trypsin-EDTA and their concentration adjusted to 75,000 cells per microliter with media. One hundred microliters of each cell suspension were placed into sterile 15 ml plastic centrifuge tubes. Twenty-five microliters of each test compound was added to appropriate tubes, followed by addition of 5 ml of warm cloning agar. The tubes were mixed well and 2 ml of the agar/cell suspension were added to duplicate wells of the 6-well plates that were coated with agar earlier. The plates were swirled and placed in the refrigerator for 5 minutes. After the plates returned to room temperature they were incubated for 10 to 14 days, until colonies were visible. The colonies were stained with INT (p-Iodonitrotetrazolium Violet) (dissolved in dH20 at 1 mg/ml and filter sterilized). One milliliter INT was added to each well and the plates incubated overnight at 37°C, 5% C0 , and "100% relative humidity. The colonies were counted using a Hamamatsu video imaging system and ImageQuant software.
TABLE 7. Clonogenic Assay Data
% of Control Colonies % of Control Colonies With No DNA Damage With DNA Damage
Compound of Example 366 3g% 2.8%
(250 nM)
EXAMPLE 490
Procedures for Western Blot determination of phosphotyrosine 15 on Cdc-2 and mobility shift of Mvt-1.
These western blot assays measure the phosphorylation state of the physiologic substrate of Weel: tyrosine 15 on Cdc2 kinase. This is accomplished by means of a phosphospecific antibody whose signal is normalized by comparison to the total amount of Cdc2 detected in the samples. The shift of the Myt-1 protein to a lower mobility on a Western blot is used as a measure of progression into M phase of the cell cycle. A. Procedure_for detecting phosphotyrosine 15, Myt-1 shift and total Cdc-2_from cultured HT-29 cells in response to potential check point abrogators ± Adriamycin and/or Nocodazole
HT-29 cells were grown in Dulbecco's Modified Eagle Medium with high glucose, supplemented with 1 mM sodium pyruvate, 2 mM L-glutamine, 16 mM HEPES, 8 mM MOPS, and 10% fetal bovine serum. The cells were incubated at 37°C, in 5% CO2, and 100% relative humidity.
Cells were grown and treated in 6-well tissue culture plates. Cells were seeded in
3 mL media at a concentration of 200,000 per mL. Once seeded the cells were allowed to attach 24 hours.
All treatments were done in duplicate wells. The wells that were treated with Adriamycin (ADR) were exposed to 1 μM ADR for 1 hour. ADR was dissolved in sterile distilled water. After the 1 hour incubation the cells were washed twice with 2 ml media and then incubated in 3 ml media for 16 hours. After the 16-hour incubation, the cells were treated with various concentrations of abrogator ± Nocodazole (NOC) at 50 ng/ml. Abrogators were dissolved in dimethylsulfoxide (DMSO) at a concentration of 10 mM and diluted with growth medium before being added to the cells and NOC was dissolved at 1 mg/mL in DMSO and diluted with growth medium before administration to the cells. The cells were incubated 6 hours with the abrogator and NOC. The duplicate wells were scraped, on ice, and combined in a 15 ml centrifuge tube. The wells were rinsed with Dulbecco's phosphate buffered saline (DPBS) without calcium and magnesium and the rinse combined with the scraped cells. The cells were centrifuged at 200 x g at 4°C for 5 minutes. The supernatant was discarded and the pellets resuspended in 100 μL DPBS. The cell suspension was then transferred to 1.5 ml eppendorf centrifuge tubes and centrifuged at 4°C for
4 minutes at 4000 φm. After the supernatant was removed, the pellet was frozen on dry ice and stored at -80°C.
The pellets were thawed on ice prior to lysis. The lysis buffer, ELB (2.5 mM HEPES (7.5), 150 mM NaCl, 25 μM NaF and 0.5% NP40 supplemented with 1 mM AEBSF, 1 mM sodium orthovanadate, and 1 mM dithiothretol, and complete protease inhibitor cocktail tablets (Roche Biochemicals). The tablets were dissolved in 2 mL distilled water and diluted 1 :25 in the lysis buffer. The pellets were suspended in 100 μl complete lysis buffer and incubated on ice for 30 minutes. Following lysis, the suspension was centrifuged at 14,000 rpm for 15 minutes at 4°C. The supernatant liquidwas collected and the protein concentration determined using the Pierce BCA protein Assay Kit per manufacturers instructions. The protein concentration was adjusted to 3 mg/mL with DPBS. The samples were then diluted 1:1 with Invitrogen 2 x tris-glycine sample buffer supplemented with 50 μl/ml 2-mercaptoethanol, boiled for 3 minutes, and stored frozen at -20°C.
Thirty micrograms of protein per lane were run on Novex pre-cast 12%, 1.5 mm, 10-well, tris-glycine polyacrylimide gels using Novex running buffer and Invitrogen (See Blue Plus 2 molecular weight standards). The gels weare run at 100 volts for 30 minutes then 125 volts for 1.5 hours. The proteins were transferred to 0.45 μm pore nitrocellulose membranes using Novex transfer buffer and the Novex X-Cell II blot module. The nitrocellulose membranes were blocked overnight at room temperature. The blocking buffer was 5 mM Tris (8.0), 150 mM NaCl, 0.1% Tween 20, 1 mM NaF, 10 mM glycerolphosphate, 100 μM sodium orthovanadate, and 3% bovine serum albumen.
After blocking, the gels were cut with a razor blade and the top portion treated with anti Myt-1 antibody diluted 1 :5000 with blocking buffer. The lower portion of the gel was treated with biotinylated antiphosphotyrosine 15, also diluted 1:5000 in blocking buffer. The membranes were incubated for 2 hours at room temperature with constant rocking. The antibody solutions were removed and the membranes were washed 3 times for 20 minutes each with TNT buffer. TNT buffer consisted of 50 mM Tris (8.0), 150 mM NaCl, and 0.1% Tween 20. Secondary antibody was then added in blocking buffer. Neutravidin HRP at 1:40,000 was used for the biotinylated phosphotyrosine 15 blots and Bio Rad goat anti rabbit at 1: 10,000 was used for the Myt-1 blots. The blots remained in secondary antibody for
1 hour at room temperature followed by three 20-minute washes with TNT buffer. Protein bands were detected using the Amersham Pharmacia ECL detection kit and Kodak Bio Max film per manufacturer's instructions.
The phosphotyrosine 15 membranes were stripped using the Chemicon International Re-Blot kit per manufacturer's instructions. The blots were then washed twice with TNT buffer and once with blocking buffer for 20 minutes each. Anti Cdc-2 (cdkl ; Labvision Corporation) were diluted 150 μl per 50 ml blocking buffer and incubated with the blots for
2 hours at room temperature followed by three 20-minute washes in TNT buffer. The secondary antibody was Bio Rad goat antimouse HRP and was diluted 1:10,000 in blocking buffer before a 1 hour incubation with the blots at room temperature. Three 20-minute washes preceded ECL detection.
B. Procedure for detecting MPM_2 in cultured HT-29 cells +/- potential checkpoint abrogators, adriamycin.and nocodazole
This assay uses polyclonal antibody to quantitate the M-phase specific histological markers in the determination of a mitotic index (fraction of cells found in mitosis).
HT-29 cells were grown in Dulbecco's Modified Eagle Medium with high glucose, supplemented with 1 mM sodium pyruvate, 2 mM L-glutamine, 16 mM HEPES, 8 mM MOPS, and 10% fetal bovine serum. They were incubated at 37°C in an atmosphere of 5% C02 and 100% relative humidity.
Cells were seeded in 96-well tissue culture plates at 100 μl per well at a concentration of 40,000 per ml. The cells were allowed to attach and begin growing for 24 hours. 100 μl of adriamycin (ADR) at 2 μM (final = 1 μM) was added to test cells and the cells incubated for
1 hour as above. Following the incubation, the plates were washed 2 times with growth media. The media was replaced with 100 μl fresh media and incubate a further 16 hours. Serial 2-fold dilutions of potential abrogators were added to the test wells. The rows that received nocodazole (NOC) have 2 μl NOC added at 2.5 μg/ml. The plates were then incubated an additional 6 hours. Following the incubation, the plates were centrifuged for 5 minutes at 4°C at 200 g. One hundred microliters of Carnoy's fixative, 3 parts methanol to 1 part acetic acid, was added directly to each well and left at room temperature for 15 minutes. The media/fixative mixture was removed by suction and replaced with ice cold ethanol:acetic acid in a 20:1 ratio. The plates were stored at 4°C until stained.
The fixed cells were stained for MPM-2 using the Upstate Biotechnology MPM-2 rhodamine detection kit per manufacturer's instructions. Briefly, the cells were washed with Dulbecco's phosphate buffered saline (DPBS) with calcium and magnesium followed by incubation with blocking buffer consisting of 8% bovine serum albumen (BSA) for a minimum of 1 hour. The cells were then washed with PBS one time and treated overnight at 4°C with primary antibody at 5 μg/ml (100 μl per well) diluted with DPBS with 1% BSA. The cells were then washed twice for 15 minutes each with DPBS and then incubated with a 1: 1000 dilution of rhodamine conjugated goat antimouse IgG in DPBS with 1% BSA for 1 hour. The secondary antibody was washed off in three 30-minute washes with DPBS. The cells were then counterstained using the Molecular Probes Mycoflour kit to stain nuclei following the instructions for the kit.
The stained cells were viewed under fluorescence microscopy using fluorescence filters suitable for detecting rhodamine and DAPI stains. Images were captured using a Spot digital camera and images analyzed using ImageQuant to quantitate total nuclei and to count MPM-2 positive cells.
MPM-2 Assay - - (Values are % of cells in M phase)
+ ADR +
+ Media + ADR + NOC NOC
Control 8.4 7.0 26.4 25.9
Compound of Example
26.4 18.9 37.2 86.2 363 @ 312.5 nM
EXAMPLE 491
Procedure for in vivo testing of Weel, Weel/Chkl or Chkl inhibitors in combination with adriamycin or cisplatin
These experiments measured the in vivo modulation of Pyl5 on Cdc2 in a tumor and assessed the therapeutic effect of Weel, Weel/Chkl or Chkl inhibitors of the present invention combined with a conventional agent. The therapeutic effect is measured by an increase in life span of treated animals.
In vivo Experiments
In vivo methods
The initial in vivo experiments demonstrate biochemical and physiological evidence of Weel, Weel/Chkl or Chkl inhibition by examining modulation of the downstream target (i.e., the phosphorylation status of Cdc2 tyrosine 15) and cell cycle effects in L1210 murine leukemia tumor cells. L1210 was chosen for its lack of p53 function, pronounced G2 accumulation in response to DNA damage, ease of propagation in mice, and rapid cycle time.
CD2F1 mice weighing 25 to 26 g were inoculated intraperitoneally (ip) with 10^ or 5 x 10^ L1210 cells and randomized into treatment groups of 3 mice each. On Day 4, 5, or 6 after tumor implantation, the mice were treated with a single injection of DNA damaging agent (cisplatin, 8 or 6 mg/kg iv), one or more injections of the compound of Example 80 (20 mg/kg ip, sc, or iv), or both agents. The injections of the compound of Example 80 were spaced 3 to 8 hours apart and were started simultaneously with the DNA damaging agent or after a delay of 8 or 16 hours. Control animals received only 0.2 ml saline iv. The DNA damaging agents were dissolved in saline and the compound of Example 80 was dissolved in 1 of 2 vehicles: (1) 10% cremaphor, 10% ethanol, and 80% H2O or (2) 5% dimethylacetamide, 25% propylene glycol, and 70% polyvinylpyrrolidine (30% w/v in H2O).
The mice were sacrificed at several time points ranging from 8 to 40 hours after commencement of treatment and the tumor cells were harvested in phosphate buffered saline -.containing 1 mM sodium orthovanadate and 5 mM EDTA. The L1210 cells were counted on a Coulter Counter and for each group an aliquot of 2.5 x 10^ cells were centrifuged and frozen as pellets and an aliquot of 2.5 x 10" was frozen in Vindelov's citrate buffer* at -80°C.
The larger pellets were homogenized for 30 seconds with a sonicator in a cold lysis buffer (RIPA) containing 25 mM Tris (base) pH 7.4, 350 mM sodium chloride, 1% nonidet P40, 5 mM EDTA (tetrasodium), 0.5% sodium deoxycholate, 0.1% sodium dodecyl sulfate, 1 mM AEBSF, 1 mM sodium fluoride, 0.5 mM sodium orthovanadate, 15 μg/ml aprotinin, 20 μM leupeptin, 10 mM β-glycerophosphate, and 1 mM DTT in H2O. The lysates were diluted 1:10 with a mixture of 4 parts RIPA and 5 parts 2 times Novex electrophoresis sample buffer which, when diluted to working concentration contained 2% sodium dodecyl sulfate, 0.0025% bromphenol blue, 10% glycerol, and 60 mM dithiothreitol in H2O. The samples were heated at 98° for 5 minutes. Duplicate Novex 4% to 20% polyacrylamide Tris-glycine 15-well 1 mm mini-gels were loaded with 15 μl/well and run at 200 V (constant) for 45 minutes. The proteins were transferred to nitrocellulose membranes in Novex transfer buffer at 25 V (constant) for 2 hours. One of each membrane was blotted for total Cdc2 protein with LabVision MS-HOP antibodies at 1 :200, followed by BioRad 172-1011 goat antimouse IgG-HRP at 1 :10,000. The other membrane was blotted for Cdc2 phosphotyrosine 15 (Ptyrl5) with biotinylated rabbit polyclonal antibodies supplied by Onyx Pharmaceuticals at 1:5000, followed by Pierce 31001 neutravidin-HRP at 1:20,000 (50 ng/ml). The antibodies were detected with Amersham ECL reagents. The blot images were captured on Kodak BioMax MR film and imaged on a Molecular Dynamics Personal Densitometer SI. Densitometry was performed with Molecular Dynamics Image QuaNT software. The densitometric values for Cdc2 Ptyrl5 were normalized for total Cdc2 protein (divided by the values for total Cdc2 to obtain a ratio of phospho:total Cdc2) and divided by the ratio of the control samples to obtain percent of control phosphorylation values for each tumor sample.
The smaller pellets were stained for DNA content by the method of Vindelov ( Vindeløv LL, Christensen IJ, and Nissen NI. A detergent-trypsin method for the preparation of nuclei for flow cytometric DNA analysis. Cytometry 1983;3: 323-327). They were analyzed for propidium iodide fluorescence on a Beckman-Coulter Elite flow cytometer. Cell cycle distributions were estimated by the broadened trapezoid model of Bagwell (Bagwell, C.B. Theoretical aspects of flow cytometry data analysis. In: K.D. Bauer, R.E. Duque, TN. Shankey, (eds.), Clinical Flow Cytometry: Principles and Application, pp. 41-61. Baltimore: Williams & Wilkins, 1993) as implemented by the Verity Software House program ModFit LT.
Subsequent in vivo experiments were designed to determine if the addition of a Weel, Weel/Chkl or Chkl inhibitor to standard chemotherapy with DΝA damaging agents results in a therapeutic gain. CD2F1 mice weighing 24 to 26 g were inoculated with 10^ L1210 cells ip and randomized into treatment groups of 6 mice each. On Days 3, 7, and 11 after implant, the mice were treated with a single iv injection of 1 of 3 dose levels of a DΝA damaging agent (cisplatin or doxorubicin) alone or in combination with 2 ip injections of 1 of 2 dose levels of the compound of Example 80. Control mice received appropriate vehicle in place of active agents. Dose levels were based on mean group body weights. Mortality data were collected over a 3-week span and the median survival times of each group were calculated. Efficacy data (%T/C) are reported as the median life span of the treated animals divided by the median life span of the control animals times 100. The maximal %T/C of the combination groups was then compared with the maximal %T/C of the DΝA damage. As shown on Table 9, the only groups to derive a measure of the therapeutic gain were associated with addition of a Weel, Weel/Chkl or Chkl inhibitor of the present invention. Table 9 Cell cycle distribution of L1210 cells
Figure imgf000303_0001
Cell cycle distribution of L1210 cells treated in vivo with cisplatin at 6mg/kg and with the compound of Example 80 at 20 mg/kg. Cells were examined 24 hours after administration of drug and compound. Values are per cent of cells examined.
All of the compositions and/or methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the compositions and/or methods and in the steps or in the sequences of steps of the methods for preparing these compounds.

Claims

CLAIMSWhat is claimed is:
1. A compound of Formula I
Figure imgf000304_0001
wherein each dashed line represents an optional bond;
Rl is hydrogen, halogen, alkyl, NR^R" or an aryl or heteroaryl ring optionally substituted with up to five substituents selected from halogen, alkyl, haloalkyl, hydroxyl, nitro, cyano, C(0)R3, OR , S(0)mR , NR3R4, OC(0)R3, NR3(CO)OR , CH2NR3R4, CH20R3,
COOR3, CONR3R4 NR3C0R4, S02NR3R4, CONHS02R3, NR3S(0)mR4, NHCONR3R4, NR3C0NΗR4; or a cycloalkyl or cycloalkenyl ring optionally substituted with up to five substituents selected from, halogen, alkyl, haloalkyl, hydroxyl, nitro, cyano, C(0)R3, OR3, S(0)mR3, NR3R , OC(0)R3, NR3(CO)OR4, CH2NR3R4,
CH2OR COOR3, CONR3R4, NR COR4, S02NR3R4, C0NHS02R3
NR3S(0)mR4, NHCONR3R4, NR CONHR4; or
a heterocyclic ring optionally substituted with up to five substituents selected from, halogen, alkyl, haloalkyl, hydroxyl, nitro, cyano, C(0)R3, OR , S(0)mR3, NR3R4, OC(0)R3, NR (CO)OR , CH2NR3R4, CH20R3, COOR3, CONR3R4, NR COR4, S02NR3R4, C0NHS02R3, NR3S(0)mR4
NHCONR3R4, NR3CONHR4; m is 0-2;
X is hydrogen or halogen;
γl is O, S(0)m, or NR10;
R9 is hydrogen, hydroxyl, halogen, NR3C(0)R4, NHCONR3R4, (C=NR3)NHR4,
NH(C=NR3)NHR4, NH(C=NH)NR3R4, NH(C=0)OR3, NR5R6, (CR5R6)r Z; r is 0-6;
R2, R7, R8 arid RlO are in each instance independently selected from ((CR^
R )nT)a(CRll Rl2)^)-Z wherein the sum n, a and b is in each instance less than 10; T may be absent, or, when present, is in each instance independently selected from O,
CONR3, CONHS02, S(0)m, NR3, NR -0, 0-S(0)m, S(0)m-0, NR3-S(0) , or S(0)2-NR3;
n is in each instance independently 0-6; a is in each instance independently 0-6; b is in each instance independently 0-6; Z is selected from hydrogen, halogen, alkyl, haloalkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, cyano, nitro, hydroxy, C(0)R3, CONHSO2R3, OR3, S(0)mR3, OS02R3, NR3R4, C02R3, CONR R4, NR3COR , S02NR3R4 0P0(0R3)(0R4), CH=CR3R4, CCR3, (C=NR3)NHR4, NH(C=NR3)NHR4, NH(C=NH)NR3R4, wherein the alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl group may be substituted with up to four groups independently selected from halogen, alkyl, hydroxyl, nitro, cyano, OR3, S(0)mR3, NR3R4, OC(0)R3, NR3(CO)OR4, C(0)R3, COOR3, CONR3R4, NR COR4, S02NR3R4, CONHS02R3, NR3s(0)mR4,
CH2NR3R4, CH2OR3, NHCONR3R4, NR3CONHR4;
R5, R6; Rl 1 and R^2 are in each instance independently selected from hydrogen, hydroxyl, alkyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, halogen, cyano, nitro, CH2NR3R4, CH2OR3, C(0)R3, OR , S(0)mR3, NR3R , COOR3, CONR3R4, S02NR3R4 , NHCONR R4, NR3CONHR4; wherein the alkyl, haloalkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl group may be substituted with up to four groups independently selected from halogen, alkyl, hydroxyl, nitro, cyano, OR3, S(0)mR3, NR3R4,
OC(0)R3, NR3(CO)OR4, C(0)R3, COOR3, CONR3R4, NR3COR4,
S02NR3R4, CONHSO2R3, NR3S(0)mR4, NHCONR3R4, NR3CONHR4;
R^ and R^ or R^ and R*2 together with the carbon atom to which they are attached may form a carbonyl group; or together with the carbon or heteratom to which they are attached may form a cycloalkyl or heterocyclyl group, said carbonyl, cycloalkyl or heterocyclyl group may be substituted with up to four groups independently selected from halogen, hydroxyl, nitro, cyano, alkyl, haloalkyl, alkyl, nitro, cyano, OR3, S(0)mR3, NR R4, OC(0)R3, NR3(C0)0R4, C(0)R3, COOR3, CONR R4, NR3COR4, S02NR3R4, CONHS02R3 ) NR3S(0)mR4, NHCONR3R4, NR3CONHR4;
R3, R4 are independently selected from hydrogen, alkyl, haloalkyl or a substituted or unsubstituted carbocyclic group selected from cycloalkyl, cycloalkenyl, heterocyclyl, aryl, and heteroaryl, wherein the said alkyl, or a substituted group may be substituted with up to 4 groups selected from halogen, hydroxyl, nitro, cyano, alkyl, haloalkyl, alkyloxy, carboxy, COOH, CONH2,
NHCOCH3, N(CH )2, NHCH3, thiomethyl, thioethyl, SOCH3, SO2CH3; R3 and R4 together with the carbon atom or heteroatom to which they are attached may form a cycloalkyl or heterocyclyl group substituted with up to four groups independently selected from halogen, hydroxyl, nitro, cyano, alkyl, haloalkyl, alkyloxy, formyl, carboxy, acetyl, CH2NH2, CH2OH, COOH, CONH2, NHCOCH3, N(CH3) , thiomethyl, thioethyl, SOCH3, S02CH3, alkoxycarbonyl, alkylcarbonyl, alkynylamino, aminoalkyl, aminoalkylcarbonyl, amino, mono- or dialkylamino, or
R3 and R4 together with the nitrogen to which they are attached may form a heterocyclic ring containing 3-8 members, up to four of which members are optionally carbonyl groups or heteroatoms independently selected from oxygen, sulfur, S(O), S(0)2, and nitrogen, wherein the carbocyclic group is unsubstituted or substituted with up to four groups independently selected from halogen, hydroxy, hydroxyalkyl, alkyl, haloalkyl, alkoxy, alkoxycarbonyl, alkylcarbonyl, alkynylamino, aminoalkyl, aminoalkylcarbonyl, amino, mono- or dialkylamino.
2. A compound of according to Claim 1 in which R is selected from an unsubstituted aryl ring or an aryl ring substituted with up to 3 substituents selected from the group consisting of halogen, haloalkyl, alkoxy, hydroxyl, nitro, or NR3R4.
3. A compound of according to Claim 1 wherein R9 is selected from a hydrogen, hydroxyl, halogen or NHCHO group.
4. A compound according to Claim 1 wherein Y is oxygen.
5. A compound according to Claim 1 wherein Y is sulfur.
6. A compound according to Claim 1 wherein Y* is NR^υ.
7. A compound according to Claim 1 wherein R9 is NR^R6 or OH, Rl is aryl, and Y* is NRlO.
8. A compound according to Claiml wherein R9 is hydroxyl, Y1 is NRlO, and the bond represented by the dashed line (C — O) is absent.
9. A compound according to Claim 3 wherein R9 is hydroxyl and R^ is not hydrogen.
10. A compound according to Claim 1 wherein R^ is not hydrogen, and R" is hydrogen.
11. A compound according to Claiml wherein R" is hydrogen and R° is ((CR5R6)nT)a(CRn R12)b)-Z; wherein T may be absent or O and Z is NR R4.
12. A compound according to Claim 1 wherein which R" is selected from halogen or hydroxyl and R8 is ((CR5R6)nT)a(CR1 1R12)b)Z wherein T and Z are absent.
13. A compound according to Claim 1 wherein R9 is selected from NR^R6 and OH, R7 is ((CR5R6)nT)a(CR1 1R12)b)Z, and Y is selected from O and NR10.
14. The compounds:
2-(4-(2,6-Dichlorophenyl)-9-hydroxy-l,3-dioxo-2,3-dihydropyrrolo[3,4- c]carbazol-6(lH)-yl)ethyl methanesulfonate;
2-(4-(2-Chlorophenyl)-9-hydroxy-l,3-dioxo-2,3-dihydropyrrolo[3,4- c]carbazol-6(lH)-yl)ethyl methanesulfonate;
3-(4-(2,6-Dichlorophenyl)-9-hydroxy-l,3-dioxo-2,3-dihydropyrrolo[3,4- c]carbazol-6(lH)-yl)-N-[2-(dimethylamino)ethyl]propanamide;
3-(4-(2-Chloro-6-methoxyphenyl)-9-hydroxy-l,3-dioxo-2,3- dihydropyrrolo[3,4-c]carbazol-6(lH)-yl)-N-[2-(dimethylamino)ethyl]propanamide;
3-(4-(2-Chlorophenyl)-9-hydroxy-l,3-dioxo-2,3-dihydropyrrolo[3,4- c]carbazol-6(lH)-yl)-N-(lH-tetraazol-5-yl)propanamide;
3-(4-(2-Chlorophenyl)-9-hydroxy-l,3-dioxo-2,3-dihydropyrrolo[3,4- c]carbazol-6(lH)-yl)-N-[2-(lH-imidazol-5-yl)ethyl]propanamide (129);
3-(4-(2-Chlorophenyl)-9-hydroxy-l,3-dioxo-2,3-dihydropyrrolo[3,4- c]carbazol-6(lH)-yl)-N-[2-(4-morpholinyl)ethyl]propanamide (121);
3-(4-(2-Chlorophenyl)-9-hydroxy-l,3-dioxo-2,3-dihydropyrrolo[3,4- c]carbazol-6(lH)-yl)-N-[2-(dimethylamino)ethyl]propanamide; 3-(4-(2-Chlorophenyl)-9-hydroxy-l,3-dioxo-2,3-dihydropyrrolo[3,4- c]carbazol-6(lH)-yl)propanenitrile;
3-(4-(2-Chlorophenyl)-9-hydroxy-l,3-dioxo-2,3-dihydropyrrolo[3,4- c]carbazol-6(lH)-yl)propanoic acid;
3-(9-Hydroxy-l,3-dioxo-4-phenyl-2,3-dihydropyrrolo[3,4-c]carbazol-6(lH)- yl)propanamide;
3-(9-Hydroxy-l,3-dioxo-4-phenyl-2,3-dihydropyrrolo[3,4-c]carbazol-6(lH)- yl)propanoic acid;
4-(2,3-Dichlorophenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione (18) 4-(2-Chloro-5-hydroxyphenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)- dione; _
4-(2,6-Dibromophenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2,6-Dichloro-3-hydroxyphenyl)-9-hydroxypyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione; ~
4-(2,6-Dichloro-4-hydroxyphenyl)-9-hydroxypyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
4-(2,6-Dichlorophenyl)-9-hydroxy-6-(2-hydroxyethyl)pyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
4-(2,6-Dichlorophenyl)-9-hydroxy-6-(3-hydroxypropyl)pyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
4-(2,6-Dichlorophenyl)-9-hydroxy-6-[3-(lH-imidazol-l-yl)propyl]pyrrolo[3,4- c]carbazole-l ,3(2H,6H)-dione;
4-(2,6-Dichlorophenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2,6-Dimethoxyphenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)- dione;
4-(2-Bromophenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-Chloro-3-hydroxyphenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)- dione;
4-(2-Chloro-4-hydroxyphenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)- dione; 4-(2-Chloro-6-hydroxyphenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)- dione;
4-(2-Chloro-6-methoxyphenyl)-9-hydroxy-6-(2-hydroxyethyl)pyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione (112);
4-(2-Chloro-6-methoxyphenyl)-9-hydroxy-6-(3-hydroxypropyl)pyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
4-(2-ChIoro-6-methoxyphenyl)-9-hydroxy-6-[3-(4- morpholinyl)propyl]pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-Chloro-6-methoxyphenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)- dione;
4-(2-Chlorophenyl)-6-(2,3-dihydroxypropyl)-9-hydroxypyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
4-(2-Chlorophenyl)-6-(2-hydroxyethyl)-9-hydroxypyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
4-(2-Chlorophenyl)-6-(3,4-dihydroxybutyl)-9-hydroxypyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
4-(2-Chlorophenyl)-6-ethyl-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)- dione;
4-(2-chlorophenyl)-9-hydroxy-6-(2-hydroxypropyl)pyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione (313).
4-(2-Chlorophenyl)-9-hydroxy-6-(3-methoxypropyl)pyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione (132).
4-(2-Chlorophenyl)-9-hydroxy-6-[(2R)-3-hydroxy-2- methylpropyl]pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-chlorophenyl)-9-hydroxy-6-[(2S)-3-hydroxy-2-methylpropyl]pyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione (314).
4-(2-Chlorophenyl)-9-hydroxy-6-[2-(lH-l,2,4-triazol-5- ylsulfinyl)ethyl]pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-Chlorophenyl)-9-hydroxy-6-[2-(lH-l,2,4-triazol-5- ylsulfonyl)ethyl]pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-Chlorophenyl)-9-hydroxy-6-[2-(lH-imidazol-2- ylsulfanyl)ethyl]pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione; 4-(2-Chlorophenyl)-9-hydroxy-6-[2-(lH-imidazol-2- ylsulfinyl)ethyl]pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-Chlorophenyl)-9-hydroxy-6-[2-(lH-imidazol-2- ylsulfonyl)ethyl]pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-Chlorophenyl)-9-hydroxy-6-[2-(lH-tetraazol-5-yl)ethyl]pyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
4-(2-Chlorophenyl)-9-hydroxy-6-[2-(4H-l,2,4-triazol-3- ylsulfanyl)ethyl]pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-Chlorophenyl)-9-hydroxy-6-[2-hydroxy-3-(4- morpholinyl)propyl]pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-Chlorophenyl)-9-hydroxy-6-[2-hydroxy-3- (methylamino)propyl]pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione (284);
4-(2-Chlorophenyl)-9-hydroxy-6-[3-(lH-imidazol-l-yl)propyl]pyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
4-(2-Chlorophenyl)-9-hydroxy-6-[3-(lH-tetraazol-5-yl)propyl]pyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
4-(2-Chlorophenyl)-9-hydroxy-6-[3-(methylsulfanyl)propyl]pyrrolo[3,4- c]carbazole-l ,3(2H,6H)-dione;
4-(2-Chlorophenyl)-9-hydroxy-6-isopropylpyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
4-(2-Chlorophenyl)-9-hydroxy-6-methylpyrrolo[3,4-c]carbazole-l,3(2H,6H)- dione;
4-(2-Chlorophenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(3-Amino-2-chlorophenyl)-9-hydroxypyrrolot3,4-c]carbazole-l,3(2H,6H)- dione;
4-(3-Aminophenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(3-Chlorophenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(4-(2-Chlorophenyl)-9-hydroxy-l,3-dioxo-2,3-dihydropyrrolo[3,4- c]carbazol-6( 1 H)-yl)butanenitrile (241 ); 4-(4-(2-Chlorophenyl)-9-hydroxy-l,3-dioxo-2,3-dihydropyrrolo[3,4- c]carbazol-6(lH)-yl)butanoic acid;
4-(4-Amino-2-bromophenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)- dione);
4-(4-Amino-2-chlorophenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)- dione;
6-(2-Chloroethyl)-4-(2-chlorophenyl)-9-hydroxypyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
6-(3-Bromopropyl)-4-(2,6-dichlorophenyl)-9-hydroxypyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione (233);
6-(3-Bromopropyl)-4-(2-chloro-6-methoxyphenyl)-9-hydroxypyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
6-(3-Bromopropyl)-4-(2-chlorophenyl)-9-hydroxypyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
6-Acetyl-4-(2-chlorophenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)- dione;
6-Butyl-4-(2-chlorophenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)- dione;
9-Hydroxy-4-(2-hydroxyphenyl)pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
9-Hydroxy-4-(2-iodophenyl)pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
9-Hydroxy-4-(2-methoxyphenyl)pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
9-Hydroxy-4-(2-nitrophenyl)pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
9-Hydroxy-4-(3-thienyl)pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
9-Hydroxy-4-(4-hydroxyphenyl)pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
9-Hydroxy-4-[2-(methylsulfanyl)phenyl]pyrrolo[3,4-c]carbazole-l,3(2H,6H)- dione;
9-Hydroxy-6-(2-hydroxyethyl)-4-(2-methoxyphenyl)pyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione; 9-Hydroxy-6-(2-hydroxyethyl)-4-phenylpyrrolo[3,4-c]carbazole-l,3(2H,6H)- dione;
9-Hydroxy-6-(3-hydroxypropyl)-4-(2-methoxyphenyl)pyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione (107);
9-Methoxy-4-(2-methoxy-5-nitrophenyl)-4,5,6,10c-tetrahydropyrrolo[3,4- c]carbazole-l,3(2H,3aH)-dione;
Methyl 3-(4-(2-chlorophenyl)-9-hydroxy-l,3-dioxo-2,3-dihydropyrrolo[3,4- c]carbazol-6(lH)-yl)propanoate (264);
N-[3-(4-(2-Chlorophenyl)-9-hydroxy-l,3-dioxo-2,3-dihydropyrrolo[3,4- c]carbazol-6(lH)-yl)propanoyl]-2-(dimethylamino)ethanesulfonamide;
N-[3-(4-(2-Chlorophenyl)-9-hydroxy-l,3-dioxo-2,3-dihydropyrrolo[3,4- c]carbazol-6(lH)-yl)propanoyl]benzenesulfonamide;
N-[3-(4-(2-Chlorophenyl)-9-hydroxy-l,3-dioxo-2,3-dihydropyrrolo[3,4- c]carbazol-6(lH)-yl)propanoyl]methanesulfonamide;
N-[4-(4-(2-Chlorophenyl)-9-hydroxy-l,3-dioxo-2,3-dihydropyrrolo[3,4- c]carbazol-6(lH)-yl)butanoyl]benzenesulfonamide
N-[4-(4-(2-Chlorophenyl)-9-hydroxy-l,3-dioxo-2,3-dihydropyrrolo[3,4- c]carbazol-6(lH)-yl)butanoyl]methanesulfonamide;
2-(9-Hydroxy-l,3-dioxo-l,2,3,6-tetrahydropyrrolo[3,4-c]carbazol-4- yl)benzonitrile;
3-(9-Hydroxy-l,3-dioxo-l,2,3,6-tetrahydro-pyrrolo[3,4-c]carbazol-4-yl)- benzonitrile;
4-(2,3-Dichlorophenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione (18); 4-(2-Chloro-5-hydroxyphenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)- dione;
4-(2,6-Dibromophenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2,6-Dichloro-3-hydroxyphenyl)-9-hydroxypyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
4-(2,6-Dichloro-4-hydroxyphenyl)-9-hydroxypyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione; 4-(2,6-Dichlorophenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2,6-Dimethoxyphenyl)-9-hydroxypyrrolo[3 ,4-c] carbazole- 1 ,3 (2H,6H)- dione;
4-(2,6-Dimethylphenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-Acetyl-phenyl)-9-hydroxy-6H-pyrrolo[3,4-c]carbazole-l,3-dione.
4-(2-Aminophenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-Bromo-4-nitrophenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)- dione;
4-(2-Bromophenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-Chloro-3-hydroxyphenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)- dione; -
4-(2-Chloro-4-hydroxyphenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)- dione;
4-(2-Chloro-4-nitrophenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)- dione;
4-(2-Chloro-6-hydroxyphenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)- dione;
4-(2-Chloro-6-methoxyphenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)- dione;
4-(2-Ethoxyphenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-Ethylphenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(3-Amino-2-chlorophenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)- dione;
4-(3-Aminophenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(3-Chlorophenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione; 4-(4-Amino-2-bromophenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)- dione);
4-(4-Amino-2-chlorophenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l ,3(2H,6H)- dione;
4-(4-Aminophenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(4-Chlorophenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(5-Amino-2-methoxyphenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)- dione;
4-[l,lø-Biphenyl]-2-yl-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-Furan-2-yl-9-hydroxy-6H-pyrrolo[3,4-c]carbazole-l,3-dione;
9-Hydroxy-4-(2-hydroxyphenyl)pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
9-Hydroxy-4-(2-iodophenyl)pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
9-Hydroxy-4-(2-methoxyphenyl)pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
9-Hydroxy-4-(2-methylsulfanyl-phenyl)-6H-pyrrolo[3,4-c]carbazole-l,3- dione;
9-Hydroxy-4-(2-nitrophenyl)pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
9-Hydroxy-4-(2-thienyl)pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
9-Hydroxy-4-(2-trifluoromethylphenyl)pyrrolo[3,4-c]carbazole-l,3(2H,6H)- dione;
9-Hydroxy-4-(3-hydroxy-4-methoxyphenyl)pyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
9-Hydroxy-4-(3-hydroxymethyl-phenyl)-6H-pyrrolo[3,4-c]carbazole-l,3- dione;
9-Hydroxy-4-(3-hydroxy-phenyl)-6H-pyrrolo[3,4-c]carbazole-l,3-dione; and
9-Hydroxy-4-(3-hydroxyphenyl)pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione; 9-Hydroxy-4-(3-nitrophenyl)pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
9-Hydroxy-4-(3-thienyl)pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
9-Hydroxy-4-(3-trifluoromethoxy-phenyl)-6H-pyrrolo[3,4-c]carbazole-l,3- dione;
9-Hydroxy-4-(4-hydroxymethylphenyl)pyrrolo[3,4-c]carbazole-l,3(2H,6H)- dione;
9-Hydroxy-4-(4-hydroxyphenyl)pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
9-Hydroxy-4-(4-trifluoromethoxy-phenyl)-6H-pyrrolo[3,4-c]carbazole-l,3- dione;
9-Hydroxy-4-[2-(hydroxymethyl)phenyl]pyrrolo[3,4-c]carbazole-l,3(2H,6H)- dione;
9-Hydroxy-4-[2-(methylsulfanyl)phenyl]pyrrolo[3,4-c]carbazole-l,3(2H,6H)- dione;
9-Hydroxy-4-[2-(methylsulfinyl)phenyl]pyrrolo[3,4-cJcarbazole-l,3(2H,6H)- dione;
9-Hydroxy-4-m-tolyl-6H-pyrrolo[3,4-c]carbazole-l,3-dione;
9-Hydroxy-4-o-tolyl-6H-pyrrolo[3,4-c]carbazole-l,3-dione;
4-(2-Chlorophenyl)-7-( 1 ,2-dihydroxyethyl)-9-hydroxy- lH-[ 1 ]benzofuro[3,2- e]isoindole-l,3(2H)-dione;
4-(2-Chlorophenyl)-7-ethyl-9-hydroxy- 1 H-[ 1 ]benzofuro[3,2-e]isoindole- l,3(2H)-dione;
4-(2-Chlorophenyl)-8-[3-(dimethylamino)propoxy]-9-hydroxy-lH- [l]benzofuro[3,2-e]isoindole-l,3(2H)-dione; and
4-(2-Chlorophenyl)-8-ethyl-9-hydroxy-lH-[l]benzofuro[3,2-e]isoindole- l,3(2H)-dione;
4-(2-Chlorophenyl)-9-hydroxy-lH-[l]benzofuro[3,2-e]isoindole-l,3(2H)- dione;
4-(2-Chlorophenyl)-9-hydroxy-8-(4-hydroxybutyl)-lH-[l]benzofuro[3,2- e]isoindole-l,3(2H)-dione;
9-Hydroxy-4-phenyl-lH-[l]benzofuro[3,2-e]isoindole-l,3(2H)-dione;.
4-(2-chlorophenyl)-9-hydroxy-6-propylpyrrolo[3,4-c]carbazole-l,3(2H,6H)- dione; l,3-Dioxo-4-phenyl-l,2,3,6-tetrahydropyrrolo[3,4-c]carbazol-9-yl dihydrogen phosphate;
2-(4-(2-chlorophenyl)-9-hydroxy-l,3-dioxo-2,3-dihydropyrrolo[3,4- c]carbazol-6(lH)-yl)acetamide;
2-{ [3-(4-(2-Chlorophenyl)-9-hydroxy-l,3-dioxo-2,3-dihydropyrrolo[3,4- c]carbazol-6(lH)-yl)propyl]amino}benzoic acid;
3-(4-(2,6-Dichlorophenyl)-9-hydroxy-l,3-dioxo-2,3-dihydropyrrolo[3,4- c]carbazol-6(lH)-yl)propanoic acid;
3-(4-(2-chlorophenyl)-9-(formylamino)-l,3-dioxo-2,3-dihydropyrrolo[3,4- c]carbazol-6(lH)-yl)-N-[2-(dimethylamino)ethyl]propanamide;
3-(4-(2-Chlorophenyl)-9-hydroxy-l,3-dioxo-2,3-dihydropyrrolo[3,4- c]carbazol-6(lH)-yl)-N-(2,2,6,6-tetramethyl-4-piperidinyl);
3-(4-(2-Chlorophenyl)-9-hydroxy-l,3-dioxo-2,3-dihydropyrrolo[3,4- c]carbazol-6(lH)-yl)-N-[2-(lH-imidazol-5-yl)ethyl]propanamide;
3-(4-(2-Chlorophenyl)-9-hydroxy-l,3-dioxo-2,3-dihydropyrrolo[3,4- c]carbazol-6(lH)-yl)-N-[2-(dimethylamino)ethyl]-N-methylpropanamide;
3-(9-amino-4-(2-chlorophenyl)-l,3-dioxo-2,3-dihydropyrrolo[3,4-c]carbazol- 6(lH)-yl)-N-[2-(dimethylamino)ethyl]propanamide;
3,9-dihydroxy-4-phenyl-3,6-dihydropyrrolo[3,4-c]carbazol-l(2H)-one;
3-[4-(2-Chloro-phenyl)-9-nitro-l,3-dioxo-2,3-dihydro-lH-pyrrolo[3,4- c]carbazol-6-yl]-propionic acid; 3-{ [3-(4-(2-Chlorophenyl)-9-hydroxy-l,3-dioxo-2,3-dihydropyrrolo[3,4- c]carbazol-6(lH)-yl)propyl]amino}benzoic acid;
4-(2,6-dichlorophenyl)-6-[3-(dimethylamino)propyl]-9-hydroxypyrrolo[3,4- cjcarbazole- 1 ,3(2H,6H)-dione;
4-(2,6-Dichlorophenyl)-6-{3-[(cis)-3,5-dimethylpiperazinyl]propyl}-9- hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2,6-dichlorophenyl)-8-[3-(dimethylamino)propoxy]-9-hydroxypyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
4-(2,6-dichlorophenyl)-8-[4-(dimethylamino)butyl]-9-hydroxy-6- methylpyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2,6-dichlorophenyl)-9-hydroxy-6-[2-(4-methyl-l- piperazinyl)ethyl]pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2,6-dichlorophenyl)-9-hydroxy-6-[2-(4-morpholinyl)ethyl]pyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
4-(2,6-dichlorophenyl)-9-hydroxy-6-[3-( 1 H-imidazol- 1 - yl)propyl]pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2,6-dichlorophenyl)-9-hydroxy-6-[3-(4-methyl-l- piperazinyl)propyl]pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2,6-dichlorophenyl)-9-hydroxy-6-[3-(4-morpholinyl)propyl]pyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
4-(2,6-dichlorophenyl)-9-hydroxy-6-[3-(dimethylamino)ethyl]pyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
4-(2,6-dichlorophenyl)-9-hydroxy-6-[3-(methylamino)propyl]pyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
4-(2,6-dichlorophenyl)-9-hydroxy-6-methyl-8-[3- (methylamino)propoxy]pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2,6-dichlorophenyl)-9-hydroxy-8-[4-(methylamino)butyl]pyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione; 4-(2-bromophenyl)-8-[3-(dimethylamino)propoxy]-9-hydroxy-6- methy lpyrrolo[3 ,4-c]carbazole- 1 ,3 (2H,6H)-dione;
4-(2-bromophenyl)-8-[3-(dimethylamino)propoxy]-9-hydroxypyrrolo[3,4- cJcarbazole-l,3(2H,6H)-dione;
4-(2-bromophenyl)-8-[4-(dimethylamino)butyl]-9-hydroxypyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
4-(2-bromophenyl)-9-hydroxy-6-methyl-8-[3- (methylamino)propoxy]pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-bromophenyl)-9-hydroxy-8-[3-(methylamino)propoxy]pyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
4-(2-bromophenyl)-9-hydroxy-8-[4-(methylamino)butyl]pyrrolo[3,4- c] carbazole- 1 ,3 (2H,6H)-di one;
4-(2-chloro-3-hydroxyphenyl)-8-[4-(methylamino)butyl]pyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
4-(2-chloro-3-hydroxyphenyl)-9-fluoro-6-(3-hydroxypropyl)-8-[4- (methylamino)butyl]pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-chloro-3-hydroxyphenyl)-9-fluoro-8-[3- (methylamino)propoxy]pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-chloro-3-hydroxyphenyl)-9-fluoro-8-[4-(methylamino)butyl]pyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
4-(2-Chloro-6-methoxyphenyl)-6-{3-[cis-3,5-dimethylpiperazinyl]propyl}-9- hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-chloro-6-methoxyphenyl)-8-[3-(dimethylamino)propoxy]-9-hydroxy-6- methylpyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-chloro-6-methoxyphenyl)-8-[3-(dimethylamino)propoxy]-9- hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-chloro-6-methoxyphenyl)-8-[4-(dimethylamino)butyl]-9-hydroxy-6- methylpyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione; 4-(2-chloro-6-methoxyphenyl)-8-[4-(dimethylamino)butyl]-9- hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-Chloro-6-methoxyphenyl)-9-hydroxy-6-[2-(4- morpholinyl)ethyl]pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-chloro-6-methoxyphenyl)-9-hydroxy-6-methyl-8-[3- (methylamino)propoxy]pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-chloro-6-methoxyphenyl)-9-hydroxy-8-[3- (methylamino)propoxy]pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-chloro-6-methoxyphenyl)-9-hydroxy-8-[4- (methylamino)butyl]pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-Chlorophenyl)-l,9-dihydroxy-6-(3-hydroxypropyl)-l,6- dihydropyrrolo[3,4-c]carbazol-3(2H)-one;
4-(2-chlorophenyl)-3,9-dihydroxy-6-(3-hydroxypropyl)-3,6- dihydropyrrolo[3,4-c]carbazol-l(2H)-one; '
4-(2-chlorophenyl)-6-(3-hydroxypropyl)-l,3-dioxo- 1,2,3,6- tetrahydropyrrolo[3,4-c]carbazol-9-ylformamide;
4-(2-Chloro-phenyl)-6-(3-hydroxy-propyl)-8-(3-pyrrolidin-l-yl-propoxy)-6H- pyrrolo[3,4-c]carbazole-l,3-dione;
4-(2-chlorophenyl)-6-(3-hydroxypropyl)-8-[3- (methylamino)propoxy]pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-Chloro-phenyl)-6-(3-hydroxy-propyl)-8-methoxy-6H-pyrrolo[3,4- c]carbazole-l,3-dione;
4-(2-Chloro-phenyl)-6-(3-hydroxy-propyl)-8-piperidin-3-yl-6H-pyrrolo[3,4- c]carbazole-l,3-dione;
4-(2-Chlorophenyl)-6-(3-hydroxypropyl)-9-methoxypyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
4-(2-Chlorophenyl)-6-[3-(cis-3,5-dimethyl-l-piperazinyl)-2-hydroxypropyl]- 9 hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione; 4-(2-Chlorophenyl)-6-[3-(dimethylamino)-2-hydroxypropyl]-9- hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-chlorophenyl)-6-[3-(dimethylamino)propyl]-9-hydroxypyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
4-(2-Chlorophenyl)-6-{3-[(cis)-3,5-dimethylpiperazinyI]propyl}-9- hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-Chlorophenyl)-6-{3-[cis-3,5-dimethylpiperazinyl]-3-oxopropyl}-9- methoxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-chlorophenyl)-6-cyclopentyl-9-hydroxypyrrolo[3,4-c]carbazole- lr3(2H,6H)-dione;
4-(2-Chloro-phenyl)-6-methyl-8-(4-methylamino-butyl)-6H-pyrrolo[3,4- c]carbazole-l,3-dione;
4-(2-Chloro-phenyl)-6-methyl-8-(4-pyrrolidin-l-yl-butyl)-6H-pyrrolo[3,4- c]carbazole-l,3-dione;
4-(2-chlorophenyl)-6-methyl-8-[(lE)-4-(methylamino)-l-butenyl]pyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
4-(2-chlorophenyl)-6-methyl-8-[3-(methylamino)propoxy]-l,3-dioxo-l, 2,3,6- tetrahydropyrrolo[3,4-c]carbazol-9-ylformamide;
4-(2-Chlorophenyl)-6-methyl-8-[3-(methylamino)propoxy]pyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
4-(2-chlorophenyl)-6-methyl-8-[4-(methylamino)butoxy]pyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
4-(2-chlorophenyl)-6-methyl-8-[4-(methylamino)butyl]pyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
4-(2-Chloro-phenyl)-6-methyl-8-piperidin-3-yl-6H-pyrrolo[3,4-c]carbazole- 1,3-dione;
4-(2-Chloro-phenyl)-6-methyl-8-piperidin-4-yl-6H-pyrrolo[3,4-c]carbazole- 1,3-dione; 4-(2-Chloro-phenyl)-6-methyl-8-piperidin-4-yl-6H-pyrrolo[3,4-c]carbazole- 1,3-dione;
4-(2-chlorophenyl)-6-methyl-9-{ [3-(l-piperidinyl)propyl]amino}pyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
4-(2-chlorophenyl)-6-methyl-9-{ [4-(methylamino)butyl]amino}pyrrolo[3,4- c]carbazole-l ,3(2H,6H)-dione;
4-(2-Chlorophenyl)-8-(l,2-dihydroxyethyl)-6-methylpyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
4-(2-Chlorophenyl)-8-(2,3-dihydroxypropoxy)-6-methylpyιτolo[3,4- c]carbazole-l ,3(2H,6H)-dione;
4-(2-Chlorophenyl)-8-(2-hydroxyethoxy)-6-methylpyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
4-(2-Chlorophenyl)-8-(2-hydroxyethyl)-6-methylpyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
4-(2-chlorophenyl)-8-(3,4-dihydroxybutoxy)-6-methylpyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
4-(2-Chloro-phenyl)-8-(3-diethylamino-propoxy)-9-hydroxy-6-(2-hydroxy- ethyl)-6H-pyrrolo[3,4-c]carbazole-l,3-dione;
4-(2-Chloro-phenyl)-8-(3-dimethylamino-propoxy)-6-(3-hydroxy-propyl)- 6H-pyrrolo[3,4-c]carbazole-l,3-dione;
4-(2-Chloro-phenyl)-8-(3-dimethylamino-propoxy)-9-fluoro-6-methyl-6H- pyrrolo[3,4-c]carbazole-l,3-dione;
4-(2-Chloro-phenyl)-8-(3-dimethylamino-propoxy)-9-hydroxy-6-(3-hydroxy- propyl)-6H-pyrrolo[3,4-c]carbazole-l,3-dione;
4-(2-chlorophenyl)-8-(3-hydroxypropoxy)-6-[3- (methylamino)propyl]pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-Chlorophenyl)-8-(3-hydroxypropoxy)-6-methylpyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione; 4-(2-Chlorophenyl)-8-(3-hydroxypropoxy)-9-methoxy-6-methylpyrrolo[3,4- c]carbazole-l ,3(2H,6H)-dione;
4-(2-Chloro-phenyl)-8-(4-dimethylamino-3-hydroxy-butoxy)-6-methyl-6H- pyrrolo[3,4-c]carbazole-l,3-dione;
4-(2-Chloro-phenyl)-8-(4-dimethylamino-butyl)-6-methyl-6H-pyrrolo[3,4- cjcarbazole- 1 ,3-dione;
4-(2-chlorophenyl)-8-(4-hydroxybutoxy)-6-methylpyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
4-(2-chlorophenyl)-8-(4-hydroxybutyl)pyrrolo[3,4-c]carbazole-l,3(2H,6H)- dione;
4-(2-Chloro-phenyl)-8-(4-hydroxy-piperidin-3-yl)-6-(3-hydroxy-propyl)- 2- aza-cyclopenta[c]fluorene-l,3-dione;
4-(2-Chloro-phenyl)-8-(4-hydroxy-piperidin-3-yl)-6-methyl-6H-pyrrolo[3,4- c]carbazole-l,3-dione;
4-(2-Chlorophenyl)-8-(hydroxymethyl)-6-methylpyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
4-(2-chlorophenyl)-8-[(lE)-4-(dimethylamino)-l-butenyl]-6- methylpyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-chlorophenyl)-8-[(lE)-4-(methylamino)-l-butenyl]pyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
4-(2-chlorophenyl)-8-[(lE)-4-hydroxy-l-butenyl]-6-methylpyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
4-(2-chlorophenyl)-8-[(lE)-4-hydroxy-l-butenyl]pyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
4-(2-Chlorophenyl)-8-[3-(cis-3,5-dimethyl-l-piperazinyl)propoxy]-6- methylpyrrolo[3,4-c]carbazole- 1 ,3(2H,6H)-dione;
4-(2-chlorophenyl)-8-[3-(dimethylamino)propoxy]-6-methyl-l,3-dioxo- l,2,3,6-tetrahydropyrrolo[3,4-c]carbazol-9-ylformamide; 4-(2-Chlorophenyl)-8-[3-(dimethylamino)propoxy]-6-methylpyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
4-(2-chlorophenyl)-8-[3-(dimethylamino)propoxy]-9-hydroxy-6-(2- hydroxyethyl)pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-chlorophenyl)-8-[3-(dimethylamino)propoxy]-9-hydroxy-6-(3- hydroxypropyl)pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-Chlorophenyl)-8-[3-(dimethylamino)propoxy]-9-hydroxy-6- methylpyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-chlorophenyl)-8-[3-(dimethylamino)propoxy]-9-hydroxypyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
4-(2-Chlorophenyl)-8-[3-(dimethylamino)propoxy]-9-methoxy-6- methylpyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-chlorophenyl)-8-[3-(methylamino)propoxy]-6-[3- (methylamino)propyl]pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-chlorophenyl)-8-[3-hydroxy-4-(l-pyrrolidinyl)butoxy]-6- methylpyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-chlorophenyl)-8-[3-hydroxy-4-(methylamino)butoxy]-6- methylpyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-chlorophenyl)-8-[4-(dimethylamino)-3-hydroxybutoxy]-6- methylρyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-chlorophenyl)-8-[4-(dimethylamino)butanoyl]-9-hydroxy-6- methylpyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-chlorophenyl)-8-[4-(dimethylamino)butyl]-6-methylpyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
4-(2-chlorophenyl)-8-[4-(dimethylamino)butyl]-9-hydroxy-6-(2- hydroxyethyl)pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-chlorophenyl)-8-[4-(dimethylamino)butyl]-9-hydroxy-6-(3- hydroxypropyl)pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione; 4-(2-chlorophenyl)-8-[4-(dimethylamino)butyl]-9-hydroxy-6-(3- hydroxypropyl)pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-chlorophenyl)-8-[4-(dimethylamino)butyl]-9-hydroxy-6- methylpyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-Chlorophenyl)-8-[4-(dimethylamino)butyl]-9-hydroxypyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
4-(2-chlorophenyl)-8-[4-(methylamino)butyl]pyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
4-(2-chlorophenyl)-8-{ [3-(dimethylamino)propyl]sulfinyl }-9-hydroxy-6- methylpyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione; and
4-(2-chlorophenyl)-8-{3-[(3,5-dimethylpiperazinyl]propoxy}-9-hydroxy-6- methylpyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-Chlorophenyl)-8-ethyl-9-hydroxy-6-methylpyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
4-(2-Chloro-phenyl)-8-hydroxy-6-(3-hydroxy-propyl)-6H-pyrrolo[3,4- cjcarbazole- 1 ,3-dione;
4-(2-Chlorophenyl)-8-hydroxy-6-methylpyrrolo[3,4-c]carbazole-l,3(2H,6H)- dione;
4-(2-chlorophenyl)-9-(hydroxymethyl)pyrrolo[3,4-c]carbazole-l,3(2H,6H)- dione;
4-(2-chlorophenyl)-9-(trifluoromethyl)pyrrolo[3,4-c]carbazole-l,3(2H.6H)- dione;
4-(2-chlorophenyl)-9-[l-hydroxy-2-(l-piperidinyl)ethyl]pyrroloL3,4- c]carbazole-l ,3(2H,6H)-dione;
4-(2-chlorophenyl)-9-[l-hydroxy-2-(4-moφholinyl)ethyl]pyrrolo[3.4- c]carbazole-l,3(2H,6H)-dione;
4-(2-chlorophenyl)-9-[l-hydroxy-2-(methylamino)ethyl]pyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione; 4-(2-chlorophenyl)-9-[2-(dimethylamino)-l-hydroxyethyl]pyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
4-(2-chlorophenyl)-9-{ [3-(l-piperidinyl)propyl]amino}pyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
4-(2-chlorophenyl)-9-{ [4-(dimethylamino)butyl]amino}-6-methylpyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
4-(2-chlorophenyl)-9-fluoro-6-(3-hydroxypropyl)-8-[4- (methylamino)butyl]pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-Chloro-phenyl)-9-fluoro-6-methyl-8-(3-methylamino-propoxy)-6H- pyrrolo[3,4-c]carbazole-l,3-dione;
4-(2-Chloro-phenyl)-9-fluoro-6-methyl-8-(3-pyrrolidin-l-yl-propoxy)-6H- pyrrolo[3,4-c]carbazole-l,3-dione;
4-(2-chlorophenyl)-9-fluoro-6-methyl-8-[3- (methylamino)propoxy]pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-chlorophenyl)-9-fluoro-6-methylpyrrolo[3,4-c]carbazole-l,3(2H,6H)- dione;
4-(2-chlorophenyl)-9-fluoro-8-(3-hydroxypropoxy)-6-[3- (methylamino)propyl]pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-Chloro-phenyl)-9-fluoro-8-(3-hydroxy-propoxy)-6-methyl-6H- pyrrolo[3,4-c]carbazole-l,3-dione;
4-(2-chlorophenyl)-9-fluoro-8-(3-hydroxypropoxy)-6-methylpyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
4-(2-chlorophenyl)-9-fluoro-8-(4-hydroxybutoxy)-6-methylpyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
4-(2-chlorophenyl)-9-fluoro-8-[3-(methylamino)propoxy]-6-[3- (methylamino)propyl]pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-Chloro-phenyl)-9-fluoro-8-hydroxy-6-methyl-6H-pyrrolo[3,4- c]carbazole-l,3-dione; 4-(2-Chloro-phenyl)-9-fluoro-8-methoxy-6-methyl-6H-pyrrolo[3,4- c]carbazole- 1 ,3-dione;
4-(2-chlorophenyl)-9-fluoropyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-chlorophenyl)-9-hydroxy-6-(2,2,2-trifluoroethyl)pyrro]o[3,4- c]carbazole-l,3(2H,6H)-dione;
4-(2-Chloro-phenyl)-9-hydroxy-6-(2-hydroxy-ethyl)-8-[3-(4-methyl- piperazin-l-yl)-propoxy]-6H-pyrrolo[3,4-c]carbazole-l,3-dione;
4-(2-Chlorophenyl)-9-hydroxy-6-(2-hydroxyethyl)-8-[3-(4- moφholinyl)propoxy]pyrrolo[3 4-c]carbazole-l,3(2H,6H)-dione;
4-(2-chlorophenyl)-9-hydroxy-6-(2-hydroxyethyl)-8-[3- (methylamino)propoxy]pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-chlorophenyl)-9-hydroxy-6-(2-hydroxyethyl)-8-[4- (methylamino)butyl]pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-chlorophenyl)-9-hydroxy-6-(2-phenylethyl)pyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
4-(2-chlorophenyl)-9-hydroxy-6-(2-propynyl)pyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
4-(2-Chlorophenyl)-9-hydroxy-6-(3-hydroxypropyl)-4,5,6,10c- tetrahydropyrrolo[3,4-c]carbazole-l,3(2H,3aH)-dione;
4-(2-Chloro-phenyl)-9-hydroxy-6-(3-hydroxy-propyl)-8-(3-pyrrolidin-l-yl- propoxy)-6H-pyrrolo[3,4-c]carbazole-l,3-dione;
4-(2-chlorophenyl)-9-hydroxy-6-(3-hydroxypropyl)-8-[3-(l- pyrrolidinyl)propoxy]pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-Chloro-phenyl)-9-hydroxy-6-(3-hydroxy-propyl)-8-[3-(4-methyl- piperazin-l-yl)-propoxy]-6H-pyrrolo[3,4-c]carbazole-l,3-dione;
4-(2-chlorophenyl)-9-hydroxy-6-(3-hydroxypropyl)-8-[3- (methylamino)propoxy]pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione; 4-(2-Chloro-phenyl)-9-hydroxy-6-(3-hydroxy-propyl)-8-piperidin-4-yl-6H- pyrrolo[3,4-c]carbazole-l,3-dione;
4-(2-chlorophenyl)-9-hydroxy-6-(4,4,4-trifluorobutyl)pyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
4-(2-chlorophenyl)-9-hydroxy-6-(4-pentenyl)pyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
4-(2-Chlorophenyl)-9-hydroxy-6,8-bis(2-hydroxyethyl)pyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
4-(2-chlorophenyl)-9-hydroxy-6-[2-(lH-imidazol-l-yl)ethyl]pyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
4-(2-chlorophenyl)-9-hydroxy-6-[2-(4-methyl-l- piperazinyl)ethyl]pyrrolo[3,4-c]carbazole- 1 ,3(2H,6H)-dione;
4-(2-chlorophenyl)-9-hydroxy-6-[2-(4-morpholinyl)ethyl]pyrrolo[3,4- - c]carbazole-T,3(2H-6H)-dione; —
4-(2-Chlorophenyl)-9-hydroxy-6-[2-(phenylsulfanyl)ethyl]pyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
4-(2-chlorophenyl)-9-hydroxy-6-[3-(4-methyl- 1 - piperazinyl)propyl]pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-chlorophenyl)-9-hydroxy-6-[3-(4-moφholinyl)propyl]pyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
4-(2-chlorophenyl)-9-hydroxy-6-[3-(dimethylamino)ethyl]pyrrolo[3,4- c]carbazole-l ,3(2H,6H)-dione;
4-(2-chlorophenyl)-9-hydroxy-6-[3-(methylamino)propyl]pyrrolo[3,4- c]carbazole-l ,3(2H,6H)-dione;
4-(2-chlorophenyl)-9-hydroxy-6-isobutylpyrrolo[3,4-c]carbazole-l,3(2H,6H)- dione;
4-(2-chlorophenyl)-9-hydroxy-6-isopentylpyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione; 4-(2-Chloro-phenyl)-9-hydroxy-6-methyl-8-(4-moφholin-4-yl-butyl)-6H- pyrrolo[3,4-c]carbazole-l,3-dione;
4-(2-Chlorophenyl)-9-hydroxy-6-methyl-8-[3-(l- pyrrolidinyl)propoxy]pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-Chlorophenyl)-9-hydroxy-6-methyl-8-[3-(4- moφholinyl)propoxy]pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-chlorophenyl)-9-hydroxy-6-methyl-8-[3- (methylamino)propoxy]pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-chlorophenyl)-9-hydroxy-6-methyl-8-[4- (methylamino)butanoyl]pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-chlorophenyl)-9-hydroxy-6-methyl-8-[4- (methylamino)butyl]pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-chlorophenyl)-9-hydroxy-6-methyl-8-{ [3- (methylamino)propyl]sulfonyl}pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione.
4-(2-chlorophenyl)-9-hydroxy-6-pentylpyrrolo[3,4-c]carbazole-l,3(2H,6H)- dione;
4-(2-Chloro-phenyl)-9-hydroxy-7-(l-hydroxy-2-methylamino-ethyl)-6-oxa-2- aza-cyclopenta[c]fluorene-l,3-dione;
4-(2-Chloro-phenyl)-9-hydroxy-7-(l-hydroxy-2-moφholin-4-yl-ethyl)-6-oxa- 2-aza-cyclopenta[c]fluorene-l,3-dione;
4-(2-Chloro-phenyl)-9-hydroxy-7-(l-hydroxy-2-piperazin-l-yl-ethyl)-6-oxa- 2-aza-cyclopenta[c]fluorene-l,3-dione;
4-(2-Chloro-phenyl)-9-hydroxy-7-[l-hydroxy-2-(2-methoxy-ethoxy)-ethyl] - 6-oxa-2-aza-cyclopenta[c]fluorene-l,3-dione;
4-(2-Chlorophenyl)-9-hydroxy-8-(2-hydroxyethyl)-6-methylpyrrolo[3,4- cjcarbazole- 1 ,3(2H,6H)-dione;
4-(2-Chloro-phenyl)-9-hydroxy-8-(4-hydroxy-butoxy)-6-methyl-6H- pyrrolo[3,4-c]carbazole-l,3-dione; 4-(2-Chloro-phenyl)-9-hydroxy-8-(4-hydroxy-butyl)-6-methyl-6H- pyrrolo[3,4-c]carbazole-l,3-dione;
4-(2-Chlorophenyl)-9-hydroxy-8-[3-(methylamino)propoxy]pyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
4-(2-Chlorophenyl)-9-hydroxy-8-[4-(l-pyrrolidinyl)butyl]-lH- [l]benzofuro[3,2-e]isoindole-l,3(2H)-dione;
4-(2-Chlorophenyl)-9-hydroxy-8-[4-(l-pyrrolidinyl)butyl]pyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
4-(2-Chlorophenyl)-9-hydroxy-8-[4-(methylamino)butyl]-6- propylpyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(2-Chlorophenyl)-9-hydroxy-8-[4-(methylamino)butyl]pyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
4-(2-methoxyphenyl)-6-methyl-l,3-dioxo-l,2,3,6-tetrahydropyrrolo[3,4- c]carbazol-9-ylformamide;
4-(2-methoxyphenyl)-6-methyl-9-(methylamino)pyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
4-(3-amino-2-chlorophenyl)-9-fluoro-6-(3-hydroxypropyl)-8-[4- (methylamino)butyl]pyrrolo[3,4-c]carbazole- 1 ,3(2H,6H)-dione;
4-(3-amino-2-chlorophenyl)-9-fluoro-8-[3- (methylamino)propoxy]pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
4-(3-amino-2-chlorophenyl)-9-fluoro-8-[4-(methylamino)butyl]pyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
4-(5-Amino-2-chlorophenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)- dione;
4-(5-Amino-2-methoxyphenyl)-9-hydroxypyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
4-{ [3-(4-(2-Chlorophenyl)-9-hydroxy-l,3-dioxo-2,3-dihydropyrrolo[3,4- c]carbazol-6(lH)-yl)propyl]amino}benzoic acid; 6-(2-aminoethyl)-4-(2-chlorophenyl)-9-hydroxypyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
6-(2-anilinoethyl)-4-(2,6-dichlorophenyl)-9-hydroxypyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
6-(2-anilinoethyl)-4-(2-chlorophenyl)-9-hydroxypyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
6-(3-aminopropyl)-9-hydroxy-4-phenylpyrrolo[3,4-c]carbazole-l,3(2H,6H)- dione;
6-(3-anilinopropyl)-4-(2,6-dichlorophenyl)-9-hydroxypyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
6-(3-anilinopropyl)-4-(2-chlorophenyl)-9-hydroxypyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
6-(3-Anilinopropyl)-9-hydroxy-4-phenylpyrrolo[3,4-c]carbazole-l,3(2H,6H)- ~dione; — —
6-(3-Bromo-propyl)-4-(2-chloro-phenyl)-8-(3-dimethylamino-propoxy)-9- hydroxy-6H-pyrrolo[3,4-c]carbazole-l,3-dione;
6-(3-butenyl)-4-(2-chlorophenyl)-9-hydroxypyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
6-[3-(Benzylamino)propyl]-9-hydroxy-4-phenylpyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
6-[3-(diethylamino)propyl]-9-hydroxy-4-phenylpyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
6-[6-(dimethylamino)hexyl]-9-hydroxy-4-phenylpyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
6-allyl-4-(2-chlorophenyl)-9-hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)- dione;
6-Benzyl-4-(2-chlorophenyl)-9- hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)- dione; 6-butyl-4-(2,6-dichlorophenyl)-8-[3-(dimethylamino)propoxy]-9- hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
6-butyl-4-(2,6-dichlorophenyl)-8-[4-(dimethylamino)butyl]-9- hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
6-butyl-4-(2,6-dichlorophenyl)-9-hydroxy-8-[3- (methylamino)propoxy]pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
6-butyl-4-(2,6-dichlorophenyl)-9-hydroxy-8-[4- (methylamino)butyl]pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
6-butyl-4-(2-chloro-6-methoxyphenyl)-8^[3-(dimethylamino)propoxy]-9- hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
6-butyl-4-(2-chloro-6-methoxyphenyl)-8-[4-(dimethylamino)butyl]-9- hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
6-butyl-4-(2-chloro-6-methoxyphenyl)-9-hydroxy-8-[3- ~(methylamino)propoxy]pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
6-butyl-4-(2-chlorophenyl)-8-[3-(dimethylamino)propoxy]-9- hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
6-butyl-4-(2-chlorophenyl)-8-[4-(dimethylamino)butyl]-9- hydroxypyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
6-butyl-4-(2-chlorophenyl)-9-hydroxy-8-[3- (methylamino)propoxy]pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
6-butyl-4-(2-chlorophenyl)-9-hydroxy-8-[4-(l-pyrrolidinyl)butyl]pyrrolo[3,4- c]carbazole-l ,3(2H,6H)-dione;
6-sec-butyl-4-(2-chIorophenyl)-9-hydroxypyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
7-(2-Amino- 1 -hydroxy-ethyl)-4-(2-chlorophenyl)-6-oxa-2-aza- cyclopenta[c]fluorene-l,3-dione;
7-(2- Amino- l-hydroxy-ethyl)-4-(2-chlorophenyl)-9-hydroxy-6-oxa-2-aza- [cjfluorene- 1 ,3-dione; 8-(l-Aminomethyl-2-hydroxy-ethyl)-4-(2-chlorophenyl)-6-methyl-6H- pyrrolo[3,4-c]carbazole-l,3-dione;
8-(2,3-Dihydroxypropyl)-9-hydroxy-6-methyl-4-phenylpyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
8-(4-aminobutyl)-4-(2-chlorophenyl)-9-hydroxy- 1 H-[ 1 ]benzofuro[3,2- e]isoindole-l,3(2H)-dione;
8-(4-aminobutyl)-4-(2-chlorophenyl)-9-hydroxy-6-methylpyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
-8-(4-aminobutyl)-4-(2-chlorophenyl)-9-hydroxypyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
8-[2-(Dimethylamino)ethyl]-9-hydroxy-6-methyl-4-phenylpyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
8-[3-(Dimethylamino)propoxy]-9-hydroxy-6-methyl-4-phenylpyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
8-[3-(Dimethylamino)propyl]-9-hydroxy-6-methyl-4-phenylpyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
8-{3-[Bis-(2-hydroxy-ethyl)-amino]-propoxy}-4-(2-chlorophenyl)-9- hydroxy-6-methyl-6H-pyrrolo[3,4-c]carbazole-l,3-dione;
8-Ethyl-9-hydroxy-6-methyl-4-phenylpyrrolo[3,4-c]carbazole-l,3(2H,6H)- dione;
8-Hydroxy-4-phenylcyclopenta[c]carbazole-l,3(2H,6H)-dione;
9-(2-amino-l-hydroxyethyl)-4-(2-chlorophenyl)pyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
9-Amino-4-(2-chlorophenyl)-6-(3-hydroxy-propyl)-6H-pyrrolo[3,4- c]carbazole-l,3-dione;
9-amino-4-(2-chlorophenyl)-6-(3-hydroxypropyl)pyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione; 9-Hydroxy-4-(2-hydroxyphenyl)-6-(3-hydroxypropyl)pyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
9-Hydroxy-4-(2-methoxyphenyl)-6-[2-(4-moφholinyl)ethyl]pyrτolo[3,4- c]carbazole-l,3(2H,6H)-dione;
9-Hydroxy-4,5-diphenylpyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
9-Hydroxy-4-phenyl-6-[3-(l-piperazinyl)propyl]pyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
9-hydroxy-4-phenyl-6-[3-(l-piperidinyl)propyl]pyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione; ~ " " "
9-hydroxy-4-phenyl-6-[3-(l-pyrrolidinyl)propyl]pyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
9-Hydroxy-5-methyl-4-phenylpyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
9-Hydroxy-6-(3-hydroxypropyl)-4-phenylpyrrolor3,4-clcarbazole- l,3(2H,6H)-dione;
9-Hydroxy-6-(6-hydroxyhexyl)-4-phenylpyrrolo[3,4-c]carbazole-l,3(2H,6H)- dione;
9-Hydroxy-6-[2-(lH-imidazol-l-yl)ethyl]-4-phenylpyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
9-Hydroxy-6-[2-(4-moφholinyl)ethyl]-4-phenylpyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
9-hydroxy-6-[2-(methylamino)ethyl]-4-phenylpyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
9-Hydroxy-6-[3-(lH-imidazol-l-yl)propyl]-4-phenylpyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
9-hydroxy-6-[3-(4-methyl-l-piperazinyl)propyl]-4-phenylpyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
9-Hydroxy-6-[3-(4-moφholinyl)propyl]-4-phenylpyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
9-Hydroxy-6-[3-(methylamino)propyl]-4-phenylpyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
9-hydroxy-6-[6-(4-methyl-l-piperazinyl)hexyl]-4-phenylpyrrolo[3,4- c]carbazole-l,3(2H,6H)-dione;
9-Hydroxy-6-methyl-4-phenylpyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione;
9-Hydroxy-8-(2-hydroxyethyl)-6-methyl-4-phenylpyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
9-Hydroxy-8-(3-hydroxypropyl)-6-methyl-4-phenylpyrrolo[3,4-c]carbazole- l,3(2H,6H)-dione;
N-[2-(Dimethylamino)ethyl]-3-(9-hydroxy-l,3-dioxo-4-phenyl-2,3- dihydropyrrolo[3,4-c]carbazol-6(lH)-yl)propanamide;
N-[2-(Dimethylamino)ethyl]-3-(9-hydroxy-4-(2-methoxyphenyl)-l,3-dioxo- 2,3-dihydropyrrolo[3,4-c]carbazol-6(lH)-yl)propanamide;
N-[4-(2-Chlorophenyl)-6-(3-hydroxy-propyl)-l,3-dioxo-l,2,3,6-tetrahydro- pyrrolo[3,4-c]carbazol-9-yl]-formamide; and
6-(2-aminoethyl)-9-hydroxy-4-phenylpyrrolo[3,4-c]carbazole-l,3(2H,6H)- dione.
15. The compounds:
4-(4-Amino-2-methoxy-phenyl)-9-hydroxy-6H-pyrrolo[3,4-c]carbazole-l,3-dione;
N-[4-(2-Chloro-phenyl)-l,3-dioxo-l,2,3,6-tetrahydro-pyrrolo[3,4-c]carbazol-9-yl]- acetamide;
N-[4-(2-Chl oro-phenyl)-6-methyl- 1 ,3-dioxo- 1 ,2,3 ,6-tetrahydro-pyrrolo[3 ,4- c]carbazol-9-yl]-4-dimethylamino-butyramide;
4-(2-Chloro-phenyl)-9-methylamino-6H-pyrrolo[3,4-c]carbazole-l,3-dione; 9-Hydroxy-4-(2-methoxy-4-nitro-phenyl)-6H-pyrrolo[3,4-c]carbazole-l,3-dione;
4-(2-Chloro-phenyl)-9-hydroxy-8-(4-moφholin-4-yl-butyl)-6H-pyrrolo[3,4- c]carbazole-l,3-dione; hydrochloride salt;
4-(2-Chloro-phenyl)-8-[3-(3,5-dimethyl-piperazin-l-yl)-propoxy]-9-hydroxy-6- methyl-6H-pyrrolo[3,4-c]carbazole-l,3-dione;
4-(2-Chloro-phenyl)-9-hydroxy-8-(3-hydroxy-propoxy)-6-methyl-6H-pyrrolo[3,4- c]carbazole-l,3-dione;
4-(2-Chloro-phenyl)-8-(4-hydroxy-butoxy)-6-methyl-6H-pyrrolo[3,4-c]carbazole-
1,3-dione;
4-(2-Chloro-phenyl)-8-(3,4-dihydroxy-butoxy)-6-methyl-6H-pyrrolo[3,4-c]carbazole-
1,3-dione;
4-(2-Chloro-phenyl)-6-methyl-8-(4-methylamino-butoxy)-6H-pyrrolo[3,4- c]carbazole-l,3-dione;
Acetic acid 4-(2-chloro-phenyl)-l,3-dioxo-l, 2,3, 6-tetrahydro-pyrrolo[3,4-c]carbazol-
9-yl ester;
4-(2-Chloro-phenyl)-9-hydroxy-8-(4-methylamino-butyl)-6H-pyrrolo[3,4- cjcarbazole- 1 ,3-dione;
2-(9-Hydroxy-l,3-dioxo-l,2,3,6-tetrahydro-pyrrolo[3,4-c]carbazol-4-yl)-benzamide;
4-(2-Chloro-phenyl)-6-methyl-8-piperidin-3-yl-6H-pyrrolo[3,4-c]carbazole-l,3-dione:
8-(3-Amino-pyrrolidine-l-carbonyl)-4-(2-chloro-phenyl)-6-methyl-6H-pyrrolo[3,4- c]carbazole-l,3-dione;hydrochloride salt;
4-(2-Chloro-phenyl)-9-pyridin-2-yl-6H-pyrrolo[3,4-c]carbazole-l,3-dione;
4-(2-Chloro-phenyl)-9-pyridin-4-yl-6H-pyrrolo[3,4-c]carbazole-l,3-dione;
4-(2-Chloro-phenyl)-8-(3-dimethylamino-propoxy)-9-hydroxy-6-(2-hydroxy-ethyl)- 6H-pyrrolo[3,4-c]carbazole-l,3-dione;
4-(2-Chloro-phenyl)-6-methyl-9-pyridin-2-yl-6H-pyrrolo[3,4-c]carbazole-l,3-dione; 4-(2-Chloro-phenyl)-9-hydroxy-6-(2-hydroxy-ethyl)-8-(3-pyrrolidin-l-yl-propoxy)- 6H-pyrrolo[3,4-c]carbazole-l,3-dione;
N-[4-(2-Chloro-phenyl)-l,3-dioxo-l,2,3,6-tetrahydro-pyrrolo[3,4-c]carbazol-9-yl]-3- piperidin-1-yl-propionamide;
4-(2-Chloro-phenyl)-9-hydroxy-6-methyl-8-(3-methylamino-propoxy)-6H- pyrrolo[3,4-c]carbazole-l,3-dione;
4-(2-Chloro-phenyl)-8-(4-hydroxy-but-l-enyl)-6-methyl-6H-pyrrolo[3,4-c]carbazole-
1,3-dione;
4-(2-Chloro-phenyl)-8-(4-hydroxy-butyl)-6-methyl-6H-pyrrolo[3,4-c]carbazole-l,3- dione;
4-(2-Chloro-phenyl)-8-(3-dimethylamino-propoxy)-9-hydroxy-6-(3-hydroxy-propyl)- 6H-pyrrolo[3,4-c]carbazole-l,3-dione;
6-(3-Bromo-propyl)-4-(2-chloro-phenyl)-8-(3-dimethylamino-propoxy)-9-hydroxy- 6H-pyrrolo[3,4-c]carbazole-l,3-dione;
4-(2-Chloro-phenyl)-8-(4-dimethylamino-3-hydroxy-butoxy)-6-methyl-6H- pyrrolo[3,4-c]carbazole-l,3-dione;hydrochloride salt;
4-(2-Chloro-phenyl)-8-hydroxy-6-(3-hydroxy-propyl)-6H-pyrrolo[3,4-c]carbazole- 1,3-dione;
4-(2-Chloro-phenyl)-8-(4-dimethylamino-butyl)-6-methyl-6H-pyrrolo[3,4- c]carbazole-l ,3-dione;
4-(2-Chloro-phenyl)-6-methyl-8-(4-pyrrolidin-l-yl-butyl)-6H-pyιτolo[3,4- cjcarbazole- 1 ,3-dione;
4-(2-Chloro-phenyl)-6-methyl-8-(4-methylamino-butyl)-6H-pyrrolo[3,4-c]carbazole- 1,3-dione;
4-(2-Chloro-phenyl)-9-hydroxy-6-(3-hydroxy-propyl)-8-(3-pyrrolidin-l-yl-propoxy)- 6H-pyrrolo[3,4-c]carbazole-l,3-dione;
4-(2-Chloro-phenyl)-8-[3-(3,5-dimethyl-piperazin-l-yl)-propoxy]-9-hydroxy-6-(3- hydroxy-propyl)-6H-pyrrolo[3,4-c]carbazole-l,3-dione; 4-(2-Chloro-phenyl)-9-hydroxy-8-(4-hydroxy-butyl)-6-methyl-6H-pyrrolo[3,4- c]carbazole-l,3-dione;
8-{ 3-[Bis-(2-hydroxy-ethyl)-amino]-propoxy }-4-(2-chloro-phenyl)-9-hydroxy-6- methyl-6H-pyrrolo[3,4-c]carbazole-l,3-dione;
4-(2-Chloro-phenyl)-9-hydroxy-6-(3-hydroxy-propyl)-8-[3-(4-methyl-piperazin-l- yl)-propoxy]-6H-pyrrolo[3,4-c]carbazole-l,3-dione;
4-(2-Chloro-phenyl)-6-(3-hydroxy-propyl)-9-nitro-6H-pyrrolo[3,4-c]carbazole-l,3- dione;
9-Amino-4-(2-chloro-phenyl)-6-(3-hydroxy-propyl)-6H-pyrrolo[3,4-c]carbazole-l,3- dione;
3-[4-(2-Chloro-phenyl)-9-nitro-l,3-dioxo-2,3-dihydro-lH-pyrrolo[3,4-c]carbazol-6- yl]-propionic acid;
4-(2-Chloro-phenyl)-9-hydroxy-8-(4-hydroxy-butoxy)-6-methyl-6H-pyrrolo[3,4- c]carbazole-l,3-dione;
4-(2-Chloro-phenyl)-6-(3-hydroxy-propyl)-8-methoxy-6H-pyrrolo[3,4-c]carbazole-
1,3-dione;
4-(2-Chloro-phenyl)-9-fluoro-8-methoxy-6-methyl-6H-pyrrolo[3,4-c]carbazole-l,3- dione;
4-(2-Chloro-phenyl)-9-fluoro-8-hydroxy-6-methyl-6H-pyrrolo[3,4-c]carbazole-l,3- dione;
4-(2-Chloro-phenyl)-8-(3-dimethylamino-propoxy)-6-(3-hydroxy-propyl)-6H- pyrrolo[3,4-c]carbazole-l,3-dione;
4-(2-Chloro-phenyl)-6-(3-hydroxy-propyl)-8-(3-pyrrolidin-l-yl-propoxy)-6H- pyrrolo[3,4-c]carbazole-l,3-dione;
4-(2-Chloro-phenyl)-9-fluoro-8-(3-hydroxy-propoxy)-6-methyl-6H-pyrτolo[3,4- c]carbazole-l,3-dione;
4-(2-Chloro-phenyl)-9-fluoro-6-methyl-8-(3-methyIamino-propoxy)-6H-pyrrolo[3,4- cjcarbazole- 1 ,3-dione;
4-(2-Chloro-phenyl)-9-hydroxy-6-methyl-8-(4-moφholin-4-yl-butyl)-6H- pyrrolo[3,4-c]carbazole-l,3-dione; 4-(2-Chloro-phenyl)-9-fluoro-6-methyl-8-(3-pyrrolidin-l-yl-propoxy)-6H- pyrrolo[3,4-c]carbazole-l,3-dione;
4-(2-Chloro-phenyl)-9-hydroxy-6-(2-hydroxy-ethyl)-8-[3-(4-methyl-piperazin-l-yl)- propoxy]-6H-pyrrolo[3,4-c]carbazole-l,3-dione;
4-(2-Chloro-phenyl)-8-(3-diethylamino-propoxy)-9-hydroxy-6-(2-hydroxy-ethyl)- 6H-pyrrolo[3,4-c]carbazole-l,3-dione;
4-(2-Chloro-phenyl)-8-(3-dimethylamino-propoxy)-9-fluoro-6-methyl-6H- pyrrolo[3,4-c]carbazole-l,3-dione;
N-[4-(2-Chloro-phenyl)-6-(3-hydroxy-propyl)-l-methylene-3-oxo-l,2,3,6-tetrahydro- pyrrolo[3,4-c]carbazol-9-yl]-formamide;
4-(2-Chloro-phenyl)-6-methyl-8-pyridin-4-yl-6H-pyrrolo[3,4-c]carbazole-l,3-dione;
4-(2-Chloro-phenyl)-9-hydroxy-6-(3-hydroxy-propyl)-8-piperidin-4-yl-6H- pyrrolo[3,4-c]carbazole-l,3-dione;
8-(3-(R)-Amino-pyrrolidine-l-carbonyl)-4-(2-chloro-phenyl)-6-methyl-6H- pyrrolo[3,4-c]carbazole-l,3-dione; hydrochloride salt;
8-(3-(S) Amino-pyrrolidine-l-carbonyl)-4-(2-chloro-phenyl)-6-methyl-6H- pyrrolo[3,4-c]carbazole-l,3-dione; hydrochloride salt;
4-(2-Chloro-phenyl)-6-methyl-8-piperidin-4-yl-6H-pyrrolo[3,4-c]carbazole-l,3- dione;
4-(2-Chloro-phenyl)-6-methyl-8-(piperazine-l-carbonyl)-6H-pyrrolo[3,4- c]carbazole-l,3-dione; hydrochloride salt;
4-(2-Chloro-phenyl)-8-(4-dimethylamino butyl)-9-hydroxy-6-methyl-6H- pyrrolo[3,4-c]carbazole-l,3-dione;
4-(2-Chloro-phenyl)-9-hydroxy-6-methyl-8-(4-pyιτolidin-l-yl-butyl)-6H-pyrrolo[3,4- c]carbazole- 1 ,3-dione;
4-(2-Chloro-phenyl)-9-hydroxy-6-methyl-8-(4-methylamino-butyl)-6H-pyrrolo[3,4- c]carbazole-l,3-dione;
[4-(2-Chloro-phenyl)-6-methyl-l,3-dioxo-l,2,3,6-tetrahydro-pyrrolo[3,4-c]carbazol-
9-yl]-urea; 4-(2-Chloro-phenyl)-9-hydroxy-8-(3-hydroxy-2-methyl-propoxy)-6-methyl-6H- pyrrolo[3,4-c]carbazole-l,3-dione;
4-(2-Chloro-phenyl)-8-(4-dimethylamino-butoxy)-9-hydroxy-6-methyl-6H- pyrrolo[3,4-c]carbazole-l,3-dione;
4-(2-Chloro-phenyl)-6-(3-methoxy-propyl)-8-piperidin-3-yl-6H-pyrrolo[3,4- c]carbazole-l,3-dione; hydrochloride salt;
4-(2-Chloro-phenyl)-6-(3-hydroxy-propyl)-8-(3-methylamino-propoxy)-6H- pyrrolo[3,4-c]carbazole-l,3-dione;
9-Bromo-4-(2-chloro-phenyl)-6-(3-hydroxy-propyl)-8-(3-methylamino-propoxy)-6H- pyrrolo[3,4-c]carbazole-l,3-dione;
4-[4-(2-Chloro-phenyl)-6-methyl-l,3-dioxo-l,2,3,6-tetrahydro-pyrrolo[3,4- c]carbazol-8-ylmethyl]-piperidine-l -carboxylic acid tert-butyl ester;
4-(2-Chloro-phenyl)-6-methyl-8-piperidin-4-ylmethyl-6H-pyrrolo[3,4-c]carbazole- 1,3-dione;
4-(2-Chloro-phenyl)-6-(3-methoxy-propyl)-8-piperidin-4-yl-6H-pyrrolo[3,4- c]carbazole-l ,3-dione;hydrochloride salt;
4-(2-Chloro-phenyl)-6-(3-hydroxy-propyl)-8-piperidin-3-yl-6H-pyrrolo[3,4- c]carbazole-l,3-dione; hydrochloride salt;
4-(2-Chloro-phenyl)-6-(3-hydroxy-propyl)-8-piperidin-4-yl-6H-pyrrolo[3,4- c]carbazole-l,3-dione; hydrochloride salt;
4-(2-Chloro-phenyl)-6-methyl-8-(perhy dro- 1 ,4-diazepine- 1 -carbonyl)-6H- pyrrolo[3,4-c]carbazole-l,3-dione; hydrochloride salt;
4-(2-Chloro-phenyl)-9-hydroxy-6-methyl-8-[4-(4-methyl-piperazin-l-yl)-butyl]-6H- pyrrolo[3,4-c]carbazole-l,3-dione;
4-(2-Chloro-phenyl)-9-hydroxy-6-methyl-8-(4-pyrrolidin-l-yl-butoxy)-6H- pyrrolo[3,4-c]carbazole-l,3-dione;
4-(2-Chloro-phenyl)-8-[4-(3,5-dimethyl-piperazin-l-yl)-butoxy]-9-hydroxy-6- methyl-6H-pyrrolo[3,4-c]carbazole-l,3-dione; 4-(2-Chloro-phenyl)-6-methyl-l,3-dioxo-l,2,3,6-tetrahydro-pyrrolo[3,4-c]carbazole- 8-carboxylic acid (2-dimethylamino-ethyl)-methyl-amide; compound with trifluoroacetic acid;
8-((S)-3-Amino-pyrrolidine-l-carbonyl)-4-(2-chloro-phenyl)-6-(2-hydroxy-ethyl)- 6H-pyrrolo[3,4-c]carbazole-l,3-dione;hydrobromide salt;
4-(2-Chloro-phenyl)-6-(2-hydroxy-ethyl)-8-piperidin-4-yl-6H-pyrrolo[3,4- c]carbazole-l,3-dione; hydrobromide salt;
9-Amino-4-(2-chloro-phenyl)-6-(2-hydroxy-ethyl)-6H-pyrrolo[3,4-c]carbazole-l,3- dione;
4-(2-Chloro-phenyl)-9-hydroxy-6-methyl-8-[3-(4-methyl-piperazin-l-yl)-propoxy]- 6H-pyrrolo[3,4-c]carbazole-l,3-dione;
3-[9-Amino-4-(2-chloro-phenyl)-l,3-dioxo-2,3-dihydro-lH-pyrrolo[3,4-c]carbazol-6- yl]-N-(2-dimethylamino-ethyl)-propionamide;
3-[4-(2-Chloro-phenyl)-9-formylamino-l,3-dioxo-2,3-dihydro-lH-pyrrolo[3,4- c]carbazol-6-yl]-N-(2-dimethylamino-ethyl)-propionamide;
9-Amino-4-(2-chloro-phenyl)-7-methoxy-6-methyl-6H-pyrrolo[3,4-c]carbazole-l,3- dione;
3-[4-(2-Chloro-phenyl)-9-hydroxy-l,3-dioxo-8-(3-pyrrolidin-l-yl-propoxy)-2,3- dihydro-lH-pyrrolo[3,4-c]carbazol-6-yl]-propionamide;
4-(2-Chloro-phenyl)-6-methyl-8-pyrrolidin-3-yl-6H-pyrrolo[3,4-c]carbazole-l,3- dione; trifluoroacetic acid salt;
4-(2-Chloro-phenyl)-6-methyl-l,3-dioxo-l,2,3,6-tetrahydro-pyrrolo[3,4-c]carbazole- 8-carboxylic acid
N-[4-(2-Chloro-phenyl)-7-methoxy-6-methyl-l,3-dioxo-l,2,3,6-tetrahydro- pyιτolo[3,4-c]carbazol-9-yl]-formamide;
4-(2-Chloro-phenyl)-7-hydroxy-6-methyl-9-nitro-6H-pyrrolo[3,4-c]carbazole-l,3- dione;
4-(2-Chloro-phenyl)-9-hydroxy-6-methyl-8-[2-(l-methyl-pyrrolidin-2-yl)-ethoxy]- 6H-pyrrolo[3,4-c]carbazole-l,3-dione; 4-(2-Chloro-phenyl)-9-hydroxy-6-methyl-8-[4-(4-methyl-piperazin-l-yl)-butoxy]- 6H-pyrrolo[3,4-c]carbazole-l,3-dione;
4-(2-Chloro-phenyl)-9-hydroxy-6-methyl-8-(4-moφholin-4-yl-butoxy)-6H- pyrrolo[3,4-c]carbazole-l,3-dione;
N-[4-(2-Chloro-phenyl)-6-(2-hydroxy-ethyl)-l,3-dioxo-l,2,3,6-tetrahydro- pyrrolo[3,4-c]carbazol-9-yl]-formamide;
4-(2-Fluoro-6-methoxy-phenyl)-9-hydroxy-6H-pyrrolo[3,4-c]carbazole-l,3-dione;
N-[4-(2-Chloro-phenyl)-6-(3-hydroxy-propyl)-8-methoxy-l,3-dioxo-l, 2,3,6- tetrahydro-pyrrolo[3,4-c]carbazol-9-yl]-acetamide;
N-[4-(2-Chloro-phenyl)-6-(3-hydroxy-propyl)-8-methoxy-l,3-dioxo-l, 2,3,6- tetrahydro-pyrrolo[3,4-c]carbazol-9-yl]-formamide;
N-[4-(2-Chloro-phenyl)-8-hydroxy-6-(3-hydroxy-propyl)-l,3-dioxo-l, 2,3,6- tetrahydro-pyrrolo[3,4-c]carbazol-9-yl]-formamide;
6-Butyl-4-(2-chloro-phenyl)-9-hydroxy-8-(3-pyrrolidin-l-yl-propoxy)-6H- pyrrolo[3,4-c]carbazole-l,3-dione;
8-(3-(S)-Amino-pyrrolidine-l-carbonyl)-4-(2-chloro-phenyl)-6-(3-hydroxy-propyl)- 6H-pyrrolo[3,4-c]carbazole-l,3-dione;
4-(2-Chloro-phenyl)-6-methyl-8-pyrrolidin-2-yl-6H-pyrrolo[3,4-c]carbazole-l,3- dione;
8-(4-Amino-butyl)-4-(2-chloro-phenyl)-6-methyl-6H-pyrrolo[3,4-c]carbazole-l,3- dione;
2-Dimethylamino-ethanesulfonic acid { 3-[9-amino-4-(2-chloro-phenyl)-l,3-dioxo- 2,3-dihydro-lH-pyrrolo[3,4-c]carbazol-6-yl]-propionyl} -amide;
2-Dimethylamino-ethanesulfonic acid { 3-[4-(2-chloro-phenyl)-9-formylamino-l,3- dioxo-2,3-dihydro-lH-pyrrolo[3,4-c]carbazol-6-yl]-propionyl}-amide;
4-(2-Chloro-phenyl)-9-hydroxy-6-methyl-8-(2-methyl-3-pyrrolidin-l-yl-propoxy)- 6H-pyrrolo[3,4-c]carbazole-l,3-dione; 4-(2-Chloro-phenyl)-9-hydroxy-8-(3-hydroxy-2,2-dimethyl-propoxy)-6-methyl-6H- pyrrolo[3,4-c]carbazole-l,3-dione;
4-(2-Chloro-phenyl)-9-methoxy-6-methyl-l,3-dioxo-l,2,3,6-tetrahydro-pyrrolo[3,4- c]carbazole-8-carboxylic acid;
4-(2-Chloro-phenyl)-9-methoxy-6-methyl-l,3-dioxo-l,2,3,6-tetrahydro-pyrrolo[3,4- c]carbazole-8-carboxylic acid amide;
4-(2-Chloro-phenyl)-9-methoxy-6-methyl-l,3-dioxo-l,2,3,6-tetrahydro-pyrrolo[3,4- c]carbazole-8-carboxylic acid (2-pyrrolidin-l-yl-ethyl)-amide;
4-(2-Chloro-phenyl)-9-hydroxy-6-methyl-l,3-dioxo-l,2,3,6-tetrahydro-pyrrolo[3,4- c]carbazole-8-carboxylic acid;
4-(2-Chloro-phenyl)-9-hydroxy-6-methyl-l,3-dioxo-l,2,3,6-tetrahydro-pyrrolo[3,4- c]carbazole-8-carboxylic acid amide;
4-(2-Chloro-phenyl)-9-hydroxy-6-methyl-l,3-dioxo-l,2,3,6-tetrahydro-pyrrolo[3,4- c]carbazole-8-carboxylic acid (2-pyrrolidin-l-yl-ethyl)-amide;
N-[4-(2-Chloro-phenyl)-7-hydroxy-6-methyl-l,3-dioxo-l,2,3,6-tetrahydro- pyrrolo[3,4-c]carbazol-9-yl]-formamide;
4-(2-Chloro-phenyl)-6 (2-hydroxy-ethyl)-l,3-dioxo-l,2,3,6-tetrahydro-pyrrolo[3,4- c]carbazole-8-carboxylic acid methyl ester;
4-(2-Chloro-phenyl)-6-methyl-l,3-dioxo-l,2,3,6-tetrahydro-pyrrolo[3,4-c]carbazole- 8-carboxylic acid (2-pyrrolidin-l-yl-ethyl)-amide;
3-[4-(2-Chloro-phenyl)-8-(3-dimethylamino-propoxy)-9-hydroxy-l,3-dioxo-2,3- dihydro-lH-pyrrolo[3,4-c]carbazol-6-yl]-propionamide;
4-(2-Chloro-phenyl)-8-[3-(ethyl-propyl-amino)-propylsulfanyl]-9-hydroxy-6-methyl- 6H-pyrrolo[3,4-c]carbazole-l,3-dione;
9-Hydroxy-6-methyl-4-phenyl-8-(3-pyrrolidin-l-yl-propoxy)-6H-pyrrolo[3,4- c]carbazole-l ,3-dione; 9-Amino-4-(2-chloro-phenyl)-6-methyl-7-vinyl-6H-pyrrolo[3,4-c]carbazole-l,3- dione;
4-(2-Chloro-phenyl)-8-(3-(R)dimethylamino-pyrrolidine-l-carbonyl)-6-(2-hydroxy- ethyl)-6H-pyrrolo[3,4-c]carbazole-l,3-dione;
N-[4-(2-Chloro-phenyl)-6-methyl-l,3-dioxo-7-vinyl-l,2,3,6-tetrahydro-pyrrolo[3,4- c]carbazol-9-yl]-formamide;
N-[4-(2-Chloro-phenyl)-7-(l,2-dihydroxy-ethyl)-6-methyl-l,3-dioxo-l,2,3,6- tetrahydro-pyrrolo[3,4-c]carbazol-9-yl]-formamide;
N-[4-(2-Chloro-phenyl)-9-hydroxy-6-methyl-l,3-dioxo-l,2,3,6-tetrahydro- pyrrolo[3,4-c]carbazole-8-carbonyl]-methanesulfonamide;
2-Dimethylamino-ethanesulfonic acid [4-(2-chloro-phenyl)-9-hydroxy-6-methyl- 1 ,3- dioxo-l,2,3,6-tetrahydro-pyrrolo[3,4-c]carbazole-8-carbonyl]-amide;
4-(2-Chloro-phenyl)-9-hydroxy-6-methyl-l,3-dioxo-l,2,3,6-tetrahydro-pyrrolo[3,4- c]carbazole-8-carboxylic acid dimethylamide;
4-(2-Chloro-phenyl)-9-hydroxy-8-(3-moφholin-4-yl-propoxy)-6H-pyrrolo[3,4- c]carbazole-l,3-dione;
4-(2-Chloro-phenyl)-9-hydroxy-6-methyl-8-(2-pyrrolidin-l-yl-ethoxy)-6H- pyrrolo[3,4-c]carbazole-l,3-dione;
8-(3-Amino-propoxy)-4-(2-chloro-phenyl)-9-hydroxy-6-methyl-6H-pyrrolo[3,4- c]carbazole-l,3-dione; hydrochloride salt;
4-(2-Chloro-phenyl)-9-hydroxy-6-methyl-8-(2-methyl-3-pyrrolidin-l-yl-propoxy)- 6H-pyrrolo[3,4-c]carbazole-l,3-dione;
4-(2-Chloro-phenyl)-6-methyl-l,3-dioxo-l,2,3,6-tetrahydro-pyrrolo[3,4-c]carbazole- 8-carboxylic acid (2-diethylamino-ethyl)-amide;
4-(2-Chloro-phenyl)-6-methyl-l,3-dioxo-l,2,3,6-tetrahydro-pyrrolo[3,4-c]carbazole- 8-carboxylic acid [3-(4-methyl-piperazin-l-yl)-propyl]-amide; 4-(2-Chloro-phenyl)-6-methyl-l,3-dioxo-l,2,3,6-tetrahydro-pyrrolo[3,4-c]carbazole- 8-carboxylic acid (3-diethylamino-2-hydroxy-propyl)-amide;
4-(2-Chloro-phenyl)-6-methyl-l,3-dioxo-l,2,3,6-tetrahydro-pyrrolo[3,4-c]carbazole- 8-carboxylic acid (3-pyrrolidin-l-yl-propyl)-amide;
4-(2-Chloro-phenyl)-8-(3-(S)-dimethylamino-pyrrolidine-l-carbonyl)-6-(2-hydroxy- ethyl)-6H-pyrrolo[3,4-c]carbazole-l,3-dione; Trifluro acetic acid salt;
4-(2-Chloro-phenyl)-6-(2-hydroxy-ethyl)-l,3-dioxo-l,2,3,6-tetrahydro-pyrrolo[3,4- c]carbazole-8-carboxylic acid (2-pyrrolidin-l-yl-ethyl)-amide;
4-(2-Chloro-phenyl)-6-(2-hydroxy-ethyl)-l,3-dioxo-l,2,3,6-tetrahydro-pyrrolo[3,4- c]carbazole-8-carboxylic acid amide;
4-(2-Chloro-phenyl)-8-(3-dimethylamino-propoxy)-9-hydroxy-6H-pyrrolo[3,4- c]carbazole-l,3-dione;
4-(2-Chloro-phenyl)-9-hydroxy-8-[3-(4-methyl-piperazin-l-yl)-propoxy]-6H- pyrrolo[3,4-c]carbazole-l,3-dione;
4-(2-Chloro-phenyl)-9-hydroxy-8-(3-pyrrolidin-l-yl-propoxy)-6H-pyrrolo[3,4- c]carbazole-l ,3-dione;
4-(2-Chloro-phenyl)-9-hydroxy-6-methyl-8-(2-moφholin-4-yl-ethoxy)-6H- pyrrolo[3,4-c]carbazole-l,3-dione;
4-(2-Chloro-phenyl)-9-hydroxy-6-methyl-8-[2-(4-methyl-piperazin-l-yl)-ethoxy]- 6H-pyrrolo[3,4-c]carbazole-l,3-dione;
N-[4-(2-Chloro-phenyl)-8-methoxy-6-methyl-l,3-dioxo-l,2,3,6-tetrahydro- pyrrolo[3,4-c]carbazol-9-yl]-formamide;
4-(2-Chloro-phenyl)-9-hydroxy-8-(3-hydroxy-propoxy)-6H-pyrrolo[3,4-c]carbazole- 1,3-dione;
4-(2-Chloro-phenyl)-9-hydroxy-6-methyl-l,3-dioxo-l,2,3,6-tetrahydro-pyrrolo[3,4- c]carbazole-8-carboxylic acid (2-dimethylamino-ethyl)-methyl-amide; 4-(2-Chloro-phenyl)-9-hydroxy-6-methyl-l,3-dioxo-l,2,3,6-tetrahydro-pyrrolo[3,4- c]carbazole-8-carboxylic acid (l-ethyl-pyrrolidin-2-ylmethyl)-amide;
4-(2-Chloro-phenyl)-9-hydroxy-6-methyl- 1 ,3-dioxo- 1 ,2,3,6-tetrahydro-pyrrolo[3,4- c]carbazole-8-carboxylic acid (3-diethylamino-propyl)-amide;
4-(2-Chloro-phenyl)-9-hydroxy-6-methyl-8-(lH-tetrazol-5-yl)-6H-pyrrolo[3,4- c]carbazole-l ,3-dione;
4-(2-Chloro-phenyl)-9-hydroxy-6-methyl-l,3-dioxo-l,2,3,6-tetrahydro-pyrrolo[3,4- c]carbazole-8-carboxylic acid [2-(l-methyl-pyrrolidin-2-yl)-ethyl]-amide;
4-(2-Chloro-phenyl)-9-hydroxy-6-(2-hydroxy-ethyl)-8-{3-[(2-hydroxy-ethyl)-methyl- amino]-propoxy}-6H-pyrrolo[3,4-c]carbazole-l,3-dione;
4-(2-Chloro-phenyl)-9-hydroxy-8-{3-[(2-hydroxy-ethyl)-methyl-amino]-propoxy}-6- methy]-6H-pyrrolo[3,4-c]carbazole-l,3-dione;
4-(2-Chloro-phenyl)-9-hydroxy-6-(2-hydroxy-ethyl)-8-(3-piperidin-l-yl-propoxy)- 6H-pyrrolo[3,4-c]carbazole-l,3-dione;
4-(2-Chloro-phenyl)-9-hydroxy-6-methyl-8-(3-piperidin-l-yl-propoxy)-6H- pyrrolo[3,4-c]carbazole-l,3-dione;
8-[3-(Benzyl-methyl-amino)-propoxy]-4-(2-chloro-phenyl)-9-hydroxy-6-(2-hydroxy- ethyl)-6H-pyrrolo[3,4-c]carbazole-l,3-dione;
8-[3-(Benzyl-methyl-amino)-propoxy]-4-(2-chloro-phenyl)-9-hydroxy-6-methyl-6H- pyrrolo[3,4-c]carbazole-l,3-dione;
4-(2-Chloro-phenyl)-9-hydroxy-6-(2-hydroxy-ethyl)-8-[3-(4-pyridin-2-yl-piperazin- l-yl)-propoxy]-6H-pyrrolo[3,4-c]carbazole-l,3-dione;
4-(2-Chloro-phenyl)-9-hydroxy-6-methyl-8-[3-(4-pyridin-2-yl-piperazin-l-yl)- propoxy]-6H-pyrrolo[3,4-c]carbazole-l,3-dione;
4-(2-Chloro-phenyl)-8-(3-dipentylamino-propoxy)-9-hydroxy-6-(2-hydroxy-ethyl)- 6H-pyrrolo[3,4-c]carbazole-l,3-dione; 4-(2-Chloro-phenyl)-8-(3-dipentylamino-propoxy)-9-hydroxy-6-methyl-6H- pyrrolo[3,4-c]carbazole-l,3-dione;
4-(2-Chloro-phenyl)-8-{ 3-[(2-dimethylamino-ethyl)-methyl-amino]-propoxy}-9- hydroxy-6-(2-hydroxy-ethyl)-6H-pyrrolo[3,4-c]carbazole-l,3-dione;
4-(2-Chloro-phenyl)-8-{ 3-[(2-dimethylamino-ethyl)-methyl-amino]-propoxy}-9- hydroxy-6-methyl-6H-pyrrolo[3,4-c]carbazole-l,3-dione;
4-(2-Chloro-phenyl)-9-hydroxy-6-(2-hydroxy-ethyl)-8-[3-(3-hydroxy-pyrrolidin-l- yl)-propoxy]-6H-pyrrolo[3,4-c]carbazole-l,3-dione;
4-(2-Chloro-phenyl)-9-hydroxy-8-[3-(3-hydroxy-pyrrolidin-l-yl)-propoxy]-6-methyl- 6H-pyrrolo[3,4-c]carbazole-l,3-dione; -
4-(2-Chloro-phenyl)-8-[3-(cyclohexyl-methyl-amino)-propoxy]-9-hydroxy-6-(2- hydroxy-ethyl)-6H-pyrrolo[3,4-c]carbazole-l,3-dione;
4-(2-Chloro-phenyl)-8-[3-(cyclohexyl-methyl-amino)-propoxy]-9-hydroxy-6-methyl-
6H-pyrrolo[3,4-c]carbazole-l,3-dione
4-(2-Chloro-phenyl)-9-hydroxy-6-(2-hydroxy-ethyl)-8-[3-(2-methyl-piperidin-l-yl)- propoxy]-6H-pyrrolo[3,4-c]carbazole-l,3-dione;
4-(2-Chloro-phenyl)-9-hydroxy-6-methyl-8-[3-(2-methyl-piperidin-l-yl)-propoxy]- 6H-pyrrolo[3,4-c]carbazole-l,3-dione;
4-(2-Chloro-phenyl)-9-hydroxy-6-(2-hydroxy-ethyl)-8-[3-(2-hydroxymethyl- piperidin- 1 -yl)-propoxy]-6H-pyrrolo[3,4-c]carbazole- 1 ,3-dione;
4-(2-Chloro-phenyl)-9-hydroxy-8-[3-(2-hydroxymethyl-piperidin-l-yl)-propoxy]-6- methyl-6H-pyrrolo[3,4-c]carbazole-l,3-dione;
4-(2-Chloro-phenyl)-9-hydroxy-6-(2-hydroxy-ethyl)-8-[3-(methyl-pyridin-3- ylmethyl-amino)-propoxy]-6H-pyrrolo[3,4-c]carbazole-l,3-dione;
4-(2-Chloro-phenyl)-9-hydroxy-6-methyl-8-[3-(methyl-pyridin-3-ylmethyl-amino)- propoxy]-6H-pyrrolo[3,4-c]carbazole-l,3-dione; 4-(2-Chloro-phenyl)-9-hydroxy-6-(2-hydroxy-ethyl)-8-[3-(2-hydroxymethyl- pyrrolidin-l-yl)-propoxy]-6H-pyrrolo[3,4-c]carbazole-l,3-dione;
4-(2-Chloro-phenyl)-9-hydroxy-8-[3-(2-hydroxymethyl-pyrrolidin-l-yl)-propoxy]-6- methyl-6H-pyrrolo[3,4-c]carbazole-l,3-dione;
4-(2-Chloro-phenyl)-8-[3-(ethyl-methyl-amino)-propoxy]-9-hydroxy-6-(2-hydroxy- ethyl)-6H-pyrrolo[3,4-c]carbazole-l,3-dione;
4-(2-Chloro-phenyl)-8-[3-(ethyl-methyl-amino)-propoxy]-9-hydroxy-6-methyl-6H- pyrrolo[3,4-c]carbazole-l,3-dione;
4-(2-Chloro-phenyl)-8-(3-dipropylamino-propoxy)-9-hydroxy-6-(2-hydroxy-ethyl)- 6H-pyrrolo[3,4-c]carbazole-l,3-dione;
4-(2-Chloro-phenyl)-8-(3-dipropylamino-propoxy)-9-hydroxy-6-methyl-6H-
- pyrrolo[3,4-c]carbazole-l,3-dione; _
4-(2-Chloro-phenyl)-8-(3-diethylamino-propoxy)-9-hydroxy-6-methyl-6H- pyrrolo[3,4-c]carbazole-l,3-dione;
8-{ 3-[Bis-(3-methyl-butyl)-amino]-propoxy}-4-(2-chloro-phenyl)-9-hydroxy-6- methyl-6H-pyrrolo[3,4-c]carbazole-l,3-dione;
4-(2-Chloro-phenyl)-8-[3-(2,6-dimethyl-piperidin-l-yl)-propoxy]-9-hydroxy-6-(2- hydroxy-ethyl)-6H-pyrrolo[3,4-c]carbazole- 1 ,3-dione;
4-(2-Chloro-phenyl)-8-[3-(2,6-dimethyl-piperidin-l-yl)-propoxy]-9-hydroxy-6- methyl-6H-pyrrolo[3,4-c]carbazole-l,3-dione;
9-Hydroxy-6-(2-hydroxy-ethyl)-4-phenyl-8-(3-pyrrolidin-l-yl-propoxy)-6H- pyrrolo[3,4-c]carbazole-l,3-dione;
4-(2-Chloro-phenyl)-8-(3-dicyclohexylamino-propoxy)-9-hydroxy-6-(2-hydroxy- ethyl)-6H-pyrrolo[3,4-c]carbazole-l,3-dione; trifluoro-acetic acid salt;
4-(2-Chloro-phenyl)-8-(3-diisopropylamino-propoxy)-9-hydroxy-6-(2-hydroxy- ethyl)-6H-pyrrolo[3,4-c]carbazole-l,3-dione; trifluoro-acetic acid salt;
9-Amino-4-(2-chloro-phenyl)-6-methyl-8-(3-pyrrolidin-l-yl-propoxy)-6H- pyrrolo[3,4-c]carbazole-l,3-dione; N-[4-(2-Chloro-phenyl)-6-methyl-l,3-dioxo-8-(3-pyrrolidin-l-yl-propoxy)-l, 2,3,6- tetrahydro-pyrrolo[3,4-c]carbazol-9-yl]-formamide;
4-(2-Chloro-phenyl)-9-hydroxy-6-methyl-l,3-dioxo-l,2,3,6-tetrahydro-pyrrolo[3,4- c]carbazole-8-sulfonic acid (2-pyrrolidin-l-yl-ethyl)-amide;
4-(2-Chloro-phenyl)-8-(3-cyclohexylamino-propoxy)-9-hydroxy-6-methyl-6H- pyrrolo[3,4-c]carbazole-l,3-dione;
4-(2-Chloro-phenyl)-9-hydroxy-6-methyl-8-(3-pyrrolidin-l-yl-propane-l-sulfinyl)- 6H-pyrrolo[3,4-c]carbazole-l,3-dione
4-(2-Chloro-phenyl)-9-hydroxy-6-methyl-8-(3-pyrrolidin- 1 -yl-propane- 1 -sulfonyl)- 6H-pyrrolo[3,4-c]carbazole-l,3-dione;
4-(2-Chloro-phenyl)-9-hydroxy-6-(2-hydroxy-ethyl)-8-(4-pyrrolidin-l-yl-butyl)-6H- pyrrolo[3,4-c]carbazole-l,3-dione;
4-(2-Chloro-phenyl)-9-hydroxy-6-(2-hydroxy-ethyl)-8-(4-moφholin-4-yl-butyl)-6H- pyrrolo[3,4-c]carbazole-l,3-dione;
4-(2-Chloro-phenyl)-9-hydroxy-6-(2-hydroxy-ethyl)-8-[4-(4-methyl-piperazin-l-yl)- butyl]-6H-pyrrolo[3,4-c]carbazole-l,3-dione;
4-(2-Chloro-phenyl)-8-[3-(ethyl-propyl-amino)-butoxy]-9-hydroxy-6-methyl-6H- pyrrolo[3,4-c]carbazole-l,3-dione;
4-(2-Chloro-phenyl)-9-hydroxy-6-methyl-8-(l-methyl-3-pyrrolidin-l-yl-propoxy)- 6H-pyrrolo[3,4-c]carbazole-l,3-dione;
9-Amino-4-(2-chloro-phenyl)-8-(4-hydroxy-butyl)-6-methyl-pyrrolo[3,4-c]carbazole- 1,3-dione;
N-[4-(2-Chloro-phenyl)-6-methyl-l,3-dioxo-8-(4-pyrrolidin-l-yl-butyl)-l,2,3,6- tetrahydro-pyrrolo[3,4-c]carbazol-9-yl]-formamide;
N- { 4-(2-Chloro-phenyl)-6-methyl-8-[4-(4-methyl-piperazin- 1 -yl)-butyl]- 1 ,3-dioxo- l,2,3,6-tetrahydro-pyrrolo[3,4-c]carbazol-9-yl} -formamide; N-[4-(2-Chloro-phenyl)-6-methyl-8-(4-moφholin-4-yl-butyl)- 1 ,3-dioxo- 1 ,2,3,6- tetrahydro-pyrrolo[3,4-c]carbazol-9-yl]-formamide;
9-Amino-4-(2-chloro-phenyl)-7-(4-hydroxy-butyl)-6-methyl-6H-pyrrolo[3,4- c]carbazole-l,3-dione;
N-[4-(2-Chloro-phenyl)-7-(4-hydroxy-butyl)-6-methyl-l,3-dioxo-l,2,3,6-tetrahydro- pyrrolo[3,4-c]carbazol-9-yl]-formamide;
N-[4-(2-Chloro-phenyl)-6-methyl-7-(4-moφholin-4-yl-butyl)-l,3-dioxo-l,2,3,6- tetrahydro-pyrrolo[3,4-c]carbazol-9-yl]-formamide;
N- { 4-(2-Chloro-phenyl)-6-methyl-7-[4-(4-methyl-piperazin- 1 -yl)-butyl]- 1 ,3-dioxo- 1 ,2,3,6-tetrahydro-pyrrolo[3,4-c]carbazol-9-yl } -formamide;
N-[4-(2-Chloro-phenyl)-7-(4-dimethylamino-butyl)-6-methyl-l,3-dioxo-l,2,3,6- tetrahydro-pyrrolo[3,4-c]carbazol-9-yl]-formamide;
N-[4-(2-Chloro-phenyl)-6-methyl- 1 ,3-dioxo-7-(4-pyrrolidin- 1 -yl-butyl)- 1 ,2,3,6- tetrahydro-pyrrolo[3,4-c]carbazol-9-yl]-formamide;
9-Amino-4-(2-chloro-phe.nyl)-6-methyl-7-(4-moφholin-4-yl-butyl)-6H-pyrrolo[3,4- c]carbazole-l,3-dione;
9-Amino-4-(2-chloro-phenyl)-6-methyl-7-[4-(4-methyl-piperazin-l-yl)-butyl]-6H- pyrrolo[3,4-c]carbazole-l,3-dione;
9-Amino-4-(2-chloro-phenyl)-7-(4-dimethylamino-butyl)-6-methyl-6H-pyrrolo[3,4- c]carbazole-l,3-dione; and
9-Amino-4-(2-chloro-phenyl)-6-methyl-7-(4-pyπ-olidin-l-yl-butyl)-6H-pyrrolo[3,4- c]carbazole-l ,3-dione.
PCT/IB2003/001417 2002-04-26 2003-04-15 Inhibitors of checkpoint kinases (wee1 and chk1) WO2003091255A1 (en)

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MXPA04010617A MXPA04010617A (en) 2002-04-26 2003-04-15 Inhibitors of checkpoint kinases (wee1 and chk1).
CA002483496A CA2483496A1 (en) 2002-04-26 2003-04-15 Inhibitors of checkpoint kinases (wee1 and chk1)
EP03720766A EP1501831A1 (en) 2002-04-26 2003-04-15 Inhibitors of checkpoint kinases (wee1 and chk1)
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EP2330105A1 (en) 2005-03-29 2011-06-08 ICOS Corporation Heteroaryl urea derivatives useful for inhibiting CHK1
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CN105622431A (en) * 2011-01-28 2016-06-01 肯塔基大学研究基金会 Stilbene analogs and methods of treating cancer
WO2016094897A1 (en) 2014-12-12 2016-06-16 The Jackson Laboratory Compositions and methods relating to the treatment of cancer, autoimmune disease, and neurodegenerative disease
WO2019165204A1 (en) 2018-02-23 2019-08-29 Newave Pharmaceutical Inc. 1,2-dihydro-3h-pyrazolo[3,4-d]pyrimidine-3-one compounds as inhibitors of wee-1 kinase
CN110872296A (en) * 2018-08-31 2020-03-10 上海弘翊生物科技有限公司 isoindoline-1H-pyrazolo [3,4-d ] pyrimidone compound, and preparation method and application thereof
CN110872296B (en) * 2018-08-31 2023-05-23 上海弘翊生物科技有限公司 dihydro-isoindole-1H-pyrazolo [3,4-d ] pyrimidinone compound, and preparation method and application thereof

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