EP1501831A1 - Inhibiteurs de checkpoint kinases (wee1 et chk1) - Google Patents

Inhibiteurs de checkpoint kinases (wee1 et chk1)

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Publication number
EP1501831A1
EP1501831A1 EP03720766A EP03720766A EP1501831A1 EP 1501831 A1 EP1501831 A1 EP 1501831A1 EP 03720766 A EP03720766 A EP 03720766A EP 03720766 A EP03720766 A EP 03720766A EP 1501831 A1 EP1501831 A1 EP 1501831A1
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EP
European Patent Office
Prior art keywords
dione
carbazole
hydroxy
pyrrolo
chloro
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
EP03720766A
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German (de)
English (en)
Inventor
Richard John Pfizer Global BOOTH
William Alexander Denny
Ellen Myra Pfizer Global DOBRUSIN
Alan John Pfizer Global KRAKER
Lorna Helen Pfizer Global MITCHELL
Jeffrey Bruce Smaill
Andrew Mark Thompson
Ho Huat Lee
Florence Oliver Joseph Mccarthy
Brian Desmond Palmer
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Warner Lambert Co LLC
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Warner Lambert Co LLC
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Filing date
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Publication of EP1501831A1 publication Critical patent/EP1501831A1/fr
Ceased legal-status Critical Current

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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

Cette invention porte sur des dérivés pyrrolocarbazole représentés par la formule (I) dans laquelle R1, R2, R7, R8, R9, X et Y sont tels que définis dans la description, lesquels dérivés inhibent de manière spécifique l'une des deux, voire les deux checkpoint kinases Wee1 et Chk1.
EP03720766A 2002-04-26 2003-04-15 Inhibiteurs de checkpoint kinases (wee1 et chk1) Ceased EP1501831A1 (fr)

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SI1869020T1 (sl) 2005-03-29 2011-02-28 Icos Corp Derivati heteroaril uree, ki so uporabni za inhibicijo chk1
AR060635A1 (es) 2006-04-27 2008-07-02 Banyu Pharma Co Ltd Derivados de 1,2-dihidro-3h-pirazolo[3,4-d]pirimidin-3-ona, composiciones farmaceuticas que los comprenden y su uso en el tratamiento del cancer
EP2073807A1 (fr) 2006-10-12 2009-07-01 Astex Therapeutics Limited Combinaisons pharmaceutiques
US8916552B2 (en) 2006-10-12 2014-12-23 Astex Therapeutics Limited Pharmaceutical combinations
WO2008133866A1 (fr) * 2007-04-25 2008-11-06 Merck & Co., Inc. Polymorphe de dérivé de dihydropyrazolopyrimidinone comme inhibiteur de la kinase weel
CA2703489A1 (fr) 2007-10-23 2009-04-30 Banyu Pharmaceutical Co., Ltd. Derive de dihydropyrazolopyrimidinone substitue par pyridone
JP2012051804A (ja) * 2008-12-26 2012-03-15 Kyoto Univ Ｅｇ５阻害剤
WO2010098367A1 (fr) * 2009-02-25 2010-09-02 Banyu Pharmaceutical Co.,Ltd. Dérivé de pyrimido-pyrimido-indazole
DK2477628T3 (en) 2009-09-15 2014-11-24 Merck Sharp & Dohme Preparation of crystalline hemihydratformer of dihydropyrazolopyrimidinon
JP2014512337A (ja) * 2011-01-28 2014-05-22 ユニバーシティ オブ ケンタッキー リサーチ ファウンデーション スチルベン類似体およびがんを処置する方法
JP6569908B2 (ja) * 2014-01-31 2019-09-04 カルナバイオサイエンス株式会社 抗がん剤組成物
TW201702218A (zh) 2014-12-12 2017-01-16 美國杰克森實驗室 關於治療癌症、自體免疫疾病及神經退化性疾病之組合物及方法
US11479555B2 (en) 2018-02-23 2022-10-25 Newave Pharmaceutical Inc. Substituted 1,2-dihydro-3H-pyrazolo[3,4-D]pyrimidin-3-ones as inhibitors of WEE-1 kinase
CN110872296B (zh) * 2018-08-31 2023-05-23 上海弘翊生物科技有限公司 一种二氢异吲哚-1H-吡唑并[3,4-d]嘧啶酮化合物、其制备方法和应用

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US5166204A (en) * 1989-11-01 1992-11-24 Toyama Chemical Co., Ltd. Isoindole derivatives and salts thereof and antitumor agent comprising the same
DE69505470T2 (de) * 1994-08-04 1999-05-12 F. Hoffmann-La Roche Ag, Basel Pyrrolocarbazol
US7122679B2 (en) * 2000-05-09 2006-10-17 Cephalon, Inc. Multicyclic compounds and the use thereof

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