WO2004058764A1 - Derives 4-phenyl-pyrimido [4,5-b]indoles - Google Patents

Derives 4-phenyl-pyrimido [4,5-b]indoles Download PDF

Info

Publication number
WO2004058764A1
WO2004058764A1 PCT/EP2003/014194 EP0314194W WO2004058764A1 WO 2004058764 A1 WO2004058764 A1 WO 2004058764A1 EP 0314194 W EP0314194 W EP 0314194W WO 2004058764 A1 WO2004058764 A1 WO 2004058764A1
Authority
WO
WIPO (PCT)
Prior art keywords
pyrimido
indole
phenyl
amino
alkyl
Prior art date
Application number
PCT/EP2003/014194
Other languages
English (en)
Inventor
Hiroki Sato
Tadashi Inoue
Tai-Wei Ly
Aiko Muramatsu
Makoto Shimazaki
Klaus Urbahns
Florian Gantner
Hiromi Okigami
Kevin B. Bacon
Hiroshi Komura
Nagahiro Yoshida
Naoki Tsuno
Original Assignee
Bayer Healthcare Ag
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Bayer Healthcare Ag filed Critical Bayer Healthcare Ag
Priority to AU2003300522A priority Critical patent/AU2003300522A1/en
Publication of WO2004058764A1 publication Critical patent/WO2004058764A1/fr

Links

Classifications

    • 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
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders

Definitions

  • the present invention relates to 4-phenyl-pyrimido[4,5-b]indoles which are useful as an active ingredient of pharmaceutical preparations.
  • the 4-phenyl-pyrimido[4,5-b]- indoles of the present invention have MKK7 and MKK4 [MAPK (mitogen activated protein kinase) kinase 7 and 4] inhibitory activity, and can be used for the prophylaxis and/or treatment of diseases associated with MKK7 and/or MKK4 activity.
  • MKK7 and MKK4 [MAPK (mitogen activated protein kinase) kinase 7 and 4] inhibitory activity
  • the 4-phenyl-pyrimido[4,5-b]indoles derivatives of the present invention are useful for treatment and prophylaxis of diseases as follows: inflammatory and immunoregulatory disorders, such as asthma, atopic dermatitis, rhinitis, allergic rhinitis, allergic diseases, COPD, septic shock, arthritis, joint diseases and myocardial injuries, as well as autoimmune pathologies such as rheumatoid arthritis, Grave's disease, and atherosclerosis as well as cancer.
  • inflammatory and immunoregulatory disorders such as asthma, atopic dermatitis, rhinitis, allergic rhinitis, allergic diseases, COPD, septic shock, arthritis, joint diseases and myocardial injuries, as well as autoimmune pathologies such as rheumatoid arthritis, Grave's disease, and atherosclerosis as well as cancer.
  • the compounds of the present invention are also useful for treatment of ischemia, myocardial injury, pulmonary hypertension, renal failure, Huntington's chorea and cardiac hypertrophy, as well as neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease and focal ischemia as well as cancer, since the diseases also relate to MKK7 and/or MKK4.
  • the mitogen-activated protein kinases are a family of serine/threonine kinases involved in the transduction of signals from the cell membrane to the nucleus in response to various types of stimuli such as lipopolysaccharide (LPS), tumor necrosis factor- ⁇ (TNF- ⁇ ), interleukins, CD40 and others. These kinases participate in a wide variety of signaling cascades controlling cellular events such as cell growth, differentiation, activation, apoptosis, stress responses, and transformation.
  • LPS lipopolysaccharide
  • TNF- ⁇ tumor necrosis factor- ⁇
  • CD40 interleukins
  • MAPKs mitogen-activated protein kinases
  • ERK extracellular-regulated kinases
  • p-38 MAPK p-38 MAPK
  • SAPK/JNK stress-activated/c-jun N-terminal kinase
  • SAPK/JNKs are activated in response to cellular "stress" such as changes in osmolarity or metabolism, ischemia, heat shock, shear stress, ceramide or inflammatory cytokines (TNF- ⁇ , IL-1) and implicated in both apoptotic and survival pathways.
  • stress such as changes in osmolarity or metabolism, ischemia, heat shock, shear stress, ceramide or inflammatory cytokines (TNF- ⁇ , IL-1) and implicated in both apoptotic and survival pathways.
  • JNKs control gene activity via phosphorylation of a variety of transcriptional factors including c-Jun, JunD, nuclear factor of activated T cells (NFAT)4, or Elk-1, all present in immune cells and known to regulate the transcription of many genes during an inflammatory response.
  • SAPK/JNKs regulate the activation and proliferation of T and B lymphocytes, activation of mast cells
  • MKK stress kinase mitogen-activated protein kinase kinase
  • JNK functions differentially in normal and tumor cells, which is supported by antisense INK oligonucleotide studies.
  • JNK is required for "stress" induced apoptosis (Garay M., Gaarde W., Monia B.P1, Nero P., and Cioffi C.L. Inhibition of hypoxia/reoxygenation-induced apoptosis by an anti-sense oligonucleo- tide targeted to JNK1 in human kidney cells, Biochem. Pharmacol. 59:1033-1043,
  • JUN kinase/stress-activated protein kinase pathway is required for epidermal growth factor stimulation of growth of human A549 lung carcinoma cells, JBC 272:33422-33429, 1997; Bost F., McKay R., Bost M., Potapova O., Dean N.M. and Mercola D., The Jun kinase 2 isoform is preferentially required for epidermal growth factor-induced transformation of human A549 lung carcinoma cells, Mol. Cell. Biol. 19:1938-1949, 1999).
  • JNK mediates both survival and apoptotic signaling.
  • MKKs MAPK kinases
  • MKK1-MKK7 MKK1, MEK2, MKK3, MKK4, MEK5, MKK6, and MKK7 are known to date with MKK7 being the most recently identified (Tournier C, Whitmarsh J., Cavanagh J., Barrett T., Davis RJ.
  • Mitogen-activated protein kinase kinase 7 is an activator of the c-Jun NH2- terminal kinase.
  • MKK4 or MKK7 have clearly shown their implication in the regulation of many inflammatory responses. Whereas MKK7 is believed to exclusively use SAPK/JNKs as substrates, MKK4 is also capable of phosphorylating p-38 MAP kinases. p-38 kinases are also involved in the control of inflammatory gene expression, especially after stimulation of cells with lipopolysaccharide and cytokines (Han J., Lee JD.,
  • p38 controls the release of IL-12 and IFN ⁇ and in B cells, CD40 cross-linking leads to rapid p38 activation and thus controls proliferation, and adhesion molecule expression.
  • p38 MAPK are activated by hypoxia and, by controlling the transcription factor ATF2, play a role in neuronal development and survival (Lee JC, Kumar S., Griswold DE., Underwood DC, Votta BJ., Adams JL. Inhibition of p38
  • a specific inhibitor of MKK7 and/or of MKK4, which is expected to block the synthesis of pro-inflammatory cytokines and the activation of various immune cells, should have a broad anti-inflammatory profile with potential for the treatment of inflammatory and immunoregulatory disorders and diseases, including asthma, rhinitis, allergic diseases, septic shock, joint diseases and myocardial injuries, as well as autoimmune pathologies such as rheumatoid arthritis, Grave's disease, and atherosclerosis. Additionally, due to the role of MKK7 and/or MKK4 in JNK activation and tumor cell survival, a specific MKK7 and/or MKK4 inhibitor should be efficacious in targeting certain cancers.
  • inhibitors should also have therapeutic potential for the treatment of renal failure, Huntington's chorea, cardiac hypertrophy and neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease and focal ischemia (Xia XG., Harding T., Weller M., Bieneman A., Uney JB., Schulz JB. Gene transfer of the JNK interacting protein- 1 protects dopaminergic neurons in the MPTP model of Parkinson's disease. Proc Natl Acad Sci USA, 98: 10433-10438, 2001).
  • WO 9842708 discloses anti-asthma agent represented by the general formula: wherein
  • R a , R'- a , R 2"la , R 2"2a , R 3"la , and R 3"2a are defined in the application.
  • R >2"- " l 1 b D , D R2 z --2b 0 , r R>4 4 --lb D , ⁇ R>4 4 - ⁇ 2b and , ⁇ R7b D are defined in the application.
  • R lc , R 2c , R 3c , R 4c , R 5c and R 6c are defined in the specification.
  • WO 9320078 discloses pharmaceutically active compound represented by the formula:
  • R 2",d , R 2"2d , R “ld , R 4 - 2d , R 56"ld , R 56"2d , R 56"3d , R 5( d and R 7d are defined in the application.
  • IN 157280 discloses the method for preparing anti hypertension agents represented by the formula:
  • WO 97/02266 discloses anti-hyperproliferative disease agents represented by the general formula:
  • WO 98/43973 also discloses anti-proliferative disease agents represented by the general formula:
  • Rid, R2d, Rjd, R 4 ', q and m' are defined in the application.
  • This invention is to provide a novel 4-phenyl-pyrimido[4,5- bjindole derivative of the formula (I), its tautomeric or stereoisomeric form, or a salt thereof:
  • R 1 represents hydrogen, halogen, cyano, azido, nitro, amino, N(C 1-6 )- alkylamino, di(C] -6 alkyl)amino, (C 1-6 )alkyl optionally substituted by cyano, nitro or mono-, di-, or tri- halogen, (C ⁇ -6 )alkylthio, (C ⁇ -6 )alkyl- sulfonyl, (C ⁇ -6 )alkoxy, (C 2-6 )alkenyl, (C 2-6 )alkynyl, or (C 3-8 )cyclo- alkyl;
  • R represents hydrogen, hydroxy, cyano, amino, carboxy, carbamoyl, (C ⁇ -6 )alkyl, (C ⁇ -6 )alkoxy, (C ⁇ -6 )alkoxycarbonyl, (C 2-6 )alkenyl, (C 2-6 )- alkynyl, (C 3-8 )cycloalkyl or benzyloxy; and
  • R represents hydrogen, halogen, hydroxy, cyano, carbamoyl, (C ⁇ -6 )alkyl, (C ⁇ -6 )alkoxy, (C 2-6 )alkenyl, (C 2-6 )alkynyl, (C 3-8 )cycloalkyl or -NR 31 R 32 , wherein
  • R 31 represents hydrogen or (C 1-6 )alkyl
  • R 32 represents hydrogen, (C -6 )alkyl, or -C(O) R 300
  • R , 300 represents phenyl or pyridyl
  • phenyl and pyridyl are optionally having one to three substituents selected from the group consisting of halogen, (C]. 6 )alkyl, (C 1-6 )alkoxy, nitro, cyano and carboxy.
  • Alkoxy illustratively and preferably represents methoxy, ethoxy, n-propoxy, iso- propoxy, tert-butoxy, n-pentoxy and n-hexoxy.
  • Alkanoyl illustratively and preferably represents acetyl and propanoyl.
  • Alkylamino represents an alkylamino radical having one or two (independently selected) alkyl substituents, illustratively and preferably representing methylamino, ethylamino, n-propylamino, isopropylamino, tert-butylamino, n-pentylamino, n- hexyl-amino, N,N-dimethylamino, N,N-di ethylamino, N-ethyl-N-methylamino, N- methyl-N-n-propylamino, N-isopropyl-N-n-propylamino, N-t-butyl-N-methylamino, N-ethyl-N-n-pentylamino and N-n-hexyl-N-methylamino.
  • Alkylammocarbonyl or alkylcarbamoyl represents an alkylammocarbonyl radical having one or two (independently selected) alkyl substituents, illustratively and preferably representing methylaminocarbonyl, ethylaminocarbonyl, n-propylamino- carbonyl, isopropylamino-carbonyl, tert-butylaminocarbonyl, n-pentylamino- carbonyl, n-hexylaminocarbonyl, N,N-dimethylaminocarbonyl, N,N-diethylamino- carbonyl, N-ethyl-N-methylaminocarbonyl, N-methyl-N-n-propylaminocarbonyl, N- isopropyl-N-n-propylaminocarbonyl, N-t-butyl-N-methylaminocarbonyl, N-ethyl-N- n-
  • Alkoxycarbonyl illustratively and preferably represents methoxycarbonyl, ethoxy- carbonyl, n-propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, n-pentoxy- carbonyl and n-hexoxycarbonyl.
  • Alkoxycarbonylammo illustratively and preferably represents methoxycarbonylamino, ethoxycarbonylamino, n-propoxycarbonylamino, isopropoxycarbonylamino, tert-butoxycarbonylamino, n-pentoxycarbonylamino and n-hexoxycarbonylamino.
  • Alkanoylamino illustratively and preferably represents acetylamino and ethyl- carbonylamino.
  • Cycloalkyl per se and in cycloalkylamino and in cycloalkylcarbonyl represents a cycloalkyl group having generally 3 to 8 and preferably 5 to 7 carbon atoms, illustra- tively and preferably representing cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • Halogen represents fluorine, chlorine, bromine and iodine.
  • This invention is also to provide a method for treating or preventing a disorder or disease associated with MKK7 and/or MKK4 activity in a human or animal subject, comprising administering to said subject a therapeutically effective amount of the 4- phenyl-pyrimido[4,5-b]indole derivative shown in the formula (I), its tautomeric or stereoisomeric form, or a physiologically acceptable salt thereof.
  • this invention is to provide a use of the 4-phenyl-pyrimido[4,5-b]indole derivative shown in the formula (I), its tautomeric or stereoisomeric form, or a physiologically acceptable salt thereof in the preparation of a medicament.
  • said medicament is suitable for treating and/or preventing a disorder or disease associated with MKK7 and/or MKK4 activity.
  • the compounds of the present invention surprisingly show excellent MKK7 and/or MKK4 inhibitory activity. They are, therefore, suitable for the production of medicament or medical composition, which may be useful to treat MKK7 and/or MKK4 related diseases.
  • the 4-phenyl-pyrimido[4,5-b]indoles derivatives of the present invention inhibit MKK7 and/or MKK4, they are useful for treatment and prophylaxis of diseases as follows:
  • inflammatory and immunoregulatory disorders such as asthma, atopic dermatitis, rhinitis, allergic rhinitis, allergic diseases, COPD, septic shock, arthritis, joint diseases and myocardial injuries, as well as autoimmune pathologies such as rheumatoid arthritis, Grave's disease, and atherosclerosis.
  • MKK7 and/or MKK4 is an important target and inhibition of MKK7 and/or MKK4 is likely to be effective in the treatment of such inflammatory and immunoregulatory disorders and diseases.
  • the compounds of the present invention are also useful for treatment of ischemia, myocardial injury, pulmonary hypertension, renal failure, Huntington's chorea and cardiac hypertrophy, as well as neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease and focal ischemia, since the diseases also relate to MKK7 and/or MKK4.
  • the compounds of formula (I) are those wherein:
  • R 1 represents hydrogen, amino, N(C 1-6 )alkylamino, di(C 1-6 alkyl)amino, (C ⁇ -6 )alkyl, or (C ⁇ -6 )alkylthio;
  • R represents hydrogen, hydroxy, cyano, ammo, or carbamoyl
  • R represents hydrogen, halogen, ammo, N(C ⁇ -6 )alkylamino, di(C 1-6- alkyl)amino, benzoylamino, (C ⁇ -6 )alkyl, or (C 1-6 )alkoxy.
  • the compounds of formula (I) are those wherein:
  • the present invention provides a medicament which include one of the compounds described above and optionally pharmaceutically acceptable excipients.
  • the compound of the formula (I) of the present invention can be, but not limited to be, prepared by combining various known methods.
  • one or more of the substituents, such as amino group, carboxyl group, and hydroxyl group of the compounds used as starting materials or intermediates are advantageously protected by a protecting group known to those skilled in the art. Examples of the protecting groups are described in "Protective Groups in Organic Synthesis "Protective Groups in Organic Synthesis (3rd Edition)" by Greene and Wuts, John Wiley and Sons, New York 1999.
  • the compound of the formula (I) of the present invention can be, but not limited to be, prepared by the method [A] below.
  • the compound (I) (wherein R 1 , R and R are the same as defined above) or a salt thereof, for example, can be prepared by the reaction of the compound of formula (II) (wherein R and R are the same as defined above, and L represents leaving group including, for instance, halogen atom such as chlorine, bromine, or iodine atom; C 6- ⁇ 0 arylsulfonyloxy group such as benzenesulfonyloxy or p-toluenesulfonyloxy; C ⁇ -4 alkylsulfonyloxy group such as methanesulfonyloxy; and halogen substituted C 1-4 alkylsulfonyloxy group such as trifluoromethanesulfonyloxy and the like.) or a salt thereof, with the compound of the general formula (III) (wherein R 3 is the same as defined above and M represents metal group including, for instance, organoborane group
  • the reaction can be advantageously carried out in the presence of a base including, for instance, cesium carbonate, sodium carbonate, potassium carbonate, barium hydroxide sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like.
  • a base including, for instance, cesium carbonate, sodium carbonate, potassium carbonate, barium hydroxide sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like.
  • This reaction can be carried out without solvent or in a solvent including, for instance, alcohol such as methanol, ethanol, 1-propanol, isopropanol and tert- butanol; ethers, such as dioxane, isopropyl ether, diethyl ether, 1 ,2-dimethoxyethane and tetrahydrofuran (THF); aromatic hydrocarbons such as benzene, toluene and xylene; nitriles such as acetonitrile; amides such as dimethylformamide (DMF) N, N- dimethylacetamide and N-methylpy ⁇ olidone; sulfoxides such as dimethylsulfoxide (DMSO); water and others.
  • a solvent including, for instance, alcohol such as methanol, ethanol, 1-propanol, isopropanol and tert- butanol; ethers, such as dioxane, isopropyl ether, die
  • the reaction temperature can be optionally set depending on the compounds to be reacted.
  • the reaction temperature is usually, but not limited to, about 10°C to 200°C and preferably about 50°C to 150°C
  • the reaction may be conducted for, usually, 30 minutes to 48 hours and preferably 1 hour to 24 hours.
  • the compound (I) can be further reacted to modify R 3 , e.g. to deprotect, or to modify R 3 to obtain the compound having amino group.
  • the compounds (III) are commercially available or can be synthesized by conven-
  • R , R and R can be optionally protected during the reaction and deprotected afterward.
  • the compound of the formula (I-i) and (I-ii) can be, but not limited to be, prepared by the methods [B], [C] or [D] below.
  • the compound of formula (I-i) (wherein R 1 and R 3 are the same as defined above) can be prepared by the reaction of the compound of formula (I-b)(wherein R 1 and R 3 are the same as defined above, and X represents hydrogen or (C 1-6 )alkyl) and ammonia.
  • the reaction can be carried out without solvent or in a solvent including, for instance, alcohols such as methanol and ethanol, 1-propanol, isopropanol and tert-butanol; water; ethers such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; amides such as N,N-dimethylformamide (DMF), N,N-dimethyl- acetamide; sulfoxides such as dimethyl sulfoxide, and others.
  • a solvent including, for instance, alcohols such as methanol and ethanol, 1-propanol, isopropanol and tert-butanol; water; ethers such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (TH
  • the reaction temperature can be optionally set depending on the compounds to be reacted.
  • the reaction temperature is usually, but not limited to, about 0°C to 60°C
  • the reaction may be conducted for, usually, 30 minutes to 48 hours and preferably 1 hour to 24 hours.
  • the reaction can be advantageously carried out using coupling agent including, for instance, carbodiimides such as N,N-dicyclohexylcarbodiimide and l-(3-dimethylaminopropyl)-3-ethyl- carbodiimide; carbonyldiazoles such as l, -carbonyldi(l,3-imiazole)(CDI) and 1,1'- carbonyldi(l,2,4-triazole)(CDT), and others.
  • coupling agent including, for instance, carbodiimides such as N,N-dicyclohexylcarbodiimide and l-(3-dimethylaminopropyl)-3-ethyl- carbodiimide; carbonyldiazoles such as l, -carbonyldi(l,3-imiazole)(CDI) and 1,1'- carbonyldi(l,2,4-triazole)(CDT), and others.
  • the compound of formula (I-i) (wherein R and R are the same as defined above) can be prepared by the hydrolysis of the compound of formula (I-c) (wherein R 1 and R 3 are the same as defined above).
  • the reaction can be carried out in a solvent including, for instance, alcohols such as methanol and ethanol, 1-propanol, isopropanol, n-butanol and tert-butanol; water; ketone such as acetone; ethers such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; amides such as N,N-dimethylformamide (DMF), N,N- dimethylacetamide, and others.
  • a solvent including, for instance, alcohols such as methanol and ethanol, 1-propanol, isopropanol, n-butanol and tert-butanol; water; ketone such as acetone; ethers such as diethyl ether, isopropyl ether, diox
  • the reaction temperature can be optionally set depending on the compounds to be reacted.
  • the reaction temperature is usually, but not limited to, about 0°C to 60°C
  • the reaction may be conducted for, usually, 30 minutes to 48 hours and preferably 1 hour to 24 hours.
  • the reaction can be advantageously conducted in the presence of a base, including, for instance, an alkali metal alkoxide such as sodium methoxide, sodium ethoxide and potassium tert-butoxide; alkali metal hydroxide such as sodium hydroxide and potassium hydroxide; alkali metal carbonates such as sodium carbonate and potassium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; alkali metal phosphate such as sodium phosphate, and others.
  • a base including, for instance, an alkali metal alkoxide such as sodium methoxide, sodium ethoxide and potassium tert-butoxide; alkali metal hydroxide such as sodium hydroxide and potassium hydroxide; alkali metal carbonates such as sodium carbonate and potassium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; alkali metal phosphate such as sodium phosphate, and others.
  • the reaction can be advantageously conducted in the presence of oxidating agent, for instance, hydrogen peroxide, manganese dioxide, dimethyl dioxirane, sodium percarbonate, sodium perborate, oxone, and the others.
  • oxidating agent for instance, hydrogen peroxide, manganese dioxide, dimethyl dioxirane, sodium percarbonate, sodium perborate, oxone, and the others.
  • the reaction can be advantageously conducted in the presence of an acid including, for instance, trifluoroacetic acid, hydrochloric acid and sulfonic acid, and others.
  • an acid including, for instance, trifluoroacetic acid, hydrochloric acid and sulfonic acid, and others.
  • the compound of formula (I-ii) (wherein R 1 and R 3 are the same as defined above), for example, can be carried out under the hydrogen atmosphere in the presence of a catalysis, such as palladium on activated carbon, palladium hydroxide on carbon, platinum on activated carbon, platinum(IV) oxide, Raney nickel, and others, in a solvent including, for instance, esters, such as ethyl acetate, ethers such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1 ,2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; alcohols such as methanol, ethanol, 1-propanol, isopropanol and tert-butanol; water, amides such as N,N-dimefhylformamide (DMF), N,N-dimethylacetamide and N-methylpyrrolidon
  • the reaction temperature can be, but not limited to, about 50°C to 100°C.
  • the reaction may be conducted for, usually, 30 minutes to 48 hours and preferably 1 to 24 hours.
  • compound 2 can be prepared by the reaction of compound 1 (wherein L' represents leaving group including, for instance, halogen atom such as chlorine, bromine, or iodine atom; C 6-10 arylsulfonyloxy group such as benzenesulfonyloxy or p-toluenesulfonyloxy; C ⁇ -4 alkylsulfonyloxy group such as methanesulfonyloxy; and halogen substituted C 1-4 alkylsulfonyloxy group such as trifluoromethanesulfonyloxy and the like, and R 2 is the same as defined above) with ethyl cyanoacetate using a base, for instance, sodium hydride.
  • L' represents leaving group including, for instance, halogen atom such as chlorine, bromine, or iodine atom
  • C 6-10 arylsulfonyloxy group such as benzenesulfonyloxy or p
  • the reaction may be carried out in a solvent including, for instance, ethers such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; amides such as N,N-dimethylformamide (DMF), N,N-dimethylacetamide and N-methyl- pyrrolidone; sulfoxides such as dimethylsulfoxide (DMSO); alcohols such as methanol, ethanol, 1-propanol, isopropanol and tert-butanol, and others.
  • ethers such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane
  • aromatic hydrocarbons such as benzene, toluene and xylene
  • two or more of the solvents selected from the listed above can be mixed and used.
  • the reaction may be carried out, usually, at room temperature to 100°C for 4 hours to 12 hours.
  • Compound 1 and ethyl cyanoacetate are commercially available or can be synthesized by conventional methods.
  • Compound 3 (wherein R 2 is the same as defined above) can be prepared by reducing nitro group of compound 2 using agent including, for instance, metals such as zinc and iron in the presence of acid including, for instance, hydrochloric acid and acetic acid.
  • agent including, for instance, metals such as zinc and iron in the presence of acid including, for instance, hydrochloric acid and acetic acid.
  • the reaction can be carried out without solvent or in a solvent including, for instance; aromatic hydrocarbons such as benzene, toluene and xylene, and others.
  • the reaction may be carried out, usually, at room temperature to 100°C for 30 minutes to 12 hours.
  • Compound 4a (wherein R 1 represents amino, (C ⁇ -6 )alkyl, (C ⁇ -6 )alkoxy, (C 2-6 )alkenyl, (C 2-6 )alkynyl, halogen substituted (C 1-6 ) alkyl, cyano, cyano(C] -6 )alkyl, (C ⁇ -6 ) alkylthio, (C 3-8 )cycloalkyl, nitro(C ⁇ -6 )alkyl or fluoro and R is the same as defined above) can be prepared by the reaction of compound 3 with appropriate cyano compounds (R 1 CN) (wherein R 1 is the same as defined above).
  • the reaction can be carried out in a solvent including, for instance, alcohols such as methanol, ethanol, 1- propanol, isopropanol and tert-butanol; ethers such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1 ,2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene, and xylene, and others.
  • a solvent including, for instance, alcohols such as methanol, ethanol, 1- propanol, isopropanol and tert-butanol; ethers such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1 ,2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene, and xylene, and others.
  • the reaction may be carried out,
  • Cyano compounds are commercially available or can be synthesized by ..conventional methods.
  • Compound 4b (wherein R is hydrogen and R is the same as defined above) can be prepared by the reaction of compound 3 with ammonium formate in a solvent such as formamide. The reaction may be carried out, usually, at 40°C to 180°C for 2 hours to two days. If desired, the resulting 4b can be further modified to introduce nitro group at the position of R 1 .
  • Ammonium formate and formamide are commercially available or can be synthesized by conventional methods.
  • the compound of formula (II) (wherein R',and R 2 are the same as defined above and L represents leaving group including, for instance, halogen atom such as chlorine, bromine, or iodine atom; C 6- ⁇ o arylsulfonyloxy group such as benzenesulfonyloxy or p-toluenesulfonyloxy; C 1- alkylsulfonyloxy group such as methanesulfonyloxy; and halogen substituted C alkylsulfonyloxy group such as trifluoromethanesulfonyloxy and the like.) can be prepared for instance, by the reaction of compound 4 with appropriate halogenating reagent including, for instance, POCl 3 , PC1 5 , SOCl 2 , and the like; or can be prepared, for instance, by the reaction of compound 4 with appropriate sulfonyl chloride.
  • appropriate halogenating reagent including, for instance, POC
  • the reaction may be carried out without solvent or in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2- dichloroethane;such as ethers such as dioxane and tetrahydrofuran (THF) and 1,2- dimethoxyethane; aromatic hydrocarbons such as benzene, toluene, and xylene, and others.
  • halogenated hydrocarbons such as dichloromethane, chloroform and 1,2- dichloroethane
  • ethers such as dioxane and tetrahydrofuran (THF) and 1,2- dimethoxyethane
  • aromatic hydrocarbons such as benzene, toluene, and xylene, and others.
  • two or more of the solvents selected from the listed above can be mixed and used.
  • the reaction can be advantageously conducted in the presence of a base, including, for instance, such as pyridine, triethylamine and N,N-diiso- propylethylamine, dimethylaniline, diethylaniline, and others.
  • a base including, for instance, such as pyridine, triethylamine and N,N-diiso- propylethylamine, dimethylaniline, diethylaniline, and others.
  • the reaction temperature is usually, but not limited to, about 40°C to 200°C and preferably about 20°C to 180°C
  • the reaction may be conducted for, usually, 30 minutes to 48 hours and preferably 2 hours to 12 hours.
  • halogenating reagents and sulfonyl chlorides are commercially available or can be synthesized by conventional methods.
  • Typical salts of the compound shown by the formula (I) include salts prepared by 5 reaction of the compounds of the present invention with a mineral or organic acid, or an organic or inorganic base. Such salts are known as acid addition and base addition salts, successively.
  • Acids to form salts include inorganic acids such as, without limitation, sulfuric acid, 10 phosphoric acid, hydrochloric acid, hydrobromic acid, hydriodic acid like, and organic acids, such as, without limitation, p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like.
  • inorganic acids such as, without limitation, sulfuric acid, 10 phosphoric acid, hydrochloric acid, hydrobromic acid, hydriodic acid like
  • organic acids such as, without limitation, p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like.
  • Base addition salts include those derived from inorganic bases, such as, without limitation, ammonium hydroxide, alkaline metal hydroxide, alkaline earth metal hydroxides, carbonates, bicarbonates, and the like, and organic bases, such as, without limitation, ethanolamine, triethylamine, tris(hydroxymethyl)aminomethane, and the like.
  • inorganic bases include, sodium hydroxide, potassium
  • the compound of the present invention or a salts thereof, depending on its substituents, may be modified to form lower alkylesters or known other esters; and/or 25 hydrates or other solvates. Those esters, hydrates, and solvates are included in the scope of the present invention.
  • the compound of the present invention may be administered in oral forms, such as, without limitation normal and enteric coated tablets, capsules, pills, powders,
  • granules, elixirs, tinctures, solution, suspensions, syrups, solid and liquid aerosols and emulsions may also be administered in parenteral forms, such as, without limitation, intravenous, intraperitoneal, subcutaneous, intramuscular, and the like forms, well-known to those of ordinary skill in the pharmaceutical arts.
  • the compounds of the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using transdermal delivery systems well-known to those of ordinary skilled in the art.
  • the dosage regimen with the use of the compounds of the present invention is selected by one of ordinary skill in the arts, in view of a variety of factors, including, without limitation, age, weight, sex, and medical condition of the recipient, the severity of the condition to be treated, the route of administration, the level of metabolic and excretory function of the recipient, the dosage form employed, the particular compound and salt thereof employed.
  • the compounds of the present invention are preferably formulated prior to admini- stration together with one or more pharmaceutically-acceptable excipients.
  • Excipients are inert substances such as, without limitation carriers, diluents, flavoring agents, sweeteners, lubricants, solubilizers, suspending agents, binders, tablet disintegrating agents and encapsulating material.
  • compositions of the present invention are pharmaceutical formulation comprising a compound of the invention and one or more pharmaceutically- acceptable excipients that are compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • Pharmaceutical formulations of the invention are prepared by combining a therapeutically effective amount of the compounds of the invention together with one or more pharmaceutically-acceptable excipients.
  • the active ingredient may be mixed with a diluent, or enclosed within a carrier, which may be in the form of a capsule, sachet, paper, or other container.
  • the carrier may serve as a diluent, which may be solid, semi-solid, or liquid material which acts as a vehicle, or can be in the form of tablets, pills, powders, lozenges, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments, containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.
  • a diluent which may be solid, semi-solid, or liquid material which acts as a vehicle, or can be in the form of tablets, pills, powders, lozenges, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments, containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.
  • the active ingredient may be combined with an oral, and non-toxic, pharmaceutically-acceptable carrier, such as, without limitation, lactose, starch, sucrose, glucose, sodium carbonate, mannitol, sorbitol, calcium carbonate, calcium phosphate, calcium sulfate, methyl cellulose, and the like; together with, optionally, disintegrating agents, such as, without limitation, maize, starch, methyl cellulose, agar bentonite, xanthan gum, alginic acid, and the like; and optionally, binding agents, for example, without limitation, gelatin, natural sugars, beta-lactose, corn sweeteners, natural and synthetic gums, acacia, tragacanth, sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like; and, optionally, lubricating agents, for example, without limitation, magnesium stearate, sodium stearate, stearic acid, sodium oleate, sodium benzoate,
  • the carrier may be a finely divided solid which is in admixture with the finely divided active ingredient.
  • the active ingredient may be mixed with a carrier having binding properties in suitable proportions and compacted in the shape and size desired to produce tablets.
  • the powders and tablets preferably contain from about 1 to about 99 weight percent of the active ingredient which is the novel composition of the present invention.
  • Suitable solid carriers are magnesium carboxymethyl cellulose, low melting waxes, and cocoa butter.
  • Sterile liquid formulations include suspensions, emulsions, syrups and elixirs.
  • the active ingredient can be dissolved or suspended in a pharmaceutically acceptable carrier, such as sterile water, sterile organic solvent, or a mixture of both sterile water and sterile organic solvent.
  • the active ingredient can also be dissolved in a suitable organic solvent, for example, aqueous propylene glycol.
  • a suitable organic solvent for example, aqueous propylene glycol.
  • Other compositions can be made by dispersing the finely divided active ingredient in aqueous starch or sodium carboxymethyl cellulose solution or in a suitable oil.
  • the formulation may be in unit dosage form, which is a physically discrete unit containing a unit dose, suitable for administration in human or other mammals.
  • a unit dosage form can be a capsule or tablets, or a number of capsules or tablets.
  • a "unit dose" is a predetermined quantity of the active compound of the present invention, calculated to produce the desired therapeutic effect, in association with one or more excipients.
  • the quantity of active ingredient in a unit dose may be varied or adjusted from about 0.1 to about 1000 milligrams or more according to the particular treatment involved.
  • Typical oral dosages of the present invention when used for the indicated effects, will range from about 0.0 lmg /kg/day to about 100 mg/kg/day, preferably from 0.1 mg/kg/day to 30 mg/kg/day, and most preferably from about 0.5 mg/kg/day to about 10 mg/kg/day.
  • parenteral administration it has generally proven advantageous to administer quantities of about 0.001 to 100 mg /kg/day, preferably from 0.01 mg/kg/day to 1 mg/kg/day.
  • the compounds of the present invention may be administered in a single daily dose, or the total daily dose may be administered in divided doses, two, three, or more times per day. Where delivery is via transdermal forms, of course, administration is continuous.
  • MS MS data were recorded on a Micromass Platform LC with Shimadzu Phenomenex ODS column(4.6 mm ⁇ X 30 mm) flushing a mixture of acetonitrile-water (9:1 to 1:9) at 1 ml/min of the flow rate.
  • Mass spectra were obtained using electrospray (ES) ionization techniques (micromass Platform LC).
  • TLC was performed on a precoated silica gel plate (Merck silica gel 60 F-254).
  • Silica gel WAKO-gel C-200 (75-
  • a plasmid containing human MKK7 open reading frame was cloned into a pGEM-T Easy vector (Promega, Madison, WI) and further into a pGEX-6P-2 vector (Pharmacia) to construct human GST(Glutathione-S-transferase)- MKK7 fusion protein.
  • This construct was coexpressed with human MEKKc (catalytic domain of MEKK (MEK (Map kinase kinase) kinase) on plasmid pBB131, in E.coli (BL21(DE3)pLysS).
  • the resulting GST-MKK7 was purified with the use of a glutathione column
  • GST-KN-SAPK ⁇ was purified with the use of glutathione column (Amersham Pharmacia Biotech AB, Uppsala, Sweden) according to the manufacturer's instruction. The purity of the protein was confirmed to be more than 90% by SDS-PAGE.
  • Biotinylation of the substrate protein was done using sulfo-NHS-LC Biotin according to the manufacturer's instructions (Pierce, Rockford, US)
  • Test compounds (2.5 ⁇ l) at various concentrations (in 1% DMSO) were added to 15 ⁇ l of reaction buffer (20mM HEPES, 0.1M NaCl, 0.1 mM Na3VO4, lOmM MgCb, ImM DTT, lmg/ml BSA, pH 7.5)) containing 0.5 ⁇ g/ml GST-MKK7 and 0.8 ⁇ M SAPK ⁇ (biotinylated GST-KN-SAPK ⁇ fusion protein).
  • reaction buffer 20mM HEPES, 0.1M NaCl, 0.1 mM Na3VO4, lOmM MgCb, ImM DTT, lmg/ml BSA, pH 7.5
  • SAPK ⁇ biotinylated GST-KN-SAPK ⁇ fusion protein
  • a plasmid containing human MKK4 open reading frame was cloned into a pGEX-2T vector (Pharmacia) to construct human GST(Glutathione-S- transferase)-MKK4 fusion protein. This construct was coexpressed with human MEKKc (catalytic domain of MEKK on plasmid pBB131) in E.coli (BL21(DE3)pLysS).
  • the resulting GST-MKK4 was purified with the use of glutathione column (Amersham Pharmacia Biotech AB, Uppsala, Sweden) according to the manufacturer's instruction. The purity of the protein was confirmed to be more than 90% by SDS-PAGE.
  • Test compounds (5 ⁇ l) at various concentrations (in 1% DMSO) were added to 30 ⁇ l of reaction buffer (20mM HEPES, 0.1M NaCl, 0.1 mM Na3VO4, lOmM MgCh, ImM DTT, lmg/ml BSA, pH 7.5)) containing 0.5 ⁇ g/ml GST-MKK4 and 6 ⁇ M ATP.
  • the kinase reaction was started by the addition of 25 ⁇ l assay buffer containing 0.48 ⁇ M SAPK ⁇ (biotinylated GST-KN-SAPK ⁇ fusion protein). After a two hours incubation period at room temperature, the reaction was stopped by the addition of 80 ⁇ l stop solution (0.1M EDTA, pH 8.0).
  • Eu-labeled anti-phosphotyrosine antibody (5ng/well;4G10, Upstate Biotechnology, Lake Placid, NY, US) was added. After incubation for 30 min., plates were again washed 3 times with TBS, and 100 ⁇ l of the ⁇ enhancement solution (Amersham Pharmacia Biotech) was added. One hour later, time- resolved fluorescence was measured by a multi-label counter (ARVO, Wallac
  • huPBMC Human peripheral blood mononucleated cells isolated using mono-poly resolving medium (Dainippon Seiyaku, Osaka, Japan) were incubated with test compounds (various concentrations in 0.1 % DMSO) for 1 hour in a 37°C CO2 incubator. Cells were then plated on 96 well plates (lxl O5 cell per well in 200 ⁇ l RPMI1640 cell culture medium) pre-coated for 3 hours with 100 ⁇ l anti-CD3 antibody (NU-T3: Nichirei) (4 ⁇ g/ml)) or without any coating (unstimulated controls). Solution was removed and plates were washed three times with 200 ⁇ l/well phosphate buffered saline (PBS).
  • PBS phosphate buffered saline
  • Anti-CD28 antibody (KOLT-2: Nichirei, Tokyo, Japan) and goat anti mouse kappa antibody (Bethyl Laboratories, Inc., Montgomery, Texas, US) was added to the wells at final concentrations of 1.5 ⁇ g/ml and 2 ⁇ g/ml, respectively. Plates were incubated for 20 hours in the incubator. Supernatant was removed and stored at -30°C in aliquots until further use. The amount of interleukin- 2 (IL-2) and interferon- ⁇ (IFN- ⁇ ) released from huPBMC was determined by commercially available ELISA (Genzyme Tech., Minneapolis, US) according to the manufacturer's instructions.
  • IL-2 interleukin- 2
  • IFN- ⁇ interferon- ⁇
  • huPBMC Human peripheral blood mononucleated cells isolated using mono-poly resolving medium were either directly used for experiments (lxl 0s cells per well in 200 ⁇ l medium) or differentiated to dendritic cells (DC) in the presence of GM-SCF
  • TNF- ⁇ and IL-12 released from cell cultures were determined by commercially available ELISA (Genzyme Tech., Minneapolis, US) according to the manufacturer's instructions.
  • mice Male Balb/c mice (20-25 g body weight) were in injected with agonistic anti-CD3
  • mice were sacrificed and the serum cytokines IL-2, IL-4 and IFN- ⁇ were determined by ELISA (Genzyme Tech., Minneapolis, US) according to the manufacturer's instruction. Data represent mean values ⁇ SD of 5-6 animals each. * p ⁇ 0.05, ** p ⁇ 0.01 vs. vehicle control (V);
  • MKK 7 kinase assay MKK 7 kinase assay
  • MKK4 kinase assay MKK4 kinase assay
  • the compounds of the present invention also show excellent selectivity, and strong activity in vivo assays. Preparing method of starting compounds
  • step A-1 a mixture of 3-fluoro-4-nitrophenol (50.00 g, 318.26 mmol), benzyl bromide (57.16 g, 334.18 mmol) and K 2 CO 3 (87.97 g, 636.53 mmol) was refluxed in acetone (750 mL) for 18 hours. After cooled to room temperature, the mixture was passed through a filter and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with 5% NaHCO 3 . The separated organic phase was washed with brine, dried over MgSO 4 and concentrated under reduced pressure. The residue was triturated with hexane, filtered and air-dried to obtain 4-benzyloxy-2-fluoronitrobenzene as a colorless solid (74.65 g, 94.9 %).
  • step A-2 to the suspension of 60% sodium hydride (9.71 g, 242.69 mmol) in 300 ml of /V,/V-dimethylformamide (DMF) were added a solution of ethyl cyanoacetate (15.10 g, 133.48 mmol) in DMF (40 mL) and 4-benzyloxy-2-fluoronitrobenzene (20.0 g, 80.9 mmol), successively, at 0°C The mixture was stirred at 70°C for 4 hours and cooled to room temperature. The resulting suspension was poured into 10 % KOH and washed with ether. The aqueous layer was acidified with 10% HC1 and extracted with ether.
  • DMF /V,/V-dimethylformamide
  • step A-3 to a mixture of acetic acid (190 mL) and toluene (380 mL) was added ethyl 5-benzyloxy-2-nitrophenylcyanoacetate (63.99 g, 188.02 mmol). The resulting mixture was stirred at 80°C to give a clear solution. The external heating was removed and zinc powder (98.33 g, 1504.14 mmol) was added slowly, portionwise. The reaction mixture was stirred at 80°C for 3 hours and passed through a filter, while the solution is hot, and the collected solid was washed with toluene.
  • step A-4 a suspension of ethyl 2-amino-5-benzyloxy-3-ethoxycarbonyl- (lH)-indole (11.36 g, 36.60 mmol), cyanamide (2.46 g, 58.55 mmol), and 36% HC1 (3 ml) in 1,4-dioxane (300 ml) was refluxed for 2 days.
  • step A-5 a mixture of 5-benzyloxy-3-ethoxycarbonyl-2-guanidyl-(lH)- indole hydrochloride (4.54 g, 11.67 mmol) and sodium hydroxide (4.67 g, 116.72 mmol) was refluxed in water (50 mL) for 6 hours. After cooled to room temperature, the precipitate was collected on a filter and air-dried to obtain 2-amino-6-benzyloxy-4-hydroxy-(9H)-pyrimido[4,5-b]indole as a crude product, that was used for the following reaction without any further purification.
  • step A-6 a mixture of 2-amino-6-benzyloxy-4-hydroxy-(9H)-pyrimido- [4,5-b]indole (1.00 g, 3.26 mmol) obtained in the step (5) and N,N-dimethyl- aniline (1.19 g, 9.79 mmol) was refluxed in phosphoryl chloride (3.0 g) for 2 hours.
  • the reaction mixture was concentrated under reduced pressure and the residual syrup was treated with ice water.
  • the resulting solid was collected on a filter and washed with ethanol and ether to afford 2-amino-6-benzyloxy- 4-chloro-(9H)-pyrimido[4,5-b]indole hydrochloride as a pale green solid.
  • This crude product was used for the following reaction without further purification.
  • step B-1 to a dry NaOMe prepared from Na (60 mg) and absolute MeOH (2 mL) was added a solution of 2-amino-5-benzyloxy-3-ethoxy- carbonyl-(lH)-indole (0.50 g, 1.61 mmol) obtained in the step A-3 for preparation of the starting compound A in formamide (15 mL). The mixture was refluxed for 18 hours and cooled to room temperature.
  • step B-2 the 6-benzyloxy-4-chloro-(9H)-pyrimido[4,5-b]indole hydrochloride as a brown solid is prepared in a similar manner as described in the step A-6 for the preparation of the starting compound A.
  • step C-l a mixture of 2-amino-5-benzyloxy-3-ethoxycarbonyl-(lH)- indole (5.00 g, 16.11) obtained in the step A-3 for preparation of the starting compound A and 4 N hydrochloric acid in 1,4-dioxane (100 ml) in aceto- nitrile (100 ml) was sti ⁇ ed at room temperature overnight. The resulting precipitate was collected by filtration, washed with 1,4-dioxane and acetonitrile and dissolved in a mixture of ethanol (85 mL) and H O (5 mL).
  • step C-2 the 6-benzyloxy-4-chloro-2-methyl-9H-pyrimido[4,5-b]- indole is prepared in a similar manner as described in the step A-6 for the preparation of the starting compound A.
  • step D-1 to a solution of 3-fluoro-4-nitrotoluene (4.83 g) in carbon tetrachloride (50 ml) were added N-bromosuccinimide (NBS, 12.6 g) and benzoyl peroxide (0.45 g). The mixture was refluxed overnight and additional
  • step D-2 a mixture of 3-fluoro-4-nitrobenzyl bromide (3.43 g) and calcium carbonate (7.63 g) in a mixture of water (40 ml) and 1,4-dioxane (40 ml) was refluxed overnight. After cooling to room temperature, the reaction mixture was passed through a paper filter to remove insoluble materials, that were washed with 1,4-dioxane (20 ml). The filtrates were combined and evaporated in vacuo. The residue was dissolved in ethyl acetate (40 ml) and washed with IN hydrochloric acid, saturated sodium bicarbonate water solution and brine, successively, to be dried over sodium sulfate. When the solvent was removed in vacuo and the residue was triturated with hexane,
  • step D-3 to a solution of 3-fluoro-4-nitrobenzyl alcohol (2.97 g) in acetone (60 ml) was added Jones reagent (13 ml), prepared from chromic acid (26.7 g) and sulfuric acid (23 ml) in water (100 ml), dropwise at 0°C. The mixture was sti ⁇ ed on a ice-bath for 0.5 hours and quenched with isopropanol (20 ml) to be concentrated in vacuo. The residue was dissolved in ethyl acetate (30 ml) and washed with water (30 ml X 3), and brine (30 ml X 1), successively.
  • step D-5 to a suspension of 60% sodium hydride (2.01 g) in N,N- dimethylformamide (DMF, 15 ml) was added a solution of ethyl cyanoacetate (5.68 g) in DMF (5 ml) at 0°C. The mixture was sti ⁇ ed at room temperature for 0.5 hours and a solution of methyl 3-fluoro-4-nitrobenzoate (5.00 g) in DMF (5 ml) was added. The mixture was sti ⁇ ed at room temperature for another 3 hours and poured into a mixture of ethyl acetate (100 ml) and IN hydrochloric acid (200 ml).
  • DMF N,N- dimethylformamide
  • step D-6 ethyl ⁇ -cyano-5-methoxycarbonyl-2-nitrophenylacetate
  • step D-7 a mixture of methyl 2-amino-3-ethoxycarbonyl-lH-indole-5- carboxylate (0.80 g) and ammonium formate (0.20 g) in formamide (4 ml) was sti ⁇ ed at 175°C under argon atmosphere overnight. After cooling to room temperature, the reaction mixture was diluted with water (40 ml) to give precipitates, that were washed with methanol (20 ml) to obtain pure methyl 4- hydroxy-9H-pyrimido[4,5-b]indole-6-carboxylate (0.413 g, 56%). (8) Methyl 4-chloro-9H-pyrimido[4,5-b]indole-6-carboxylate
  • step D-8 to a solution of methyl 4-hydroxy-9H-pyrimido[4,5-b]indole- 6-carboxylate (0.35 g) and N,N-dimethylaniline (0.52 g) in 1,4-dioxane (2 ml) was added phosphoryl chloride (1.4 ml). The mixture was sti ⁇ ed at 100°C for 6 hours and, after cooling to room temperature, poured into crushed ice. When this quenching was completed, precipitates resulted in to be collected by a paper filter and dried at 80°C in vacuo for 5 hours. Resulting solid was suspended in methanol and passed through a filter paper to obtain methyl 4- chloro-9H-pyrimido[4,5-b]indole-6-carboxylate as a pale yellow solid (0.298 g, 79%).
  • step E-l a mixture of methyl 2-amino-3-ethoxycarbonyl-lH- indole-5- carboxylate (0.48 g), obtained in step D-6 of starting compound D, and 4 N hydrochloric acid in 1,4-dioxane (5 ml) in acetonitrile (5 ml) was sti ⁇ ed at room temperature overnight. The resulting precipitate was collected by filtration, washed with 1,4-dioxane and acetonitrile to give 3-ethyl 5-methyl 2-(acetoimidoylamino)-lH-indole-3,5-dicarboxylate hydrochloride as a white solid (0.537 g, 87%).
  • step E-2 to a suspension of 3-ethyl 5-methyl 2-(acetoimidoylamino)- lH-indole-3,5-dicarboxylate hydrochloride (0.540 g) in methanol (5 ml) was added a solution of sodium bicarbonate (0.500 g) in water (5 ml), and the mixture was sti ⁇ ed at 60°C for 1.5 hours.
  • step E-3 the methyl 4-chloro-2-methyl-9H-pyrimido[4,5-b]indole-6- carboxylate as a brown solid is prepared in a similar manner as described in the step D-8 for the preparation of starting compound D.
  • step D-8 the preparation of starting compound D.
  • the 4-chloro-9H-pyrimido[4,5-b]indole-6-carbonitrile is prepared from 3-bromo-4- nitrobenzonitrile in a similar manner as described in the preparation of starting compound D, the methyl 4-chloro-9H-pyrimido[4,5-b]indole-6-carboxylate.
  • step G-1 a suspension of ethyl 2-amino-6-cyanoindole-3-carboxylate (0.96 g) obtained in preparation of starting compound F and cyanamide (0.88 g) in 1,4-dioxane (50 ml) was added 36% hydrochrolic acid (0.84 ml). The mixture was refluxed for 2 days and, after cooling to room temperature, concentrated in vacuo. The residue was washed with diethylether and triturated with methanol to give precipitates, that was collected by a paper filter and washed with methanol. The collected solid was dried at 85°C in vacuo to give a colorless solid (0.72 g, 66%).
  • step G-2 the 2-Amino-4-chloro-6-cyano-9H-pyrimido[4,5-b]indole hydrochloride Salt a yellow solid is prepared from 2-amino-6-cyano-4- hydroxy-9H-pyrimido[4,5-b]indole in a similar manner as described in step D-8 of [starting compound Dj.
  • step H-l to a mixture of ethyl 2-amino-5-cyano-lH-indole-3-carb- oxylate (1.72 g) and methylthiocyanate (37 ml) was added 4 N HCI in 1,4- dioxane (37 ml). The mixture was sti ⁇ ed at room temperature overnight, at 60°C for 1 hour, then cooled to room temperature. The resulting precipitate was collected by filtration, washed with diethyl ether to give the ethyl 5- cyano-2-(methylsulfanylimidoylamino)-lH-indole-3-carboxylate hydrochloride (2.54 g, 100%) as an orange solid.
  • step H-2 to a suspension of ethyl 5-cyano-2-(mefhylsulfanylimidoyl- amino)-lH-indole-3 -carboxylate hydrochloride (6.58 g) in ethanol (120 ml) and water (20 ml) was added sodium hydroxide (2.17 g). The mixture was sti ⁇ ed at 50°C for 0.5 hours, and concentrated in vacuo. The residue was suspended in ethanol, and then neutrallized with aqueous 4 N HCI solution.
  • step 3 to a suspension of 2-(methylsulfanyl)-4-oxo-4,9-dihydro-3H- pyrimido[4,5- ⁇ ]indole-6-carbonitrile (2.34 g) and NN-dimethylaniline (3 ml) in 1,4-dioxane (9 ml) was added phosphorus oxichloride (10.4 ml). The mixture was sti ⁇ ed at 100°C overnight. After cooling, the reaction mixture was poured into ice water, and the mixture was sti ⁇ ed at 0°C for 15 minutes.
  • Example 1-4 to 1-18 as shown in Table 1 were synthesized.

Abstract

La présente invention concerne des dérivés 4-phényl-pyrimido [4,5-b]indoles convenant comme principes actifs de spécialités pharmaceutiques. Les dérivés 4-phényl-pyrimido [4,5-b]indoles de la présente invention, qui font preuve d'une activité inhibitrice des MKK7 et MKK4, conviennent pour le traitement et la prophylaxie d'affections associée à l'activité des MKK7 et MKK4. Les affections ainsi concernées sont essentiellement des troubles inflammatoires et immunorégulateurs, mais également des pathologies telles que l'asthme, la dermite atopique, la rhinite, la rhinite allergique, les allergies, la broncho-pneumopathie chronique obstructive, le choc septique, l'arthrite, les maladies articulaires et les lésions myocardiques, ainsi que des pathologies auto-immunes telles que l'arthrite rhumatoïde, la maladie de Basedow, et l'athérosclérose ainsi que le cancer. Les composés de l'invention sont également indiqués dans le cas d'ischémie, de lésion myocardique, d'hypertension pulmonaire, d'insuffisante rénale, de chorée de Huntington, et d'hypertrophie cardiaque, ainsi que de troubles neurodégénératifs tels que la maladie de Parkinson, la maladie d'Alzheimer et l'ischémie focale.
PCT/EP2003/014194 2002-12-27 2003-12-13 Derives 4-phenyl-pyrimido [4,5-b]indoles WO2004058764A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003300522A AU2003300522A1 (en) 2002-12-27 2003-12-13 4-phenyl-pyrimido (4,5-b) indole derivatives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP02029029 2002-12-27
EP02029029.2 2002-12-27

Publications (1)

Publication Number Publication Date
WO2004058764A1 true WO2004058764A1 (fr) 2004-07-15

Family

ID=32668748

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2003/014194 WO2004058764A1 (fr) 2002-12-27 2003-12-13 Derives 4-phenyl-pyrimido [4,5-b]indoles

Country Status (2)

Country Link
AU (1) AU2003300522A1 (fr)
WO (1) WO2004058764A1 (fr)

Cited By (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010048446A2 (fr) 2008-10-22 2010-04-29 Genentech, Inc. Modulation de la dégénérescence d'axons
JP2012501984A (ja) * 2008-09-08 2012-01-26 ウニヴェルシダ’デリ ストゥディ ディ ミラノ−ビコッカ ＮＰＭ−ＡＬＫ、ＲＥＴおよびＢＣＲ−ＡＢＬのα−カルボリン阻害剤
US20120238751A1 (en) * 2011-03-15 2012-09-20 Trius Therapeutics, Inc. Tricyclic gyrase inhibitors
WO2013110198A1 (fr) 2012-01-27 2013-08-01 Université de Montréal Dérivés de pyrimido[4,5-b]indole et leur utilisation dans l'expansion des cellules souches hématopoïétiques
US20140343051A1 (en) * 2013-05-17 2014-11-20 Rsem Limited Partnership Methods to modulate acute myeloid leukemia stem/progenitor cell expansion and/or differentiation
JP2016512198A (ja) * 2013-03-06 2016-04-25 アロステロス セラピューティクス， インコーポレイテッド ＣａＭＫＩＩ阻害剤及びその使用
EP3011970A2 (fr) 2009-10-22 2016-04-27 F. Hoffmann-La Roche AG Modulation de la dégénérescence axonale
WO2016191879A1 (fr) 2015-06-05 2016-12-08 Héma-Québec Méthodes pour cultiver et/ou différencier des cellules souches hématopoïétiques en progéniteurs, et utilisations correspondantes
CN107208111A (zh) * 2014-09-18 2017-09-26 蒙特利尔大学 用于增强病毒基因转移至人造血细胞的化合物和方法
US10190096B2 (en) * 2014-12-18 2019-01-29 President And Fellows Of Harvard College Methods for generating stem cell-derived β cells and uses thereof
US10253298B2 (en) 2014-12-18 2019-04-09 President And Fellows Of Harvard College Methods for generating stem cell-derived beta cells and methods of use thereof
US10655106B2 (en) 2013-06-11 2020-05-19 President And Fellows Of Harvard College SC-beta cells and compositions and methods for generating the same
US10759792B2 (en) 2014-09-05 2020-09-01 The Johns Hopkins University CaMKII inhibitors and uses thereof
WO2020225077A1 (fr) * 2019-05-03 2020-11-12 Idorsia Pharmaceuticals Ltd Dérivés de pyrimido[4,5-b]indole en tant qu'inhibiteurs de pdhk1
WO2021018820A1 (fr) * 2019-07-29 2021-02-04 Heparegenix Gmbh Inhibiteurs de protéine kinase de pyrazolo-pyridine substitués par hétéroaryle pour favoriser la régénération du foie ou réduire ou prévenir la mort des hépatocytes
WO2021119834A1 (fr) * 2019-12-18 2021-06-24 Universite De Montreal Modulateurs de l'adaptateur de cullin 3 kbtbd4 en tant que composés anticancéreux
US11085025B2 (en) 2014-12-18 2021-08-10 President And Fellows Of Harvard College Serum-free in vitro directed differentiation protocol for generating stem cell-derived beta cells and uses thereof
EP2247558B1 (fr) 2008-02-14 2022-02-02 Eli Lilly and Company Nouveaux agents d'imagerie pour la détection d'une dysfonction neurologique
US11466256B2 (en) 2018-08-10 2022-10-11 Vertex Pharmaceuticals Incorporated Stem cell derived islet differentiation
US11731968B2 (en) 2018-06-21 2023-08-22 Heparegenix Gmbh Tricyclic protein kinase inhibitors for promoting liver regeneration or reducing or preventing hepatocyte death
US11858927B2 (en) 2018-01-31 2024-01-02 Heparegenix Gmbh Protein kinase MKK4 inhibitors for promoting liver regeneration or reducing or preventing hepatocyte death
US11912701B2 (en) 2018-07-16 2024-02-27 Heparegenix Gmbh Protein kinase inhibitors for promoting liver regeneration or reducing or preventing hepatocyte death
US11945795B2 (en) 2017-11-15 2024-04-02 Vertex Pharmaceuticals Incorporated Islet cell manufacturing compositions and methods of use

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998042708A2 (fr) * 1997-01-08 1998-10-01 Pharmacia & Upjohn Company Amines tricycliques pharmaceutiquement actives
WO2003037898A1 (fr) * 2001-10-31 2003-05-08 Bayer Healthcare Ag Derives de pyrimido [4,5-b] indole

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998042708A2 (fr) * 1997-01-08 1998-10-01 Pharmacia & Upjohn Company Amines tricycliques pharmaceutiquement actives
WO2003037898A1 (fr) * 2001-10-31 2003-05-08 Bayer Healthcare Ag Derives de pyrimido [4,5-b] indole

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
BOROVIK, V. P. ET AL: "Synthesis of functional 2-substituted 4-phenyl-9H-pyrimido[4,5- b]indoles", RUSSIAN CHEMICAL BULLETIN (TRANSLATION OF IZVESTIYA AKADEMII NAUK, SERIYA KHIMICHESKAYA) (2002), 51(11), 2129-2133, XP002279589 *
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; BOROVIK, V. P. ET AL: "Synthesis of 2-substituted pyrimido[4,5-b]indoles and N-phenyl-2,2-diethoxy-3-arylideneindolines", XP002279590, retrieved from STN Database accession no. 84:121769 *
V SB., KHIMIYA I FARMAKOL. INDOL'N. SOEDINENII (1975) 50 FROM: REF. ZH., KHIM. 1975, ABSTR. NO. 23ZH233 *

Cited By (46)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2247558B1 (fr) 2008-02-14 2022-02-02 Eli Lilly and Company Nouveaux agents d'imagerie pour la détection d'une dysfonction neurologique
JP2012501984A (ja) * 2008-09-08 2012-01-26 ウニヴェルシダ’デリ ストゥディ ディ ミラノ−ビコッカ ＮＰＭ−ＡＬＫ、ＲＥＴおよびＢＣＲ−ＡＢＬのα−カルボリン阻害剤
WO2010048446A2 (fr) 2008-10-22 2010-04-29 Genentech, Inc. Modulation de la dégénérescence d'axons
EP3011970A2 (fr) 2009-10-22 2016-04-27 F. Hoffmann-La Roche AG Modulation de la dégénérescence axonale
US20120238751A1 (en) * 2011-03-15 2012-09-20 Trius Therapeutics, Inc. Tricyclic gyrase inhibitors
US10858360B2 (en) 2011-03-15 2020-12-08 Merck Sharp & Dohme Corp. Tricyclic gyrase inhibitors
JP2014508173A (ja) * 2011-03-15 2014-04-03 トリウス セラピューティックス インコーポレイテッド 三環式ジャイレース阻害薬
US9732083B2 (en) * 2011-03-15 2017-08-15 Merck Sharp & Dohme Corp. Tricyclic gyrase inhibitors
US20150011543A1 (en) * 2012-01-27 2015-01-08 Universite De Montreal Pyrimido[4,5-b]indole derivatives and use thereof in the expansion of hematopoietic stem cells
JP2015504902A (ja) * 2012-01-27 2015-02-16 ユニヴェルスィテ・ドゥ・モントリオール ピリミド［４，５−ｂ］インドール誘導体及び造血幹細胞の増殖におけるその使用
US10336747B2 (en) 2012-01-27 2019-07-02 Université de Montréal Pyrimido[4,5-B]indole derivatives and use thereof in the expansion of hematopoietic stem cells
US20170334904A1 (en) * 2012-01-27 2017-11-23 Université de Montréal Pyrimido[4,5-b]indole derivatives and use thereof in the expansion of hematopoietic stem cells
US9409906B2 (en) 2012-01-27 2016-08-09 Universite De Montreal Pyrimido[4,5-B]indole derivatives and use thereof in the expansion of hematopoietic stem cells
KR102098122B1 (ko) 2012-01-27 2020-04-07 유니버시떼 드 몬트리얼 피리미도[4,5-b]인돌 유도체 및 조혈 줄기 세포의 증식에서의 이의 용도
CN104144931A (zh) * 2012-01-27 2014-11-12 蒙特利尔大学 嘧啶并[4,5-b]吲哚衍生物及其在造血干细胞的扩增中的应用
KR20140121454A (ko) * 2012-01-27 2014-10-15 유니버시떼 드 몬트리얼 피리미도[4,5-b]인돌 유도체 및 조혈 줄기 세포의 증식에서의 이의 용도
WO2013110198A1 (fr) 2012-01-27 2013-08-01 Université de Montréal Dérivés de pyrimido[4,5-b]indole et leur utilisation dans l'expansion des cellules souches hématopoïétiques
JP2016512198A (ja) * 2013-03-06 2016-04-25 アロステロス セラピューティクス， インコーポレイテッド ＣａＭＫＩＩ阻害剤及びその使用
US9757378B2 (en) * 2013-05-17 2017-09-12 Universite De Montreal Methods to modulate acute myeloid leukemia stem/progenitor cell expansion and/or differentiation
US20140343051A1 (en) * 2013-05-17 2014-11-20 Rsem Limited Partnership Methods to modulate acute myeloid leukemia stem/progenitor cell expansion and/or differentiation
US10655106B2 (en) 2013-06-11 2020-05-19 President And Fellows Of Harvard College SC-beta cells and compositions and methods for generating the same
US11162078B2 (en) 2013-06-11 2021-11-02 President And Fellows Of Harvard College SC-beta cells and compositions and methods for generating the same
US11104883B2 (en) 2013-06-11 2021-08-31 President And Fellows Of Harvard College SC-beta cells and compositions and methods for generating the same
US11078463B2 (en) 2013-06-11 2021-08-03 President And Fellows Of Harvard College SC-beta cells and compositions and methods for generating the same
US11325908B2 (en) 2014-09-05 2022-05-10 The Johns Hopkins University CaMKII inhibitors and uses thereof
US10759792B2 (en) 2014-09-05 2020-09-01 The Johns Hopkins University CaMKII inhibitors and uses thereof
CN107208111B (zh) * 2014-09-18 2021-07-06 蒙特利尔大学 用于增强病毒基因转移至人造血细胞的化合物和方法
CN107208111A (zh) * 2014-09-18 2017-09-26 蒙特利尔大学 用于增强病毒基因转移至人造血细胞的化合物和方法
US11085026B2 (en) 2014-12-18 2021-08-10 President And Fellows Of Harvard College Serum-free in vitro directed differentiation protocol for generating stem cell-derived beta cells and uses thereof
US11155787B2 (en) 2014-12-18 2021-10-26 President And Fellows Of Harvard College Methods for generating stem cell-derived beta cells and methods of use thereof
US10927350B2 (en) 2014-12-18 2021-02-23 President And Fellows Of Harvard College Methods for generating stem cell-derived beta cells and uses thereof
US11085025B2 (en) 2014-12-18 2021-08-10 President And Fellows Of Harvard College Serum-free in vitro directed differentiation protocol for generating stem cell-derived beta cells and uses thereof
US11085027B2 (en) 2014-12-18 2021-08-10 President And Fellows Of Harvard College Serum-free in vitro directed differentiation protocol for generating stem cell-derived beta cells and uses thereof
US10253298B2 (en) 2014-12-18 2019-04-09 President And Fellows Of Harvard College Methods for generating stem cell-derived beta cells and methods of use thereof
US10190096B2 (en) * 2014-12-18 2019-01-29 President And Fellows Of Harvard College Methods for generating stem cell-derived β cells and uses thereof
WO2016191879A1 (fr) 2015-06-05 2016-12-08 Héma-Québec Méthodes pour cultiver et/ou différencier des cellules souches hématopoïétiques en progéniteurs, et utilisations correspondantes
US11945795B2 (en) 2017-11-15 2024-04-02 Vertex Pharmaceuticals Incorporated Islet cell manufacturing compositions and methods of use
US11858927B2 (en) 2018-01-31 2024-01-02 Heparegenix Gmbh Protein kinase MKK4 inhibitors for promoting liver regeneration or reducing or preventing hepatocyte death
US11731968B2 (en) 2018-06-21 2023-08-22 Heparegenix Gmbh Tricyclic protein kinase inhibitors for promoting liver regeneration or reducing or preventing hepatocyte death
US11912701B2 (en) 2018-07-16 2024-02-27 Heparegenix Gmbh Protein kinase inhibitors for promoting liver regeneration or reducing or preventing hepatocyte death
US11466256B2 (en) 2018-08-10 2022-10-11 Vertex Pharmaceuticals Incorporated Stem cell derived islet differentiation
US11525120B2 (en) 2018-08-10 2022-12-13 Vertex Pharmaceuticals Incorporated Stem cell derived islet differentiation
WO2020225077A1 (fr) * 2019-05-03 2020-11-12 Idorsia Pharmaceuticals Ltd Dérivés de pyrimido[4,5-b]indole en tant qu'inhibiteurs de pdhk1
WO2021018820A1 (fr) * 2019-07-29 2021-02-04 Heparegenix Gmbh Inhibiteurs de protéine kinase de pyrazolo-pyridine substitués par hétéroaryle pour favoriser la régénération du foie ou réduire ou prévenir la mort des hépatocytes
WO2021119834A1 (fr) * 2019-12-18 2021-06-24 Universite De Montreal Modulateurs de l'adaptateur de cullin 3 kbtbd4 en tant que composés anticancéreux
CN114845719A (zh) * 2019-12-18 2022-08-02 蒙特利尔大学 作为抗癌化合物的cullin 3连接蛋白kbtbd4的调节剂

Also Published As

Publication number Publication date
AU2003300522A1 (en) 2004-07-22

Similar Documents

Publication Publication Date Title
WO2004058764A1 (fr) Derives 4-phenyl-pyrimido [4,5-b]indoles
WO2003037898A1 (fr) Derives de pyrimido [4,5-b] indole
JP6867417B2 (ja) キナーゼ阻害剤としてのｎ−（置換フェニル）−スルホンアミド誘導体
EP1556384B1 (fr) Composes pyrimido presentant une activite antiproliferative
EP2947084B1 (fr) Composé hétérocyclique à cinq et six chaînons, procédé de préparation, composition pharmaceutique et application associés
US20060276497A1 (en) Novel multicyclic compounds and the use thereof
US20080269238A1 (en) Thiazolopyrimidine Derivative
Havlicek et al. 8-Azapurines as new inhibitors of cyclin-dependent kinases
WO2012098068A1 (fr) Pyrazolopyrimidines en tant qu'inhibiteurs de dyrk1a et dyrk1b
CZ164196A3 (en) Pyrimidine derivatives with condensed heterocyclic ring and pharmaceutical compositions based thereon
BRPI0622030A2 (pt) Derivados de purina 7-substituída, para imunossupressão
ZA200209065B (en) Novel multicyclic compounds and the use thereof.
US20080242667A1 (en) Pyrimidinyl-Pyrazole Inhibitors of Aurora Kinases
EP0861253A1 (fr) Composes hetero-aromatiques bicycliques utilises comme inhibiteurs de proteine tyrosine kinase
JP2002504552A (ja) ６，９−ジ置換２−［トランス−（４−アミノシクロヘキシル）アミノ］プリン
CA2211669A1 (fr) Pyrazolo [3,4-d] pyrimidin-4-one a substitution en position 6 et leurs compositions et procedes d'utilisation
BG106568A (bg) 5-(2-заместени-5-хетероциклилсулфонилпирид-3-ил)-дихидропиразоло[4,3-d]пиримидин-7-они като фосфодиестеразни инхибитори
WO2004113303A1 (fr) Dérivés d'indazole/pyrzolo[4,3-c]pyridine utilisés comme inhibiteurs de jnk, compositions et méthode s'y rapportant et produite intermédiaire
MX2007013383A (es) Formas solidas de 1-(5-(1h-1,2,4-triazol-5-il)(1h-indazol-3-il))-3 -(2-piperidiletoxi)benceno.
EP2838901B1 (fr) Dérivés de 6-(4-(1-amino-3-hydroxycyclobutyl)phényl)-5-phényl(furo, thiéno ou pyrrolo)[2,3-d]pyrimidin-4-one pour le traitement du cancer
JP2020512315A (ja) Ｍｋ２阻害剤として有用なヘテロアリール化合物
JP2020511468A (ja) Ｍｋ２阻害剤の重水素化アナログおよびその使用
TWI472530B (zh) 蛋白質激酶抑制劑
EP1636235B1 (fr) Derives de pyridinyl-pyrazolo-pyrimidinones inhibiteurs de la phosphodiesterase vii
US6291447B1 (en) Granulatimide compounds and uses thereof

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): BW GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: JP

WWW Wipo information: withdrawn in national office

Country of ref document: JP