WO2004096808A1 - Triazine compounds and their use - Google Patents

Triazine compounds and their use Download PDF

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Publication number
WO2004096808A1
WO2004096808A1 PCT/GB2004/001761 GB2004001761W WO2004096808A1 WO 2004096808 A1 WO2004096808 A1 WO 2004096808A1 GB 2004001761 W GB2004001761 W GB 2004001761W WO 2004096808 A1 WO2004096808 A1 WO 2004096808A1
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WIPO (PCT)
Prior art keywords
pyrazol
triazino
dimethyl
indole
benzyl
Prior art date
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PCT/GB2004/001761
Other languages
French (fr)
Inventor
William Harris
Derek Edward John
Stuart Firth-Clark
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De Novo Pharmaceuticals Limited
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Publication of WO2004096808A1 publication Critical patent/WO2004096808A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • Alzheimer's disease is the most common form of dementia among older people, and affects parts of the brain that control thought, memory and language. Susceptibility to Alzheimer's disease increases with age, but the disease is not a normal part of the ageing process.
  • Alzheimer's disease is associated with regions of accumulated proteins in the brain. These dense regions, termed “amyloid plaques” and “neurofibrilliary tangles", contain ⁇ -amyloid precursor protein ( ⁇ -APP). ⁇ -APP is degraded by ⁇ -amyloid converting enzyme (BACE, also known as ⁇ - secretase) to produce ⁇ -amyloid peptide A ⁇ 40/42, which accumulates in the plaques.
  • BACE ⁇ -amyloid converting enzyme
  • a first-aspect of the invention is a compound of formula (I)
  • R 1 is hydrogen, alkyl, -alkyl-aryl, -alkyl-heterocycloalkyl or -alkyl-O- heterocycloalkyl;
  • R 2 is hydrogen, hydroxy, amino, nitro, alkoxy, alkyl, aryl or heteroaryl
  • R 3 is hydrogen, alkyl or aryl
  • R 4 is hydrogen, alkyl, aryl, heteroaryl, -CH(aryl) 2 , -alkyl-aryl or -C(O)O- alkyl;
  • R 5 is alkyl, hydroxy or amino; or a pharmaceutically acceptable salt thereof.
  • Compounds of the invention may act as inhibitors of BACE and as a consequence may have utility in the treatment or prevention of diseases or conditions in which BACE is implicated. In particular, they may have utility in the treatment or prevention of a disease or condition associated with the deposition and/or elevated levels of amyloid beta peptide (A ⁇ ), for example Alzheimer's disease.
  • a ⁇ amyloid beta peptide
  • Another aspect of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier or diluent.
  • R 1 is preferably hydrogen, methyl, ethyl, propyl, isopropyl, butyl, pyrazol-1-yIethyl, hydroxyethyl, (2-tetrahydro-pyran-2-yloxy)ethyl or benzyl.
  • R 2 is preferably hydrogen.
  • R 3 is preferably hydrogen, methyl or phenyl.
  • R 4 is hydrogen, methyl, ethyl, propyl, butyl or-C(O)OCH 2 CH 3 .
  • R 4 examples include phenyl, -CH(phenyl) 2 , benzyl, 1 -phenylethyl, 2- phenylethyl, naphthylmethyl, quinolin-4-yl and pyridin-2-yl, any of which is optionally substituted.
  • R 5 is preferably hydrogen, methyl, hydroxy or amino.
  • alkyl refers to an optionally substituted straight or branched chain alkyl moiety having from one to six carbon atoms. The term includes, for example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl and the like. The group may be substituted with one or more substituents selected from hydroxy, amino, halogen and the like.
  • C.,. 6 alkyl has the same meaning.
  • alkoxy refers to a straight or branched chain alkoxy group containing one to six carbon atoms.
  • the term includes, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentoxy, hexoxy and the like.
  • C.,. ⁇ alkoxy has the same meaning.
  • halogen refers to F, CI, Br or I.
  • heterocycloalkyl refers to a saturated heterocyclic moiety having from three to seven ring carbon atoms and one or more ring heteroatoms selected from nitrogen, oxygen and sulphur.
  • the term includes, for example, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl and the like.
  • aryl refers to an optionally substituted aromatic ring system having six to fourteen ring carbon atoms.
  • the group may be a polycyclic ring system, having two or more rings, at least one of which is aromatic. This term includes, for example, phenyl and naphthyl.
  • the group may be substituted with one or more substituents selected from alkoxy, alkylamino, dialkylamino, halogen, hydroxy, nitro, benzyloxy, -OC(O)C(O)O-alkyl, -CF 3 , -S(O) 2 -alkyl, -OC(O)-alkyl, alkyl, -C(O)O-alkyl and -C(O)OH and the like.
  • substituents selected from alkoxy, alkylamino, dialkylamino, halogen, hydroxy, nitro, benzyloxy, -OC(O)C(O)O-alkyl, -CF 3 , -S(O) 2 -alkyl, -OC(O)-alkyl, alkyl, -C(O)O-alkyl and -C(O)OH and the like.
  • heteroaryl refers to an optionally substituted aromatic ring system having from four to fourteen ring carbon atoms and, in addition, at least one ring heteroatom selected from nitrogen, oxygen and sulphur.
  • the group may be a polycyclic ring system, having two or more rings, at least one of which is aromatic.
  • the term includes, for example, furanyl, thiophenyl, pyridyl, indolyl, quinolyl and the like.
  • the group may be substituted with, for example, one or more of the substituents named in the definition of "aryl".
  • Preferred compounds of the invention include: 2-(3,5-dimethyl-pyrazol-1-yl)-9-ethyl-9H-1 ,3,4,9-tetraaza-fluorene; 2-(3,5-dimethyl-pyrazol-1-yl)-9-methyl-9H-1,3,4,9-tetraaza-fluorene; 9-benzyl-2-(3,5-dimethyl-pyrazol-1-yl)-9H-1 ,3,4,9-tetraaza-fluorene; 9-benzyl-2-(4-benzyl-3,5-dimethyl-pyrazol-1-yl)-9H-1 ,3,4,9-tetraaza- fluorene;
  • Compounds of the invention may be chiral. They may be in the form of a single enantiomer or diastereomer, or a racemate.
  • the compounds of the invention may be prepared in racemic form, or ⁇ prepared in individual enantiomeric form by specific synthesis or resolution as will be appreciated in the art.
  • the compounds may, for example, be resolved into their enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid followed by fractional crystallisation and regeneration of the free base.
  • the 0 enantiomers of the novel compounds may be separated by HPLC using a chiral column.
  • a compound of the invention may be in a protected amino, protected hydroxy or protected carboxy form.
  • protected amino refers to amino, hydroxy and ⁇ carboxy groups which are protected in a manner familiar to those skilled in the art.
  • an amino group can be protected by a benzyloxycarbonyl, tert- butoxycarbonyl, acetyl or like group, or in the form of a phthalimido or like group.
  • a carboxyl group can be protected in the form of a readily cleavable ester such as the methyl, ethyl, benzyl or tert-butyl ester.
  • a hydroxy group can be protected 0 by an alkyl or like group.
  • Compounds of the invention may be in the form of pharmaceutically acceptable salts, for example, addition salts of inorganic or organic acids.
  • inorganic acid addition salts include, for example, salts of hydrobromic acid, hydrochloric acid, nitric acid, phosphoric acid and sulphuric acid.
  • Organic acid 5 addition salts include, for example, salts of acetic acid, benzenesulphonic acid, benzoic acid, camphorsulphonic acid, citric acid, 2-(4-chlorophenoxy)-2- methylpropionic acid, 1 ,2-ethanedisulphonic acid, ethanesulphonic acid, ethylenediaminetetraacetic acid (EDTA), fumaric acid, glucoheptonic acid, gluconicacid, glutamicacid, N-glycolylarsanilicacid, 4-hexylresorcinol, hippuric 0 acid, 2-(4-hydroxybenzoyl)benzoicacid, 1-hydroxy-2-naphthoicacid, 3-hydroxy- 2-naphthoic acid, 2-hydroxyethanesulphonic acid, lactobionic acid, n-dodecyl sulphuric acid, maleic acid, malic acid, mandelic acid, methanesulphonic acid, methyl s
  • Salts may also be formed with inorganic bases.
  • inorganic base salts include, for example, salts of aluminium, bismuth, calcium, lithium, magnesium, potassium, sodium, zinc and the like.
  • Organic base salts include, for example, 0 salts of N, N'-dibenzylethylenediamine, choline (as a counterion), diethanolamine, ethanolamine, ethylenediamine, N,N' -bis(dehydroabietyl)ethylenediamine, N-methylglucamine, procaine, tris(hydroxymethyl)aminomethane ("TRIS”) and the like.
  • TIS tris(hydroxymethyl)aminomethane
  • Such salts may be used in therapy.
  • Such salts may be prepared by reacting the compound with a suitable acid or base in a conventional manner.
  • a compound of the invention may be prepared by any suitable method known in the art and/or by the following processes (in which X is a leaving group 0 such as CI or Br):
  • Any mixtures of final products or intermediates obtained can be separated on the basis of the physico-chemical differences of the constituents, in a known manner, into the pure final products or intermediates, for example by chromatography, distillation, fractional crystallisation, or by the formation of a salt if appropriate or possible under the circumstances.
  • the activity and selectivity of the compounds may be determined by any suitable assay known in the art.
  • the active compound may be administered orally, intravenously, rectally, parenterally, by inhalation (pulmonary delivery), topically, ocularly, nasally, orto the buccal cavity.
  • Oral administration is preferred.
  • a composition of the present invention may take the form of any of the known pharmaceutical compositions for such methods of administration.
  • the compositions may be formulated in a manner known to those skilled in the art so as to give a controlled release, for example rapid release or sustained release, of the compounds of the present invention.
  • Pharmaceutically acceptable carriers suitable for use in such compositions are well known in the art.
  • the compositions of the invention may contain 0.1-99% by weight of active compound.
  • the compositions of the invention are generally prepared in unit dosage form. Preferably, a unit dose comprises the active ingredient in an amount of 1- ⁇ 00 mg.
  • the excipients used in the preparation of these compositions are the excipients known in the art.
  • Appropriate dosage levels may be determined by any suitable method known to one skilled in the art. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health and sex of the patient; diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the disease undergoing treatment.
  • compositions for oral administration include known pharmaceutical forms for such administration, for example tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups and elixirs.
  • Compositions intended for oral use may be prepared according to any method known to the art.
  • the compositions may contain one or more agents such as sweetening agents, flavouring agents, colouring agents and preserving agents, in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example corn starch or alginic acid; binding agents, for example starch gelatin, acacia, microcrystalline cellulose or polyvinyl pyrrolidone; and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent for example calcium carbonate, calcium phosphate or kaolin
  • water or an oil medium for example peanut oil, liquid paraffin or olive oil.
  • Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids, for example polyoxyethylene sorbitan monooleate.
  • suspending agents for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl pyrrolidone, gum tragacanth and gum
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl or n-propyl p- hydroxybenzoate, one or more colouring agents, one or more flavouring agents, and one or more sweetening agents, such as sucrose or saccharin.
  • preservatives for example ethyl or n-propyl p- hydroxybenzoate
  • colouring agents for example ethyl or n-propyl p- hydroxybenzoate
  • flavouring agents such as sucrose or saccharin.
  • sweetening agents such as sucrose or saccharin.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol.
  • Sweetening agents, such as those set forth above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable sweetening, flavouring and colouring agents may also be present.
  • the pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin, or mixtures of these.
  • Suitable emulsifying agents may be naturally occurring gums, for example gum acacia or gum tragacanth, naturally occurring phosphatides, for example soya bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavouring agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavouring and colouring agents.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be in a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1 ,3- butanediol.
  • Suitable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid, find use in the preparation of injectables.
  • the compounds of the invention may also be administered in the form of suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Such materials are cocoa butter and polyethylene glycols.
  • compositions for topical administration may also be suitable for use in the present invention.
  • the active compound may be dispersed in a pharmaceutically acceptable cream, ointment or gel.
  • a suitable cream may be. prepared by incorporating the active compound in a topical vehicle such as light liquid paraffin, dispersed in a aqueous medium using surfactants.
  • An ointment may be prepared by mixing the active compound with a topical vehicle such as a mineral oil or wax.
  • a gel may be prepared by mixing the active compound with a topical vehicle comprising a gelling agent.
  • Topically administrable compositions may also comprise a matrix in which the pharmaceutically active compounds of the present invention are dispersed so that the compounds are held in contact with the skin in order to administer the compounds transdermally.
  • Oven-dried alumina ( ⁇ g, ⁇ O mmol) was stirred with a 1M solution of potassium tert-butoxide in tetrahydrofuran ( ⁇ ml, ⁇ mmol) under nitrogen for 10 minutes. Solvent was evaporated under vacuo to give a free-flowing solid. The vigorously stirred solid under nitrogen was treated dropwise with pentane-2,4- dione ( ⁇ 01 mg, ⁇ mmol). After stirring for 40 minutes the mixture was treated with benzyl bromide (8 ⁇ mg, ⁇ mmol) and stirred for ⁇ hours. The solid was applied to a short silica gel column and eluted with dichloromethane.
  • the 1-ethyl-1H-indole-2,3-dione used as the starting material was prepared as follows. Isatin (3 g, 20 mmol), potassium carbonate ( ⁇ .6 g, 40 mmol) and iodomethane (3.43 g, 22 mmol) were stirred in tetrahydrofuran (100 ml) under nitrogen and treated with tetra-n-butyl ammonium hydrogen sulphate (100 mg). The mixture was heated at reflux, cooled to room temperature and the solvent ⁇ evaporated. The residue was partitioned between dichloromethane (100 ml) and water (100 ml).
  • Example 6 3-[4-(2-benzyloxy-benzyl)-3,5-dimethyl-pyrazol-1 -yl]-5W-1 ,2,4- triazino[5,6- ⁇ ]indole
  • Intermediate 4 10 mg, ⁇ O ⁇ mol
  • Intermediate 6 ⁇ O mg, 170 ⁇ mol
  • Example 8 2-[3,5-dimethyl-1-(5/y-1,2,4-triazino[5,6- )]indol-3-yl)-1H-pyrazol- 4-ylmethyl]-phenol In a manner analogous to Example 7, using Intermediate 9 in place of
  • Example 36 acetic acid 4-[3,5-dimethyl-1-(5-methyl-5tf-1,2,4-triazino[5,6- 6]indol-3-yl)-1 Y-pyrazol-4-ylmethyl]-phenyl ester
  • Example 26 In a manner analogous to that of Example 36, using 3-[3,5-dimethyl-1 -(5- methyl-6H-1 ,2,4-triazino[5,6-b]indol-3-yl)-1 H-pyrazol-4-ylmethyl]-phenol (Example 26, 10 mg, 26 ⁇ mol) was prepared the title compound (5.67 mg, 51 %). Hplc/ms (positive ion) Rt 4.19 min, m/z 427 (M+H + ).
  • Example 38 acetic acid 2-[3,5-dimethyl-1-(5-methyl-5W-1,2,4-triazino[5,6- 6]indol-3-yl)-1 //-pyrazol-4-ylmethyl]-phenyl ester
  • Example 20 In a manner analogous to that of Example 36, using 2-[3,5-dimethyl-1 -(5- methyl-5H-1 ,2,4-triazino[5,6-i ]indol-3-yl)-1 H-pyrazol-4-ylmethyl]-phenol (Example 20, 10 mg, 26 ⁇ mol) was prepared the title compound (2 mg, 18%). Hplc/ms (positive ion) Rt 4.18 min, m/z 427 (M+H + ).
  • Example 40 5-ethyl-3-[4-(2-fluoro-benzyl)-3,5-dimethyl-pyrazol-1 -yl]-5H- 1,2,4-triazino[5,6-b]indole
  • Example 48 3-[4-(2-benzyloxy-benzyl)-3,5-dimethyl-pyrazol-1 -yl]-5-ethyl-5 Y- 1 ,2,4-triazino[5,6-J ]indole
  • Example 54 3-[3,5-dimethyl-4-(4-trifluoromethyl-benzyl)-pyrazol-1 -yl]-5- ethyl-5H-1,2,4-triazino[5,6-6]indole
  • Example 60 3-(3,5-dimethyl-4-phenethyl-pyrazol-1 -yl)-5-ethyl-5H-1 ,2,4- triazino[5,6-/)]indole
  • Example 61 4-[1-(5-ethyl-5W-1,2,4-triazino[5,6- ⁇ ]indol-3-yl)-3,5-dimethyl-1 H- pyrazol-4-ylmethyl]-benzoic acid methyl ester
  • Example 63 4-[1-(5-ethyl-5H-1,2,4-triazino[5,6-i ]indol-3-yl)-3,5-dimethyl-1W- pyrazol-4-ylmethyl]-benzoic acid
  • Example 4 In a manner analogous to Example 64, using 3-(4-ethyl-3,5-dimethyl- pyrazol-1-yl)-5H-1,2,4-triazino[5,6-rj]indole (Example 4, 50 mg, 170 ⁇ mol), was prepared the title compound (10 mg, 18%). Hplc/ms (positive ion) Rt 4.3 min, m/z 321 (M+H + ).
  • Example 5 In a manner analogous to Example 64, using 3-(4-benzyl-3,5-dimethyl- pyrazol-1 -yl)-5/-/-1 ,2,4-triazino[5,6-6]indole (Example 5, 30 mg, 85 ⁇ mol) and 1 - iodopropane (16 mg, 94 ⁇ mol), was prepared the title compound (5 mg, 15%). Hplc/ms (positive ion) Rt 4.85 min, m/z 397 (M+H + ).
  • Example 4 In a manner analogous to Example 64, using 3-(4-ethyl-3,5-dimethyl- pyrazol-1-yl)-5H-1 ,2,4-triazino[5,6-fo]indole (Example 4, 50 mg, 170 ⁇ mol) and 1 -iodopropane (32 mg, 190 ⁇ mol), was prepared the title compound (15 mg, 26%). Hplc/ms (positive ion) Rt 4.53 min, m/z 335 (M+H + ).
  • Example 69 3-(3,5-dimethyl-4- ⁇ ropyl-pyrazol-1-yl)-5-propyl-5W-1,2,4- triazino[5,6-6]indole
  • Example 70 5-butyl-3-(3,5-dimethyl-pyrazol-1 -yl)-5W-1 ,2,4-triazino[5,6- ⁇ ]indole
  • Example 72 3-(4-benzyl-3,5-dimethyl-pyrazol-1 -yl)-5-butyl-5A -1 ,2,4- triazino[5,6- ⁇ ]indole
  • Example 73 5-butyl-3-(3,5-dimethyl-4-naphthalen-2-ylmethyl-pyrazol-1-yl)- 5H-1 ,2,4-triazino[5,6-Z ⁇ ]indole
  • 3-(3,5-dimethyl-4- naphthalen-2-ylmethyl-pyrazol-1-yl)-5H-1 ,2,4-triazino[5,6-J ]indole (Example 11 , 30 mg, 74 ⁇ mol) and 1-bromobutane (1 mg, 80 ⁇ mol), was prepared the title compound (5 mg, 15%).
  • Example 12 In a manner analogous to Example 64, using 3-[4-(2-fluoro-benzyl)-3, ⁇ - dimethyl-pyrazol-1-yl]-6W-1,2,4-triazino[5,6-Jb]indole (Example 12, 30 mg, 74 ⁇ mol) and 1-bromobutane (11 mg, 80 ⁇ mol), was prepared the title compound (5 mg, 16%). Hplc/ms (positive ion) Rt 5.12 min, m/z 429 (M+H + ).
  • Example 75 5-butyl-3-[3,5-dimethyl-4-(3-trifluoromethyl-benzyl)-pyrazol-1 - yl]-5tf-1,2,4-triazino[5,6-Jb]indole
  • Example 13 In a manner analogous to Example 64, using 3-[3,5-dimethyl-4-(3- trifluoromethyl-benzyl)-pyrazol-1 -yl]-6H-1 ,2,4-triazino[5,6-6]indole (Example 13, 30 mg, 71 ⁇ mol) and 1-bromobutane (11 mg, 80 ⁇ mol), was prepared the title compound (5 mg, 15%). Hplc/ms (positive ion) Rt 5.34 min, m/z 479 (M+H + ).
  • Example 76 5-butyl-3-(4-ethyl-3,5-dimethyl-pyrazol-1-yl)-5W-1,2,4- triazino[5,6- ⁇ ]indole
  • Example 4 In a manner analogous to Example 64, using 3-(4-ethyl-3,5-dimethyl- pyrazol-1 -yl)-5/-/-1,2,4-triazino[5,6- ]indole (Example 4, 50 mg, 170 ⁇ mol) and 1-bromobutane (26 mg, 190 ⁇ mol), was prepared the title compound (15 mg, 25%). Hplc/ms (positive ion) Rt 4.8 min, m/z 349 (M+H + ).
  • Example 77 5-benzyl-3-(3,4,5-trimethyl-pyrazol-1 -yl)-5//-1 ,2,4-triazino[5,6- ⁇ ]indole
  • Example 78 3-(4-benzyl-3,5-dimethyl-pyrazol-1 -yl)-5-isobutyl-5H-1 ,2,4- triazino[5,6- ⁇ ]indole
  • Example 6 In a manner analogous to Example 64, using 3-(4-benzyl-3,5-dimethyl- pyrazol-1-yl)-5H-1 ,2,4-triazino[ ⁇ ,6-b]indole (Example 6, 50 mg, 140 ⁇ mol) and 1 -iodo-2-methylpropane (28 mg, 150 ⁇ mol), was prepared the title compound (25 mg, 44%). Hplc/ms (positive ion) Rt ⁇ .05 min, m/z 411 (M+H + ).
  • Example 79 5-benzyl-3-(3,5-dimethyl-4-propyl-pyrazol-1-yl)-5W-1,2,4- triazino[5,6-i ]indole ⁇
  • benzyl bromide 24 mg, 140 ⁇ mol
  • Hplc/ms (positive ion) Rt 4.94 min, m/z 397 (M+H + ).
  • Example 80 oxalic acid 4-[3,5-dimethyl-1-(5-methyl-5H-1,2,4-triazino[5,6- b]indol-3-yl)-1/Y-pyrazol-4-ylmethyl]-phenyl ester ethyl ester
  • Example 81 5-isobutyl-3-(3,4,5-trimethyl-pyrazol-1 -yl)-5H-1 ,2,4-triazino[5,6- ⁇ ]indole
  • Example 82 3-(4-ethyl-3,5-dimethyl-pyrazol-1 -yl)-5-isobutyl-5W-1,2,4- 0 triazino[5,6-b]indole
  • Example 4 3-(4-ethyl-3,5-dimethyl- pyrazol-1-yl)-5H-1,2,4-triazino[5,6-b]indole (Example 4, 50 mg, 170 ⁇ mol) and 1 -iodo-2-methylpropane (35 mg, 190 ⁇ mol), was prepared the title compound (10 mg, 17%). Hplc/ms (positive ion) Rt 4.76 min, m/z 349 (M+H + ).
  • Example 83 3-(3,5-dimethyl-4-propyl-pyrazol-1-yl)-5-isobutyl-5W-1,2,4- triazino[5,6- ⁇ ]indole
  • Example 84 3-(3,5-dimethyl-4-propyl-pyrazol-1-yl)-5-isobutyl-5H-1,2,4- triazino[5,6-J ]indole
  • a mixture of 3-(3,5-dimethyl-4-propyl-pyrazol-1 -yl)-6H-1 ,2,4-triazino[5,6- £>]indole (30 mg, 100 ⁇ mol, prepared as in Example 64), potassium carbonate (42 mg, 300 ⁇ mol) and 1-(2-chloroethyl)-pyrrolidine hydrochloride (19 mg, 110 ⁇ mol) in acetone (2 ml) was heated to 100°C in a sealed vial under microwave conditions for 8 minutes.
  • Example 88 3-[3,5-dimethyl-4-(1 -phenyl-ethyl)-pyrazol-1 -yl]-5-ethyl-5W- 1 ,2,4-triazino[5,6- ⁇ ]indole
  • Example 92 5-methyl-3-(4-quinolin-4-yl-pyrazol-1 -yl)-5W-1 ,2,4-triazino[5,6- ⁇ ]indole
  • Example 93 5-methyl-3-(4-pyridin-2-yl-pyrazol-1-yl)-5H-1,2,4-triazino[5,6- ⁇ ]indole
  • 2-pyridin-2-yl- malonaldehyde 20 mg, 134 ⁇ mol
  • Example 95 3-(3,5-dimethyl-4-propyl-pyrazol-1 -yl)-5-[2-(tetrahydro-pyran-2- yloxy)-ethyl]-5tf-1,2,4-triazino[5,6-*)]indole
  • Example 96 5-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-3-(3,4,5-trimethyl- pyrazol-1 -yl)-5H-1 ,2,4-triazino[5,6-D]indole
  • Example 97 3-(4-benzyl-3,5-dimethyl-pyrazol-1 -yl)-5-[2-(tetrahydro-pyran-2- yloxy)-ethyl]-5W-1,2,4-triazino[5,6-6]indole
  • Example 5 In a manner analogous to Example 64, using 3-(4-benzyl-3, ⁇ -dimethyl- pyrazol-1-yl)-5r-/-1 ,2,4-triazino[5,6-ib]indole (Example 5, 70 mg, 200 ⁇ mol) and 2-(2-bromoethoxy)-tetrahydropyran (46 mg, 220 ⁇ mol), was prepared the title compound (90 mg, 93%). Hplc/ms (positive ion) Rt 4.85 min, m/z 483 (M+H + ).
  • Example 4 In a manner analogous to Example 64, using 3-(4-ethyl-3,5-dimethyl- pyrazol-1-yl) ⁇ 5/-/-1 ,2,4-triazino[5,6-j ]indole (Example 4, 58 mg, 200 ⁇ mol) and 2-(2-bromoethoxy)-tetrahydropyran (46 mg, 220 ⁇ mol), was prepared the title compound (60 mg, 71%). Hplc/ms (positive ion) Rt 4.53 min, m/z 421 (M+H + ).
  • Example 99 2-[3-(4-benzyl-3,5-dimethyl-pyrazol-1 -yl)-1,2,4-triazino[5,6- b]indol-5-yl]-ethanol
  • Example 97 10 mg, 21 ⁇ mol
  • Example 97 10 mg, 21 ⁇ mol
  • Hplc/ms (positive ion) Rt 4.09 min, m/z 399 (M+H + ).
  • Example 100 Activity Assay
  • the reaction was started with the addition of 1 ⁇ g/ml recombinant human soluble BACE-1. After 3 hours the fluorescence increase was measured in the plate reader at 365ex/485em.
  • the EDANS-DABCYL peptide substrate becomes slightly fluorescent upon enzymatic cleavage due to disruption of the resonance energy transfer between the EDANS donor and DABCYL quenching acceptor in the intact substrate.

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Abstract

A compound of formula (I) wherein R1 is hydrogen, alkyl, -alkyl-aryl, -alkyl-heterocycloalkyl or -alkyl-0-heterocycloalkyl; R2 is hydrogen, hydroxy, amino, nitro, alkoxy, alkyl, aryl or heteroaryl; R3 is hydrogen, alkyl or aryl; R4 is hydrogen, alkyl, aryl, heteroaryl, -CH(aryl)2, -alkyl-aryl or -C(0)0-alkyl; and R5 is alkyl, hydroxy or amino; or a pharmaceutically acceptable salt thereof; is new for use in therapy, e.g. in the treatment of Alzheimer's disease.

Description

TRIAZINE COMPOUNDS AND THEIR USE
Field of the Invention
This invention relates to compounds and their therapeutic use. Background to the Invention Alzheimer's disease (AD) is the most common form of dementia among older people, and affects parts of the brain that control thought, memory and language. Susceptibility to Alzheimer's disease increases with age, but the disease is not a normal part of the ageing process.
Alzheimer's disease is associated with regions of accumulated proteins in the brain. These dense regions, termed "amyloid plaques" and "neurofibrilliary tangles", contain β-amyloid precursor protein (β-APP). β-APP is degraded by β-amyloid converting enzyme (BACE, also known as β- secretase) to produce β-amyloid peptide Aβ 40/42, which accumulates in the plaques. Research has shown that the activity of BACE is an early step in the pathogenesis pathway common to all familial and sporadic forms of AD; thus inhibitors of BACE may have therapeutic utility in the treatment of this disease.
The following compounds are known:
2-(3,5-dimethyl-pyrazol-1-yl)-9-ethyl-9H-1,3,4,9-tetraaza-fluorene;
2-(3,5-dimethyl-pyrazol-1-yl)-9-methyl-9H-1,3,4,9-tetraaza-fluorene; 9-benzyl-2-(3,5-dimethyl-pyrazol-1 -yl)-9H-1 ,3,4,9-tetraaza-fluorene;
9-benzyl-2-(4-benzyl-3,5-dimethyl~pyrazol-1-yl)-9H-1 ,3,4,9-tetraaza- fluorene;
4-benzyl-2-(9-benzyl-9H-1 ,3,4,9-tetraaza-fluoren-2-yl)-5-methyl-2H- pyrazol-3-ol; 2-(4-butyl-3,5-dimethyl-pyrazol-1 -yl)-9-ethyl-9H-1 ,3,4,9-tetraaza-fluorene;
2-(4-benzyl-3,5-dimethyl-pyrazol-1-yl)-9-ethyl-9H-1 ,3,4,9-tetraaza- fluorene;
3-(3,5-dimethyl-pyrazol-1 -yl)-5H-1 ,2,4-triazino[5,6-b]indole;
5-methyl-2-(5H-1,2,4-triazino[5,6- ]indol-3-yl)-2r7-pyrazol-3-ol; 5-(4-chloro-phenyl)-2-(5H-1,2,4-triazino[5,6-b]indol-3-yl)-2W-pyrazol-3-ol;
S^S.δ-dimethyl-pyrazol-l-y -δ-fluoro-δH-l^^-triazinofδ.β-bjindole; 5-amino-1 -(5-ethyl-5H-1 ,2,4-triazino[5,6-ι ]indol-3-yl)-1 H-pyrazole-4- carboxylic acid ethyl ester;
5-amino-1 -(5H-1 ,2,4-triazino[5,6-b]indol-3-yl)-1 H-pyrazole-4-carboxylic acid ethyl ester; 5-phenyl-2-(5H-1 ,2,4-triazino[5,6-b]indol-3-yl)-2H-pyrazol-3-ylamine;
2-(5-methyl-5H-1 ,2,4-triazino[5,6-b]indol-3-yl)-5-phenyl-2H-pyrazol-3- ylamine;
5-(4-chloro-phenyl)-2-(5-methyl-5H-1 ,2,4-triazino[5,6-b]indol-3-yl)-2H- pyrazol-3-ylamine; 5-(4-bromo-phenyl)-2-(5-methyl-5H-1 ,2,4-triazino[5,6-b]indol-3-yl)-2H- pyrazol-3-ylamine;
5-(4-bromo-phenyl)-2-(5H-1 ,2,4-triazino[5,6-b]indol-3-yl)-2/-/-pyrazol-3- ylamine;
5-(4-chloro-phenyl)-2-(5H-1,2,4-triazino[5,6-b]indol-3-yl)-2H-pyrazol-3- ylamine;
2-(8-bromo-5H-1 ,2,4-triazino[5,6-b]indol-3-yl)-5-phenyl-2H-pyrazol-3- ylamine;
2-(8-bromo-5/-/-1 ,2,4-triazino[5,6-b]indol-3-yl)-5-(4-chloro-phenyl)-2H- pyrazol-3-ylamine; and 5-(4-bromo-phenyl)-2-(8-bromo-5H-1 ,2,4-triazino[5I6-b]indol-3-yl)-2/-/- pyrazol-3-ylamine. Summary of the Invention
A first-aspect of the invention is a compound of formula (I)
Figure imgf000003_0001
wherein
R1 is hydrogen, alkyl, -alkyl-aryl, -alkyl-heterocycloalkyl or -alkyl-O- heterocycloalkyl;
R2 is hydrogen, hydroxy, amino, nitro, alkoxy, alkyl, aryl or heteroaryl; R3 is hydrogen, alkyl or aryl;
R4 is hydrogen, alkyl, aryl, heteroaryl, -CH(aryl)2, -alkyl-aryl or -C(O)O- alkyl; and
R5 is alkyl, hydroxy or amino; or a pharmaceutically acceptable salt thereof. These compounds are new, for use in therapy. With the exception of the compounds identified in the Background section of the present specification, they are new per se.
Compounds of the invention may act as inhibitors of BACE and as a consequence may have utility in the treatment or prevention of diseases or conditions in which BACE is implicated. In particular, they may have utility in the treatment or prevention of a disease or condition associated with the deposition and/or elevated levels of amyloid beta peptide (Aβ), for example Alzheimer's disease.
Another aspect of the invention is a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier or diluent. Description of the Invention
For the present invention, certain compounds and combinations of substituents are preferred; in particular, see the sub-claims. With regard to formula (I), R1 is preferably hydrogen, methyl, ethyl, propyl, isopropyl, butyl, pyrazol-1-yIethyl, hydroxyethyl, (2-tetrahydro-pyran-2-yloxy)ethyl or benzyl. R2 is preferably hydrogen. R3 is preferably hydrogen, methyl or phenyl. Preferably R4 is hydrogen, methyl, ethyl, propyl, butyl or-C(O)OCH2CH3. Other preferences for R4 include phenyl, -CH(phenyl)2, benzyl, 1 -phenylethyl, 2- phenylethyl, naphthylmethyl, quinolin-4-yl and pyridin-2-yl, any of which is optionally substituted. R5 is preferably hydrogen, methyl, hydroxy or amino. The term "alkyl" as used herein refers to an optionally substituted straight or branched chain alkyl moiety having from one to six carbon atoms. The term includes, for example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl and the like. The group may be substituted with one or more substituents selected from hydroxy, amino, halogen and the like. "C.,.6 alkyl" has the same meaning.
The term "alkoxy" as used herein refers to a straight or branched chain alkoxy group containing one to six carbon atoms. The term includes, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentoxy, hexoxy and the like. "C.,.β alkoxy" has the same meaning.
The term "halogen" as used herein refers to F, CI, Br or I.
The term "heterocycloalkyl" as used herein refers to a saturated heterocyclic moiety having from three to seven ring carbon atoms and one or more ring heteroatoms selected from nitrogen, oxygen and sulphur. The term includes, for example, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl and the like.
The term "aryl" as used herein refers to an optionally substituted aromatic ring system having six to fourteen ring carbon atoms. The group may be a polycyclic ring system, having two or more rings, at least one of which is aromatic. This term includes, for example, phenyl and naphthyl. The group may be substituted with one or more substituents selected from alkoxy, alkylamino, dialkylamino, halogen, hydroxy, nitro, benzyloxy, -OC(O)C(O)O-alkyl, -CF3, -S(O)2-alkyl, -OC(O)-alkyl, alkyl, -C(O)O-alkyl and -C(O)OH and the like.
The term "heteroaryl" as used herein refers to an optionally substituted aromatic ring system having from four to fourteen ring carbon atoms and, in addition, at least one ring heteroatom selected from nitrogen, oxygen and sulphur. The group may be a polycyclic ring system, having two or more rings, at least one of which is aromatic. The term includes, for example, furanyl, thiophenyl, pyridyl, indolyl, quinolyl and the like. The group may be substituted with, for example, one or more of the substituents named in the definition of "aryl".
Preferred compounds of the invention include: 2-(3,5-dimethyl-pyrazol-1-yl)-9-ethyl-9H-1 ,3,4,9-tetraaza-fluorene; 2-(3,5-dimethyl-pyrazol-1-yl)-9-methyl-9H-1,3,4,9-tetraaza-fluorene; 9-benzyl-2-(3,5-dimethyl-pyrazol-1-yl)-9H-1 ,3,4,9-tetraaza-fluorene; 9-benzyl-2-(4-benzyl-3,5-dimethyl-pyrazol-1-yl)-9H-1 ,3,4,9-tetraaza- fluorene;
4-benzyl-2-(9-benzyl-9H-1 ,3,4,9-tetraaza-fluoren-2-yl)-5-methyl-2H- pyrazol-3-ol;
2-(4-butyl-3,5-dimethyl-pyrazol-1-yl)-9-ethyl-9H-1 ,3,4,9-tetraaza-fluorene; 2-(4-benzyl-3,5-dimethyl-pyrazol-1-yl)-9-ethyl-9H-1 ,3,4,9-tetraaza- fluorene;
9-methyl-2-(5-methyl-3-phenyl-pyrazol-1-yl)-9H-1,3,4,9-tetraaza-fluorene; 2-(3,5-dimethyl-4-propyl-pyrazol-1-yl)-9-methyl-9H-1 ,3,4,9-tetraaza- fluorene;
5-amino-1 -(9-methyl-9H-1 ,3,4,9-tetraaza-fluoren-2-yl)-1 H-pyrazole-4- carboxylic acid ethyl ester;
3-(4-ethyl-3,5-dimethyl-pyrazol-1-yl)-5H-1,2,4-triazino[5,6-b]indole; 3-(4-benzyl-3,5-dimethyl-pyrazol-1-yl)-5H-1 ,2,4-triazino[5,6-b]indole; 3-[4-(2-benzyloxy-benzyl)-3,5-dimethyl-pyrazol-1-yl]-5H-1,2,4-triazino[5,6- bjindole; 4-[3,5-dimethyl-1 -(5H-1 ,2,4-triazino[5,6-b]indol-3-yl)-1 H-pyrazol-4- ylmethylj-phenol;
2-[3,5-dimethyl-1 -(5H-1 ,2,4-triazino[5,6-b]indol-3-yl)-1 H-pyrazol-4- ylmethylj-phenol;
3-[3,5-dimethyl-1 -(5H-1 ,2,4-triazino[5,6-b]indol-3-yl)-1 H-pyrazol-4- ylmethylj-phenol;
3-[4-(3,5-dimethoxy-benzyl)-3,5-dimethyl-pyrazol-1-yl]-5H-1 ,2,4- triazino[5,6-b]indole;
3-(3,5-dimethyl-4-naphthalen-2-ylmethyl-pyrazol-1-yl)-5H-1 ,2,4- triazino[5,6-b]indole; 3-[4-(2-fluoro-benzyl)-3,5-dimethyl-pyrazol-1-yl]-5H-1 ,2I4-triazino[5,6- bjindole;
3-[3,5-dimethyl-4-(3-trifluoromethyl-benzyl)-pyrazol-1 -yl]-5H-1 ,2,4- triazino[5,6-b]indole;
3-[4-(2-methoxy-benzyl)-3,5-dimethyl-pyrazol-1-yl]-5-methyl-5H-1 ,2,4- triazino[5,6-b]indole;
3-[4-(3-fluoro-benzyl)-3,5-dimethyl-pyrazol-1-yl]-5-methyl-5H-1 ,2,4- triazino[5,6-b]indole;
3-[4-(3-methoxy-benzyl)-3,5-dimethyl-pyrazol-1-yl]-5-methyl-5H-1 ,2,4- triazino[5,6-b]indole;
3-[4-(3,5-dimethoxy-benzyl)-3,5-dimethyl-pyrazol-1-yl]-5-methyl-5H-1,2,4- triazino[5,6-b]indole; 3-[3,5-dimethyl-4-(2-nitro-benzyl)-pyrazol-1 -yl]-5-methyl-5H-1 ,2,4- triazino[5,6-b]indole;
3-[4-(2-fluoro-benzyl)-3,5-dimethyl-pyrazol-1-yl]-5-methyl-5H-1 ,2,4- triazino[5,6-b]indole;
2-[3,5-dimethyl-1 -(5-methyl-5H-1 ,2,4-triazino[5,6-b]indol-3-yl)-1 H-pyrazol- 4-ylmethyl]-phenol;
3-[4-(4-methoxy-benzyl)-3,5-dimethyl-pyrazol-1-yl]-5-methyl-5H-1 ,2,4- triazino[5,6-b]indole;
3-[4-(2-benzyloxy-benzyl)-3,5-dimethyl-pyrazol-1-yl]-5-methyl-5H-1,2,4- triazino[5,6-b]indole; 3-(3,5-dimethyl-4-naphthalen-2-ylmethyl-pyrazol-1 -yl)-5-methyl-5H-1 ,2,4- triazino[5,6-b]indole;
3-[3,5-dimethyl-4-(4-nitro-benzyl)-pyrazol-1-yl]-5-methyl-5H-1 ,2,4- triazino[5,6-b]indole;
4-[3,5-dimethyl-1 -(5-methyl-5H-1 ,2,4-triazino[5,6-b]indol-3-yl)-1 H-pyrazol- 4-ylmethyl]-phenol;
3-[3,5-dimethyl-1 -(5-methyl-5H-1 ,2,4-triazino[5,6-b]indol-3-yl)-1 H-pyrazol- 4-ylmethyl]-phenol;
3-[3,5-dimethyl-4-(4-trifluoromethyl-benzyl)-pyrazol-1-yl]-5-methyl-5H- 1 ,2,4-triazino[5,6-b]indole; 3-[4-(4-methanesulphonyl-benzyl)-3,5-dimethyl-pyrazol-1-yl]-5-methyl-5H-
1 ,2,4-triazino[5,6-b]indole;
3-[3,5-dimethyl-4-(2-trifluoromethyl-benzyl)-pyrazol-1-yl]-5-methyl-5H- 1 ,2,4-triazino[5,6-b]indole;
3-[3,5-dimethyl-4-(3-trifluoromethyl-benzyl)-pyrazol-1-yl]-5-methyl-5H- 1 ,2,4-triazino[5,6-b]indole;
3-[3,5-dimethyl-4-(2-methyl-benzyl)-pyrazol-1-yl]-5-methyl-5H-1 ,2,4- triazino[5,6-b]indole;
3-[3,5-dimethyl-4-(3-methyl-benzyl)-pyrazol-1-yl]-5-methyl-5H-1 ,2,4- triazino[5,6-b]indole;
3-(3,5-dimethyl-4-phenethyl-pyrazol-1-yl)-5-methyl-5H-1,2,4-triazino[5,6- bjindole; 4-[3,5-dimethyl-1 -(5-methyl-5H-1 ,2,4-triazino[5,6-b]indol-3-yl)-1 H-pyrazol-
4-ylmethyl]-benzoic acid methyl ester;
3-[3,5-dimethyI-1 -(5-methyl-5H-1 ,2,4-triazino[5,6-b]indol-3-yl)-1 H-pyrazol- 4-ylmethyl]-benzoic acid methyl ester; acetic acid 4-[3,5-dimethyl-1 -(5-methyl-5H-1 ,2,4-triazino[5,6-b]indol-3-yl)- 1 H-pyrazol-4-ylmethyl]-phenyl ester; acetic acid 3-[3,5-dimethyl-1 -(5-methyl-5H-1 ,2,4-triazino[5,6-b]indol-3-yl)- 1 H-pyrazol-4-ylmethyl]-phenyl ester; acetic acid 2-[3,5-dimethyl-1-(5-methyl-5H-1,2,4-triazino[5,6-b]indol-3-yl)- 1 H-pyrazol-4-ylmethyl]-phenyl ester; 5-ethyl-3-[4-(2-methoxy-benzyl)-3,5-dimethyl-pyrazol-1 -yl]-5H-1 ,2,4- triazino[5,6-b]indole;
5-ethyl-3-[4-(2-fluoro-benzyl)-3,5-dimethyl-pyrazol-1 -yl]-5H-1 ,2,4- triazino[5,6-b]indole;
5-ethyl-3-[4-(3-fluoro-benzyl)-3,5-dimethyl-pyrazol-1-yl]-5H-1 ,2,4- triazino[5,6-b]indole;
5-ethyl-3-[4-(4-fluoro-benzyl)-3,5-dimethyl-pyrazol-1-yl]-5H-1 ,2,4- triazino[5,6-b]indole;
5-ethyl-3-[4-(3-methoxy-benzyl)-3,5-dimethyl-pyrazol-1-yl]-5H-1 ,2,4- triazino[5,6-b]indole; 3-[4-(3,5-dimethoxy-benzyl)-3,5-dimethyl-ρyrazol-1 -yl]-5-ethyl-5H-1 ,2,4- triazino[5,6-b]indole;
3-[3,5-dimethyl-4-(2-nitro-benzyl)-pyrazol-1-yl]-5-ethyl-5H-1 ,2,4- triazino[5,6-b]indole;
2-[1 -(5-ethyl-5H-1 ,2,4-triazino[5,6-b]indol-3-yl)-3,5-dimethyl-1 H-pyrazol-4- ylmethylj-phenol;
5-ethyl-3-[4-(4-methoxy-benzyl)-3,5-dimethyl-pyrazol-1 -yl]-5H-1 ,2,4- triazino[5,6-b]indole;
3-[4-(2-benzyloxy-benzyl)-3,5-dimethyl-pyrazol-1-yl]-5-ethyl-5H-1 ,2,4- triazino[5,6-b]indole;
3-(3,5-dimethyl-4-naphthalen-2-ylmethyl-pyrazol-1-yl)-5-ethyl-5H-1 ,2,4- triazino[5,6-b]indole; 3-[3,5-dimethyl-4-(3-nitro-benzyl)-pyrazol-1-yl]-5-ethyl-5H-1 ,2,4- triazino[5,6-b]indole;
3-[3,5-dimethyl-4-(4-nitro-benzyl)-pyrazol-1-yl]-5-ethyl-5H-1 ,2,4- triazino[5,6-b]indole;
4-[1 -(5-ethyl-5H-1 ,2,4-triazino[5,6-b]indol-3-yl)-3,5-dimethyl-1 H-pyrazol-4- ylmethylj-phenol;
3-[1 -(5-ethyl-5H-1 ,2,4-triazino[5,6-b]indol-3-yl)-3,5-dimethyl-1 H-pyrazol-4- ylmethylj-phenol;
3-[3,5-dimethyl-4-(4-trifluoromethyl-benzyl)-pyrazol-1-yl]-5-ethyl-5H-1,2,4- triazino[5,6-b]indole; 5-ethyl-3-[4-(4-methanesulphonyl-benzyl)-3,5-dimethyl-pyrazol-1-yl]-5H-
1 ,2,4-triazino[5,6-b]indole;
3-[3,5-dimethyl-4-(2-trifluoromethyl-benzyl)-pyrazol-1-yl]-5-ethyl-5H-1 ,2,4- triazino[5,6-b]indole;
3-[3,5-dimethyl-4-(3-trifluoromethyl-benzyl)-pyrazol-1-yl]-5-ethyl-5H-1,2,4- triazιno[5,6-b]indole;
3-[3,5-dimethyl-4-(2-methyl-benzyl)-pyrazol-1 -yl]-5-ethyl-5H-1,2,4- triazino[5,6-b]indole;
3-[3,5-dimethyl-4-(3-methyl-benzyl)-pyrazol-1-yl]-5-ethyl-5H-1 ,2,4- triazino[5,6-b]indole; 3-(3,5-dimethyl-4-phenethyl-pyrazol-1 -yl)-5-ethyl-5H-1 ,2,4-triazino[5,6- bjindole;
4-[1 -(5-ethyl-5H-1 ,2,4-triazino[5,6-b]indol-3-yl)-3,5-dimethyl-1 H-pyrazol-4- ylmethylj-benzoic acid methyl ester;
3-[1 -(5-ethyl-5H-1 ,2,4-triazino[5,6-b]indol-3-yl)-3,5-dimethyl-1 H-pyrazol-4- ylmethylj-benzoic acid methyl ester;
4-[1 -(5-ethyl-5H-1 ,2,4-triazino[5,6-b]indol-3-yl)-3,5-dimethyl-1 H-pyrazol-4- ylmethylj-benzoic acid;
3-(3,5-dimethyl-4-propyl-pyrazol-1-yl)-5-ethyl-5H-1 ,2,4-triazino[5,6- bjindole;
5-ethyl-3-(4-ethyl-3,5-dimethyl-pyrazol-1-yl)-5H-1,2,4-triazino[5,6-b]indole;
3-(4-benzyl-3,5-dimethyl-pyrazol-1-yl)-5-propyl-5H-1 ,2,4-triazino[5,6- bjindole;
5-propyl-3-(3,4,5-trimethyl-pyrazol-1-yl)-5H-1 ,2,4-triazino[5,6-b]indole;
3-(4-ethyl-3,5-dimethyl-pyrazol-1 -yl)-5-propyl-5H-1 ,2,4-triazino[5,6- bjindole;
3-(3,5-dimethyl-4-propyl-pyrazol-1 -yl)-5-propyl~5H-1 ,2,4-triazino[5,6- b]indole;
5-butyl-3-(3,5-dimethyl-pyrazol-1-yl)-5H-1 ,2,4-triazino[5,6-b]indole;
5-butyl-3-(3,4,5-trimethyl-pyrazol-1-yl)-5H-1 ,2,4-triazino[5,6-b]indole;
3-(4-benzyl-3,5-dimethyl-pyrazol-1 -yl)-5-butyl-5H-1 ,2,4-triazino[5,6- b]indole; 5-butyl-3-(3,5-dimethyl-4-naphthalen-2-ylmethyl-pyrazol-1 -yl)-5H-1 ,2,4- triazino[5,6-b]indole;
5-butyl-3-[4-(2-fluoro-benzyl)-3,5-dimethyl-pyrazol-1 -yl]-5H-1 ,2,4- triazino[5,6-b]indole;
5-butyl-3-[3,5-dimethyl-4-(3-trifluoromethyl-benzyl)-pyrazol-1-yl]-5H-1 ,2,4- triazino[5,6-b]indole;
5-butyl-3-(4-ethyl-3,5-dimethyl-pyrazol-1-yl)-5H-1,2,4-triazino[5,6-b]indole;
5-benzyl-3-(3,4,5-trimethyl-pyrazol-1-yl)-5H-1 ,2,4-triazino[5,6-b]indole;
3-(4-benzyl-3,5-dimethyl-pyrazol-1-yl)-5-isobutyl-5H-1 ,2,4-triazino[5,6- bjindole; 5-benzyl-3-(3,5-dimethyl-4-propyl-pyrazol-1 -yl)-5H-1 ,2,4-triazino[5,6- bjindole; oxalic acid 4-[3,5-dimethyl-1 -(5-methyl-5H-1 ,2,4-triazino[5,6-b]indol-3-yl)- 1 H-pyrazol-4-ylmethyl]-phenyl ester ethyl ester;
5-isobutyl-3-(3,4,5-trimethyl-pyrazol-1-yl)-5H-1 ,2,4-triazino[5,6-b]indole;
S^-ethyl-S.S-dimethyl-pyrazol-l-y -S-isobutyl-δH-l^^-triazinotδ.θ- bjindole; 3-(3,5-dimethyl-4-propyl-pyrazol-1-yl)-δ-isobutyl-δH-1,2,4-triazino[δ,6- bjindole;
3-(3,5-dimethyl-4-propyl-pyrazol-1 -yl)-δ-(2-pyrrolidin-1 -yl-ethyl)-5H-1 ,2,4- triazino[δ,6-b]indole;
2-[3-(3,δ-dimethyl-4-propyl-pyrazol-1-yl)-1,2,4-triazino[δ,6-b]indol-δ-yl]- ethanol;
3-[3,5-dimethyl-4-(1 -phenyl-ethyi)-pyrazol-1 -yl]-5-methyl-δH-1 ,2,4- triazino[δ,6-b]indole;
3-(4-benzhydryl-3,5-dimethyl-pyrazol-1-yl)-δ-methyl-δH-1,2,4-triazino[5,6- bjindole; 3-[3,δ-dimethyl-4-(1 -phenyl-ethyl)-pyrazol-1-yl]-δ-ethyl-5H-1 ,2,4- triazino[δ,6-b]indole;
3-(4-benzhydryl-3,δ-dimethyl-pyrazol-1-yl)-δ-ethyl-δH-1,2,4-triazino[δ,6- bjindole;
3-[4-(4-methoxy-phenyl)-pyrazol-1-yl]-δ-methyl-δH-1 ,2,4-triazino[δ,6- bjindole;
3-[4-(3-bromo-phenyl)-pyrazol-1-yl]-5-methyl-δH-1 ,2,4-triazino[δ,6- bjindole; δ-methyl-3-(4-quinolin-4-yl-pyrazol-1-yl)-δH-1 ,2,4-triazino[δ,6-b]indole; δ-methyl-3-(4-pyridin-2-yl-pyrazol-1-yl)-δH-1,2,4-triazino[5,6-b]indole; 3-[4-(4-bromo-phenyl)-pyrazol-1 -yl]-δ-methyl-δH-1 ,2,4-triazino[δ,6- bjindole;
3-(3,δ-dimethyl-4-propyl-pyrazol-1-yl)-δ-[2-(tetrahydro-pyran-2-yloxy)- ethyl]-δH-1 ,2,4-triazino[δ,6-b]indole; δ-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-3-(3,4,5-trimethyl-pyrazol-1-yl)-δH- 1 ,2,4-triazino[δ,6-b]indole;
3-(4-benzyl-3,5-dimethyl-pyrazol-1-yl)-δ-[2-(tetrahydro-pyran-2-yloxy)- ethyl]-δH-1,2,4-triazino[5,6-b]indole; 3-(4-ethyl-3,5-dimethyl-pyrazol-1-yl)-δ-[2-(tetrahydro-pyran-2-yloxy)- ethyl]-5H-1 ,2,4-triazino[5,6-b]indole; and
2-[3-(4-benzyl-3,5-dimethyl-pyrazol-1-yl)-1,2,4-triazino[δ,6-b]indol-5-yl]- ethanol. 5 Alternative names for the first three compounds listed above are, respectively:
5-methyl-3-(5-methyl-3-phenyl-pyrazol-1-yl)-5 -/-1,2,4-triazino[δ,6- ]indole;
3-(3,δ-dimethyl-4-propyl-pyrazol-1-yl)-δ-methyl-δH-1 ,2,4-triazino[δ,6- bjindole; and 0 δ-amino-1 -(δ-methyl-δH-1 ,2,4-triazino[δ,6-J ]indol-3-yl)-1 H-pyrazole-4- carboxylic acid ethyl ester.
Compounds of the invention may be chiral. They may be in the form of a single enantiomer or diastereomer, or a racemate.
The compounds of the invention may be prepared in racemic form, or δ prepared in individual enantiomeric form by specific synthesis or resolution as will be appreciated in the art. The compounds may, for example, be resolved into their enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid followed by fractional crystallisation and regeneration of the free base. Alternatively, the 0 enantiomers of the novel compounds may be separated by HPLC using a chiral column.
A compound of the invention may be in a protected amino, protected hydroxy or protected carboxy form. The terms "protected amino", "protected hydroxy" and "protected carboxy" as used herein refer to amino, hydroxy and δ carboxy groups which are protected in a manner familiar to those skilled in the art. For example, an amino group can be protected by a benzyloxycarbonyl, tert- butoxycarbonyl, acetyl or like group, or in the form of a phthalimido or like group. A carboxyl group can be protected in the form of a readily cleavable ester such as the methyl, ethyl, benzyl or tert-butyl ester. A hydroxy group can be protected 0 by an alkyl or like group.
Some compounds of the formula may exist in the form of solvates, for example hydrates, which also fall within the scope of the present invention. Compounds of the invention may be in the form of pharmaceutically acceptable salts, for example, addition salts of inorganic or organic acids. Such inorganic acid addition salts include, for example, salts of hydrobromic acid, hydrochloric acid, nitric acid, phosphoric acid and sulphuric acid. Organic acid 5 addition salts include, for example, salts of acetic acid, benzenesulphonic acid, benzoic acid, camphorsulphonic acid, citric acid, 2-(4-chlorophenoxy)-2- methylpropionic acid, 1 ,2-ethanedisulphonic acid, ethanesulphonic acid, ethylenediaminetetraacetic acid (EDTA), fumaric acid, glucoheptonic acid, gluconicacid, glutamicacid, N-glycolylarsanilicacid, 4-hexylresorcinol, hippuric 0 acid, 2-(4-hydroxybenzoyl)benzoicacid, 1-hydroxy-2-naphthoicacid, 3-hydroxy- 2-naphthoic acid, 2-hydroxyethanesulphonic acid, lactobionic acid, n-dodecyl sulphuric acid, maleic acid, malic acid, mandelic acid, methanesulphonic acid, methyl sulphuric acid, mucic acid, 2-naphthalenesulphonic acid, pamoic acid, pantothenic acid, phosphanilic acid ((4-aminophenyl)phosphonic acid), picric δ acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, terephthalic acid, p-toluenesulphonic acid, 10-undecenoic acid and the like.
Salts may also be formed with inorganic bases. Such inorganic base salts include, for example, salts of aluminium, bismuth, calcium, lithium, magnesium, potassium, sodium, zinc and the like. Organic base salts include, for example, 0 salts of N, N'-dibenzylethylenediamine, choline (as a counterion), diethanolamine, ethanolamine, ethylenediamine, N,N' -bis(dehydroabietyl)ethylenediamine, N-methylglucamine, procaine, tris(hydroxymethyl)aminomethane ("TRIS") and the like.
It will be appreciated that such salts, provided that they are δ pharmaceutically acceptable, may be used in therapy. Such salts may be prepared by reacting the compound with a suitable acid or base in a conventional manner.
A compound of the invention may be prepared by any suitable method known in the art and/or by the following processes (in which X is a leaving group 0 such as CI or Br):
Figure imgf000014_0001
(VIII)
Figure imgf000014_0002
It will be understood that the processes detailed above are solely for the purpose of illustrating the invention and should not be construed as limiting. A process utilising similar or analogous reagents and/or conditions known to one skilled in the art may also be used to obtain a compound of the invention.
Any mixtures of final products or intermediates obtained can be separated on the basis of the physico-chemical differences of the constituents, in a known manner, into the pure final products or intermediates, for example by chromatography, distillation, fractional crystallisation, or by the formation of a salt if appropriate or possible under the circumstances.
The activity and selectivity of the compounds may be determined by any suitable assay known in the art.
In therapeutic use, the active compound may be administered orally, intravenously, rectally, parenterally, by inhalation (pulmonary delivery), topically, ocularly, nasally, orto the buccal cavity. Oral administration is preferred. Thus, a composition of the present invention may take the form of any of the known pharmaceutical compositions for such methods of administration. The compositions may be formulated in a manner known to those skilled in the art so as to give a controlled release, for example rapid release or sustained release, of the compounds of the present invention. Pharmaceutically acceptable carriers suitable for use in such compositions are well known in the art. The compositions of the invention may contain 0.1-99% by weight of active compound. The compositions of the invention are generally prepared in unit dosage form. Preferably, a unit dose comprises the active ingredient in an amount of 1-δ00 mg. The excipients used in the preparation of these compositions are the excipients known in the art.
Appropriate dosage levels may be determined by any suitable method known to one skilled in the art. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health and sex of the patient; diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the disease undergoing treatment.
Compositions for oral administration include known pharmaceutical forms for such administration, for example tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups and elixirs. Compositions intended for oral use may be prepared according to any method known to the art. The compositions may contain one or more agents such as sweetening agents, flavouring agents, colouring agents and preserving agents, in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example corn starch or alginic acid; binding agents, for example starch gelatin, acacia, microcrystalline cellulose or polyvinyl pyrrolidone; and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids, for example polyoxyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl or n-propyl p- hydroxybenzoate, one or more colouring agents, one or more flavouring agents, and one or more sweetening agents, such as sucrose or saccharin.
Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable sweetening, flavouring and colouring agents may also be present.
The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin, or mixtures of these. Suitable emulsifying agents may be naturally occurring gums, for example gum acacia or gum tragacanth, naturally occurring phosphatides, for example soya bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavouring agents.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavouring and colouring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be in a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1 ,3- butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid, find use in the preparation of injectables.
The compounds of the invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.
Compositions for topical administration may also be suitable for use in the present invention. The active compound may be dispersed in a pharmaceutically acceptable cream, ointment or gel. A suitable cream may be. prepared by incorporating the active compound in a topical vehicle such as light liquid paraffin, dispersed in a aqueous medium using surfactants. An ointment may be prepared by mixing the active compound with a topical vehicle such as a mineral oil or wax. A gel may be prepared by mixing the active compound with a topical vehicle comprising a gelling agent. Topically administrable compositions may also comprise a matrix in which the pharmaceutically active compounds of the present invention are dispersed so that the compounds are held in contact with the skin in order to administer the compounds transdermally.
The following Examples illustrate the invention.
In the Examples, analytical hplc was carried out with a Waters 2δ2δ LC pump and Waters Xterra C18 column (δμm, δOmm x 4.6mm). Mobile phases A (0.1 % formic acid in 10mM aqueous ammonium acetate) and B (0.1 % formic acid in acetonitrile) were used. Elution with 6% B was held for 1 minute, raised to 9δ% B over 4.δ minutes and held for 1 minute at a flow rate of 2 or 34ml/minute. Photodiode array detection was by a Waters 996, range 210-3δ0nm UV. The mass spectrometer was a Micromass ZQ operating in electrospray ionisation mode. Intermediate 1 : 9-Methyl-1 ,9-dihydro-1 ,3,4,9-tetraaza-f luorene-2-thione
See Gladych etal, J. Med. Chem., 3, 1δ, (1972). An alternative name for this compound is δ-Methyl-4,5-dihydro-1 ,2,4-triazino[δ,6-b]indole-3-thione. 1 -Methyl Isatin (1.0 g, 6.2 mmol), thiosemicarbazide (0.56δ g, 6.2 mmol) and potassium carbonate (1.28 g, 9.26 mmol) were suspended in water (40 ml) then brought to reflux. Reflux was maintained for 16 hours. The mixture was then cooled to room temperature, filtered and acidified with glacial acetic acid. The resulting yellow precipitate was filtered and dried under vacuum to give the product, 1.175 g (87.6%), hplc/ms (positive ion) Rt 2.49 min, m/z 217 (M+H+). Intermediate 2: (9-Methyl-9H-1 ,3,4,9-tetraaza-fluoren-2-yl)-hydrazine
See Ram, Arch. Pharm. (Weinheim), 313, 108-113, (1980). An alternative name for this compound is (δ-Methyl-δH-1 ,2,4-triazino[δ,6-/b]indol-3- yl)-hydrazine
A solution of Intermediate 1 (0.4 g, 1.8δ mmol) in hydrazine hydrate (4 ml) was refluxed for 4 hours. On cooling, the yellow precipitate was filtered, washed with water (10 ml), then methanol (2 ml) and dried under vacuum to give the product, 0.298 g (75.1%), NMR (d6-DMSO) δ (300MHz): 3.7 (s, 3H); 4.4 (bs, 2H); 7.3δ (t, 1H); 7.δδ (m, 2H); 8.1 (d, 1 H); 8.7 (bs, 1H). Intermediate 3: 4,5-dihydro-1 ,2,4-triazino[5,6-jb]indole-3-thione
Isatin (10 g, 68 mmol), thiosemicarbazide (6.2 g, 68 mmol) and potassium carbonate (14.1 g, 102 mmol) were suspended in water (340 ml) then brought to reflux. Reflux was maintained for 16 hours. The mixture was cooled to room temperature, filtered and the solid washed with water (δO ml). The solid was dried under vacuum to give the product, 4.5 g (33%), as a yellow solid, hplc/ms (positive ion) Rt 2.7 min, m/z 203 (M+H+). Intermediate 4: (5W-1,2,4-triazino[5,6-ύ]indol-3-yl)-hydrazine
In a manner analogous to that of Intermediate 2, using Intermediate 3 (1.0 g, 4.95 mmol) in place of Intermediate 1 , was prepared the title compound (0.99 g, 100%) as a yellow solid, hplc/ms (positive ion) Rt 1.41 min, m/z 201 (M+H+). Intermediate 5: 3-benzyl-pentane-2,4-dione
Oven-dried alumina (δ g, δO mmol) was stirred with a 1M solution of potassium tert-butoxide in tetrahydrofuran (δ ml, δ mmol) under nitrogen for 10 minutes. Solvent was evaporated under vacuo to give a free-flowing solid. The vigorously stirred solid under nitrogen was treated dropwise with pentane-2,4- dione (δ01 mg, δ mmol). After stirring for 40 minutes the mixture was treated with benzyl bromide (8δδ mg, δ mmol) and stirred for δ hours. The solid was applied to a short silica gel column and eluted with dichloromethane. The eluate was concentrated and the residue purified by flash chromatography eluting with 10% ethyl acetate/hexane. Concentration of product-containing fractions gave the title compound (37δ mg, 40%) Rf (10% ethyl acetate/hexane) 0.3; NMR (CDCI3) δ (300MHz): 2.0δ (s, 4.8H); 2.1 (s, 1.2H); 3.1 (d, 0.4H); 3.7 (s, 1.6H); 4.0 (t, 0.2H); 7.0-7.4 (m, δH) [mixture of keto and enol forms]. Intermediate 6: 3-(2-benzyloxy-benzyl)-pentane-2,4-dione
A mixture of 2-benzyloxy benzyl alcohol (2.57 g, 12 mmol), chlorodiphenylphosphine (3.5 g, 16 mmol) and imidazole (1.85 g, 27 mmol) were stirred in toluene (150 ml) under nitrogen. A solution of iodine (4.06 g, 16 mmol) in toluene (50 ml) was added dropwise over 15 minutes and the reaction mixture stirred at room temperature for 30 minutes. The reaction mixture was poured into saturated aqueous sodium bicarbonate (300 ml) and the layers separated. The organic phase was washed with saturated aqueous sodium thiosulphate (100 ml), then water (100 ml) and dried over sodium sulphate, filtered and evaporated. The residue was subjected to chromatography on silica gel eluted with dichloromethane. Evaporation of product containing fractions gave 1- benzyloxy-2-iodomethyl-benzene (3.33 g, 86%) as a red oil. A solution of 1 -benzyloxy-2-iodomethyl benzene (3.24 g, 10 mmol) in methyl ethyl ketone (20 ml) was treated with sodium acetyl acetonate (1.23 g, 10 mmol). The mixture was heated at reflux for 1 hour then evaporated to dryness. Water (40 ml) was added and extracted with diethyl ether (3 x 20 ml). The combined extracts were concentrated and the residue subjected to chromatography on silica gel eluted with hexane for 2 minutes then a gradient to 25% ethyl acetate/hexane over 15 minutes. Evaporation of product containing fractions gave the title compound (1.79 g, 60%) as a clear oil. NMR (CDCI3) δ (300MHz): 2.02 (s, 3H); 2.0δ (s, 3H); 3.1 (d, 1 H); 3.7 (s, 1 H); 4.1 (t, 0.5H); 5.1 (d, 2H); 6.8-7.4 (m, 9H) [mixture of keto and enol forms]. Intermediate 7: 3-(4-benzyloxy-benzyl)-pentane-2,4-dione
In a manner analogous to Example 6, using 4-benzyloxy-benzyl alcohol (8 g, 37 mmol) in place of 2-benzyloxy-benzyl alcohol, was prepared the title compound (1.41g, 19%) as a clear oil. NMR (CDCI3) δ (300MHz): 2.0δ (s, 3H); 2.1 (s, 3H); 3.1 (d, 1H); 3.7 (s, 1H); 4.0 (t, O.δH); δ.1 (d, 2H); 6.8-7.4 (m, 9H) [mixture of keto and enol forms].
Intermediate 8: 3-(4-hydroxy-benzyl)-pentane-2,4-dione δ A solution of Intermediate 7 (1.4 g, 4.7 mmol) in methanol (20 ml) was hydrogenated over 10% palladium on carbon at atmospheric pressure for 2 hours. The suspension was filtered, the filtrate concentrated and the residue purified by flash chromatography on silica gel eluted with 1 :1 ethyl acetate hexane to give the title compound (310 mg, 32%). NMR (CDCI3) δ (300MHz): 2.0δ (s, 2H); 2.1 (s, 4H); 3.1 (d, 1.3H); 3.6 (s, 0.7H); 4.0 (t, 0.7H); 6.8-7.0 (2q, 4H) [mixture of keto and enol forms]. Intermediate 9: 3-(2-hydroxy-benzyl)-pentane-2,4-dione
In a manner analogous to Intermediate 8, starting from 3-(2-benzyloxy- benzyl)-pentane-2,4-dione (Intermediate 6, 3δ0 mg, 1.18 mmol), was obtained the title compound (210 mg, 86%). Intermediate 10: 3-(3-benzyloxy-benzyl)-pentane-2,4-dione
In a manner analogous to Intermediate 6, using 3-benzyloxy-benzyl alcohol (2.δ7 g, 12 mmol) in place of 2-benzyloxy-benzyl alcohol, was prepared the title compound (1.9g, δ3%) as a clear oil. 0 Intermediate 11: 3-(3-hydroxy-benzyl)-pentane-2,4-dione
In a manner analogous to Intermediate 8, starting from 3-(3-benzyloxy- benzyl)-pentane-2,4-dione (Intermediate 10, 1.9 g, 6.4 mmol), was prepared the title compound (400 mg, 30%). Intermediate 12: 3-(3,5-dimethoxy-benzyl)-pentane-2,4-dione
In a manner analogous to Intermediate δ, starting from 3,δ-dimethoxy- benzyl bromide (878 mg, 3.8 mmol), was prepared the title compound (189 mg, 30%). Intermediate 13: 3-naphthalen-2-ylmethyl-pentane-2,4-dione
In a manner analogous to Intermediate 5, starting from 2-bromomethyl naphthalene (840 mg, 3.8 mmol), was prepared the title compound (376 mg, 41 %). NMR (CDCI3) δ (300MHz): 2.05 (s, 5H); 2.1 (s, 1 H); 3.2 (d, 0.3H); 3.9 (s, 1.7H); 4.1 (t, 0.15H); 7.3-7.9 (m, 7H) [mixture of keto and enol forms]. Intermediate 14: 3-(2-fluoro-benzyl)-pentane-2,4-dione
In a manner analogous to Intermediate δ, starting from 2-fluoro-benzyl bromide (718 mg, 3.8 mmol), was prepared the title compound (374 mg, 47%). NMR (CDCI3) δ (300MHz): 2.05 (s, 4.6H); 2.1 (s, 1.4H); 3.1 (d, 0.45H); 3.7 (s, 1.55H); 4.05 (t, 0.22H); 7.0-7.3 (m, 4H) [mixture of keto and enol forms]. Intermediate 15: 3-(3-trifluoromethyl-benzyl)-pentane-2,4-dione
In a manner analogous to Intermediate 5, starting from 3-trifluoromethyl- benzyl bromide (778 mg, 4 mmol), was prepared the title compound (412 mg, 40%). Intermediate 16: 3-(2-methoxy-benzyl)-pentane-2,4-dione
A mixture of sodium acetyl acetonate (1.0 g, 7.14 mmol) and 2-methoxy- benzyl chloride (1 ml, 7.14 mmol) in methyl ethyl ketone (10 ml) was heated at reflux under nitrogen for 2 hours. Solvent was evaporated and the residue extracted with diethyl ether (3 x 100 ml). The combined extracts were dried over sodium sulphate, filtered and evaporated. Flash chromatography on silica gel eluted with a gradient of δ% ethyl acetate/hexane to 2δ% ethyl acetate/hexane over 25 minutes and concentration of product containing fractions gave the title compound (873 mg, δ6%).
Intermediate 17: 3-(3-fluoro-benzyl)-pentane-2,4-dione
In a manner analogous to Intermediate 6, starting from 3-fluoro-benzyl bromide (718 mg, 3.8 mmol), was prepared the title compound (292 mg, 37%). NMR (CDCI3) δ (300MHz): 2.0δ (s, 4.5H); 2.1 (s, 1.5H); 3.1 (d, O.δH); 3.7 (s, 1.δH); 4.0 (t, 0.2δH); 6.7-7.3 (m, 4H) [mixture of keto and enol forms]. Intermediate 18: 3-(3-methoxy-benzyl)-pentane-2,4-dione
In a manner analogous to Intermediate δ, starting from 3-methoxy-benzyl bromide (764 mg, 3.8 mmol), was prepared the title compound (460 mg, δδ%). NMR (CDCI3) δ (300MHz): 2.0δ (s, 4.5H); 2.1 (s, 1.5H); 3.1 (d, O.δH); 3.7 (s, 1.5H); 3.9 (s, 3H); 4.0 (t, 0.2δH); 6.7-7.3 (m, 4H) [mixture of keto and enol forms]. Intermediate 19: 3-(2-nitro-benzyl)-pentane-2,4-dione In a manner analogous to Intermediate δ, starting from 2-nitro-benzyl bromide (821 mg, 3.8 mmol), was prepared the title compound (376 mg, 42%). NMR (CDCI3) δ (300MHz): 2.05 (s, 4H); 2.2 (s, 2H); 3.4 (d, 0.7H); 4.0 (s, 1.3H); 4.1 (t, 0.3δH); 7.3-8.0 (m, 4H) [mixture of keto and enol forms]. Intermediate 20: 3-(4-methoxy-benzyl)-pentane-2,4-dione
In a manner analogous to Intermediate δ, starting from 4-methoxy-benzyl chloride (62δ mg, 4 mmol), was prepared the title compound (315 mg, 36%). NMR (CDCI3) δ (300MHz): 2.05 (s, 4.4H); 2.1 (s, 1.6H); 3.1 (d, O.δH); 3.6 (s, 1.5H); 3.8 (s, 3H); 3.9 (t, 0.2δH); 6.8-7.1 (2q, 4H) [mixture of keto and enol forms]. intermediate 21: 3-(4-nitro-benzyl)-pentane-2,4-dione
In a manner analogous to Intermediate δ, starting from 4-nitro-benzyl bromide (821 mg, 3.8 mmol), was prepared the title compound (213 mg, 24%). NMR (CDCI3) δ (300MHz): 2.0δ (s, 4H); 2.15 (s, 2H); 3.2 (d, 0.66H); 3.8 (s, 1.34H); 4.0 (t, 0.33H); 7.3 (m, 2H); 8.2 (m, 2H) [mixture of keto and enol forms]. Intermediate 22: 3-(4-trifluoromethyl-benzyl)-pentane-2,4-dione
In a manner analogous to Intermediate δ, starting from 4-trifluoromethyl- benzyl chloride (821 mg, 4 mmol), was prepared the title compound (300 mg,
29%). NMR (CDCI3) δ (300MHz): 2.0δ (s, 3.3H); 2.1 (s, 2.7H); 3.2 (d, 1H); 3.8 (s, 1 H); 4.0 (t, O.δH); 7.3 (m, 2H); 7.5 (m, 2H) [mixture of keto and enol forms].
Intermediate 23: 3-(4-methanesulphonyl-benzyl)-pentane-2,4-dione
In a manner analogous to Intermediate δ, starting from 4- methanesulphonyl-benzyl bromide (996 mg, 4 mmol), was prepared the title compound (3δ0 mg, 33%). NMR (CDCI3) δ (300MHz): 2.0δ (s, 4H); 2.1 (s, 2H); 3.05 (2s, 3H); 3.2 (d, 0.66H); 3.8 (s, 1.34H); 4.0 (t, 0.33H); 7.4 (m, 2H); 7.9 (m, 2H) [mixture of keto and enol forms]. Intermediate 24: 3-(2-trifluoromethyl-benzyl)-pentane-2,4-dione
In a manner analogous to Intermediate δ, starting from 2-trifluoromethyl- benzyl bromide (778 mg, 3.2 mmol), was prepared the title compound (200 mg, 24%). Intermediate 25: 3-(2-methyl-benzyl)-pentane-2,4-dione In a manner analogous to Intermediate δ, starting from 2-methyl-benzyl bromide (740 mg, 4 mmol), was prepared the title compound (6δ6 mg, 80%). NMR (CDCI3) δ (300MHz): 2.0 (s, 3H); 2 1 (s, 3H); 2.2δ (2s, 3H); 3.1 (d, 1 H); 3.6 (s, 1H); 4.0 (t, O.δH); 6.9 - 7.2 (m, 4H) [mixture of keto and enol forms], δ Intermediate 26: 3-(3-methyl-benzyl)-pentane-2,4-dione
In a manner analogous to Intermediate δ, starting from 2-methyl-benzyl bromide (740 mg, 4 mmol), was prepared the title compound (609 mg, 62%). NMR (CDCI3) δ (300MHz): 2.0δ (s, 3H); 2.1 (s, 3H); 2.3 (2s, 3H); 3.1 (d, 1 H); 3.6 (s, 1 H); 4.0 (t, O.δH); 6.9 - 7.2 (m, 4H) [mixture of keto and enol forms]. Intermediate 27: 3-phenethyl-pentane-2,4-dione
In a manner analogous to Intermediate δ, starting from 2-bromoethyl benzene (740 mg, 4 mmol), was prepared the title compound (601 mg, 74%). Intermediate 28: 4-(2-acetyl-3-oxo-butyl)-benzoic acid methyl ester
In a manner analogous to Intermediate δ, starting from 4-bromomethyl benzoic acid methyl ester (1.83 g, 8 mmol), was prepared the title compound (680 mg, 34%). NMR (CDCI3) δ (300MHz): 2.0δ (s, 3.3H); 2.1 (s, 2.7H); 3.2 (d, 0.8H); 3.7δ (s, 1.2H); 3.9 (2s, 3H); 4.0 (t, 0.4H); 7.2 (m, 2H); 8.0 (m, 2H) [mixture of keto and enol forms].
Intermediate 29: 3-(2-acetyl-3-oxo-butyl)-benzoic acid methyl ester 0 In a manner analogous to Intermediate δ, starting from 3-bromomethyl benzoic acid methyl ester (916 mg, 8 mmol), was prepared the title compound (332 mg, 33%). NMR (CDCI3) δ (300MHz): 2.0δ (s, 3H); 2.1 (s, 3H); 3.2 (d, 1 H); 3.7δ (s, 1 H); 3.9 (s, 3H); 4.0 (t, O.δH); 7.3δ (m, 2H); 7.9 (m, 2H) [mixture of keto and enol forms]. Intermediate 30: 5-ethyl-4,5-dihydro-1 ,2,4-triazino[5,6-b]indole-3-thione
In a manner analogous to Intermediate 3, using 1-ethyl-1/-/-indole-2,3- dione (2.29 g, 13 mmol) in place of isatin, was prepared the title compound (2.63 g, 88%). NMR (d6-DMSO) δ (300MHz): 1.5 (t, 3H); 4.25 (q, 2H); 7.5 (m, 1 H); 7,75 (m, 2H); 8.1 (d, 1 H).
The 1-ethyl-1H-indole-2,3-dione used as the starting material was prepared as follows. Isatin (3 g, 20 mmol), potassium carbonate (δ.6 g, 40 mmol) and iodomethane (3.43 g, 22 mmol) were stirred in tetrahydrofuran (100 ml) under nitrogen and treated with tetra-n-butyl ammonium hydrogen sulphate (100 mg). The mixture was heated at reflux, cooled to room temperature and the solvent δ evaporated. The residue was partitioned between dichloromethane (100 ml) and water (100 ml). The aqueous phase was extracted with dichloromethane (2 x δO ml) and the combined organic fractions treated with activated charcoal, filtered and concentrated. Crystallisation of the residue from dichloromethane/hexane gave 1-ethyl-1/-/~indole-2,3-dione (2.97 g) in two crops. Hplc/ms (positive ion) Rt 2.89 min, m/z 176 (M+H+). Intermediate 31 : (5-ethyl-5H-1 ^^-triazinofδ.β-ύlindol-S-ylJ-hydrazine
In a manner analogous to Intermediate 4, using δ-ethyl-4,δ-dihydro-1 ,2,4- triazino[5,6-b]indoIe-3-thione (Intermediate 30, 1 g, 4.34 mmol), was prepared the title compound (907 mg, 91%). Hplc/ms (positive ion) Rt 2.2δ min, m/z 229 (M+H+). Intermediate 32: 3-(4-fluoro-benzyl)-pentane-2,4-dione
In a manner analogous to Intermediate δ, starting from 4-fluorobenzyl bromide (718 mg, 3.8 mmol), was prepared the title compound (273 mg, 3δ%). NMR (CDCI3) δ (300MHz): 2.0δ (s, 4.3H); 2.1 (s, 1.7H); 3.2 (d, O.δH); 3.7δ (s, 0 1.δH); 4.0 (t, 0.25H); 6.9 - 7.1 (m, 4H) [mixture of keto and enol forms]. Intermediate 33: 3-(3-nitro-benzyl)-pentane-2,4-dione
In a manner analogous to Intermediate δ, starting from 3-nitro-benzyl bromide (821 mg, 3.8 mmol), was prepared the title compound (231 mg, 26%). NMR (CDCI3) δ (300MHz): 2.0δ (s, 4.3H); 2.1 (s, 1.7H); 3.2 (d, O.δH); 3.75 (s, 1.5H); 4.0 (t, 0.2δH); 6.9 - 7.1 (m, 4H) [mixture of keto and enol forms]. Intermediate 34: 3-(1-phenyl-ethyl)-pentane-2,4-dione
In a manner analogous to Intermediate δ, starting from (1-bromoethyl)- benzene (740 mg, 4 mmol), was prepared the title compound (200 mg, 25%). NMR (CDCI3) δ (300MHz): 1.2 (d, 1.5H); 1.5 (d, 1.5H); 1.85 (s, 3H); 2.27 (s, 3H); 3.6 (m, O.δH); 4.0δ (d, O.δH); 4.9δ (m, O.δH); 7.15-7.4 (m, δH) [mixture of keto and enol forms]. Intermediate 35: 3-benzhydryl-pentane-2,4-dione
In a manner analogous to Intermediate 6, starting from benzhydryl bromide (989 mg, 4 mmol), was prepared the title compound (300 mg, 28%). Example 1 : 9-Methyl-2-(5-methyl-3-phenyl-pyrazol-1 -yl)-9H-1 ,3,4,9-tetraaza- fluorene
To a stirred solution of Intermediate 2 (10mg, 0.0466 mmol) and benzoylacetone (37.3mg, 0.23 mmol) in anhydrous ethanol (1 ml), was added one drop of glacial acetic acid. The mixture was then heated to 140°C in a sealed vial under microwave conditions for 4 minutes. On cooling, 2 drops of aqueous ammonia were added and the resulting precipitate was filtered and dried under vacuum to give the product as a yellow solid, 5.19 mg (33.1 %), hplc/ms (positive ion) Rt 4.21 min, m/z 341 (M+H+).
Example 2: 2-(3,5-Dimethyl-4-propyl-pyrazol-1-yl)-9-methyl-9H-1 ,3,4,9- tetraaza-fluorene
To a stirred solution of Intermediate 2 (10mg, 0.0466 mmol) and 3-propyl- 2,4-pentanedione (32.7 mg, 0.23 mmol) in anhydrous ethanol (1 ml) was added one drop of glacial acetic acid. The mixture was then heated to 140°C in a sealed vial under microwave conditions for 5 minutes. On cooling, the resulting precipitate was filtered and dried under vacuum to give the product as a yellow solid, 6.60 mg (44.8%), hplc/ms (positive ion) Rt 4.41 min, m/z 321 (M+H+). Example 3: 5-Amino-1-(9-methyI-9H-1,3,4,9-tetraaza-fluoren-2-yl)- 1H-pyrazole-4-carboxylic acid ethyl ester
A solution of Intermediate 2 (1 Omg, 0.0466 mmol) and 2-cyano-3-ethoxy- acrylic acid ethyl ester (10 mg, 0.082 mmol) in anhydrous ethanol (1 ml) was heated to 140° C in a sealed vial under microwave conditions for δ minutes. On cooling, the resulting precipitate was filtered and dried under vacuum to give the product as a yellow solid, 12.85mg (81.7%), hplc/ms (positive ion) Rt 3.47 min, m/z 338 (M+H+). Example 4:3-(4-ethyl-3,5-dimethyl-pyrazol-1 -yl)-5A/-1 ,2,4-triazino[5,6-b] indole
A solution of (6/-/-1 ,2,4-triazino[δ,6-fc]indol-3-yl)-hydrazine (Intermediate 4 , 100 mg, O.δ mmol) in 20% acetic acid/ethanol (2 ml) was treated with 3-ethyl- pentane-2,4-dione (320 mg, 2.δ mmol) and heated to 140°C in a sealed vial under microwave conditions for δ minutes. On cooling, the resulting precipitate was filtered and dried under vacuum to give the product (50 mg, 34%) as a pale yellow solid, hplc/ms (positive ion) Rt 3.77 min, m/z 293 (M+H+). Example 5: 3-(4-benzyl-3,5-dimethyl-pyrazol-1 -yl)-5 /-1,2,4-triazino[5,6- ϋ]indole
A solution of (δ/-/-1 ,2,4-triazino[δ,6-fc>]indol-3-yl)-hydrazine (Intermediate 4, 200 mg, 1 mmol) in 20% acetic acid/ethanol (3 ml) was treated with 3-benzyl- pentane-2,4-dione (Intermediate δ, 9δ0 mg, 5 mmol) and heated to 140°C in a sealed vial under microwave conditions for 20 minutes. The reaction mixture was cooled to room temperature and filtered. The solid was washed with ethanol (2 ml) and dried in vacuo to give the product (180 mg, 51 %) as a pale yellow solid, hplc/ms (negative ion) Rt 4.17 min, m/z 353 (M-H"). Example 6: 3-[4-(2-benzyloxy-benzyl)-3,5-dimethyl-pyrazol-1 -yl]-5W-1 ,2,4- triazino[5,6-ϋ]indole In a manner analogous to that of Example 5, using Intermediate 4 (10 mg, δO μmol) and Intermediate 6 (δO mg, 170 μmol) was prepared the title compound (δ mg, 22%) as a pale yellow solid after preparative hplc. Hplc/ms (negative ion) Rt 4.79 min, m/z 4δ9 (M-H").
Example 7: 4-[3,5-dimethyl-1-(5W-1,2,4-triazino[5,6- )]indol-3-yl)-1W-pyrazol- 4-yImethyl]-phenol
A solution of (δH-1 ,2,4-triazino[δ,6-έ>]indol-3-yl)-hydrazine (Intermediate 4, 10 mg, δO μmol) in 20% acetic acid/ethanol (1 ml) was treated with 3-(4- hydroxy-benzyl)-pentane-2,4-dione (Intermediate 8, 30 mg, 14δ μmol) and heated to 140°C in a sealed vial under microwave conditions for 20 minutes. The reaction mixture was cooled, diluted with water (1 ml) and the suspension filtered. The solid was dried to give the title compound (14 mg, 76%). Hplc/ms (negative ion) Rt 3.56 min, m/z 369 (M-H").
Example 8: 2-[3,5-dimethyl-1-(5/y-1,2,4-triazino[5,6- )]indol-3-yl)-1H-pyrazol- 4-ylmethyl]-phenol In a manner analogous to Example 7, using Intermediate 9 in place of
Intermediate 8, was prepared the title compound (14 mg, 76%). Hplc/ms (negative ion) Rt 3.69 min, m/z 369 (M-H").
Example 9: 3-[3,5-dimethyl-1 -(5/Y-1 ,2,4-triazino[5,6-/)]indol-3-yl)-1 H-pyrazol- 4-ylmethyl]-phenol
In a manner analogous to Example 7, using Intermediate 11 in place of Intermediate 8, was prepared the title compound (1δ mg, 81%). Hplc/ms (negative ion) Rt 3.64 min, m/z 369 (M-H").
Example 10: 3-[4-(3,5-dimethoxy-benzyl)-3,5-dimethyl-pyrazol-1-yl]-5W-1, 2,4- triazino[5,6-6]indole
In a manner analogous to Example δ, using Intermediate 4 (8.8 mg, 44 μmol) and Intermediate 12 (33 mg, 132 μmol), was prepared the title compound (14 mg, 77%). Hplc/ms (negative ion) Rt 4.12 min, m/z 413 (M-H"). Example 11: 3-(3,5-dimethyl-4-naphthalen-2-ylmethyl-pyrazol-1-yl)-5A -1, 2,4- triazino[5,6-Jb]indole In a manner analogous to Example 5, using Intermediate 4 (50 mg, 250 μmol) and Intermediate 13 (180 mg, 750 μmol), was prepared the title compound (64 mg, 63%). Hplc/ms (negative ion) Rt 4.59 min, m/z 403 (M-H"). Example 12: 3-[4-(2-fluoro-benzyl)-3,5-dimethyl-pyrazol-1 -yl]-5W-1,2,4- triazino[5,6-r]indole
In a manner analogous to Example 5, using Intermediate 4 (δO mg, 250 μmol) and Intermediate 14 (156 mg, 750 μmol), was prepared the title compound (40 mg, 43%). Hplc/ms (negative ion) Rt 4.26 min, m/z 371 (M-H"). Example 13: 3-[3,5-dimethyl-4-(3-trifluoromethyl-benzyl)-pyrazol-1-yl]-5H- 1 ,2,4-triazino[5,6-6]indole
In a manner analogous to Example 5, using Intermediate 4 (δO mg, 250 μmol) and Intermediate 1 δ (193 mg, 7δ0 μmol), was prepared the title compound (40 mg, 38%). Hplc/ms (negative ion) Rt 4.63 min, m/z 421 (M-H").
Example 14: 3-[4-(2-methoxy-benzyl)-3,5-dimethyl-pyrazol-1-yl]-5-methyI-
5W-1,2,4-triazino[5,6-£]indole
In a manner analogous to Example 6, using Intermediate 2 (10 mg, 47 μmol) and Intermediate 16 (61 mg, 232 μmol), was prepared the title compound (17 mg, 90%). Hplc/ms (positive ion) Rt 4.34 min, m/z 399 (M+H+). Example 15: 3-[4-(3-fluoro-benzyl)-3,5-dimethyl-pyrazol-1 -yl]-5-methyl-5W- 1 ,2,4-triazino[5,6-j ]indole
In a manner analogous to Example 5, using Intermediate 2 (9.4 mg, 44 μmol) and Intermediate 17 (46 mg, 220 μmol), was prepared the title compound (3 mg, 18%). Hplc/ms (positive ion) Rt 4.46 min, m/z 387 (M+H+). Example 16: 3-[4-(3-methoxy-benzyl)-3,5-dimethyl-pyrazol-1-yl]-5-methyl- 5W-1,2,4-triazino[5,6-6]indole
In a manner analogous to Example 5, using Intermediate 2 (9.4 mg, 44 μmol) and Intermediate 18 (48 mg, 220 μmol), was prepared the title compound (7 mg, 40%). Hplc/ms (positive ion) Rt 4.34 min, m/z 399 (M+H+). Example 17: 3-[4-(3,5-dimethoxy-benzyl)-3,5-dimethyl-pyrazol-1-yl]-5- methyl-5W-1,2,4-triazino[5,6-6]indole
In a manner analogous to Example 6, using Intermediate 2 (9.4 mg, 44 μmol) and Intermediate 18 (48 mg, 220 μmol), was prepared the title compound (7 mg, 40%). Hplc/ms (positive ion) Rt 4.34 min, m/z 399 (M+H+). Example 18: 3-[3,5-dimethyl-4-(2-nitro-benzyl)-pyrazol-1 -yl]-5-methyl-5W- 1 ,2,4-triazino[5,6-/>]indole
In a manner analogous to Example 5, using Intermediate 2 (9.4 mg, 44 μmol) and Intermediate 18 (52 mg, 220 μmol), was prepared the title compound (9 mg, 60%). Hplc/ms (positive ion) Rt 4.3 min, m/z 414 (M+H+). Example 19: 3-[4-(2-fluoro-benzyl)-3,5-dimethyl-pyrazol-1-yl]-5-methyl-5f/- 1,2,4-triazino[5,6-ϋ]indole
In a manner analogous to Example 5, using Intermediate 2 (9.4 mg, 44 μmol) and Intermediate 14 (46 mg, 220 μmol), was prepared the title compound (12 mg, 70%). Hplc/ms (positive ion) Rt 4.47 min, m/z 387 (M+H+). Example 20: 2-[3,5-dimethyl-1-(5-methyl-5H-1,2,4-triazino[5,6- )]indol-3-yl)- 1 H-pyrazol-4-yImethyl]-phenol
In a manner analogous to Example 5, using Intermediate 2 (10 mg, 47 μmol) and Intermediate 14 (30 mg, 145 μmol), was prepared the title compound (5 mg, 28%). Hplc/ms (positive ion) Rt 3.85 min, m/z 385 (M+H+).
Example 21 : 3-[4-(4-methoxy-benzyl)-3,5-dimethyl-pyrazoM-yl]-5-methyl- 5H-1 ,2,4-triazino[5,6-/>]indole
In a manner analogous to Example 5, using Intermediate 2 (9.4 mg, 44 μmol) and Intermediate 20 (48 mg, 219 μmol), was prepared the title compound (6 mg, 34%). Hplc/ms (positive ion) Rt 4.34 min, m/z 399 (M+H+). Example 22: 3-[4-(2-benzyloxy-benzyl)-3,5-dimethyl-pyrazol-1 -yl]-5-methyl- 5W-1 ,2,4-triazino[5,6-6]indole
In a manner analogous to Example 5, using Intermediate 2 (10 mg, 47 μmol) and Intermediate 6 (50 mg, 168 μmol), was prepared the title compound (7 mg, 31%). Hplc/ms (positive ion) Rt 5.02 min, m/z 475 (M+H+). Example 23: 3-(3,5-dimethyl-4-naphthalen-2-ylmethyl-pyrazol-1 -yl)-5-methyl- 5H-1 ,2,4-triazino[5,6- )]indole
In a manner analogous to Example 5, using Intermediate 2 (9.4 mg, 44 μmol) and Intermediate 13 (53 mg, 219 μmol), was prepared the title compound (5 mg, 27%). Hplc/ms (positive ion) Rt 4.83 min, m/z 419 (M+H+).
Example 24: 3-[3,5-dimethyl-4-(4-nitro-benzyl)-pyrazol-1 -yl] -5-methyl -5 H- 1 ,2,4-triazino[5,6- >]indole
In a manner analogous to Example 5, using Intermediate 2 (9.4 mg, 44 μmol) and Intermediate 21 (52 mg, 219 μmol), was prepared the title compound (2.3 mg, 13%). Hplc/ms (positive ion) Rt 4.33 min, m/z 414 (M+H+). Example 25: 4-[3,5-dimethyl-1 -(5-methyl -5H-1 ,2,4-triazino[5,6-6]indol-3-yl)- 1 H-pyrazol-4-ylmethyl]-phenol
In a manner analogous to Example 5, using Intermediate 2 (10 mg, 47 μmol) and Intermediate 8 (30 mg, 145 μmol), was prepared the title compound (14 mg, 77%). Hplc/ms (positive ion) Rt 3.7 min, m/z 385 (M+H+). Example 26: 3-[3,5-dimethyl-1-(5-methyl-5W-1,2,4-triazino[5,6- )]indol-3-yl)- 1 H-pyrazol-4-ylmethyl]-phenol
In a manner analogous to Example 5, using Intermediate 2 (10 mg, 47 μmol) and Intermediate 11 (30 mg, 145 μmol), was prepared the title compound (14.5 mg, 80%). Hplc/ms (positive ion) Rt 3.8 min, m/z 385 (M+H+).
Example 27: 3-[3,5-dimethyl-4-(4-trifluoromethyl-benzyl)-ρyrazol-1 -yl]-5- methyl-5rY-1,2,4-triazino[5,6-/ ]indoIe
In a manner analogous to Example 5, using Intermediate 2 (9.4 mg, 44 μmol) and Intermediate 22 (34 mg, 132 μmol), was prepared the title compound (10 mg, 52%). Hplc/ms (positive ion) Rt 4.77 min, m/z 437 (M+H+). Example 28: 3-[4-(4-methanesulphonyl-benzyl)-3,5-dimethyl-pyrazol-1 -yl]-5- methyl-δH-l^^-triazinotδ.β-ύlindole
In a manner analogous to Example 5, using Intermediate 2 (9.4 mg, 44 μmol) and Intermediate 23 (35 mg, 132 μmol), was prepared the title compound (10 mg, 61%). Hplc/ms (positive ion) Rt 3.7 min, m/z 447 (M+H+). Example 29: 3-[3,5-dimethyl-4-(2-trifluoromethyl-benzyl)-pyrazol-1 -yl]-5- methyl-5W-1,2,4-triazino[5,6-*)]indole
In a manner analogous to Example 5, using Intermediate 2 (9.4 mg, 44 μmol) and Intermediate 24 (34 mg, 132 μmol), was prepared the title compound (7 mg, 36%). Hplc/ms (positive ion) Rt 4.86 min, m/z 437 (M+H+).
Example 30: 3-[3,5-dimethyl-4-(3-trifluoromethyl-benzyl)-pyrazol-1 -yl]-5- methyl-5W-1,2,4-triazino[5,6-i)]indole
In a manner analogous to Example 5, using Intermediate 2 (9.4 mg, 44 μmol) and Intermediate 16 (34 mg, 132 μmol), was prepared the title compound (9 mg, 47%). Hplc/ms (positive ion) Rt 4.75 min, m/z 437 (M+H+). Example 31 : 3-[3,5-dimethyl-4-(2-methyl-benzyl)-pyrazol-1 -yl]-5-methyl-5H- 1 ,2,4-triazino[5,6-b]indole
In a manner analogous to Example 5, using Intermediate 2 (9.4 mg, 44 μmol) and Intermediate 2δ (27 mg, 132 μmol), was prepared the title compound (5 mg, 30%). Hplc/ms (positive ion) Rt 4.64 min, m/z 383 (M+H+). Example 32: 3-[3,5-dimethyI-4-(3-methyl-benzyl)-pyrazol-1 -yl]-5-methyl-5H- 1,2,4-triazino[5,6-b]indole
In a manner analogous to Example 5, using Intermediate 2 (9.4 mg, 44 μmol) and Intermediate 26 (27 mg, 132 μmol), was prepared the title compound (7 mg, 42%). Hplc/ms (positive ion) Rt 4.68 min, m/z 383 (M+H+).
Example 33: 3-(3,5-dimethyl-4-phenethyl-pyrazol-1 -yl)-5-methyl-5H-1 ,2,4- triazino[5,6-ϋ]indole
In a manner analogous to Example 5, using Intermediate 2 (9.4 mg, 44 μmol) and Intermediate 27 (27 mg, 132 μmol), was prepared the title compound (10 mg, 59%). Hplc/ms (positive ion) Rt 4.69 min, m/z 383 (M+H+). Example 34: 4-[3,5-dimethyl-1-(5-methyl-5W-1,2,4-triazino[5,6-d]indol-3-yl)- 1tf-pyrazol-4-ylmethyI]-benzoic acid methyl ester
In a manner analogous to Example 5, using Intermediate 2 (47 mg, 440 μmol) and Intermediate 28 (165 mg, 660 μmol), was prepared the title compound (67 mg, 36%). Hplc/ms (positive ion) Rt 4.28 min, m/z 427 (M+H+). Example 35: 3-[3,5-dimethyI-1 -(5-methyl-5W-1 ,2,4-triazino[5,6-6]indol-3-yl)- 1W-pyrazol-4-ylmethyl]-benzoic acid methyl ester
In a manner analogous to Example 5, using Intermediate 2 (47 mg, 440 μmol) and Intermediate 29 (165 mg, 660 μmol), was prepared the title compound (66 mg, 36%). Hplc/ms (positive ion) Rt 4.28 min, m/z 427 (M+H+).
Example 36: acetic acid 4-[3,5-dimethyl-1-(5-methyl-5tf-1,2,4-triazino[5,6- 6]indol-3-yl)-1 Y-pyrazol-4-ylmethyl]-phenyl ester
A mixture of 4-[3,5-dimethyl-1-(5-methyl-5rV-1 ,2,4-triazino[5,6-b]indol-3- yl)-1 H-pyrazol-4-ylmethyl]-phenol (Example 25, 10 mg, 26μmol) and pyridine (10 μL, 124 μmol) in dry acetonitrile (1 ml) was treated with acetyl chloride (10 μL, 140 μmol) and heated to 150°C in a sealed vial under microwave conditions for 2 minutes. The mixture was cooled to room temperature and treated with water (1 ml). The suspension was filtered and the solid washed with water (1 ml), hexane (1 ml) and dried in vacuo to give the title compound (2.07 mg, 18%). Hplc/ms (positive ion) Rt 4.18 min, m/z 427 (M+H+). Example 37: acetic acid 3-[3,5-dimethyl-1-(5-methyl-5H-1,2,4-triazino[5,6- i)]indol-3-yl)-1 H-pyrazol-4-ylmethyl]-phenyl ester
In a manner analogous to that of Example 36, using 3-[3,5-dimethyl-1 -(5- methyl-6H-1 ,2,4-triazino[5,6-b]indol-3-yl)-1 H-pyrazol-4-ylmethyl]-phenol (Example 26, 10 mg, 26μmol) was prepared the title compound (5.67 mg, 51 %). Hplc/ms (positive ion) Rt 4.19 min, m/z 427 (M+H+).
Example 38: acetic acid 2-[3,5-dimethyl-1-(5-methyl-5W-1,2,4-triazino[5,6- 6]indol-3-yl)-1 //-pyrazol-4-ylmethyl]-phenyl ester
In a manner analogous to that of Example 36, using 2-[3,5-dimethyl-1 -(5- methyl-5H-1 ,2,4-triazino[5,6-i ]indol-3-yl)-1 H-pyrazol-4-ylmethyl]-phenol (Example 20, 10 mg, 26μmol) was prepared the title compound (2 mg, 18%). Hplc/ms (positive ion) Rt 4.18 min, m/z 427 (M+H+).
Example 39: 5-ethyl-3-[4-(2-methoxy-benzyl)-3,5-dimethyl-pyrazol-1 -yl]-5H- 1,2,4-triazino[5,6-ϋ]indole
In a manner analogous to Example 14, using (5-ethyl-5H-1 ,2,4- triazino[δ,6-J ]indol-3-yl)-hydrazine (Intermediate 31 , 10 mg, 44 μmol) was prepared the title compound (8 mg, 44%). Hplc/ms (positive ion) Rt 4.66 min, m/z 413 (M+H+).
Example 40: 5-ethyl-3-[4-(2-fluoro-benzyl)-3,5-dimethyl-pyrazol-1 -yl]-5H- 1,2,4-triazino[5,6-b]indole
In a manner analogous to Example 12, using (5-ethyl-6H-1,2,4- triazino[δ,6-jb]indol-3-yl)-hydrazine (Intermediate 31 , 10 mg, 44 μmol) in place of Intermediate 4, was prepared the title compound (5 mg, 28%). Hplc/ms (positive ion) Rt 4.67 min, m/z 401 (M+H+).
Example 41 : 5-ethyl-3-[4-(3-fluoro-benzyl)-3,5-dimethyl-pyrazol-1-yl]-5W- 1 ,2,4-triazino[5,6- )]indole
In a manner analogous to Example 15, using (5-ethyl-5H-1 ,2,4- triazino[5,6-ib]indol-3-yl)-hydrazine (Intermediate 31, 10 mg, 44 μmol) in place of Intermediate 2, was prepared the title compound (4 mg, 23%). Hplc/ms (positive ion) Rt 4.64 min, m/z 401 (M+H+). Example 42: 5-ethyl-3-[4-(4-fluoro-benzyl)-3,5-dimethyl-pyrazol-1 -yl]-5W- 1 ,2,4-triazino[5,6-Jb]indole
In a manner analogous to Example 15, using (δ-ethyl-5H-1 ,2,4- triazino[5,6-jb]indol-3-yl)-hydrazine (Intermediate 31 , 10 mg, 44 μmol) in place of Intermediate 2 and Intermediate 32 in place of Intermediate 17, was prepared the title compound (7 mg, 40%). Hplc/ms (positive ion) Rt 4.64 min, m/z 401
(M+H+).
Example 43: 5-ethyl-3-[4-(3-methoxy-benzyl)-3,5-dimethyl-pyrazol-1 -yl]-5H- 1 ,2,4-triazino[5,6-ϋ]indole
In a manner analogous to Example 16, using (5-ethyl-6H-1 ,2,4- triazino[5,6-£>]indol-3-yl)-hydrazine (Intermediate 31 , 10 mg, 44 μmol) in place of Intermediate 2, was prepared the title compound (6 mg, 28%). Hplc/ms (positive ion) Rt 4.56 min, m/z 413 (M+H+).
Example 44: 3-[4-(3,5-dimethoxy-benzyl)-3,5-dimethyl-pyrazol-1 -yl]-5-ethyl- 5W-1 ,2,4-triazino[5,6-6]indole
In a manner analogous to Example 17, using (5-ethyl-5/7-1 ,2,4- triazino[5,6-£>]indol-3-yl)-hydrazine (Intermediate 31, 10 mg, 44 μmol) in place of Intermediate 2, was prepared the title compound (5 mg, 26%). Hplc/ms (positive ion) Rt 4.52 min, m/z 443 (M+H+). Example 45: 3-[3,5-dimethyl-4-(2-nitro-benzyl)-pyrazol-1 -yl]-5-ethyl-5tf-1 ,2,4- triazino[5,6-ϋ]indole
In a manner analogous to Example 18, using (5-ethyl-5H-1 ,2,4- tπazino[5,6-ιb]indol~3-yl)-hydrazine (Intermediate 31, 10 mg, 44 μmol) in place of Intermediate 2, was prepared the title compound (10 mg, 53%). Hplc/ms (positive ion) Rt 4.47 min, m/z 428 (M+H+).
Example46:2-[1-(5-ethyl-5H-1,2,4-triazino[5,6-fe]indol-3-yl)-3,5-dimethyl-1H- pyrazol-4-ylmethyl]-phenol
In a manner analogous to Example 8, using (5-ethyl-5H-1 ,2,4-triazino[5,6- J ]indol-3-yl)-hydrazine (Intermediate 31, 10 mg, 44 μmol) in place of Intermediate 4, was prepared the title compound (1.5 mg, 9%). Hplc/ms (positive ion) Rt 4.03 min, m/z 399 (M+H+). Example 47: 5-ethyl-3-[4-(4-methoxy-benzyl)-3,5-dimethyl-pyrazol-1 -yl]-5H- 1,2,4-triazino[5,6-6]indole
In a manner analogous to Example 20, using (5-ethyl-5/- -1 ,2,4- triazino[5,6-b]indol-3-yl)-hydrazine (Intermediate 31 , 10 mg, 44 μmol) in place of Intermediate 2, was prepared the title compound (5 mg, 28%). Hplc/ms (positive ion) Rt 4.54 min, m/z 413 (M+H+).
Example 48: 3-[4-(2-benzyloxy-benzyl)-3,5-dimethyl-pyrazol-1 -yl]-5-ethyl-5 Y- 1 ,2,4-triazino[5,6-J ]indole
In a manner analogous to Example 6, using (5-ethyl-5H-1 ,2,4-triazino[5,6- i ]indol-3-yl)-hydrazine (Intermediate 31, 10 mg, 44 μmol) in place of Intermediate 4, was prepared the title compound (7 mg, 33%). Hplc/ms (positive ion) Rt 5.19 min, m/z 489 (M+H+).
Example 49: 3-(3,5-dimethyl-4-naphthalen-2-ylmethyl-pyrazol-1 -yl)-5-ethyl- 5H-1 ,2,4-triazino[5,6-Λ]indole
In a manner analogous to Example 11, using (5-ethyl-5H-1 ,2,4- triazino[5,6π ]indol-3-yl)-hydrazine (Intermediate 31, 10 mg, 44 μmol) in place of Intermediate 4, was prepared the title compound (3.3 mg, 17%). Hplc/ms (positive ion) Rt 5.04 min, m/z 433 (M+H+)-
Example 50: 3-[3,5-dimethyl-4-(3-nitro-benzyl)-pyrazol-1 -yl]-5-ethyl-5H-1,2,4- triazino[5,6-ύ]indole
In a manner analogous to Example 5, using (5-ethyl-5H-1 ,2,4-triazino[5,6- £>]indol-3-yl)-hydrazine (Intermediate 31 , 10 mg, 44 μmol) and 3-(3-nitro-benzyl)- pentane-2,4-dione (Intermediate 33, 52 mg, 220 μmol), was prepared the title compound (3.4 mg, 18%). Hplc/ms (positive ion) Rt 4.5 min, m/z 428 (M+H+). Example 51 : 3-[3,5-dimethyl-4-(4-nitro-benzyl)-pyrazol-1 -yl]-5-ethyl-5W-1,2,4- triazino[5,6-J ]indole
In a manner analogous to Example 24, using (5-ethyl-5H-1 ,2,4- triazino[5,6-fc]indol-3-yl)-hydrazine (Intermediate 31 , 10 mg, 44 μmol) in place of Intermediate 2, was prepared the title compound (4.5 mg, 24%). Hplc/ms (positive ion) Rt 4.51 min, m/z 428 (M+H+). Example 52: 4-[1-(5-ethyl-5 -1,2,4-triazino[5,6- )]indol-3-yl)-3,5-dimethyl-1H- pyrazol-4-ylmethyl]-phenol
In a manner analogous to Example 7, using (5-ethyl-5H-1 ,2,4-triazino[5,6- ι ]indol-3-yl)-hydrazine (Intermediate 31 , 10 mg, 44 μmol) in place of Intermediate 4, was prepared the title compound (13 mg, 74%). Hplc/ms (positive ion) Rt 3.92 min, m/z 399 (M+H+).
Example 53: 3-[1-(5-ethyl-5W-1,2,4-triazino[5,6-6]indol-3-yl)-3,5-dimethyl-1W- pyrazol-4-ylmethyl]-phenol
In a manner analogous to Example 9, using (5-ethyl-5H-1 ,2,4-triazino[5,6- jfc>]indol-3-yl)-hydrazine (Intermediate 31 , 10 mg, 44 μmol) in place of Intermediate 4, was prepared the title compound (9 mg, 51 %). Hplc/ms (positive ion) Rt 3.99 min, m/z 399 (M+H+).
Example 54: 3-[3,5-dimethyl-4-(4-trifluoromethyl-benzyl)-pyrazol-1 -yl]-5- ethyl-5H-1,2,4-triazino[5,6-6]indole
In a manner analogous to Example 27, using (5-ethyl-5/-/-1 ,2,4- triazino[5,6-£>]indol-3-yl)-hydrazine (Intermediate 31 , 10 mg, 44 μmol) in place of Intermediate 2, was prepared the title compound (10 mg, 50%). Hplc/ms (positive ion) Rt 4.97 min, m/z 451 (M+H+).
Example 55: 5-ethyl-3-[4-(4-methanesulphonyl-benzyl)-3,5-dimethyl-pyrazol- 1-yl]-5H-1,2,4-triazino[5,6-/>]indole
In a manner analogous to Example 28, using (5-ethyl-5H-1 ,2,4- triazino[5,6-J ]indol-3-yl)-hydrazine (Intermediate 31 , 10 mg, 44 μmol) in place of Intermediate 2, was prepared the title compound (1 mg, 5%). Hplc/ms (positive ion) Rt 3.92 min, m/z 461 (M+H+).
Example 56: 3-[3,5-dimethyl-4-(2-trif luoromethyl-benzyl)-pyrazol-1 -yl]-5- ethyl-5H-1,2,4-triazino[5,6-i)]indole
In a manner analogous to Example 29, using (5-ethyl-5r7-1 ,2,4- triazino[5,6-ιb]indol-3-yl)-hydrazine (Intermediate 31 , 10 mg, 44 μmol) in place of Intermediate 2, was prepared the title compound (2 mg, 10%). Hplc/ms (positive ion) Rt 5.06 min, m/z 451 (M+H+). Example 57: 3-[3,5-dimethyl-4-(3-trifluoromethyl-benzyl)-pyrazol-1 -yl]-5- ethyl-5W-1,2,4-triazino[5,6-b]indole
In a manner analogous to Example 30, using (5-ethyl-5/V-1,2,4- triazino[5,6-ιb]indol-3-yl)-hydrazine (Intermediate 31, 10 mg, 44 μmol) in place of Intermediate 2, was prepared the title compound (8 mg, 40%). Hplc/ms (positive ion) Rt 4.94 min, m/z 451 (M+H+).
Example 58: 3-[3,5-dimethyl-4-(2-methyl-benzyl)-pyrazol-1 -yl]-5-ethyl-5W- 1,2,4-triazino[5,6-/>]indole
In a manner analogous to Example 31 , using (5-ethyl-5H-1 ,2,4- triazino[5,6-6]indol-3-yl)-hydrazine (Intermediate 31, 10 mg, 44 μmol) in place of Intermediate 2, was prepared the title compound (8 mg, 46%). Hplc/ms (positive ion) Rt 4.85 min, m/z 397 (M+H+).
Example 59: 3-[3,5-dimethyl-4-(3-methyl-benzyl)-pyrazol-1 -yl]-5-ethyl-5W- 1 ,2,4-triazino[5,6-J ]indole
In a manner analogous to Example 32, using (5-ethyl-5H-1,2,4- triazino[5,6-b]indol-3-yl)-hydrazine (Intermediate 31, 10 mg, 44 μmol) in place of Intermediate 2, was prepared the title compound (9 mg, 52%). Hplc/ms (positive ion) Rt 4.86 min, m/z 397 (M+H+).
Example 60: 3-(3,5-dimethyl-4-phenethyl-pyrazol-1 -yl)-5-ethyl-5H-1 ,2,4- triazino[5,6-/)]indole
In a manner analogous to Example 33, using (5-ethyl-5 -/-1 ,2,4- triazino[5,6-Jb]indol-3-yl)-hydrazine (Intermediate 31 , 10 mg, 44 μmol) in place of Intermediate 2, was prepared the title compound (7 mg, 40%). Hplc/ms (positive ion) Rt 4.89 min, m/z 397 (M+H+).
Example 61 : 4-[1-(5-ethyl-5W-1,2,4-triazino[5,6-ύ]indol-3-yl)-3,5-dimethyl-1 H- pyrazol-4-ylmethyl]-benzoic acid methyl ester
In a manner analogous to Example 34, using (5-ethyl-5/-/-1 ,2,4- triazino[5,6-Jb]indol-3-yl)-hydrazine (Intermediate 31 , 50 mg, 220 μmol) in place of Intermediate 2, was prepared the title compound (73 mg, 75%). Hplc/ms (positive ion) Rt 4.49 min, m/z 441 (M+H+). Example 62: 3-[1-(5-ethyl-5W-1,2,4-triazino[5,6-j ]indol-3-yl)-3,5-dimethyl-1 H- pyrazol-4-ylmethyl]-benzoic acid methyl ester
In a manner analogous to Example 35, using (5-ethyl-5H-1,2,4- triazino[5,6-j ]indol-3-yl)-hydrazine (Intermediate 31 , 50 mg, 220 μmol) in place of Intermediate 2, was prepared the title compound (50 mg, 52%). Hplc/ms (positive ion) Rt 4.49 min, m/z 441 (M+H+).
Example 63: 4-[1-(5-ethyl-5H-1,2,4-triazino[5,6-i ]indol-3-yl)-3,5-dimethyl-1W- pyrazol-4-ylmethyl]-benzoic acid
A stirred solution of 4-[1-(5-ethyl-5H-1,2,4-triazino[5,6-jb]indol-3-yl)-3,5- dimethyl-1 H-pyrazol-4-ylmethyl]-benzoic acid methyl ester (Example 61 , 22 mg, 50 μmol) 3:1 tetrahydrofuran/water (2 ml) was treated with lithium hydroxide (12 mg, 500 μmol) and stirred at room temperature for 17 hours. Solvent was evaporated and the residue dissolved in water, acidified with 1M hydrochloric acid, and extracted with dichloromethane (3 x 5 ml). The combined extracts were dried over magnesium sulphate, filtered and evaporated to give the title compound (15 mg, 70%). Hplc/ms (positive ion) Rt 3.86 min, m/z 427 (M+H+). Example 64: 3-(3,5-dimethyl-4-propyl-pyrazol-1 -yl)-5-ethyl-5W-1 ,2,4- triazino[5,6-ϋ]indole
A solution of (5H-1 ,2,4-triazino[5,6-j ]indol-3-yl)-hydrazine (Intermediate 4 , 300 mg, 1.5 mmol) in 20% acetic acid/ethanol (4 ml) was treated with 3- propyl-pentane-2,4-dione (1.065 g, 7.5 mmol) and heated to 140°C in a sealed vial under microwave conditions for 5 minutes. On cooling, the resulting precipitate was filtered and dried under vacuum to give 3-(3,5-dimethyl-4-propyl- pyrazol-1 -yl)-5H-1 ,2,4-triazino[5,6-fo]indole (315 mg, 70%) as a pale yellow solid.
A solution of the product (40 mg, 130 μmol) in acetone (2ml) was treated with potassium carbonate (37 mg, 260 μmol) and ethyl iodide (22 mg, 140 μmol) then heated to 100°C in a sealed vial under microwave conditions for 8 minutes. Solvent was evaporated and the residue purified by preparative hplc to give the title compound (15 mg, 35%). Hplc/ms (positive ion) Rt 4.57 min, m/z 335 (M+H+). Example 65: 5-ethyl-3-(4-ethyl-3,5-dimethyl-pyrazol-1-yl)-5tf-1,2,4- triazino[5,6-J ]indole
In a manner analogous to Example 64, using 3-(4-ethyl-3,5-dimethyl- pyrazol-1-yl)-5H-1,2,4-triazino[5,6-rj]indole (Example 4, 50 mg, 170 μmol), was prepared the title compound (10 mg, 18%). Hplc/ms (positive ion) Rt 4.3 min, m/z 321 (M+H+).
Example 66: 3-(4-benzyl-3,5-dimethyl-pyrazol-1-yl)-5-propyl-5W-1,2,4- triazino[5,6-ϋ]indole
In a manner analogous to Example 64, using 3-(4-benzyl-3,5-dimethyl- pyrazol-1 -yl)-5/-/-1 ,2,4-triazino[5,6-6]indole (Example 5, 30 mg, 85 μmol) and 1 - iodopropane (16 mg, 94 μmol), was prepared the title compound (5 mg, 15%). Hplc/ms (positive ion) Rt 4.85 min, m/z 397 (M+H+).
Example 67: 5-propyl-3-(3,4,5-trimethyl-pyrazol-1 -yl)-5W-1 ,2,4-triazino[5,6- ϋ]indole
A solution of (5H-1 ,2,4-triazino[5,6-r]indol-3-yl)-hydrazine (Intermediate 4 , 300 mg, 1.5 mmol) in 20% acetic acid/ethanol (4 ml) was treated with 3- methyl-pentane-2,4-dione (855 mg, 7.5 mmol) and heated to 140°C in a sealed vial under microwave conditions for 5 minutes. On cooling, the resulting precipitate was filtered and dried under vacuum to give 3-(3,4,5-trimethyl- pyrazol-1 -yl)-5H-1 ,2,4-triazino[5,6-ιb]indole (330 mg, 80%) as a pale yellow solid. The product (50 mg, 180 μmol) in acetone (2 ml) was treated with potassium carbonate (50 mg, 360 μmol), 1 -iodopropane (34 mg, 200 μmol) and heated to 100°C in a sealed vial under microwave conditions for 8 minutes. Solvent was evaporated and the residue purified by preparative hplc to give the title compound (10 mg, 17%). Hplc/ms (positive ion) Rt 4.28 min, m/z 321 (M+H+). Example 68: 3-(4-ethyl-3,5-dimethyl-pyrazol-1-yl)-5-propyl-5H-1,2,4- triazino[5,6-ϋ]indole
In a manner analogous to Example 64, using 3-(4-ethyl-3,5-dimethyl- pyrazol-1-yl)-5H-1 ,2,4-triazino[5,6-fo]indole (Example 4, 50 mg, 170 μmol) and 1 -iodopropane (32 mg, 190 μmol), was prepared the title compound (15 mg, 26%). Hplc/ms (positive ion) Rt 4.53 min, m/z 335 (M+H+). Example 69: 3-(3,5-dimethyl-4-ρropyl-pyrazol-1-yl)-5-propyl-5W-1,2,4- triazino[5,6-6]indole
In a manner analogous to Example 64, using 1 -iodopropane (44 mg, 260 μmol), was prepared the title compound (15 mg, 33%). Hplc/ms (positive ion) Rt 4.8 min, m/z 349 (M+H+).
Example 70: 5-butyl-3-(3,5-dimethyl-pyrazol-1 -yl)-5W-1 ,2,4-triazino[5,6- ϋ]indole
A mixture of (5ry-1,2,4-triazino[δ,6-j ]indol-3-yl)-hydrazine (300 mg, 1.5 mmol) and pentane-2,4-dione (750 mg, 7.5 mmol) in 20% acetic acid/ethanol (4 ml) was heated to 140°C in a sealed vial under microwave conditions for 5 minutes. The reaction mixture was cooled to room temperature and the suspension filtered to give 3-(3,5-dimethyl-pyrazol-1-yl)-δ - -1,2,4-triazino[5,6- j ]indole (360 mg, 91%) as a pale yellow solid. The product (60 mg, 190μmol) in acetone (2 ml) was treated with potassium carbonate (64 mg, 380 μmol) and 1-bromobutane (29 mg, 210 μmol). The mixture was heated to 100°C in a sealed vial under microwave conditions for 8 minutes. The reaction mixture was cooled to room temperature, filtered and the filtrate evaporated. The residue was triturated with diethyl ether, filtered and dried to give the title compound (δ mg, 8%). Hplc/ms (positive ion) Rt 4.38 min, m/z 321 (M+H+). Example 71: 5-butyl-3-(3,4,5-trimethyl-pyrazol-1-yl)-5 y-1,2,4-triazino[5,6- frpndole
In a manner analogous to Example 70, using 3-methyl pentane-2,4-dione in place of pentane-2,4-dione, was prepared the title compound (7 mg, 12%). Hplc/ms (positive ion) Rt 4.68 min, m/z 335 (M+H+).
Example 72: 3-(4-benzyl-3,5-dimethyl-pyrazol-1 -yl)-5-butyl-5A -1 ,2,4- triazino[5,6-ϋ]indole
In a manner analogous to Example 66, using 1-bromobutane (13 mg, 94 μmol), was prepared the title compound (5 mg, 14%). Hplc/ms (positive ion) Rt 5.1 min, m/z 411 (M+H+).
Example 73: 5-butyl-3-(3,5-dimethyl-4-naphthalen-2-ylmethyl-pyrazol-1-yl)- 5H-1 ,2,4-triazino[5,6-Zϊ]indole In a manner analogous to Example 64, using 3-(3,5-dimethyl-4- naphthalen-2-ylmethyl-pyrazol-1-yl)-5H-1 ,2,4-triazino[5,6-J ]indole (Example 11 , 30 mg, 74 μmol) and 1-bromobutane (1 mg, 80 μmol), was prepared the title compound (5 mg, 15%). Hplc/ms (positive ion) Rt 5.47 min, m/z 461 (M+H+)÷ Example 74: 5-butyl-3-[4-(2-fluoro-benzyl)-3,5-dimethyl-pyrazol-1-yl]-5W- 1,2,4-triazino[5,6-&]indole
In a manner analogous to Example 64, using 3-[4-(2-fluoro-benzyl)-3,δ- dimethyl-pyrazol-1-yl]-6W-1,2,4-triazino[5,6-Jb]indole (Example 12, 30 mg, 74 μmol) and 1-bromobutane (11 mg, 80 μmol), was prepared the title compound (5 mg, 16%). Hplc/ms (positive ion) Rt 5.12 min, m/z 429 (M+H+). Example 75: 5-butyl-3-[3,5-dimethyl-4-(3-trifluoromethyl-benzyl)-pyrazol-1 - yl]-5tf-1,2,4-triazino[5,6-Jb]indole
In a manner analogous to Example 64, using 3-[3,5-dimethyl-4-(3- trifluoromethyl-benzyl)-pyrazol-1 -yl]-6H-1 ,2,4-triazino[5,6-6]indole (Example 13, 30 mg, 71 μmol) and 1-bromobutane (11 mg, 80 μmol), was prepared the title compound (5 mg, 15%). Hplc/ms (positive ion) Rt 5.34 min, m/z 479 (M+H+). Example 76: 5-butyl-3-(4-ethyl-3,5-dimethyl-pyrazol-1-yl)-5W-1,2,4- triazino[5,6-ϋ]indole
In a manner analogous to Example 64, using 3-(4-ethyl-3,5-dimethyl- pyrazol-1 -yl)-5/-/-1,2,4-triazino[5,6- ]indole (Example 4, 50 mg, 170 μmol) and 1-bromobutane (26 mg, 190 μmol), was prepared the title compound (15 mg, 25%). Hplc/ms (positive ion) Rt 4.8 min, m/z 349 (M+H+). Example 77: 5-benzyl-3-(3,4,5-trimethyl-pyrazol-1 -yl)-5//-1 ,2,4-triazino[5,6- ϋ]indole
In a manner analogous to Example 67, using benzyl bromide (34 mg, 200 μmol) in place of 1 -iodopropane, was prepared the title compound (30 mg, 45%). Hplc/ms (positive ion) Rt 4.49 min, m/z 369 (M+H+).
Example 78: 3-(4-benzyl-3,5-dimethyl-pyrazol-1 -yl)-5-isobutyl-5H-1 ,2,4- triazino[5,6-ϋ]indole
In a manner analogous to Example 64, using 3-(4-benzyl-3,5-dimethyl- pyrazol-1-yl)-5H-1 ,2,4-triazino[δ,6-b]indole (Example 6, 50 mg, 140 μmol) and 1 -iodo-2-methylpropane (28 mg, 150 μmol), was prepared the title compound (25 mg, 44%). Hplc/ms (positive ion) Rt δ.05 min, m/z 411 (M+H+). Example 79: 5-benzyl-3-(3,5-dimethyl-4-propyl-pyrazol-1-yl)-5W-1,2,4- triazino[5,6-i ]indole δ In a manner analogous to Example 64, using benzyl bromide (24 mg, 140 μmol), was prepared the title compound (20 mg, 39%). Hplc/ms (positive ion) Rt 4.94 min, m/z 397 (M+H+).
Example 80: oxalic acid 4-[3,5-dimethyl-1-(5-methyl-5H-1,2,4-triazino[5,6- b]indol-3-yl)-1/Y-pyrazol-4-ylmethyl]-phenyl ester ethyl ester
In a manner analogous to Example 36, using ethyl chlorooxalate (10 μL, 90 μmol) in place of acetyl chloride, was prepared the title compound (8.9 mg, 71%). Hplc/ms (positive ion) Rt 4.31 min, m/z 485 (M+H+). Example 81 : 5-isobutyl-3-(3,4,5-trimethyl-pyrazol-1 -yl)-5H-1 ,2,4-triazino[5,6- ϋ]indole
In a manner analogous to Example 67, using 3-(3,4,5-trimethyl-pyrazol-1 - yl)-δH-1 ,2,4-triazino[5,6-b]indole (80 mg, 290 μmol) and 1 -iodo-2-methylpropane (69 mg, 320 μmol), was prepared the title compound (10 mg, 10%). Hplc/ms (positive ion) Rt 4.53 min, m/z 335 (M+H+).
Example 82: 3-(4-ethyl-3,5-dimethyl-pyrazol-1 -yl)-5-isobutyl-5W-1,2,4- 0 triazino[5,6-b]indole
In a manner analogous to Example 64, using 3-(4-ethyl-3,5-dimethyl- pyrazol-1-yl)-5H-1,2,4-triazino[5,6-b]indole (Example 4, 50 mg, 170 μmol) and 1 -iodo-2-methylpropane (35 mg, 190 μmol), was prepared the title compound (10 mg, 17%). Hplc/ms (positive ion) Rt 4.76 min, m/z 349 (M+H+). Example 83: 3-(3,5-dimethyl-4-propyl-pyrazol-1-yl)-5-isobutyl-5W-1,2,4- triazino[5,6-ύ]indole
In a manner analogous to Example 64, using 1 -iodo-2-methylpropane (26 mg, 140 μmol), was prepared the title compound (5 mg, 11 %). Hplc/ms (positive ion) Rt 5.01 min, m/z 363 (M+H+).
Example 84: 3-(3,5-dimethyl-4-propyl-pyrazol-1-yl)-5-isobutyl-5H-1,2,4- triazino[5,6-J ]indole A mixture of 3-(3,5-dimethyl-4-propyl-pyrazol-1 -yl)-6H-1 ,2,4-triazino[5,6- £>]indole (30 mg, 100 μmol, prepared as in Example 64), potassium carbonate (42 mg, 300 μmol) and 1-(2-chloroethyl)-pyrrolidine hydrochloride (19 mg, 110 μmol) in acetone (2 ml) was heated to 100°C in a sealed vial under microwave conditions for 8 minutes. After cooling to room temperature, solvent was evaporated and the residue subjected to preparative HPLC to give the title compound (1δmg, 37%). Hplc/ms (positive ion) Rt 3.2 min, m/z 404 (M+H+). Example 85: 2-[3-(3,5-dimethyl-4-propyl-pyrazol-1-yl)-1,2,4-triazino[5,6- ϋ]indol-5-yl]-ethanol
A solution of 3-(3,5-dimethyl-4-propyl-pyrazol-1 -yl)-5-[2-(tetrahydro-pyran- 2-yloxy)-ethyl]-5H-1,2,4-triazino[δ,6-b]indole (Example 96, 10 mg, 23 μmol) in 4:2:1 acetic acid:tetrahydrofuran:water (1 ml) was heated to 100°C in a sealed vial under microwave conditions for 10 minutes. After cooling to room temperature, solvent was evaporated and the residue subjected to preparative HPLC to give the title compound (5 mg, 62%). Hplc/ms (positive ion) Rt 3.89 min, m/z 351 (M+H+).
Example 86: 3-[3,5-dimethyl-4-(1 -phenyl-ethyl)-pyrazol-1 -yl] -5-methyl -5 H- 1 ,2,4-triazino[5,6-b]indole
In a manner analogous to Example 2, using 3-(1-phenyl-ethyl)-pentane- 2,4-dione (Intermediate 34, 45 mg, 219 μmol) in place of 3-propyl-2,4- pentanedione, was prepared the title compound (13 mg, 77%). Hplc/ms (positive ion) Rt 4.62 min, m/z 383 (M+H+).
Example 87: 3-(4-benzhydryl-3,5-dimethyl-pyrazol-1 -yl)-5-methyl-5W-1 ,2,4- triazino[5,6-J ]indole
In a manner analogous to Example 2, using 3-benzhydryl-pentane-2,4- dione (Intermediate 35, 55 mg, 219 μmol) in place of 3-propyl-2,4-pentanedione, was prepared the title compound (7 mg, 36%). Hplc/ms (positive ion) Rt 4.99 min, m/z 445 (M+H+).
Example 88: 3-[3,5-dimethyl-4-(1 -phenyl-ethyl)-pyrazol-1 -yl]-5-ethyl-5W- 1 ,2,4-triazino[5,6- }]indole
In a manner analogous to Example 86, using (δ-ethyl-δH-1 ,2,4- triazino[5,6-ώ]indol-3-yl)-hydrazine (Intermediate 31 , 10 mg, 44 μmol), was prepared the title compound (3 mg, 17%). Hplc/ms (positive ion) Rt 4.83 min, m/z 397 (M+H+).
Example 89: 3-(4-benzhydryl-3,5-dimethyl-pyrazol-1 -yl)-5-ethyl-5W-1 ,2,4- triazino[5,6-£)]indole
In a manner analogous to Example 87, using (δ-ethyl-5H-1 ,2,4- triazino[δ,6-b]indol-3-yl)-hydrazine (Intermediate 31 , 10 mg, 44 μmol), was prepared the title compound (1.6 mg, 8%). Hplc/ms (positive ion) Rt 5.18 min, m/z 459 (M+H+).
Example 90: 3-[4-(4-methoxy-phenyl)-pyrazol-1-yl]-5-methyl-5H-1,2,4- triazino[5,6-ϋ]indole
A solution of (δ-methyl-5/- -1,2,4-triazino[5,6-/9]indol-3-yl)-hydrazine (Intermediate 2, 9.4 mg, 44 μmol) and 2-(4-methoxy-phenyl)-malonaldehyde (24 mg, 136 μmol) in 4:1 ethanol:aceticacid (1 ml) was heated at 140°C in a sealed vial under microwave conditions for δ minutes. After cooling to room temperature, the mixture was treated with water (1 ml) and the precipitate filtered. The solid was washed with water (1 ml), hexane (2 ml) and dried in vacuo to give the title compound (10 mg, 64%). Hplc/ms (positive ion) Rt 4.16 min, m/z 367 (M+H+). Example 91: 3-[4-(3-bromo-phenyl)-pyrazol-1-yl]-5-methyl-5W-1,2,4- triazino[5,6- )]indole
In a manner analogous to Example 90, using 2-(3-bromophenyl)- malonaldehyde (30 mg, 132 μmol), was prepared the title compound (8 mg, 45%). Hplc/ms (positive ion) Rt 4.63 min, m/z 405 (M+H+). Example 92: 5-methyl-3-(4-quinolin-4-yl-pyrazol-1 -yl)-5W-1 ,2,4-triazino[5,6- ϋ]indole
In a manner analogous to Example 90, using 2-quinolin-4-yl- malonaldehyde (26 mg, 130 μmol), was prepared the title compound (8 mg, 48%). Hplc/ms (positive ion) Rt 3.5 min, m/z 378 (M+H+). Example 93: 5-methyl-3-(4-pyridin-2-yl-pyrazol-1-yl)-5H-1,2,4-triazino[5,6- ϋ]indole In a manner analogous to Example 90, using 2-pyridin-2-yl- malonaldehyde (20 mg, 134 μmol), was prepared the title compound (2.6 mg, 17%). Hplc/ms (positive ion) Rt 3.35 min, m/z 328 (M+H+). Example 94: 3-[4-(4-bromo-phenyl)-pyrazol-1 -yl]-5-methyl-5H-1 ,2,4- triazino[5,6-ϋ]indole
In a manner analogous to Example 90, using 2-(4-bromophenyl)- malonaldehyde (30 mg, 132 μmol), was prepared the title compound (7 mg, 39%). Hplc/ms (positive ion) Rt 4.65 min, m/z 406 (M+H+). Example 95: 3-(3,5-dimethyl-4-propyl-pyrazol-1 -yl)-5-[2-(tetrahydro-pyran-2- yloxy)-ethyl]-5tf-1,2,4-triazino[5,6-*)]indole
In a manner analogous to Example 64, using 3-(3,5-dimethyl-4-propyl- pyrazol-1-yl)-5H-1,2,4-triazino[5,6-ib]indole (60 mg, 163 μmol) and 2-(2- bromoethoxy)-tetrahydropyran (37 mg, 180 μmol), was prepared the title compound (70 mg, 100%). Hplc/ms (positive ion) Rt 4.79 min, m/z 435 (M+H+). Example 96: 5-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-3-(3,4,5-trimethyl- pyrazol-1 -yl)-5H-1 ,2,4-triazino[5,6-D]indole
In a manner analogous to Example 67, using 2-(2~bromoethoxy)- tetrahydropyran (41 mg, 198 μmol), was prepared the title compound (20 mg, 27%). Hplc/ms (positive ion) Rt 4.29 min, m/z 407 (M+H+). Example 97: 3-(4-benzyl-3,5-dimethyl-pyrazol-1 -yl)-5-[2-(tetrahydro-pyran-2- yloxy)-ethyl]-5W-1,2,4-triazino[5,6-6]indole
In a manner analogous to Example 64, using 3-(4-benzyl-3,δ-dimethyl- pyrazol-1-yl)-5r-/-1 ,2,4-triazino[5,6-ib]indole (Example 5, 70 mg, 200 μmol) and 2-(2-bromoethoxy)-tetrahydropyran (46 mg, 220 μmol), was prepared the title compound (90 mg, 93%). Hplc/ms (positive ion) Rt 4.85 min, m/z 483 (M+H+). Example 98: 3-(4-ethyl-3,5-dimethyl-pyrazol-1 -yl)-5-[2-(tetrahydro-pyran-2- yloxy)-ethyl]-5H-1,2,4-triazino[5,6-J ]indole
In a manner analogous to Example 64, using 3-(4-ethyl-3,5-dimethyl- pyrazol-1-yl)^5/-/-1 ,2,4-triazino[5,6-j ]indole (Example 4, 58 mg, 200 μmol) and 2-(2-bromoethoxy)-tetrahydropyran (46 mg, 220 μmol), was prepared the title compound (60 mg, 71%). Hplc/ms (positive ion) Rt 4.53 min, m/z 421 (M+H+). Example 99: 2-[3-(4-benzyl-3,5-dimethyl-pyrazol-1 -yl)-1,2,4-triazino[5,6- b]indol-5-yl]-ethanol
In a manner analogous to Example 85, using 3-(4-benzyl-3,5-dimethyl- pyrazol-1-yl)-5-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-5/- -1 ,2,4-triazino[5,6-o]indole (Example 97, 10 mg, 21 μmol), was prepared the title compound (5 mg, 60%). Hplc/ms (positive ion) Rt 4.09 min, m/z 399 (M+H+). Example 100: Activity Assay
The compounds of Examples 1, 3, 26, 28, 56, 73, 79, 80, 82, 84, 85, 87, 90 and 95 were tested for their inhibitory activity towards BACE.
All enzyme assays were performed at 20° C on an AlphaFusion (Packard Instruments) using 384 well plates (Greiner Bio-One Ltd). The assay volume was 30 μl. Inhibitors were dissolved in dimethyl sulphoxide (DMSO) and added into a well with 50 mM sodium acetate buffer pH 4.5 and 10 μM EDANS- EVNLDAEFK-DABCYL peptide substrate. The DMSO concentration was set at 10% in the assay.
The reaction was started with the addition of 1 μg/ml recombinant human soluble BACE-1. After 3 hours the fluorescence increase was measured in the plate reader at 365ex/485em. The EDANS-DABCYL peptide substrate becomes slightly fluorescent upon enzymatic cleavage due to disruption of the resonance energy transfer between the EDANS donor and DABCYL quenching acceptor in the intact substrate.
The activities (IC50 values in μM) of the tested Example compounds are tabulated below. The results demonstrate the desirability of compounds of the invention.
Figure imgf000046_0001
Figure imgf000047_0001

Claims

1. A compound for use in therapy, wherein the compound is of formula (I)
Figure imgf000048_0001
wherein
R1 is hydrogen, alkyl, -alkyl-aryl, -alkyl-heterocycloalkyl or -alkyl-O- heterocycloalkyl;
R2 is hydrogen, hydroxy, amino, nitro, alkoxy, alkyl, aryl or heteroaryl;
R3 is hydrogen, alkyl or aryl;
R4 is hydrogen, alkyl, aryl, heteroaryl, -CH(aryl)2, -alkyl-aryl or -C(O)O- alkyl; and
R5 is alkyl, hydroxy or amino; or a pharmaceutically acceptable salt thereof.
2. A compound as defined in clam 1 , independent of use, with the proviso that the compound is not a compound selected from:
2-(3,5-dimethyl-pyrazol-1-yl)-9-ethyl-9H-1 ,3,4,9-tetraaza-fluorene;
2-(3,5-dimethyl-pyrazol-1-yl)-9-methyl-9H-1,3,4,9-tetraaza-fluorene;
9-benzyl-2-(3,5-dimethyl-pyrazol-1-yl)-9H-1 ,3,4,9-tetraaza-fluorene;
9-benzyl-2-(4-benzyl-3,5-dimethyl-pyrazol-1-yl)-9H-1 ,3,4,9-tetraaza- fluorene;
4-benzyl-2-(9-benzyl-9H-1 ,3,4,9-tetraaza-fluoren-2-yl)-5-methyl-2H- pyrazol-3-ol;
2-(4-butyl-3,5-dimethyl-pyrazol-1-yl)-9-ethyl-9H-1,3,4,9-tetraaza-fluorene;
2-(4-benzyl-3,5-dimethyl-pyrazol-1-yl)-9-ethyl-9H-1 ,3,4,9-tetraaza- fluorene; 3-(3,5-dimethyl-pyrazol-1 -yl)-5H-1 ,2,4-tπ*azino[5,6-b]indole;
5-methyl-2-(5 -/-1,2,4-triazino[5,6-b]indol-3-yl)-2H-pyrazol-3-ol;
5-(4-chloro-phenyl)-2-(5H-1,2,4-triazino[5,6-b]indol-3-yl)-2H-pyrazol-3-ol;
3-(3,5-dimethyl-pyrazol-1-yl)-8-fluoro-5H-1,2,4-triazino[5,6-b]indole; 5-amino-1 -(5-ethyl-5H-1 ,2,4-triazino[5,6-b]indol-3-yl)-1 H-pyrazole-4- carboxylic acid ethyl ester;
5-amino-1 -(5H-1 ,2,4-triazino[5,6-£>]indol-3-yl)-1 H-pyrazole-4-carboxylic acid ethyl ester;
5-phenyl-2-(5H-1 ,2,4-triazino[5,6-£)]indol-3-yl)-2H-pyrazol-3-ylamine;
2-(5-methyl-5H-1 ,2,4-triazino[5,6- 3]indol-3-yl)-5-phenyl-2H-pyrazol-3- ylamine;
5-(4-chloro-phenyl)-2-(5-methyl-5H-1,2,4-triazino[5,6-i ]indol-3-yl)-2H- pyrazol-3-ylamine;
5-(4-bromo-phenyl)-2-(5-methyl-5H-1,2,4-triazino[5,6-b]indol-3-yl)-2H- pyrazol-3-ylamine;
5-(4-bromo-phenyl)-2-(5H-1,2,4-triazino[5,6-b]indol-3-yl)-2H-pyrazol-3- ylamine;
5-(4-chloro-phenyl)-2-(5 -/-1,2,4-triazino[5,6-b]indol-3-yl)-2H-pyrazol-3- ylamine; 2-(8-bromo-5H-1 ,2,4-triazino[5,6-fo]indol-3-yl)-δ-phenyl-2H-pyrazol-3- ylamine;
2-(8-bromo-5H-1,2,4-triazino[6,6- )]indol-3-yl)-5-(4-chloro-phenyl)-2H- pyrazol-3-ylamine; and δ-(4-bromo-phenyl)-2-(8-bromo-5/-/-1 ,2,4-triazino[δ,6- )]indol-3-yl)-2H- pyrazol-3-ylamine.
3. A compound according to claim 1 or claim 2, wherein R1 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, pyrazol-1 -ylethy I, hydroxyethyl, (2- tetrahydro-pyran-2-yloxy)ethyl or benzyl.
4. A compound according to any preceding claim, wherein R2 is hydrogen.
5. A compound according to any preceding claim, wherein R3 is hydrogen, methyl or phenyl.
6. A compound according to any preceding claim, wherein R4 is hydrogen, methyl, ethyl, propyl, butyl or -C(O)O-CH2CH3.
7. A compound according to any of claims 1 to 5, wherein R4 is phenyl, -CH(phenyl)2, benzyl, 1 -phenylethyl, 2-phenylethyl or napthylmethyl, any of which is optionally substituted.
8. A compound according to any of claims 1 to 5, wherein R4 is quinolin-4-yl or pyridin-2-yl, either of which is optionally substituted.
9. A compound according to any preceding claim, wherein R5 is hydrogen, methyl, hydroxy or amino.
10. A compound according to claim 1 or claim 2, selected from: 9-methyl-2-(5-methyl-3-phenyl-pyrazol-1-yl)-9H-1 ,3,4,9-tetraaza-fluorene; 2-(3,5-dimethyl-4-propyl-pyrazol-1-yl)-9-methyl-9H-1 ,3,4,9-tetraaza- fluorene; and
5-amino-1 -(9-methyl-9H-1 ,3,4,9-tetraaza-fluoren-2-yl)-1 H-pyrazole-4- carboxylic acid ethyl ester.
11. A compound according to claim 1 or claim 2, selected from: 3-(4-ethyl-3,5-dimethyl-pyrazol-1-yl)-5H-1,2,4-triazino[5,6-b]indole; 3-(4-benzyl-3,5-dimethyl-pyrazol-1-yl)-5H-1,2,4-triazino[5,6-b]indole; 3-[4-(2-benzyloxy-benzyl)-3,5-dimethyl-pyrazol-1-yl]-5H-1,2,4-triazino[5,6- b]indole; 4-[3,5-dimethyl-1-(5H-1,2l4-triazino[5,6-b]indol-3-yl)-1 H-pyrazol-4- ylmethyl]-phenol;
2-[3,5-dimethyl-1 -(5H-1 ,2,4-triazino[5,6-b]indol-3-yl)-1 H-pyrazol-4- ylmethyl]-phenol;
3-[3,5-dimethyl-1 -(5H-1 ,2,4-triazino[5,6-b]indol-3-yl)-1 H-pyrazol-4- ylmethyl]-phenol;
3-[4-(3,5-dimethoxy-benzyl)-3,5-dimethyl-pyrazol-1-yl]-5H-1 ,2,4- triazino[5,6-b]indole;
3-(3,5-dimethyl-4-naphthalen-2-ylmethyl-pyrazol-1-yl)-5H-1 ,2,4- triazino[5,6-b]indole;
3-[4-(2-fluoro-benzyl)-3,5-dimethyl-pyrazol-1-yl]-5H-1,2,4-triazino[5,6- bjindole;
3-[3,5-dimethyl-4-(3-trifluoromethyl-benzyI)-pyrazol-1-yl]-5H-1 ,2,4- triazino[5,6-b]indole;
3-[4-(2-methoxy-benzyl)-3,δ-dimethyl-pyrazol-1-yl]-5-methyl-5H-1,2,4- triazino[5,6-b]indole;
3-[4-(3-fluoro-benzyl)-3,5-dimethyl-pyrazol-1-yl]-5-methyl-5H-1 ,2,4- triazino[5,6-b]indole;
3-[4-(3-methoxy-benzyl)-3,5-dimethyl-pyrazol-1-yl]-5-methyl-5H-1 ,2,4- t azino[5,6-b]indole;
3-[4-(3,5-dimethoxy-benzyl)-3,5-dimethyl-pyrazol-1-yl]-5-methyl-5H-1,2,4- triazino[δ,6-b]indole;
3-[3,δ-dimethyl-4-(2-nitro-benzyl)-pyrazol-1-yl]-5-methyl-δH-1,2,4- triazino[δ,6-b]indole;
3-[4-(2-fluoro-benzyl)-3,5-dimethyl-pyrazol-1-yl]-5-methyl-5H-1 ,2,4- triazino[5,6-b]indole;
2-[3,5-dimethyl-1 -(5-methyl-5H-1 ,2,4-triazino[5,6-b]indol-3-yl)-1 H-pyrazol- 4-ylmethyl]-phenol;
3-[4-(4-methoxy-benzyl)-3,5-dimethyl-pyrazol-1-yl]-5-methyl-5H-1 ,2,4- triazino[5,6-b]indole;
3-[4-(2-benzyloxy-benzyl)-3,5-dimethyl-pyrazol-1-yl]-5-methyl-5H-1,2,4- triazino[5,6-b]indole; 3-(3,5-dimethyl-4-naphthalen-2-ylmethyl-pyrazol-1 -yl)-5-methyl-5H-1 ,2,4- triazino[5,6-b]indole;
3-[3,5-dimethyl-4-(4-nitro-benzyl)-pyrazol-1 -yl]-5-methyl-5H-1 ,2,4- triazino[5,6-b]indole;
4-[3,5-dimethyl-1 -(5-methyl-5H-1 ,2,4-triazino[5,6-b]indol-3-yl)-1 H-pyrazol- 4-ylmethyl]-phenol;
3-[3,5-dimethyl-1 -(5-methyl-5H-1 ,2,4-triazino[5,6-b]indol-3-yl)-1 H-pyrazol- 4-ylmethyl]-phenol;
3-[3,5-dimethyl-4-(4-trifluoromethyl-benzyl)-pyrazol-1-yl]-5-methyl-5H- 1 ,2,4-triazino[5.6-b]indole;
3-[4-(4-methanesulphonyl-benzyl)-3,5-dimethyl-pyrazol-1-yl]-5-methyl-5H- 1 ,2,4-triazino[5,6-b]indole;
3-[3,5-dimethyl-4-(2-trifluoromethyl-benzyl)-pyrazol-1-yl]-5-methyl-5H- 1 ,2,4-triazino[5,6-b]indole;
3-[3,δ-dimethyl-4-(3-trifluoromethyl-benzyl)-pyrazol-1-yl]-δ-methyl-δH- 1 ,2,4-triazino[δ,6-b]indole;
3-[3,δ-dimethyl-4-(2-methyl-benzyl)-pyrazol-1-yl]-δ-methyl-δH-1 ,2,4- triazino[5,6-b]indole;
3-[3,δ-dimethyl-4-(3-methyl-benzyl)-pyrazol-1-yl]-5-methyl-δH-1 ,2,4- triazino[5,6-b]indole;
3-(3,δ-dimethyl-4-phenethyl-pyrazol-1-yl)-δ-methyl-5H-1,2,4-triazino[5,6- b]indole;
4-[3,δ-dimethyl-1 -(δ-methyl-δH-1 ,2,4-triazino[δ,6-b]indol-3-yl)-1 H-pyrazol- 4-ylmethyl]-benzoic acid methyl ester;
3-[3,δ-dimethyl-1 -(δ-methyl-5H-1 ,2,4-triazino[δ,6-b]indol-3-yl)-1 H-pyrazol- 4-ylmethyl]-benzoic acid methyl ester; acetic acid 4-[3,δ-dimethyl-1 -(δ-methyl-δH-1 ,2,4-triazino[5,6-b]indol-3-yl)- 1 H-pyrazol-4-ylmethyl]-phenyl ester; acetic acid 3-[3,5-dimethy!-1 -(5-methyl-δH-1 ,2,4-triazino[5,6-b]indol-3-yl)- 1 H-pyrazol-4-ylmethyl]-phenyl ester; acetic acid 2-[3,5-dimethyl-1 -(δ-methyl-δH-1 ,2,4-triazino[δ,6-b]indol-3-yl)- 1 H-pyrazol-4-ylmethyl]-phenyl ester; δ-ethyl-3-[4-(2-methoxy-benzyl)-3,δ-dimethyl-pyrazol-1-yl]-δH-1 ,2,4- triazino[5,6-b]indole;
5-ethyl-3-[4-(2-fluoro-benzyl)-3,δ-dimethyl-pyrazol-1 -yl]-δH-1 ,2,4- triazino[δ,6-b]indole; δ-ethyl-3-[4-(3-fluoro-benzyl)-3,δ-dimethyl-pyrazol-1-yl]-δH-1 ,2,4- triazino[δ,6-b]indole; δ-ethyl-3-[4-(4-fluoro-benzyl)-3,δ-dimethyl-pyrazol-1-yl]-5H-1 ,2,4- triazino[δ,6-b]indole; δ-ethyl-3-[4-(3-methoxy-benzyl)-3,δ-dimethyl-pyrazol-1-yl]-δH-1 ,2,4- triazino[5,6-b]indole;
3-[4-(3,δ-dimethoxy-benzyl)-3,5-dimethyl-pyrazol-1-yl]-δ-ethyl-δH-1,2,4- triazino[5,6-b]indole;
3-[3,δ-dimethyl-4-(2-nitro-benzyl)-pyrazol-1 -yl]-δ-ethyl-δH-1 ,2,4- triazino[5,6-bJindole;
2-[1 -(5-ethyl-5H-1 ,2,4-triazino[5,6-b]indol-3-yl)-3,δ-dimethyl-1 H-pyrazol-4- ylmethyl]-phenol; δ-ethyl-3-[4-(4-methoxy-benzyl)-3,5-dimethyl-pyrazol-1-yl]-5H-1 ,2,4- triazino[δ,6-b]indole;
3-[4-(2-benzyloxy-benzyl)-3,δ-dimethyl-pyrazol-1-yl]-δ-ethyl-δH-1 ,2,4- triazino[δ,6-b]indole;
3-(3,δ-dimethyl-4-naphthalen-2-ylmethyl-pyrazol-1-yl)-δ-ethyl-δH-1,2,4- triazino[δ,6-b]indole;
3-[3,δ-dimethyl-4-(3-nitro-benzyl)-pyrazol-1 -yl]-δ-ethyl-δH-1 ,2,4- triazino[5,6-b]indole;
3-[3,δ-dimethyl-4-(4-nitro-benzyl)-pyrazol-1-yl]-5-ethyl-5H-1 ,2,4- triazino[δ,6-b]indole;
4-[1 -(δ-ethyl-δH-1 ,2,4-triazino[δ,6-b]indol-3-yl)-3,δ-dimethyl-1 H-pyrazol-4- ylmethyl]-phenol;
3-[1 -(δ-ethyl-δH-1 ,2,4-triazino[δ,6-b]indol-3-yl)-3,δ-dimethyl-1 H-pyrazol-4- ylmethyl]-phenol;
3-[3,δ-dimethyl-4-(4-trifluoromethyl-benzyl)-pyrazol-1-yl]-δ-ethyl-δH-1,2,4- triazino[δ,6-b]indole; δ-ethyl-3-[4-(4-methanesulphonyl-benzyl)-3,δ-dimethyl-pyrazol-1-yl]-δH-
1 ,2,4-triazino[δ,6-b]indole;
3-[3,δ-dimethyl-4-(2-trifluoromethyl-benzyl)-pyrazol-1-yl]-δ-ethyl-5H-1,2,4- triazino[δ,6-b]indole;
3-[3,δ-dimethyl-4-(3-trifluoromethyl-benzyl)-pyrazol-1-yl]-δ-ethyl-δH-1,2,4- triazino[5,6-b]indole;
3-[3,δ-dimethyl-4-(2-methyl-benzyl)-pyrazol-1-yl]-δ-ethyl-δH-1 ,2,4- triazino[δ,6-b]indole;
3-[3,δ-dimethyl-4-(3-methyl-benzyl)-pyrazol-1-yl]-5-ethyl-δH-1 ,2,4- triazino[δ,6-b]indole;
3-(3,δ-dimethyl-4-phenethyl-pyrazol-1-yl)-δ-ethyl-δH-1 ,2,4-triazino[5,6- b]indole;
4-[1 -(5-ethyl-5H-1 ,2,4-triazino[δ,6-b]indol-3-yl)-3,δ-dimethyl-1 H-pyrazol-4- ylmethyl]-benzoic acid methyl ester;
3-[1 -(5-ethyl-δH-1 ,2,4-triazino[δ,6-b]indol-3-yl)-3,5-dimethyl-1 H-pyrazol-4- ylmethylj-benzoic acid methyl ester;
4-[1 -(δ-ethyl-5H-1 ,2,4-triazino[5,6-b]indol-3-yl)-3,δ-dimethyl-1 H-pyrazol-4- ylmethylj-benzoic acid;
3-(3,δ-dimethyl-4-propyl-pyrazol-1-yl)-δ-ethyl-δH-1 ,2,4-triazino[δ,6- b]indole; δ-ethyl-3-(4-ethyl-3,δ-dimethyl-pyrazol-1-yl)-5H-1,2,4-triazino[δ,6-b]indole;
3-(4-benzyl-3,δ-dimethyl-pyrazol-1-yl)-δ-propyl-δH-1 ,2,4-triazino[δ,6- bjindole; δ-propyl-3-(3,4,δ-trimethyl-pyrazol-1-yl)-δH-1,2,4-triazino[δ,6-b]indole;
3-(4-ethyl-3,δ-dimethyl-pyrazol-1-yl)-5-propyl-5H-1 ,2,4-triazino[δ,6- b]indole;
3-(3,δ-dimethyl-4-propyl-pyrazol-1-yl)-δ-propyI-δH-1 ,2,4-triazino[δ,6- b]indole; δ-butyl-3-(3,δ-dimethyl-pyrazol-1-yl)-δH-1,2,4-triazino[δ,6-b]indole; δ-butyl-3-(3,4,5-trimethyl-pyrazol-1-yl)-5H-1 ,2,4-triazino[δ,6-b]indole;
3-(4-benzyl-3,δ-dimethyl-pyrazol-1-yl)-δ-butyl-δH-1 ,2,4-triazino[δ,6- b]indole; 5-butyl-3-(3,5-dimethyl-4-naphthalen-2-ylmethyl-pyrazol-1-yl)-δH-1,2,4- triazino[δ,6-b]indole;
5-butyl-3-[4-(2-fluoro-benzyl)-3,δ-dimethyl-pyrazol-1-yl]-δH-1 ,2,4- triazino[δ,6-b]indole; δ-butyl-3-[3,δ-dimethyl-4-(3-trifluoromethyl-benzyl)-ρyrazol-1-yl]-δH-1,2,4- triazino[δ,6-b]indole; δ-butyl-3-(4-ethyl-3,δ-dimethyl-pyrazol-1-yl)-δH-1,2,4-triazino[δ,6-b]indole; δ-benzyl-3-(3,4,δ-trimethyl-pyrazol-1-yl)-δH-1,2,4-triazino[6,6-b]indole;
3-(4-benzyl-3,δ-dimethyl-pyrazol-1-yl)-5-isobutyl-5H-1,2,4-triazino[δ,6- b]indole; δ-benzyl-3-(3,δ-dimethyl-4-propyl-pyrazol-1-yl)-δH-1 ,2,4-triazino[δ,6- b]indole; oxalic acid 4-[3,δ-dimethyl-1-(δ-methyl-δH-1 ,2,4-triazino[5,6-b]indol-3-yl)- δ4
1 H-pyrazol-4-ylmethyl]-phenyl ester ethyl ester; δ-isobutyl-3-(3,4,δ-trimethyl-pyrazol-1-yl)-δH-1,2,4-triazino[δ,6-b]indole;
3-(4-ethyl-3,δ-dimethyl-pyrazol-1-yl)-δ-isobutyl-5H-1 ,2,4-triazino[5,6- bjindole; 3-(3,δ-dimethyl-4-propyl-pyrazol-1 -yl)-δ-isobutyl-δH-1 ,2,4-triazino[δ,6- b]indole;
3-(3,5-dimethyl-4-propyl-pyrazol-1 -yl)-5-(2-pyrrolidin-1 -yl-ethyl)-5H-1 ,2,4- triazino[δ,6-b]indole;
2-[3-(3,δ-dimethyl-4-propyl-pyrazol-1-yl)-1l2,4-triazino[δ,6-b]indol-δ-yl]- ethanol;
3-[3,5-dimethyl-4-(1 -phenyl-ethyl)-pyrazol-1 -yl]-5-methyl-δH-1 ,2,4- triazino[δ,6-b]indole;
3-(4-benzhydryl-3,δ-dimethyl-pyrazol-1-yl)-δ-methyl-δH-1,2,4-triazino[δ,6- bjindole;
3-[3,δ-dimethyl-4-(1 -phenyl-ethyl)-pyrazol-1-yl]-δ-ethyl-δH-1 ,2,4- triazino[δ,6-b]indole;
3-(4-benzhydryl-3,δ-dimethyl-pyrazol-1-yl)-δ-ethyl-δH-1 ,2,4-triazino[δ,6- b]indole;
3_[4_(;4-methoxy-phenyl)-pyrazol-1-yl]-δ-methyl-5H-1 ,2,4-triazino[5,6- b]indole;
3-[4-(3-bromo-phenyl)-pyrazol-1-yl]-δ-methyl-δH-1 ,2,4-triazino[δ,6- b]indole; δ-methyl-3-(4-quinolin-4-yl-pyrazol-1-yl)-δH-1 ,2,4-triazino[δ,6-b]indole; δ-methyl-3-(4-pyridin-2-yl-pyrazol-1-yl)-δH-1,2,4-triazino[δ,6-b]indole;
3-[4-(4-bromo-phenyl)-pyrazol-1-yl]-δ-methyl-δH-1 ,2,4-triazino[δ,6- b]indole;
3-(3,δ-dimethyl-4-propyl-pyrazol-1-yl)-δ-[2-(tetrahydro-pyran-2-yloxy)- ethyl]-δH-1,2,4-triazino[δ,6-b]indole; δ-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-3-(3,4,δ-trimethyl-pyrazol-1-yl)-δH- 1 ,2,4-triazino[δ,6-b]indole;
3-(4-benzyl-3,δ-dimethyl-pyrazol-1-yl)-δ-[2-(tetrahydro-pyran-2-yloxy)- ethyl]-δH-1,2,4-triazino[δ,6-b]indole; δδ
3-(4-ethyl-3,δ-dimethyl-pyrazol-1-yl)-δ-[2-(tetrahydro-pyran-2-yloxy)- ethyl]-δH-1 ,2,4-triazino[δ,6-b]indole; and
2-[3-(4-benzyl-3,δ-dimethyl-pyrazol-1-yl)-1,2,4-triazino[δ,6-b]indol-δ-yl]- ethanol. δ 12. A pharmaceutical composition comprising a compound according to any preceding claim, together with a pharmaceutically acceptable carrier or diluent. 13. Use of a compound of any of claims 1 to 11, for the manufacture of a medicament for the treatment or prevention of Alzheimer's disease.
PCT/GB2004/001761 2003-04-28 2004-04-27 Triazine compounds and their use WO2004096808A1 (en)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2566333A1 (en) * 2010-05-07 2013-03-13 The Board of Trustees of The Leland Stanford Junior University Identification of stabilizers of multimeric proteins
US10172959B2 (en) 2014-08-14 2019-01-08 Mamoun M. Alhamadsheh Systems for stabilizing and delivering active agents
US10513497B2 (en) 2017-02-17 2019-12-24 Eidos Therapeutics, Inc. Process for preparing AG-10, its intermediates, and salts thereof
US11058668B2 (en) 2018-03-23 2021-07-13 Eidos Therapeutics, Inc. Methods of treating TTR amyloidosis using AG10
US11260047B2 (en) 2018-08-17 2022-03-01 Eidos Therapeutics, Inc. Formulations of AG10

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1233021A2 (en) * 2001-02-20 2002-08-21 Pfizer Products Inc. An inhibitor of Beta amyloid cleavage enzyme
US20030078166A1 (en) * 2000-09-15 2003-04-24 Robert Davies Pyrazole compounds useful as protein kinase inhibitors
WO2004063196A1 (en) * 2003-01-14 2004-07-29 De Novo Pharmaceuticals Limited 1,2,4-triazin-3-yl-hydrazine or 5h-1,2,4-triazino’5,6-b!indol-3-yl-hydrazine compounds as inhibitors of bace useful in the treatment of alzheimer

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030078166A1 (en) * 2000-09-15 2003-04-24 Robert Davies Pyrazole compounds useful as protein kinase inhibitors
EP1233021A2 (en) * 2001-02-20 2002-08-21 Pfizer Products Inc. An inhibitor of Beta amyloid cleavage enzyme
WO2004063196A1 (en) * 2003-01-14 2004-07-29 De Novo Pharmaceuticals Limited 1,2,4-triazin-3-yl-hydrazine or 5h-1,2,4-triazino’5,6-b!indol-3-yl-hydrazine compounds as inhibitors of bace useful in the treatment of alzheimer

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ESHBA N H ET AL: "Synthesis of some substituted 1,2,4-triazino[5,6-b]indole derivatives as potential antiviral and anticancer agents", PHARMAZIE, VEB VERLAG VOLK UND GESUNDHEIT. BERLIN, DD, vol. 42, no. 10, 1987, pages 664 - 666, XP009029588, ISSN: 0031-7144 *

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2566333A4 (en) * 2010-05-07 2014-04-02 Univ Leland Stanford Junior Identification of stabilizers of multimeric proteins
US8877795B2 (en) 2010-05-07 2014-11-04 The Board Of Trustees Of The Leland Stanford Junior University Identification of stabilizers of multimeric proteins
US9308209B2 (en) 2010-05-07 2016-04-12 The Board Of Trustees Of The Leland Stanford Junio Identification of stabilizers of multimeric proteins
US10039726B2 (en) 2010-05-07 2018-08-07 The Board Of Trustees Of The Leland Stanford Junior University Identification of stabilizers of multimeric proteins
US10278929B2 (en) 2010-05-07 2019-05-07 The Board Of Trustees Of The Leland Stanford Junior University Identification of stabilizers of multimeric proteins
EP2566333A1 (en) * 2010-05-07 2013-03-13 The Board of Trustees of The Leland Stanford Junior University Identification of stabilizers of multimeric proteins
US11337935B2 (en) 2010-05-07 2022-05-24 The Board Of Trustees Of The Leland Stanford Junior University Identification of stabilizers of multimeric proteins
US11129902B2 (en) 2014-08-14 2021-09-28 Mamoun M. Alhamadsheh Enhanced SN-38 anticancer agent
US10172959B2 (en) 2014-08-14 2019-01-08 Mamoun M. Alhamadsheh Systems for stabilizing and delivering active agents
US10363318B2 (en) 2014-08-14 2019-07-30 Mamoun M. Alhamadsheh Enhanced active agents
US10596269B2 (en) 2014-08-14 2020-03-24 Mamoun M. Alhamadsheh Delivering enhanced active agents
US10772967B2 (en) 2014-08-14 2020-09-15 Mamoun M. Alhamadsheh Enhanced anticancer agent
US10513497B2 (en) 2017-02-17 2019-12-24 Eidos Therapeutics, Inc. Process for preparing AG-10, its intermediates, and salts thereof
US11078162B2 (en) 2017-02-17 2021-08-03 Eidos Therapeutics, Inc. Processes for preparing AG-10, its intermediates, and salts thereof
US11919865B2 (en) 2017-02-17 2024-03-05 Eidos Therapeutics, Inc. Processes for preparing AG-10, its intermediates, and salts thereof
US11058668B2 (en) 2018-03-23 2021-07-13 Eidos Therapeutics, Inc. Methods of treating TTR amyloidosis using AG10
US11260047B2 (en) 2018-08-17 2022-03-01 Eidos Therapeutics, Inc. Formulations of AG10
US12005043B2 (en) 2018-08-17 2024-06-11 Eidos Therapeutics, Inc. Formulations of AG10

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