+

WO2006048745A1 - Methodes de preparation de composes d'indazole - Google Patents

Methodes de preparation de composes d'indazole Download PDF

Info

Publication number
WO2006048745A1
WO2006048745A1 PCT/IB2005/003300 IB2005003300W WO2006048745A1 WO 2006048745 A1 WO2006048745 A1 WO 2006048745A1 IB 2005003300 W IB2005003300 W IB 2005003300W WO 2006048745 A1 WO2006048745 A1 WO 2006048745A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
compound
alkyl
aryl
acid
Prior art date
Application number
PCT/IB2005/003300
Other languages
English (en)
Inventor
Srinivasan Babu
Raymond Dagnino, Jr.
Michael Allen Ouellette
Bing Shi
Qingping Tian
Scott Edward Zook
Original Assignee
Pfizer Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pfizer Inc. filed Critical Pfizer Inc.
Priority to BRPI0517921-1A priority Critical patent/BRPI0517921A/pt
Priority to MX2007003603A priority patent/MX2007003603A/es
Priority to AU2005300311A priority patent/AU2005300311A1/en
Priority to CA002586176A priority patent/CA2586176A1/fr
Priority to RU2007114112/04A priority patent/RU2007114112A/ru
Priority to EP05796299A priority patent/EP1809625A1/fr
Priority to JP2007538538A priority patent/JP2008518901A/ja
Publication of WO2006048745A1 publication Critical patent/WO2006048745A1/fr
Priority to IL182096A priority patent/IL182096A0/en
Priority to NO20072747A priority patent/NO20072747L/no

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • the present invention relates to methods for preparing indazole compounds, and intermediates thereof, which are useful as modulators and/or inhibitors of protein kinases.
  • U.S. Patent Nos. 6,531 ,491 and 6,534,524 are directed to indazole compounds that modulate and/or inhibit the activity of certain protein kinases such as VEGF-R (vascular endothelial cell growth factor receptor), FGF-R (fibroblast growth factor receptor), CDK (cyclin-dependent kinase) complexes,
  • VEGF-R vascular endothelial cell growth factor receptor
  • FGF-R fibroblast growth factor receptor
  • CDK cyclin-dependent kinase
  • CHK1 also known as lymphocyte-specific tyrosine kinase
  • TEK also known as Tie-2
  • FAK focal adhesion kinase
  • phosphorylase kinase Such compounds are useful for the treatment of cancer and other diseases associated with angiogenesis or cellular proliferation mediated by protein kinases.
  • R 10 is independently selected from hydrogen, halogen, and lower-alkyl; and pharmaceutically acceptable prodrugs, pharmaceutically acceptable metabolites, and pharmaceutically acceptable salts thereof.
  • the invention relates to methods for preparing a compound of formula I:
  • R 4 is (C 1 to C 12 ) alkyl, (C 3 to C 12 ) cycloalkyl, (5 to 12-membered) heterocycloalkyl, (C 6 to C 12 ) aryl, or (5 to 12-membered) heteroaryl, and R 4 is substituted with 0 to 4 R 5 groups; each R 5 is independently halogen, (C 1 to C 8 ) alkyl, (C 2 to C 8 ) alkenyl, (C 2 to C 8 ) alkynyl, -OH, -NO 2 , -CN, -CO 2 H, -0(C 1 to C 8 alkyl), (C 6 to C 12 ) aryl, (C 6 to C 12 ) aryl (C 1 to C 8 ) alkyl, -CO 2 CH 3 , -CONH 2 , -OCH 2 CONH 2 , -NH 2 , -SO 2 NH 2 , halo substituted (C 1 to C 12 ) alky
  • Il III IV wherein the reaction occurs in the presence of a catalyst and a base; W is a protecting group; X is an activated substituent group; and R 1 , R 2 , and R 3 are as described above; and b) deprotecting the compound of formula IV to provide the compound of formula I.
  • the invention relates to method for preparing a compound of formula I, wherein the catalyst is a palladium catalyst. In another aspect, the invention relates to methods for preparing a compound of formula
  • the invention relates to methods for preparing a compound of formula I, wherein the base is selected from the group consisting of potassium carbonate, sodium carbonate, cesium carbonate, sodium t-butoxide, potassium t-butoxide, triethylamine, and mixtures thereof.
  • the invention relates to methods for preparing a compound of formula I, wherein the base is cesium carbonate.
  • the invention relates to methods for preparing a compound of formula I, further comprising a solvent in the reaction between the compound of formula Il and the compound of formula III.
  • the invention relates to methods for preparing a compound of formula I, wherein the solvent is N, N-dimethyl formamide.
  • the invention relates to methods for preparing a compound of formula I, wherein the reaction is carried out at about 80°C. In another aspect, the invention relates to methods for preparing a compound of formula
  • W is a tetrahydropyran protecting group or a trimethylsilylethoxymethyl protecting group.
  • the invention relates to methods for preparing a compound of formula I, wherein the activated substituent group X is chloride, bromide, or iodide. In another aspect, the invention relates to methods for preparing a compound of formula
  • the invention relates to methods for preparing a compound of formula I, wherein the protecting group W is tetrahydropyran, and the process of deprotecting comprises reacting the compound of formula IV with an acid in an alcoholic solvent.
  • the invention relates to methods for preparing a compound of formula
  • the acid is methanesulfonic acid or is p-toluenesulfonic acid
  • the alcoholic solvent is methanol, ethanol, n-propanol or isopropanol.
  • the invention relates to methods for preparing a compound of formula I, wherein the compound of formula Il has formula V, and the compound of formula III has formula Vl:
  • the invention relates to methods for preparing a compound of formula I, wherein the compound of formula IV has formula VII:
  • the invention relates to methods for preparing a compound of formula I, wherein the compound of formula I has formula VIII:
  • the invention relates to methods for preparing a compound of formula
  • R 4 is (C 1 to C 12 ) alkyl, (C 3 to C 12 ) cycloalkyl, (5 to 12-membered) heterocycloalkyl, (C 6 to C 12 ) aryl, or (5 to 12-membered) heteroaryl, and R 4 is substituted with 0 to 4 R 5 groups; each R 5 is independently halogen, (C 1 to C 8 ) alkyl, (C 2 to C 8 ) alkenyl, (C 2 to C 8 ) alkynyl, -OH, -NO 2 , -CN, -CO 2 H, -0(C 1 to C 8 alkyl), (C 6 to C 12 ) aryl, (C 6 to C 12 ) aryl (C 1 to C 8 ) alkyl,
  • W is a protecting group; and X is an activated substituent group; comprising: a) reacting a compound of formula IX with a diazotizing agent to form a diazonium salt; and b) treating the diazonium salt with a metal halide,
  • the invention relates to methods for preparing a compound of formula II, wherein the activated substituent group X is iodide.
  • the invention relates to methods for preparing a compound of formula II, wherein the diazotizing agent is sodium nitrite or t-butyl nitrite.
  • the invention relates to methods for preparing a compound of formula II, wherein the diazotizing agent is sodium nitrite, and the metal halide is potassium iodide.
  • the invention relates to methods for preparing a compound of formula II, further comprising a catalytic amount of iodine. In another aspect, the invention relates to methods for preparing a compound of formula
  • ⁇ T- is used in structural formulas herein to depict the bond that is the point of attachment of the moiety or substituent to the core or backbone structure.
  • substituents it is meant to indicate that the group in question may optionally be substituted by one or more of the substituents provided.
  • the number of substituents a group in the compounds of the invention may have depends on the number of positions available for substitution. For example, an aryl ring in the compounds of the invention may contain from 1 to 5 additional substituents, depending on the degree of substitution present on the ring. The maximum number of substituents that a group in the compounds of the invention may have can be easily determined.
  • react refers to a chemical process or processes in which two or more reactants are allowed to come into contact with each other to effect a chemical change or transformation. For example, when reactant A and reactant B are allowed to come into contact with each other to afford a new chemical compound(s) C, A is said to have “reacted” with B to produce C.
  • protect refers to a process in which a functional group in a chemical compound is selectively masked by a non-reactive functional group in order to allow a selective reaction(s) to occur elsewhere on said chemical compound.
  • non-reactive functional groups are herein termed "protecting groups.”
  • nitrogen protecting group refers to those groups that are capable of selectively masking the reactivity of a nitrogen (N) group.
  • suitable protecting group refers to those protecting groups that are useful in the preparation of the compounds of the present invention. Such groups are generally able to be selectively introduced and removed using mild reaction conditions that do not interfere with other portions of the subject compounds.
  • Protecting groups that are suitable for use in the processes and methods of the present invention are well known. The chemical properties of such protecting groups, methods for their introduction and their removal can be found, for example, in T. Greene and P.
  • leaving group refers to a chemical functional group that generally allows a nucleophilic substitution reaction to take place at the atom to which it is attached.
  • the -Cl group is generally referred to as a leaving group because it allows nucleophilic substitution reactions to take place at the carbonyl carbon.
  • Suitable leaving groups are well known, and can include halides, aromatic heterocycles, cyano, amino groups (generally under acidic conditions), ammonium groups, alkoxide groups, carbonate groups, formates, and hydroxy groups that have been activated by reaction with compounds such as carbodiimides.
  • suitable leaving groups include, but are not limited to, chloride, bromide, iodide, cyano, imidazole, and hydroxy groups that have been allowed to react with a carbodiimide such as dicyclohexylcarbodiimide (optionally in the presence of an additive such as hydroxybenzotriazole) or a carbodiimide derivative.
  • a carbodiimide such as dicyclohexylcarbodiimide (optionally in the presence of an additive such as hydroxybenzotriazole) or a carbodiimide derivative.
  • activated substituent group refers to a chemical functional group that generally allows a substitution reaction to take place at the atom to which it is attached.
  • the -I group is generally referred to as an activated substituent group because it allows substitution reactions to take place at the aryl carbon.
  • Suitable activated substituent groups are well known, and can include halides (chloride, bromide, iodide), activated hydroxyl groups (e.g., triflate, mesylate, and tosylate), and diazonium salts.
  • alkyl represents a straight- or branched-chain saturated hydrocarbon, containing 1 to 10 carbon atoms which may be unsubstituted or substituted by one or more of the substituents described below.
  • exemplary alkyl substituents include, but are not limited to methyl (Me), ethyl (Et), propyl, isopropyl, butyl, isobutyl, t-butyl, and the like.
  • alkenyl represents a straight- or branched-chain hydrocarbon, containing one or more carbon-carbon double bonds and having 2 to 10 carbon atoms which may be unsubstituted or substituted by one or more of the substituents described below.
  • alkenyl substituents include, but are not limited to ethenyl, propenyl, butenyl, allyl, pentenyl and the like.
  • phenyl refers to a fully unsaturated 6-membered carbocyclic group.
  • a "phenyl” group may also be referred to herein as a benzene derivative.
  • heteroaryl refers to a group comprising an aromatic monovalent monocyclic, bicyclic, or tricyclic group, containing 5 to 18 ring atoms, including 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, which may be unsubstituted or substituted by one or more of the substituents described below.
  • heteroaryl is also intended to encompass the N-oxide derivative (or N-oxide derivatives, if the heteroaryl group contains more than one nitrogen such that more than one N-oxide derivative may be formed) of the nitrogen-containing heteroaryl groups described herein.
  • heteroaryl groups include, but are not limited to, thienyl, pyrrolyl, imidazolyl, pyrazolyl, furyl, isothiazolyl, furazanyl, isoxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, benzo[b]thienyl, naphtho[2,3-b]thianthrenyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathienyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxyalinyl, quinzolinyl, benzothiazolyl, benzimidazolyl, te
  • N-oxide derivatives of heteroaryl groups include, but are not limited to, pyridyl N-oxide, pyrazinyl N-oxide, pyrimidinyl N-oxide, pyridazinyl N-oxide, triazinyl N-oxide, isoquinolyl N-oxide, and quinolyl N-oxide.
  • heteroaryl groups include the following moieties: wherein R is H, alkyl, hydroxyl or is a suitable nitrogen protecting group.
  • halide represents fluoro, chloro, bromo or iodo substituents.
  • a desired salt may be prepared by any suitable method known in the art, including treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosidyl acid, such as glucuronic acid or galacturonic acid, alpha-hydroxy acid, such as citric acid or tartaric acid, amino acid, such as aspartic acid or glutamic acid, aromatic acid, such as benzoic acid or cinnamic acid, sulfonic acid, such as
  • a desired salt may be prepared by any suitable method known to the art, including treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary, or tertiary); an alkali metal or alkaline earth metal hydroxide; or the like.
  • suitable salts include organic salts derived from amino acids such as glycine and arginine; ammonia; primary, secondary, and tertiary amines; and cyclic amines, such as piperidine, morpholine, and piperazine; as well as inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.
  • the compounds of the present invention may contain at least one chiral center and may exist as single stereoisomers (e.g., single enantiomers or single diastereomers), any mixture of stereoisomers (e.g., any mixture of enantiomers or diastereomers) or racemic mixtures thereof. It is specifically contemplated that, unless otherwise indicated, all stereoisomers, mixtures and racemates of the present compounds are encompassed within the scope of the present invention.
  • stereoisomeric purity refers to the "enantiomeric” purity and/or “diastereomeric” purity of a compound.
  • stereoisomerically pure form is meant to encompass those compounds that contain from at least about 95% to at least about 99%, and all values in between, of a single stereoisomer.
  • substantially enantiomerically pure as used herein is meant to encompass those compounds that contain from at least about 90% to at least about 95%, and all values in between, of a single stereoisomer.
  • diastereomerically pure is meant to encompass those compounds that contain from at least about 95% to at least about 99%, and all values in between, of a single diastereoisomer.
  • substantially diastereomerically pure is meant to encompass those compounds that contain from at least about 90% to at least about 95%, and all values in between, of a single diastereoisomer.
  • racemic or “racemic mixture,” as used herein, refer to a mixture containing equal amounts of stereoisomeric compounds of opposite configuration.
  • a racemic mixture of a compound containing one stereoisomeric center would comprise equal amount of that compound in which the stereoisomeric center is of the (S)- and (R)-configurations.
  • enantiomerically enriched is meant to refer to those compositions wherein one stereoisomer of a compound is present in a greater amount than the opposite stereoisomer.
  • diastereomerically enriched refers to those compositions wherein one diastereomer of compound is present in amount greater than the opposite diastereomer.
  • the compounds of the present invention may be obtained in stereoisomerically pure (i.e., enantiomerically and/or diastereomerically pure) or substantially stereoisomerically pure (i.e., substantially enantiomerically and/or diastereomerically pure) form.
  • stereoisomerically pure i.e., enantiomerically and/or diastereomerically pure
  • substantially stereoisomerically pure i.e., substantially enantiomerically and/or diastereomerically pure
  • Such compounds may be obtained synthetically, according to the procedures described herein using stereoisomerically pure or substantially stereoisomerically pure materials.
  • these compounds may be obtained by resolution/separation of mixtures of stereoisomers, including racemic and diastereomeric mixtures, using known procedures.
  • Exemplary methods that may be useful for the resolution/separation of stereoisomeric mixtures include derivitation with stereochemical ⁇ pure reagents to form diastereomeric mixtures, chromatographic separation of diastereomeric mixtures, chromatographic separation of enantiomeric mixtures using chiral stationary phases, enzymatic resolution of covalent derivatives, and crystallization/re-crystallization.
  • Other useful methods may be found in Enantiomers, Racemates, and Resolutions, J. Jacques, et a!., 1981 , John Wiley and Sons, New York, NY, the disclosure of which is incorporated herein by reference.
  • Preferred stereoisomers of the compounds of this invention are described herein. Detailed Description of the Invention
  • the compounds of formula I can be prepared from 6-nitroindazole.
  • the indazole ring can be substituted at the C-3 position with an R 1 group as described herein, using commonly known reagents and reactions.
  • the C-3 position of the indazole ring can be functionalized by reacting 6-nitroindazole with iodine (I 2 ) in the presence of a base such as potassium carbonate (K 2 CO 3 ), and in a solvent such as DMF, to provide 3-iodo-6-nitro-indazole.
  • a base such as potassium carbonate (K 2 CO 3 )
  • DMF solvent
  • the C-3 position of the indazole ring can then be elaborated to a desired R 1 group using known reactions, such as a Suzuki reaction or a Heck reaction.
  • the intermediates useful for the preparation of the compounds of formula I may require the use of protecting groups.
  • the nucleophilic indazole ring nitrogen (N-1) may require masking through use of a suitable protecting group.
  • the substituents on these intermediates are themselves not compatible with the synthetic methods of this invention, the substituents may be protected with suitable protecting groups that are stable to the reaction conditions used in these methods.
  • the protecting groups may be removed at a suitable point in the reaction sequence of the method to provide a desired intermediate or target compound. Suitable protecting groups and the methods for protecting and de-protecting different substituents using such suitable protecting groups are well known, examples of which may be found in T. Greene and P. Wuts, supra.
  • a suitable nitrogen protecting group, W is one that is stable to the reaction conditions in which the compounds of formula Il are allowed to react with the compounds of formula III to provide the compounds of formula IV. Furthermore, such a protecting group should be chosen so that it can be subsequently removed to provide the compounds of formula I. As indicated above, suitable nitrogen protecting groups are well known, and any nitrogen protecting group that is useful in the methods of preparing the compounds of this invention or may be useful in the protein kinase inhibitory compounds of this invention may be used.
  • Exemplary nitrogen protecting groups include silyl, substituted silyl, alkyl ether, substituted alkyl ether, cycloalkyl ether, substituted cycloalkyl ether, alkyl, substituted alkyl, carbamate, urea, amide, imide, enamine, sulfenyl, sulfonyl, nitro, nitroso, oxide, phosphinyl, phosphoryl, silyl, organometallic, borinic acid and boronic acid groups. Examples of each of these groups, methods for protecting nitrogen moieties using these groups and methods for removing these groups from nitrogen moieties are disclosed in T. Greene and P. Wuts, supra.
  • suitable nitrogen protecting groups useful as W include, but are not limited to, silyl protecting groups (e.g., SEM: trimethylsilylethoxymethyl, TBDMS: tert-butyldimethylsilyl); alkyl ether protecting groups such as cycloalkyl ethers (e.g., THP: tetrahydropyran); carbamate protecting groups such as alkyloxycarbonyl (e.g., Boc: t-butyloxycarbonyl), aryloxycarbonyl (e.g., Cbz: benzyloxycarbonyl, and FMOC: fluorene-9-methyloxycarbonyl), alkyloxycarbonyl (e.g., methyloxycarbonyl), alkylcarbonyl or arylcarbonyl, substituted alkyl, especially arylalkyl (e.g., trityl (triphenylmethyl), benzyl and substituted benzyl), and the like.
  • W is a silyl protecting group (e.g., SEM: trimethylsilylethoxymethyl, TBDMS: tert- butyldimethylsilyl)
  • silyl protecting groups may be attached to nitrogen moieties and hydroxyl groups via their silyl chlorides (e.g., SEMCI: trimethylsilylethoxymethyl chloride, TBDMSCI: tert-butyldimethylsilyl chloride) in the presence of a suitable base (e.g., potassium carbonate), catalyst (e.g., 4-dimethylaminopyridine (DMAP)), and solvent (e.g, N,N-dimethyl formamide).
  • a suitable base e.g., potassium carbonate
  • catalyst e.g., 4-dimethylaminopyridine (DMAP)
  • solvent e.g, N,N-dimethyl formamide
  • Such silyl protecting groups may be cleaved by exposure of the subject compound to a source of fluoride ions, such as the use of an organic fluoride salt such as a tetraalkylammonium fluoride salt, or an inorganic fluoride salt.
  • Suitable fluoride ion sources include, but are not limited to, tetramethylammonium fluoride, tetraethylammonium fluoride, tetrapropylammonium fluoride, tetrabutylammonium fluoride, sodium fluoride, and potassium fluoride.
  • silane protecting groups may be cleaved under acidic conditions using organic or mineral acids, with or without the use of a buffering agent.
  • suitable acids include, but are not limited to, hydrofluoric acid, hydrochloric acid, sulfuric acid, nitric acid, acetic acid, citric acid, and methanesulfonic acid.
  • suitable Lewis acids include, but are not limited to, dimethylbromo borane, triphenylmethyl tetrafluoroborate, and certain Pd (II) salts.
  • Such silane protecting groups can also be cleaved under basic conditions that employ appropriate organic or inorganic basic compounds.
  • such basic compounds include, but are not limited to, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, and potassium hydroxide.
  • the cleavage of a silane protecting group may be conducted in an appropriate solvent that is compatible with the specific reaction conditions chosen and will not interfere with the desired transformation.
  • suitable solvents are, for example, alkyl esters, alkylaryl esters, aryl esters, alkyl ethers, aryl ethers, alkylaryl esters, cyclic ethers, hydrocarbons, alcohols, halogenated solvents, alkyl nitriles, aryl nitriles, alkyl ketones, aryl ketones, alkylaryl ketones, or non-protic heterocyclic compounds.
  • suitable solvents include, but are not limited to, ethyl acetate, isobutyl acetate, isopropyl acetate, n-butyl acetate, methyl isobutyl ketone, dimethoxyethane, diisopropyl ether, chlorobenzene, dimethyl formamide, dimethyl acetamide, propionitrile, butyronitrile, t-amyl alcohol, acetic acid, diethyl ether, methyl-t-butyl ether, diphenyl ether, methylphenyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1 , 4-dioxane, pentane, hexane, heptane, methanol, ethanol, 1-propanol, 2-propanol, t-butanol, n-butanol, 2-butanol, dichloromethane, chloroform, 1 ,
  • W is a cyclic ether protecting group (e.g., a tetrahydropyran (THP) group)
  • THP tetrahydropyran
  • such cyclic ethers may be attached to nitrogen moieties and hydroxy! groups via their enol ethers (e.g., dihydropyran (DHP)) in the presence of a suitable acid (e.g., para-toluenesulfonic acid or methanesulfonic acid), and solvent (e.g., dichloromethane).
  • DHP dihydropyran
  • Such cyclic ether groups may be cleaved by treating the subject compound with organic or inorganic acids or Lewis acids.
  • a particular reagent will depend upon the type of ether present as well as the other reaction conditions.
  • suitable reagents include, but are not limited to, hydrochloric acid, sulfuric acid, nitric acid, para-toluenesulfonic acid, methanesulfonic acid, or Lewis acids such as boron trifluoride etherate.
  • solvents that are compatible with the specific reaction conditions chosen and will not interfere with the desired transformation.
  • suitable solvents are, for example, alkyl esters, alkylaryl esters, aryl esters, alkyl ethers, aryl ethers, alkylaryl esters, cyclic ethers, hydrocarbons, alcohols, halogenated solvents, alkyl nitriles, aryl nitriles, alkyl ketones, aryl ketones, alkylaryl ketones, or non-protic heterocyclic compounds.
  • suitable solvents include, but are not limited to, ethyl acetate, isobutyl acetate, isopropyl acetate, n-butyl acetate, methyl isobutyl ketone, dimethoxyethane, diisopropyl ether, chlorobenzene, dimethyl formamide, dimethyl acetamide, propionitrile, butyronitrile, t-amyl alcohol, acetic acid, diethyl ether, methyl-t-butyl ether, diphenyl ether, methylphenyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1 ,4-dioxane, pentane, hexane, heptane, methanol, ethanol, 1-propanol, 2-propanoI, t-butanol, n-butanol, 2-butanol, dichloromethane, chloroform, 1
  • N-1 indazole ring nitrogen Protection of the N-1 indazole ring nitrogen is accomplished by reacting 3-iodo-6- nitroindazole with 3,4-dihydro-2H-pyran and methanesulfonic acid in a solvent, such as DMF, tetrahydrofuran (THF), and methylene chloride (CH 2 CI 2 ) to provide 3-iodo-6-nitro-1- (tetrahydropyran-2-yl)-1 H-indazole.
  • a solvent such as DMF, tetrahydrofuran (THF), and methylene chloride (CH 2 CI 2 )
  • R 1 is C 1 -C 8 alkyl, -OH, -NO 2 , -CN, -CO 2 H, -0(C 1 -C 8 alkyl), -aryl, -aryl(C r C 8 alkyl), -CO 2 CH 3 , -CONH 2 , -OCH 2 CONH 2 , -NH 2 , -SO 2 NH 2 , haloalkyl, or -O(haloalkyl), may require the use suitable protecting groups.
  • Suitable hydroxyl protecting groups that are useful in the present invention include, but are not limited to, alkyl or aryl esters, alkyl silanes, aryl silanes or alkylaryl silanes, alkyl or aryl carbonates, benzyl groups, substituted benzyl groups, ethers, or substituted ethers.
  • the various hydroxyl protecting groups can be applied and suitably cleaved utilizing a number of known reaction conditions. The particular conditions used will depend on the particular protecting group as well as the other functional groups contained in the subject compound. Furthermore, suitable conditions include the use of an appropriate solvent that is compatible with the reaction conditions utilized and will not interfere with the desired transformation.
  • Suitable solvents useful in applying the various protecting groups and their subsequent removal may include alkyl esters, alkylaryl esters, aryl esters, alkyl ethers, aryl ethers, alkylaryl esters, cyclic ethers, hydrocarbons, alcohols, halogenated solvents, alkyl nitriles, aryl nitriles, alkyl ketones, aryl ketones, alkylaryl ketones, and non-protic heterocyclic compounds.
  • suitable solvents include, but are not limited to, ethyl acetate, isobutyl acetate, isopropyl acetate, n-butyl acetate, methyl isobutyl ketone, dimethoxyethane, diisopropyl ether, chlorobenzene, dimethyl formamide, dimethyl acetamide, propionitrile, butyronitrile, t-amyl alcohol, acetic acid, diethyl ether, methyl-t-butyl ether, diphenyl ether, methylphenyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1 ,4-dioxane, pentane, hexane, heptane, methanol, ethanol, 1-propanol, 2-propanol, t-butanol, n-butanol, 2-butanol, dichloromethane, chloroform, 1
  • the C-3 position of the indazole ring can be elaborated to a desired R 1 group through a Suzuki or Heck reaction, using the appropriate catalyst, ligand, aryl, heteroaryl and/or olefinic species.
  • the Suzuki reaction is a palladium catalyzed coupling reaction in which the reaction of an optionally substituted aryl boronic acid or an optionally substituted heteroaryl boronic acid is coupled with a substituted aryl group or a substituted heteroaryl group, in which the substituents on the aryl group or the heteroaryl group are halide, triflate, or a diazonium salt, which produces a di-aryl species.
  • Useful palladium catalysts for the Suzuki reaction includes but are not limited to Pd(C 17 H 14 O) x , Pd(PPh 3 ) 4 ⁇ and [Pd(OAc) 2 ] 3 , and the like.
  • a base such as an inorganic base or an organic base (e.g., organic amine) is also required to neutralize the liberated acid.
  • organic base e.g., organic amine
  • R 1 is a substituted or unsubstituted aryl group, or is a substituted or unsubstituted heteroaryl group
  • the compounds of formula I can be prepared by a Suzuki reaction between an optionally substituted aryl or heteroaryl boronic acid and a substituted aryl or heteroaryl group, in which the substituents on the aryl or heteroaryl group are halide, triflate, or a diazonium salt.
  • a Heck reaction involves the catalytic coupling of C-C bonds, where a vinylic hydrogen is replaced by a vinyl, aryl, or benzyl group, with the latter being introduced as a halide, diazonium salt, aryl triflate or hypervalent iodo compound.
  • R vinyl, aryl, or benzyl
  • Palladium in the form of Pd(II) salts or complexes and Pd(O), with 1-5% mole concentration, is the most widely used metal catalyst for these types of reactions.
  • a base such as an inorganic base or an organic base (e.g., organic amine) is also required to neutralize the liberated acid.
  • Typical catalysts for use in the Heck reaction include but are not limited to Pd(dppf)CI 2 /CH 2 CI 2 , [Pd(OAc) 2 ] 3 , trans-PdCI 2 (CH 3 CN) 2 , Pd(C 17 H 14 O) x , and Pd(0)-phosphine complexes such as Pd(PPh 3 ) 4 and trans-PdCI 2 (PPh 3 ) 2 or in situ catalysts such as Pd(OAc) 2 /PPh 3 , and the like.
  • Chelated phosphines with larger bite angles such as Cp 2 Fe(PPh 2 J 2 and Ph 2 P(CH 2 ) 2 .
  • PPh 2 are useful with catalysts such as Pd(OAc) 2 , (pi-allyl)Pd complexes, Pd 2 (dba) 3 , Pd(dba) 2 and PdCI 2 , and the like.
  • the presence of phosphines "stabilize" these catalysts.
  • these types of reactions are conducted in polar aprotic mediums (sigma donor type solvents such as acetonitrile, N,N-dimethyl formamide, dimethyl sulfoxide or dimethylacetamide).
  • the reaction time and temperature depend on the nature of the organic halide to be activated, lodo derivatives are more reactive and hence auxiliary ligands (phosphines) may not be required.
  • polar solvents such as N,N-dimethyl formamide, dimethylacetamide and N-methylpyrrolidine in combination with sodium acetate as a base are especially beneficial.
  • the compounds of formula I can be prepared by a Heck reaction between a compound containing a vinylic hydrogen and a compound containing a vinyl, aryl, or benzyl group which is substituted with a halide, halide, diazonium salt, aryl triflate or hypervalent iodo compound.
  • a Heck reaction between 3-iodo-6-nitro-1-(tetrahydropyran-2-yl)-1H-indazole and 2-vinyl pyridine is accomplished by heating these reactants in the presence of a catalyst such as palladium(ll) acetate (Pd(OAc) 2 ), a ligand such as tri-o-tolylphosphine, a suitable base such as N,N-diisopropylethyl-amine, and a solvent such as DMF to provide 6-nitro-3-((E)-2-pyridin-2-yl- vinyl)-1-(tetrahydropyran-2-yl)-1H-indazole.
  • a catalyst such as palladium(ll) acetate (Pd(OAc) 2 )
  • a ligand such as tri-o-tolylphosphine
  • suitable base such as N,N-diisopropylethyl-amine
  • solvent such as DMF
  • the compounds of formula I contain an indazole ring and phenyl ring that are bridged by a sulfide group.
  • Such sulfide linked ring structures are obtained by coupling an indazole derivative which is substituted with an activated substituent group X (compound of formula II) with a thiophenol derivative (compound of formula III).
  • Suitable activated substituent groups for X include but are not limited to halides (e.g., chloride, bromide, iodide), hydroxyl derivatives (e.g., triflate, mesylate, and tosylate groups), and diazonium salts.
  • Derivatization of the 6-nitroindazole ring compounds described above, with an activated substituent X group can be accomplished by reduction of the 6-nitro group to the 6-amino indazole compound, followed by diazotization, and optionally, displacement of N 2 with a nucleophile such as a halide, water, or aqueous base.
  • a nucleophile such as a halide, water, or aqueous base.
  • 6-nitroindazole ring compounds can be converted to 6-amino indazole compounds by a reduction.
  • the reduction of nitro groups to amino groups are well known.
  • Metals, such as Fe (iron), Zn (zinc), Sn (tin) and In (indium) can be used with a H + source to reduce a nitro group to an amino group by a sequence of single electron transfer (SET)/protonation reactions.
  • 6-nitro-3-(E)-2-pyridin-2-yl-vinyl)-1-(tetrahydropyran-2-yl)-1H-indazole is reduced to the 6- amino compound by treatment with iron metal in the presence of an aqueous solution of ammonium chloride to provide 6-amino-3-(E)-2-pyridin-2-yl-vinyl)-1-(tetrahydropyran-2-yl)-1 H- indazole.
  • Diazotizing reagents useful for converting an amino group to a diazonium salt include but are not limited to sodium nitrite and tert-butyl nitrite. These diazotizing reactions require the presence of a strong acid such as hydrochloric acid to convert the amino group into the diazonium salt.
  • Alkali metal halides, such as lithium, sodium and potassium halides are a convenient source of nucleophilic halide anions. Hydroxyl groups are easily converted into triflate, mesylate and tosylate groups using standard procedures.
  • the coupling reaction between the compounds of formula Il and the compounds of formula III to provide the compounds of formula IV is accomplished in the presence of a catalyst, a base, and optionally, one or more solvents.
  • the catalyst may be either a palladium or a copper catalyst. Methods that use palladium or copper catalysts to couple aryl sulfides to aryl compounds containing an activated substituent X are well known.
  • palladium catalysts which are useful in the above coupling reaction include but are not limited to Pd(dppf)CI 2 -CH 2 CI 2 , [Pd(P'-Bu 3 )( ⁇ -Br)] 2 , Pd(PCy 3 ) 2 CI 2 , Pd(P(o-tolyl) 3 ) 2 CI 2 , [Pd(P(OPh-2,4-t- BuJ) 2 CI] 2 , FibreCat® 1007 (PCy 2 -fibre/Pd(OAc) 2 ), FibreCat® 1026 (PCy 2 -fibre/PdCI 2 /CH 3 CN), FibreCat® 1001 (PPh 2 -fibre/Pd(OAc) 2 ), Pd(dppf)CI 2 , Pd(dppb)CI 2 , Pd(d(dppe)CI 2 , Pd(PPh 3 ) 4 , Pd(PPh 3 )CI 2 , and the like
  • phosphine ligands are also complexes to the palladium catalyst, for example: Pd 2 (dba) 3 complexed to a phospine ligand such as 2-(tert-butyl 2 - phosphino)biphenyl; Pd(dba) 2 complexed to P(t-Bu) 3 ; Pd(OAc) 2 complexed to (o-biphenyl)P(t- Bu) 2 ; and Pd 2 (dba) 3 complexed to (o-biphenyl)P(t-Cy) 2 .
  • Pd 2 (dba) 3 complexed to a phospine ligand such as 2-(tert-butyl 2 - phosphino)biphenyl
  • Pd(dba) 2 complexed to P(t-Bu) 3 Pd(OAc) 2 complexed to (o-biphenyl)P(t- Bu) 2
  • Copper catalysts which are useful in the above coupling reaction include those catalysts in which the copper is complexed with one or more ligands, including but not limited to Cul/ethylene glycol complex; CuBr/DBU complex, Cu(PPh 3 )Br; and Cu(PPh 3 )Br additionally complexed to 1 ,10-phenanthroline or neocuproine (e.g., Cu(phen) (PPh 3 )Br and Cu(neocup)(PPh 3 )Br, respectively), and the like.
  • ligands including but not limited to Cul/ethylene glycol complex
  • CuBr/DBU complex Cu(PPh 3 )Br
  • Cu(PPh 3 )Br additionally complexed to 1 ,10-phenanthroline or neocuproine (e.g., Cu(phen) (PPh 3 )Br and Cu(neocup)(PPh 3 )Br, respectively), and the like.
  • Bases which are useful in the above coupling reaction include but are not limited to potassium carbonate, sodium carbonate, cesium carbonate, sodium tert-butoxide, potassium tert- butoxide, potassium phenoxide, triethylamine, and the like, or mixtures thereof.
  • Solvents may be used in such coupling reactions including but not limited to toluene, xylenes, diglyme, tetrahydrofuran, dimethylethyleneglycol, and the like, or mixtures thereof.
  • the activated substituent X in the compounds of formula III should be such that it provides sufficient reactivity to react with the compounds of formula Il to provide the compounds of formula IV.
  • Compounds of formula III that contain such activated substituents may be prepared, isolated and/or purified, and subsequently reacted with the compounds of formula II.
  • compounds of formula III with suitable activated substituents may be prepared and further reacted without isolation or further purification with the compounds of formula Il to afford the compounds of formula IV.
  • suitable activated substituent groups for X are halogens (e.g., Cl, Br, and I); derivatized hydroxyl groups (e.g., triflate, mesylate, and tosylate); and diazonium salts.
  • 6-iodo-3-((E)-2-pyridin-2-yl-vinyl)-1-(tetrahydropyroan-2-yl)-1 H-indazole is reacted with a catalytic amount of Pd(dppf)CI 2 -CH 2 CI 2 , cesium carbonate and 2-mercapto-N-methylbenzamide in DMF at 80 0 C to provide 6-(2-mercapto-N-methylbenzamide)-3-((E)-2-pyridin-2-yI-vinyl)-1- (tetrahydropyroan-2-yl)-1H-indazole.
  • suitable reagents and reaction conditions for deprotecting the N-1 indazole ring nitrogen group, W are well known.
  • suitable reagents include, but are not limited to, hydrochloric acid, sulfuric acid, nitric acid, para-toluenesulfonic acid, methanesulfonic acid, or Lewis acids such as boron trifluoride etherate. These reactions may be conducted in solvents that are compatible with the specific reaction conditions chosen and will not interfere with the desired transformation.
  • palladium removal can be accomplished using 10% cysteine-silica as discussed in a U.S. provisional patent application entitled Methods for the Removal of Heavy Metals, attorney docket number PC032215, filed on November 1, 2004, and is hereby incorporated by reference in its entirety. Palladium removal can also be combined with conditions that allow crystallization of the synthesized compounds in various polymorphic forms.
  • Form IV when a compound of formula I is prepared where R1 is 2-vinyl pyridine, R2 is methyl, and R3 are each hydrogen, the polymorphic form designated as Form IV can be produced by refluxing in tetrahydrofuran, N,N-dimethyl formamide, and methanol, followed by the addition of acetic acid and xylenes.
  • the formation and characterization of Form IV, as well as other polymorphs, is discussed in more detail in a U.S.
  • 2,2'-dithiosalicylic acid is treated with reagents such as thionyl chloride or oxalyl chloride in the presence of a suitable base such as sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, a trialkylamine, triethylamine for example, or a heteroaromatic base such as pyridine to provide the 2,2'-dithiosaIicylic acid dichloride.
  • a suitable base such as sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, a trialkylamine, triethylamine for example, or a heteroaromatic base such as pyridine
  • a suitable base such as sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, a trialkylamine, triethylamine for example, or a heteroaromatic base such as
  • reaction conditions chosen will depend on the specific subject compound and reagents chosen.
  • Other suitably functionalized thiophenol compounds may be generated using appropriately functionalized disulfides as starting materials.
  • the resulting sulfides (compounds of formula III) should be protected from light to prevent disulfide formation.
  • These sulfides may be isolated and further reacted with the compounds of formula Il or they may be reacted with the compounds of formula Il without isolation or further purification.
  • Another synthetic route to the compounds of formula I is provided in the Examples section below.
  • indazole compounds of formula I which are useful as modulators and/or inhibitors of protein kinases. These compounds, prepared by the methods of the present invention, are useful as anti-angiogenesis agents and as agents for modulating and/or inhibiting the activity of protein kinases, thus providing treatments for cancer or other diseases associated with cellular proliferation mediated by protein kinases.
  • Infrared spectra were recorded on a Perkin-Elmer FT-IR Spectrometer as neat oils, as KBr pellets, or as CDCI 3 solutions, and when reported are in wave numbers (cm "1 ).
  • the mass spectra were obtained using LC/MS or APCI. All melting points are uncorrected.AII final products had greater than 95% purity (by HPLC at wavelengths of 220nm and 254nm).
  • DMF means N,N-dimethyl formamide
  • THF means tetrahydrofuran
  • Et means ethyl
  • Ac means acetyl
  • Me means methyl
  • Ph means phenyl
  • HI means hydrochloric acid
  • EtOAc means ethyl acetate
  • Na 2 CO 3 means sodium carbonate
  • NaHCO 3 means sodium hydrogen carbonate (sodium bicarbonate)
  • NaOH means sodium hydroxide
  • Na 2 S 2 O 3 means sodium thiosulfate
  • NaCI means sodium chloride
  • Et 3 N means triethylamine
  • H 2 O means water
  • KOH means potassium hydroxide
  • K 2 CO 3 means potassium carbonate
  • MeOH means methanol
  • i-PrOAc means isopropyl acetate
  • MgSO 4 means isopropyl acetate
  • MgSO 4 means isopropyl acetate
  • MgSO 4 means isoprop
  • 6-Nitroindazole 45.08 Kg is dissolved in DMF (228 Kg) and powdered potassium carbonate (77 Kg) is added while the solution temperate is maintained at ⁇ 3O 0 C.
  • a solution of iodine (123 Kg) dissolved in DMF (100 Kg) is added over 5 to 6 hours while the reaction temperature is maintained ⁇ 35 0 C. (Caution: the reaction is exothermic).
  • the reaction mixture is agitated for 1 to 5 hours at 22 0 C (until the reaction is complete by HPLC).
  • the mixture is then added to a solution of sodium thiosulfate (68 Kg) and potassium carbonate (0.46 Kg) dissolved in water (455 Kg) while the solution temperature is maintained ⁇ 30 0 C.
  • the mixture is agitated for
  • 3-iodo-6-nitroindazole (74.6 Kg) is dissolved in methylene chloride (306 Kg) and THF (211 L), and methanesulfonic acid (3.0 Kg) is carefully added. (Caution: residual sodium bicarbonate may cause CO 2 to be evolved. Monitor the pressure in the reactor).
  • a solution of DHP (55 Kg) in methylene chloride (97 Kg) is added over 5 to 6 hours while the reaction temperature is maintained at ⁇ 22 0 C. The mixture is agitated at 22 0 C for 2 to 6 hours (until the reaction is complete by HPLC).
  • the mixture is then carefully added to an aqueous solution of 10% NaHCO 3 (37 Kg of NaHCO 3 dissolved in 370 Kg water) while the solution temperature is maintained at 22 0 C. (Caution: CO 2 is evolved. Monitor the pressure in the reactor).
  • the mixture is agitated for 1 hour at 22 0 C and the layers separated.
  • the organic layer is washed with an aqueous solution of 10% NaCI (407 Kg) and the layers separated.
  • the organic layer is concentrated at 55 0 C and atmospheric pressure to cut the volume to half (ca. 500 L), then under reduced pressure to remove the remaining solvents.
  • the concentrate (ca.138 L) is co- evaporated with acetonitrile (1 x 224 Kg, 1 x 75 Kg, 1 x 60 Kg) at 55 0 C under reduced pressure until the final volume is ca. 80 L.
  • the resulting slurry is diluted with acetonitrile (60 Kg) and is agitated for 8 hours at -5 0 C.
  • the slurry is filtered, and the solids are rinsed with cold acetonitrile (15 Kg).
  • the solids are dried at room temperature under reduced pressure to provide 77.6 Kg of 3-iodo-6-nitro-1-(tetrahydropyran-2-yl)-1H-indazole (80.5% yield with a purity of 95% by HPLC).
  • Example 3 Preparation of 6-nitro-3-((E)-2-pyridin-2-yl-vinylV1-(tetrahvdropyran-2-yl)-1 H-indazole
  • 3-iodo-6-nitro-1-(tetrahydropyran-2-yl)-1 H-indazole (77 Kg) is added to a solution of 2- vinyl pyridine (31 Kg), N,N-diisopropylethylamine (51 Kg), and tri-o-tolylphosphine (5.414 Kg) in DMF (163 Kg).
  • Pd(OAc) 2 (1.503 Kg) is added and the mixture is agitated for 12 to 18 hours at 100 0 C (until the reaction is complete by HPLC). The mixture is then cooled to 45 0 C and isopropanol (248 Kg) is added.
  • the mixture is agitated for 30 minutes at 45 0 C, diluted with water (1,238 L), and the mixture is agitated at 22 0 C for 1 to 2 hours.
  • the resulting slurry is filtered, rinsed with water (77 L), and the solids are combined with isopropanol (388 Kg).
  • the mixture is agitated for 30 to 90 minutes at 55 0 C, then for 30 to 90 minutes at 1O 0 C, filtered, and the solids are washed with cold (ca. 10 0 C) isopropanol (2 x 30 L).
  • 6-nitro-3-(E)-2-pyridin-2-yl-vinyl)-1-(tetrahydropyran-2-yl)-1H-indazole (61.4 Kg) is dissolved in an aqueous solution of ammonium chloride (71.4 Kg of NH 4 CI in 257 Kg water) and ethanol (244 Kg) is added. Iron powder (39 Kg) is added and the mixture is agitated for 2 to 8 hours at 50 0 C (until the reaction is complete by HPLC). (Add more iron powder (ca. 9.8 Kg) if the reaction is not complete after 8 hours). The mixture is then cooled to 22 0 C and THF (1 ,086 Kg) is added.
  • the mixture is agitated for 1 hour at 22 0 C, and filtered through diatomaceous earth (ca. 5 Kg).
  • the cake is rinsed with THF (214 Kg), and the filtrate is concentrated at 50 0 C under reduced pressure to a volume of ca. 305 L.
  • the concentrate is cooled to 22 0 C, diluted with water (603 Kg), and agitated at 22 0 C for 1 hour.
  • the mixture is filtered, rinsed with heptanes (62 Kg), dried in a vacuum oven for 24 to 48 hours (50 0 C and 25 mm Hg) to provide 51.5 Kg of 6-amino-3-((E)- 2-pyridin-2-yl-vinyl)-1-(tetrahydropyran-2-yl)-1 H-indazole (91.8% yield with a purity of 95% by HPLC).
  • Methylene chloride (4 L) at O 0 C is added over 10 minutes to the diazonium salt solution at O 0 C, and a solution of potassium iodide (1.062 Kg) and iodine (396 g) dissolved in water (3 L) at O 0 C is added over 1.5 hours.
  • the reaction mixture is agitated for 3 hours at O 0 C (until complete by HPLC).
  • the mixture is then poured into a solution of 20% aqueous sodium hydrogen sulfite (2 Kg sodium thiosulfate in 10 L water) and methylene chloride (4 L) at O 0 C, agitated, and the layers separated.
  • the aqueous layer is extracted with methylene chloride (2 x 4 L) at O 0 C and combined.
  • a solution of 28% aqueous ammonium hydroxide (1 L) and water (2 L) is added, and the mixture is agitated for 30 minutes at 10 0 C, and allowed to settle for 24 hours to afford a clear phase separation.
  • the layers are separated and the aqueous layer is extracted with methylene chloride (2 x 6 L).
  • the combined organic layers (ca. 35 L) are loaded onto a glass fritted column (7 in. ID and 20 in.
  • 2-mercapto-N-methylbenzamide (17.2 Kg) is added and the mixtu re is agitated for 4 to 16 hours at 8O 0 C (until the reaction is complete by HPLC).
  • the mixture is then cooled to 22 0 C and ethyl acetate (412 Kg) is added and the mixture is agitated for 1 hour at 22 0 C.
  • Water (686 Kg) is added and the mixture is agitated at 22 0 C for 2 hours.
  • the mixture is f ⁇ Itered and the solids are washed with ethyl acetate (62 Kg), water (137 Kg), and ethyl acetate (62 Kg).
  • the solids are dissolved in THF (93.3 Kg) and methylene chloride (686 Kg), and the solution is eluted through a column containing sand (25 Kg, at the bottom of the column), Florisil (453 Kg, in the middle of the column) and sand (97.8 Kg, on the top of the column), with a solution of THF (15.4 Kg) and methylene chloride (113 Kg) 35 0 C, followed by five portions of THF (31 Kg) and methylene chloride (226 Kg) 35 0 C.
  • the fractions containing the product are collected and concentrated under reduced pressure to a volume of ca. 103 L.
  • Ethyl acetate (20 ⁇ Kg) is added, and the solution is concentrated under reduced pressure to a volume of ca. 172 L.
  • Water (69 g) is added and the solution is agitated for 2 hours at 22 0 C.
  • the solids are filtered, washed with ethyl acetate (62 Kg), and dried in a vacuum oven for 24 to 48 hours (55 0 C and 25 mm Hg) to provide 20.2 Kg of 6-(2-mercapto-N-methylbenzamide)-3-((E)-2-pyridin-2-yl-vinyl)-1 -(tetrahydropyroan-2-yl)-1 H- indazole as a light brown solid (54% yield with a purity of 98%).
  • the mixture is agitated for 30 minutes at 65 0 C, cooled to 3 0 C, and the solids are filtered and washed with cold ethyl acetate (61 Kg). This sequence removes any residual methanol since trace amounts of methanol may prevent the formation of the desired polymorph form III during the neutralization step.
  • the solids are transferred to a reactor, diluted with ethyl acetate (82 Kg), agitated for 3 minutes at O 0 C, and neutralized by addition of 5% aqueous sodium bicarbonate solution (175 Kg) (aqueous phase pH ⁇ 7). Caution: carbon dioxide is evolved.
  • the slurry is agitated for 2 hours at 22 0 C and a sample is withdrawn (60 ml_) to check the pH and to test for polymorph form. If the DSC indicates that the conversion of polymorph form Vl to polymorph form III ( ⁇ Vz ethyl acetate solvate) is not complete, continue the agitation at 22 0 C and check DSC every 4 hours until the formation of polymorph form III is confirmed. A long period of agitation (ca. 16 hours) may be required for the complete polymorph conversion.
  • Example 7 If 6-(2-mercapto-N-methylbenzamide)-3-((E)-2-pyridin-2-yl-vinyl)-1-H-indazc>le from Example 7 is an off-white solid (polymorph III), then proceed with Example 8a.
  • 2.423 Kg is added to methanol (75 L) and the mixture is agitated for 1.5 hours at 1 5 to 25 0 C.
  • the slurry is filtered, and the solids are washed with methanol (12.5 L) and dried in a vacuum oven at room temperature for 24 hours.
  • the dried solids are added to a solution of scetic acid (100 L) at ca. 35 0 C, and the mixture is agitated for 45 minutes at ca. 35 0 C until a clear solution is obtained.
  • the solution is cooled to room temperature and activated carbon (Darco G- ⁇ 0, 2.5 Kg) is added.
  • the mixture is stirred at room temperature for 2 to 3 hours, filtered through Celite (3.0 Kg), and the filtrate is concentrated at 7O 0 C under reduced pressure to a volume of 25 L.
  • the solution is cooled to 25 0 C and xylenes (25 L) are added.
  • the solution is heated to 7O 0 C, and concentrated at 7O 0 C under reduced pressure to a volume of 25 L. This procedure is repeated four times until solids appear.
  • 2,2'-dithiosalicylic acid (421 g) is dissolved in toluene (1.7 L) and thionyl chloride (212 mL) and DMF (7 ml_) are added, and the mixture is agitated for 20 hours at 82 0 C. The mixture is then cooled to 7O 0 C and hexanes (2 L) are added. Further cooling to 10 0 C provides a solid precipitate.
  • 2,2'-dithiosalicylic acid dichloride (90 g) dissolved in THF (500 mL) is added to a solution of 2 M methyl amine in THF (655 mL) in over 40 minutes at 0 0 C, and agitated at room temperature for 16 hours. The mixture is then diluted with water (200 mL) and the resulting slurry is filtered. The solids are washed with water (2x 50 mL), dried in a vacuum oven for 16 hours (55 0 C and 25 mm Hg) to provide 50 g of 2,2'-dithio-N-methylbenzamide (65% yield with a purity of 86% by HPLC).
  • 2,2'-dithio-N-methylbenzamide (967.2 g) is suspended in ethanol (9.0 L) and cooled to O 0 C.
  • Sodium borohydride (253 g) is added in portions over 4 hours, and the mixture is agitated for 5 hours at O 0 C.
  • 3 M hydrochloric acid (3.15 L) is then added to the mixture in over 15 minutes which adjusted the pH to 1.73.
  • the mixture is concentrated under reduced pressure and 45 0 C to remove the ethanol.
  • the concentrate is diluted with ethyl acetate (8 L) and water (4 L) and agitated for 20 minutes. The layers are allowed to separate (30 minutes), and the aqueous layer is removed. Solids and an emulsion remain in the organic layer.
  • 2-(3-lodo-1H-indazol-6-ylsulfanyl)-N-methyl-benzamide (239.19 g), 2-vinyIpyridine (75.7 mL, 702 Mmol), Pd(OAc) 2 (6.56 g), P(O-ToI) 3 (23.12 g), Proton Sponge (187.82 g), LiBr (314.59 g), and DMA (3.1 L, 3.5 mL/g) were added to a 5 L 3-neck flask, equipped with a mechanical stirrer and a temperature probe. The mixture was degassed three times by alternately connecting to house vacuum and nitrogen.
  • the mixture was then heated to 110 0 C in one hour and the temperature was maintained at 110 0 C for 24 hours, at which time all of the 2-(3-lodo-1 H-indazol- 6-ylsulfanyl)-N-methyl-benzamide was consumed (HPLC).
  • HPLC 2-(3-lodo-1 H-indazol- 6-ylsulfanyl)-N-methyl-benzamide was consumed.
  • the mixture was transferred to a 22 L extractor and followed by the addition of 5.5 L of CH 2 CI 2 , 5.5 L of water and 275 mL of 37% aqueous HCI. After agitation and partitioning, the organic phase was extracted twice with 2.0 L of water and 100 mL of 37% HCI. At this stage, the organic phase (HPLC) did not contain any significant amount of the final product (HPLC), and was discarded.
  • An aqueous solution of NaHSO 3 was prepared by adding 13.6 g of solid NaHSO 3 into 250 mL of Dl water with strong stirring. 6-iodoindazole (30.0 g), followed by DMF (60 mL) were added to a 500 mL three-neck flask that was fitted with a mechanical stirrer, a temperature probe, and a 100 mL dropping funnel. After the stirring had begun, the flask was immersed in an ice/water bath. After 30 mintues, KOH was added in one portion, and the resulting mixture was stirred for an additional 30 minutes. A solution of 54.3g of I 2 in 55 mL of DMF (total volume was 71 mL) was added to the dropping funnel and the run-in started.
  • N-1 THP 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridine-2-yl)ethenyl]indazole (355 g) was suspended in 2,485 ml_ of methanol, after which p-toluenesulfonic acid monohydrate (718 g) was added. The mixture was then heated to 65 0 C (hard reflux) for 4 hours under argon while the reaction was monitored by HPLC (gluco method). Heating continued until less than 1% of the N-1 THP protected starting material persisted. The heating was then removed and the reaction was cooled to room temperature.
  • the solid was filtered and the wet cake was washed with methanol (2 volumes, 710 mL) then the solids were rinsed with ethyl acetate (2 volumes, 710 mL).
  • the wet cake was transferred to a reactor containing sodium bicarbonate (126.84 g), deionized water (1800 mL), and ethyl acetate (975 mL), which was then stirred for 2 hours at 2O 0 C.
  • the solids were filtered and washed with 5 volumes of deionized water (1800 mL), then with 2 volumes of ethyl acetate (760 mL), and then dried in a vacuum oven at 40 0 C for 16 hours.
  • the mixture was heated to 100 0 C and the temperature was maintained at 100 0 C overnight, at which time all the starting material was consumed (HPLC). After cooling, the mixture was poured into 800 ml_ of saturated NaHCO 3 and 400 ml_ of EtOAc was added. The mixture was stirred for half an hour at which time a thick precipitate formed. The solid was filtered off and the filtrate was allowed to partition. After partitioning, the aqueous layer was extracted twice with 300 ml_ of EtOAc. The combined organic layers were washed twice with water, dried over MgSO 4 and concentrated. The residue crystallized on standing at room temperature. The solid was treated with 20 ml_ of EtOAc and filtered.
  • the residue was pre- adsorbed onto silica gel and subjected to flash chromatography, using hexanes/EtOAc (2:1 , 1 :1 , 1 :2, 1 :3) to yield 21.77 g of the final product.
  • 2-(3-lodo-1 H-indazol-6-ylsulfanyl)-N-methyl-benzamide (2.30 g), 2-ethynylpyridine (0.25 mL), Pd(PPh 3 J 2 CI 2 (128 mg), CuI (64 mg), (/-Pr) 2 NEt (0.50 mL), and N,N-dimethylformamide (15 mL) were added to a 50 mL 3-neck flask, equipped with a stirring bar and a temperature probe. The mixture was degassed by alternately connecting to house vacuum and nitrogen three times, and heated at 66 0 C for one hour.
  • the mixture was filtered through a medium sintered glass fritted funnel, and the cake was washed with a solution of 500 mL of DMA and 500 mL of THF.
  • the cake was further washed with 2.0 L of THF and the filtrate was collected into a separate flask.
  • the volatile parts in the latter filtrate were removed in vacuo and the residue was combined with the main filtrate.
  • the combined filtrate was recharged back into the 12 L flask, followed by 800 g of 10% cysteine-silica.
  • the flask was equipped with a mechanical stirrer and stirred over the weekend at room temperature.
  • the mixture was then filtered through a medium sintered glass fritted funnel and the silica was washed with a mixture of solvents of 500 ml.
  • the cake was charged to a 5 L 3-neck flask, followed by 1.6 L of THF and 160 mL of DMF.
  • the flask was equipped with a mechanical stirrer, a reflux condenser and the mixture was heated at reflux for 8 hours. After cooling overnight, the mixture was filtered through sharkskin filter paper and sucked dry.
  • the cake was charged to a 5 L 3-neck flask and 1.6 L of MeOH was added.
  • the flask was equipped with a mechanical stirrer, a water condenser and the contents were heated at reflux for 6 hours. After cooling overnight, the mixture was filtered through sharkskin filter paper and sucked dry.
  • the cake was dissolved into 1.6 L of HOAc with the assistance of gentle heating in the water bath of a rotary evaporator.
  • the solution was filtered through #3 filter paper and the total volume of the filtrate was reduced to ⁇ 500 mL in volume on the rotary evaporator at 60 °C/60 mmHg.
  • the bulk of the mixture remained a yellow solution and a small amount of precipitate formed.
  • To the flask was charged 500 mL of xylenes (precipitate formed) and the total volume was reduced to -500 mL in volume on the rotary evaporator at 60°C/60 mmHg. The process was repeated two more times. After cooling, the mixture was filtered, the cake was washed with 500 mL of xylenes and sucked dry. The cake was transferred to a glass dish and further dried at 80°C/27 inch vacuum overnight.
  • the cake was off-white in color and weighed 108.38g.
  • X-ray powder diffraction analysis indicated that a crystalline form was present, which was characterized as Form IV by a powder X- ray diffraction pattern comprising peaks at the following approximate diffraction angles (20): 8.9, 12.0, 14.6, 15.2, 15.7, 17.8, 19.2, 20.5, 21.6, 23.2, 24.2, 24.8, 26.2, and 27.5.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne des méthodes de préparation de composés d'indazole de formule (I) ou des sels ou des solvates correspondants acceptables pharmaceutiquement. Des composés de formule (I) sont utilisés en tant qu'agents antiangiogéniques et agents de modulation et/ou d'inhibition de l'activité de protéines kinases, ce qui permet donc fournir des traitements contre le cancer ou d'autres maladies associées à la prolifération cellulaire médiée par protéines kinases.
PCT/IB2005/003300 2004-11-02 2005-10-21 Methodes de preparation de composes d'indazole WO2006048745A1 (fr)

Priority Applications (9)

Application Number Priority Date Filing Date Title
BRPI0517921-1A BRPI0517921A (pt) 2004-11-02 2005-10-21 métodos para preparar compostos de indazol
MX2007003603A MX2007003603A (es) 2004-11-02 2005-10-21 Metodos para preparar compuestos de indazol.
AU2005300311A AU2005300311A1 (en) 2004-11-02 2005-10-21 Methods for preparing indazole compounds
CA002586176A CA2586176A1 (fr) 2004-11-02 2005-10-21 Methodes de preparation de composes d'indazole
RU2007114112/04A RU2007114112A (ru) 2004-11-02 2005-10-21 Способ получения индазольных соединений
EP05796299A EP1809625A1 (fr) 2004-11-02 2005-10-21 Methodes de preparation de composes d'indazole
JP2007538538A JP2008518901A (ja) 2004-11-02 2005-10-21 インダゾール化合物を調製するための方法
IL182096A IL182096A0 (en) 2004-11-02 2007-03-21 Methods for preparing indazole compounds
NO20072747A NO20072747L (no) 2004-11-02 2007-05-30 Fremgangsmate for fremstilling av indazolforbindelser

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US62457504P 2004-11-02 2004-11-02
US60/624,575 2004-11-02

Publications (1)

Publication Number Publication Date
WO2006048745A1 true WO2006048745A1 (fr) 2006-05-11

Family

ID=35528034

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2005/003300 WO2006048745A1 (fr) 2004-11-02 2005-10-21 Methodes de preparation de composes d'indazole

Country Status (15)

Country Link
EP (1) EP1809625A1 (fr)
JP (1) JP2008518901A (fr)
KR (1) KR20070058689A (fr)
CN (1) CN101044138A (fr)
AR (1) AR051753A1 (fr)
AU (1) AU2005300311A1 (fr)
BR (1) BRPI0517921A (fr)
CA (1) CA2586176A1 (fr)
IL (1) IL182096A0 (fr)
MX (1) MX2007003603A (fr)
NO (1) NO20072747L (fr)
RU (1) RU2007114112A (fr)
TW (1) TW200614990A (fr)
WO (1) WO2006048745A1 (fr)
ZA (1) ZA200702317B (fr)

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008044045A1 (fr) 2006-10-12 2008-04-17 Astex Therapeutics Limited Combinaisons pharmaceutiques
WO2008044041A1 (fr) 2006-10-12 2008-04-17 Astex Therapeutics Limited Combinaisons pharmaceutiques
EP2163544A1 (fr) * 2008-09-16 2010-03-17 Pfizer, Inc. Méthodes de préparation de composés d' indazole
US8354528B2 (en) 2007-10-25 2013-01-15 Genentech, Inc. Process for making thienopyrimidine compounds
WO2013046133A1 (fr) 2011-09-30 2013-04-04 Pfizer Inc. Compositions pharmaceutiques de n-méthyl-2-[3-((e)-2-pyridin-2-yl-vinyl)-1h-indazol-6-ylsulfanyl-benzamide
WO2013068909A1 (fr) 2011-11-11 2013-05-16 Pfizer Inc. N-méthyl-2-[3-((e)-2-pyridin-2-yl-vinyl)-1h-indazol-6-ylsulfanyl]-benzamide pour le traitement de la leucémie myéloïde chronique
CN103570696A (zh) * 2013-11-06 2014-02-12 湖南欧亚生物有限公司 一种阿西替尼中间体的制备方法以及在制备阿西替尼中的应用
US8791140B2 (en) 2007-04-05 2014-07-29 Pfizer Inc. Crystalline forms of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyondazole suitable for the treatment of abnormal cell growth in mammals
EP2792360A1 (fr) 2013-04-18 2014-10-22 IP Gesellschaft für Management mbH (1aR,12bS)-8-cyclohexyl-11-fluoro-N-((1-methylcyclopropyl)sulfonyl)-1a-((3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl)-1,1a,2,2b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxamide pour utilisation dans le traitement de HCV
WO2015067224A1 (fr) 2013-11-08 2015-05-14 Zentiva, K.S. Sels de 6-[2- (méthylcarbamoyl) phénylsulfanyl]-3-e-[2-(pyridin-2-yl) éthanyl]indazole
EP3127900A4 (fr) * 2014-03-31 2017-02-22 Senju Pharmaceutical Co., Ltd. Dérivé alcynylique d'indazole et son utilisation
US9580406B2 (en) 2015-04-28 2017-02-28 Signa S.A. De C.V. Processes for the preparation of axitinib
EP3498734A1 (fr) 2014-02-04 2019-06-19 Pfizer Inc Combinaison d'un antagoniste pd-1 et d'un inhibiteur vegfr pour le traitement du cancer
WO2020128893A1 (fr) 2018-12-21 2020-06-25 Pfizer Inc. Traitements combinés de cancer comprenant un agoniste de tlr
US10695426B2 (en) 2014-08-25 2020-06-30 Pfizer Inc. Combination of a PD-1 antagonist and an ALK inhibitor for treating cancer
US10800846B2 (en) 2015-02-26 2020-10-13 Merck Patent Gmbh PD-1/PD-L1 inhibitors for the treatment of cancer
WO2020212253A1 (fr) 2019-04-18 2020-10-22 Synthon B.V. Procédé de préparation d'axitinib, procédé de purification de l'intermédiaire 2-((3-iodo-1h-indazol-6-yl)thio)-n-méthylbenzamide, procédé de purification d'axitinib par l'intermédiaire du sel d'axitinib hcl, forme solide du sel d'axitinib hcl
US10869924B2 (en) 2015-06-16 2020-12-22 Merck Patent Gmbh PD-L1 antagonist combination treatments
US11274154B2 (en) 2016-10-06 2022-03-15 Pfizer Inc. Dosing regimen of avelumab for the treatment of cancer
WO2023166420A1 (fr) 2022-03-03 2023-09-07 Pfizer Inc. Anticorps multispécifiques et leurs utilisations

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103387565B (zh) * 2013-07-29 2014-10-29 苏州明锐医药科技有限公司 阿西替尼的制备方法
CN104072484B (zh) * 2014-07-07 2016-07-06 渤海大学 氮-(4-(芳巯基)-1氢-吲唑-3-基)-1-(芳杂环取代)甲基亚胺类化合物及其药学上可接受的盐及其制备方法和应用
US10118890B2 (en) 2014-10-10 2018-11-06 The Research Foundation For The State University Of New York Trifluoromethoxylation of arenes via intramolecular trifluoromethoxy group migration
CN112209861A (zh) * 2019-07-11 2021-01-12 鲁南制药集团股份有限公司 一种阿昔替尼中间体化合物及其制备方法
CN112442010B (zh) * 2019-08-30 2023-10-03 润佳（苏州）医药科技有限公司 一类前药化合物及其在治疗癌症方面的应用
CN111440102B (zh) * 2020-04-26 2022-02-15 大连凯飞化学股份有限公司 一种二硫代二苯甲酰胺类化合物的制备方法
CN114591338B (zh) * 2022-03-31 2023-05-09 苏州欧康维视生物科技有限公司 一种Syk和VEGFR2双靶点抑制剂的制备方法及其用途

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001002369A2 (fr) * 1999-07-02 2001-01-11 Agouron Pharmaceuticals, Inc. Composes d'indazole et compositions pharmaceutiques inhibant les proteines kinases, et procedes d'utilisation de ceux-ci
WO2004056806A1 (fr) * 2002-12-19 2004-07-08 Pfizer Inc. Composes de 2-(1h-indazol-6-ylamino)-benzamides en tant qu'inhibiteurs de proteines kinases utiles pour le traitement de maladies ophtalmiques
US20040192653A1 (en) * 2003-03-03 2004-09-30 Mark Munson P38 inhibitors and methods of use thereof
WO2005094823A1 (fr) * 2004-03-30 2005-10-13 Kyowa Hakko Kogyo Co., Ltd. INHIBITEUR DE Flt-3

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001002369A2 (fr) * 1999-07-02 2001-01-11 Agouron Pharmaceuticals, Inc. Composes d'indazole et compositions pharmaceutiques inhibant les proteines kinases, et procedes d'utilisation de ceux-ci
WO2004056806A1 (fr) * 2002-12-19 2004-07-08 Pfizer Inc. Composes de 2-(1h-indazol-6-ylamino)-benzamides en tant qu'inhibiteurs de proteines kinases utiles pour le traitement de maladies ophtalmiques
US20040192653A1 (en) * 2003-03-03 2004-09-30 Mark Munson P38 inhibitors and methods of use thereof
WO2005094823A1 (fr) * 2004-03-30 2005-10-13 Kyowa Hakko Kogyo Co., Ltd. INHIBITEUR DE Flt-3

Cited By (34)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008044041A1 (fr) 2006-10-12 2008-04-17 Astex Therapeutics Limited Combinaisons pharmaceutiques
WO2008044045A1 (fr) 2006-10-12 2008-04-17 Astex Therapeutics Limited Combinaisons pharmaceutiques
EP4249063A2 (fr) 2007-04-05 2023-09-27 Pfizer Products Inc. Formes cristallines de 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-e-[2-(pyridin-2-yl)ethenyl]indazole utiles pour le traitement d'une croissance cellulaire anormale chez des mammiferes
EP4074702A1 (fr) 2007-04-05 2022-10-19 Pfizer Products Inc. Formes cristallines de 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-e-[2-(pyridin-2-yl)ethenyl]indazole utiles pour le traitement d'une croissance cellulaire anormale chez des mammiferes
US8791140B2 (en) 2007-04-05 2014-07-29 Pfizer Inc. Crystalline forms of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyondazole suitable for the treatment of abnormal cell growth in mammals
JP2014193900A (ja) * 2007-04-05 2014-10-09 Pfizer Products Inc Ｖｅｇｆ−ｒ阻害剤の新規結晶形
EP3252047A2 (fr) 2007-04-05 2017-12-06 Pfizer Products Inc. Formes cristallines de 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-e-[2-(pyridin-2-yl)ethenyl]indazole utiles pour le traitement d'une croissance cellulaire anormale chez des mammiferes
US8354528B2 (en) 2007-10-25 2013-01-15 Genentech, Inc. Process for making thienopyrimidine compounds
US8431694B1 (en) * 2007-10-25 2013-04-30 Genentech, Inc. Process for making thienopyrimidine compounds
EP2163544A1 (fr) * 2008-09-16 2010-03-17 Pfizer, Inc. Méthodes de préparation de composés d' indazole
WO2013046133A1 (fr) 2011-09-30 2013-04-04 Pfizer Inc. Compositions pharmaceutiques de n-méthyl-2-[3-((e)-2-pyridin-2-yl-vinyl)-1h-indazol-6-ylsulfanyl-benzamide
US9205078B2 (en) 2011-11-11 2015-12-08 Pfizer Inc. N-methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-1H-indazol-6-ylsulfanyl]-benzamide for the treatment of chronic myelogenous leukemia
WO2013068909A1 (fr) 2011-11-11 2013-05-16 Pfizer Inc. N-méthyl-2-[3-((e)-2-pyridin-2-yl-vinyl)-1h-indazol-6-ylsulfanyl]-benzamide pour le traitement de la leucémie myéloïde chronique
EP2792360A1 (fr) 2013-04-18 2014-10-22 IP Gesellschaft für Management mbH (1aR,12bS)-8-cyclohexyl-11-fluoro-N-((1-methylcyclopropyl)sulfonyl)-1a-((3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl)-1,1a,2,2b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxamide pour utilisation dans le traitement de HCV
CN103570696B (zh) * 2013-11-06 2016-02-24 湖南欧亚生物有限公司 一种阿西替尼中间体的制备方法以及在制备阿西替尼中的应用
CN103570696A (zh) * 2013-11-06 2014-02-12 湖南欧亚生物有限公司 一种阿西替尼中间体的制备方法以及在制备阿西替尼中的应用
WO2015067224A1 (fr) 2013-11-08 2015-05-14 Zentiva, K.S. Sels de 6-[2- (méthylcarbamoyl) phénylsulfanyl]-3-e-[2-(pyridin-2-yl) éthanyl]indazole
EP3498734A1 (fr) 2014-02-04 2019-06-19 Pfizer Inc Combinaison d'un antagoniste pd-1 et d'un inhibiteur vegfr pour le traitement du cancer
EP3971209A1 (fr) 2014-02-04 2022-03-23 Pfizer Inc. Combinaison d'un antagoniste pd-1 et d'un inhibiteur vegfr pour le traitement du cancer
US10570202B2 (en) 2014-02-04 2020-02-25 Pfizer Inc. Combination of a PD-1 antagonist and a VEGFR inhibitor for treating cancer
CN106458920A (zh) * 2014-03-31 2017-02-22 千寿制药株式会社 炔基吲唑衍生物及其用途
RU2667486C2 (ru) * 2014-03-31 2018-09-20 Сэндзю Фармацевтикал Ко., Лтд. Производное алкинилиндазола и его применение
JPWO2015152117A1 (ja) * 2014-03-31 2017-04-13 千寿製薬株式会社 アルキニルインダゾール誘導体及びその用途
US9617222B1 (en) 2014-03-31 2017-04-11 Senju Pharmaceutical Co., Ltd. Alkynyl indazole derivative and use thereof
EP3127900A4 (fr) * 2014-03-31 2017-02-22 Senju Pharmaceutical Co., Ltd. Dérivé alcynylique d'indazole et son utilisation
US10695426B2 (en) 2014-08-25 2020-06-30 Pfizer Inc. Combination of a PD-1 antagonist and an ALK inhibitor for treating cancer
US10800846B2 (en) 2015-02-26 2020-10-13 Merck Patent Gmbh PD-1/PD-L1 inhibitors for the treatment of cancer
US9580406B2 (en) 2015-04-28 2017-02-28 Signa S.A. De C.V. Processes for the preparation of axitinib
US10869924B2 (en) 2015-06-16 2020-12-22 Merck Patent Gmbh PD-L1 antagonist combination treatments
US11274154B2 (en) 2016-10-06 2022-03-15 Pfizer Inc. Dosing regimen of avelumab for the treatment of cancer
WO2020128893A1 (fr) 2018-12-21 2020-06-25 Pfizer Inc. Traitements combinés de cancer comprenant un agoniste de tlr
WO2020212253A1 (fr) 2019-04-18 2020-10-22 Synthon B.V. Procédé de préparation d'axitinib, procédé de purification de l'intermédiaire 2-((3-iodo-1h-indazol-6-yl)thio)-n-méthylbenzamide, procédé de purification d'axitinib par l'intermédiaire du sel d'axitinib hcl, forme solide du sel d'axitinib hcl
WO2023166420A1 (fr) 2022-03-03 2023-09-07 Pfizer Inc. Anticorps multispécifiques et leurs utilisations
WO2023166418A2 (fr) 2022-03-03 2023-09-07 Pfizer Inc. Anticorps multispécifiques et leurs utilisations

Also Published As

Publication number Publication date
CN101044138A (zh) 2007-09-26
MX2007003603A (es) 2007-05-21
BRPI0517921A (pt) 2008-10-21
ZA200702317B (en) 2008-09-25
AU2005300311A1 (en) 2006-05-11
CA2586176A1 (fr) 2006-05-11
RU2007114112A (ru) 2008-12-10
NO20072747L (no) 2007-07-31
EP1809625A1 (fr) 2007-07-25
TW200614990A (en) 2006-05-16
KR20070058689A (ko) 2007-06-08
AR051753A1 (es) 2007-02-07
IL182096A0 (en) 2007-07-24
JP2008518901A (ja) 2008-06-05

Similar Documents

Publication Publication Date Title
WO2006048745A1 (fr) Methodes de preparation de composes d'indazole
TWI658042B (zh) 雜環化合物的合成
EP2190804B1 (fr) Procédé et intermédiaires de préparation d'inhibiteurs de l'intégrase
CN101094836A (zh) 制备吲唑化合物的方法
US20070203196A1 (en) Methods of preparing indazole compounds
US7232910B2 (en) Methods of preparing indazole compounds
EP3325485B1 (fr) Procédés de préparation de dérivés de benzodiazépine cytotoxiques
CN102712585A (zh) 中性内肽酶抑制剂中间体和其制备方法
EP1140933B1 (fr) Procede de preparation de derives de deaza-adenosine n6-substitues
JP5017101B2 (ja) 不斉四置換炭素原子含有化合物の製法
JP5787893B2 (ja) ビフェニルイミダゾール化合物の調製方法
US5817823A (en) Method for synthesizing 2-substituted imidazoles
EP4196131A1 (fr) Synthèse de nucléotides fluorés
EP1814859A2 (fr) Procedes de preparation de composes indazole
JP7315805B1 (ja) 単環ピリジン誘導体の合成中間体の製造方法
EP2163544A1 (fr) Méthodes de préparation de composés d' indazole
CN118401509A (zh) 制备(2R,3S)-2-(苯并[d]咪唑丙基)哌啶-3-醇衍生物的方法
JPH0812670A (ja) 新規なピロリジン誘導体
CA2584617A1 (fr) Procede servant a produire un derive de benzo[c]phenanthridine

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

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

AL Designated countries for regional patents

Kind code of ref document: A1

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

DPE2 Request for preliminary examination filed before expiration of 19th month from priority date (pct application filed from 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 182096

Country of ref document: IL

WWE Wipo information: entry into national phase

Ref document number: MX/a/2007/003603

Country of ref document: MX

WWE Wipo information: entry into national phase

Ref document number: 2005300311

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 2384/DELNP/2007

Country of ref document: IN

ENP Entry into the national phase

Ref document number: 2005300311

Country of ref document: AU

Date of ref document: 20051021

Kind code of ref document: A

WWP Wipo information: published in national office

Ref document number: 2005300311

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 200580036153.0

Country of ref document: CN

WWE Wipo information: entry into national phase

Ref document number: 2007538538

Country of ref document: JP

WWE Wipo information: entry into national phase

Ref document number: 12007500938

Country of ref document: PH

Ref document number: 07042929

Country of ref document: CO

Ref document number: 1020077009804

Country of ref document: KR

WWE Wipo information: entry into national phase

Ref document number: 2586176

Country of ref document: CA

Ref document number: 554867

Country of ref document: NZ

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 2005796299

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 2007114112

Country of ref document: RU

WWP Wipo information: published in national office

Ref document number: 2005796299

Country of ref document: EP

ENP Entry into the national phase

Ref document number: PI0517921

Country of ref document: BR

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载