[go: up one dir, main page]

WO2009111260A1 - Pyrazolo[1,5-a]pyrimidines substituées par phénylsulfonamide, leurs procédés de préparation et leurs utilisations - Google Patents

Pyrazolo[1,5-a]pyrimidines substituées par phénylsulfonamide, leurs procédés de préparation et leurs utilisations Download PDF

Info

Publication number
WO2009111260A1
WO2009111260A1 PCT/US2009/035243 US2009035243W WO2009111260A1 WO 2009111260 A1 WO2009111260 A1 WO 2009111260A1 US 2009035243 W US2009035243 W US 2009035243W WO 2009111260 A1 WO2009111260 A1 WO 2009111260A1
Authority
WO
WIPO (PCT)
Prior art keywords
pyridin
pyrimidin
ylpyrazolo
formula
methoxyphenyl
Prior art date
Application number
PCT/US2009/035243
Other languages
English (en)
Inventor
Dan Maarten Berger
Jeremy Ian Levin
Minu Dhanjisha Dutia
Emily Boucher Norton
George Diamantidis
Original Assignee
Wyeth
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 Wyeth filed Critical Wyeth
Publication of WO2009111260A1 publication Critical patent/WO2009111260A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to new pyrazolo[1 ,5-a]pyrimidine compositions that are useful for inhibiting abnormal growth of certain cell types.
  • the invention is directed to certain phenylsulfonamide substituted, pyrazolo[1,5-a]pyrimidines, their corresponding pharmaceutically acceptable salts and methods for their preparation and use.
  • the phenylsulfonamide substituted, pyrazolo[1 ,5-a]pyrimidines inhibit growth of tumor cells, which contain oncogenic forms of Receptor Tyrosine Kinases, K-Ras and Raf kinases.
  • Raf is a multigene family expressing oncoprotein kinases: Raf-1 , A-Raf and B-Raf, as described in publications by McCubrey et al., in Leukemia, 12(12), 1903-1929 (1998); by
  • Raf kinases are functionally present in certain human hematopoietic cells, and their aberrant expression can result in abrogation of cytokine dependency. Their regulatory mechanisms differ in that C-Raf and A-Raf appear to require additional serine and tyrosine phosphorylation within the N region of the kinase domain for full activity, as described by Mason et al., in EMBO J. 18, 2137-2148 (1999). In addition B-Raf kinase appears to have a much higher basal kinase activity than either A-Raf kinase or C-Raf kinase.
  • the three Raf kinases play critical roles in the transmission of mitogenic and anti-apoptotic signals.
  • B-Raf kinase is frequently mutated in various human cancers, as described by Wan et al., in Cell 116, 855-867 (2004), indicating that specific Raf kinases are associated with cancer.
  • the cytoplasmic serine/threonine kinase B-Raf kinases and receptor tyrosine kinases of the platelet-derived growth factor receptor (PDGFR) family are frequently activated in cancer by mutations of an equivalent amino acid.
  • B-Raf kinase is one of three known Raf oncoprotein kinases involved in transmission of mitogenic and anti-apoptotic signals.
  • B-Raf encodes a Ras-regulated kinase that mediates cell growth and malignant transformation pathway activation that controls cell growth and survival.
  • Activation of a Ras/Raf/MEK pathway results in a cascade of events from the cell surface to the cell nucleus, ultimately affecting cell proliferation, apoptosis, differentiation and transformation.
  • Activating B-Raf mutations have been found in 66% of malignant melanomas and in a smaller fraction of other cancers including those of the colorectum, as reported by Davies H., et al. (2002) Nature 417:906 and by Rajagopalan H., etal. (2002) Nature
  • B-Raf has been shown to be frequently mutated in various human cancers, as described by Wan et al. (2004) Cell 116, 855-867. B-Raf mutations also account for the MAP kinase pathway activation common in non-small cell lung carcinomas (NSCLC). Certain B-Raf mutations reported to date in NSCLC are non-V600 (89%; P ⁇ IO ⁇ 7 ), strongly suggesting that B-Raf mutations in NSCLC are qualitatively different from those in melanomas.
  • Raf kinases are also key components of signal transduction pathways by which specific extracellular stimuli elicit precise cellular responses in mammalian cells.
  • Activated cell surface receptors activate Ras/Rap proteins at the inner aspect of the plasma membrane, which in turn recruit and activate Raf proteins.
  • Activated Raf proteins phosphorylate and activate the intracellular protein kinases MEK1 and MEK2.
  • activated MEKs catalyze phosphorylation and activation of p42/p44 mitogen-activated protein kinase (MAPK).
  • MAPK mitogen-activated protein kinase
  • a variety of cytoplasmic and nuclear substrates of activated MAPK are directly or indirectly associated with the cellular response to cellular environmental change.
  • B-Raf mutations have been shown to predict sensitivity to pharmacological MEK inhibition by small molecule inhibitors by limiting tumor growth in B-Raf mutant xenografts, as described by Solit et a., in Nature, Letters to Editor, Nov. 6, 2005.
  • Three distinct genes have been identified in mammals that encode Raf proteins; A-Raf, B-Raf and C-Raf (also known as Raf-1) and isoformic variants that result from differential splicing of mRNA are known.
  • WO 2006084015 describes certain substituted phenyl and substituted cyclic pyrazolo[1 ,5-a]pyrimidines as B-Raf kinase inhibitors and the treating of diseases associated with B-Raf kinase. Neither publication discloses phenylsulfonamide substituted, pyrazolo[1 ,5-a]pyrimidine compounds.
  • Phenylsulfonamide substituted, pyrazolo[1 ,5-a]pyrimidine compounds of the present invention fulfill this unmet need and are useful in the treatment of specific diseases associated with certain Raf kinases in mammals.
  • Another unmet need addressed by the present invention is that certain Raf kinases inhibitors are useful in treating cancer and comprise one component of a particular cancer therapy.
  • R 1 is a 5-7 membered heterocyclyl ring or heteroaryl ring, said ring comprising 1-3 heteroatoms selected from N, O and S, and said ring optionally substituted with one to two substituents selected from -J, -NO 2 , -CN, -N 3 , -CHO, -CF 3 , -OCF 3 , -R 5 , -OR 5 , -S(O) m R 5 , -S(O) m NR s R 5 , - NR 5 R 5 , -NR 5 S(O) m R 5 , -OR 7 OR 5 , -OR 7 NR 5 R 5 , -N(R 5 JR 7 OR 5 , -N(R 5 JR 7 NR 5 R 5 , -NR 5 C(O)R 5 , - C(O)R 5 , -C(O)OR 5 , -C(O)NR 5 R 5 , -OC(
  • R is a monocyclic aryl ring, a 6-14 membered monocyclic or bicycllc heteroaryl ring comprising
  • R 3 and R 4 are each independently selected from H, alkyl of 1-8 carbon atoms, cycloalkyl of 3 to 8 atoms and a 5-7 membered monocyclic heteroaryl, said alkyl, cyloalkyl and heteroaryl optionally substituted with one to four substituents selected from -J, -NO 2 , -CN, -N 3 , -CHO, -CF 3 , -OCF 3 , -R 5 , -OR 5 , NR 5 R 5 , -N(R 5 )R 7 OR 5 , -N(R 5 )R 7 NR 5 R 5 and heteroaryl;
  • R 5 is independently selected from H, alkyl of 1-8 carbon atoms, c/s-alkenyl of 2-6 carbon atoms, frans-alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms and cycloalkyl of 3-7 carbons; or the two R 5 substituents in NR 5 R 5 , together with the nitrogen to which they are attached, join to form a substituted ring comprising 2-7 carbon atoms, or a 5 to 8 atom ring, optionally comprising one to two additional heteroatoms selected from O, N and S(0) m ;
  • R 6 is a divalent group selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, and alkynyl of 2-6 carbon atoms;
  • R 7 is a divalent alkyl group of 2-6 carbon atoms
  • J is fluoro, chloro, bromo, or iodo
  • n is an integer of 0-2.
  • the invention provides a compound of formula B: and pharmaceutically acceptable salts thereof;
  • R is selected from -J, -NO 2 , -CN, -N 3 , -CHO, -CF 3 , -OCF 3 , -R 5 , -OR 5 , -NR 5 R 5 , OR 7 OR 5 , - OR 7 NR 5 R 5 , -N(R 5 )R 7 OR 5 , -N(R 5 JR 7 NR 5 R 5 , -R 6 OR 5 , -R 6 OR 7 OR 5 , -R 6 OR 7 OR 5 , -R 6 OR 7 NR 5 R 5 , -R 6 N(R 5 )R 7 OR 5 , -R 6 N(R 5 )R 7 NR 5 R 5 and -R 6 NR 5 R 5 ; and R 1 -R 7 are as defined above.
  • the present invention also provides a pharmaceutical composition comprising a compound of formula A or formula B and a pharmaceutically acceptable carrier.
  • the present invention also provides pharmaceutical compositions comprising compounds of formula A or formula B in combination with other kinase-inhibiting pharmaceutical compositions or chemotherapeutic agents, and a pharmaceutically acceptable carrier.
  • the present invention provides a method for making a compound of formula B:
  • R is selected from H, -J, -NO 2 , -CN, -N 3 , - CHO, -CF 3 , -OCF 3 , -R 5 , -OR 5 , -NR 5 R 5 , -OR 7 OR 5 , -OR 7 NR 5 R 5 , -N(R 5 )R 7 OR 5 , -N(R 5 JR 7 NR 5 R 5 , - R 6 OR 5 , -R 6 OR 7 OR 5 , -R 6 OR 7 NR 5 R 5 , -R 6 N(R 5 JR 7 OR 5 , -R 6 N(R 5 JR 7 NR 5 R 5 and -R 6 NR 5 R 5 ; and R 1 - R 4 are defined above.
  • the present invention also provides a method for making a compound of formula B:
  • the present invention provides additional independent steps of separating compounds of formula 4a and 4b prior to the halogenation step, separating compounds of formula 5a and 5b prior to the palladium catalyzed, Suzuki coupling step and separating compounds of formula A and B after the palladium catalyzed, Suzuki coupling step, respectively.
  • the invention also provides methods for inhibiting Raf kinase activity in a cell comprising contacting a cell with a compound of formula A or formula B, whereby the compound inhibits activity of a Raf kinase selected from A-Raf kinase, B-Raf kinase, mutant B-Raf kinase, and C-Raf kinase.
  • the present invention also provides a method of treating an A-Raf kinase, B-Raf kinase, mutant B-Raf kinase, or C-Raf kinase dependent condition, said condition comprising cancer or inflammation, by administering to a patient a pharmaceutically effective amount of a compound of formula A or formula B.
  • the present invention provides methods of treating mammalian diseases associated with a Raf kinase selected from A-Raf kinase, B-Raf kinase, mutant B-Raf kinase, and C-Raf kinase by administering to a patient a compound of formula A or formula B.
  • the present invention provides a method of treating cancer by administering to a patient a compound of formula A or formula B, wherein the cancer is selected from the group consisting of: breast, kidney, bladder, thyroid, mouth, larynx, esophagus, stomach, colon, ovary, lung, pancreas, skin, liver, prostate and brain cancer.
  • alkyl refers to the radical of saturated aliphatic groups of 1 to 8 carbon atoms, including straight-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups. In one embodiment, a straight chain or branched chain alkyl has 6 or fewer carbon atoms in its backbone.
  • alkyl can be used alone or as part of a chemical name, such as "alkylamine”.
  • alkenyl and alkynyl refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one double or triple carbon-carbon bond, respectively.
  • cycloalkyl refers to the radical of saturated cycloaliphatic rings of 3 to 10 carbon atoms, including unbranched cycloalkyl rings and branched cycloalkyl rings.
  • aryl refers to an aromatic carbocyclic moiety, e.g. having from 6-20 carbon atoms, which may be a single ring
  • aryl (monocyclic) or multiple rings fused together or linked covalently, wherein at least one of the rings is aromatic. Any suitable ring position of the aryl moiety may be covalently linked to the defined chemical structure. Examples of aryl include phenyl and napthyl.
  • the aryl group may be optionally substituted. In addition to other optional substituents, the aryl group may be substituted by an oxo substituent meaning one of the ring carbon atoms is part of a carbonyl group.
  • heteroaryl as used herein means an aromatic heterocyclic ring system, e.g. having from 5-20 ring atoms, which may be a single ring or multiple rings fused together or linked covalently, wherein at least one of the rings is aromatic.
  • the rings may contain one or more heteroatoms, e.g. 1 to 3 heteroatoms, selected from nitrogen, oxygen, or sulfur, wherein the nitrogen or sulfur atom(s) are optionally oxidized, or the nitrogen atom(s) are optionally quaternized. Any suitable ring position of the heteroaryl moiety may be covalently linked to the defined chemical structure.
  • the heteroaryl group may be optionally substituted. In addition to other optional substituents, the heteroaryl group may be substituted by an oxo substituent meaning one of the ring carbon atoms is part of a carbonyl gr ⁇ up.
  • heterocyclic can be used interchangeably to refer to a stable, saturated or partially unsaturated monocyclic or multicyclic heterocyclic ring system having from 6 to 20 ring members, e.g. having from 5 to 7 ring members.
  • the heterocyclic ring members are carbon atoms and one or more heteroatoms, e.g. 1 to 3 heteroatoms, selected from nitrogen, oxygen, and sulfur atoms, wherein the nitrogen or sulfur atom(s) are optionally oxidized, or the nitrogen atom(s) are optionally quaternized.
  • the heterocyclic, heterocycle or heterocyclyl group may be optionally substituted.
  • heterocyclic, heterocycle or heterocyclyl group may be substituted by an oxo substituent meaning one of the ring carbon atoms is part of a carbonyl group.
  • the heterocyclic, heterocycle or heterocyclyl group may contain one of more fused rings.
  • substituted is contemplated to include all permissible substituents of organic compounds.
  • suitable substituents of organic compounds include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds as well as inorganic substituents such as halogen or amino.
  • the substituents can be one or more and the same or different for appropriate organic compounds.
  • the heteroatoms such as nitrogen may have hydrogen substituents, halogen substituents and/or any suitable substituents of organic compounds described herein which satisfy the valencies of the heteroatoms. This invention is not intended to be limited in any manner by the suitable substituents of organic compounds.
  • pharmaceutically acceptable carrier includes pharmaceutically acceptable diluents and excipients.
  • the term "individual”, “subject” or “patient,” used interchangeably, refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.
  • the invention provides a compound of formula A or formula B:
  • R, R -R , J and m are defined as above.
  • R 1 examples include, but are not limited to for example, thienyl, furyl, pyridinyl, piperidinyl and morpholinyl.
  • the heterocyclic ring or heteroaryl ring may be substituted to the pyrazolofi , 5-a]py ⁇ midine ring framework in any acceptable position.
  • R 1 is 4-pyridinyl or 4-morpholinyl, optionally substituted with one to four substituents selected from -J, -NO 2 , -CN, -N 3 , -CHO, -CF 3 , -OCF 3 , -R 5 , -OR 5 , -S(O) m R 5 , - NR 5 R 5 , -NR 5 S(O) m R 5 , -S(O) m NR 5 R 5 , -OR 7 OR 5 , -OR 7 NR 5 R 5 , -N(R 5 )R 7 OR 5 , -N(R 5 )R 7 NR 5 R 5 , - NR 5 C(O)R 5 , -C(O)R 5 , -C(O)OR 5 , -C(O)NR 5 R 5 , -OC(O)R 5 , -OC(O)OR 5 , -OC(O)NR 5 R 5
  • R 2 examples include, but are not limited to, halogen substituted phenyl,
  • R 2 is an aryl ring or a bicyclic ring of formula
  • 3 ⁇ iinn refers to a 5-7 membered heteroaryl ring comprising 1-3 heteroatoms selected from N, O and S, said ring optionally substituted with one to four substituents selected from -J, - NO 2 , -CN, -N 3 , -CHO, -CF 3 , -OCF 3 , -R 5 , -OR 5 , -S(O) m R 5 , -NR 5 R 5 , -NR 5 S(O) m R s , -S(O) m NR 5 R 5 , - OR 7 OR 5 , -OR 7 NR 5 R 5 , -N(R 5 JR 7 OR 5 , -N(R 5 JR 7 NR 5 R 5 , -NR 0 C(O)R 5 , -C(O)R 5 , -C(O)OR 5 , - C(O)NR 5 R 5 , -OC(O)R 5
  • R 6 C(O)NR 5 R 5 , -R 6 OC(O)R 5 , -R 6 OC(O)OR 5 , -R 6 OC(O)NR 5 R 5 , -R 6 NR 5 C(O)R 5 , -R 6 NR 5 C(O)OR 5 and -R 6 NR 5 C(O)NR 5 R 5 .
  • R 2 is a phenyl ring or an indazolyl ring, optionally substituted with one to four substituents selected from -J, -NO 2 , -CN, -N 3 , -CHO, -CF 3 ,
  • R 6 OC(O)NR 5 R 5 , -R 6 NR 5 C(O)R 5 , -R 6 NR 5 C(O)OR 5 and -R 6 NR 5 C(O)NR 5 R 5 .
  • R 2 is selected from halogen substituted phenyl, CrC 6 alkylsulfonamido substituted phenyl, carbamate substituted phenyl, CrC 6 alkoxy substituted phenylcarbamate, benzonitrile, hydroxyl substituted benzonitrile, C 1 -C 6 alkoxy substituted benzonitrile, hydroxyphenyl, Ci-C 6 alkyl substituted hydroxyphenyl, halogen substituted hydroxyphenyl, C 1 -C 6 alkoxyphenyl, halogen substituted CrC 6 alkoxyphenyl, hydroxypyridinyl, C 1 -C 6 alkoxypyridinyl, amino phenyl, halogen substituted amino phenyl, hydroxyl substituted amino phenyl, formamide substituted phenyl, hydroxyl substituted phenylformamide, C 1 -C 6 alkoxy substituted phenylformamide, C 1 -C 6 alkoxy
  • R 3 is H.
  • R 3 is independently selected from alkyl of 1-6 carbon atoms, cycloalkyl of 3 to 8 atoms and monocyclic heteroaryl, said alkyl, branched alkyl, cyloalkyl and heteroaryl optionally substituted with one to four substituents selected from -J, -NO 2 , -CN, -N 3 , -CHO, -CF 3 , -OCF 3 , -R 5 , -OR 5 , NR 5 R 5 , -N(R 5 JR 7 OR 5 , -N(R 5 )R 7 NR S R 5 and heteroaryl.
  • R 4 is H.
  • R 4 is independently selected from alkyl of 1-6 carbon atoms, cycloalkyl of 3 to 8 atoms and monocyclic heteroaryl, said alkyl, branched alkyl, cyloalkyl and heteroaryl optionally substituted with one to four substituents selected from -J, -NO 2 , -CN, -N 3 , -CHO, -CF 3 , -OCF 3 , -R 5 , -OR 5 ,
  • the compounds of this invention may be prepared from: (a) commercially available starting materials (b) known starting materials which may be prepared as described in literature procedures or (c) new intermediates described in the schemes and experimental procedures herein.
  • Reactions are performed in a solvent appropriate to the reagents and materials employed and suitable for the transformation being effected. It is understood by those skilled in the art of organic synthesis that the various functionalities present on the molecule must be consistent with the chemical transformation proposed. This may necessitate judgement as to the order of synthetic steps.
  • ketones of formula 1 which are commercially available or can be synthesized by the methods described in U.S. Patent No. 5,459,131 , are reacted with acetals of N,N-dialkylformamides or acetals of N,N-dialkylacetamides, carried out in an inert solvent or without a solvent to yield enaminone compounds, namely 3-dialkylamino-2- propen-1 -ones of formula 2, wherein R 3 and R 4 are defined above.
  • R is selected from -J, -NO 2 , -CN, -N 3 , -CHO, -CF 3 , -OCF 3 , -R 5 , -OR 5 , -NR 5 R 5 , -OR 7 OR 5 , -OR 7 NR 5 R 5 , -N(R 5 )R 7 OR 5 , -N(R 5 JR 7 NR 5 R 5 , -R 6 OR 5 , -R 6 OR 7 OR 5 , -R 6 OR 7 OR 5 , -R 6 OR 7 NR 5 R 5 , -R 6 N(R 5 )R 7 OR 5 , -R 6 N(R 5 JR 7 NR 5 R 5 and -R 6 NR 5 R 5 ; and R 1 -R 7 are as described above.
  • an enaminone of formula 2 where R 3 and R 4 are defined above, can react with an aminopyrazole of formula 3a, where R 1 is defined above, in weak acid such as glacial acetic acid or in an inert solvent such as toluene, acetonitrile or dimethoxyethane, at reflux temperature for several hours, or without solvent at 50-150° C, to provide compounds of formula 4a and 4b.
  • weak acid such as glacial acetic acid
  • an inert solvent such as toluene, acetonitrile or dimethoxyethane
  • Compounds 4a and 4b can be separated, chromatographically or via recrystallization, and halogenated to afford the corresponding halo-pyrazole derivative using N- halosuccinimides at room temperature to 50° C in chlorinated hydrocarbon solvents to give either a compound of formula 5a or a compound of formula 5b.
  • the mixture of compounds 4a and 4b can be halogenated under these conditions with subsequent separation of compounds 5a and 5b.
  • the halopyrazole compounds 5a and 5b are subjected to palladium catalyzed coupling reactions with organometallic reagents R 2 -M(L) n where M is tin, zinc or other suitable metal.
  • Suzuki couplings with aryl or heteroaryl boronic acids or boronate esters can be carried out to provide the compounds of the invention.
  • Pyrazolo[1 ,5-a]pyrimidines are prepared by condensation of 3-aminopyrazoles and substituted 3-aminopyrazoles with 1 ,3-dicarbonyl compounds as described in J. Med. Chem., 18, 645 (1974); J. Med. Chem. 18, 460 (1975); J. Med. Chem., 20, 386 (1977); Synthesis, 673 (1982) and references contained therein.
  • Intermediate compounds 9 can be converted to substituted aminopyrazole compounds 3 by subsequent reaction with hydrazine hydrate in a suitable solvent such as ethanol.
  • a suitable solvent such as ethanol.
  • Substituted ester compounds of formula 6 and substituted acetonitrile compounds of formula 7 can be obtained from commercial sources or readily prepared by numerous literature procedures by those skilled in the art.
  • R 1 - R 4 substituents can be further modified by known methods by those skilled in the art to provide new substituents.
  • Exemplary compounds of formula A prepared by methods of the present invention include the following compounds:
  • the compounds of formula A or formula B may be obtained as inorganic or organic salts using methods known to those skilled in the art, for example Richard C. Larock,
  • salts of the compounds of formula A or formula B with an acidic moiety may be formed from organic and inorganic bases.
  • alkali metals or alkaline earth metals such as sodium, potassium, lithium, calcium, or magnesium or organic bases and N- tetraalkylammonium salts such as N-tetrabutylammonium salts.
  • salts may be formed from organic and inorganic acids.
  • salts may be formed from acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, naphthalenesulfonic, benzenesulfonic, toluenesulfonic, camphorsulfonic, and similarly known acceptable acids.
  • Suitable examples of pharmaceutically acceptable salts include, but are not limited, to sulfate; citrate, acetate; oxalate; chloride; bromide; iodide; nitrate; bisulfate; phosphate; acid phosphate; isonicotinate; lactate; salicylate; acid citrate; tartrate; oleate; tannate; pantothenate; bitartrate; ascorbate; succinate; maleate; gentisinate; fumarate; gluconate; glucaronate; saccharate; formate; benzoate; glutamate; methanesulfonate; ethanesulfonate; benzenesulfonate; p- toluenesulfonate; pamoate (i.e., 1 ,1'-methylene-bis-(2-hydroxy-3-naphthoate)); and salts of fatty acids such as caproate, laurate, myristate
  • the present invention accordingly provides a pharmaceutical composition, which comprises an effective amount of a compound of formula A or formula B in combination or association with a pharmaceutically acceptable carrier.
  • the compounds are usefully employed in an amount to detectably inhibit Raf kinase activity and in treating diseases associated with Raf kinases.
  • Pharmaceutical compositions are prepared in accordance with acceptable pharmaceutical procedures, such as described in Remingtons Pharmaceutical Sciences, 17th edition, ed. Alfonoso R. Gennaro, Mack Publishing Company, Easton, Pa. (1985).
  • Pharmaceutically acceptable carriers are those that are compatible with the other ingredients in the formulation and biologically acceptable.
  • the term "effective amount" refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes one or more of the following: (1) preventing the disease; for example, preventing a disease, condition or disorder in an individual that may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease; (2) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting or slowing further development of the pathology and/or symptomatology); and (3) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology).
  • the compounds of this invention may be formulated neat or may be combined with one or more pharmaceutically acceptable carriers for administration.
  • suitable carriers include but are not limited to, for example, solvents, diluents and the like, and may be administered orally in such forms as tablets, capsules, dispersible powders, granules, or suspensions containing, for example, from about 0.05 to 5% of suspending agent, syrups containing, for example, from about 10 to 50% of sugar, and elixirs containing, for example, from about 20 to 50% ethanol, and the like, or parenterally in the form of sterile injectable solution or suspension containing from about 0.05 to 5% suspending agent in an isotonic medium.
  • Such pharmaceutical preparations may contain, for example, from about 0.05 up to about 90% of the active ingredient in combination with the carrier, more usually between about 5% and 60% by weight.
  • the formulations are administered transdermal ⁇ which includes all methods of administration across the surface of the body and the inner linings of body passages including epithelial and mucosal tissues.
  • Such administration may be in the form of a lotion, cream, colloid, foam, patch, suspension, or solution.
  • the effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration and the severity of the condition being treated. However, in general, satisfactory results are obtained when the compounds of the invention are administered at a daily dosage of from about 0.5 to about 1000 mg/kg of animal body weight, optionally given in divided doses two to four times a day, or in sustained release form. For most large mammals the total daily dosage is from about 1 to 1000 mg, preferably from about 2 to 500 mg.
  • Dosage forms suitable for internal use comprise from about 0.5 to 1000 mg of the active compound in intimate admixture with a solid or liquid pharmaceutically acceptable carrier. This dosage regimen may be adjusted to provide the optimal therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation.
  • the compounds of this invention may be administered orally as well as by intravenous, intramuscular, or subcutaneous routes.
  • Solid carriers include starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin, while liquid carriers include sterile water, polyethylene glycols, non-ionic surfactants and edible oils such as corn, peanut and sesame oils, as are appropriate to the nature of the active ingredient and the particular form of administration desired.
  • Adjuvants customarily employed in the preparation of pharmaceutical compositions may be advantageously included, such as flavoring agents, coloring agents, preserving agents, and antioxidants, for example, vitamin E, ascorbic acid, BHT and BHA.
  • compositions from the standpoint of ease of preparation and administration are solid compositions, particularly tablets and hard-filled or liquid-filled capsules. Oral administration of the compounds is sometimes desirable.
  • the compounds of this invention may also be administered parenterally or intraperitoneally.
  • Solutions or suspensions of these active compounds as a free base or pharmacologically acceptable salt may be prepared in water suitably mixed with a surfactant such as hydroxy-propylcellulose.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists.
  • the carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
  • cancer and “cancerous” refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth.
  • a “tumor” comprises one or more cancerous cells. Examples of cancer treated by compounds of the present invention include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies.
  • cancers include squamous cell cancer (e.g., epithelial squamous cell cancer), lung cancer including small-cell lung cancer, non- small cell lung cancer ("NSCLC”), adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer including gastrointestinal cancer, pancreatia cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, as well as head and neck cancer.
  • squamous cell cancer e.g., epithelial squamous cell cancer
  • lung cancer including small-cell lung cancer, non- small cell lung cancer (“NSCLC”), adenocar
  • the compounds of this invention may be administered in combination with other antitumor substances or with radiation therapy. These other substances or radiation treatments may be given at the same or at different times as the compounds of this invention. These combined therapies may effect synergy and result in improved efficacy.
  • the compounds of this invention may be used in combination with mitotic inhibitors such as taxol or vinblastine, alkylating agents such as cisplatin or cyclophosamide, antimetabolites such as 5-fluorouracil or hydroxyurea, DNA intercalators such as adriamycin or bleomycin, topoisomerase inhibitors such as etoposide or camptothecin, antiangiogenic agents such as angiostatin, and antiestrogens such as tamoxifen.
  • mitotic inhibitors such as taxol or vinblastine
  • alkylating agents such as cisplatin or cyclophosamide
  • antimetabolites such as 5-fluorouracil or hydroxyurea
  • DNA intercalators such as adriamycin or bleomycin
  • topoisomerase inhibitors such as etoposide or camptothecin
  • antiangiogenic agents such as angiostatin
  • antiestrogens such as tamoxifen
  • an "effective amount" of a compound means either directly administering such compound, or administering a prodrug, derivative, or analog which will form an effective amount of the compound within the body.
  • Methods of administration of a pharmaceutical composition of the invention are not specifically restricted, and can be administered in various preparations depending on the age, sex, and symptoms of the patient.
  • tablets, pills, solutions, suspensions, emulsions, granules and capsules may be orally administered.
  • Injection preparations may be administered individually or mixed with injection transfusions such as glucose solutions and amino acid solutions intravenously. If necessary, the injection preparations are administered singly intramuscularly, intracutaneously, subcutaneously or intraperitoneally. Suppositories may be administered into the rectum.
  • the amount of the compound of formula A or formula B contained in a pharmaceutical composition according to the present invention is not specifically restricted, however, the dose should be sufficient to treat, ameliorate, or reduce the targeted symptoms.
  • the dosage of a pharmaceutical composition according to the present invention will depend on the method of use, the age, sex, and condition of the patient.
  • the present invention also provides methods of inhibition and treatment further comprising administering an additional inhibitor of an oncoprotein kinase of the Ras/Raf/MEK pathway.
  • compositions of the present invention may comprise the compound of the present invention alone or in combination with other oncoprotein kinase- inhibiting compounds or chemotherapeutic agents.
  • Chemotherapeutic agents include, but are not limited to exemestane, formestane, anastrozole, letrozole, fadrozole, taxane and derivatives such as paclitaxel or docetaxel, encapsulated taxanes, CPT-11, camptothecin derivatives, anthracycline glycosides, e.g., doxorubicin, idarubicin, epirubicin, etoposide, navelbine, vinblastine, carboplatin, cisplatin, estramustine, celecoxib, tamoxifen, raloxifen, Sugen SU-5416,
  • Step 1 To a 5 mL solution of dry EtOH was added 0.73 g (31.84 mmol) of Na metal (after removal of mineral oil with hexane). The mixture was stirred, with heating at 45°C for 1 hour until the solution turned clear. A mixture of 3 g (20.38 mmol) of the 3- (methoxyphenyl)acetonitrile and 3.9 g (28.66 mmol) of methyl isonicotinate in 26 mL of dry EtOH was added and the resulting brown solution was heated under reflux for 3 hours.
  • Step 2 A mixture of 1.7 g (6.74 mmol) of 2-(3-methoxyphenyl)-3-oxo-3-pyridin-4-yl- propionitrile and 17 mL POCI 3 was heated at 80° C for 18 hours. After cooling, the POCI 3 was evaporated off. To the residue was added toluene, which was evaporated off to dryness. This step was repeated to fully remove POCI 3 . Ice and saturated sodium bicarbonate was added to the residue, and a solid precipitated out, provided 1 g of 3-chloro-2-(3-methoxyphenyl)-3-pyridin- 4-yl-acrylonitrile (II) as a white solid (57%). MS 271.1 [M+H].
  • Step 3 A mixture of 1 g (3.69 mmol) of 3 ⁇ chloro-2-(3-methoxyphenyl)-3-pyridin-4-yl- acrylonitrile and 0.9 mL (18.6 mmol) hydrazine hydrate in 30 mL of ethanol was heated to reflux for 6.5 hours. The mixture was allowed to cool to room temperature and solvent was removed by evaporation. Aqueous sodium bicarbonate was stirred into the residue, and the resulting solid was collected by filtration. The solid was washed with water, then dried under vacuum to provide 0.92 g (94%) of 4-[3-methoxyphenyl]-5-pyridin-4-yl-1 H-pyrazo(-3-amine. MS 267.2 [M+H].
  • Step 1 3-acetyl-N,N-dimethylbenzenesulfonamide.
  • Dimethylamine hydrochloride (933 mg, 11.4 mmol, 1.25 eq) and N,N-diisopropylethyIamine (2.4 mL, 13.7 mmol, 1.5 eq) were added and the reaction was stirred at room temperature 48 hours.
  • Step 3 3-[3-(3-hydroxyphenyl)-2-pyridin-4-ylpyrazolo[1 ,5-a]pyrimidin-7-yl]-N,N- dimethylbenzenesulfonamide
  • Step 1 N,N-dimethyl-3-(2-(pyridin-4-yl)pyrazolo[1 ,5-a]pyrimidin-7- yl)benzenesulfonamide
  • Step 2 3-(3-iodo-2-(pyridin-4-yl)pyrazolo[1 ,5-a]pyrimidin-7-yl)-N,N- dimethylbenzenesulfonamide
  • N,N-dimethyl-3-(2-(pyridin-4-yl)pyrazolo[1 ,5-a]pyrimidin-7- yl)benzenesulfonamide (238 mg, 0.63 mmol) in chloroform (23 mL) was added N- iodosuccinimide (282 mg, 1.25 mmol, 2 eq).
  • N-iodosuccinimide (282 mg, 1.25 mmol, 2 eq).
  • the reaction mixture was stirred at room temperature 1.5 hours then treated with additional N-iodosuccinimide (563 mg, 4 eq).
  • the reaction mixture was stirred at room temperature 3 additional hours, diluted with chloroform, washed (2 x, saturated sodium thiosulfate solution), dried over magnesium sulfate, filtered and then concentrated.
  • Step 3 3-(3-(1 H-indazol-4-yl)-2-(pyridin-4-yl)pyrazolo[1 ,5-a]pyrimidin-7-yl)-N,N- dimethylbenzenesulfonamide
  • reaction flask was evacuated and filled with nitrogen three times, then heated at 80° C overnight.
  • the reaction mixture was cooled, diluted with methylene chloride, washed (2 x, with saturated sodium bicarbonate solution), then dried over sodium sulfate, filtered and concentrated.
  • Step 1 3-acetyl-N-[2-(dimethylamino)ethyl]-N-methyIbenzenesulfonamide
  • Step 2 N-[2-(dimethylamino)ethyl]-3-[(2E)-3-(dimethylamino)prop-2-enoyl]-N- methylbenzenesulfonamide
  • step 2 1.69 g (5 mmol) of N-[2-(dimethylamino)ethyI]-3- [(2E)-3-(dimethylamino)prop-2-enoyl]-N-methylbenzenesulfonamide was prepared from the reaction of 1.42 g (5 mmol) of 3-acetyl-N-[2-(dimethylamino)ethyl]-N-methylbenzenesulfonamide with N,N-dimethylformamide dimethyl acetal. MS [M + H] 340.3.
  • Step 3 N-[2-(dimethyiamino)ethyl]-3-[3-(3-methoxyphenyl)-2-pyridin-4- ylpyrazolo[1 ,5-a]pyrimidin-7-yl]-N-methylbenzenesulfonamide
  • N-[2-(dimethylamino)ethyl]-3-[3-(3-methoxyphenyl)- 2-pyridin-4-ylpyrazolo[1 ,5-a]pyrimidin-7-yl]-N-methylbenzenesulfonamide 52% yield
  • N-[2-(dimethylamino)ethyl]-3-[(2E)-3-(dimethylamino)prop-2-enoyl]- N-methylbenzenesulfonamide 4-[3-methoxyphenyl]-5-pyridin-4-yl-1 H-pyrazol-3-amine.
  • Step 2 4-Bromo-1 ,3-dihydro-benzoimidazol-2-one
  • Step 3 4-(4,4,5,5-Tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-1 ,3-dihydro-benzoimidazol- 2-one
  • Step 4 N,N-dimethyl-3-(3-(2-oxo-2,3-dihydro-1 H-benzo[d]imidazol-4-yl)-2-(pyridin-4- yl)pyrazolo[1 ,5-a]pyrimidin-7-yl)benzenesulfonarnide
  • reaction was irradiated in the microwave at 100 0 C for 30 minutes. Additional catalyst was added (PdCI 2 (dppf) 11.6 mg, 0.014 mmol) and reacted again at 100° C for 30 minutes. The reaction mixture was cooled, diluted with methylene chloride, washed (2 x, saturated sodium bicarbonate solution), dried over sodium sulfate, filtered and concentrated. The crude reaction mixture was purified by column chromatography (eluted with 10% acetone in methylene chloride then 5% methanol in methylene chloride).
  • Step 4 7-Methoxy-4-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-1 H-indazole
  • Step 5 3-[3-(7-Methoxy-1 H-indazol-4-yl)-2-pyridin-4-ylpyrazolo[1 ,5-a]pyrimidin-7-yl]- N,N-dimethylbenzenesulfonamide
  • Step 1 3-acetyl-N-[2-(dimethylamino)ethyl]benzenesulfonamide
  • Step 2 N-[2-(dimethylamino)ethyl]-3-[(2E)-3-(dimethylamino)prop-2- enoyljbenzenesulfonamide
  • Step 3 N-[2-(dimethylamino)ethyl]-3-[3-(3-methoxyphenyl)-2-pyridin-4- ylpyrazolo[1 ,5-a]pyrimidin-7-yl]benzenesulfonamide
  • N-[2-(dimethylamino)ethyl]-3-[3-(3-methoxyphenyl)- 2-pyridin-4-ylpyrazolo[1 ,5-a]pyrimidin-7-yl]benzenesulfonamide (65% yield) was prepared by the reaction of N-[2-(dimethylamino)ethyl]-3-[(2E)-3-(dimethylamino)prop-2- enoyljbenzenesulfonamide with 4-[3-methoxyphenyl]-5-pyridin-4-yl-1 H-pyrazol-3-amine. MS [M + H] 529.2.
  • Step 1 3-acetyl-N-[3-(dimethylamino)propyl]benzenesulfonamide
  • Step 2 3-[(2E)-3-(dimethylamino)prop-2-enoyl]-N-[3(dimethylamino)propyl]- benzenesulfonamide
  • step 2 3-[(2E)-3-(dimethylamino)prop-2-enoyl]-N- [3(dimethylamino)propyl]-benzenesulfonamide was prepared from the reaction of 3-acetyl-N-[3- (dimethylamino)propyl]benzenesulfonamide with 1 ,1-di-tert-butoxy-N,N-dimethylmethanamine in quantitative yield. MS [M + H] 340.2.
  • Step 3 N-[3-(dimethylamino)propyl]-3-[3-(3-methoxyphenyl)-2-pyridin-4- ylpyrazolo[1 ,5-a]pyrimidin-7-yl]benzenesulfonamide
  • N-[3-(dimethylamino)propyl]-3-[3-(3-methoxyphenyI)- 2-pyridin-4-ylpyrazolo[1 ,5-a]pyrimidin-7-yl]benzenesulfonamide 75% yield was prepared by the reaction of 3-[(2E)-3-(dimethylamino)prop-2-enoyl]-N-[3(dimethylamino)propyl]- benzenesulfonamide with 4-[3-methoxyphenyl]-5-pyridin-4-yl-1 H-pyrazol-3-amine.
  • N-[2-(dimethylamino)ethyl]-3-[3-(3-hydroxyphenyl)-2-pyridin- 4-ylpyrazolo[1 ,5-a]pyrimidin-7-yl]-N-methylbenzenesulfonamide (85% yield) was prepared from the reaction of N-[2-(dimethylamino)ethyl]-3-[3-(3-methoxyphenyl)-2-pyridin-4-ylpyrazolo[1 ,5- a]pyrimidin-7-yl]-N-methylbenzenesulfonamide with boron tribromide.
  • Example 16 N-(3-hydroxypropyI)-3-[3-(3-rnethoxyphenyl)-2-pyridirt-4- ylpyrazolo[1 ,5-a]pyrimidin-7-yl]benzenesulfonamide
  • Step 1 3-acetyI-N-(3-hydroxypropyI)benzenesulfonamide
  • Step 2 3-[(2E)-3-(dimethylamino)prop-2-enoyI]-N-(3-hydroxypropyI)- benzenesulfonamide
  • step 2 3-[(2E)-3-(dimethy!amino)prop-2-enoy!]-N-(3- hydroxypropy!-benzenesu!fonamide was prepared from the reaction of 3-acetyI-N-(3- hydroxypropy!)benzenesu!fonamide with 1 ,1-di-tert-butoxy-N,N-dimethyImethanamine in 86% yield. MS [M + H] 313.2.
  • Step 3 N-(3-hydroxypropyI)-3-[3-(3-methoxyphenyI)-2-pyridin-4-yIpyrazoIo[1 ,5- a]pyrimidin-7-yI]benzenesulfonamide
  • N-(3-hydroxypropyl)-3-[3-(3-methoxyphenyl)-2- pyridin-4-ylpyrazolo[1 ,5-a]pyrimidin-7-yl]benzenesulfonamide (4% yield) was prepared by the reaction of 3-[(2E)-3-(dimethylamino)prop-2-enoyl]-N-(3-hydroxypropyl)-benzenesulfonamide with 4-[3-methoxyphenyl]-5-pyridin-4-yl-1H-pyrazol-3-amine. MS [M + H] 516.3.
  • Step 1 3-Acetyl-N-(3-dimethylaminopropyl)-N-methyl-benzenesulfonamide
  • Step 2 3-f(2E)-3-(dimethylamino)prop-2-enoyl]-N-f3-(dimethylamino)propyl]-N- methylbenzenesulfonamide
  • step 2 3-[(2E)-3-(dimethylamino)prop-2-enoyl]-N-[3- (dimethylamino)propyl]-N-methylbenzenesulfonamide was prepared from the reaction of 3- acetyl-N-(3-dimethylaminopropyl)-N-methyl-benzenesulfonamide with N,N-dimethylformamide dimethyl acetal in quantitative yield. MS [M + H] 354.3.
  • Step 3 N-[3-(dimethylamino)propyl]-3-[3-(3-methoxyphenyl)-2-pyridin-4- ylpyrazolof1 ,5-a]pyrimidin-7-yl]-N-methylbenzenesulfonamide
  • N-[3-(dimethylamino)propyl]-3-[3-(3-methoxyphenyl)- 2-pyridin-4-ylpyrazolo[1 ,5-a]pyrimidin-7-yl]-N-methylbenzene-sulfonamide 95% yield
  • 3-f(2E)-3-(dimethylamino)prop-2-enoyl]-N-[3-(dimethylamino)propyl]- N-methylbenzene-sulfonamide 4-[3-methoxyphenyl]-5-pyridin-4-yl-1 H-pyrazol-3-amine.
  • step 3 3-[3-(4-chloro-3-methoxyphenyl)-2-pyridin-4- ylpyrazolo[1 ,5-a]pyrimidin-7-yl]-N,N-dimethylbenzenesulfonamide (31% yield) was prepared by the reaction of 3-(3-(dimethylamino)acryloyl)-N,N-dimethylbenzenesulfonamide with 4-(4-chloro- 3-methoxyphenyl)-5-pyridin-4-yl-1H-pyrazol-3-amine. MS [M + H] 520.0.
  • step 3 3-[3-(4-chloro-3-hydroxyphenyl)-2-pyridin-4- ylpyrazolo[1 ,5-a]pyrimidin-7-yl]-N,N-dimethylbenzenesulfonamide (60% yield) was prepared by the reaction of 3-(3-(dimethylamino)acryloyl)-N,N-dimethylbenzenesulfonamide with 5-(3-amino- 5-pyridin-4-yl-1 H-pyrazol-4-yl)-2-chlorophenol. MS [M + H] 506.2.
  • Step 1 3-acetyl-N-[3-(1 H-imidazol-1-yl)propyl]benzenesulfonamide
  • Step 2 3-[(2E)-3-(Dimethylamino)prop-2-enoyl]-N-[3-(1 H-imidazol-1-yl)propyl]-N- methylbenzenesulfonamide Using the procedure of Example 1 , step 2, 3-[(2E)-3-(dimethylamino)prop-2-enoyl]-N-[3-(1H- imidazol-1-yl)propyl]-N-methylbenzenesulfonarnide was prepared from the reaction of 3-acetyl- N-[3-(1 H-imidazol-1-yl)propyl]benzenesulfonamide with N,N-dimethylformamide dimethyl acetal in 97% yield. MS [M + H] 377.2.
  • Step 3 N-[3-(1 H-imidazol-1-yl)propyl]-3-[3-(3-methoxyphenyl)-2-pyridin-4- ylpyrazolo[1 ,5-a]pyrimidin-7-yl]-N-methylbenzenesulfonamide
  • N-[3-(1 H-imidazol-1-yl)propyl]-3-[3-(3- methoxyphenyl)-2-pyridin-4-ylpyrazolo[1 ,5-a]pyrimidin-7-yl]-N-methylbenzene-sulfonamide 98% yield
  • Step 1 3-acetyl-N-(2-(diethylamino)ethyl)-N-ethylbenzenesulfonamide
  • Step 2 N-(2-(diethylamino)ethyl)-3-(3-(dimethylamino)acryloyl)-N- ethylbenzenesulfonamide
  • N-(2-(diethylamino)ethyl)-3-(3- (dimethylamino)acryloyl)-N-ethylbenzenesulfonamide was prepared from the reaction of 3- acetyl-N-(2-(diethylamino)ethyl)-N-ethylbenzenesulfonamide with N,N-dimethylformamide 5 dimethyl acetal in 90% yield, MS [M + H] 382.1.
  • Step 3 N-[2-(diethylamino)ethyl]-N-ethyl-3-[3-(3-methoxyphenyl)-2-pyridin-4- ylpyrazolo[1 ,5-a]pyrimidin-7-yl]benzenesulfonarnide
  • N-[2-(diethylamino)ethyl]-N-ethyl-3-[3-(3- methoxyphenyl)-2-pyridin-4-ylpyrazolo[1 ,5-a]pyrimidin-7-yl]benzenesulfonamide (73% yield)0 was prepared by the reaction of N-(2-(diethylamino)ethyl)-3-(3-(dimethylamino)acryloyl)-N- ethylbenzenesulfonamide with 4-[3-methoxyphenyl]-5-pyridin-4-yl-1 H-pyrazol-3-amine. MS [M + H] 585.5.
  • the compounds of this invention are therefore useful as antineoplastic agents.
  • these compounds are useful in treating, inhibiting the growth of, or eradicating neoplasms such as those of the breast, kidney, bladder, thyroid, mouth, larynx, esophagus, stomach, colon, ovary, lung, pancreas, liver, prostate and skin.
  • Compounds of the invention are useful as anti-inflammation agents and possess activity against inflammation associated with Raf kinases.
  • Raf Kinase inhibitors for B-Raf kinase, mutant B-Raf kinase and C-Raf kinase, which are associated with inhibiting growth of tumor cells containing oncogenic forms of Receptor Yrosine Kinases, K-Ras and Raf kinases.
  • B-RAF KINASE Reagents: Flag/GST-tagged recombinant human B-Raf produced in Sf9 insect cells, human non-active Mek-1-GST (recombinant protein produced in E. coli); and a phospho-MEK1 specific poly-clonal Ab from Cell Signaling Technology (Cat. #9121).
  • B-Rafl Kinase Assay Procedure B-Raf-1 is used to phosphorylate GST-MEK1. MEK1 phosphorylation is measured by a phospho-specific antibody (from Cell Signaling Technology, Cat. #9121) that detects phosphorylation of two serine residues at positions 217 and 221 on MEKL
  • Assay Dilution Buffer 20 mM MOPS, pH 7.2, 25 mM ⁇ -glycerol phosphate, 5mM EGTA, 1 mM sodium orthovanadate, 1mM dithiothreitol, 0.01% Triton X-100.
  • Magnesium/ATP Cocktail ADB solution (minus Triton X-100) plus 200 ⁇ M cold ATP and 40 mM magnesium chloride.
  • Active Kinase Active B-Raf: Used at 0.2 nM per assay point. 5.
  • Non-active GST-MEK1 Used at 2.8 nM final concentration).
  • C-Raf kinase was purchased from Upstate, Lake Placid, NY and used at a concentration of 0.215 nM per assay point.
  • B-Raf IC 50 determinations were performed on compounds of formula A from single point assays with > 80 % inhibition.
  • IC 50 determinations - Typically the B-Raf assay was run at compound concentrations from 1 ⁇ M to 3 nM or 0.1 ⁇ M to 300 pM in half log dilutions.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention porte sur des pyrazolo[1,5-a]pyrimidines substituées par phénylsulfonamide. Les composés de l'invention inhibent de façon sélective l'activité Raf kinase et sont utiles pour le traitement de troubles associés avec des Raf kinases. Formule (I)
PCT/US2009/035243 2008-02-29 2009-02-26 Pyrazolo[1,5-a]pyrimidines substituées par phénylsulfonamide, leurs procédés de préparation et leurs utilisations WO2009111260A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US6767008P 2008-02-29 2008-02-29
US61/067,670 2008-02-29

Publications (1)

Publication Number Publication Date
WO2009111260A1 true WO2009111260A1 (fr) 2009-09-11

Family

ID=40626779

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2009/035243 WO2009111260A1 (fr) 2008-02-29 2009-02-26 Pyrazolo[1,5-a]pyrimidines substituées par phénylsulfonamide, leurs procédés de préparation et leurs utilisations

Country Status (1)

Country Link
WO (1) WO2009111260A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9408885B2 (en) 2011-12-01 2016-08-09 Vib Vzw Combinations of therapeutic agents for treating melanoma
WO2018146253A1 (fr) 2017-02-10 2018-08-16 INSERM (Institut National de la Santé et de la Recherche Médicale) Procédés et compositions pharmaceutiques pour le traitement de cancers associés à l'activation de la voie mapk
WO2019133810A1 (fr) 2017-12-28 2019-07-04 Tract Pharmaceuticals, Inc. Systèmes de culture de cellules souches pour cellules souches épithéliales colonnaires, et leurs utilisations
CN115969980A (zh) * 2022-12-30 2023-04-18 深圳开悦生命科技有限公司 Rna解旋酶dhx33抑制剂在制备用于治疗胃癌的药物中的应用
JP2025505553A (ja) * 2022-02-15 2025-02-28 ノヴォ ノルディスク アー／エス ピラゾロピリミジン、それらを含む組成物、およびその使用

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060063784A1 (en) * 2004-09-17 2006-03-23 Wang Yanong D Method of using substituted pyrazolo [1,5-a] pyrimidines
WO2006084015A2 (fr) * 2005-02-04 2006-08-10 Genentech, Inc. Composes inhibiteurs de raf et procedes

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060063784A1 (en) * 2004-09-17 2006-03-23 Wang Yanong D Method of using substituted pyrazolo [1,5-a] pyrimidines
WO2006084015A2 (fr) * 2005-02-04 2006-08-10 Genentech, Inc. Composes inhibiteurs de raf et procedes

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ALBINI, A.; SPORN, M.B.: "The tumor microenvironment as a target for chemoprevention", NATURE REVIEWS CANCER, vol. 7, February 2007 (2007-02-01), pages 139 - 147, XP002529722 *
SRIDHAR, S.S. ; HEDLEY, D. ; SIU, L.L.: "Raf kinase as a target for anticancer therapeutics", MOLECULAR CANCER THERAPEUTICS, vol. 4, April 2005 (2005-04-01), Philadelphia (US), pages 677 - 685, XP002529721 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9408885B2 (en) 2011-12-01 2016-08-09 Vib Vzw Combinations of therapeutic agents for treating melanoma
WO2018146253A1 (fr) 2017-02-10 2018-08-16 INSERM (Institut National de la Santé et de la Recherche Médicale) Procédés et compositions pharmaceutiques pour le traitement de cancers associés à l'activation de la voie mapk
WO2019133810A1 (fr) 2017-12-28 2019-07-04 Tract Pharmaceuticals, Inc. Systèmes de culture de cellules souches pour cellules souches épithéliales colonnaires, et leurs utilisations
JP2025505553A (ja) * 2022-02-15 2025-02-28 ノヴォ ノルディスク アー／エス ピラゾロピリミジン、それらを含む組成物、およびその使用
JP7731007B2 (ja) 2022-02-15 2025-08-28 ノヴォ ノルディスク アー／エス ピラゾロピリミジン、それらを含む組成物、およびその使用
CN115969980A (zh) * 2022-12-30 2023-04-18 深圳开悦生命科技有限公司 Rna解旋酶dhx33抑制剂在制备用于治疗胃癌的药物中的应用
CN115969980B (zh) * 2022-12-30 2023-10-24 深圳开悦生命科技有限公司 Rna解旋酶dhx33抑制剂在制备用于治疗胃癌的药物中的应用

Similar Documents

Publication Publication Date Title
TWI772386B (zh) 雜芳基并[4,3-c]嘧啶-5-胺類衍生物、其製備方法及其在醫藥上的使用
TWI662026B (zh) 吡啶酮類衍生物、其製備方法及其在醫藥上的應用
WO2009108827A1 (fr) Pyrazolo[1,5-a]pyrimidines tricycliques condensées, procédés pour les préparer et leurs utilisations
JP6445684B2 (ja) Ｆｇｆｒキナーゼ阻害剤としてのインダゾール系化合物およびその製造と使用
WO2020156311A1 (fr) Inhibiteur de dérivé de pyridazine, son procédé de préparation et son utilisation
TW202110841A (zh) Ｍａｔ２ａ之雜雙環抑制劑及用於治療癌症之使用方法
TW200906834A (en) Axl kinase inhibitors
WO2013170770A1 (fr) Dérivés d'acétylène ayant une activité antitumorale
CN106187915A (zh) 具有alk与egfr双重活性的抑制剂及其制备方法和应用
WO2020001350A1 (fr) Inhibiteur r-egf, son procédé de préparation et son utilisation
JP2020015670A (ja) Ｅｎｐｐ１阻害剤及びその用途
WO2022105908A1 (fr) Inhibiteur d'egfr, son procédé de préparation et son utilisation pharmaceutique
WO2009111260A1 (fr) Pyrazolo[1,5-a]pyrimidines substituées par phénylsulfonamide, leurs procédés de préparation et leurs utilisations
WO2022095904A1 (fr) Composé pyrazolopyridazinone, composition pharmaceutique le contenant et son utilisation
CN118221698A (zh) Kras g12d抑制剂
WO2020001351A1 (fr) Inhibiteur r-egf, son procédé de préparation et son utilisation
US20140371221A1 (en) Quinoline compound composing 1,2,4-triazine-dione and use thereof
US20090082354A1 (en) Pyrazolo[5, 1-c] [1,2,4] triazines, methods for preparation and use thereof
JP2021527071A (ja) Ｅｐａｃ阻害剤としてのチエノ［２，３−ｂ］ピリジン誘導体及びその医薬用途
CN112225742A (zh) 一种抑制vegfr活性的化合物、制备方法及应用
JP2022527279A (ja) キノリン誘導体及び癌の治療のためのその使用
TWI812302B (zh) 作為ｒｏｎ抑制劑之新穎尿素衍生物化合物
WO2014000686A1 (fr) Composé pyrimidobenzoazépine et son utilisation comme médicament antitumoral
TWI896726B (zh) 一種ｅｇｆｒ抑制劑及其製備方法和應用
EP4620957A1 (fr) Composés d'imidazo[4,5-b]pyridin-7-amine se liant à l'aurora kinase a et leurs utilisations

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 09718050

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 09718050

Country of ref document: EP

Kind code of ref document: A1