WO2009108827A1 - Pyrazolo[1,5-a]pyrimidines tricycliques condensées, procédés pour les préparer et leurs utilisations - Google Patents

Pyrazolo[1,5-a]pyrimidines tricycliques condensées, procédés pour les préparer et leurs utilisations Download PDF

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WO2009108827A1
WO2009108827A1 PCT/US2009/035393 US2009035393W WO2009108827A1 WO 2009108827 A1 WO2009108827 A1 WO 2009108827A1 US 2009035393 W US2009035393 W US 2009035393W WO 2009108827 A1 WO2009108827 A1 WO 2009108827A1
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ring
formula
pyridin
pyrazolo
carbon atoms
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Jeremy Ian Levin
George Diamantidis
Jonathan David Bloom
Christoph Wolfgang Zapf
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Wyeth
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/20—Spiro-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed systems contains four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/20—Spiro-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 fused, tricyclic pyrazolo[1 ,5-a]pyrimidines, their corresponding pharmaceutically acceptable salts and methods for their preparation and use.
  • the fused, tricyclic pyrazolo[1 ,5- a]pyrimidines inhibit growth of tumor cells, which are associated with oncogenic forms of Receptor Tyrosine Kinases, K-Ras and Raf kinases.
  • Raf is a multigene family expressing oncoprotein kinases: A-Raf, B-Raf and C-Raf (also known as Raf-1 ), as described in publications by McCubrey et al., in Leukemia, 12(12), 1903-1929 (1998); by Ikawa et al., in MoI. and Cell. Biol. 8(6), 2651-2654 (1988); by Sithanandarn et al., in Oncogene 5, 1775-1780 (1990); by Konishi et al., in Biochem. and Biophys. Res. Comm. 216(2), 526-534 (1995).
  • 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 1 16, 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 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., et al. (2002) Nature 418, 934.
  • B-Raf has been shown to be frequently mutated in various human cancers, as described by Wan et al. (2004) Cell 1 16, 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 ⁇ I0 "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 SoNt 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 RaM ) and isoformic variants that result from differential splicing of mRNA are known.
  • the invention provides a compound of formula A or of formula B:
  • R 1 is a 5-7 membered heterocyclic or heteroaryl ring, said ring comprising 1-3 heteroatoms selected from N, O and S, and said ring optionally substituted with one to four substituents selected from -J, -NO 2 , -CN, -N 3 , -CHO, -CF 3 , -OCF 3 , -R 7 , -OR 7 , -S(O) m R 7 , -NR 7 R 7 , - NR 7 S(O) m R 7 , -OR 9 OR 7 , -OR 9 NR 7 R 7 , -N(R 7 )R 9 OR 7 , -N(R 7 )R 9 NR 7 R 7 , -NR 7 C(O)R 7 , -C(O)R 7 , - C(O)OR 7 , -C(O)NR 7 R 7 , -OC(O)OR 7 , -C(O)NR 7 R 7
  • R 2 is an aryl ring, a 10-14 membered bicyclic aryl ring, or a 10-14 membered bicyclic 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 7 , -OR 7 , - S(O) m R 7 , -NR 7 R 7 , -NR 7 S(O) m R 7 , -OR 9 OR 7 , -OR 9 NR 7 R 7 , -N(R 7 )R 9 OR 7 , -N(R 7 )R 9 NR 7 R 7 , - NR 7 C(O)R 7 , -C(O)R 7 , -C(O)OR 7 , -C(O)NR 7 R 7 , -OC
  • R 3 , R 4 , R 5 , R 6 , R 11 , R 12 , R 13 , R 14 , and R 15 are independently selected from H, J, -C(O)OR 7 , - C(O)NR 7 R 7 , -NR 7 C(O)R 7 , -OR 7 , -CN, alkyl of 1-6 carbon atoms, branched alkyl of 1-8 carbon atoms, cycloalkyl ring of 3-10 carbons, aryl, 5-7 membered heterocyclic ring, 5-10 membered heteroaryl ring, said heterocyclic or heteroaryl ring comprising 1-3 heteroatoms selected from N, O and S, wherein said alkyl, branched alkyl, cycloalkyl, heterocyclic, heteroaryl and aryl rings are optionally substituted with one to four substituents selected from -J, -NO 2 , -CN, -N 3 , -CHO, - CF 3
  • R 7 is independently H, or is independently selected from alkyl of 1-6 carbon atoms, branched alkyl of 1-8 carbon atoms, c/s-alkenyl of 2-6 carbon atoms, a frans-alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, an aryl ring, and a 5-10 membered heteroaryl ring, optionally substituted with one to four substituents selected from -J, -NO 2 , -CN, -N 3 , -CHO, -CF 3 , -OCF 3 , - R, -OR, -S(O) m R, -NRR, -NRS(O) m R, -OR 9 OR, -OR 9 NRR, -N(R)R 9 OR, -N(R)R 9 NRR, - NRC(O)R, -C(O)R, -C(O)OR, -C(O)
  • R 8 is a divalent group independently selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, aryl, heteroaryl, cycloalkyl, and cycloheteroalkyl;
  • R 9 is independently a divalent alkyl group of 2-6 carbon atoms
  • R 10 is independently selected from a cycloalkyl ring of 3-10 carbons, a bicycloalkyl ring of 3-10 carbons, an aryl ring, a 5-7 membered heterocyclic ring, a 5-7 membered heteroaryl ring, each heterocyclic ring or heteroaryl ring comprising 1-3 heteroatoms selected from N, O and S, and a heteroaryl ring fused to one to three aryl or heteroaryl rings; wherein any of the aryl, cycloalkyl, heterocyclic or heteroaryl rings is optionally substituted with one to four substituents selected from -H, -aryl, -CH 2 -aryl, -NH-aryl, -O-aryl, -S(O) m -aryl, -J, -NO 2 , -CN, -N 3 , -CHO, -CF 3
  • J is fluoro, chloro, bromo, or iodo
  • X is N, or C-R 11 ;
  • Y is N, or C-R 13 ;
  • n is an integer of 0-2;
  • Z is a divalent group independently selected from a bond, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, O, and -NR 7 .
  • the present invention also provides a pharmaceutical composition
  • 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 compounds or chemotherapeutic agents, and a pharmaceutically acceptable carrier.
  • the present invention provides a method for making a compound of formula A or of formula B:
  • a method for making a compound of formula A or formula B comprising the step of reacting a compound of formula A or formula B with a diol in the presence of an acid, wherein R 4 and R 5 together form a carbonyl in a compound of formula A or formula B.
  • the present invention also provides a method for making a compound of formula A or of formula B and pharmaceutically acceptable salts thereof; comprising the steps of: (a) reacting an enaminone of formula 2 with an aminopyrazole of formula 3a:
  • the present invention provides additional independent steps of separating compounds of formula 4 and 5 prior to the halogenation step, separating compounds of formula 6 and 7 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 present invention also provides intermediate compounds of formula 10 or formula 11 :
  • the resulting aminopyrazoles prepared from the intermediates provide an alternative method for preparing an alternative method for making compounds of formula A and of formula B.
  • 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, B-Raf kinase mutants, 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 methods of treating cancer 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 1-8 carbon atoms, including straight-chain alkyl groups, and branched-chain alkyl groups. In one embodiment, a straight chain or branched chain alkyl comprises 1-6 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 3-8 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 (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.
  • heteroaryl examples include 3- pyridinyl, 4-pyridinyl, 1-H-indazol-4-yl, or indol-1-yl.
  • the heteroaryl group may be optionally substituted.
  • the heteroaryl group may be substituted by an oxo substituent meaning one of the ring carbon atoms is part of a carbonyl group.
  • heterocyclic can be used interchangeably to refer to a stable, saturated or partially unsaturated monocyclic or multicyclic heterocyclic ring system, including a spirocyclic and bridged heterocyclic ring system, e.g. having from 5 to 10 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.
  • fused, tricyclic pyrazolo[1 ,5-a]pyrimidines refers to a fused three ring system, wherein the ring fused to the pyrazolo[1 ,5-a]pyrimidine ring comprises a cycloalkyl, or heterocyclyl ring.
  • fused, spirotricyclic pyrazolo[1 ,5-a]pyrimidines refers to a fused three ring system wherein the ring fused to the tricyclic pyrazolo[1 ,5-a]pyrimidine ring comprises a spirocyclic ring. Suitable examples of such ring systems are provided in the Examples section of the specification.
  • bicyclic aryl ring or heteroaryl ring refers to a ring framework of formula
  • the symbol I ⁇ 7 —) / refers to a 5-7 membered heteroaryl ring containing 1-3 heteroatoms selected from N, O or S.
  • Het refers to a 6-membered heteroaryl ring containing 1-2 nitrogen atoms. Either bridged bicyclic heteroaryl ring is substituted with one to four substituents, each substituent independently selected from -J, -NO 2 , -CN, -N 3 , -CHO, -CF 3 , -OCF 3 , -R 7 , -OR 7 , -S(O) m R 7 , -NR 7 R 7 , and -NR 7 S(O) m R 7 .
  • 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 of formula B:
  • R 1 - R 15 , X, Y and Z are as defined above.
  • R 1 examples include, but are not limited to, thienyl, furyl, indolyl, pyrrolyl, thiophenyl, benzofuryl, benzothiophenyl, quinolyl, isoquinolyl, imidazolyl, thiazolyl, oxazolyl, pyridinyl, pyrrolidyl, oxolanyl, thiolanyl, piperidinyl, piperazinyl, thiazolyl, triazolyl, pyrazolyl, pyrazinyl, pyridazinyl, pyrimidinyl, and morpholinyl.
  • 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 7 , -OR 7 , -S(O ) m R 7 , - NR 7 R 7 , -NR 7 S(O) m R 7 , -OR 9 OR 7 , -OR 9 NR 7 R 7 , -N(R 7 )R 9 OR 7 , -N(R 7 )R 9 NR 7 R 7 , -NR 7 C(O)R 7 , - C(O)R 7 , -C(O)OR 7 , -C(O)NR 7 R 7 ,
  • R 2 examples include, but are not limited to, halogen substituted phenyl, C 1 -C 6 alkylsulfonamido substituted phenyl, carbamate substituted phenyl, C 1 -C 6 alkoxy substituted phenylcarbamate, benzonitrile, hydroxyl substituted benzonitrile, C 1 -C 6 alkoxy substituted benzonitrile, hydroxyphenyl (phenol), C 1 -C 6 alkyl substituted hydroxyphenyl (phenol), halogen substituted hydroxyphenyl (phenol), C 1 -C 6 alkoxyphenyl, halogen substituted C 1 -C 6 alkoxyphenyl, hydroxypyridinyl, C 1 -C 6 alkoxypyridinyl, amino phenyl (aniline), halogen substituted amino phenyl (aniline), hydroxyl substituted amino phenyl (aniline), formamide substituted phenyl, hydroxyl substituted
  • R 2 examples include, but are not limited to, indolyl, benzotriazolyl, oxindolyl, benzothiazolonyl and benzooxazolonyl.
  • the monocyclic aryl ring and the bicyclic heteroaryl ring may be substituted to the pyrazolo[1 ,5-a]pyrimidine ring framework in any acceptable position.
  • R 2 is an aryl ring or a bicyclic ring of formula
  • ⁇ y 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 7 , -OR 7 , -S(0) m R 7 , -NR 7 R 7 , -NR 7 S(O) m R 7 , -OR 9 OR 7 , - OR 9 NR 7 R 7 , -N(R 7 )R 9 OR 7 , -N(R 7 )R 9 OR 7 , -N(R 7 )R 9 NR 7 R 7 , -NR 7 C(O)R 7 , -C(O)R 7 , -C(O)OR 7 , -C(O)NR 7 R 7 , -OC(O)R 7 , -OC(O)
  • 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 , -OCF 3 , -R 7 , -OR 7 , -S(O) m R 7 , -NR 7 R 7 , -NR 7 S(O) m R 7 , -OR 9 OR 7 , -OR 9 NR 7 R 7 , -N(R 7 )R 9 OR 7 , - N(R 7 )R 9 NR 7 R 7 , -NR 7 C(O)R 7 , -C(O)R 7 , -C(O)OR 7 , -C(O)NR 7 R 7 , -OC(O)R 7 , -OC(O)OR 7 , - OC(O)NR 7 R 7 , NR 7 C
  • 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, CrC 6 alkoxy substituted benzonitrile, hydroxyphenyl, C-i-C ⁇ alkyl substituted hydroxyphenyl, halogen substituted hydroxyphenyl, d-C 6 alkoxyphenyl, halogen substituted CrC 6 alkoxyphenyl, hydroxypyridinyl, C-i-C ⁇ alkoxypyridinyl, amino phenyl, halogen substituted amino phenyl, hydroxyl substituted amino phenyl, formamide substituted phenyl, hydroxyl substituted phenylformamide, C-i-C ⁇ alkoxy substituted phenylformamide, C-i-C
  • X is N and R 4 and R 12 join together with the atoms to which they are attached forming a ring.
  • Y is N and R 6 and R 14 join together with the atoms to which they are attached, forming a ring.
  • X is C-R 11 and R 6 and R 11 join together with the atoms to which they are attached, forming a ring.
  • X is C- R 11 and R 4 and R 5 join together with the atoms to which they are attached, forming a ring.
  • 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.
  • cyclic ketones of formula 1 are reacted with acetals of N,N- dialkylformamides or acetals of ⁇ /, ⁇ /-dialkylacetamide, carried out in an inert solvent or without a solvent to provide enaminones of formula 2.
  • compounds of the invention are available through reacting compounds of formula A or formula B with diols in the presence of acids such as mineral acids, organic acids including toluenesulfonic acid, or Lewis acids.
  • acids such as mineral acids, organic acids including toluenesulfonic acid, or Lewis acids.
  • R 2 is a methoxyphenyl moiety, or other masked phenol
  • the corresponding phenol is provided by reaction with pyridine hydrochloride at elevated temperature, or boron tribromide.
  • Compounds of the invention may also be synthesized according to the route shown in Scheme 2.
  • an enaminone of formula 2 with an aminopyrazole of formula 3a 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, provides compounds of formula 4 and 5.
  • One or both of compounds of formula 4 and 5 are halogenated to afford one or both of corresponding halo-pyrazole compounds of formula 6 and 7, using ⁇ /-halosuccininmides at room temperature to 50° C in chlorinated hydrocarbon solvents.
  • Compounds 4 and 5 can be separated prior to a halogenating step, using chromatography or using recrystallization.
  • the mixture of compounds of formula 4 and 5 can be halogenated under these conditions with subsequent separation of compounds of formula 6 and 7.
  • One or both of the halopyrazoles compounds of formula 6 and 7 are subjected to palladium catalyzed, Suzuki coupling reactions using aryl or heteroaryl boronic acids or corresponding boronate esters to provide one or both of compounds of the invention.
  • Various 3-amino-4- pyrazoles are disclosed in U.S. Patent Nos. 4,236,005; 4,281 ,000; 4,521 ,422; 4,626,538; 4,654347; and 4,900,836.
  • the condensation reaction of substituted acetonitriles of formula 9, wherein R 2 is as defined above or hydrogen, with substituted esters of formula 8 can be carried out in the presence of a base such as, but not limited to sodium ethoxide, in a suitable solvent such as ethanol to provide intermediate compounds of formula 10.
  • a base such as, but not limited to sodium ethoxide
  • Intermediate compounds of formula 10 can subsequently be reacted with hydrazine hydrate in a suitable solvent such as ethanol to provide aminopyrazole compounds of formula 3 where R 1 and R 2 are defined above.
  • reaction with phosphorus oxychloride at elevated temperatures, typically at reflux provides intermediate compounds of formula 11.
  • Intermediate compounds of formula 1 1 can be converted to substituted aminopyrazole compounds of formula 3 by subsequent reaction with hydrazine hydrate in a suitable solvent such as ethanol.
  • Substituted esters of formula 8 and substituted acetonitrile compounds of formula 9 can be obtained from commercial sources or readily prepared by numerous literature procedures by those skilled in the art.
  • Aminopyrazole compounds of formula 3 can also be prepared from an alternative route starting from aldehyde compounds of formula 12, as shown in Scheme 3. In the first step of this alternative route, aldehyde compounds of formula 12, which are commercially available or can be prepared by known methods, are reacted typically at room temperature with phosphonate compounds of formula 13 (which can be prepared using the procedure described in Tet.
  • the crude 3-chloropropenals are treated with hydroxylamine in a suitable solvent such as dimethylformamide, typically at room temperature, to provide the corresponding 3-chloropropenal oximes, which are then treated with a suitable dehydrating agent such as, but not limited to for example, phosphorus oxychloride, typically at room temperature, to give the corresponding 3-chloroacrylonitriles.
  • a suitable dehydrating agent such as, but not limited to for example, phosphorus oxychloride, typically at room temperature
  • the intermediate 3- chloroacrylonitriles can then be converted into the desired substituted aminopyrazole compounds of formula 3 by subsequent reaction with hydrazine hydrate in a suitable solvent such as ethanol.
  • the present invention also provides another method for making a compound of formula A or of formula B comprising the steps of using intermediates of formula 10 or an alternative aminopyrazole intermediate of formula 11.
  • a condensation reaction of substituted acetonitriles of formula 9, wherein R 2 is as defined above or hydrogen, with substituted esters of formula 8 can be carried out in the presence of a base such as, but not limited to sodium ethoxide, in a suitable solvent such as ethanol to provide intermediate compounds of formula 10.
  • Intermediate compounds of formula 10 can subsequently be reacted with hydrazine hydrate in a suitable solvent such as ethanol to provide aminopyrazole compounds of formula 3 where R 1 and R 2 are herein before defined.
  • intermediate compounds of formula 10 it is necessary to first react with phosphorus oxychloride at elevated temperatures, typically at reflux, to provide intermediate compounds of formula 11.
  • Intermediate compounds of formula can be converted to substituted aminopyrazole compounds of formula 3 by subsequent reaction with hydrazine hydrate in a suitable solvent such as ethanol.
  • the present invention provides a method for making a compound of formula A or of formula B:
  • one method of preparing compounds of formula A or formula B, where R 4 and R 5 together form a carbonyl comprises the step of reacting the compounds of formula A or formula B with diols in the presence of acids such as mineral acids, organic acids including toluenesulfonic acid, or Lewis acids.
  • acids such as mineral acids, organic acids including toluenesulfonic acid, or Lewis acids.
  • the present invention provides a method for making a compound of formula A or of formula B:
  • Exemplary compounds of formula A or of formula B 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, myri
  • 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.
  • 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.
  • the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • 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 of 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,
  • Example 1 Ethyl 3-(3-hydroxyphenyl)-2-pyridin-4-yl-7,8,9,10-tetrahydro-6H-6,9- epiminocyclohepta[e]pyrazolo[1 ,5-a]pyrimidine-12-carboxylate
  • Step 1 To a solution of 2.Og (0.010 mmol) of N-carbethoxy-4-tropinone was added 9 ml. of ⁇ /, ⁇ /-dimethylformamide dimethyl acetal and the resulting mixture was heated to reflux for 12 hours, then cooled to room temperature and concentrated in vacuo and used without further purification.
  • Step 2 To 1.825 g (7.24 mmol) of the enaminone from Step 1 in 25 mL of acetic acid was added 1.20 g (7.50 mmol) of 5-pyridin-4-yl-2H-pyrazol-3-ylamine and the resulting mixture was heated at 85-95° C for 4 hours, then let cool to room temperature and concentrated in vacuo.
  • Step 3 To a mixture of 0.246g (0.705 mmol) of ethyl 2-pyridin-4-yl-7,8,9,10- tetrahydro- ⁇ H- ⁇ -epiminocyclohepta ⁇ pyrazoloti ⁇ -alpyrimidine- ⁇ -carboxylate from Step 2 in 30 mL of chloroform was added 1.03 g (4.58 mmol) of N-iodosuccinimide and the resulting mixture was stirred at room temperature for 4 hours and then diluted with chloroform/methanol (10:1 ). The organics were washed with sodium bisulfite solution and then water, dried over sodium sulfate, filtered and the concentrated in vacuo.
  • Step 4 To a solution of 0.193g (0.406 mmol) of ethyl 3-iodo-2-pyridin-4-yl-7,8,9,10- tetrahydro- ⁇ H- ⁇ . ⁇ -epiminocycloheptateJpyrazoloti . ⁇ -aJpyrimidine-i 2-carboxylate (Example 1 ,
  • Step 3 in 5.4 mL of dimethoxyethane and 1.5 mL of water was added 0.1 12g (0.813 mmol) of potassium carbonate and 0.1 12g (0.813 mmol) of 3-hydroxyphenyl boronic acid.
  • the resulting mixture was degassed with a stream of nitrogen for 10 minutes and then 0.034g (0.041 mmol) of [1 ,1 '-bis(diphenylphosphino)ferrocene]dichloropalladium (II), complex with dichloromethane, was added and the resulting mixture was heated to 100° C in a sealed tube for 4 hours and then let cool to room temperature.
  • the reaction mixture was filtered, and the filtrate was extracted with chloroform/methanol (10:1 ).
  • Step 1 ⁇ -Benzenesulfonyl- ⁇ -methyl- ⁇ -aza-bicyclo ⁇ .iJoctan ⁇ -one (0.085g, 0.304 mmol), prepared according to the procedure of Takahashi, et al., Chem. Lett., (1989), 593-596, was dissolved in 1 ml. of ⁇ /, ⁇ /-dimethylformamide dimethyl acetal and heated to 100° C. After 5 hours, the solvent was removed under reduced pressure to give a brown, viscous oil.
  • Step 2 To 77 ml. of dry ethanol was added 1.93 g (83.8 mmol) of sodium metal (after removal of mineral oil with hexane) and the mixture was stirred at room temperature for 30 minutes until the metal had completely dissolved. A mixture of 9.67 g (53.74 mmol) of 4-chloro- 3-methoxy-benzeneacetonitrile and 10.38 g (75.57 mmol) of methyl isonicotinate in 10 ml. of dry ethanol was then added and the resulting brown solution was heated at reflux for 2.5 hours. After cooling, the solvent was evaporated and ice was added to the resulting mixture followed by extraction with ether. The aqueous layer was neutralized with acetic acid, cooled and diluted with water. Collection of the resulting precipitate and drying in vacuo gave 13 g (84% yield) of 2- (4-chloro-3-methoxyphenyl)-3-oxo-3-pyridin-4-ylpropanenitrile.
  • Step 3 A solution of ⁇ -benzenesulfonyl-S-dimethylaminomethylene- ⁇ -methyl- ⁇ -aza- bicyclo [3.2.1] octan-2-one (0.065g, 0.29 mmol) and 5-(3-amino-5-pyridin-4-yl-1 H-pyrazol-4-yl)- 2-chlorophenol (0.083g, 0.3 mmol) in acetic acid was heated at 100° C for 19 hours. The reaction mixture was then cooled and the solvent was removed in vacuo. The residue was diluted in ethyl acetate (10 mL) and the organics were washed with saturated aqueous sodium bicarbonate (2x5 mL) and brine (5 mL).
  • Step 1 8-Methyl-2-oxo-8-aza-bicyclo[3.2.1]octane-6-carboxylic acid methyl ester (1.7 g, 8.62 mmol), prepared according to the procedure of Sawa, et al., Bioorg. Med. Chem. Lett., 8, (1998) 647-652, was dissolved in ⁇ /, ⁇ /-dimethylformamide dimethyl acetal (25 ml.) and heated to 100° C for 5 hours. The solvent was then removed under reduced pressure to give a brown viscous oil.
  • Step 2 A solution of methyl (3Z)-3-[(dimethylamino)methylene]-8-methyl-2-oxo-8- azabicyclo[3.2.1]octane-6-carboxylate (0.167g, 0.66 mmol) and 5-(3-amino-5-pyridin-4-yl-1 H- pyrazol-4-yl)-2-chlorophenol (0.190 g, 0.66 mmol) in acetic acid (5ml_) was heated at 100 0 C for 19 hours. The reaction mixture was then cooled and the solvent was removed in vacuo.
  • Step 1 According to the procedure of Takahashi, et ai, Chem. Lett., (1989), 593-
  • Step 3 ⁇ -Benzyl- ⁇ -t ⁇ henylsulfonyO- ⁇ -azabicyclo ⁇ e.iJoctane-one (0.420 g, 1.18 mmol) was dissolved in ⁇ /, ⁇ /-dimethylformamide dimethyl acetal (25 ml.) and heated to 100° C for 7 hours. The solvent was then removed under reduced pressure to give a brown, viscous oil.
  • Step 4 A solution of 8-benzyl-3-[(dimethylamino)methylene]-6-(phenylsulfonyl)-8- azabicyclo[3.2.1]octan-2-one (0.229 g, 0.56 mmol) and 4-(4-chloro-3-methoxyphenyl)-5-pyridin- 4-yl-1 H-pyrazol-3-amine (0.184 g, 0.62 mmol), prepared according to the procedure of Example 2, Step 2, in acetic acid (5ml_) was heated at 100° C for 19 hours.
  • Step 1 To a solution of 2.Og (12.8 mmol) of 1 ,4-cyclohexanedione mono-ethylene ketal was added 9 mL of ⁇ /, ⁇ /-dimethylformamide dimethyl acetal and the resulting mixture was heated to reflux for 12 hours and then cooled to room temperature, then concentrated in vacuo and used without further purification.
  • Step 2 To 0.528 g (2.50 mmol) of the enaminone from Step 1 in 10 mL of acetic acid was added 0.4Og (2.50 mmol) of 5-pyridin-4-yl-2h-pyrazol-3-ylamine and the resulting mixture was heated at 85-95° C for 4 hours and then let cool to room temperature and concentrated in vacuo. The residue was diluted with chloroform and organics were washed with saturated sodium bicarbonate solution, then dried over sodium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate/hexanes
  • Step 3 To a mixture of 0.152g (0.494 mmol) of 2'-pyridin-4-yl-8',9'-dihydro-6'H- spiro[1 ,3-dioxolane-2,7'-pyrazolo[1 ,5-a]quinazoline] from Step 2 in 20 mL of chloroform was added 0.722g (3.208 mmol) of N-iodosuccinimide and the resulting mixture was stirred at room temperature for 4 hours and then filtered.
  • Step 4 To a solution of 0.165g (0.378 mmol) of 3'-iodo-2'-pyridin-4-yl-8',9'-dihydro- 6'H-spiro[1 ,3-dioxolane-2,7'-pyrazolo[1 ,5-a]quinazoline] from Step 3 in 5 mL of dimethoxyethane and 1.4 mL of water was added 0.104g (0.754 mmol) of potassium carbonate and 0.104g (0.756 mmol) of 3-hydroxyphenyl boronic acid.
  • Example 8 3'-(3-Methoxyphenyl)-2'-pyridin-4-yl-8',9'-dihydro-6'H-spiro[1 ,3- dioxolane-2,7'-pyrazolo[1 ,5-a]quinazoline]
  • Step 1 1 ,3-Cyclohexanedione (5.2 g, 46 mmol) and ⁇ /, ⁇ /-dimethylformamide dimethyl acetal (5.5 g, 46 mmol) were heated at 100° C for 2 hours. Upon cooling, an orange solid precipitated, which was stirred with ether (50 ml.) and collected by filtration to give 6.7 g of 2-dimethylaminomethylene-cyclohexane-1 ,3-dione as an orange powder.
  • Step 2 To 5 ml. of dry ethanol was added 0.73 g (31.84 mmol) of sodium metal (after removal of mineral oil with hexane) and the mixture was stirred at 45° C for 1 hour until the solution turned clear. A mixture of 3 g (20.38 mmol) of 3-(methoxyphenyl)acetonitrile and 3.9 g (28.66 mmol) of methyl isonicotinate in 26 ml. of dry ethanol was then added and the resulting brown solution was heated at reflux for 3 hours.
  • Step 3 4-(3-Methoxy-phenyl)-5-pyridin-4-yl-2H-pyrazol-3-ylamine (490 mg, 1.84 mmol) and 2-dimethylaminomethylene-cyclohexane-1 ,3-dione (310 mg, 1.84) were heated in acetic acid (4 mL) for 1 hour at 100° C. Upon cooling, a beige precipitate formed.
  • Step 4 3-(3-Methoxyphenyl)-2-pyridin-4-yl-8,9-dihydropyrazolo[1 ,5-a]quinazolin- 6(7H)-one (400 mg, 1.1 mmol) was dissolved in dichloromethane (20 mL) and to this solution was added ethylene glycol (1 mL), triethyl orthoformate (1 mL), and p-toluenesulfonic acid (278 mg, 1.6 mmol). A small portion of 4A sieves was then added to the reaction mixture and the reaction was stirred for 1 hour.
  • Example 1 3-(2'-Pyridin-4-yl-8',9'-dihydro-7'H-spiro[1 ,3-dioxolane-2,6'- pyrazolo[1 ,5-a]quinazolin]-3'-yl)phenol
  • Step 1 A solution of the product of Example 10, 3'-(3-methoxyphenyl)-2'-pyridin-4- yl-8',9'-dihydro-7'H-spiro[1 ,3-dioxolane-2,6'-pyrazolo[1 ,5-a]quinazoline] (150 mg, 0.35 mmol), in dichloromethane (10 mL) was cooled to 0 0 C and to this was added a 1 M solution of boron tribromide (1.7 mL, 1.7 mmol). The ice bath was removed and the orange suspension allowed to warm to room temperature and stirred for 30 minutes.
  • Step 2 3-(3-Hydroxyphenyl)-2-pyridin-4-yl-8,9-dihydropyrazolo[1 ,5-a]quinazolin- 6(7H)- one (87 mg, 0.24 mmol) was dissolved in dichloromethane (5 ml.) and to this solution was added ethylene glycol (0.25 ml_), triethyl orthoformate (0.25 ml.) and p-toluenesulfonic acid (50 mg, 1.6 mmol). To the resulting mixture was added a small portion of 4A molecular sieves and the reaction was stirred for 1 hour.
  • Step 1 A solution of 4-piperidinemethanol (5.76 g, 50.0 mmol) and triethylamine (7.30 ml_, 52.5 mmol, 1.05 equiv.) in dichloromethane (150 ml.) was cooled to 0 0 C. A solution of di-terf-butyl dicarbonate (11.46 g, 52.5 mmol, 1.05 equiv.) in dichloromethane (2O mL) was added via an addition funnel, leading to a gentle boiling of the solvent. The reaction was allowed to proceed for 16 hours during which the reaction had reached room temperature.
  • Step 2 terf-Butyl 4-(hydroxymethyl)piperidine-1-carboxylate (9.0 g, 41.9 mmol) was dissolved in dichloromethane (84 ml.) and cooled to 0° C. Dess-Martin periodinane (19.5 g, 46.0 mol) was dissolved in dichloromethane (153 ml_, 0.3 M) and added dropwise to the alcohol via addition funnel. After 3 hours, consumption of the starting material was confirmed by TLC analysis (ethyl acetate:hexanes, 3:7). The reaction was quenched by the addition of a 1 :1 mixture of sodium bicarbonate and sodium thiosulfate (200 mL).
  • Step 3 te/t-Butyl 4-formylpiperidine-i-carboxylate (4.07 g, 19.1 mmol) was dissolved in ethanol (120 ml.) to which 3-buten-2-one (1.72 ml_, 21.0 mmol, 1.1 equiv.) was added. A solution of potassium hydroxide (0.54 g, 9.55 mmol, 0.5 equiv.) in ethanol (15 ml.) was added dropwise to the reaction. The reaction was allowed to stir at 70° C over night after which the solvent was removed under reduced pressure. The residue was dissolved in an aqueous solution of sodium bicarbonate (100 ml.) and extracted three times with ethyl acetate (75 ml_).
  • Step 4 terf-Butyl 9-oxo-3-azaspiro[5.5]undec-7-ene-3-carboxylate (1.69 g, 6.37 mmol) was dissolved in ethyl acetate (86 ml.) to which palladium on charcoal (169 mg) was added. The reaction was allowed to stir under an atmosphere of hydrogen for 3 hours, after which the solids were removed by filtration through a plug of Magnesol. The filtrate was concentrated under reduced pressure to give terf-butyl 9-oxo-3-azaspiro[5.5]undecane-3- carboxylate, as a slightly yellow oil (1.57g, 92%).
  • Step 5 terf-Butyl 9-oxo-3-azaspiro[5.5]undecane-3-carboxylate (629 mg, 2.35 mmol) was heated to 1 10° C in the presence of ⁇ /, ⁇ /-dimethylformamide dimethyl acetal (0.94 ml_, 7.06 mmol, 3 equiv.). The progress of the reaction was monitored by 1 H-NMR spectroscopy by removing 3 ⁇ l_ of the reaction and diluting it into CDCI 3 .
  • Step 6 The crude terf-butyl 8-((dimethylamino)methylene)-9-oxo-3- azaspiro[5.5]undecane-3-carboxylate from Step 5 (710 mg) was dissolved in ethanol (4.5 ml.) and treated with acetic acid (1.26 ml_, 22.04 mmol) and 4-(3-methoxyphenyl)-5-pyridin-4-yl-1 H- pyrazol-3-amine (556 mg, 2.20 mmol). The mixture was stirred at 80° C for 4.5 hours, after which volatile compounds were removed under reduced pressure.
  • Examples 13a and 13b 3'-(3-Methoxyphenyl)-2'-pyridin-4-yl-8',9'-dihydro-6'H- spiro[piperidine-4,7'-pyrazolo[1 ,5-a]quinazoline] and 3'-(3-methoxyphenyl)-2'-pyridin-4-yl-5',6'- dihydro-8'H-spiro[piperidine-4,7'-pyrazolo[5, 1 -b]quinazoline]
  • 4,7'-pyrazolo[1 ,5-a]quinazoline]-1-carboxylate (150 mg, 0.29 mmol) was dissolved in dichloromethane (5 ml.) and treated with trifluoroacetic acid (0.5 ml_). After stirring for 1.5 hours at room temperature, the reaction was complete by mass spectrometric analysis. The reaction was extracted with 10% sodium carbonate (20 ml.) and the aqueous layer was washed twice with dichloromethane (10 ml_).
  • Step 1 To a solution of the product of Example 10, Step 2, 3-(3-methoxyphenyl)-2- pyridin-4-yl-8,9-dihydropyrazolo[1 ,5-a]quinazolin-6(7H)-one (496 mg, 1.34 mmol), in 5 ml. of anhydrous tetrahydrofuran was added allylmagnesium bromide (1.47 mmol, 1.47 ml. of a 1.0 M ether solution). The mixture was stirred at room temperature for 1 hour, then saturated ammonium chloride was added, and the mixture was extracted into ethyl acetate.
  • Step 2 6-Allyl-3-(3-methoxyphenyl)-2-pyridin-4-yl-6,7,8,9-tetrahydropyrazolo[1 ,5- a]quinazolin-6-ol (365 mg, 0.88 mmol) was dissolved in dichloromethane (10 ml.) and cooled to 0° C. Bromine was added dropwise until the persistence of yellow color. The ice bath was removed and the mixture was stirred for 30 minutes at room temperature. The mixture was then partitioned between ethyl acetate and water. The ethyl acetate solution was dried over magnesium sulfate, then filtered and concentrated in vacuo to give a brown oil.
  • the brown oil was purified by column chromatography eluting with 3% methanol/dichloromethane to give 410 mg of 3-(4-bromo-3-methoxyphenyl)-6-(2,3-dibromopropyl)-2-pyridin-4-yl-6,7,8,9- tetrahydropyrazolo[1 ,5-a]quinazolin-6-ol as a yellow foam.
  • Step 3 The 3-(4-bromo-3-methoxyphenyl)-6-(2,3-dibromopropyl)-2-pyridin-4-yl- 6,7,8,9-tetrahydropyrazolo[1 ,5-a]quinazolin-6-ol (300 mg, 0.46 mmol) is dissolved in anhydrous tetrahydrofuran (5 ml.) and sodium hydride (200 mg) was added. Stirring was continued until gas evolution ceased. The mixture was then partitioned between ethyl acetate and water. The ethyl acetate solution was dried over magnesium sulfate, filtered and concentrated in vacuo to give a brown oil.
  • 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-Raf 1 Kinase Assay Procedure B-RaM 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, 1 mM 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.
  • Non-active GST-MEK1 Used at 2.8 nM final concentration).
  • B-Raf IC 50 determinations were performed on compounds of formula A or formula B from single point assays with > 80 % inhibition.
  • IC50 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.
  • Compounds of formula A exhibited IC50 values rangng from 1 ⁇ M to 0.1 nM against B-Raf kinase, indicating that the compounds are effective inhibitors of B-Raf kinase.
  • Compounds of formula A are also expected to be effective inhibitors of other Raf kinases, including mutant B-Raf kinase and C-Raf kinase.

Abstract

L’invention concerne des composés de pyrazolo[1,5-a]pyrimidines tricycliques condensées de formule A ou de formule B et leurs sels de qualité pharmaceutique, qui inhibent sélectivement une activité de Raf kinase et qui sont utiles pour traiter des troubles à médiation par certaines Raf kinases.
PCT/US2009/035393 2008-02-29 2009-02-27 Pyrazolo[1,5-a]pyrimidines tricycliques condensées, procédés pour les préparer et leurs utilisations WO2009108827A1 (fr)

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