WO2021142420A1 - Inhibiteurs pyrazolo [1,5-a] pyrimidine-7 (4h)-one de dynéine - Google Patents

Inhibiteurs pyrazolo [1,5-a] pyrimidine-7 (4h)-one de dynéine Download PDF

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WO2021142420A1
WO2021142420A1 PCT/US2021/012917 US2021012917W WO2021142420A1 WO 2021142420 A1 WO2021142420 A1 WO 2021142420A1 US 2021012917 W US2021012917 W US 2021012917W WO 2021142420 A1 WO2021142420 A1 WO 2021142420A1
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mixture
alkyl
mmol
compound according
optionally substituted
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PCT/US2021/012917
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Inventor
Tarun M. Kapoor
Cristina C. SANTAROSSA
Yasuhiro Hirata
Hideki Furukawa
Yuta Tanaka
Sachie TAKASHIMA
Yayoi YOSHITOMI
Yoshiyuki Fukase
Kazuyoshi Aso
Michael A. Foley
Peter T. Meinke
Original Assignee
Kapoor Tarun M
Santarossa Cristina C
Yasuhiro Hirata
Hideki Furukawa
Yuta Tanaka
Takashima Sachie
Yoshitomi Yayoi
Yoshiyuki Fukase
Kazuyoshi Aso
Foley Michael A
Meinke Peter T
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Application filed by Kapoor Tarun M, Santarossa Cristina C, Yasuhiro Hirata, Hideki Furukawa, Yuta Tanaka, Takashima Sachie, Yoshitomi Yayoi, Yoshiyuki Fukase, Kazuyoshi Aso, Foley Michael A, Meinke Peter T filed Critical Kapoor Tarun M
Publication of WO2021142420A1 publication Critical patent/WO2021142420A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention relates to substituted pyrazolo[ 1 ,5-a/]pyrimidin-7(4H )-ones that are selective inhibitors of members of the family of AAA+ ATPases.
  • the compounds are useful as anticancer agents and as probes of the function of dynein-dependent systems.
  • AAA+ ATPases associated with diverse cellular activities
  • the AAA+ (ATPases associated with diverse cellular activities) superfamily of enzymes couples ATP hydrolysis with the generation of mechanical force to regulate diverse aspects of prokaryote and eukaryote biology.
  • These complex proteins typically form ring- shaped hexamers with a central pore, and ATP-dependent conformational changes that propagate through these molecular machines can promote DNA replication, the disassembly of membrane-fusing complexes during organelle biogenesis and vesicular transport, the trafficking of cellular cargos along microtubules, and the unfolding of proteins for proteolysis.
  • One of the subclasses of AAA+ ATPases includes dynein 1 and dynein 2.
  • Cytoplasmic dynein 1 acts in concert with dynactin and the nuclear protein NuMA to crosslink and focus the minus ends of microtubules within the mitotic spindle. These actions create the canonical fusiform shape and localize g-tubulin-containing, microtubule-nucleating complexes to the spindle poles. Cytoplasmic dynein 1 inhibition, by blocking antibodies or dominant negative constructs, disrupts mitotic spindle assembly, resulting in splayed microtubule ends and reduced g-tubulin recruitment.
  • Dynein 2 is integral in protein trafficking mechanisms within the primary cilium, where it is involved in moving macromolecules along the axoneme.
  • Intraflagellar retrograde trafficking utilizes cytoplasmic dynein 2 and the IFTA complex.
  • Dynein 2 is required for assembly and length regulation of the primary cilium and loss of its function blocks Hedgehog signaling.
  • Selective small molecule inhibitors of dyneins are therefore useful both as probes of dynein function and as potential antitumor agents.
  • the invention relates to pyrazolo -ones of formula A compound of formula I:
  • R 6 and R 7 together with the carbon to which they are attached, form a 3-, 4-, 5-, 6-, or 7-member aliphatic carbocyclyl ring, or, R 6 and R 7 are independently chosen from: H and (Ci-C3)alkyl; and n2 is zero or 1; and
  • R 8 is (Ci-Cio)hydrocarbyl
  • Q 6 is chosen from: a direct bond, -0-, -S-, -OCH2-, -CF2-, -NH-, -CoC-, -CH2NH- , and -NHSO2-;
  • Ar 2 is a monocyclic optionally substituted aryl ring or monocyclic aliphatic heterocycle, wherein the optional substituents are selected from one or more of: halogen, nitrile, (Ci-C3)alkylthio, perfluoro(Ci-C3)alkyl, -CoCH, and additionally, when Q 6 is other than -0-, methoxy.
  • the invention in another aspect, relates to a method of inhibiting the growth of a solid tumor comprising bringing said solid tumor into contact with a compound of formula I.
  • the invention in another aspect, relates to method of inhibiting intraflagellar transport in a cell comprising bringing said cell into contact with a compound of formula I.
  • the invention relates to method of blocking hedgehog signaling in a cell comprising bringing said cell into contact with a compound of formula I
  • Antitumor compounds of the invention are inhibitors of hedgehog signaling.
  • the inhibition of hedgehog signaling has been shown to be effective in vivo in treating solid tumors, particularly basal cell carcinoma, glioblastoma and medulloblastoma.
  • Rudin et ak N. Engl. J. Med 361, 1173-1178 (2009), demonstrated that administration to a human patient of GDC-0449, a small molecule inhibitor of the hedgehog pathway, resulted in regression of medulloblastoma.
  • Von Hoff et al., N. Engl. J. Med 361, 1164-1172 (2009), administered GDC-0449 to 33 human patients with basal cell carcinoma and observed clinically significant response.
  • Embodiments of the invention relate to pyrazolo[l,5-a]pyrimidin-7(4i )-ones of formula I:
  • R 1 is -Q ⁇ Ar 1 .
  • Q 1 is a direct bond.
  • Q 1 is -(CH 2 ) ni -C(R 6 R 7 )-(CH 2 )n 2 - wherein nl is zero or 1 (particularly zero) and n2 is zero or 1 (particularly zero).
  • R 6 and R 7 together with the carbon to which they are attached, form a 3-, 4-, 5-, 6-, or 7-member aliphatic carbocyclyl ring, particularly a cyclopropyl ring.
  • R 6 and R 7 are independently chosen from: H and (Ci-C3)alkyl.
  • Ar 1 is a monocyclic, optionally substituted aryl ring. In other embodiments, Ar 1 is a monocyclic, optionally substituted heteroaryl ring. In both embodiments, the optional substituents are selected from one or more of: halogen, perfluoro(Ci-C3)alkyl, and (Ci-C3)alkyl, particularly chloro and trifluorom ethyl.
  • Ar 1 is a monocyclic or polycyclic, optionally substituted carbocycle, wherein the optional substituents are selected from one or more of: halogen, perfluoro(Ci-C3)alkyl, and (Ci-C3)alkyl, particularly chloro and trifluorom ethyl.
  • R 5 is (Ci-C3)alkylsulfonylamino. In some embodiments, R 5 is (C 8 -Cio)hydrocarbyl. In some embodiments, R 5 is (Ci-C3)alkoxy. In some embodiments, R 5 is (Ci-Cv)cycloalkyl. In some embodiments, R 5 is carboxy.
  • R 5 is -Q 6 -Ar 2 .
  • Q 6 is chosen from a direct bond, -0-, -S-, -OCH2-, -CF2-, -NH-, -CoC-, -CH2NH-, and -NHSO2-, and, Ar 2 is a monocyclic optionally substituted aryl ring or a monocyclic, optionally substituted heteroaryl ring.
  • the optional substituents for Ar 2 are selected from: halogen, nitrile, (Ci-C3)alkylthio, perfluoro(Ci- C3)alkyl, -CoCH, and additionally, when Q 6 is other than -0-, methoxy.
  • Alkyl is intended to include linear and branched hydrocarbon structures. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, s-and t-butyl, n-pentyl, and the like. Preferred alkyl groups are those of C20 or below. Cycloalkyl includes cyclic hydrocarbon groups of from 3 to 8 carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, adamantyl and the like.
  • Alkoxy or alkoxyl refers to alkyl groups of from 1 to 8 carbon atoms of a straight, branched, or cyclic configuration and combinations thereof attached to the parent structure through an oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like. Lower-alkoxy refers to groups containing one to four carbons.
  • Oxaalkyl refers to alkyl residues in which one or more carbons (and their associated hydrogens) have been replaced by oxygen. Examples include methoxypropoxy, 3,6,9-trioxadecyl and the like.
  • the term oxaalkyl is intended as it is understood in the art [see Naming and Indexing of Chemical Substances for Chemical Abstracts, published by the American Chemical Society, 196, but without the restriction of 127(a)], i.e. it refers to compounds in which the oxygen is bonded via a single bond to its adjacent atoms (forming ether bonds); it does not refer to doubly bonded oxygen, as would be found in carbonyl groups.
  • Aryl and heteroaryl mean a 5- or 6-membered aromatic or heteroaromatic ring containing 0-3 heteroatoms selected from O, N, or S; a bicyclic 9- or 10-membered aromatic or heteroaromatic ring system containing 0-3 heteroatoms selected from O, N, or S; or a tricyclic 13- or 14-membered aromatic or heteroaromatic ring system containing 0-3 heteroatoms selected from O, N, or S.
  • the aromatic 6- to 14-membered carbocyclic rings include, e.g., benzene, naphthalene, indane, tetralin, and fluorene and the 5- to 10-membered aromatic heterocyclic rings include, e.g.
  • aryl and heteroaryl refer to residues in which one or more rings are aromatic, but not all need be.
  • Arylalkyl means an aryl ring attached to an alkyl residue in which the point of attachment to the parent structure is through the alkyl. Examples are benzyl, phenethyl and the like. Heteroaryl alkyl means an a heteroaryl ring attached through an alkyl residue to the parent structure. Examples include, e.g. , pyridinylmethyl, pyrimidinylethyl and the like.
  • Ci to Cio hydrocarbon or hydrocarbyl means a linear, branched, or cyclic residue comprised of hydrogen and carbon as the only elemental constituents and includes alkyl, cycloalkyl, polycycloalkyl, alkenyl, alkynyl, aryl and combinations thereof. Examples include benzyl, phenethyl, cyclohexylmethyl, cyclopropylmethyl, cyclobutylmethyl, allyl and camphoryl.
  • carbocycle is intended to include ring systems in which the ring atoms are all carbon but of any oxidation state.
  • C3-C10 carbocycle refers to both non-aromatic and aromatic systems, including such systems as cyclopropane, cyclobutane, cyclopentane, cyclohexane, benzene, cyclohexene and cyclohexadiene;
  • C8-C12) carbopolycycle refers to such systems as norbornane, decalin, indane, adamantane and naphthalene.
  • Carbocycle if not otherwise limited, refers to monocycles, bicycles and polycycles.
  • Heterocycle means a cycloalkyl or aryl residue in which one to three of the carbons is replaced by a heteroatom such as oxygen, nitrogen or sulfur. Heteroaryls form a subset of heterocycles.
  • heterocycles include pyrrolidine, pyrazole, pyrrole, imidazole, indole, quinoline, isoquinoline, tetrahydroisoquinoline, benzofuran, benzodioxan, benzodioxole (commonly referred to as methylenedioxyphenyl, when occurring as a substituent), tetrazole, morpholine, thiazole, pyridine, pyridazine, pyrimidine, pyrazine, thiophene, furan, oxazole, oxazoline, isoxazole, dioxane, tetrahydrofuran and the like.
  • substituted refers to the replacement of one or more hydrogen atoms in a specified group with a specified radical.
  • Oxo is also included among the substituents referred to in “optionally substituted”; it will be appreciated by persons of skill in the art that, because oxo is a divalent radical, there are circumstances in which it will not be appropriate as a substituent (e.g. on phenyl). Although in most cases of “optionally substituted” residues, 1, 2 or 3 hydrogen atoms are replaced with a specified radical, in the case of fluoroalkyl residues, more than three hydrogen atoms can be replaced by fluorine; indeed, all available hydrogen atoms could be replaced by fluorine, e.g. perfluoropropyl.
  • the compounds of this invention can exist in radiolabeled form, i.e., the compounds may contain one or more atoms containing an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Alternatively, a plurality of molecules of a single structure may include at least one atom that occurs in an isotopic ratio that is different from the isotopic ratio found in nature.
  • Radioisotopes of hydrogen, carbon, phosphorous, fluorine, chlorine and iodine include, for example, 2 H, 3 ⁇ 4, 11 C, 13 C, 14 C, 15 N, 35 S, 18 F, 36 C1, 123 I, 125 I, 131 I and 133 I.
  • Radiolabeled compounds of formulae I and II of this invention can generally be prepared by methods well known to those skilled in the art. Conveniently, such radiolabeled compounds can be prepared by carrying out the procedures disclosed in the Examples and Schemes by substituting a readily available radiolabeled reagent for a non-radiolab el ed reagent.
  • the compounds of formula I When the compounds of formula I are to be employed as antitumor agents in vivo , they may be administered as the raw chemical, but it is preferable to present them as a pharmaceutical composition.
  • the present invention provides a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt or solvate thereof, together with one or more pharmaceutically carriers thereof and optionally one or more other therapeutic ingredients.
  • the carrier(s) must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • the compositions may be formulated for oral, topical or parenteral administration. For example, they may be given intravenously, intraarterially, subcutaneously, and directly into the CNS - either intrathecally or intracerebroventricularly.
  • Formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous and intraarticular), rectal and topical (including dermal, buccal, sublingual and intraocular) administration.
  • the compounds are preferably administered orally or by injection (intravenous or subcutaneous).
  • the precise amount of compound administered to a patient will be the responsibility of the attendant physician. However, the dose employed will depend on a number of factors, including the age and sex of the patient, the precise disorder being treated, and its severity. Also, the route of administration may vary depending on the condition and its severity.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide sustained, delayed or controlled release of the active ingredient therein.
  • a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be
  • Formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti -oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient.
  • Formulations for parenteral administration also include aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose of multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze- dried (lyophilized) condition requiring only the addition of a sterile liquid carrier, for example saline, phosphate-buffered saline (PBS) or the like, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • Formulations for rectal administration may be presented as a suppository with the usual carriers such as cocoa butter or polyethylene glycol.
  • Formulations for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis such as sucrose and acacia or tragacanth, and pastilles comprising the active ingredient in a basis such as gelatin and glycerin or sucrose and acacia.
  • Preferred unit dosage formulations are those containing an effective dose, as herein below recited, or an appropriate fraction thereof, of the active ingredient.
  • formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
  • treatment or “treating,” or “palliating” or “ameliorating” refer to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and/or a prophylactic benefit.
  • therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated.
  • a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological systems associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient may still be afflicted with the underlying disorder.
  • Solvents and reagents were purchased from VWR or Sigma Aldrich. All reactions involving air- or moisture-sensitive compounds were performed under nitrogen atmosphere using dried glassware. 'H and 13 C NMR spectra were recorded at 500MHz and 125Mz respectively, on a Bruker Advance III HD 500 MHz NMR spectrometer equipped with a TCI cryogenic probe with enhanced 'H and 13 C detection. All data was collected at 298 K, signals were reported in ppm, internally referenced for 'H and 13 C to chloroform signal at 7.26 ppm or 77.0 ppm; to DMSO signal at 2.50 ppm or 39.5 ppm, or TMS at 0 ppm.
  • NHMDS (1 M, 134.15 mL) was slowly added to a solution of cyclopropanecarbonitrile (61.1, 6.00 g, 89.4 mmol) in THF (50 mL) at room temperature.
  • the reaction mixture was stirred for 20 minutes and then a solution l-(bromomethyl)-4-chloro-benzene (16.5 g, 80.4 mmol) in THF was added.
  • the mixture was heated to reflux for 3 hours and then quenched with a saturated aqueous solution of ammonium chloride.
  • the separated aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over NaiSCL and concentrated in vacuo.
  • the mixture was extracted with ethyl acetate (150 mL*3).
  • the combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, concentrated in vacuum.
  • the mixture was extracted with ethyl acetate (100 mL*3).
  • the combined organic layers were washed with brine (100 mL*2), dried over anhydrous sodium sulfate, concentrated in vacuum to give the red gum.
  • Hydrogen peroxide (2.5 g, 23.5 mmol, 2.12 mL, 32% purity, 6.2 eq) was added drop wise over a period of 30 mins via syringe pump and keeping the temperature at 20 ⁇ 40°C. After addition, the mixture was stirred at 45 °C for additional 1 hour. LCMS showed desired product was detected. The mixture poured into ice water (500 mL) and then extracted with ethyl acetate (300 mL*3). The combined organic layers were washed with saturated sodium sulfite solution (200 mL) and brine (200 mL*3), dried over anhydrous sodium sulfate, concentrated in vacuum.
  • Example 103 (96.3 mg, 205.98 umol, 35.81% yield, 97.4% purity) as a white solid.
  • Step 1 Tert-butyl 4-(2,2-dicyano-l-methylsulfanyl-vinyl)piperazine-l-carboxylate
  • Step 2 Tert-butyl 4-(5-amino-4-cyano-lH-pyrazol-3-yl)piperazine-l-carboxylate
  • Step 3 Tert-butyl 4-[5-amino-4-cyano-l-(3,3,3-trifluoropropanoyl)pyrazol-3-yl] piperaz ine-l-carboxylate
  • Step 4 Tert-butyl 4-[3-cyano-7-oxo-6-(trifluoromethyl)-4H-pyrazolo[l,5-a]pyrimidin-2 -yl]piperazine- 1 -carboxylate
  • Step 5 7-oxo-2-piperazin-l-yl-6-(trifluoromethyl)-4H-pyrazolo[l,5-a]pyrimidine-3- carbonitrile
  • Step 6 7-oxo-6-(trifluoromethyl)-2-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-l- yl]-4H-pyrazolo[l,5-a]pyrimidine-3-carbonitrile
  • Step 2 Tert-butyl 4-(5-amino-4-cyano-lH-pyrazol-3-yl)piperazine-l-carboxylate
  • Step 3 Tert-butyl4-[5-amino-4-cyano-l-(3,3,3-trifluoropropanoyl)pyrazol-3- yl]piperazine-l- carboxylate
  • Step 4 Tert-butyl4-[3-cyano-7-oxo-6-(trifluoromethyl)-4H-pyrazolo[l,5-a]pyrimidin- 2-yl] piperazine- 1-carboxylate
  • Step 5 7-oxo-2-piperazin-l-yl-6-(trifluoromethyl)-4H-pyrazolo[l,5-a]pyrimidine-3- carbonitrile
  • Step 6 7-oxo-6-(trifluoromethyl)-2-[4-[4-(trifluoromethyl)phenyl]piperazin-l-yl]-4H- pyrazolo[l,5-a]pyrimidine-3-carbonitrile
  • Step 1 Tert-butyl 4-(trifluoromethylsulfonyloxy)-3,6-dihydro-2H-pyridine-l- carboxylate
  • Step 2 Tert-butyl 4-[4-(trifluoromethyl)phenyl]-3,6-dihydro-2H-pyridine-l- carboxylate
  • Step 3 Tert-butyl 4-[4-(trifluoromethyl)phenyl]piperidine-l-carboxylate
  • Step 5 2-[methylsulfanyl-[4-[4-(trifluoromethyl)phenyl]-l- piperidyl]methylene]propanedinitrile
  • Step 6 5-amino-3-[4-[4-(trifluoromethyl)phenyl]-l-piperidyl]-lH-pyrazole-4- carbonitrile
  • Step 7 7-oxo-2-[4-[4-(trifluoromethyl)phenyl]-l-piperidyl]-4H-pyrazolo[l,5- a]pyrimidine-3-carbonitrile
  • Step 8 7-oxo-6-(trifluoromethyl)-2-[4-[4-(trifluoromethyl)phenyl]-l-piperidyl]-4H- pyrazolo[l,5-a]pyrimidine-3-carbonitrile
  • the residue was purified by neutral prep-HPLC (column: Agela Durashell C18 150*25 5u;mobile phase: [water(10mMNH4HCO3)-ACN];B%: 31%-61%,10min) to give 7-oxo-6-(trifluoromethyl)-2-[4-[4-(trifluoromethyl)phenyl]-l- piperidyl]-4H-pyrazolo[l,5-a]pyrimidine-3-carbonitrile (10.3 mg).
  • Step 1 Methyl (E)-2-(4-chlorophenyl)-3-(dimethylamino)prop-2-enoate
  • Step 3 Tert-butyl 4-[l-(trifluoromethyl)-3-bicyclo[l.l.l]pentanyl]piperazine-l- carboxylate [00165] To a solution of l-(trifluoromethyl)bicyclo[l .1. l]pentan-3 -amine hydrochloride (500 mg, 2.67 mmol) in MeOH (16 mL) was added tert-butyl N,N-bis(2-oxoethyl)carbamate (1.34 g, 6.66 mmol) at 25 °C and the mixture stirred for 0.5 h.
  • Step 4 l-[l-(trifluoromethyl)-3-bicyclo[l.l.l]pentanyl]piperazine
  • Step 5 2-[methylsulfanyl-[4-[l-(trifluoromethyl)-3-bicyclo[ 1.1.1 ]pentanyl]piperazin- 1- yl]methylene]propanedinitrile
  • Step 6 5-amino-3-[4-[l-(triiluoromethyl)-3-bicyclo[l.l.l]pentanyl]piperazin-l-yl]-lH- pyrazole-4-carbonitrile
  • Step 7 6-(4-chlorophenyl)-7-oxo-2-[4-[l-(trifluoromethyl)-3- bicyclo[ 1.1.1 ]pentanyl]piperazin- 1 -yl]-4H-pyrazolo[ 1 ,5-a]pyrimidine-3 -carbonitrile
  • Step 1 Methyl (E)-2-(4-chlorophenyl)-3-(dimethylamino)prop-2-enoate
  • a mixture of methyl 2-(4-chlorophenyl)acetate (6 g, 32.50 mmol, 1 eq), 1-tert-butoxy- N,N,N',N'-tetramethyl-methanediamine (11.33 g, 65.00 mmol, 13.42 mL, 2 eq) was degassed and purged with N2 3 times, and then the mixture was stirred at 100 °C for 15 h under N2 atmosphere. The mixture was cooled and concentrated under reduced pressure. The residue was purified by silica column (Petroleum ether/Ethyl acetate 20/1 to 3/1) to give the title compound (6 g) as a white solid.
  • Step 2 Tert-butyl 4-[4-(trifluoromethyl)phenyl]piperazine-l-carboxylate
  • Step 3 l-[4-(trifluoromethyl)phenyl]piperazine
  • Step 5 5-amino-3-[4-[l-(trifluoromethyl)-3-bicyclo[l.l.l]pentanyl]piperazin-l-yl]-lH- pyrazole-4-carbonitrile
  • Step 6 6-(4-chlorophenyl)-7-oxo-2-[4-[4-(trifluoromethyl)phenyl]piperazin-l-yl]-4H- pyrazolo[l,5-a]pyrimidine-3-carbonitrile
  • Example 120 [00194] A solution of 5-amino-3-[4-(4-chlorophenyl)cyclohexyl]-lH-pyrazole-4-carbonitrile (50.0 mg, 166 umol), 5-chloro-2-fluoro-benzoic acid (31.9 mg, 182 umol) and Hunig's base (107 mg, 831 umol, 145 uL) in EtOAc (1.00 mL) was stirred at 60°C overnight. The mixture was concentrated in vacuo. The residue was purified by ISCO (10%-70% EtOAc in Hexane) to give a solid.
  • NIH-3T3 cells stably expressing a Gli -dependent luciferase reporter were cultured in DMEM containing 10% bovine calf serum (BCS).
  • DMEM fetal bovine calf serum
  • DMEM +0.5% BCS low serum media
  • SAG smoothened agonist
  • test compound for 28-32 hours.

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Abstract

Les pyrazolo[1,5-a]pyrimidine-7(4H)-ones de formule I inhibent le transport intraflagellaire et sont utiles en tant qu'agents anticancéreux et en tant que sondes de la fonction de systèmes dépendant de la dynéine.
PCT/US2021/012917 2020-01-10 2021-01-11 Inhibiteurs pyrazolo [1,5-a] pyrimidine-7 (4h)-one de dynéine WO2021142420A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003101993A1 (fr) * 2002-06-04 2003-12-11 Neogenesis Pharmaceuticals, Inc. Composes de pyrazolo(1,5a)pyrimidine servant d'agents antiviraux
WO2018213712A1 (fr) * 2017-05-18 2018-11-22 Kapoor Tarun M Agents antitumoraux à base de pyrazoloquinazolinone
WO2019115404A1 (fr) * 2017-12-13 2019-06-20 Syngenta Participations Ag Composés hétérocycliques mésoioniques à activité pesticide

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