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WO2018011160A1 - Composés de 6,7-dihydro-4h-pyrazolo[1,5-a]pyrazine pour le traitement de maladies infectieuses - Google Patents

Composés de 6,7-dihydro-4h-pyrazolo[1,5-a]pyrazine pour le traitement de maladies infectieuses Download PDF

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Publication number
WO2018011160A1
WO2018011160A1 PCT/EP2017/067315 EP2017067315W WO2018011160A1 WO 2018011160 A1 WO2018011160 A1 WO 2018011160A1 EP 2017067315 W EP2017067315 W EP 2017067315W WO 2018011160 A1 WO2018011160 A1 WO 2018011160A1
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Prior art keywords
methyl
oxo
pyrazolo
dihydro
pyrazine
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Ceased
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PCT/EP2017/067315
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English (en)
Inventor
Taishan HU
Buyu KOU
Xianfeng Lin
Haixia Liu
Zhisen ZHANG
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F Hoffmann La Roche AG
Hoffmann La Roche Inc
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F Hoffmann La Roche AG
Hoffmann La Roche Inc
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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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • 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
    • C07D471/02—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 two hetero rings
    • C07D471/08—Bridged systems
    • 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
    • C07D487/08—Bridged systems
    • 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
    • C07D487/10—Spiro-condensed systems
    • 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
    • C07D491/02—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 two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/08—Bridged systems

Definitions

  • the present invention relates to organic compounds useful for therapy and/or prophylaxis in a mammal, and in particular for treating hepatitis B virus infection, and their pharmaceutical activity, manufacture, pharmaceutical compositions containing them and their potential use as medicaments.
  • FIELD OF THE INVENTION The present invention relates to compounds of the formula (I),
  • Hepatitis B virus infection is a major public health problem worldwide, roughly 30% of the world's population show serological evidence of current or past infection.
  • HBV Hepatitis B virus
  • HCC hepatocellular carcinoma
  • HBV infection ranked in the top health priorities in the world, and was the tenth leading cause of death (780,000 deaths per year).
  • Recent studies have shown that progression to liver cirrhosis and HCC in patients with chronic HBV infection is significantly associated with circulating HBV DNA levels.
  • antiviral therapy against HBV is critical to prevent the progression to cirrhosis or development of HCC.
  • HBV is a small, enveloped virus that belongs to the Hepadnaviridae family. It contains a partly double-stranded DNA genome with approximately 3200 base pairs. HBV have a strong preference for infecting human hepatocytes.
  • the life cycle begins when HBV attaches to the host cell membrane via its envelope proteins.
  • the precise mechanism of viral entry has not been fully elucidated.
  • the viral relaxed circular DNA (rcDNA) containing nucleocapsids are released into the cytoplasm and transported to the nucleus.
  • the rcDNA is repaired by both viral and cellular enzymes to form covalently closed circular DNA (cccDNA).
  • cccDNA covalently closed circular DNA
  • sgRNA subgenomic RNA
  • pgRNA pregenomic RNA
  • the pgRNA is translated into the core protein and the viral polymerase.
  • the sgRNA is translated into the regulatory X protein and the three envelope proteins.
  • Self-assembly of the RNA-containing viral nucleocapsid takes place via complex formation of the pgRNA with the core protein and the polymerase.
  • the pgRNA is reverse transcribed into negative-strand DNA.
  • rcDNA is then generated by plus-strand synthesis from the negative-strand DNA.
  • the nucleocapsids are either re-imported to the nucleus for cccDNA amplification or enveloped and released via the endoplasmic reticulum (ER).
  • the reverse transcriptase lacks proofreading activity; thus, mutations of the viral genome are frequent and result in the coexistence of genetically distinct viral species in infected individuals (quasispecies).
  • CHB chronic hepatitis B
  • IFN interferon
  • PEG-IFN conventional IFN and PEG-IFN
  • NUCs nucleos(t)ide analogues
  • PEG-IFN has the advantage of a finite duration of use, whereas the use of NUCs is indefinite.
  • the major drawback of PEG-IFN is its high frequency of adverse events. Some viral genotypes do not show good responses to interferon therapy. Long-term use of NUCs, on the other hand, poses the risk of drug resistance.
  • the ultimate goal of antiviral therapy for CHB is to prevent progression to cirrhosis or HCC via eradication of HBV or persistent viral suppression. The majority of currently treated patients fail to achieve this goal.
  • nucleocapsid assembly is a critical step for HBV genome replication.
  • nucleocapsid assembly is an evolutionary constraint process that limits the diversity of HBV, and it is highly sensitive to even subtle molecular disturbances. Both assembly and disassembly of nucleocapsid make the process an attractive therapeutic target for the development of new antiviral therapies against various HBV genotypes and drug resistance isolates. A few capsid related anti-HBV compounds have been reported.
  • heteroaryldihydropyrimidines including compounds named Bay 41-4109, Bay 38-7690 and Bay 39-5493 (Deres K. et al. Science 2003, 893), and phenylpropenamide derivatives such as AT-61 and AT-130 (Feld J. et al. Antiviral Research 2007, 168-177).
  • HAP heteroaryldihydropyrimidines
  • C 1-6 alkyl denotes a monovalent linear or branched saturated hydrocarbon group of 1 to 6 carbon atoms.
  • C1-6alkyl has 1 to 6 carbon atoms, and in more particular embodiments 1 to 4 carbon atoms.
  • Examples of C 1-6 alkyl include, but not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl and tert-butyl.
  • halo or“halogen” are used interchangeably herein and denote fluoro, chloro, bromo or iodo.
  • haloC 1-6 alkyl denotes a C 1-6 alkyl group wherein at least one of the hydrogen atoms of the C 1-6 alkyl group has been replaced by same or different halogen atoms, particularly fluoro atoms.
  • haloC 1-6 alkyl include monofluoro-, difluoro- or trifluoro-methyl, - ethyl or -propyl, for example 3,3,3-trifluoropropyl, 2-fluoroethyl, trifluoroethyl, fluoromethyl, difluoromethyl, difluoroethyl or trifluoromethyl.
  • pyrimidinyloxy denotes pyrimidinyl-O-.
  • diastereomer denotes a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g. melting points, boiling points, spectral properties, activities and reactivities.
  • enantiomers denotes two stereoisomers of a compound which are non- superimposable mirror images of one another.
  • pharmaceutically acceptable salts denotes salts which are not biologically or otherwise undesirable.
  • Pharmaceutically acceptable salts include both acid and base addition salts.
  • pharmaceutically acceptable acid addition salt denotes those pharmaceutically acceptable salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, and organic acids selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, maloneic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene
  • pharmaceutically acceptable base addition salt denotes those pharmaceutically acceptable salts formed with an organic or inorganic base.
  • acceptable inorganic bases include sodium, potassium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts.
  • Salts derived from pharmaceutically acceptable organic nontoxic bases includes salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethylamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperizine, piperidine, N-ethylpiperidine, and polyamine resins.
  • substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethy
  • Racemates can be separated according to known methods into the enantiomers.
  • diastereomeric salts which can be separated by crystallization are formed from the racemic mixtures by reaction with an optically active acid such as e.g. D- or L-tartaric acid, mandelic acid, malic acid, lactic acid or camphorsulfonic acid.
  • R 1 is , wherein R 5 , R 6 and R 7 are independently selected from H or C 1- 6 alkyl;
  • R 2 is H
  • R 3 is C 1-6 alkyl
  • R 4 is phenyl which is three times substituted by halogen; or pyridinyl which is once or twice substituted by substituents independently selected from halogen and haloC 1- 6 alkyl;
  • a further embodiment of present invention is (ii) a compound of formula (I), wherein
  • R 2 is H
  • R 3 is methyl
  • R 4 is trifluorophenyl, chloropyridinyl, difluoropyridinyl, fluorochloropyridinyl,
  • a further embodiment of present invention is (iii) a compound of formula (I), wherein
  • R 1 is , wherein R 5 , R 6 and R 7 are C 1-6 alkyl;
  • R 2 is H
  • R 3 is C 1-6 alkyl
  • R 4 is phenyl three times substituted by halogen, or pyridinyl substituted by haloC 1-6 alkyl.
  • a further embodiment of present invention is (iv) a compound of formula (I), wherein R 1 is
  • R 2 is H
  • R 3 is methyl
  • R 4 is trifluorophenyl or difluoromethylpyridinyl.
  • particular compounds of the present invention are (v) selected from:
  • R 8 is H, pyridinyl or haloC 1-6 alkyl
  • R 9 is H, pyridinyl or C 1- 6 alkyl
  • R 2 is H
  • R 3 is C 1-6 alkyl
  • R 4 is phenyl which is three times substituted by halogen
  • a further embodiment of the present invention is (viii) a compound of formula (I), wherein R 1 is , wherein R 8 is H, pyridinyl or trifluoromethyl; R 9 is H, pyridinyl or methyl;
  • R 2 is H
  • R 3 is methyl
  • R 4 is trifluorophenyl.
  • particular compounds of the present invention are (ix) selected from:
  • R 10 is H, halogen or hydroxy
  • R 11 is H or halogen
  • R 12 is H, cyano, hydroxy, pyridinyl or pyrimidinyloxy
  • R 13 is H, C 1-6 alkyl or morpholinylcarbonyl
  • R 14 is H, C 1-6 alkyl, C 1-6 alkylaminocarbonyl or (C 1- 6 alkyl) 2 aminoC 1-6 alkyl;
  • R 2 is H or C 1-6 alkyl
  • R 3 is C 1-6 alkyl
  • R 4 is phenyl which is three times substituted by halogen; or pyridinyl which is once or twice substituted by substituents independently selected from halogen and haloC 1- 6 alkyl;
  • R 1 is , wherein R 10 is H, fluoro or hydroxy; R 11 is H or fluoro; R 12 is H, cyano, hydroxy, pyridinyl or pyrimidinyloxy; R 13 is H, methyl or
  • R 14 is H, methyl, methylaminocarbonyl or
  • R 2 is H or methyl
  • R 3 is methyl
  • R 4 is trifluorophenyl, difluoropyridinyl or difluoromethylpyridinyl.
  • a further embodiment of the present invention is (xii) a compound of formula (I), wherein
  • R 1 is , wherein R 10 is H; R 11 is H; R 12 is cyano, hydroxy or
  • R 13 is H
  • R 14 is H or C 1-6 alkyl
  • R 2 is H or C 1-6 alkyl
  • R 3 is C 1-6 alkyl
  • R 4 is phenyl which is three times substituted by halogen
  • pyridinyl which is once or twice substituted by substituents independently selected from halogen and haloC 1- 6 alkyl.
  • a further embodiment of the present invention is (xiii) a compound of formula (I), wherein
  • R 2 is H or methyl
  • R 3 is methyl
  • R 4 is trifluorophenyl, difluoropyridinyl or difluoromethylpyridinyl.
  • particular compounds of the present invention are (xiv) selected from:
  • R 2 is H
  • R 3 is C 1-6 alkyl
  • R 4 is phenyl which is three times substituted by halogen; or pyridinyl which is once or twice substituted by substituents independently selected from halogen and haloC 1- 6 alkyl;
  • a further embodiment of the present invention is (xvii) a compound of formula (I), wherein
  • R 1 is 5-oxo-4-azaspiro[2.4]heptan-4-yl; 2-oxo-3H-benzimidazol-1-yl; 6-acetyl-4-oxo-3,6- diazabicyclo[3.1.1]heptan-3-yl; 8-acetyl-4-oxo-3,8-diazabicyclo[3.2.1]octan-3-yl; 8- ethylsulfonyl-4-oxo-3,8-diazabicyclo[3.2.1]octan-3-yl; 8-methyl-4-oxo-3,8- diazabicyclo[3.2.1]octan-3-yl; 4-oxo-3,7-diazabicyclo[3.3.1]nonan-3-yl; 7-acetyl-4- oxo-3,7-diazabicyclo[3.3.1]nonan-3-yl; 2-tert-butylcarbonyl-7-oxo-2,
  • R 3 is methyl
  • R 4 is trifluorophenyl, chloropyridinyl, difluoropyridinyl, difluoromethylpyridinyl or
  • a further embodiment of the present invention is (xviii) a compound of formula (I), wherein
  • R 1 is oxooxaazaspiro[2.4]heptanyl substituted by C 1-6 alkyl;
  • R 2 is H
  • R 3 is C 1-6 alkyl
  • R 4 is pyridinyl which is once or twice substituted by substituents independently selected from halogen and haloC 1-6 alkyl.
  • a further embodiment of the present invention is (xix) a compound of formula (I), wherein R 1 is 7-methyl-5-oxo-4-oxa-6-azaspiro[2.4]heptan-6-yl;
  • R 2 is H
  • R 3 is methyl
  • R 4 is difluoropyridinyl or difluoromethylpyridinyl.
  • particular compounds of the present invention are (xx) selected from:
  • R 1 to R 4 are defined above;
  • the acid can be, for example, HCl in EtOAc and TFA in DCM;
  • phosgene equivalent can be, for example, triphosgene and carbonyldiimidazole.
  • a compound of formula (I) when manufactured according to the above process is also an object of the invention.
  • PHARMACEUTICAL COMPOSITIONS AND ADMINISTRATION Another embodiment provides pharmaceutical compositions or medicaments containing the compounds of the invention and a therapeutically inert carrier, diluent or excipient, as well as methods of using the compounds of the invention to prepare such compositions and medicaments.
  • compounds of formula (I) may be formulated by mixing at ambient temperature at the appropriate pH, and at the desired degree of purity, with physiologically acceptable carriers, i.e., carriers that are non-toxic to recipients at the dosages and concentrations employed into a galenical administration form.
  • the pH of the formulation depends mainly on the particular use and the concentration of compound, but preferably ranges anywhere from about 3 to about 8.
  • a compound of formula (I) is formulated in an acetate buffer, at pH 5.
  • the compounds of formula (I) are sterile.
  • the compound may be stored, for example, as a solid or amorphous composition, as a lyophilized formulation or as an aqueous solution. Compositions are formulated, dosed, and administered in a fashion consistent with good medical practice.
  • Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners.
  • The“effective amount” of the compound to be administered will be governed by such considerations, and is the minimum amount necessary to the suppression of serum HBV DNA levels, or HBeAg seroconversion to HBeAb, or HBsAg loss, or normalization of alanine aminotransferase levels and improvement in liver histology. For example, such amount may be below the amount that is toxic to normal cells, or the mammal as a whole.
  • the pharmaceutically effective amount of the compound of the invention administered parenterally per dose will be in the range of about 0.01 to 100 mg/kg, alternatively about 0.1 to 20 mg/kg of patient body weight per day, with the typical initial range of compound used being 0.3 to 15 mg/kg/day.
  • oral unit dosage forms such as tablets and capsules, contain from about 0.1 to about 1000 mg of the compound of the invention.
  • the compounds of the invention may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal and epidural and intranasal, and, if desired for local treatment, intralesional administration.
  • Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.
  • the compounds of the present invention may be administered in any convenient administrative form, e.g., tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc.
  • Such compositions may contain components conventional in pharmaceutical preparations, e.g., diluents, carriers, pH modifiers, sweeteners, bulking agents, and further active agents.
  • a typical formulation is prepared by mixing a compound of the present invention and a carrier or excipient.
  • Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, e.g., Ansel, Howard C., et al., Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004;
  • the formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament).
  • buffers stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing
  • An example of a suitable oral dosage form is a tablet containing about 0.1 mg to 1000 mg of the compound of the invention compounded with about 30 mg to 90 mg anhydrous lactose, about 5 mg to 40 mg sodium croscarmellose, about 5 mg to 30 mg polyvinylpyrrolidone (PVP) K30, and about 1 mg to 10 mg magnesium stearate.
  • the powdered ingredients are first mixed together and then mixed with a solution of the PVP.
  • the resulting composition can be dried, granulated, mixed with the magnesium stearate and compressed to tablet form using
  • an aerosol formulation can be prepared by dissolving the compound, for example 5 mg to 400 mg, of the invention in a suitable buffer solution, e.g. a phosphate buffer, adding a tonicifier, e.g. a salt such sodium chloride, if desired.
  • the solution may be filtered, e.g., using a 0.2 micron filter, to remove impurities and contaminants.
  • An embodiment therefore, includes a pharmaceutical composition comprising a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition comprising a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or excipient.
  • the compounds of the invention can inhibit HBV’s DNA synthesis and reduce HBV DNA levels. Accordingly, the compounds of the invention are useful for the treatment or prophylaxis of HBV infection.
  • the invention relates to the use of a compound of formula (I) for the treatment or prophylaxis of HBV infection.
  • the use of a compound of formula (I) for the preparation of medicaments useful in the treatment or prophylaxis diseases that are related to HBV infection is an object of the invention.
  • the invention relates in particular to the use of a compound of formula (I) for the preparation of a medicament for the treatment or prophylaxis of HBV infection.
  • Another embodiment includes a method for the treatment or prophylaxis of HBV infection which method comprises administering an effective amount of a compound of formula (I), a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt thereof.
  • a compound of formula (I) 1,2-dichloroethylene
  • DIAD diisopropyl azodicarboxylate
  • DIPEA N,N-diisopropylethylamine
  • HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate
  • PE petroleum ether
  • pgRNA pre-genomic RNA
  • LC/MS spectra of compounds were obtained using a LC/MS (Waters TM Alliance 2795- Micromass ZQ), LC/MS conditions were as follows (running time 6 mins): Acidic condition: A: 0.1% formic acid in H 2 O; B: 0.1% formic acid in acetonitrile; Basic condition: A: 0.1% NH 3 ⁇ H 2 O in H 2 O; B: acetonitrile; Neutral condition: A: H 2 O; B: acetonitrile.
  • Mass spectra (MS): generally only ions which indicate the parent mass are reported, and unless otherwise stated the mass ion quoted is the positive mass ion (MH) + .
  • NMR Spectra were obtained using Bruker Avance 400 MHz. The microwave assisted reactions were carried out in a Biotage Initiator Sixty microwave synthesizer. All reactions involving air-sensitive reagents were performed under an argon atmosphere. Reagents were used as received from commercial suppliers without further purification unless otherwise noted.
  • the following examples are intended to illustrate the meaning of the present invention but should by no means represent a limitation within the meaning of the present invention: PREPARATIVE EXAMPLES The invention will be more fully understood by reference to the following examples. They should not, however, be construed as limiting the scope of the invention.
  • Step 1 preparation of tert-butyl N-[(1S)-2-hydroxy-1-methyl-ethyl]-N-(1H-pyrazol-5- ylmethyl)carbamate (compound I-1b)
  • compound I-1a 1H-pyrazole-5-carbaldehyde
  • MeOH 300 mL
  • (2S)-2-aminopropan-1-ol 41.2 g, 675 mmol
  • Step 2 preparation of [(2S)-2-[tert-butoxycarbonyl(1H-pyrazol-5- ylmethyl)amino]propyl] methanesulfonate (compound I-1c)
  • Step 3 preparation of tert-butyl (6S)-6-methyl-6,7-dihydro-4H-pyrazolo[1,5- a]pyrazine-5-carboxylate (compound I-1d)
  • Step 4 preparation of tert-butyl (6S)-3-iodo-6-methyl-6,7-dihydro-4H-pyrazolo[1,5- a]pyrazine-5-carboxylate (compound I-1):To a solution of tert-butyl 6-methyl-6,7-dihydro- 4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 53c, 3.3 g, 14.8 mmol) in CH 3 CN (40 mL) was added NIS (5.0 g, 22.1 mmol) slowly. The reaction mixture was stirred at room temperature for 16 hours and then extracted with EtOAc (50 mL), washed with brine (50 mL). The organic layer was dried over Na 2 SO 4 and concentrated, and the residue was purified by column
  • Step 3 Preparation of 2-((2S,3S)-3-(4-bromo-1H-pyrazol-1-yl)butan-2-yl)isoindoline- 1,3-dione (compound I-2d)
  • Step 6 Preparation of (6S,7S)-5-benzyl-3-bromo-6,7-dimethyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine (compound I-2g)
  • (2S,3S)-N-benzyl-3-(4-bromo-1H-pyrazol-1-yl)butan-2-amine (compound I-2f, 4 g, 13 mmol) in acetonitrile (50 mL) was added paraformaldehyde (1.95 g, 64.9 mmol) and 2,2,2-trifluoroacetic acid (296 mg, 2.6 mmol), and the reaction mixture was stirred at 70 o C for 6 hours.
  • Step 7 Preparation of tert-butyl (6S,7S)-6,7-dimethyl-6,7-dihydro-4H-pyrazolo[1,5- a]pyrazine-5-carboxylate (compound I-2h)
  • Step 8 Preparation of tert-butyl (6S,7S)-3-iodo-6,7-dimethyl-6,7-dihydro-4H- pyrazolo[1,5-a]pyrazine-5-carboxylate (compound I-2)
  • Step 1 preparation of (S)-tert-butyl (1-oxopropan-2-yl)carbamate (compound I-3b) To a solution of (S)-tert-butyl (1-hydroxypropan-2-yl)carbamate (compound I-3a, 8.76 g, 50 mmol) in DCM (200 mL) was added Dess-Martin periodinane (31.8 g, 75 mmol) slowly. After stirred at room temperature for 2 hours, the reaction mixture was filtered through silica gel. The filtrate was concentrated in vacuo to give compound I-3b as a colorless oil (10 g).
  • Step 2 preparation of tert-butyl N-[(1S)-2-hydroxy-1-methyl-propyl]carbamate (compound I-3c)
  • Step 3 preparation of tert-butyl (3S)-3-(benzylamino)butan-2-ol (compound I-3d)
  • a mixture of tert-butyl ((2S)-3-hydroxybutan-2-yl)carbamate (compound I-3c, 8 g, 25.4 mmol) and trifluoroacetic acid (28.9 g, 19.5 mL, 254 mmol) in DCM (40 mL) was stirred at room temperature for 1 hour.
  • reaction mixture was concentrated in vacuo and the residue was dissolved in DCM (100 mL), to which benzaldehyde (2.69 g, 25.4 mmol) and sodium triacetoxyborohydride (10.8 g, 50.7 mmol) were added.
  • the reaction mixture was stirred at room temperature for 16 hours, then poured into 250 mL saturated aqueous NaHCO 3 and extracted with EtOAc (200 mL) twice. The combined organic phase was dried over Na 2 SO 4 and
  • the compound I-3 was prepared in analogy to compound I-2 by using (2S)-N-benzyl-3- (4-bromo-1H-pyrazol-1-yl)butan-2-amine (compound I-3f) instead of (2S,3S)-N-benzyl-3-(4- bromo-1H-pyrazol-1-yl)butan-2-amine (compound I-2f).
  • Intermediate I-3 was obtained as colorless oil (550 mg).
  • Intermediae I-5 was prepared in analogy to Intermediate I-4 by using 2-chloropyridin-4- amine instead of 3,4,5-trifluoroaniline. Intermediae I-5 was obtained as a white solid. LCMS (M+H + ): 249. Intermediate I-6
  • Step 3 preparation of methyl tert-butyl N-[(1S)-2-hydroxy-1,2-dimethyl- propyl]carbamate (compound 1d)
  • Step 5 preparation of tert-butyl (6S)-6-methyl-3-[(4S)-4,5,5-trimethyl-2-oxo- oxazolidin-3-yl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 1f)
  • Step 6 preparation of (4S)-4,5,5-trimethyl-3-[(6S)-6-methyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-3-yl]oxazolidin-2-one (compound 1g)
  • Step 7 preparation of (6S)-6-methyl-N-(3,4,5-trifluorophenyl)-3-[(4S)-4,5,5-trimethyl- 2-oxo-oxazolidin-3-yl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide
  • Example 1 To a mixture of (4S)-4,5,5-trimethyl-3-[(6S)-6-methyl-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazin-3-yl]oxazolidin-2-one (compound 1g, 40.0 mg, 0.13 mmol) and TEA (40.5 mg, 0.40 mmol) in DMF (5.0 mL) was added phenyl N-(3,4,5-trifluorophenyl)carbamate (Intermediate I- 4, 35.5 mg, 0.13 mmol).
  • Example 1 (41.2 mg) as a colorless oil.
  • Example 2 1 H NMR (400MHz, CHLOROFORM-d) ppm 7.79 (s, 1H), 7.39 (s, 1H), 7.25 - 7.13 (m, 2H), 5.18 - 4.96 (m, 2H), 4.37 - 4.16 (m, 2H), 4.07 - 3.92 (m, 2H), 1.60 (s, 3H), 1.44 (s
  • Example 2 was prepared in analogy to Example 1 by using (2R)-2-aminopropanoic acid instead of (2S)-2-aminopropanoic acid (compound 1a).
  • Example 2 (37 mg) was obtained as a colorless oil.
  • Example 3 was prepared in analogy to Example 1 by using phenyl N-(6-chloro-5- fluoro-3-pyridyl)carbamate (Intermediate I-7) instead of phenyl N-(3,4,5- trifluorophenyl)carbamate (Intermediate I-4).
  • Example 3 (30 mg) was obtained as a white solid.
  • Example 4 was prepared in analogy to Example 1 by using phenyl N-[2- (difluoromethyl)-4-pyridyl]carbamate (Intermediate I-8) instead of phenyl N-(3,4,5- trifluorophenyl)carbamate (Intermediate I-4).
  • Example 4 (25 mg) was obtained as a white solid.
  • Example 5 was prepared in analogy to Example 1 by using phenyl N-(2-chloro-4- pyridyl)carbamate (Intermediates I-5) instead of phenyl N-(3,4,5-trifluorophenyl)carbamate (Intermediate I-4).
  • Example 5 (15 mg) was obtained as a white solid.
  • Example 6 was prepared in analogy to Example 1 by using phenyl N-(2- trifluoromethyl-4-pyridyl)carbamate (Intermediate I-6) instead of phenyl N-(3,4,5- trifluorophenyl)carbamate (Intermediate I-4).
  • Example 6 (15 mg) was obtained as a white solid.
  • Example 7 As two separated isomers, Example 7-1 and
  • Example 7-1 8 mg, white solid, LCMS (M+H + ): 424.2, 1 H NMR (400MHz,
  • Example 7-2 40 mg, white solid, LCMS (M+H + ): 424.2, 1 H NMR (400MHz,
  • Example 9 Preparation of (6S)-6-methyl-3-[(4S)-4-methyl-2-oxo-oxazolidin-3-yl]-N-(3,4,5- trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide (Example 9)
  • the Example 9 was prepared in analogy to Example 1 by using (4S)-4-methyloxazolidin-2- one (compound 9b) instead of (4S)-4,5,5-trimethyloxazolidin-2-one (compound 1e).
  • Example 10
  • Step 1 preparation of 1,1,1-trifluoro-3-nitro-propan-2-ol (compound 10b)
  • compound 10a 2,2,2-trifluoroethane-1,1-diol
  • CH 3 NO 2 29.5 g, 484.7 mmol
  • Na 2 CO 3 1.8 g, 16.2 mmol
  • the reaction mixture was partitioned between EtOAc (400 mL) and H 2 O (200 mL). The organic phase was washed with brine (200 mL), dried over Na2SO4, and concentrated to give compound 10b (35.0 g, crude) as green-yellow liquid which was used in next step directly.
  • Step 3 preparation of (4R)-4-phenyl-3-[(1S)-2,2,2-trifluoro-1- (nitromethyl)ethyl]oxazolidin-2-one (compound 10d)
  • Step 4 preparation of (4R)-3-[(1S)-1-(aminomethyl)-2,2,2-trifluoro-ethyl]-4-phenyl- oxazolidin-2-one (compound 10e)
  • Step 5 preparation of (5S)-1-[(1R)-2-hydroxy-1-phenyl-ethyl]-5- (trifluoromethyl)imidazolidin-2-one (compound 10f)
  • compound 10f To a solution of (4R)-3-[(1S)-1-(aminomethyl)-2,2,2-trifluoro-ethyl]-4-phenyl-oxazolidin- 2-one (compound 10e, 11.5 g, 41.95 mmol) in MeOH (120 ml) was added NaOH (10.1 g, 251.74 mmol). The reaction mixture was stirred for 2 hours at 80 o C.
  • Step 6 preparation of tert-butyl (6S)-3-[(4S)-3-[(1R)-2-hydroxy-1-phenyl-ethyl]-2-oxo- 4-(trifluoromethyl)imidazolidin-1-yl]-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5- carboxylate (compound 10g)
  • Compound 10g was prepared in analogy to tert-butyl (6S)-6-methyl-3-[(4S)-4,5,5- trimethyl-2-oxo-oxazolidin-3-yl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 1f) by using (5S)-1-[(1R)-2-hydroxy-1-phenyl-ethyl]-5- (trifluoromethyl)imidazolidin-2-one (compound 10f) instead of (4S)-4,5,5-trimethyloxazolidin- 2-one (compound 1e).
  • Compound 10g was obtained as a brown solid (0.42 g).
  • Step 7 preparation of tert-butyl (6S)-6-methyl-3-[(4S)-2-oxo-4- (trifluoromethyl)imidazolidin-1-yl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 10h)
  • Example 10 Preparation of (6S)-6-methyl-3-[(4S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl]-N- (3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide (Example 10)
  • the Example 10 was prepared in analogy to Example 1 by using tert-butyl (6S)-6-methyl-3- [(4S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5- carboxylate (compound 10h) instead of tert-butyl (6S)-6-methyl-3-[(4S)-4,5,5-trimethyl-2-oxo- oxazolidin-3-yl]-6,7-dihydro-4H-pyrazolo[1,5-
  • Example 10 (41 mg) was obtained as a white solid.
  • Example 11 Example 11
  • Step 1 preparation of tert-butyl N-[(1S)-2-[(4-methoxyphenyl)methylamino]-1- methyl-ethyl]carbamate (compound 11b)
  • compound 11a 4.0 g, 22.8 mmol
  • Et 3 N 6.9 g, 68.4 mmol
  • DCM 150 mL
  • Step 3 preparation of(4S)-1-[(4-methoxyphenyl)methyl]-4-methyl-3-[(6S)-6-methyl- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl]imidazolidin-2-one (compound 11d)
  • Step 4 preparation of (5S)-5-methyl-1-[(6S)-6-methyl-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazin-3-yl]imidazolidin-2-one (compound 11e)
  • Step 5 preparation of (6S)-6-methyl-3-[(5S)-5-methyl-2-oxo-imidazolidin-1-yl]-N- (3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide (Example 11)
  • Step 1 preparation of tert-butyl N-[(1S)-2-[methoxy(methyl)amino]-1-methyl-2-oxo- ethyl]carbamate (compound 12b)
  • Step 2 preparation of tert-butyl N-[(1S)-1-methyl-2-oxo-propyl]carbamate
  • Step 4 Preparation of tert-butyl (6S)-3-[(4S,5S)-4,5-dimethyl-2-oxo-oxazolidin-3-yl]-6- methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 12f-1) and tert- butyl (6S)-3-[(4S,5R)-4,5-dimethyl-2-oxo-oxazolidin-3-yl]-6-methyl-6,7-dihydro-4H- pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 12f-2)
  • Example 12 was prepared in analogy to Example 1 by using tert-butyl (6S)-3-[(4S,5S)- 4,5-dimethyl-2-oxo-oxazolidin-3-yl]-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5- carboxylate (compound 12f-1) instead of tert-butyl (6S)-6-methyl-3-[(4S)-4,5,5-trimethyl-2-oxo- oxazolidin-3-yl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 1f) and phenyl N-[2-(difluoromethyl)-4-pyridyl]carbamate (Intermediate I-8) instead of phenyl N-(3,4,5- trifluorophenyl)carbamate (Intermediate I-4).
  • Example 12 (30 mg) was obtained as white solid.
  • Example 13 was prepared in analogy to Example 1 by using tert-butyl (6S)-3- [(4S,5R)-4,5-dimethyl-2-oxo-oxazolidin-3-yl]-6-methyl-6,7-dihydro-4H-pyrazolo[1,5- a]pyrazine-5-carboxylate (compound 12f-2) instead of tert-butyl (6S)-6-methyl-3-[(4S)-4,5,5- trimethyl-2-oxo-oxazolidin-3-yl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate
  • Example 16 was prepared in analogy to Example 1 by using tert-butyl (6S)-3-[(4S,5S)- 4,5-dimethyl-2-oxo-oxazolidin-3-yl]-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5- carboxylate (compound 12f-1) instead of tert-butyl (6S)-6-methyl-3-[(4S)-4,5,5-trimethyl-2-oxo- oxazolidin-3-yl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 1f) and phenyl N-(2,6-difluoro-4-pyridyl)carbamate (Intermediate I-9) instead of phenyl N-(3,4,5- trifluorophenyl)carbamate (Intermediate I-4).
  • Example 16 (22 mg) was obtained as white solid.
  • Example 17 Example 17
  • Example 17 was prepared in analogy to Example 1 by using tert-butyl (6S)-3- [(4S,5R)-4,5-dimethyl-2-oxo-oxazolidin-3-yl]-6-methyl-6,7-dihydro-4H-pyrazolo[1,5- a]pyrazine-5-carboxylate (compound 12f-2) instead of tert-butyl (6S)-6-methyl-3-[(4S)-4,5,5- trimethyl-2-oxo-oxazolidin-3-yl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 1f) and phenyl N-(2,6-difluoro-4-pyridyl)carbamate (Intermediate I-9) instead of phenyl N-(3,4,5-trifluorophenyl)carbamate (Intermediate I-4).
  • Example 17 (28 mg) was obtained as white solid.
  • Example 18
  • Example 18 was prepared in analogy to Example 1 by using phenyl N-(2,6-difluoro-4- pyridyl)carbamate (Intermediate I-9) instead of phenyl N-(3,4,5-trifluorophenyl)carbamate (Intermediate I-4).
  • Example 18 (34 mg) was obtained as a white solid.
  • Example 19 was prepared in analogy to Example 1 by using 5,5-dimethyloxazolidin- 2-one (compound 19b) instead of (4S)-4,5,5-trimethyloxazolidin-2-one (compound 1e) and phenyl N-(2,6-difluoro-4-pyridyl)carbamate (Intermediate I-9) instead of phenyl N-(3,4,5- trifluorophenyl)carbamate (Intermediate I-4).
  • Example 19 (44 mg) was obtained as a white solid.
  • the compound 20b was prepared in analogy to 5,5-dimethyloxazolidin-2-one (compound 19b) by using 1-(aminomethyl)cyclopropanol instead of 1-amino-2-methyl-propan-2- ol(compound 19a) and The compound 20b (330.0 mg) was obtained as a white solid.
  • Example 20 was prepared in analogy to Example 1 by using 4-oxa-6- azaspiro[2.4]heptan-5-one (compound 20b) instead of (4S)-4,5,5-trimethyloxazolidin-2-one (compound 1e) and phenyl N-(2-chloro-4-pyridyl)carbamate (Intermediate I-5) instead of phenyl N-(3,4,5-trifluorophenyl)carbamate (Intermediate I-4).
  • Example 20 (15 mg) was obtained as a white solid.
  • Example 21 was prepared in analogy to Example 1 by using 4-oxa-6- azaspiro[2.4]heptan-5-one (compound 20b) instead of (4S)-4,5,5-trimethyloxazolidin-2-one (compound 1e) and phenyl N-(2,6-difluoro-4-pyridyl)carbamate (Intermediate I-9) instead of phenyl N-(3,4,5-trifluorophenyl)carbamate (Intermediate I-4).
  • Example 21(34 mg) was obtained as a white solid.
  • Example 22 was prepared in analogy to Example 1 by using 4-oxa-6- azaspiro[2.4]heptan-5-one (compound 20b) instead of (4S)-4,5,5-trimethyloxazolidin-2-one (compound 1e) and phenyl N-[2-(difluoromethyl)-4-pyridyl]carbamate (Intermediate I-8) instead of phenyl N-(3,4,5-trifluorophenyl)carbamate (Intermediate I-4).
  • Example 22 (40 mg) was obtained as a white solid.
  • Example 23 was prepared in analogy to Example 1 by using 4-oxa-6- azaspiro[2.4]heptan-5-one (compound 20b) instead of (4S)-4,5,5-trimethyloxazolidin-2-one (compound 1e) and phenyl N-(2-trifluoromethyl-4-pyridyl)carbamate (Intermediate I-6) instead of phenyl N-(3,4,5-trifluorophenyl)carbamate (Intermediate I-4).
  • Example 22 (40 mg) was obtained as white solid.
  • Example 24 was prepared in analogy to Example 1 by using (7S)-7-methyl-4-oxa-6- azaspiro[2.4]heptan-5-one (compound 24b) instead of (4S)-4,5,5-trimethyloxazolidin-2-one (compound 1e) and phenyl N-(2,6-difluoro-4-pyridyl)carbamate (Intermediate I-9) instead of phenyl N-(3,4,5-trifluorophenyl)carbamate (Intermediate I-4).
  • Example 24 (15 mg) was obtained as a white solid.
  • Example 25 was prepared in analogy to Example 1 by using (7S)-7-methyl-4-oxa-6- azaspiro[2.4]heptan-5-one (compound 24b) instead of (4S)-4,5,5-trimethyloxazolidin-2-one (compound 1e) and phenyl N-[2-(difluoromethyl)-4-pyridyl]carbamate (Intermediate I-8) instead of phenyl N-(3,4,5-trifluorophenyl)carbamate (Intermediate I-4).
  • Example 25 (20 mg) was obtained as a white solid.
  • Step 1 preparation of (3aR,7aR)-1,3,3a,4,5,6,7,7a-octahydrobenzimidazol-2-one (compound 26b)
  • Step 2 preparation of tert-butyl (6S)-3-[(3aR,7aR)-2-oxo-3a,4,5,6,7,7a-hexahydro- 3H-benzimidazol-1-yl]-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 26c)
  • Step 3 preparation of (3aR,7aR)-3-[(6S)-6-methyl-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazin-3-yl]-3a,4,5,6,7,7a-hexahydro-1H-benzimidazol-2-one 2,2,2-trifluoroacetic acid (compound 26d)
  • the mixture of tert-butyl (6S)-3-[(3aR,7aR)-2-oxo-3a,4,5,6,7,7a-hexahydro-3H- benzimidazol-1-yl]-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate compound 26c, 260 mg, 692 ⁇ mol
  • 2,2,2-trifluoroacetic acid (2.0 mL) in DCM (5.0 mL) was stirred at room temperature for 30 minutes.
  • the reaction mixture was concentrated to afford crude compound 26d
  • Step 1 preparation of (3aR,6aS)-3,3a,4,5,6,6a-hexahydrocyclopenta[d]oxazol-2-one (compound 27b)
  • Step 2 preparation of tert-butyl (6S)-3-[(3S,6aS)-2-oxo-4,5,6,6a-tetrahydro-3aH- cyclopenta[d]oxazol-3-yl]-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 27c)
  • Step 3 preparation of (6S)-3-[(3aR,6aS)-2-oxo-4,5,6,6a-tetrahydro-3aH- cyclopenta[d]oxazol-3-yl]-6-methyl-N-(3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5- a]pyrazine-5-carboxamide (Example 27)
  • Example 28 was prepared in analogy to Example 27 by using tert-butyl 2-oxo- 1,3a,4,5,6,6a-hexahydrocyclopenta[d]imidazole-3-carboxylate (compound 28b) instead of (3aR,6aS)-3,3a,4,5,6,6a-hexahydrocyclopenta[d]oxazol-2-one (compound 27b).
  • Example 28 120 mg was obtained as a white solid, LCMS (M+H+): 435.2, 1 H NMR (400MHz,
  • Example 29 was prepared in analogy to Example 27 by using (1R,2S)-2- aminocyclopentanol hydrochloride instead of (1S,2R)-2-aminocyclopentanol hydrochloride (compound 27a).
  • Example 29 (80 mg) was obtained as a white solid.
  • Step 2 Preparation of tert-butyl (6S)-6-methyl-3-(2-oxo-3a,4,6,6a- tetrahydrofuro[3,4-d]oxazol-3-yl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 30c)
  • Step 3 Preparation of (6S)-6-methyl-3-(2-oxo-3a,4,6,6a-tetrahydrofuro[3,4- d]oxazol-3-yl)-N-(3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5- carboxamide
  • 6S tert-butyl-6-methyl-3-(2-oxo-3a,4,6,6a-tetrahydrofuro[3,4-d]oxazol- 3-yl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 30c, 420 mg, 1.15 mmol) in DCM (10 mL) was added TFA (3 mL), the mixture was stirred at room temperature for 30 min, then concentrated.
  • Step 1 preparation of dimethyl 1,3-dibenzyl-2-oxo-imidazolidine-4,5-dicarboxylate (compound 31b)
  • Step 4 preparation of 3-benzyl-3a,4,6,6a-tetrahydro-1H-furo[3,4-d]imidazol-2-one (compound 31e)
  • Step 5 preparation of tert-butyl (6S)-3-(1-benzyl-2-oxo-3a,4,6,6a-tetrahydrofuro[3,4- d]imidazol-3-yl)-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate
  • Step 6 preparation of tert-butyl (6S)-6-methyl-3-(2-oxo-3a,4,6,6a-tetrahydro-1H- furo[3,4-d]imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate
  • Example 31 was prepared in analogy to Example 1 by using tert-butyl (6S)-6-methyl- 3-(2-oxo-3a,4,6,6a-tetrahydro-1H-furo[3,4-d]imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[1,5- a]pyrazine-5-carboxylate (compound 31g) instead of tert-butyl (6S)-6-methyl-3-[(4S)-4,5,5- trimethyl-2-oxo-oxazolidin-3-yl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 1f).
  • Example 31 (6.2 mg) was obtained as white solid.
  • Example 32 Example 32
  • Step 6 preparation of [4-benzyloxy-2-(tert-butoxycarbonylamino)cyclopentyl] methanesulfonate (compound 32g)
  • Step 8 preparation of tert-butyl N-[2-amino-4-benzyloxy-cyclopentyl]carbamate (compound 32i)
  • Step 9 preparation of 5-benzyloxy-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[d]imidazol- 2-one (compound 32j)
  • Step 10 preparation of tert-butyl (6S)-3-(5-benzyloxy-2-oxo-1,3a,4,5,6,6a- hexahydrocyclopenta[d]imidazol-3-yl)-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine- 5-carboxylate (compound 32k)
  • Compound 32k was prepared in analogy to tert-butyl (6S)-6-methyl-3-[(4S)-4,5,5- trimethyl-2-oxo-oxazolidin-3-yl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 1f) by using 5-benzyloxy-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[d]imidazol-2-one (compound 32j) instead of (4S)-4,5,5-trimethyloxazolidin-2-one (compound 1e).
  • Compound 32k was obtained as a brown solid (115.0 mg).
  • Step 12 preparation of 5-hydroxy-3-[(6S)-6-methyl-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazin-3-yl]-1,3a,4,5,6,6a-hexahydrocyclopenta[d]imidazol-2-one (compound 32m)
  • Step 13 preparation of (6S)-3-(5-hydroxy-2-oxo-1,3a,4,5,6,6a- hexahydrocyclopenta[d]imidazol-3-yl)-6-methyl-N-(3,4,5-trifluorophenyl)-6,7-dihydro-4H- pyrazolo[1,5-a]pyrazine-5-carboxamide (Example 32)
  • Example 33 was prepared in analogy to Example 1 by using 3-hydroxy-4-(2- pyridyl)pyrrolidin-2-one (compound 33c-1 or 33c-2) instead of (4S)-4,5,5-trimethyloxazolidin-2- one (compound 1e).
  • Cis-isomer 33c-1 gave two isomers of Example 33, Example 33-1 and Example 33-2, after SFC separation (Chiralcel OD-3100 ⁇ 4.6 mm ID, 3um; mobile phase, methanol (0.05% DEA) in CO 2 from 5% to 40%).
  • Example 33-2 (6 mg), white solid, LCMS (M+H + ): 487.3.
  • 1 H NMR 400MHz, MeOD
  • Trans-isomer 33c-2 gave another two isomers of Example 33, Example 33-3 and Example 33-4, after SFC separation (Chiralpak AS-3100 ⁇ 4.6mm ID, 3um; mobile phase, ethanol (0.05% DEA) in CO 2 from 5% to 40%)
  • Example 33-3 (7 mg), white solid. LCMS (M+H + ): 487.3.
  • Example 33-4 (7 mg), white solid, LCMS (M+H + ): 487.3.
  • Step 1 preparation of tert-butyl N-[(1S)-2-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5- ylidene)-2-hydroxy-1-methyl-ethyl]carbamate (compound 37b)
  • Step 4 preparation of (4S,5S)-4-hydroxy-5-methyl-pyrrolidin-2-one (compound 37e)
  • compound 37e tert-butyl (2S,3S)-3-hydroxy-2-methyl-5-oxo-pyrrolidine-1- carboxylate (compound 37d, 1.8 g, 8.36 mmol) in DCM (60 mL) was added TFA (6 mL) dropwise at 0°C.
  • the reaction was stirred at 0°C for 1 hour and then stirred at room temperature for 14 hours.
  • the reaction was concentrated and then toluene (50mL) was added to the residue, and the solution was concentrated to afford crude compound 37e (1.0 g) as a brown oil.
  • Example 37 was prepared in analogy to Example 1 by using (4S,5S)-4-hydroxy-5- methyl-pyrrolidin-2-one (compound 37e) instead of (4S)-4,5,5-trimethyloxazolidin-2-one (compound 1e).
  • Example 37 was obtained (628.0 mg) as a yellow solid.
  • Step 1 preparation of methyl 3-[benzyl-[(1S)-1-phenylethyl]amino]butanoate (compound 38b)
  • n-Butyllithium solution (46.0 mL, 115.0 mmol) was added dropwise to a solution of (1S)- N-benzyl-1-phenyl-ethanamine (compound 38a, 25.0 g, 118.3 mmol) in THF (270 mL) at -10 o C under nitrogen.
  • the resulting red solution of lithium amide was cooled to -78 o C and a solution of methyl (E)-but-2-enoate (10.7 g, 106.5 mmol) in THF (30 mL) was added by cannula.
  • the reaction mixture was stirred at -78 o C for 1 hour, then quenched with saturated ammonium chloride solution, and extracted with EtOAc twice.
  • Step 2 preparation of O4-ethyl O1-methyl 2-[1-[benzyl-[(1S)-1- phenylethyl]amino]ethyl]butanedioate (compound 38c)
  • Step 4 preparation of tert-butyl (6S)-3-[(2S,3S)-3-methoxycarbonyl-2-methyl-5-oxo- pyrrolidin-1-yl]-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate
  • Example 38 was prepared according to the following scheme:
  • Step 1 preparation of (2S,3S)-1-[(6S)-5-tert-butoxycarbonyl-6-methyl-6,7-dihydro- 4H-pyrazolo[1,5-a]pyrazin-3-yl]-2-methyl-5-oxo-pyrrolidine-3-carboxylic acid (compound 38f)
  • Step 6 preparation of tert-butyl (6S)-6-methyl-3-[(2S,3S)-2-methyl-3-(morpholine-4- carbonyl)-5-oxo-pyrrolidin-1-yl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 38g)
  • Example 39 was obtained as a solid (38.6 mg).
  • Step 1 preparation of ethyl 1-[(2,4-dimethoxyphenyl)methyl]-4-hydroxy-5-oxo-2H- pyrrole-3-carboxylate (compound 40a)
  • Step 2 preparation of ethyl 4-hydroxy-5-oxo-1,2-dihydropyrrole-3-carboxylate (compound 40b)
  • Step 3 preparation of ethyl 4-hydroxy-5-oxo-pyrrolidine-3-carboxylate (compound 40c)
  • ethyl 4-hydroxy-5-oxo-1,2-dihydropyrrole-3-carboxylate compound 40b, 15.0 g, 87.7 mmol
  • EtOH 200 mL
  • ammonium chloride 23.4 g, 438.2 mmol
  • zinc powder 28.6 g, 438.2 mmol
  • the mixture was stirred at 80 o C for 18 hours and filtered.
  • the filtrate was concentrated and purified by reversed-phase column chromatography to give compound 40c (63.0 g, crude) as a yellow oil.
  • Step 4 preparation of ethyl 4-[tert-butyl(dimethyl)silyl]oxy-5-oxo-pyrrolidine-3- carboxylate (compound 40d)
  • Step 5 tert-butyl (6S)-3-[3-[tert-butyl(dimethyl)silyl]oxy-4-ethoxycarbonyl-2-oxo- pyrrolidin-1-yl]-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (I-40)
  • An oven-dried sealable Schlenk tube was charged with (1R,2R)-N1,N2- dimethylcyclohexane-1,2-diamine (0.42 g, 3.0 mmol), K 3 PO 4 (7.0 g, 33.0 mmol), evacuated and backfilled with argon.
  • Example 40 was prepared according to the following scheme.
  • Step 1 preparation of 1-[(6S)-5-tert-butoxycarbonyl-6-methyl-6,7-dihydro-4H- pyrazolo[1,5-a]pyrazin-3-yl]-4-[tert-butyl(dimethyl)silyl]oxy-5-oxo-pyrrolidine-3- carboxylic acid (compound 40f)
  • Step 2 preparation of tert-butyl (6S)-3-[3-[tert-butyl(dimethyl)silyl]oxy-4-carbamoyl- 2-oxo-pyrrolidin-1-yl]-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 40g)
  • Step 3 preparation of tert-butyl (6S)-3-[3-[tert-butyl(dimethyl)silyl]oxy-4-cyano-2- oxo-pyrrolidin-1-yl]-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 40h)
  • Step 4 preparation of (6S)-3-[3-[tert-butyl(dimethyl)silyl]oxy-4-cyano-2-oxo- pyrrolidin-1-yl]-6-methyl-N-(3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5- a]pyrazine-5-carboxamide (compound 40i)
  • Step 5 preparation of (6S)-3-(3,4-trans-4-cyano-3-hydroxy-2-oxo-pyrrolidin-1-yl)-6- methyl-N-(3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide (Example 40)
  • Example 41 was obtained as a solid (9.7 mg). LCMS (M+H + ): 435. 1 H NMR (400MHz,
  • Step 1 preparation of tert-butyl (6S)-3-[(2S,3S)-3-carbamoyl-2-methyl-5-oxo- pyrrolidin-1-yl]-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate
  • Step 2 preparation of tert-butyl (6S)-3-[(2S,3S)-3-cyano-2-methyl-5-oxo-pyrrolidin-1- yl]-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 42c)
  • Step 3 preparation of (6S)-3-[(2S,3S)-3-cyano-2-methyl-5-oxo-pyrrolidin-1-yl]-N-[2- (difluoromethyl)-4-pyridyl]-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5- carboxamide (Example 42)
  • Step 1 Preparation of tert-butyl (6S)-3-(3,3-difluoro-2-oxo-pyrrolidin-1-yl)-6- methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 43a)
  • Step 2 Preparation of (6S)-3-(3,3-difluoro-2-oxo-pyrrolidin-1-yl)-6-methyl-N-(3,4,5- trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide
  • Example 43 To a solution of tert-butyl (6S)-3-(3,3-difluoro-2-oxo-pyrrolidin-1-yl)-6-methyl-6,7- dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 43a, 280 mg, 786 ⁇ mol) in DCM (10 mL) was added TFA (3 mL).
  • Example 44 was obtained as a solid (14.6 mg). LCMS (M+H + ): 449.
  • Example 45
  • Example 45 was prepared in analogy to Example 42 by using phenyl N-(2,6-difluoro- 4-pyridyl)carbamate (Intermediate I-9) instead of phenyl N-[2-(difluoromethyl)-4- pyridyl]carbamate (Intermediate I-8).
  • Example 52 50 mg was obtained as white solid.
  • Step 1 preparation of ethyl 4-[(S)-tert-butylsulfinyl]iminopentanoate (compound 47b)
  • a mixture of 5-methyl-3H-furan-2-one (compound 47a, 2.0 g, 20.4 mmol), (S)-2- methylpropane-2-sulfinamide (2.7 g, 22.4 mmol), EtOH (940.0 mg, 20.4 mmol) and Ti(OEt) 4 (9.3 g, 40.8 mmol) in THF (150.0 mL) was stirred at 60 o C for 16 hours under N 2 .
  • the reaction was quenched with saturated aqueous NaHCO3 (60.0 mL) and then filtered.
  • Step 2 preparation of ethyl (4S)-4-[[(S)-tert-butylsulfinyl]amino]pentanoate
  • Step 4 preparation of tert-butyl (6S)-6-methyl-3-[(2S)-2-methyl-5-oxo-pyrrolidin-1- yl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 47e)
  • Step 6 preparation of (6S)-3-[(5S)-3-hydroxy-5-methyl-2-oxo-pyrrolidin-1-yl]-6- methyl-N-(3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide (Example 47)
  • Example 49 was obtained as a a white solid (32 mg).
  • the tittle compound was prepared according to following scheme:
  • Step 1 preparation of tert-butyl 6-[(6S)-6-methyl-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazin-3-yl]-7-oxo-2,6-diazaspiro[3.4]octane-2-carboxylate (compound 53b)
  • Step 2 preparation of tert-butyl 6-[(6S)-5-[(3-chloro-4-fluoro-phenyl)carbamoyl]-6- methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-3-yl]-7-oxo-2,6-diazaspiro[3.4]octane-2- carboxylate (Example 53)
  • Step 1 preparation of tert-butyl (6S)-3-(4-methoxycarbonyl-2-oxo-pyrrolidin-1-yl)-6- methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 54a )
  • a mixture of tert-butyl (6S)-3-iodo-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5- carboxylate (Intermediate I-1, 364 mg, 1.0 mmol), methyl 5-oxopyrrolidine-3-carboxylate (286 mg, 2.0 mmol), (1S,2S)-cyclohexane-1,2-diamine (46 mg, 0.4 mmol), CuI (38 mg, 0.2 mmol) and K 3 PO 4 (636 mg, 3 mmol) in DMSO (10 mL) under N 2 was stirred at microwave for 2 hours at room
  • Step 2 preparation of 1-[(6S)-5-tert-butoxycarbonyl-6-methyl-6,7-dihydro-4H- pyrazolo[1,5-a]pyrazin-3-yl]-5-oxo-pyrrolidine-3-carboxylic acid (compound 54b )
  • Step 3 preparation of tert-butyl (6S)-3-(4-carbamoyl-2-oxo-pyrrolidin-1-yl)-6- methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 54c )
  • Step 4 preparation of tert-butyl (6S)-3-(4-cyano-2-oxo-pyrrolidin-1-yl)-6-methyl-6,7- dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 54d )
  • Step 5 preparation of (6S)-3-(4-cyano-2-oxo-pyrrolidin-1-yl)-N-(2,6-difluoro-4- pyridyl)-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide
  • Example 54 A mixture of tert-butyl (6S)-3-(4-cyano-2-oxo-pyrrolidin-1-yl)-6-methyl-6,7-dihydro-4H- pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 54d, 200 mg, 579 ⁇ mol) and 2,2,2- trifluoroacetic acid (446 ⁇ L, 5.79 mmol) in isopropyl acetate (1 mL) was stirred at 70 o C for 2 hours.
  • Example 54-2 70 mg, white solid.
  • Step 1 preparation of tert-butyl (6S)-6-methyl-3-[(2S,3S)-2-methyl-5-oxo-3- pyrimidin-2-yloxy-pyrrolidin-1-yl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 56a)
  • Step 2 preparation of (6S)-N-(2,6-difluoro-4-pyridyl)-6-methyl-3-[(2S,3S)-2-methyl-5- oxo-3-pyrimidin-2-yloxy-pyrrolidin-1-yl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5- carboxamide (Example 56)
  • Example 62c methyl 3-methyl-5- oxo-pyrrolidine-3-carboxylate (compound 62c) instead of methyl 5-oxopyrrolidine-3- carboxylate.
  • Example 62 was obtained as a solid (25.0 mg).
  • Example 64 was prepared in analogy to Example 53 by using phenyl N-(2,6-difluoro- 4-pyridyl)carbamate (Intermediate I-9) instead of phenyl N-[2-(difluoromethyl)-4- pyridyl]carbamate (Intermediate I-8).
  • Example 64 60 mg was obtained as a white solid.
  • Example 65 and 66 was prepared in analogy to Example 54 by using tert-butyl (6S,7S)-3-iodo-6,7-dimethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate
  • Example 65 Separation of the final product by SFC (chiral column, chiralpak® IC, 5 ⁇ m, 30 ⁇ 250 mm; mobile phase, 60% CO2 and 40% MeOH (MeOH+0.5% NH3H2O); flow rate 80 mL/min, back pressure 100 bar) gave Example 65 as two isomers, Example 65-1 and Example 65-2.
  • Example 65-1 was obtained (60 mg) as white solid.
  • Example 65-2 was obtained (60 mg) as white solid.
  • Example 67 was prepared in analogy to Example 54 by using tert-butyl (6S,7S)-3- iodo-6,7-dimethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (Intermediate I-2) instead of tert-butyl (6S)-3-iodo-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5- carboxylate (Intermediate I-1).
  • Example 67-1 and Example 67-2.
  • Example 67-1 was obtained (60 mg) as white solid.
  • Example 67-2 was obtained (40 mg) as white solid.
  • Example 68 Example 68
  • Example 68 was prepared in analogy to Example 54 by using tert-butyl (6S,7R)-3- iodo-6,7-dimethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (intermediate I-3) instead of tert-butyl (6S)-3-iodo-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5- carboxylate (Intermediate I-1).
  • Example 68 Separation of the final product with SFC (chiral column, chiralpak® IC, 5 ⁇ m, 30 ⁇ 250 mm; mobile phase, 70% CO2 and 30% MeOH (MeOH+0.5% NH 3 H 2 O); flow rate 80 mL/min, back pressure 100 bar) gave Example 68 as two isomers, Example 68-1 and Example 68-2.
  • Example 68-1 was obtained (48 mg) as white solid.
  • Example 68-2 was obtained (53 mg) as white solid.
  • Example 71 Example 71
  • Step 1 preparation of tert-butyl (6S)-3-[2-(aminomethyl)-5-oxo-pyrrolidin-1-yl]-6- methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 71b)
  • Step 2 preparation of tert-butyl (6S)-3-[2-[(dimethylamino)methyl]-5-oxo-pyrrolidin- 1-yl]-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 71c)
  • compound 71b 90.0 mg, 0.26 mmol
  • 1,3,5-trioxane 232.01 mg, 2.58 mmol
  • Step 3 preparation of (6S)-3-[2-[(dimethylamino)methyl]-5-oxo-pyrrolidin-1-yl]-6- methyl-N-(3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide (Example 71)
  • Example 71 was prepared in analogy to Example 1 by using tert-butyl (6S)-3-[2- [(dimethylamino)methyl]-5-oxo-pyrrolidin-1-yl]-6-methyl-6,7-dihydro-4H-pyrazolo[1,5- a]pyrazine-5-carboxylate (compound 71c) instead of tert-butyl (6S)-6-methyl-3-[(4S)-4,5,5- trimethyl-2-oxo-oxazolidin-3-yl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 1f).
  • Example 71 (6.1 mg) was obtained as a colorless oil.
  • LCMS (M+H) + : 451.0, 1 H NMR (400MHz, METHANOL-d 4 ) ⁇ ppm 8.43 (br s, 1H), 7.67 - 7.46 (m, 1H), 7.40 - 7.23 (m, 2H), 5.01 (br s, 2H), 4.48 (d, J 16.9 Hz, 1H), 4.39 - 4.26 (m, 2H), 4.23 - 4.10 (m, 1H), 2.87 - 2.62 (m, 3H), 2.60 - 2.53 (m, 1H), 2.52 - 2.40 (m, 6H), 2.16 - 2.06 (m, 2H), 1.40 - 1.13 (m, 3H).
  • Example 72
  • Example 72 was prepared in analogy to Example 54 by using tert-butyl (6S,7R)-3- iodo-6,7-dimethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (Intermediate I-3) instead of tert-butyl (6S)-3-iodo-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5- carboxylate (Intermediate I-1) and phenyl N-(3,4,5-trifluorophenyl)carbamate (Intermediate I-4) instead of phenyl N-(2,6-difluoro-4-pyridyl)carbamate (Intermediate I-9).
  • Example 72 Separation of the final product by SFC (chiral column, chiralpak® AD-H, 5 ⁇ m, 20 ⁇ 250 mm; mobile phase, 70% CO 2 and 30% MeOH (MeOH+0.5%NH 3 H 2 O); flow rate 65 mL/min, back pressure 100 bar) gave Example 72 as two isomers, Example 72-1 and Example 72-2.
  • Example 72-1 was obtained (40 mg) as a white solid.
  • Example 72-2 was obtained (27 mg) as a white solid.
  • Step 1 preparation of tert-butyl (6S)-6-methyl-3-[2-oxo-4-(2-pyridyl)imidazolidin-1- yl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate & tert-butyl (6S)-6-methyl-3-[2- oxo-5-(2-pyridyl)imidazolidin-1-yl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 79b & 80b) An oven-dried sealable Schlenk tube were charged with (S)-tert-butyl 3-iodo-6-methyl-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (Intermediate I-1, 500 mg, 1.38 mmol), K 3 PO 4 (584 mg, 2.75 mmol), Cu
  • Step 2 preparation of (6S)-6-methyl-3-[2-oxo-4-(2-pyridyl)imidazolidin-1-yl]-N- (3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide (Example 79) and (6S)-6-methyl-3-[2-oxo-5-(2-pyridyl)imidazolidin-1-yl]-N-(3,4,5-trifluorophenyl)- 6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide (Example 80)
  • Step 1 preparation of 3-[(6S)-6-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3- yl]-8-oxa-3-azabicyclo[3.2.1]octan-4-one (compound 83b)
  • the compound 83b was prepared in analogy to compound 11d by using 8-oxa-3- azabicyclo[3.2.1]octan-4-one (compound 83a, for its synthesis refer to Synthesis, 2011, 1113) instead of (4S)-1-[(4-methoxyphenyl)methyl]-4-methyl-imidazolidin-2-one (compound 11c).
  • Compound 83b (15 mg) was obtained as white solid.
  • Step 2 preparation of (6S)-6-methyl-3-(4-oxo-8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-N- (3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide (Example 83)
  • Step 1 Preparation of tert-butyl (6S)-6-methyl-3-(4-oxo-3,8- diazabicyclo[3.2.1]octan-3-yl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 84a)
  • Example 85 was obtained as a white solid.
  • Step 1 Preparation of tert-butyl 3-[(6S)-6-methyl-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazin-3-yl]-4-oxo-3,7-diazabicyclo[3.3.1]nonane-7-carboxylate (compound 87a)
  • Example 87 As two isomers, Example 87-1 (10 mg) and Example 87-2 (8 mg) as white powders.
  • Example 87-1 LCMS (M+1): 449.
  • Example 87-2 LCMS (M+1): 449.
  • Example 88 1 H NMR (400MHz, METHANOL-d 4 ) ⁇ pp
  • Example 88 as two isomers, Example 88-1 (6 mg) and Example 88-2 (5 mg), as white powders.
  • Example 88-1 LCMS (M+1): 491.
  • Example 88-2 LCMS (M+1): 491.
  • Example 91 was obtained as a white solid (60 mg).
  • Step 1 preparation of benzyl 6-oxo-3-oxa-7,9-diazabicyclo[3.3.1]nonane-9- carboxylate (compound 93b)
  • Step 2 preparation of benzyl 7-[(6S)-5-tert-butoxycarbonyl-6-methyl-6,7-dihydro- 4H-pyrazolo[1,5-a]pyrazin-3-yl]-6-oxo-3-oxa-7,9-diazabicyclo[3.3.1]nonane-9-carboxylate (compound 93c)
  • the compound 93c was prepared in analogy to compound 1f by using benzyl 6-oxo-3-oxa- 7,9-diazabicyclo[3.3.1]nonane-9-carboxylate (compound 93b) instead of(4S)-4,5,5- trimethyloxazolidin-2-one (compound 1e).
  • Compound 93c (30 mg) was obtained as a white solid.
  • Step 3 preparation of tert-butyl (6S)-6-methyl-3-(6-oxo-3-oxa-7,9- diazabicyclo[3.3.1]nonan-7-yl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 93d)
  • Step 4 preparation of tert-butyl (6S)-3-(9-acetyl-6-oxo-3-oxa-7,9- diazabicyclo[3.3.1]nonan-7-yl)-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5- carboxylate (compound 93e)
  • Step 5 preparation of (6S)-3-(9-acetyl-6-oxo-3-oxa-7,9-diazabicyclo[3.3.1]nonan-7-yl)- 6-methyl-N-(3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide (Example 93)
  • Example 93 was prepared in analogy to Example 1 by using b tert-butyl (6S)-3-(9-acetyl- 6-oxo-3-oxa-7,9-diazabicyclo[3.3.1]nonan-7-yl)-6-methyl-6,7-dihydro-4H-pyrazolo[1,5- a]pyrazine-5-carboxylate (compound 93e) instead of tert-butyl (6S)-6-methyl-3-[(4S)-4,5,5- trimethyl-2-oxo-oxazolidin-3-yl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate
  • Step 1 preparation of ethyl 2-cyano-3-hydroxy-2-methyl-propanoate (compound 94b)
  • ethyl 2-cyanopropanoate 40.0 g, 314.6 mmol
  • ethanol 400 mL
  • potassium carbonate 124.4 g, 943.8 mmol
  • paraformaldehyde 14.2 g, 471.9 mmol
  • the reaction mixture was stirred at 25 o C for 12 hours.
  • the reaction mixture was filtered and the filtrate was concentrated.
  • the residue was dissolved in ethyl acetate, washed with brine.
  • the organic phase was concentrated, then purified by column chromatography to give compound 94b (16.0 g) as colorless oil.
  • Step 2 preparation of ethyl 2-(aminomethyl)-3-hydroxy-2-methyl-propanoate hydrochloride (compound 94c)
  • ethyl 2-cyano-3-hydroxy-2-methyl-propanoate compound 94b, 16.0 g, 101.8 mmol
  • platinum oxide 2.3 g, 10.2 mmol
  • hydrogen chloride 4 M in dioxane, 50.9 mL, 203.6 mmol.
  • the reaction mixture was stirred at 25 o C for 12 hours under hydrogen atmosphere (50 Psi).
  • the reaction mixture was filtered and the filtrate was concentrated to give compound 94c (19.4 g, crude) as a colorless oil.
  • Step 3 preparation of O3-tert-butyl O5-ethyl 5-methyl-2-oxo-1,3-oxazinane-3,5- dicarboxylate (compound 94d)
  • the reaction mixture was stirred for 12 h at 25 o C.
  • the reaction mixture was filtered and the filtrate was concentrated, the obtained residue was partitioned between water and ethyl acetate.
  • the organic phase was washed with brine, concentrated and the residue was purified by column
  • Step 4 preparation of ethyl 5-methyl-2-oxo-1,3-oxazinane-5-carboxylate (compound 94e)
  • Step 5 preparation of 5-methyl-2-oxo-1,3-oxazinane-5-carboxylic acid (compound 94f)
  • Step 6 preparation of 5-methyl-2-oxo-1,3-oxazinane-5-carboxamide (compound 94g)
  • 5-methyl-2-oxo-1,3-oxazinane-5-carboxylic acid compound 94f, 500 mg, 3.14 mmol
  • 4-methylmorpholine 518 ⁇ L, 4.71 mmol
  • isobutyl chloroformate 491 ⁇ L, 3.77 mmol
  • Step 7 preparation of 5-methyl-2-oxo-1,3-oxazinane-5-carbonitrile (compound 94h)
  • Step 8 preparation of tert-butyl (6S)-3-(5-cyano-5-methyl-2-oxo-1,3-oxazinan-3-yl)- 6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 94i)

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  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Communicable Diseases (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Virology (AREA)
  • Pharmacology & Pharmacy (AREA)
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Abstract

La présente invention concerne des composés de la formule (I) ou des sels pharmaceutiquement acceptables, un énantiomère ou un diastéréomère de ces derniers, où R1 à R4 sont tels que décrits ci-dessus. Les composés peuvent être utiles pour le traitement ou la prophylaxie d'une infection par le virus de l'hépatite B.
PCT/EP2017/067315 2016-07-14 2017-07-11 Composés de 6,7-dihydro-4h-pyrazolo[1,5-a]pyrazine pour le traitement de maladies infectieuses Ceased WO2018011160A1 (fr)

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