USRE49338E1 - Phthalazinone derivatives and manufacturing process thereof - Google Patents

Phthalazinone derivatives and manufacturing process thereof Download PDF

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USRE49338E1
USRE49338E1 US16/447,174 US201416447174A USRE49338E US RE49338 E1 USRE49338 E1 US RE49338E1 US 201416447174 A US201416447174 A US 201416447174A US RE49338 E USRE49338 E US RE49338E
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carbonyl
phthalazin
fluoro
azetidine
benzyl
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Jae-Hoon Kang
Hong-Sub Lee
Yoon-Suk Lee
Joon-Tae Park
Kyung-Mi An
Jin-Ah Jeong
Kyung-Sun Kim
Jeong-Geun Kim
Chang-Hee Hong
Sun-Young Park
Dong-Keun Song
Yong-Don Yun
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Idience Co Ltd
IL Dong Pharmaceutical Co Ltd
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Idience Co Ltd
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Assigned to IL DONG PHARMACEUTICAL CO., LTD. reassignment IL DONG PHARMACEUTICAL CO., LTD. DEMERGER CONVEYANCE EFFECTIVE AUG. 2, 2016 Assignors: IL DONG HOLDINGS CO., LTD.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/08—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing alicyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to phthalazinone derivates, isomers, pharmaceutically acceptable salt thereof and on its study for medicinal uses.
  • TNBC Poly ADP ribose polymerase
  • the PARP is the one of repairing enzyme for damaged single-stranded DNA breakes.
  • the damage of single strand consecutively generates defects in double-stranded DNA.
  • the defects of double strand can be recovered by BRCA protein complex.
  • the cancer patients who inheritantly lost repairing path of BRCA protein complex by the mutation of BRCA1/BRCA2 can increase dependancy on the PARP pathway of DNA repairing.
  • the cancer cell has higher dependance on PARP path than normal cell.
  • the PARP inhibitors fundamentally block the repairing system of cancer cell following apoptosis of cancer cell.
  • PARP-1 the most thoroughly studied and PARP-2 being its closest relative.
  • PARP-1 accounts for >90% of the ADP-ribosylation within the cell. Because of the structural homology between PARP-1 and PARP-2, most PARP-1 inhibitors also inhibit PARP-2.
  • the PARP-1 enzyme is a 113 kDa protein with three major structural domains, a DNA binding domain with two zinc fingers, a 55 kDa catalytic domain, which utilizes nicotinamide adenine dinucleotide (NAD+) as a substrate to construct polymers of ADP-ribose on histones and other nuclear acceptor proteins including the automodification domain of PARP-1 itself. It is published and generally accepted that the catalytic activity of PARP-1 is stimulated by DNA damage caused by peroxidation, irradiation, and DNA-damaging chemicals, chemotherapeutic agents.
  • NAD+ nicotinamide adenine dinucleotide
  • PARP-1 enzyme binds to damaged DNA and stimulates polymerization of ADP-ribose resulting in the unwinding of DNA from histones and exposing the damaged DNA for repairing. Accordingly, PARP-1 is associated with DNA repairing and maintenance.
  • TNBC breast cancer is associated with BRCA1 and BRCA2 gene mutations.
  • the central role of the BRCA gene is the recovery of double stranded brake (DSB) through homologous recombination (HR).
  • DSB double stranded brake
  • HR homologous recombination
  • PARP-1 inhibition will lead to an increase in single strand breaks (SSB), the preponderance of these SSBs will eventually lead to increased DSBs.
  • SSB single strand breaks
  • the increase of DSBs in BRCA1/BRCA2 gene mutation cancer patients in the presence of HR deficient cell types leads to chromosomal aberrations and instability of the genome resulting in cell death.
  • a conventionally known PARP inhibitor Olaparib (WO2002036576, WO2003093261, US2004876080, US2005059663) are developed for the treatment of cancer, such as, specifically, stomach cancer, ovarian cancer, breast cancer.
  • PARP inhibitors As anticancer agents PARP inhibitors, has been progressed with respect to the prior published clinical literature, has a new mechanism of action for the treatment of cancer. PARP inhibitors are development as first target for personalized medicine based on personal genetic mutation so that worldwide attention is focused. PARP inhibitors have been reported to exhibit in particular a significant effect on cancer caused by genetic mutations in BRCA1/2, and the present invention with new mechanism for the treatment of cancer patients with genetic variation in BRCA1/2 genes is expected to open a new chapter.
  • An object of the present invention is to provide a novel phthalazinone derivative and a process method for preparing.
  • the object of the present invention is to provide medical use for useful treatment of diseases improved by PARP inhibition, or cancers caused by generic defect of BRCA1, BRCA2, and ERG fusion gene.
  • the present invention provides a compound represented by Formula I, racemic, enantiomer, diastereoisomer thereof, or pharmaceutically acceptable salt thereof.
  • n 1 or 2
  • n 0, 1 or 2
  • L is oxygen, methylene, carbonyl, CONHCH 2 , NR c1 CH 2 , NR c2 CO, NR c3 , CONR c4 or CH 2 NR c5 (especially, R c1 , R c2 , R c3 , R c4 and R c5 is each independently oxygen hydrogen, C 1-4 alkylamine, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl or 3-8 membered heterocycle),
  • R X is hydrogen, cyano, hydroxyl, trifluoromethyl, C 1-6 alkyl or C 3-8 cycloalkyl,
  • R Y is hydrogen, amide, cyano, hydroxyl, trifluoromethyl, halo, ester, C 1-4 alkylamine, C 1-6 alkyl, C 1-6 methoxyalkyl or C 2-6 alkynyl,
  • Z is unsubstituted, C 1-6 alkyl, C 1-6 methoxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, C 6-10 aromatic cycle or 3-8 membered heterocycle having 1-3 nitrogens,
  • p and q is each independently from 1 to 3
  • W is CR d1 R d2 or NR d3 (especially, R d1 , R d2 and R d3 is each independently hydrogen, fluoro or C 1-6 alkyl),
  • R 1 , R 2 and R 3 is each independently hydrogen or C 1-6 alkyl.
  • the present invention provides a pharmaceutical composition for treating cancers comprising the compound represented by Formula I, racemic, enantiomer, diastereoisomer thereof, or pharmaceutically acceptable salt thereof.
  • the present invention provides a preparation method of the compound represented by Formula I, racemic, enantiomer, diastereoisomer thereof, or pharmaceutically acceptable salt thereof.
  • the compounds of the present invention are highly active in the suppression of PARP, and according to its pharmaceutical compositions are expected to be useful for therapeutic applications which are improved by suppression of PARP activity, and cancer with mutated BRCA1, BRCA2 and ERG fusion gene in mono or combination treatment with radiation and with chemotherapy.
  • the present invention provides a compound represented by Formula I, racemic, enantiomer, diastereoisomer thereof, or pharmaceutically acceptable salt thereof.
  • n 1 or 2
  • n 0, 1 or 2
  • L is oxygen, methylene, carbonyl, CONHCH 2 , NR c1 CH 2 , NR c2 CO, NR c3 , CONR c4 or CH 2 NR c5 (especially, R c1 , R c2 , R c3 , R c4 and R c5 is each independently oxygen hydrogen, C 1-4 alkylamine, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl or 3-8 membered heterocycle),
  • R X is hydrogen, cyano, hydroxyl, trifluoromethyl, C 1-6 alkyl or C 3-8 cycloalkyl,
  • R Y is hydrogen, amide, cyano, hydroxyl, trifluoromethyl, halo, ester, C 1-4 alkylamine, C 1-6 alkyl, C 1-6 methoxyalkyl or C 2-6 alkynyl,
  • Z is unsubstituted, C 1-6 alkyl, C 1-6 methoxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, C 6-10 aromatic cycle or 3-8 membered heterocycle having 1-3 nitrogens,
  • p and q is each independently from 1 to 3
  • W is CR d1 R d2 or NR d3 (especially, R d1 , R d2 and R d3 is each independently hydrogen, fluoro or C 1-6 alkyl),
  • R 1 , R 2 and R 3 is each independently hydrogen or C 1-6 alkyl.
  • the compound of Formula I is preferably selected form i) or Vii) disclosed below:
  • L is methylene, carbonyl, CONHCH 2 , NR c1 CH 2 , NR c2 CO, NR c3 , CONR c4 or CH 2 NR c5 (especially, R c1 , R c2 , R c3 , R c4 and R c5 is each independently hydrogen, C 1-6 alkyl, C 2-6 alkynyl or C 3-8 cycloalkyl), R X is hydrogen, cyano, hydroxyl, trifluoromethyl, methyl, ethyl or cyclopropyl, R Y is hydrogen, dimethylamide, cyano, hydroxyl, trifluoromethyl, halo, ethylester, dimethylamine, methyl, methoxymethyl or propargyl, Z is unsubstituted, C 1-6 alkyl, C 1-6 methoxyalkyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 6-10 aromatic cycle or 3-8
  • W is CR d1 R d2 or NR d3 (especially R d1 , R d2 and R d3 is each independently hydrogen, fluoro or methyl).
  • R 1 , R 2 and R 3 is each independently hydrogen, methyl or ethyl.
  • L is NR c1 CH 2 , CONR c4 or CH 2 NR c5 (especially, R c1 , R c4 and R c5 is each independently hydrogen, methyl, ethyl, propyl, propargyl or cyclopropyl),
  • L is methylene or carbonyl
  • Z is
  • L is CONHCH 2 or NR c2 CO (especially, R c2 is hydrogen, methyl, ethyl or propyl), Z is
  • C 1-4 alkylamine is a saturated hydrocarbonyl amine with linear or branched chains of 1-4 carbon atoms.
  • exemplary alkylamines include, but are not limited, to methylamine, ethylamine, propylamine, butylamine, 1-methylethylamine, diethylamine or dimethylamine.
  • C 1-6 alkyl is a saturated hydrocarbonyl amine with linear or branched chains of 1-6 carbon atoms.
  • exemplary alkyl include, but are not limited, to methyl, ethyl, propyl, butyl, pentyl, hexyl, 1-methylethyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, 1-methylbutyl, 1,1-dimethylpropyl, 1-methylpentyl or 1,1-dimethylbutyl.
  • C 1-6 alkoxy is an OR group with R as defined above.
  • exemplary alkoxy with 1-6 carbon atoms include, but are not limited, to methoxy, ethoxy, propoxy, butoxy, 1-methylethoxy, 1,1-dimethylethoxy, 1-methylpropoxy, 2-methylpropoxy or cyclopropylmethoxy.
  • halo C 1-6 alkyl is intended as a C 1-6 alkyl radical having one or more hydrogen atoms replaced by a halogen atoms defined above.
  • exemplary haloalkyl include, but are not limited, to difluoromethyl or trifluoromethyl.
  • halo is intended as bromine, fluorine, or chlorine atom.
  • C 2-6 alkenyl is intended as a linear or branched hydrocarbonyl chain of 2-6 carbon atoms and at least one carbon-carbon double bond.
  • Alkenyls have a “cis” or “trans” and “E” or “Z” double bond configuration.
  • Exemplary alkenyl include, but are not limited, to crotyl (—CH 2 CH ⁇ CHCH 3 ), vinyl (—CH ⁇ CH 2 ) or allyl (—CH 2 CH ⁇ CH 2 ).
  • C 2-6 alkynyl is intended as a linear or branched hydrocarbonyl radical with 2-6 carbon atoms and at least one carbon-carbon triple bond.
  • exemplary alkynyl include, but are not limited, to ethynyl(—C ⁇ CH) or propargyl (—CH 2 C ⁇ CH).
  • C 3-8 cycloalkyl is intended as a saturated hydrocarbonyl ring with 3-8 carbon atoms.
  • exemplary cycloalkyl include, but are not limited, to cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • C 3-8 cycloalkenyl is intended as an unsaturated hydrocarbonyl ring with 3-8 carbon atoms and at least one carbon-carbon double bond.
  • Alkenyls have a “cis” or “trans” and “E” or “Z” double bond configuration.
  • Exemplary cycloalkenyl include, but are not limited, to cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, 1,3-cyclohexadiene, 1,4-cyclohexadiene, cycloheptenyl, cyclooctenyl or 1,5-cyclooctadiene.
  • C 6-10 aromatic cycle is intended as an aromatic hydrocarbonyl radical with 6-10 carbon atoms.
  • Exemplary aromatic ring include, but are not limited, to phenyl or naphthyl.
  • heterocycle is intended as a saturated or partially unsaturated hydrocarbonyl mono-tricyclic ring with at least one nitrogen atom.
  • exemplary mono heterocycles with 5-6 atoms include, but are not limited, to pyrrolidinyl, piperidinyl, pyrollyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, triazolyl, thiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, or triazinyl.
  • exemplary bicyclic aromatic ring include, but are not limited, to benzothiazolyl, benzoxazolyl, benzoxazinone, benzoxadiazolyl, 1,3-benzodioxolyl, benzofuryl, benzopyrazinyl, indolyl, indazolyl, benzimidazolyl, benzopyranyl, pyrolopyridanyl, furopyridinyl, or imidazothiazolyl.
  • pharmaceutically acceptable when referring to a component of a pharmaceutical composition means that the component, when administered to an animal, does not have undue adverse effects such as excessive toxicity, irritation, or allergic response commensurate with a reasonable benefit/risk ratio.
  • treatment covers any treatment of a disease in a mammal, particularly a human, and includes inhibiting the disease, i.e., arresting its development; or relieving the disease, i.e. causing regression of the disease and/or its symptoms or conditions and slowing disease progression.
  • the term “therapeutically effective amount” means an amount of a compound of the present invention that ameliorates, attenuates or eliminates a particular disease or condition or prevents or delays the onset of a particular disease or condition.
  • the therapeutically effective amount of the drug may reduce the number of cancer cells; reduce the tumor size; inhibit (i.e., slow to some extent and preferably stop) cancer cell infiltration into peripheral organs; inhibit (i.e., slow to some extent and preferably stop) tumor metastasis; inhibit, to some extent, tumor growth; and/or relieve to some extent one or more of the symptoms associated with the cancer.
  • the drug may prevent growth and/or kill existing cancer cells, it may be cytostatic and/or cytotoxic.
  • the compounds of the invention may contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the invention, including but not limited to, diastereomers, enantiomers and atropisomers, as well as mixtures thereof such as racemic mixtures, form part of the present invention.
  • a specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture.
  • a 50:50 mixture of enantiomers is referred to as a racemic-mixture or a racemate.
  • Diastereomer refers to 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, and reactivities. Mixtures of diastereomers may separate under high resolution analytical procedures such as electrophoresis and chromatography.
  • Enantiomers refer to two stereoisomers of a compound which are non-superimposable mirror images of one another.
  • phrases “pharmaceutically acceptable salt” as used herein, refers to pharmaceutically acceptable organic or inorganic salts of a compound of the invention.
  • Exemplary salts include, but are not limited, to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate “mesylate”, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1′-methylene-bis-(
  • a pharmaceutically acceptable salt may involve the inclusion of another molecule such as an acetate ion, a succinate ion or other counter ion.
  • the counter ion may be any organic or inorganic moiety that stabilizes the charge on the parent compound.
  • a pharmaceutically acceptable salt may have more than one charged atom in its structure. Instances where multiple charged atoms are part of the pharmaceutically acceptable salt can have multiple counter ions. Hence, a pharmaceutically acceptable salt can have one or more charged atoms and/or one or more counter ion.
  • the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methane-sulfonic acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic
  • the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, or the like.
  • suitable salts include, but are not limited to, organic salts derived from amino acids, such as glycine and arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines, such as piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
  • the present invent ion provides a method of preparing the compound represented by Formula I or a pharmaceutically approved salt thereof.
  • a preparation method of the present invention is shown in the following.
  • n and R, illustrated in Scheme 1, are defined as below:
  • n 1 or 2;
  • n 0, 1 or 2
  • L is oxygen, methylene, carbonyl, CONHCH 2 , NR c1 CH 2 , NR c2 CO, NR c3 , CONR c4 or CH 2 NR c5 (especially, R c1 , R c2 , R c3 , R c4 and R c5 is each independently oxygen hydrogen, C 1-4 alkylamine, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl or 3-8 membered heterocycle),
  • R X is hydrogen, cyano, hydroxyl, trifluoromethyl, C 1-6 alkyl or C 3-8 cycloalkyl,
  • R Y is hydrogen, amide, cyano, hydroxyl, trifluoromethyl, halo, ester, C 1-4 alkylamine, C 1-6 alkyl, C 1-6 methoxyalkyl or C 2-6 alkynyl,
  • Z is unsubstituted, C 1-6 alkyl, C 1-6 methoxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, C 6-10 aromatic cycle or 3-8 membered heterocycle having 1-3 nitrogens,
  • p and q is each independently from 1 to 3
  • W is CR d1 R d2 or NR d3 (especially, R d1 , R d2 and R d3 is each independently hydrogen, fluoro or C 1-6 alkyl),
  • R 1 , R 2 and R 3 is each independently hydrogen or C 1-6 alkyl.
  • the preparation method of the Formula I comprise:
  • Step 2 Preparing a compound of Formula 6 from a compound of Formula 4 and 5 which reacted with olefination reaction (Step 2)
  • Step 3 Preparing a compound of Formula I from a compound of Formula 6 and hydrazine monohydrate which reacted with condensation reaction (Step 3)
  • the compound of Formula 4 can be prepared from Formula 2 by amide coupling in the above Step 1.
  • An Amide coupling reaction is carried out with 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) and 4-(Dimethylamino)pyridine (DMAP) or O-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU) and N,N-diisopropyl ethylamine (DIPEA).
  • solvents useful in the react ion include chloroform or dimethyl formamide.
  • the reaction is heated to 20 ⁇ 35° C. for 1 ⁇ 30 hours, so as to obtain the compound of Formula 4.
  • the compound of Formula 6 can be prepared from Formula 4 by olefination in the above Step 2.
  • An olefination reaction is carried out with Formula 5 in basic condition.
  • solvent useful in the reaction include THF.
  • the reaction is cooled to 0° C. for 1 ⁇ 5 hours, so as to abtain the compound of Formula 6.
  • the compound of Formula I can be prepared from Formula 6 by condensation in the above Step 3.
  • a condensation reaction is carried out with hydrazine monohydrate.
  • Example of solvent useful in the react ion includes water.
  • the react ion is heated to 30 ⁇ 70° C. for 20 hours, so as to obtain the compound of Formula I.
  • the present invention provides another method of preparing the compound represented by Formula I or a pharmaceutically approved salt thereof.
  • n 1 or 2;
  • R 4 and R 5 is each independently tert-butyldimethylsiloxyl
  • n 0, 1 or 2
  • L is oxygen, methylene, carbonyl, CONHCH 2 , NR c1 CH 2 , NR c2 CO, NR c3 , CONR c4 or CH 2 NR c5 (especially, R c1 , R c2 , R c3 , R c4 and R c5 is each independently oxygen hydrogen, C 1-4 alkylamine, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl or 3-8 membered heterocycle),
  • R X is hydrogen, cyano, hydroxyl, trifluoromethyl, C 1-6 alkyl or C 3-8 cycloalkyl,
  • R Y is hydrogen, amide, cyano, hydroxyl, trifluoromethyl, halo, ester, C 1-4 alkylamine, C 1-6 alkyl, C 1-6 methoxyalkyl or C 2-6 alkynyl,
  • Z is unsubstituted, C 1-6 alkyl, C 1-6 methoxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, C 6-10 aromatic cycle or 3-8 membered heterocycle having 1-3 nitrogens,
  • p and q is each independently from 1 to 3
  • W is CR d1 R d2 or NR d3 (especially, R d1 , R d2 and R d3 is each independently hydrogen, fluoro or C 1-6 alkyl),
  • R 1 , R 2 and R 3 is each independently hydrogen or C 1 - 6 alkyl.
  • Another preparation method of the Formula I comprises
  • Step 2 Preparing a compound of Formula 9 from a compound of Formula 8 and 5 which reacted with olefination reaction (Step 2)
  • Step 3 Preparing a compound of Formula 10 from a compound of Formula 9 and hydrazine monohydrate which reacted with condensation reaction (Step 3)
  • Step 5 Preparing a compound of Formula I from a compound of Formula 11 which reacted with amide coupling, substitution and reductive amination reaction (Step 5)
  • the compound of Formula 8 can be prepared from Formula 7 by amide coupling in the above Step 1.
  • An Amide coupling reaction is carried out with 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) and 4-(Dimethylamino)pyridine (DMAP) or O-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU) and N,N-diisopropyl ethylamine (DIPEA).
  • solvents useful in the react ion include chloroform or dimethyl formamide. The react ion is heated to 20 ⁇ 35° C. for 1 ⁇ 30 hours, so as to obtain the compound of Formula 8.
  • the compound of Formula 9 can be prepared from Formula 8 by olefination in the above Step 2.
  • An olefination reaction is carried out with Formula 5 in basic condition.
  • solvent useful in the reaction include THF.
  • the reaction is cooled to 0° C. for 1 ⁇ 5 hours, so as to abtain the compound of Formula 9.
  • the compound of Formula 10 can be prepared from Formula 9 by condensation in the above Step 3.
  • a condensation reaction is carried out with hydrazine monohydrate.
  • Example of solvent useful in the reaction includes water. The reaction is heated to 30 ⁇ 70° C. for 20 hours, so as to obtain the compound of Formula 10.
  • the compound of Formula 11 can be prepared from Formula 10 by carboxybenzyl or tert-butyloxycarbonyl
  • the compound of Formula I can be prepared from Formula 11 by amide coupling, substitution and reductive amination reaction.
  • a step 5 of the Scheme 2 is described in more detail as follows.
  • the compound of Formula I can be prepared with amide coupling, substitution and reductive amination.
  • the reaction is carried out with 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) and 4-(Dimethylamino)pyridine (DMAP) or O-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU) and N,N-diisopropyl ethylamine (DIPEA).
  • solvents useful in the react ion include chloroform or dimethylformamide, so as to obtain the compound of Formula I. An example is illustrated below.
  • the compound of Formula I can be prepared with from substitution.
  • mesylate compound is prepared from alcohol compound by reaction with methanesulfonyl chloride in dichloromethane. And then, desired functional group can be introduced by reaction of mesylate compound with
  • the present invention provides a pharmaceutical omposition for treating cancers comprising the compound of Formula I, racemic, enantiomer, diastereoisomer thereof, or pharmaceutically acceptable salt thereof.
  • the cancers may be caused by PARP activity, or generic defect of BRCA1, BRCA2, and ERG fusion gene.
  • Exemplary cancers include, but are not limited to breast cancer, ovarian cancer, pancreatic cancer, gastric cancer, lung cancer, colorectal cancer, brain tumor, prostate cancer and Ewings sarcoma.
  • the term “generic defect” is intended as gene mutation, gene deficiency or defect of gene expression, but is not limited thereto.
  • the present invention provides a method of treating cancers in a subject in need thereof, comprising administering an effective amount of the pharmaceutical composition to the subject.
  • the dosage of pharmaceutical composition of the present invention may vary depending on the patient's weight, age, gender, physical condition, diet, the time and mode of administration, excretion rates, and the severity of illness. Mammals (including human) are desirable for the individual without limit.
  • compositions suitable for the delivery of compounds of the present invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation may be found, for example, in Remingtons Pharmaceutical Sciences, 19th Edition (Mack Publishing Company, 1995).
  • the present invention provides compound, specifically, active in inhibiting the activity of PARP.
  • Compounds of the invention can be used in cancer treatment through inhibition of PARP.
  • Exemplary include lung cancer, gastrointestinal cancer, prostate cancer, uterine cancer, or especially breast cancer, or ovarian cancer.
  • Compounds of the invent ion may be combined in a pharmaceutical combination formulation, or dosing regimen as combination therapy, with a second compound having anti-cancer properties or at least two kinds of pharmaceutical active ingredients.
  • agents include: oxaliplatin (ELOXATIN®, Sanofi), bortezomib (VELCADE®, Millennium Pharm.), sutent (SUNITINIB®, SU11248, Pfizer), letrozole (FEMARA®, Novartis), imatinib mesylate (GLEEVEC®, Novartis), XL-518 (Mek inhibitor, Exelixis, WO 2007/044515), ARRY-886 (Mek inhibitor, AZD6244, Array Bio-Pharma, Astra Zeneca), SF-1126 (PI3K inhibitor, Semafore Pharmaceuticals), BEZ-235 (PI3K inhibitor, Novartis), XL-147 (PI3K inhibitor, Exelixis), PTK787/ZK 222584 (Novartis), fulvestrant (FASLODEX®, AstraZeneca), leucovorin (folinic acid), rapamycin (sirolimus, RAPA
  • dynemicin dynemicin A
  • bisphosphonates such as clodronate
  • an esperamicin as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores
  • aclacinomysins actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin,
  • compounds of the invention especially formula I or pharmaceutically acceptable salt can be administered simultaneously, gradually, or individually with at least one of therapeutic agents.
  • the compounds of the invent ion may be administered orally.
  • Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, and/or buccal, lingual, or sublingual administration by which the compound enters the blood stream directly from the mouth.
  • Formulations suitable for oral administration include solid plugs, solid microparticulates, semi-solid and liquid (including multiple phases or dispersed systems) such as tablets; soft or hard capsules containing multi- or nanoparticulates, liquids, emulsions or powders; lozenges (including liquid-lled); chews; gels; fast dispersing dosage forms; lms; ovules; sprays; and buccal/mucoadhesive patches.
  • Liquid (including multiple phases and dispersed systems) formulations include emulsions, suspensions, solutions, syrups and elixirs.
  • Such formulations may be presented as llers in soft or hard capsules (made, for example, from gelatin or hydroxypropylmethylcellulose) and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents.
  • a carrier for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil
  • emulsifying agents and/or suspending agents may also be prepared by the reconstitution of a solid, for example, from a sachet.
  • the compounds of the invention may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, 11 (6), 981-986 by Liang and Chen (2001).
  • the immediate release portion may comprise a disintegrant.
  • disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, powdered cellulose, lower alkyl-substituted hydroxypropyl cellulose, polacrilin potassium, starch, pregelatinized starch, sodium alginate, and mixtures thereof.
  • the disintegrant will comprise from 1 wt % to 80 wt %, preferably from 5 wt % to 60 wt % of the layer.
  • matrix materials, fillers, or diluents include lactose, mannitol, xylitol, dextrose, sucrose, sorbitol, compressible sugar, microcrystalline cellulose, powdered cellulose, starch, pregelatinized starch, dextrates, dextran, dextrin, dextrose, maltodextrin, calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, magnesium carbonate, magnesium oxide, poloxamers, polyethylene oxide, hydroxypropyl methyl cellulose and mixtures thereof.
  • the compounds may also be blended with conventional excipients such as binders, including gelatin, pregelatinized starch, and the like; lubricants, such as hydrogenated vegetable oil, stearic acid, and the like; diluents, such as lactose, mannose, and sucrose; disintegrants, such as carboxymethylcellulose and sodium starch glycolate; suspending agents, such as povidone, polyvinyl alcohol, and the like; absorbants, such as silicon dioxide; preservatives, such as methylparaben, propylparaben, and sodium benzoate; surfactants; such as sodium lauryl sulfate, polysorbate 80, and the like; flavorants; and sweeteners.
  • binders including gelatin, pregelatinized starch, and the like
  • lubricants such as hydrogenated vegetable oil, stearic acid, and the like
  • diluents such as lactose, mannose, and sucrose
  • disintegrants such as carboxymethylcellulose and
  • the surfactants would comprise of 0.2 wt % to 5 wt % and the absorbants would comprise from 0.2 wt % to 1 wt %.
  • Another excipients include one or more of: anti-oxidants, colourants, flavouring agents, preservatives and taste-masking agents.
  • Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tabletting.
  • the final formulation may comprise one or more layers and may be coated or uncoated; it may even be encapsulated.
  • Sol id formulations for oral administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release
  • the compounds of the invention may also be administered directly into the blood stream, into muscle, or into an internal organ.
  • Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous.
  • Suitable devices for parenteral administration includes needle (including microneedle) injectors, needle-free injectors and infusion techniques.
  • needle including microneedle
  • needle-free injectors and infusion techniques.
  • An example of a needle free injection is PowderjectTM.
  • Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohy-drates and buffering agents (preferably, to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile nonaqueous solution or as a powdered, dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.
  • excipients such as salts, carbohy-drates and buffering agents (preferably, to a pH of from 3 to 9)
  • a suitable vehicle such as sterile, pyrogen-free water.
  • parenteral formulations under sterile conditions may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.
  • a proper dosage form such as combination with solubility enhancer can increase solubility of compound of formula I used in non-oral solution.
  • Formulations for parenteral administration may be formulated to be immediate and/or modified/controlled release.
  • Controlled/modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • compounds of the invent ion may be formulated as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active compound. Examples of such formulations include drug-coated stents and PGLA microspheres.
  • the compounds of the invention may also be administered topically to the skin or mucosa, that is, dermally or transdermally.
  • Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages and microemulsions.
  • Li-posomes may also be used.
  • the precise daily dose administered depends on various factors such as the age, sex, weight and condition of the patient being treated.
  • the amount of dose can be selected within the bounds of goal achieving treatment effect without harmful or serious adverse effect.
  • the dosage of the compound of invention may be administered in an effective amount raging from 0.05 to 1000 mg daily on patients.
  • the following dosage levels and other dosage levels herein are for the average human subject having a weight range of about 65 to 70 kg. The skilled person will readily be able to determine the dosage levels required for a subject whose weight falls outside this range, such as children and the elderly.
  • Step 1 Preparation of ((R)-benzyl(1-(2-fluoro-5-formylbenzoyl)pyrrolidin-3-yl)carbamate
  • Step 2 Preparation of (R,Z)-benzyl(1-(2-fluoro-5-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)benzoyl)pyrrolidin-3-yl)carbamate
  • Step 1 The intermediate compound (Step 1)(236 mg, 0.62 mmol) and triethylamine (0.12 mL, 0.81 mmol) was added to a solution of dimethyl (3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (220 mg, 0.91 mmol) in THF (1.7 mL) and stirred for 5 hours at 0° C.
  • Step 3 Preparation of (R)-benzyl(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pyrrolidin-3-yl)carbamate
  • Step 2 Hydrazine monohydrate (19 uL, 0.38 mmol) was added to a suspension of the intermediate compound (Step 2)(164 mg, 0.35 mmol) in water (1.5 mL) and stirred for 2 hours at 40° C. The reaction was cooled to room temperature and concentrated in vacuum. Water was added to the react ion mixture and the product was extracted into dichloromethane.
  • Step 4 Preparation of (R)-4-(3-(3-aminopyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one
  • step 3 (100 mg, 0.20 mmol) and 10 wt. % Pd/C (10 mg) in methanol (30 mL) was hydrogenated at atmosphere for 6 h.
  • the reaction mixture was filtered, evaporated in vacuum and purified using silica chromatography to afford the title compound (63 mg, 85%).
  • Step 2 Preparation of (S,Z)-benzyl(1-(2-fluoro-5-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)benzoyl)pyrrolidin-3-yl)carbamate
  • This compound was made using the procedure described for example 1 (Step 2).
  • this intermediate compound (Step 1) was reacted with dimethyl (3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (102 mg, 0.42 mmol) and triethyl amine (88 uL, 0.63 mmol) to afford the intermediate compound (S,Z)-benzyl (1-(2-fluoro-5-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)benzoyl)pyrrolidin-3-yl)carbamate (117 mg, 57%).
  • Step 3 Preparation of (S)-benzyl(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pyrrolidin-3-yl)carbamate
  • This compound was made using the procedure described for example 1 (Step 3).
  • this intermediate compound (Step 2) was reacted with hydrazine monohydrate (24 uL, 0.48 mmol) to afford the intermediate compound (S)-benzyl (1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl) benzoyl)pyrrolidin-3-yl)carbamate (58 mg, 48%).
  • Step 4 Preparation of (S)-4-(3-(3-aminopyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one
  • Step 1 Preparation of benzyl(1-(2-fluoro-5-formylbenzoyl)azetidin-3-yl)carbamate
  • Step 2 Preparation of (Z)-benzyl(1-(2-fluoro-5-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)benzoyl)azetidin-3-yl)carbamate
  • This compound was made using the procedure described for example 1 (Step 2).
  • this intermediate compound (Step 1) (604 mg, 1.69 mmol) was reacted with dimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (410 mg, 1.69 mmol) and triethylamine (0.35 mL, 2.54 mmol) to afford the intermediate compound (Z)-benzyl (1-(2-fluoro-5-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)benzoyl)azetidin-3-yl)carbamate (497 mg, 62%).
  • Step 3 Preparation of benzyl(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)carbamate
  • This compound was made using the procedure described for example 1 (Step 3).
  • this intermediate compound (Step 2)(497 mg, 1.05 mmol) was reacted with hydrazine monohydrate (0.1 mL, 2.1 mmol) to afford the intermediate compound benzyl (1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)carbamate (261 mg, 51%).
  • Step 4 Preparation of 4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one
  • Step 1 Preparation of (R)-3-(3-((tert-butyldimethylsilyl)oxy)pyrrolidine-1-carbonyl)-4-fluorobenzaldehyde
  • Step 2 Preparation of (R,Z)-3-(3-(3-((tert-butyldimethylsilyl)oxy)pyrrolidine-1-carbonyl)-4-fluorobenzylidene)isobenzofuran-1(3H)-one
  • This compound was made using the procedure described for example 1 (Step 2).
  • this intermediate compound (Step 1) (377 mg, 1.07 mmol) was reacted with dimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (260 mg, 1.07 mmol) and trietylamine (0.22 mL, 1.61 mmol) to afford the intermediate compound (R,Z)-3-(3-(3-((tert-butyldimethylsilyl)oxy)pyrrolidine-1-carbonyl)-4-fluorobenzyidene)isobenzofuran-1(3H)-one (300 mg, 60%).
  • Step 3 Preparation of ((R)-4-(3-(3-((tert-butyldimethylsilyl)oxy)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one
  • This compound was made using the procedure described for example 1 (Step 3).
  • this intermediate compound (Step 2) (300 mg, 0.64 mmol) was reacted with hydrazine monohydrate (63 uL, 1.28 mmol) to afford the intermediate compound (R)-4-(3-(3-((tert-butyldimethylsilyl)oxy)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (148 mg, 48%).
  • step 3 (148 mg, 0.30 mmol) in THF (3 mL) cooled to 0° C. was added 1M solution of tetra-n-butylammonium fluoride in THF (TBAF, 0.60 mL, 0.60 mmol), and the mixture was stirred at room temperature for 3 h.
  • the reaction mixture was concentrated in vacuum, added dichloromethane and washed with sat. NH 4 Cl (ag) and water.
  • the combined organic layers were dried over MgSO 4 , filtered, evaporated in vacuum and purified using silica chromatography to afford the title compound (101 mg, 92%).
  • Step 1 Preparation of (S)-3-(3-((tert-butyldimethylsilyl)oxy)pyrrolidine-1-carbonyl)-4-fluorobenzaldehyde
  • Step 2 Preparation of (S,Z)-3-(3-(3-((tert-butyldimethylsilyl)oxy)pyrrolidine-1-carbonyl)-4-fluorobenzylidene)isobenzofuran-1(3H)-one
  • This compound was made using the procedure described for example 1 (Step 2).
  • this intermediate compound (Step 1) (377 mg, 1.07 mmol) was reacted with dimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (260 mg, 1.07 mmol) and trietylamine (0.22 mL, 1.61 mmol) to afford the intermediate compound (S,Z)-3-(3-(3-((tert-butyldimethylsilyl)oxy)pyrrolidine-1-carbonyl)-4-fluorobenzylidene)isobenzofuran-1(3H)-one (300 mg, 60%).
  • Step 3 Preparation of (S)-4-(3-(3-((tert-butyldimethylsilyl)oxy)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one
  • This compound was made using the procedure described for example 1 (Step 3).
  • this intermediate compound (Step 2) (300 mg, 0.64 mmol) was reacted with hydrazine monohydrate (63 uL, 1.28 mmol) to afford the intermediate compound (S)-4-(3-(3-((tert-butyldimethylsilyl)oxy)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (148 mg, 48%).
  • Step 1 Preparation of 3-(3-((tert-butyldimethylsilyl)oxy)azetidine-1-carbonyl)-4-fluorobenzaldehyde
  • Step 2 Preparation of (Z)-3-(3-(3-((tert-butyldimethylsilyl)oxy)azetidine-1-carbonyl)-4-fluorobenzylidene)isobenzofuran-1(3H)-one
  • This compound was made using the procedure described for example 1 (Step 2).
  • this intermediate compound (Step 1) (378 mg, 1.12 mmol) was reacted with dimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (271 mg, 1.12 mmol) and trietylamine (0.23 mL, 1.68 mmol) to afford the intermediate compound (Z)-3-(3-(3-((tert-butyldimethylsilyl)oxy)azetidine-1-carbonyl)-4-fluorobenzylidene)isobenzofuran-1(3H)-one (284 mg, 56%).
  • Step 3 Preparation of 4-(3-(3-((tert-butyldimethylsilyl)oxy)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one
  • This compound was made using the procedure described for example 1 (Step 3).
  • this intermediate compound (Step 2)(284 mg, 0.62 mmol) was reacted with hydrazine monohydrate (61 uL, 1.26 mmol) to afford the intermediate compound 4-(3-(3-((tert-butyldimethylsilyl)oxy)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (149 mg, 51%).
  • Step 1 Preparation of 3-(3-(((tert-butyldimethylsilyl)oxy)methyl)azetidine-1-carbonyl)-4-fluorobenzaldehyde
  • Step 2 Preparation of (Z)-3-(3-(3-(((tert-butyldimethylsilyl)oxy)methyl)azetidine-1-carbonyl)-4-fluorobenzylidene)isobenzofuran-1(3H)-one
  • This compound was made using the procedure described for example 1 (Step 2).
  • this intermediate compound (Step 1) (378 mg, 1.12 mmol) was reacted with dimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (271 mg, 1.12 mmol) and trietylamine (0.23 mL, 1.68 mmol) to afford the intermediate compound (Z)-3-(3-(3-(((tert-butyldimethylsilyl)oxy)methyl)azetidine-1-carbonyl)-4-fluorobenzylidene)isobenzofuran-1(3H)-one (284 mg, 56%).
  • Step 3 Preparation of 4-(3-(3-(((tert-butyldimethylsilyl)oxy)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one
  • This compound was made using the procedure described for example 1 (Step 3).
  • this intermediate compound (Step 2)(284 mg, 0.63 mmol) was reacted with hydrazine monohydrate (61 uL, 1.25 mmol) to afford the intermediate compound 4-(3-(3-(((tert-butyldimethylsilyl)oxy)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (149 mg, 51%).
  • Step 4 Preparation of 4-(4-fluoro-3-(3-(hydroxymethyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one
  • Step 1 Preparation of (R)—N-(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pyrrolidin-3-yl)cyclopropanecarboxamide
  • Step 1 Preparation of N-(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)cyclopropanecarboxamide
  • Step 1 Preparation of (S)—N-(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pyrrolidin-3-yl)cyclopropanecarboxamide
  • Step 1 Preparation of (R)—N-(1-(2-fluoro-5-formylbenzoyl)pyrrolidin-3-yl)-N-methylcyclopropanecarboxamide
  • Step 2 Preparation of (R,Z)—N-(1-(2-fluoro-5-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)benzoyl)pyrrolidin-3-yl)-N-methylcyclopropanecarboxamide
  • Trietylamine (0.38 mL, 2.21 mmol) was added drop-wide to a solution of the intermediate compound (Step 1)(470 mg, 1.48 mmol) and dimethyl (3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (357 mg, 1.48 mmol) in THF (1.7 mL) and stirred for 5 hours at 0° C.
  • Step 3 Preparation of (R)—N-(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pyrrolidin-3-yl)-N-methylcyclopropanecarboxamide
  • Step 1 Preparation of N-(1-(2-fluoro-5-formylbenzoyl)azetidin-3-yl)-N-methylcyclopropanecarboxamide
  • Step 2 Preparation of (Z)—N-(1-(2-fluoro-5-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)benzoyl)azetidin-3-yl)-N-methylcyclopropanecarboxamide
  • This compound was made using the procedure described for example 11 (Step 2).
  • this intermediate compound (Step 1) (256 mg, 0.84 mmol) was reacted with dimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (204 mg, 0.84 mmol) and trietylamine (0.17 mL, 1.26 mmol) to afford the intermediate compound (Z)—N-(1-(2-fluoro-5-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)benzoyl)azetidin-3-yl)-N-methylcyclopropanecarboxamide (202 mg, 57%).
  • Step 3 Preparation of N-(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)-N-methylcyclopropanecarboxamide
  • Step 1 Preparation of (S)—N-(1-(2-fluoro-5-formylbenzoyl)pyrrolidin-3-yl)-N-methylcyclopropanecarboxamide
  • Step 2 Preparation of (S,Z)—N-(1-(2-fluoro-5-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)benzoyl)pyrrolidin-3-yl)-N-methylcyclopropanecarboxamide
  • This compound was made using the procedure described for example 11 (Step 2).
  • this intermediate compound (Step 1) (470 mg, 1.48 mmol) was reacted with dimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (357 mg, 1.48 mmol) and trietylamine (0.31 mL, 2.12 mmol) to afford the intermediate compound (S,Z)—N-(1-(2-fluoro-5-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)benzoyl)pyrrolidin-3-yl)-N-methylcyclopropanecarboxamide (397 mg, 62%).
  • Step 3 Preparation of (S)—N-(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pyrrolidin-3-yl)-N-methylcyclopropanecarboxamide
  • Step 1 Preparation of 3-(3-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)azetidine-1-carbonyl)-4-fluorobenzaldehyde
  • Step 2 Preparation of (Z)-3-(1-(2-fluoro-5-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)benzoyl)azetidin-3-yl)-5,5-dimethylimidazolidine-2,4-dione
  • This compound was made using the procedure described for example 11 (Step 2).
  • this intermediate compound (Step 1) (152 mg, 0.45 mmol) was reacted with dimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (111 mg, 0.45 mmol) and trietylamine (96 uL, 0.68 mmol) to afford the intermediate compound (Z)-3-(1-(2-fluoro-5-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)benzoyl)azetidin-3-yl)-5,5-dimethylimidazolidine-2,4-dione (89 mg, 43%).
  • Step 3 Preparation of 3-(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)-5,5-dimethylimidazolidine-2,4-dione
  • Step 1 Preparation of (R)-3-(3-(2,5-dioxoimidazolidin-1-yl)pyrrolidine-1-carbonyl)-4-fluorobenzaldehyde
  • Step 2 Preparation of (R,Z)-3-(1-(2-fluoro-5-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)benzoyl)pyrrolidin-3-yl)imidazolidine-2,4-dione
  • This compound was made using the procedure described for example 11 (Step 2).
  • this intermediate compound (Step 1) (158 mg, 0.50 mmol) was reacted with dimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (120 mg, 0.50 mmol) and trietylamine (58 uL, 0.42 mmol) to afford the intermediate compound (R,Z)-3-(1-(2-fluoro-5-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)benzoyl)pyrrolidin-3-yl)imidazolidine-2,4-dione (93 mg, 43%).
  • Step 3 Preparation of (R)-3-(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pyrrolidin-3-yl)imidazolidine-2,4-dione
  • Step 1 Preparation of (R)-3-(3-(3-ethyl-2,5-dioxoimidazolidin-1-yl)pyrrolidine-1-carbonyl)-4-fluorobenzaldehyde
  • Step 2 Preparation of (R,Z)-1-ethyl-3-(1-(2-fluoro-5-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)benzoyl)pyrrolidin-3-yl)imidazolidine-2,4-dione
  • This compound was made using the procedure described for example 11 (Step 2).
  • this intermediate compound (Step 1) (197 mg, 0.56 mmol) was reacted with dimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (137 mg, 0.56 mmol) and trietylamine (0.12 mL, 0.85 mmol) to afford the intermediate compound (R,Z)-1-ethyl-3-(1-(2-fluoro-5-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)benzoyl)pyrrolidin-3-yl)imidazolidine-2,4-dione (134 mg, 51%).
  • Step 3 Preparation of (R)-1-ethyl-3-(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pyrrolidin-3-yl)imidazolidine-2,4-dione
  • Step 1 Preparation of 4-fluoro-3-(3-(4-fluoropiperidine-1-carbonyl)azetidine-1-carbonyl)benzaldehyde
  • Step 2 Preparation of (Z)-3-(4-fluoro-3-(3-(4-fluoropiperidine-1-carbonyl)azetidine-1-carbonyl)benzylidene)isobenzofuran-1(3H)-one
  • This compound was made using the procedure described for example 11 (Step 2).
  • this intermediate compound (Step 1) (261 mg, 0.64 mmol) was reacted with dimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (156 mg, 0.64 mmol) and trietylamine (0.13 mL, 0.96 mmol) to afford the intermediate compound (Z)-3-(4-fluoro-3-(3-(4-fluoropiperidine-1-carbonyl)azetidine-1-carbonyl)benzylidene)isobenzofuran-1(3H)-one (140 mg, 48%).
  • Step 3 Preparation of 4-(4-fluoro-3-(3-(4-fluoropiperidine-1-carbonyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one
  • Step 1 Preparation of 3-(3-(3,3-difluoroazetidine-1-carbonyl)azetidine-1-carbonyl)-4-fluorobenzaldehyde
  • Step 2 Preparation of (Z)-3-(3-(3-(3,3-difluoroazetidine-1-carbonyl)azetidine-1-carbonyl)-4-fluorobenzylidene)isobenzofuran-1(3H)-one
  • This compound was made using the procedure described for example 11 (Step 2).
  • this intermediate compound (Step 1) (222 mg, 0.68 mmol) was reacted with dimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (164 mg, 0.68 mmol) and trietylamine (0.14 mL, 1.02 mmol) to afford the intermediate (Z)-3-(3-(3-(3,3-difluoroazetidine-1-carbonyl)azetidine-1-carbonyl)-4-fluorobenzylidene)isobenzofuran-1(3H)-one (145 mg, 48%).
  • Step 3 Preparation of 4-(3-(3-(3,3-difluoroazetidine-1-carbonyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one
  • Step 1 Preparation of 3-(3-(3,3-difluoropyrrolidine-1-carbonyl)azetidine-1-carbonyl)-4-fluorobenzaldehyde
  • Step 2 Preparation of (Z)-3-(3-(3-(3,3-difluoropyrrolidine-1-carbonyl)azetidine-1-carbonyl)-4-fluorobenzylidene)isobenzofuran-1(3H)-one
  • This compound was made using the procedure described for example 11 (Step 2).
  • this intermediate compound (Step 1) (214 mg, 0.63 mmol) was reacted with dimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (152 mg, 0.63 mmol) and trietylamine (0.13 mL, 0.94 mmol) to afford the intermediate compound (Z)-3-(3-(3-(3,3-difluoropyrrolidine-1-carbonyl)azetidine-1-carbonyl)-4-fluorobenzylidene)isobenzofuran-1(3H)-one (138 mg, 48%).
  • Step 3 Preparation of 4-(3-(3-(3,3-difluoropyrrolidine-1-carbonyl-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one
  • Step 1 Preparation of 3-(3-(3,3-difluoropyrrolidine-1-carbonyl)pyrrolidine-1-carbonyl)-4-fluorobenzaldehyde
  • Step 2 Preparation of (Z)-3-(3-(3-(3,3-difluoropyrrolidine-1-carbonyl)pyrrolidine-1-carbonyl)-4-fluorobenzylidene)isobenzofuran-1(3H)-one
  • This compound was made using the procedure described for example 11 (Step 2).
  • this intermediate compound (Step 1) (218 mg, 0.62 mmol) was reacted with dimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (149 mg, 0.62 mmol) and trietylamine (0.13 mL, 0.93 mmol) to afford the intermediate compound (Z)-3-(3-(3-(3,3-difluoropyrrolidine-1-carbonyl)pyrrolidine-1-carbonyl)-4-fluorobenzylidene)isobenzofuran-1(3H)-one (139 mg, 48%).
  • Step 3 Preparation of 4-(3-(3-(3,3-difluoropyrrolidine-1-carbonyl)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one
  • Step 2 Preparation of (R,Z)—N-(cyclopropylmethyl)-1-(2-fluoro-5-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)benzoyl)pyrrolidine-3-carboxamide
  • This compound was made using the procedure described for example 11 (Step 2).
  • this intermediate compound (Step 1) (266 mg, 0.84 mmol) was reacted with dimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (203 mg, 0.84 mmol) and trietylamine (0.18 mL, 1.26 mmol) to afford the intermediate compound (R,Z)—N-(cyclopropylmethyl)-1-(2-fluoro-5-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)benzoyl)pyrrolidine-3-carboxamide (186 mg, 51%).
  • Step 3 Preparation of (R)—N-(cyclopropylmethyl)-1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pyrrolidine-3-carboxamide
  • Step 1 Preparation of 4-fluoro-3-(3-(pyrrolidine-1-carbonyl)azetidine-1-carbonyl)benzaldehyde
  • Step 2 Preparation of (Z)-3-(4-fluoro-3-(3-(pyrrolidine-1-carbonyl)azetidine-1-carbonyl)benzylidene)isobenzofuran-1(3H)-one
  • This compound was made using the procedure described for example 11 (Step 2).
  • this intermediate compound (Step 1)(244 mg, 0.80 mmol) was reacted with dimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (194 mg, 0.80 mmol) and trietylamine (0.17 mL, 1.21 mmol) to afford the intermediate compound (Z)-3-(4-fluoro-3-(3-(pyrrolidine-1-carbonyl)benzylidene)isobenzofuran-1(3H)-one (172 mg, 51%).
  • Step 1 Preparation of (R)-3-(3-(3-(dimethylamino)pyrrolidine-1-carbonyl)azetidine-1-carbonyl)-4-fluorobenzaldehyde
  • Step 2 Preparation of (R,Z)-3-(3-(3-(3-(dimethylamino)pyrrolidine-1-carbonyl)azetidine-1-carbonyl)-4-fluorobenzylidene)isobenzofuran-1(3H)-one
  • This compound was made using the procedure described for example 11 (Step 2).
  • this intermediate compound (Step 1) (150 mg, 0.44 mmol) was reacted with dimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (106 mg, 0.44 mmol) and trietylamine (92 uL, 0.65 mmol) to afford the intermediate compound (R,Z)-3-(3-(3-(3-(3-(dimethylamino)pyrrolidine-1-carbonyl)azetidine-1-carbonyl)-4-fluorobenzylidene)isobenzofuran-1(3H)-one (102 mg, 51%).
  • Step 3 Preparation of (R)-4-(3-(3-(3-(dimethylamino)pyrrolidine-1-carbonyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one
  • Step 1 Preparation of (S)-3-(3-(3-(dimethylamino)pyrrolidine-1-carbonyl)azetidine-1-carbonyl)-4-fluorobenzaldehyde
  • Step 2 Preparation of (S,Z)-3-(3-(3-(3-(dimethylamino)pyrrolidine-1-carbonyl)azetidine-1-carbonyl)-4-fluorobenzylidene)isobenzofuran-1(3H)-one
  • This compound was made using the procedure described for example 11 (Step 2).
  • this intermediate compound (Step 1) (150 mg, 0.44 mmol) was reacted with dimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (106 mg, 0.44 mmol) and trietylamine (92 uL, 0.65 mmol) to afford the intermediate compound (S,Z)-3-(3-(3-(3-(3-(dimethylamino)pyrrolidine-1-carbonyl)azetidine-1-carbonyl)-4-fluorobenzylidene)isobenzofuran-1(3H)-one (102 mg, 51%).
  • Step 3 Preparation of (S)-4-(3-(3-(3-(dimethylamino)pyrrolidine-1-carbonyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one
  • Step 1 Preparation of 4-(3-(3-(cyclobutylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one
  • Step 1 Preparation of 4-(3-(3-(cyclopropylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one
  • Step 1 Preparation of 4-(3-(3-(cyclopentylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one
  • Step 1 Preparation of 4-(3-(3-(cyclohexylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one
  • Step 1 Preparation of (R)-4-(3-(3-(cyclopropylamino)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one
  • Step 1 Preparation of (R)-4-(3-(3-(cyclobutylamino)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one
  • Step 1 Preparation of (R)-4-(3-(3-(cyclopentylamino)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one
  • Step 1 Preparation of 4-(4-fluoro-3-(3-(isopropylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one
  • Step 1 Preparation of 4-(3-(3-((cyclopropylmethyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one
  • Step 1 Preparation of 4-(3-(3-(bis(cyclopropylmethyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one
  • Step 1 Preparation of 4-(4-fluoro-3-(3-(isobutylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one
  • Step 1 Preparation of 4-(4-fluoro-3-(3-((1-hydroxypropan-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one
  • Step 1 Preparation of 4-(4-fluoro-3-(3-(neopentylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one
  • Step 1 Preparation of 4-(3-(3-((2,2-dimethylcyclopentyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one
  • Step 1 Preparation of ethyl 2-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)amino)cyclopent-1-enecarboxylate
  • Step 1 Preparation of 4-(4-fluoro-3-(3-(pentan-3-ylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one
  • Step 1 Preparation of 4-(4-fluoro-3-(3-((3-methylbutan-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one
  • Step 1 Preparation of 4-(3-(3-((1-cyclopropylethyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one
  • Step 1 Preparation of 4-(3-(3-(bicyclo[2.2.1]heptan-2-ylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one
  • Step 1 Preparation of 4-(3-(3-(sec-butylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one
  • Step 1 Preparation of 4-(3-(3-((dicyclopropylmethyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one
  • Step 1 Preparation of 4-(4-fluoro-3-(3-((4-methylpentan-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one
  • Step 1 Preparation of 4-(4-fluoro-3-(3-((3-hydroxybutan-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one
  • Step 1 Preparation of 4-(4-fluoro-3-(3-(pentan-2-ylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one
  • Step 1 Preparation of 4-(4-fluoro-3-(3-((1-(1-methylcyclopropyl)ethyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one
  • Step 1 Preparation of 4-(4-fluoro-3-(3-((3,3,3-trifluoro-2-methylpropyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one
  • Step 1 Preparation of 4-(3-(3-(allylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one
  • Step 1 Preparation of 4-(4-fluoro-3-(3-(isopentylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one
  • Step 1 Preparation of 4-(3-(3-(butylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one
  • Step 1 Preparation of 4-(4-fluoro-3-(3-((3-methylbut-2-en-1-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one
  • Step 1 Preparation of 4-(3-(3-((cyclopentylmethyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one
  • Step 1 Preparation of 4-(4-fluoro-3-(3-((4,4,4-trifluorobutyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one
  • Step 1 Preparation of 4-(4-fluoro-3-(3-(pentylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one
  • Step 1 Preparation of 4-(3-(3-((2-cyclopropylethyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one
  • Step 1 Preparation of 4-(4-fluoro-3-(3-(propylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one
  • Step 1 Preparation of 4-(4-fluoro-3-(3-((pyridin-4-ylmethyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one
  • isonicotinaldehyde (26 uL, 0.28 mmol) was added to a solution of 4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (example 3)(100 mg, 0.28 mmol) in 1,2-dichloroethane (1.1 mL) and stirred for 30 min then acetic acid (31 uL, 0.54 mmol) and sodium triacetoxyborohydride (114 mg, 0.54 mmol) was added to the reaction mixture at 0° C. and stirred for 12 hours. The reaction mixture was concentrated in vacuum, added 2N NaOH(aq) and extracted into dichloromethane.
  • Step 2 Preparation of 4-(4-fluoro-3-(3-(methyl(pyridin-4-ylmethyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one
  • Step 1 Preparation of (R)-4-(4-fluoro-3-(3-((pyridin-4-ylmethyl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one
  • Step 2 Preparation of (R)-4-(4-fluoro-3-(3-(methyl(pyridin-4-ylmethyl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one
  • This compound was made using the procedure described for example 60 (Step 2).
  • this intermediate compound (Step 1) (106 mg, 0.23 mmol) was reacted with K 2 CO 3 (51 mg, 0.48 mmol) and iodomethane (33 uL, 0.48 mmol) to afford the title compound (98 mg, 91%).
  • Step 1 Preparation of (S)-4-(4-fluoro-3-(3-((pyridin-4-ylmethyl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one
  • Step 2 Preparation of (S)-4-(4-fluoro-3-(3-(methyl(pyridin-4-ylmethyl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one
  • This compound was made using the procedure described for example 60 (Step 2).
  • this intermediate compound (Step 1) (106 mg, 0.24 mmol) was reacted with K 2 CO 3 (51 mg, 0.48 mmol) and iodomethane (33 uL, 0.48 mmol) to afford the title compound (98 mg, 91%).
  • Step 1 Preparation of (S)-4-(4-fluoro-3-(3-((pyridin-2-ylmethyl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one
  • Step 2 Preparation of (S)-4-(4-fluoro-3-(3-(methyl(pyridin-2-ylmethyl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one
  • Step 1 Preparation of (R)-4-(4-fluoro-3-(3-((pyridin-2-ylmethyl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one
  • Step 2 Preparation of (R)-4-(4-fluoro-3-(3-(methyl(pyridin-2-ylmethyl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one
  • Step 1 Preparation of 4-(4-fluoro-3-(3-((pyridin-2-ylmethyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one
  • Step 2 Preparation of 4-(4-fluoro-3-(3-(methyl(pyridin-2-ylmethyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one
  • This compound was made using the procedure described for example 60 (Step 2).
  • this intermediate compound (Step 1) (108 mg, 0.24 mmol) was reacted with K 2 CO 3 (51 mg, 0.48 mmol) and iodomethane (33 uL, 0.48 mmol) to afford the title compound (99 mg, 91%).
  • Step 1 Preparation of 4-(4-fluoro-3-(3-((pyridin-3-ylmethyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one
  • Step 2 Preparation of 4-(4-fluoro-3-(3-(methyl(pyridin-3-ylmethyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one
  • This compound was made using the procedure described for example 60 (Step 2).
  • this intermediate compound (Step 1) (108 mg, 0.24 mmol) was reacted with K 2 CO 3 (51 mg, 0.48 mmol) and iodomethane (33 uL, 0.48 mmol) to afford the title compound (99 mg, 91%).
  • Step 1 Preparation of (S)-4-(4-fluoro-3-(3-((pyridin-3-ylmethyl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one
  • Step 2 Preparation of (S)-4-(4-fluoro-3-(3-(methyl(pyridin-3-ylmethyl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one
  • This compound was made using the procedure described for example 60 (Step 2).
  • this intermediate compound (Step 1) (86 mg, 0.19 mmol) was reacted with K 2 CO 3 (52 mg, 0.38 mmol) and iodomethane (24 uL, 0.38 mmol) to afford the title compound (98 mg, 91%).
  • Step 1 Preparation of (R)-4-(4-fluoro-3-(3-((pyridin-3-ylmethyl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one
  • Step 2 Preparation of (R)-4-(4-fluoro-3-(3-(methyl(pyridin-3-ylmethyl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one
  • This compound was made using the procedure described for example 60 (Step 2).
  • this intermediate compound (Step 1) (86 mg, 0.19 mmol) was reacted with K 2 CO 3 (52 mg, 0.38 mmol) and iodomethane (24 uL, 0.38 mmol) to afford the title compound (98 mg, 91%).
  • Step 1 Preparation of 4-(3-(3-(cyclopropylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one
  • Step 2 Preparation of 4-(3-(3-(cyclopropyl(methyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one
  • This compound was made using the procedure described for example 60 (Step 2).
  • this intermediate compound (Step 1) (58 mg, 0.16 mmol) was reacted with K 2 CO 3 (44 mg, 0.32 mmol) and iodomethane (33 uL, 0.32 mmol) to afford the title compound (62 mg, 95%).
  • Step 1 Preparation of 4-(3-(3-(cyclopropylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one
  • Step 2 Preparation of 4-(3-(3-(cyclopropyl(ethyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one
  • This compound was made using the procedure described for example 60 (Step 2).
  • this intermediate compound (Step 1) (58 mg, 0.16 mmol) was reacted with K 2 CO 3 (44 mg, 0.32 mmol) and iodoethane (33 uL, 0.32 mmol) to afford the title compound (58 mg, 91%).
  • Step 1 Preparation of 4-(3-(3-(cyclobutylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one
  • Step 2 Preparation of 4-(3-(3-(cyclobutyl(methyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one
  • This compound was made using the procedure described for example 60 (Step 2).
  • this intermediate compound (Step 1)(84 mg, 0.21 mmol) was reacted with K 2 CO 3 (57 mg, 0.41 mmol) and iodomethane (25 uL, 0.41 mmol) to afford the title compound (82 mg, 93%).
  • Step 1 Preparation of 4-(3-(3-(cyclopentylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one
  • Step 2 Preparation of 4-(3-(3-(cyclopentyl(prop-2-yn-1-yl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one
  • This compound was made using the procedure described for example 60 (Step 2).
  • this intermediate compound (Step 1) (74 mg, 0.18 mmol) was reacted with K 2 CO 3 (49 mg, 0.35 mmol) and 1N solution of propargyl bromide in toluene (0.35 mL, 0.35 mmol) to afford the title compound (67 mg, 81%).
  • Step 1 Preparation of 4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one
  • Step 2 Preparation of 4-(3-(3-(3,3-difluoropyrrolidin-1-yl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one
  • Step 1 Preparation of 4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one
  • Step 2 Preparation of 4-(4-fluoro-3-(3-(4-fluoropiperidin-1-yl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one
  • Step 2 This compound was made using the procedure described for example 73 (Step 2). Thus, this intermediate compound (Step 1)(162 mg, 0.46 mmol) was reacted with 4-fluoropiperidine (43 uL, 0.46 mmol) and sodium triacetoxyborohydride (227 mg, 1.07 mmol) to afford the title compound (145 mg, 72%).
  • Step 1 Preparation of 4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one
  • Step 2 Preparation of 4-(3-([1,3′-biazetidine]-1′-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one
  • Step 1 Preparation of 4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one
  • Step 2 Preparation of 4-(4-fluoro-3-(3-(pyrrolidin-1-yl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one
  • Step 2 This compound was made using the procedure described for example 73 (Step 2). Thus, this intermediate compound (Step 1)(162 mg, 0.46 mmol) was reacted with pyrrolidine (38 uL, 0.46 mmol) and sodium triacetoxyborohydride (227 mg, 1.07 mmol) to afford the title compound (159 mg, 85%).
  • Step 1 Preparation of 4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one
  • Step 2 Preparation of 4-(4-fluoro-3-(3-(piperidin-1-yl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one
  • Step 2 This compound was made using the procedure described for example 73 (Step 2). Thus, this intermediate compound (Step 1)(162 mg, 0.46 mmol) was reacted with piperidine (43 uL, 0.46 mmol) and sodium triacetoxyborohydride (227 mg, 1.07 mmol) to afford the title compound (162 mg, 85%).
  • Step 1 Preparation of 4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one
  • Step 2 Preparation of 4-(4-fluoro-3-(3-(4-methylpiperazin-1-yl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one
  • Step 2 This compound was made using the procedure described for example 73 (Step 2). Thus, this intermediate compound (Step 1)(162 mg, 0.46 mmol) was reacted with 1-methylpiperazine (50 uL, 0.46 mmol) and sodium triacetoxyborohydride (227 mg, 1.07 mmol) to afford the title compound (90 mg, 45%).
  • Step 1 Preparation of 4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one
  • Step 2 Preparation of 4-(4-fluoro-3-(3-(phenylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one
  • This compound was made using the procedure described for example 73 (Step 2).
  • this intermediate compound (Step 1) (162 mg, 0.46 mmol) was reacted with aniline (42 uL, 0.46 mmol), titanium(IV) epoxide (Ti[OCH 2 (CH 3 ) 4 ], 96 mL, 46 mmol) and sodium triacetoxyborohydride (227 mg, 1.0 mmol) to afford the title compound (43 mg, 22%).
  • Step 1 Preparation of 4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one
  • Step 2 Preparation of 4-(4-fluoro-3-(3-((1-(trifluoromethyl)cyclopropyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one
  • This compound was made using the procedure described for example 73 (Step 2).
  • this intermediate compound (Step 1)(162 mg, 0.46 mmol) was reacted with 1-(trifluoromethyl)cyclopropylamine (74 mg, 0.46 mmol) and sodium triacetoxyborohydride (227 mg, 1.07 mmol) to afford the title compound (51 mg, 24%).
  • Step 1 Preparation of 4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one
  • Step 2 Preparation of 4-(4-fluoro-3-(3-(prop-2-yn-1-ylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one
  • This compound was made using the procedure described for example 73 (Step 2).
  • this intermediate compound (Step 1)(162 mg, 0.46 mmol) was reacted with propargylamine (29 uL, 0.46 mmol) and sodium triacetoxyborohydride (227 mg, 1.07 mmol) to afford the title compound (134 mg, 66%).
  • Step 1 Preparation of 4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one
  • Step 2 Preparation of (S)-4-(4-fluoro-3-(3-((1-methoxypropan-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one
  • Step 1 Preparation of 4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one
  • Step 2 Preparation of (R)-4-(4-fluoro-3-(3-((1-methoxypropan-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one
  • Step 2 This compound was made using the procedure described for example 73 (Step 2). Thus, this intermediate compound (Step 1)(162 mg, 0.46 mmol) was reacted with (R)-1-methoxypropane-2-amine (48 uL, 0.4 mmol) and sodium triacetoxyborohydride (227 mg, 1.07 mmol) to afford the title compound (125 mg, 64%).
  • Step 1 Preparation of 4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one
  • Step 2 Preparation of 4-(4-fluoro-3-(3-((1-(hydroxymethyl)cyclopropyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one
  • This compound was made using the procedure described for example 73 (Step 2).
  • this intermediate compound (Step 1)(162 mg, 0.46 mmol) was reacted with (1-aminocyclopropyl)methanol (40 mg, 0.46 mmol) and sodium triacetoxyborohydride (227 mg, 1.07 mmol) to afford the title compound (84 mg, 43%).
  • Step 1 Preparation of 4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one
  • Step 2 Preparation of 4-(4-fluoro-3-(3-((1-methylcyclopropyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one
  • This compound was made using the procedure described for example 73 (Step 2).
  • this intermediate compound (Step 1)(162 mg, 0.46 mmol) was reacted with 1-methylcyclopropanamine (43 uL, 0.46 mmol) and sodium triacetoxyborohydride (227 mg, 1.07 mmol) to afford the title compound (35 mg, 19%).
  • Step 1 Preparation of 4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one
  • Step 2 Preparation of (R)-4-(3-(3-((3,3-dimethylbutan-2-yl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one
  • Step 1 Preparation of 4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one
  • Step 2 Preparation of (S)-4-(3-(3-((3,3-dimethylbutan-2-yl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one
  • Step 1 Preparation of 4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one
  • Step 2 Preparation of (R)-4-(4-fluoro-3-(3-((3-methylbutan-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one
  • Step 1 Preparation of 4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one
  • Step 2 Preparation of (S)-4-(4-fluoro-3-(3-((3-methylbutan-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one
  • Step 1 Preparation of 4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one
  • Step 2 Preparation of 4-(4-fluoro-3-(3-((1-(methoxymethyl)cyclopropyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one
  • Step 1 Preparation of 4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one
  • Step 2 Preparation of 4-(3-(3-(but-3-yn-1-ylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one
  • Step 1 Preparation of 4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one
  • Step 2 Preparation of 4-(4-fluoro-3-(3-((2-methylallyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one
  • Step 1 Preparation of 4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one
  • Step 2 Preparation of 4-(4-fluoro-3-(3-((3-hydroxy-2,2-dimethylpropyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one
  • Step 2 This compound was made using the procedure described for example 73 (Step 2).
  • the intermediate compound (Step 1)(162 mg, 0.46 mmol) was reacted with 3-amino-2,2-dimethylpropan-1-ol (47 mg, 0.46 mmol), and sodium triacetoxyborohydride (227 mg, 1.07 mmol) to afford the title compound (24 mg, 12%).
  • Step 1 Preparation of 4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one
  • Step 2 Preparation of 1-(((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)amino)methyl)cyclopropanecarbonitrile
  • Step 2 This compound was made using the procedure described for example 73 (Step 2).
  • the intermediate compound (Step 1)(162 mg, 0.46 mmol) was reacted with 1-(aminomethyl)cyclopropanecarbonitrile (44 mg, 0.46 mmol), and sodium triacetoxyborohydride (227 mg, 1.07 mmol) to afford the title compound (91 mg, 46%).
  • Step 1 Preparation of 4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one
  • Step 2 Preparation of 4-(4-fluoro-3-(3-((2,2,2-trifluoroethyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one
  • Step 2 This compound was made using the procedure described for example 73 (Step 2).
  • the intermediate compound (Step 1)(162 mg, 0.46 mmol) was reacted with 2,2,2-trifluoroethaneamine (36 uL, 0.46 mmol), and sodium triacetoxyborohydride (227 mg, 1.07 mmol) to afford the title compound (200 mg, 60%).
  • Step 1 Preparation of 4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one
  • Step 2 Preparation of (R)-tert-butyl-3-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidine-3-yl)amino)pyrrolidin-1-carboxylate
  • the intermediate compound (Step 1, 162 mg, 0.46 mmol) was added to a solution of (R)-tert-butyl-3-aminopyrrolidin-1-carboxylate (25 uL, 0.46 mmol) in dichloromethane (3 mL), methanol (1 mL) and stirred for 30 min then acetic acid (36 uL, 0.69 mmol) and sodium triacetoxyborohydride (144 mg, 0.69 mmol) was added to the reaction mixture at 0° C. and stirred for 12 hours. The reaction mixture was concentrated in vacuo, added 2N NaOH(aq) and extracted into dichloromethane.
  • Step 3 Preparation of (R)-4-(4-fluoro-3-(3-(pyrrolidin-3-ylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one
  • Step 2 The intermediate compound (Step 2)(122 mg, 0.20 mmol) in dichloromethane (4 mL) cooled to 0° C. was added 1.0 N HCl solution (0.40 mL, 0.40 mmol), and the mixture was stirred at room temperature for 3 h. The react ion mixture was concentrated in vacuo, added dichloromethane and washed with 2N NaOH(aq) and water. The combined organic layers were dried over MgSO 4 , filtered, evaporated in vacuo and purified using silica chromatography to afford the title compound (76 mg, 90%).
  • Step 1 Preparation of 4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one
  • Step 2 Preparation of (S)-tert-butyl-3-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidine-3-yl)amino)pyrrolidin-1-carboxylate
  • Step 2 This compound was made using the procedure described for example 96 (Step 2).
  • the intermediate compound (Step 1)(162 mg, 0.46 mmol) was reacted with (S)-tertbutyl-3-aminopyrrolidin-1-carboxylate (25 uL, 0.46 mmol), and sodium triacetoxyborohydride (144 mg, 0.69 mmol) to afford the title compound (122 mg, 43%).
  • Step 3 Preparation of (S)-4-(4-fluoro-3-(3-(pyrrolidin-3-ylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one
  • Step 1 Preparation of 1-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)amino)cyclopentanecarbonitrile
  • Step 1 Preparation of 1-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)amino)cyclobutanecarbonitrile
  • Step 1 Preparation of 2-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)amino)propanenitrile
  • Step 1 Preparation of 2-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)amino)butanenitrile
  • Step 1 Preparation of 2-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)amino)-3-methylbutanenitrile
  • Step 1 Preparation of 2-cyclopropyl-2-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)amino)acetonitrile
  • Step 1 Preparation of 4-(4-fluoro-3-(3-((1-(trifluoromethyl)cyclobutyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one
  • Step 1 Preparation of (S)-4-fluoro-3-(3-(methyl(pyrimidin-2-yl)amino)pyrrolidine-1-carbonyl)benzaldehyde
  • Step 2 Preparation of (S,Z)-3-(4-fluoro-3-(3-(methyl(pyrimidin-2-yl)amino)pyrrolidine-1-carbonyl)benzylidene)isobenzofuran-1(3H)-one
  • Step 2 This compound was made using the procedure described for example 11 (Step 2).
  • the intermediate compound (Step 1) (154 mg, 0.47 mmol) was reacted with dimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (114 mg, 0.47 mmol), triethylamine (98 uL, 0.47 mmol) to afford intermediate compound (S,Z)-3-(4-fluoro-3-(3-(methyl(pyrimidin-2-yl)amino)pyrrolidine-1-carbonyl)benzylidene)isobenzofuran-1(3H)-one (107 mg, 51%).
  • Step 3 Preparation of (S)-4-(4-fluoro-3-(3-(methyl(pyrimidin-2-yl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one)
  • Step 1 Preparation of (S)-4-fluoro-3-(3-(methyl(pyrimidin-2-yl)amino)pyrrolidine-1-carbonyl)benzaldehyde
  • Step 2 Preparation of (S,Z)-3-(4-fluoro-3-(3-(methyl(pyrimidin-2-yl)amino)pyrrolidine-1-carbonyl)benzylidene)isobenzofuran-1(3H)-one
  • Step 2 This compound was made using the procedure described for example 11 (Step 2).
  • intermediate compound (Step 1) (149 mg, 0.43 mmol) was dimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphate (105 mg, 0.43 mmol), triethylamine (92 uL, 0.66 mmol) to afford (S,Z)-3-(4-fluoro-3-(3-(methyl(pyrimidin-2-yl)amino)pyrrolidine-1-carbonyl)benzylidene)isobenzofuran-1(3H)-one (102 mg, 51%).
  • Step 3 Preparation of (S)-4-(3-(3-(methyl(pyrimidin-2-yl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one
  • Step 1 Preparation of 4-fluoro-3-(3-(methyl(pyrimidin-2-yl)amino)azetidine-1-carbonyl)benzaldehyde
  • Step 2 Preparation of (Z)-3-(4-fluoro-3-(3-(methyl(pyrimidin-2-yl)amino)azetidine-1-carbonyl)benzylidene)isobenzofuran-1(3H)-one
  • Step 2 This compound was made using the procedure described for example 11 (Step 2).
  • the intermediate compound (Step 1) (202 mg, 0.65 mmol) was reacted with dimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (156 mg, 0.65 mmol), triethylamine (0.13 mL, 0.96 mmol) to afford intermediate compound (Z)-3-(4-fluoro-3-(3-(methyl(pyrimidin-2-yl)amino)azetidine-1-carbonyl)benzylidene)isobenzofuran-1(3H)-one (169 mg, 61%).
  • Step 3 Preparation of 4-(4-fluoro-3-(3-(methyl(pyrimidin-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one
  • Step 1 Preparation of 4-fluoro-3-(3-(methyl(pyrimidin-2-yl)amino)azetidine-1-carbonyl)benzaldehyde
  • Step 2 Preparation of (Z)-3-(4-fluoro-3-(3-(methyl (pyrimidin-2-yl)amino)azetidine-1-carbonyl)benzylidene)isobenzofuran-1(3H)-one
  • Step 2 This compound was made using the procedure described for example 11 (Step 2).
  • the intermediate compound (Step 1) (195 mg, 0.59 mmol) was reacted with dimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (144 mg, 0.59 mmol), triethylamine (0.12 mL, 0.89 mmol) to afford intermediate compound (Z)-3-(4-fluoro-3-(3-(methyl(pyrimidin-2-yl)amino)azetidine-1-carbonyl)benzylidene) isobenzofuran-1(3H)-one (161 mg, 61%).
  • Step 3 Preparation of 4-(4-fluoro-3-(3-(methyl(pyrimidin-2- y l)amino)azetidine-1-carbonyl)benzyl) phthalazin-1(2H)-one
  • Step 2 Preparation of (Z)-3-(4-fluoro-3-(3-(pyrimidin-2-ylamino)azetidine-1-carbonyl)benzylidene)isofuran-1(3H)-one
  • Step 2 This compound was made using the procedure described for example 11 (Step 2).
  • the intermediate compound (Step 1) (233 mg, 0.78 mmol) was reacted with dimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (188 mg, 0.78 mmol), triethylamine (0.16 mL, 1.16 mmol) to afford intermediate compound (Z)-3-(4-fluoro-3-(3-(pyrimidin-2-ylamino)azetidine-1-carbonyl)benzylidene)isofuran-1(3H)-one (197 mg, 61%).
  • Step 3 Preparation of 4-(4-fluoro-3-(3-(pyrimidin-2-ylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one
  • Step 2 This compound was made using the procedure described for example 11 (Step 2).
  • the intermediate compound (Step 1) (252 mg, 0.80 mmol) was reacted with dimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (195 mg, 0.80 mmol), triethylamine (0.17 mL, 1.20 mmol) to afford intermediate compound (S,Z)-3-(4-fluoro-3-(3-(pyrimidin-2-ylamino)pyrrolidine-1-carbonyl)benzylidene)isofuran-1(3H)-one (138 mg, 40%).
  • Step 3 Preparation of (S)-4-(4-fluoro-3-(3-(pyrimidin-2-ylamino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one
  • Step 1 Preparation of (S)-3-(3-((6-chloropyridazin-3-yl)(methyl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzaldehyde
  • Step 2 Preparation of (S,Z)-3-(3-(3-((6-chloropyridazin-3-yl)(methyl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzylidene)isofuran-1(3H)-one
  • Step 2 This compound was made using the procedure described for example 11 (Step 2).
  • the intermediate compound (Step 1) (115 mg, 0.31 mmol) was reacted with dimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (77 mg, 0.31 mmol), triethylamine (66 uL, 0.48 mmol) to afford intermediate compound (S,Z)-3-(3-(3-((6-chloropyridazin-3-yl)(methyl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzylidene)isofuran-1(3H)-one (85 mg, 56%).
  • Step 3 Preparation of (S)-4-(3-(3-((6-chloropyridazin-3-yl)(methyl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one
  • Step 1 Preparation of (S)-3-(3-((6-chloropyridazin-3-yl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzaldehyde
  • Step 2 Preparation of (S,Z)-3-(3-(3-((6-chloropyridazin-3-yl)amino)pyrrolidine-1-carbonyl)-4-fluoro benzylidene) isofuran-1(3H)-one
  • Step 2 This compound was made using the procedure described for example 11 (Step 2).
  • the intermediate compound (Step 1) (158 mg, 0.45 mmol) was reacted with dimethyl(3-oxo-1,3-dihydroi sobenzofuran-1-yl)phosphonate (109 mg, 0.45 mmol), triethylamine (95 uL, 0.68 mmol) to afford intermediate compound (S,Z)-3-(3-(3-((6-chloropyridazin-3-yl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzylidene)isofuran-1(3H)-one (117 mg, 56%).
  • Step 3 Preparation of (S)-4-(3-(3-((6-chloropyridazin-3-yl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one
  • Step 1 Preparation of (S)-4-fluoro-3-(3-(methyl(pyridazin-3-yl)amino)pyrrolidine-1-carbonyl)benzaldehyde
  • Step 2 Preparation of (S,Z)-3-(4-fluoro-3-(3-(methyl(pyridazin-3-yl)amino)pyrrolidine-1-carbonyl)benzylidene)isofuran-1(3H)-one
  • Step 2 This compound was made using the procedure described for example 11 (Step 2).
  • the intermediate compound (Step 1) (172 mg, 0.55 mmol) was reacted with dimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (132 mg, 0.55 mmol), triethylamine (0.12 mL, 0.55 mmol) to afford intermediate compound (S,Z)-3-(4-fluoro-3-(3-(methyl(pyridazin-3-yl)amino)pyrrolidine-1-carbonyl)benzylidene)isofuran-1(3H)-one (132 mg, 56%).
  • Step 3 Preparation of (S)-4-(4-fluoro-3-(3-(methyl(pyridazin-3-yl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one
  • Step 1 Preparation of 3-(3-((6-chloropyridazin-3-yl)amino)azetidine-1-carbonyl)-4-fluorobenzaldehyde
  • Step 2 Preparation of (Z)-3-(3-(3-((6-chloropyridazin-3-yl)amino)azetidine-1-carbonyl)-4-fluorobenzylidene)isofuran-1(3H)-one

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KR20220125183A (ko) 2021-03-04 2022-09-14 아이디언스 주식회사 Parp 억제제에 내성을 가진 환자군의 암 치료제로서의 프탈라지논 유도체의 항암제 용도
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