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• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
  • C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
  • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
  • C07D211/74—Oxygen atoms
  • C07D211/76—Oxygen atoms attached in position 2 or 6
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
  • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
  • C07D211/74—Oxygen atoms
• • 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
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/45—Non condensed piperidines, e.g. piperocaine having oxo groups directly attached to the heterocyclic ring, e.g. cycloheximide
• • 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
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
  • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• • 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
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • 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
  • C07D401/02—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 two hetero rings
  • C07D401/12—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 two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

• MDM2 inhibits p53 activity through three mechanisms: 1) acts as an E3 ubiquitin ligase to promote p53 degradation; 2) binds to and blocks the p53 transcriptional activation domain; and 3) exports p53 from the nucleus to the cytoplasm . All three mechanisms will be blocked by cancelling the MDM2-p53 interaction.
• This therapeutic strategy can be targeted to p53 wild-type tumors, and studies have shown that the use of small molecule MDM2 inhibitors has the potential to reduce tumor growth in vitro and in vivo. Further, in patients with p53-inactivated tumors, since wild-type p53 is stabilized in normal tissues after inhibiting MDM2, it is possible to selectively protect normal tissues from damage.
• the object of the present invention is to provide a new MDM2 inhibitor.
• Each R is independently selected from the group consisting of H, cyano, halogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 alkoxy, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 6 -C 10 aryl, or substituted or unsubstituted 5- with 5 to 3 heteroatoms selected from the group consisting of N, S and O 10-membered heteroaryl;
• Rc is selected from the group consisting of H, cyano, halogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 alkoxy;
• the compound of formula I has a structure described by the following formula IV:
• the "isomer” refers to a chiral center Optically active isomer.
• a method for preparing a compound of formula I as described in the first aspect of the invention comprises or is performed by the following step (1), step (2) or step (3) :
• alkenyl includes linear or branched alkenyl.
• C 2 -C 6 alkenyl refers to a straight or branched chain alkenyl group having 2 to 6 carbon atoms, such as vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2 -Butenyl, or a similar group.
• tautomers means that structural isomers with different energies can exceed low energy barriers, thereby converting each other.
• proton tautomers ie, proton shifts
• Valence tautomers include interconversions through the reorganization of some bonding electrons.
• solvate refers to a complex of a compound of the present invention coordinated with a solvent molecule to form a specific ratio.
• a compound of the invention refers to a compound represented by Formula I, and also includes various crystalline forms, pharmaceutically acceptable salts, hydrates, or solvates of compounds of Formula I:
• Each R is independently selected from the group consisting of H, cyano, halogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 alkoxy, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 6 -C 10 aryl, or substituted or unsubstituted 5- with 5 to 3 heteroatoms selected from the group consisting of N, S and O 10-membered heteroaryl;
• Z 1 is selected from the group consisting of: H, a substituted or unsubstituted C 1 -C 6 alkyl group, a substituted or unsubstituted C 1 -C 6 alkoxy group, a substituted or unsubstituted C 3 -C 8 ring Alkyl (including monocyclic, paracyclic or bridged ring forms), substituted or unsubstituted C 6 -C 10 aryl;
• n and p are each independently 1, 2, 3 or 4;
• Rd and Re are each independently selected from the group consisting of: H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C 6 -C 10 aryl; or
• the Rd and Re form a 4-8 membered heterocyclic ring with an adjacent N atom, and the heterocyclic ring contains 1-2 nitrogen atoms and 0-1 S or O atoms;
• substituted refers to being substituted with one or more (e.g., 2, 3, 4, etc.) substituents selected from the group consisting of: halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, halogenated C3-C8 cycloalkyl, oxo, -CN, hydroxyl, amino, Carboxyl, unsubstituted or substituted with one or more substituents selected from the group consisting of: C6-C10 aryl, halogenated C6-C10 aryl, having 1-3 selected from N 5-10 membered heteroaryl groups of heteroatoms of S, O and O, halogenated 5-10 membered heteroaryl groups having 1-3 heteroatoms selected from N, S and O; said substituents are selected from Lower group: halogen, C
• the additional condition is that when Z 4 is When Q is
• pharmaceutically acceptable salt refers to a salt of a compound of the present invention and an acid or base suitable for use as a medicament.
• Pharmaceutically acceptable salts include inorganic and organic salts.
• One preferred class of salts is the salt of a compound of the invention with an acid.
• Suitable cations for salt formation include cations of alkali metals and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, etc., and non-toxic ammonium, quaternary ammonium, and amine cations, including (but not limited to) Ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.
• said m, n, p, Z 1 , Z 2 , Z 3 , Z 4 , Q, R are each independently a group or a value corresponding to each compound in Table A or Table B.
• the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these, and the like.
• suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these, and the like.
• a safe and effective amount of a compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dose when administered is a pharmaceutically considered effective dose.
• a mammal such as a human
• the dosage is usually 1 to 2000 mg, preferably 20 to 500 mg.
• the specific dosage should also consider factors such as the route of administration, the patient's health, etc., which are all within the skill of a skilled physician.
• Step 3 5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyltetrahydro-2H-pyran-2-one
• Step 9 2,2,2-trifluoroacetyl N-(((S) -2-((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- ( 4-chlorophenyl) -3-methyl-2-oxopiperidin-1-yl) -3-methylbutyl) (isopropyl) (oxy) -16-sulfone fluorenylamine)
• Step 11 2-((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-1-((2S) -3-methyl 1- (2-propylsulfonefluorenyl) butyl-2-)-2-oxopiperidin-3-yl) acetic acid
• Step 3 2-((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-1-((2S) -3-methyl Synthesis of 1- (N-methyl-2-propylsulfonefluorenyl) butyl-2-)-2-oxopiperidin-3-yl) acetic acid
• Step 1 N-(((S) -2-((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3- Synthesis of methyl-2-oxopiperidin-1-yl) -3-methylbutyl) (isopropyl) (oxo) -16-sulfinyl) cyanamide
• Step 1 4- (2-((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-1-((2S) -3 -Methyl-1- (N- (2,2,2-trifluoroacetyl) -2-propylsulfonefluorenyl) butyl-2-)-2-oxopiperidin-3-yl) acetamide Of methyl benzoate
• HTRF2 assay When the titer of the MDM2 inhibitor increases, a modified HTRF assay (HTRF2 assay) is performed. All assay conditions were the same as above except for the following reagent concentration changes: 0.2nM GST-hMDM2 (1-188), 0.5nM biotinylated-p53 (1-83), 0.18nM SA-XLent, and 100mM KF.
• SJSA-1 cells were seeded at a density of 3 ⁇ 10 4 cells / well in 100 ul of growth medium (RPMI1640; 10 mM HEPES; 1 mM sodium pyruvate); 1X penicillin-streptomycin -Glutamine (PSQ); and 10% fetal bovine serum (all reagents were obtained from Invitrogen; Carlsbad, CA).
• the cells were cultured at 37 ° C. and 5% CO 2 overnight.
• hMDM2 inhibitors were serially diluted in DMSO (Sigma-Aldrich; St. Louis, MO). 5 ul of each compound dilution was added to 245 ul of filtered assay medium (RPMI1640, 10 mM HEPES, 1 mM sodium pyruvate, and 1 XPSQ) containing 10% FBS. Alternatively, the assay is also performed in the presence of 10% human serum or 10% mouse serum, or in the absence of any serum. The growth medium was removed from the inoculated SJSA-1 cells and replaced with 100 ul / well of assay medium. 100 ul of the medium containing the diluted inhibitor was then added to each well to a final volume of 200 ul.

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