WO2016140501A1 - N-oxyde de pyridine pour activateur d'inhibiteurs d'homologue 2 de zeste - Google Patents

N-oxyde de pyridine pour activateur d'inhibiteurs d'homologue 2 de zeste Download PDF

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Publication number
WO2016140501A1
WO2016140501A1 PCT/KR2016/002070 KR2016002070W WO2016140501A1 WO 2016140501 A1 WO2016140501 A1 WO 2016140501A1 KR 2016002070 W KR2016002070 W KR 2016002070W WO 2016140501 A1 WO2016140501 A1 WO 2016140501A1
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alkyl
methyl
amino
ethyl
heterocycloalkyl
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PCT/KR2016/002070
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English (en)
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Sunmi SHIN
Seongrim BYEON
Hyangmi KIM
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Kainos Medicine, Inc.
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Publication of WO2016140501A1 publication Critical patent/WO2016140501A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/89—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom
    • 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
    • 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
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/576—Six-membered rings
    • C07F9/58—Pyridine rings

Definitions

  • R 1 , R 2 , R 3 and R 4 are each independently hydrogen, (Ci-C 4 )alkoxy, (Ci-C 8 )alkyl, (Ci-C 4 )alkoxy-(C]-C 4 )alkyl, halo(d-C 4 )alkyl, halo(C]-C 4 )alkoxy, (C 3 -C I0 )cycloalkyl, hydroxy(C C 4 )alkyl, (C 3 -Ci 0 )cycloalkyl-(Ci-C 4 )alkyl, R a -0-C(0)-NH-(Ci-C 4 )alkyl, heterocycloalkyl, heterocycloalkyl-(Ci-C 4 )alkyl, (C 2 -C 6 )alkynyl, (C 6 -Ci 0 )aryl, (C 6 - Cio)aryl-(Ci-C 4 )alkyl, hetero
  • R 7 is hydrogen, (Ci-C 8 )alkyl, (C 3 -C 10 )cycloalkyl, (C 3 -Ci 0 )cycloalkyl-(Ci-C 4 )alkyl, heterocycloalkyl, heterocycloalkyl-(Ci-C4)alkyl, (C6-Cio)aryl, (C 6 -Cio)aryl-(Ci-C 4 )alkyl, heteroaryl, heteroaryl-(C 1 -C 4 )alkyl, -C(0)R a , -C(0)OR a , -C(0)NR a R b , -C(0)-N(R a )-NR a R b , -S(0) 2 R a , -S(0) 2 -NR a R , R a R b N-(Ci-C 4 )alkyl, wherein said (C 3 -C 10 )cycloalkyl, hetero
  • heterocycloalkyl moieties each independently have a saturated 3- to 10- membered monocyclic or polycyclic ring;
  • haloalkyl refers to any alkyl group having one or more hydrogen atoms replaced by a halogen atom.
  • haloalkyl include -CF 3 , -CHF 2 , - CH 2 F, and the like.
  • X 2 is N or CR 6 ;
  • X 4 is N or CR 6 ;
  • the present invention provides compounds of formula (la), wherein X 1 is CR 6 ; Y is O or S; and Z is CR 5 .
  • the present invention provides compounds of formula (lb), wherein X 2 , X 3 and X 4 are each independently N or CR 6 .
  • the present invention provides compounds of formula (lb), wherein X 2 is CR 6 ; and X 3 and X 4 are each independently N or CR .
  • the present invention provides compounds of formula (lb), wherein X 3 is CR 6 ; and X 2 and X 4 are each independently N or CR .
  • the present invention provides compounds of formula (lb), wherein X 2 and X 3 are CR 6 ; and X 4 is N or CR 6 .
  • the present invention provides compounds of formula (Ic), wherein X 2 is CR 6 ; and X 3 and X 4 are each independently N or CR .
  • the present invention provides compounds of formula (Ic), wherein X 4 is CR 6 ; and X 2 and X 3 are each independently N or CR .
  • the present invention provides compounds of formula (Ic), wherein X 2 and X 4 are CR 6 ; and X 3 is N or CR 6 .
  • the present invention provides compounds of formula (I), wherein R is (Q-C ⁇ alkyl or halogen.
  • the present invention provides compounds of formula (I), wherein R 5 is (C 3 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyl-oxy, heterocycloalkyl-oxy, heterocycloalkyl, -NH((C 3 -C 6 )cycloalkyl), -N((Ci-C 3 )alkyl)((C 3 -C 6 )cycloalkyl), - NH(heterocycloalkyl), or -N((Ci-C 3 )alkyl)(heterocycloalkyl), wherein said (C 3 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyl-oxy, heterocycloalkyl-oxy, heterocycloalkyl, or (C 3 -C 6 )cycloalkyl is each independently unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of halogen, hydroxy, (
  • the present invention provides compounds of formula (I), wherein R 5 is (C 3 -C 6 )alkoxy, (C 3 -Cio)cycloalkyl-oxy, or heterocycloalkyl-oxy, each of which is independently unsubstituted or substituted with hydroxy, (Ci-C 3 )alkoxy, amino, - NH(C,-C 3 )alkyl, -N((C, 0 C 3 )alkyl) 2 , (d-C 3 )alkyl, -C(0)OR ⁇ -C(0)-NR a R b , -S(0) 2 -NR a R b , phenyl, or heteroaryl, wherein R a and R b are the same as defined in formula (I).
  • the present invention provides compounds of formula (I), wherein R 5 is (C 3 -C 6 )cycloalkyl-oxy which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of halogen, -OR a , -NR a R b , nitro, -C(0)OR a , -C(0)-NR a R b , -S(0) 2 -NR a R b , (C 6 -Ci 0 )aryl, and heteroaryl, wherein R a and R b are the same as defined in formula (I).
  • the present invention provides compounds of formula (I), wherein R 5 is (C 3 -C 6 )cycloalkyl-oxy which is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of halogen, hydroxy, (Ci-C 3 )alkoxy, amino, -NH(Ci-C 3 )alkyl, -N((C,-C 3 )alkyl) 2 , (C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy-(C 1 -C 3 )alkyl, amino(Ci- C 3 )alkyl, ((C 1 -C 3 )alkyl)NH-(C 1 -C 3 )alkyl, ((C 1 -C 3 )alkyl) 2 N-(C,-C 3 )alkyl, (C 3 - Cio)cycloalkyl, cyano, -C(0)OR a , -C
  • the present invention provides compounds of formula (I), wherein R 5 is heterocycloalkyl-oxy which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of halogen, -OR a , -NR a R b , nitro, (Ci- C 3 )alkyl, R a R b N-(Ci-C 3 )alkyl, R a O-(Ci-C 3 )alkyl, (C 3 -Ci 0 )cycloalkyl, cyano, -C(0)OR a , - C(0)-NR a R b , -S(0) 2 -NR a R b , phenyl, and heteroaryl, wherein R a and R b are the same as defined in formula (I).
  • the present invention provides compounds of formula (I), wherein R 5 is heterocycloalkyl-oxy which is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of halogen, hydroxy, (Ci-C 3 )alkoxy, amino, -NH(Ci-C 3 )alkyl, -N((C,-C 3 )alkyl) 2 , (Ci-C 3 )alkyl, (C,-C 3 )alkoxy-(Ci-C 3 )alkyl, amino(C,- C 3 )alkyl, ((C 1 -C 3 )alkyl)NH-(C 1 -C 3 )alkyl, ((C,-C 3 )alkyl) 2 N-(C 1 -C 3 )alkyl, (C 3 - Ci 0 )cycloalkyl, cyano, -C(0)OR a , -C(0)-NR a R b
  • the present invention provides compounds of formula (I), wherein R 5 is -NR a R b ;
  • R a is azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, or tetrahydropyranyl, each of which is independently unsubstituted or substituted with one or two (C
  • R b is hydrogen or (Ci-C 4 )alkyl.
  • the present invention provides compounds of formula (I), wherein R 5 is -NR a R b ; R a is azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, or tetrahydropyranyl; and R b is methyl or ethyl.
  • the present invention provides compounds of formula (I), wherein R 5 is -NR a R b ; R a is cyclohexyl which is unsubstituted or substituted with -N((Cr C 2 )alkyl) 2 ; and R b is methyl or ethyl.
  • the present invention provides compounds of formula (I), wherein R 5 is (C 2 -C 4 )alkenyl which is unsubstituted or substituted with 1 or 2 substituents selected from (C 3 -C 6 )cycloalkyl, 5- or 6-membered heterocycloalkyl, phenyl, or 5- or 6- membered heteroaryl, each of which is independently unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of halogen, (d-C 4 )alkyl, halo(Ci- C 4 )alkyl, -C(0)-(Ci-C 4 )alkyl, -C(0)0-(Ci-C 4 )alkyl, -NR a R b , -NH-C(0)OR a , hydroxy, oxo, (Ci-C 4 )alkoxy, and (Ci-C )alkoxy-(Ci-C 4 )alkyl, or any
  • the present invention provides compounds of formula (I), wherein R 5 is (C 2 -C 4 )alkenyl which is unsubstituted or substituted with cyclohexyl, piperidinyl, or tetrahydropyranyl, each of which is independently unsubstituted or substituted with (Ci-C 4 )alkyl, halo(Ci-C 4 )alkyl, amino, -NH(C 1 -C 4 )alkyl, or -N((C r C 4 )alkyl) 2 .
  • the present invention provides compounds of formula (I), wherein R 6 is pyridinyl which is unsubstituted or substituted with -NR a R b or R a R N-(Ci- C4)alkyl, wherein R a and R b are the same as defined in formula (I).
  • the present invention provides compounds of formula (I), wherein R 6 is hydrogen, halogen, (Ci-C 4 )alkyl, or (Ci-C 4 )alkoxy.
  • the present invention provides compounds of formula (I), wherein R 6 is hydrogen or halogen.
  • the present invention provides compounds of formula (I), wherein R 6 is hydrogen, chloro.
  • the present invention provides compounds of formula (I), wherein R 7 is hydrogen, (Ci-C )alkyl, (C 3 -C 6 )cycloalkyl, phenyl, or heteroaryl, wherein said phenyl or heteroaryl is each independently unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of (Ci-C 4 )alkoxy, -NR a R b , R a R b N-(Ci- C 4 )alkyl, (C 1 -C 4 )alkyl-heterocycloalkyl, halogen, (Ci-Q)alkyl, (C3-C] 0 )cycloalkyl, and (Ci-C 4 )alkyl, wherein R a and R b are the same as defined in formula (I).
  • the present invention provides compounds of formula (I), wherein R 8 is (Ci-Cg)alkyl, (C4-Cg)cycloalkyl, heterocycloalkyl, (C 6 -C 10 )aryl, or heteroaryl, each of which is independently unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of halogen, -OR a , -NR a R b , -NH-C(0)OR a , nitro, (d- C 3 )alkyl, R a R b N-(C r C 3 )alkyl, R a O-(Ci-C 3 )alkyl, (C 3 -C ]0 )cycloalkyl, cyano, -C(0)OR a , - C(0)-NR a R b , -S(0) 2 -NR a R b , (C 6 -Ci 0 )aryl, and heteroaryl,
  • R 1 and R 3 are hydrogen, and R 2 and R 4 are each independently (d-C 4 )alkoxy, (Ci- C 8 )alkyl, halo(Ci-C 4 )alkyl, halo(Ci-C 4 )alkoxy, (C 2 -C 6 )alkynyl, (C 3 -Ci 0 )cycloalkyl, (C 6 - C 10 )aryl-(d-C 4 )alkyl, -SR a , -S(0)R a , -S(0) 2 R a , -OR a or halogen, or R 3 and R 4 taken together with the carbon atoms to which they are bonded form a 5- to 8-membered carbocyclic or heterocyclic ring, wherein said ring is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of hydroxy, halogen, nitro, (Ci-C 4 )alkyl,
  • R 9 , R a and R b are the same as defined in formula (I);
  • the present invention further provides a pharmaceutical composition (also referred to as pharmaceutical formulation) comprising a compound of formula (I) or pharmaceutically acceptable salt thereof and one or more excipients (also referred to as carriers and/or diluents in the pharmaceutical arts).
  • the excipients are acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof (i.e., the patient).
  • Suitable pharmaceutically acceptable excipients will vary depending upon the particular dosage from chosen for a particular function that they may serve in the composition. For example, certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the production of uniform dosage forms.
  • Certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the production of stable dosage forms. Certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the carrying or transporting of the compound or compounds of the present invention once administered to the patient from one organ, or portion of the body, to another organ, or portion of the body. Certain pharmaceutically acceptable excipients may be chosen for their ability to enhance patient compliance.
  • compositions of the present invention are prepared using techniques and method known to those skilled in the art. Some of the methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).
  • compositions may be unit dose containing a predetermined amount of active ingredient per unit dose.
  • a unit may contain a therapeutically effective dose of the compound of formula (I) or salt thereof or a fraction of a therapeutically effective the desired therapeutically effective dose.
  • Preferred unit dosage formulations are those containing a daily dose or sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient.
  • such pharmaceutical compositions may be prepared by any of the methods well-known in the pharmacy art.
  • compositions may be adapted for administration by any appropriate route, for example, by oral (including buccal or sublingual), rectal, nasal, topical (including buccal or sublingual), vaginal, or parenteral (including subcutaneous, intramuscular, intravenous, or intradermal) routes.
  • oral including buccal or sublingual
  • rectal nasal
  • topical including buccal or sublingual
  • vaginal or parenteral
  • parenteral including subcutaneous, intramuscular, intravenous, or intradermal
  • Such composition may be prepared by any method known in the art of pharmacy, for example, by bringing into association of the active ingredient with the excipient(s).
  • compositions When adapted for oral administration, pharmaceutical compositions may be in discrete units such as tablets or capsules; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; oil-in-water liquid emulsions or water-in-oil liquid emulsions.
  • the compound or salt thereof of the present invention or the pharmaceutical composition of the present invention may also be incorporated into a candy, a wafer, and/or tongue tape formulation for administration as a "quick-dissolve" medicine.
  • the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like.
  • an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like.
  • Powders or granules are prepared by comminuting carrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavoring, preservative, dispersing, and coloring agents can also be present.
  • Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant, and pressing into tablets.
  • a powder mixture is prepared by mixing the compound, suitably comminuted, with a diluent or base as described above, and optionally, with a binder such as carboxymethylcellulose, alginate, gelatin, or polyvinyl pyrrolidone, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt, and/or an absorption agent such as bentonite, kaolin or dicalcium phosphate.
  • a binder such as carboxymethylcellulose, alginate, gelatin, or polyvinyl pyrrolidone
  • a solution retardant such as paraffin
  • a resorption accelerator such as a quaternary salt
  • an absorption agent such as bentonite, kaolin or dicalcium phosphate.
  • the powder mixture can be granulated by wetting a binder such as syrup, starch paste, acadia mucilage, or solutions of cellulosic or polymeric materials and forcing through a screen.
  • a binder such as syrup, starch paste, acadia mucilage, or solutions of cellulosic or polymeric materials
  • the powder mixture can be run through the tablet machine and the result is imperfectly formed slugs broken into granules.
  • the granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc, or mineral oil. The lubricated mixture is then compressed into tablets.
  • Oral fluids such as solutions, syrups and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of active ingredient.
  • Syrups can be prepared by dissolving the compounds or salts of the present invention in a suitably flavored aqueous solution, while elixirs are prepared through the use of a non-toxic alcoholic vehicle.
  • Suspension can be formulated by dispersing the compounds or salts of the present invention in a non-toxic vehicle.
  • Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavor additives such as peppermint oil, natural sweeteners, saccharin, or other artificial sweeteners, and the like, can also be added.
  • tablets and capsules are preferred for delivery of the pharmaceutical composition.
  • co-administering and derivatives thereof as used herein refers to either simultaneous administration or any manner of separate sequential administration of an EZH2 inhibiting compound, as described herein, and a further active ingredient or ingredients, known to be useful in the treatment of cancer, including chemotherapy and radiation treatment.
  • active ingredient(s) includes any compound or therapeutic agent known to or that demonstrates advantageous properties when administered to a patient in need of treatment for cancer.
  • the compounds are administered in a close time proximity to each other.
  • the compounds are administered in the same dosage form, e.g., one compound may be administered topically and another compound may be administered orally.
  • compositions adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations.
  • compositions adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidant, buffers, bacteriostats and solutes which render the composition isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the pharmaceutical compositions may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • the inventive method for the treatment or prevention of diseases mediated by EZH2 in a mammal comprises administering a therapeutically effective amount of the compound according to the present invention to the mammal in need thereof.
  • Scheme 1 shows the synthesis of a pyridine N-oxide compound 7 through a general route A that utilizes well-established chemistry.
  • Fluoro group in the compound 1 can be converted to cyano group in the compound
  • Pyridine N-oxide 6 can be synthesized by subjecting the compound 5 to a reaction with meta-chloroperoxybenzoic acid in dichloromethane at room temperature (step 5). Boc-protected amine group in the compound 6 can be converted to free amine group in the compound 7 by trifluoroacetic acid in dichloromethane at room temperature (step 6).
  • R alkyl, sulfonate, alkoxyl
  • the compound 9 can be synthesized by treatment of a commercially available compound 8 with l,3-dibromo-5,5-dimethylimidazolidine-2,4-dione or nitration of the compound 16 in concentrated sulfuric acid and nitric acid at room temperature (step 1).
  • the compound 11 can be synthesized by esterification of the compound 9, followed by reduction by iron in ethanol (steps 2 and 3). After continuous reductive amination (steps 4 and 5), Suzuki coupling reaction and ester hydrolysis, compound 15 was synthesized (steps 6 and 7).
  • Amine compound 11 was converted to the compound 18 by continuous two reductive amination in dichloroethane (steps 1 and 2).
  • the compound 23 can be synthesized by Sonogashira coupling reaction of the compound 21 followed by hydrolysis of ester (steps 6 and 7).
  • Scheme 4 shows the synthesis of the compound 29 through a general route D that utilizes well-established chemistry.
  • Amine compound 11 was converted to the compound 25 by continuous two reductive animation in dichloroethane (steps 1 and 2).
  • Protected amine group in the compound 25 can be converted to free amine group in the compound 26 by trifluoroacetic acid in dichloromethane at room temperature (step 3).
  • step 3 After amide coupling reaction, alkylation and then hydrolysis of ester, the compound 29 was synthesized (steps 4 to 6).
  • Scheme 5 shows the synthesis of a pyridine N-oxide compound 16 through amide coupling reaction (general route E) with HATU that utilizes well-established chemistry.
  • Step 6 2-(aminomethyl)-3-methoxy-5-methylpyridine 1 -oxide
  • Step 3 tert-butyl ((3-ethyl-5-methylpyridin-2-yl)methyl)carbamate
  • Step 3 tert-butyl ((5-methyl-3-(prop-l-yn-l-yl)pyridin-2-yl)methyl)carbamate
  • Step 4 2-(((tert-butoxycarbonyl)amino)methyl)-5-methyl-3-(prop-l-yn-l- yl)pyridine 1 -oxide
  • Step 3 tert-butyl ((3-benzyl-5-methylpyridin-2-yl)methyl)carbamate
  • Step 4 3-benzyl-2-(((tert-butoxycarbonyl)amino)methyl)-5-methylpyridine 1- oxide
  • Step 3 tert-butyl ((3-cyclopropyl-5-methylpyridin-2-yl)methyl)carbamate
  • Step 4 2-(((tert-butoxycarbonyl)amino)methyl)-3 -cyclopropyl-5 -methylpyridine
  • Step 5 tert-butyl ((3-fluoro-5-methylpyridin-2-yl)methyl)carbamate
  • Step 7 2-(aminomethyl)-3-fluoro-5-methylpyridine 1-oxide.
  • 3-amino-5-methylpicolinonitrile (200.0 mg, 1.5 mmol) was dissolved in concentrated hydrochloric acid (2 ml) and cooled to 0 °C.
  • Sodium nitrite (120.0 mg, 1.5 mmol) was dissolved in water (1.5 ml) and added dropwise to the reaction mixture at this temperature.
  • copper (I) chloride (180.0 mg, 1.8 mmol) was added slowly. Vigorous gas evolution was observed and the reaction mixture was stirred for an additional hour at 0 °C, quenched by pouring onto a 1 : 1 mixture of concentrated ammonium hydroxide/water (9 ml) and extracted with dichloromethane.
  • Step 3 tert-butyl ((3-chloro-5-methylpyridin-2-yl)methyl)carbamate
  • Step 4 2-(((tert-butoxycarbonyl)amino)methyl)-3-chloro-5-methylpyridine 1- oxide
  • Step 1 tert-butyl ((3,5-dimethylpyridin-2-yl)methyl)carbamate
  • Step 1 3-(difluoromethoxy)-5-niethylpicolinonitrile
  • Step 2 tert-butyl ((3-(difluoromethoxy)-5-methylpyridin-2-yl)methyl)carbamate
  • Step 3 2-(((tert-butoxycarbonyl)amino)methyl)-3-(difluoromethoxy)-5- methylpyridine 1 -oxide
  • Step 4 2-(aminomethyl)-3-(difluoromethoxy)-5-methylpyridine 1 -oxide
  • Step 3 tert-butyl ((5-chloro-3-ethylpyridin-2-yl)methyl)carbamate
  • Step 5 2-(aminomethyl)-5-chloro-3-ethylpyridine 1 -oxide
  • Step 3 tert-butyl ((3-(l,l-difluoroethyl)-5-methylpyridin-2-yl)methyl)carbamate
  • Step 4 2-(((tert-butoxycarbonyl)amino)methyl)-3 -( 1 , 1 -difluoroethyl)-5- methylpyridine 1 -oxide
  • Step 5 tert-butyl ((6-fluoro-4-methylisoquinolin-l-yl)methyl)carbamate
  • Step 5 1 -(((tert-butoxycarbonyl)amino)methyl)-6-fluoro-4-methylisoquinoline
  • Step 4 methyl 5-bromo-2-methyl-3-((tetrahydro-2H-pyran-4-yl)amino)benzoate
  • Step 5 methyl 5-bromo-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2- methylbenzoate
  • the reaction mixture was diluted with 10% methanol in dichloromethane and extracted with water. The combined organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica column chromatography (25% ethyl acetate in hexane to 4% methanol in dichloromethane) to obtain the title compound as oil (2.4 g, 99% yield).
  • Step 1 methyl 4'-(diisopropoxyphosphoryl)-5-(ethyl(tetrahydro-2H-pyran-4- yl)amin -4-methyl-[l , 1 '-biphenyl]-3-carboxylate
  • Step 2 4'-(diisopropoxyphosphoryl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4- methyl- [1 , 1 '-biphenyl]-3-carboxylic acid
  • Step 1 methyl 5-(6-((tert-butoxycarbonyl)amino)pyridin-3-yl)-3- (ethyl(tetrahydro-2H-pyran i--4-yl)amino)-2-methylbenzoate
  • Step 2 5-(6-((tert-butoxycarbonyl)amino)pyridin-3-yl)-3-(ethyl(tetrahydro-2H- pyran-4- l)amino)-2-methylbenzoic acid
  • Step 1 methyl 5-chloro-2-methyl-3-((tetrahydro-2H-pyran-4-yl)amino)benzoate
  • Step 2 methyl 5-chloro-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2- methylbenzoate
  • Step 1 methyl 3-(((lR,4R)-4-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-5- chloro-2-methylbenzoate
  • Step 2 methyl 3-(((lS,4S)-4-((tert- butoxycarbonyl)amino)cyclohexyl)(ethyl)amino)-5-chloro-2-methylbenzoate
  • Step 3 methyl 3-(((l S,4S)-4-((tert- butoxycarbonyl)(methyl)amino)cyclohexyl)(ethyl)amino)-5-chloro-2-methylbenzoate
  • Step 4 methyl 5-chloro-3-(ethyl((l S,4S)-4-(methylamino)cyclohexyl)amino)-2- methyl benzoate
  • Step 1 methyl 5-bromo-3-(((lR,4R)-4-((tert- butoxycarbonyl)amino)cyclohexyl)amino)-2-methylbenzoate
  • Step 2 methyl 5-bromo-3-(((l S,4S)-4-((tert- butoxycarbonyl)amino)cyclohexyl)(ethyl)amino)-2-methylbenzoate
  • Step 3 methyl 5-bromo-3-(((l S,4S)-4-((tert- butoxycarbonyl)(methyl)amino)cyclohexyl)(ethyl)amino)-2-methylbenzoate
  • Step 5 methyl 5-bromo-3-(ethyl((l S,4S)-4-((2- methoxyethyl)(methyl)amino)cyclohexyl)amino)-2-methylbenzoate
  • Step 6 methyl 3-(ethyl((l S,4S)-4-((2- methoxyethyl)(methyl)amino)cyclohexyl)amino)-2-methyl-5-(3-m rpholinoprop- 1 -yn- 1 - yl)b
  • Step 7 3-(ethyl((l S,4S)-4-((2-methoxyethyl)(methyl)amino)cyclohexyl)amino)-2- methyl-5-(3-morpholinoprop-l-yn-l-yl)benzoic acid
  • Step 1 methyl 5-bromo-3-(((l S,4S)-4-((2,2- difluoroethyl)(methyl)amino)cyclohexyl)(ethyl)amino)-2-methylbenzoate
  • Step 2 methyl 3-(((l S,4S)-4-((2,2- difluoroethyl)(methyl)amino)cyclohexyl)(ethyl)amino)-2-methyl-5-(3 -morpholinoprop- 1 - yn-l-yl)benzoate
  • Step 7 3-(((l S,4S)-4-((2,2- difluoroethyl)(methyl)amino)cyclohexyl)(ethyl)amino)-2-methyl-5-(3-morpholinoprop-l- yn-l-yl)benzoic acid
  • Step 5 tert-butyl 4-((5-chloro-3-(methoxycarbonyl)-2- methylphenyl)(ethyl)amino)piperidine- 1 -carboxylate
  • Step 7 methyl 3-((l-acetylpiperidin-4-yl)(ethyl)amino)-5-chloro-2- methylbenzoate
  • the reaction mixture was concentrated in vacuo.
  • the residue was diluted with 10% methanol in dichloromethane and water.
  • the organic layer was combined and concentrated in vacuo.
  • the residue was purified by silica column chromatography (5% methanol in dichloromethane) to obtain the title compound as oil (125 mg, 99% yield).
  • Step 8 3-((l-acetylpiperidin-4-yl)(ethyl)amino)-5-chloro-2-methylbenzoic acid
  • Step 1 tert-butyl 4-((5-bromo-3-(methoxycarbonyl)-2- methylphenyl)amino)piperidine- 1 -carboxylate
  • Step 2 tert-butyl 4-((5-bromo-3-(methoxycarbonyl)-2- methylphenyl)(ethyl)amino)piperidine- 1 -carboxylate
  • Step 3 tert-butyl 4-(ethyl(4'-hydroxy-5-(methoxycarbonyl)-4-methyl-[l,l'- biphenyl]-3-yl)amino)piperidine- 1 -carboxylate
  • the reaction mixture was heated at 100 °C for 5 h, diluted with 10% methanol in dichloromethane and filtered. The filtrate was concentrated, diluted with water and extracted with 10 % methanol in dichloromethane. The combined organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica column chromatography (20 % ethyl acetate in hexane) to obtain the title compound as oil (85 mg, 83% yield).
  • Step 4 tert-butyl 4-(ethyl(5-(methoxycarbonyl)-4'-(2-methoxyethoxy)-4-methyl- [1,1 -biphenyl] -3 -yl)amino)piperidine-l -carboxylate
  • Step 5 methyl 5-(ethyl(piperidin-4-yl)amino)-4'-(2-methoxyethoxy)-4-methyl- [1 , l'-biphenyl]-3-carboxylate
  • Step 6 methyl 5-((l-acetylpiperidin-4-yl)(ethyl)amino)-4'-(2-methoxyethoxy)-4- methyl-[ 1 , 1 '-biphenyl]-3-carboxylate
  • the reaction mixture was stirred at room temperature for 20 h, diluted with 10% methanol in dichloromethane and extracted with water. The combined organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica column chromatography (2.5% methanol in dichloromethane) to obtain the title compound as oil (23 mg, 99% yield).
  • Step 7 5-((l-acetylpiperidin-4-yl)(ethyl)amino)-4'-(2-methoxyethoxy)-4-methyl- [1,1 -biphenyl] -3 -carboxylic acid
  • Methyl 6-bromo-l-isopropyl-lH-indazole-4-carboxylate 54 mg, 0.182 mmol
  • 1- methyl-4- [5 -(4,4,5 ,5 -teyramethyl- 1 ,3 ,2-dioxaborolan-2-yl)-2-pyridinyl]piperazine 83 mg, 0.274 mmol
  • DME/water 3/1, 3 ml
  • Step 2 1 -isopropyl-6-(6-(4-methylpiperazin- 1 -yl)pyridin-3 -yl)- 1 H-indazole-4- carboxylic acid
  • reaction mixture was stirred at room temperature for 18 h.
  • the reaction mixture was extracted by 5% methanol in dichloromethane.
  • the combined organic solvent was dried over magnesium sulfate and concentrated under reduced pressure.
  • the residue was purified by silica column chromatography (5 to 10% methanol in dichloromethane) to obtain the title compound as a solid (25 mg, 38% yield).
  • reaction mixture was stirred at 80 °C for 2 h.
  • the reaction mixture was extracted by 5% methanol in dichloromethane.
  • the combined organic solvent was dried over magnesium sulfate and concentrated under reduced pressure.
  • the residue was purified by silica column chromatography (5 to 10% methanol in dichloromethane) to obtain the title compound as a solid (0.02 g, 20% yield).
  • reaction mixture was stirred at 40 °C for 4 h.
  • the reaction mixture was extracted by 5% methanol in dichloromethane.
  • the combined organic solvent was dried over magnesium sulfate and concentrated under reduced pressure.
  • the residue was purified by silica column chromatography (5 to 10% methanol in dichloromethane) to obtain the title compound as a solid (30 mg, 34% yield).
  • reaction mixture was stirred at 80 °C for 2 h.
  • the reaction mixture was extracted by 5% methanol in dichloromethane.
  • the combined organic solvent was dried over magnesium sulfate and concentrated under reduced pressure.
  • the residue was purified by silica column chromatography (5 to 10% methanol in dichloromethane) to obtain the title compound as a solid (12 mg, 36% yield).
  • reaction mixture was stirred at 40 °C for 2 h.
  • the reaction mixture was extracted by 5% methanol in dichloromethane.
  • the combined organic solvent was dried over magnesium sulfate and concentrated under reduced pressure.
  • the residue was purified by silica column chromatography (5 to 10% methanol in dichloromethane) to obtain the title compound as oil (20 mg, 45% yield).
  • Example 7 3-(difluoromethoxy)-2-((5-(ethyI(tetrahydro-2H-pyran-4- yl)amino)-4-methyI-4'-(morpholinomethyl)-[l, -biphenyl]-3-ylcarboxamido)methyl)- 5-methylpyridine 1 -oxide
  • reaction mixture was stirred at 40 °C for 3.5 h.
  • the reaction mixture was extracted by 10% methanol in dichloromethane.
  • the combined organic solvent was dried over magnesium sulfate and concentrated under reduced pressure.
  • the residue was purified by silica column chromatography (4% methanol in dichloromethane) to obtain the title compound as oil (8 mg, 27% yield).
  • reaction mixture was extracted by 10% methanol in dichloromethane.
  • the combined organic solvent was dried over magnesium sulfate and concentrated under reduced pressure.
  • the residue was purified by silica column chromatography (5% methanol in dichloromethane) to obtain the title compound as oil (4 mg, 11% yield).
  • reaction mixture was stirred at 40 °C for 2 h.
  • the reaction mixture was extracted by 5% methanol in dichloromethane.
  • the combined organic solvent was dried over magnesium sulfate and concentrated under reduced pressure.
  • the residue was purified by silica column chromatography (5 to 10% methanol in dichloromethane) to obtain the title compound as a solid (4 mg, 17% yield).
  • reaction mixture was stirred at 40 °C for 6 h.
  • the reaction mixture was extracted by 5% methanol in dichloromethane.
  • the combined organic solvent was dried over magnesium sulfate and concentrated under reduced pressure.
  • the residue was purified by silica column chromatography (5 to 10% methanol in dichloromethane) to obtain the title compound as a solid (30 mg, 37% yield).
  • Example 12 3-(l,l-difluoroethyl)-2-((5-(ethyl(tetrahydro-2H-pyran-4- yl)amino)-4-methyl-4'-(morpholinomethyl)-[l,l'-biphenyI]-3-ylcarboxamido)methyl)- 5-methyl ridine 1-oxide
  • reaction mixture was stirred at 40 °C for 3 h.
  • the reaction mixture was extracted by 5% methanol in dichloromethane.
  • the combined organic solvent was dried over magnesium sulfate and concentrated under reduced pressure.
  • the residue was purified by HPLC to obtain the title compound as oil (6 mg, 16% yield).
  • reaction mixture was stirred at 40 °C for 2 h.
  • the reaction mixture was extracted by 5% methanol in dichloromethane.
  • the combined organic solvent was dried over magnesium sulfate and concentrated under reduced pressure.
  • the residue was purified by silica column chromatography (5 to 10% methanol in dichloromethane) to obtain the title compound as a solid (10 mg, 25% yield).
  • Step 1 2-((5-(6-((tert-butoxycarbonyl)amino)pyridin-3-yl)-3-(ethyl(tetrahydro- 2H-pyran-4-yl)amino)-2-methylbenzamido)methyl)-3,5-dimethylpyridine 1 -oxide
  • reaction mixture was stirred at 40 °C for 5 h.
  • the reaction mixture was extracted by 5% methanol in dichloromethane.
  • the combined organic solvent was dried over magnesium sulfate and concentrated under reduced pressure.
  • the residue was purified by silica column chromatography (5 to 10% methanol in dichloromethane) to obtain the title compound as a solid (90 mg, 63% yield).
  • Step 2 2-((5-(6-aminopyridin-3-yl)-3 -(ethyl (tetrahy dro-2H-pyran-4-yl)amino)-2- methylb ne 1 -oxide
  • reaction mixture was stirred at 40 °C for 2 h.
  • the reaction mixture was extracted by 5% methanol in dichloromethane.
  • the combined organic solvent was dried over magnesium sulfate and concentrated under reduced pressure.
  • the residue was purified by silica column chromatography (50% ethyl acetate in hexane) to obtain the title compound as a solid (0.02 g, 38% yield).
  • Step 1 2-((3-((l-(tert-butoxycarbonyl)piperidin-4-yl)(ethyl)amino)-5-chloro-2- methylbenzamido)methyl)-3,5-dimethylpyridine 1 -oxide
  • reaction mixture was stirred at room temperature for 20 h.
  • the reaction mixture was extracted by 10% methanol in dichloromethane.
  • the combined organic solvent was dried over magnesium sulfate and concentrated under reduced pressure.
  • the residue was purified by silica column chromatography (2% methanol in dichloromethane) to obtain the title compound as oil (3 mg, 7% yield).
  • Example 22 3-chloro-2-((3-(ethyl((lS,4S)-4-((2- methoxyethyl)(methyl)amino)cyclohexyl)amino)-2-methyl-5-(3-morpholinoprop-l-yn- l-yl)benzamido)methyl)-5-methylpyridine 1-oxide
  • reaction mixture was stirred at room temperature for 20 h.
  • the reaction mixture was extracted with 10% methanol in dichloromethane.
  • the combined organic solvent was dried over magnesium sulfate and concentrated under reduced pressure.
  • the residue was purified by silica column chromatography (5 to 10% methanol in dichloromethane) to obtain the title compound as oil (10 mg, 39% yield).
  • reaction mixture was stirred at room temperature for 6 h.
  • the reaction mixture was extracted with 10% methanol in dichloromethane.
  • the combined organic solvent was dried over magnesium sulfate and concentrated under reduced pressure.
  • the residue was purified by silica column chromatography (5% ammonium hydroxide solution and 10% methanol in dichloromethane) to obtain the title compound as oil (13 mg, 43% yield).
  • reaction mixture was stirred at room temperature for 20 h.
  • the reaction mixture was extracted with 10% methanol in dichloromethane.
  • the combined organic solvent was dried over magnesium sulfate and concentrated under reduced pressure.
  • the residue was purified by silica column chromatography (5 to 10% methanol in dichloromethane) to obtain the title compound as oil (4 mg, 11% yield).
  • the reaction mixture was stirred at room temperature for 4 days.
  • the reaction mixture was concentrated in vacuo.
  • the residue was purified by reverse phase Agilent HPLC (50-95% C3 ⁇ 4CN/water +0.01% formic acid, LUNA C8, 100 A column, 250 X 10 mm, 10 ⁇ ) to obtain the title compound as colorless oil (4.4 mg, 17% yield).
  • EZH2 binding assays were done for the inhibition of the test compounds using HotSpot HMT assay protocol using the EZH2.
  • Complex of human EZH2 (GenBank Accession No. NM_001203247), co-expressed in baculovirus expression system with N- terminal His-tag was used as the enzyme target and histone H4 peptide (1-21) K5/8/ 12/ 16 Ac-Bio tin was used as a substrate.
  • Pfeiffer cell proliferation assays were done to measure the 50% inhibition concentration of tested compound on Pfeiffer cell lines using standard CTG assay.
  • Pfeiffer cell 500-1000 cell/150-200 ⁇ , each well, 5-7 day assay
  • Culture media is purchased from GIBCO, USA.
  • 96- Well Flat Clear Bottom Black Polystyrene TC-Treated Microplate Cat# 3603, Corning®
  • CellTiter-Glo® Luminescent Cell Viability Assay Cat. No.: G7572, Promega. Store at -20°C
  • Table 1 shows the activity of selected compounds of this invention in the EZH2 enzyme inhibition assay and Pfeiffer cell proliferation assay.
  • A indicates an IC 50 value of greater than 1 ⁇ and less than 100 nM
  • B indicates an IC 50 value of 100 nM to 1000 nM
  • C indicates an IC 5 o value of greater than 1000 nM and less than 1 ⁇ ;
  • the compounds of Examples 1 to 25 exhibited good EZH2 binding activity, and anti-proliferative activity on Pfeiffer cells.

Abstract

La présente invention concerne un composé N-oxyde de pyridine, ou un sel pharmaceutiquement acceptable ou un stéréoisomère de celui-ci qui inhibe l'activateur de l'homologue 2 de zeste (EZH2) et est donc utile pour inhiber la prolifération des cellules cancéreuses et/ou induire leur apoptose.
PCT/KR2016/002070 2015-03-04 2016-03-02 N-oxyde de pyridine pour activateur d'inhibiteurs d'homologue 2 de zeste WO2016140501A1 (fr)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9718838B2 (en) 2015-08-27 2017-08-01 Eli Lilly And Company Inhibitors of EZH2
WO2021249305A1 (fr) * 2020-06-08 2021-12-16 南京明德新药研发有限公司 Composé biphényle
CN114907300A (zh) * 2021-02-08 2022-08-16 上海医药工业研究院 他泽司他关键中间体的制备方法及其中间体
CN114907299A (zh) * 2021-02-08 2022-08-16 上海医药工业研究院 他泽司他关键中间体的新盐型、其制备方法及其中间体
WO2023211195A1 (fr) * 2022-04-28 2023-11-02 Sk Biopharmaceuticals Co., Ltd. Composés n-oxydes et leur utilisation

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WO2004026873A1 (fr) * 2002-09-18 2004-04-01 Ono Pharmaceutical Co., Ltd. Derives triazaspiro[5.5]undecanes et medicaments les contenant en tant que principe actif
WO2005012256A1 (fr) * 2003-07-22 2005-02-10 Astex Therapeutics Limited Composes 1h-pyrazole 3,4-disubstitues et leur utilisation en tant que kinases dependant des cyclines (cdk) et modulateurs de la glycogene synthase kinase-3 (gsk-3)
WO2005097750A1 (fr) * 2004-03-30 2005-10-20 Aventis Pharmaceuticals Inc. Pyridones substitues inhibiteurs de la poly(adp-ribose) polymerase (parp)
WO2007147874A1 (fr) * 2006-06-22 2007-12-27 Biovitrum Ab (Publ) Dérivés de pyridine et de pyrazine utilisés en tant qu'inhibiteurs de la kinase mnk
WO2014055634A1 (fr) * 2012-10-02 2014-04-10 Yale University Identification de petites molécules inhibitrices d'histone déméthylase à de domaine jumonji 1a (jarid1a) et 1b (jarid1b) interactif riche en at,

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Publication number Priority date Publication date Assignee Title
WO2004026873A1 (fr) * 2002-09-18 2004-04-01 Ono Pharmaceutical Co., Ltd. Derives triazaspiro[5.5]undecanes et medicaments les contenant en tant que principe actif
WO2005012256A1 (fr) * 2003-07-22 2005-02-10 Astex Therapeutics Limited Composes 1h-pyrazole 3,4-disubstitues et leur utilisation en tant que kinases dependant des cyclines (cdk) et modulateurs de la glycogene synthase kinase-3 (gsk-3)
WO2005097750A1 (fr) * 2004-03-30 2005-10-20 Aventis Pharmaceuticals Inc. Pyridones substitues inhibiteurs de la poly(adp-ribose) polymerase (parp)
WO2007147874A1 (fr) * 2006-06-22 2007-12-27 Biovitrum Ab (Publ) Dérivés de pyridine et de pyrazine utilisés en tant qu'inhibiteurs de la kinase mnk
WO2014055634A1 (fr) * 2012-10-02 2014-04-10 Yale University Identification de petites molécules inhibitrices d'histone déméthylase à de domaine jumonji 1a (jarid1a) et 1b (jarid1b) interactif riche en at,

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9718838B2 (en) 2015-08-27 2017-08-01 Eli Lilly And Company Inhibitors of EZH2
WO2021249305A1 (fr) * 2020-06-08 2021-12-16 南京明德新药研发有限公司 Composé biphényle
CN114907300A (zh) * 2021-02-08 2022-08-16 上海医药工业研究院 他泽司他关键中间体的制备方法及其中间体
CN114907299A (zh) * 2021-02-08 2022-08-16 上海医药工业研究院 他泽司他关键中间体的新盐型、其制备方法及其中间体
WO2023211195A1 (fr) * 2022-04-28 2023-11-02 Sk Biopharmaceuticals Co., Ltd. Composés n-oxydes et leur utilisation

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