WO2021182914A1 - Nouveau composé inhibiteur de cdk7 ou sel pharmaceutiquement acceptable de celui-ci - Google Patents

Nouveau composé inhibiteur de cdk7 ou sel pharmaceutiquement acceptable de celui-ci Download PDF

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WO2021182914A1
WO2021182914A1 PCT/KR2021/003100 KR2021003100W WO2021182914A1 WO 2021182914 A1 WO2021182914 A1 WO 2021182914A1 KR 2021003100 W KR2021003100 W KR 2021003100W WO 2021182914 A1 WO2021182914 A1 WO 2021182914A1
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formula
compound
oxalate
pharmaceutically acceptable
salt
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Korean (ko)
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이광옥
유자경
이준희
이미정
이강우
민지은
최은호
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영진약품 주식회사
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    • 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
    • C07D417/02—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 two hetero rings
    • C07D417/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4436—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom
    • 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
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to novel compounds of formula (I), pharmaceutically acceptable salts, hydrates, solvates, hydrates of salts, or solvates of salts thereof.
  • novel compound of the present invention exhibits high CDK7 inhibitory activity, it can be usefully used for the treatment or prevention of CDK7-related diseases.
  • Protein kinase refers to a protein that plays a central role in the regulation of a wide variety of cellular processes and control of cellular functions. Kinase activity is observed in a number of disease states, including benign and malignant proliferative disorders, as well as those resulting from inappropriate activation of the immune and nervous systems. Oncogenesis is closely related to genetic modification of cyclin-dependent kinase (CDK) and its regulators, suggesting that CDK inhibitors may be useful anticancer therapeutics.
  • CDK cyclin-dependent kinase
  • CDKs form a complex with cyclin proteins and activate them by phosphorylation of serine or threonine residues on the substrate.
  • CDK1, CDK2, CDK4, and CDK6 regulate the entry into each phase of the cell cycle by phosphorylating molecules important in the cell cycle.
  • CDK2/cyclin E is essential to enter the S phase
  • CDK2/cyclin A is essential just before the transition from S phase to G2 phase.
  • CDK8 and CDK9 are also involved in gene transcription.
  • CDK activation is completed by phosphorylation by CDK-activating kinase (CAK), and the CDK7/cyclin H complex acts as a CAK.
  • CDK7 phosphorylates the C-terminal domain (CTD) of RNA polymerase (RNAP) II, thereby regulating the expression of oncogenic transcription factors that induce cancer cell growth and survival. That is, CDK7 is the only CDK involved in transcription and regulating the cell cycle by simultaneously acting as a CAK and phosphorylating CTD.
  • cancer cells have the characteristics of increased genetic heterogeneity compared to normal cells, they can inhibit cancer cell growth or induce apoptosis by targeting driver mutations of major oncogenes.
  • transcriptional regulatory kinases such as CDK7 (Yubao Wang et al., Cell 163, 174-186, September 24, 2015). Accordingly, there is a need for compounds that treat diseases and disorders associated with selective transcriptional CDKs, particularly CDK7.
  • the present inventors have researched and developed novel compounds that selectively inhibit CDK7, and pharmaceutically acceptable salts, hydrates, solvates, hydrates of salts, and solvates of salts with improved physicochemical stability and solubility of the compounds.
  • the present invention was completed.
  • Patent Document 1 International Publication WO 2014/063068 A1
  • Patent Document 2 International Publication WO 2015/058140 A1
  • An object of the present invention is to provide a novel compound having excellent CDK7 inhibitory activity.
  • Another object of the present invention is to provide pharmaceutically acceptable salts, hydrates, solvates, hydrates of salts, and solvates of salts of the novel compounds, which have excellent physicochemical stability and solubility.
  • Another object of the present invention is to provide a method for preparing pharmaceutically acceptable salts, hydrates, solvates, hydrates of salts, and solvates of salts of the novel compounds.
  • Another object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising the novel compound, a pharmaceutically acceptable salt, hydrate, solvate, hydrate of a salt, or a solvate of a salt thereof.
  • Another object of the present invention is to provide a pharmaceutical composition for preventing or treating CDK7-related diseases, including the novel compound, a pharmaceutically acceptable salt, hydrate, solvate, salt hydrate, or salt solvate thereof.
  • the present invention provides a compound of formula (I): or a pharmaceutically acceptable salt thereof.
  • Ra is linear C 1 -C 3 alkyl unsubstituted or substituted with halogen
  • Rb is cyano or halo, Rc is H;
  • the pharmaceutically acceptable salt of the compound of formula (I) is oxalate, hydrochloride, benzenesulfonate, hemifumarate, succinate, hemmaleate, nicotinate, tosylate, glycolate, hemi Sulfonate, tartrate, maleate, aspartate, malate, citrate, malonate, phosphate, glutamate, camphorsulfonate, 3-hydroxy-2-naphthoate, mesylate, and 4-hydroxy- It may be selected from the group consisting of benzoates.
  • the tartrate may be L-tartrate
  • the aspartate may be L-aspartate
  • the glutamate may be L-glutamate
  • the camphorsulfonate may be (+)-camphorsulfonate.
  • it may be oxalate, hydrochloride, benzenesulfonate, hemifumarate, succinate, hemmaleate, glycolate, or nicotinate, and more preferably, hydrochloride or oxalate.
  • the pharmaceutically acceptable salt of the compound of formula (I) may be in the form of a hydrate or solvate.
  • the solvate of the pharmaceutically acceptable salt of the compound of formula (I) is acetone, ethanol, methanol, 1-butanol, 2-butanol, 1-propanol, ethyl acetate, diethyl ether, methyl tertbutyl It may be formed by one or more solvents selected from the group consisting of ether and heptane, but is not limited thereto.
  • the present invention provides a compound selected from the group consisting of compounds of formulas (II) to (VIII), or a pharmaceutically acceptable salt thereof.
  • the pharmaceutically acceptable salts of the compounds of formulas (II) to (VIII) are oxalate, hydrochloride, benzenesulfonate, hemifumarate, succinate, hemmaleate, nicotinate, tosylate, glycolate, hemisulfonate, tartrate, maleate, aspartate, malate, citrate, malonate, phosphate, glutamate, camphorsulfonate, 3-hydroxy-2-naphthoate, mesylate, and 4 -Hydroxy-benzoate may be selected from the group consisting of.
  • the tartrate may be L-tartrate
  • the aspartate may be L-aspartate
  • the glutamate may be L-glutamate
  • the camphorsulfonate may be (+)-camphorsulfonate.
  • it may be oxalate, hydrochloride, benzenesulfonate, hemifumarate, succinate, hemmaleate, glycolate, or nicotinate, and more preferably, hydrochloride or oxalate.
  • the pharmaceutically acceptable salt of the compound of formulas (II) to (VIII) may be in the form of a hydrate or a solvate.
  • the solvate of a pharmaceutically acceptable salt of a compound of Formulas (II) to (VIII) is acetone, ethanol, methanol, 1-butanol, 2-butanol, 1-propanol, ethyl acetate, diethyl ether. , methyl tertiary butyl ether, and may be formed by one or more solvents selected from the group consisting of heptane, but is not limited thereto.
  • the present invention provides a compound of formula (VI) or a pharmaceutically acceptable salt thereof.
  • the pharmaceutically acceptable salt of the compound of formula (VI) is selected from the group consisting of oxalate, hydrochloride, benzenesulfonate, hemifumarate, succinate, hemmaleate, glycolate, and nicotinate. may be selected, and preferably, hydrochloride or oxalate.
  • the pharmaceutically acceptable salt of the compound of formula (VI) may be in the form of a hydrate or solvate.
  • the solvate of the pharmaceutically acceptable salt of the compound of formula (VI) is acetone, ethanol, methanol, 1-butanol, 2-butanol, 1-propanol, ethyl acetate, diethyl ether, methyltertbutyl It may be formed by one or more solvents selected from the group consisting of ether and heptane, but is not limited thereto.
  • the present invention provides an oxalate salt of a compound of formula (VI).
  • the present invention provides a hydrate of the oxalate salt of the compound of formula (VI).
  • the hydrate of the oxalate salt of the compound of formula (VI) may be amorphous.
  • the present invention provides solvates of the oxalates of the compounds of formula (VI).
  • the solvate of the oxalate salt of the compound of formula (VI) is acetone, ethanol, methanol, 1-butanol, 2-butanol, 1-propanol, ethyl acetate, diethyl ether, methyltertiarybutyl ether, and heptane. It may be formed by one or more solvents selected from the group consisting of, preferably, it may be an acetone solvate of oxalate.
  • the acetone solvate of the oxalate salt of the compound of formula (VI) may be in crystalline form, preferably 7.4°, 8.3°, 9.3°, 10.1°, 11.2°, 11.5°, 12.6°, 15.2 °, 16.5°, 16.9°, 17.4°, 17.8°, 18.6°, 19.8°, 20.3°, 21.6°, 22.1°, 22.9°, 23.6°, 24.4°, 25.5°, 26.6°, 29.0° and 31.5° It may be a crystalline form showing an X-ray diffraction (XRD) spectrum comprising characteristic peaks at four or more diffraction angles 2 ⁇ 0.2° selected from the group consisting of, and more preferably, X-ray diffraction as shown in FIG. 1 . (XRD) spectrum.
  • XRD X-ray diffraction
  • the present invention provides the anhydride of the oxalate salt of the compound of formula (VI).
  • the anhydride of the oxalate salt of the compound of formula (VI) may be in crystalline form, preferably 8.3°, 13.7°, 14.9°, 15.3°, 16.0°, 16.7°, 16.9°, 17.6°, Characteristic at 4 or more diffraction angles 2 ⁇ ⁇ 0.2° selected from the group consisting of 18.4°, 18.8°, 19.2°, 19.9°, 20.7°, 21.4°, 21.9°, 22.7°, 23.8°, 25.3°, and 25.6° It may be a crystalline form exhibiting an X-ray diffraction (XRD) spectrum including peaks, and more preferably, a crystalline form having an X-ray diffraction (XRD) spectrum as shown in FIG. 3 .
  • XRD X-ray diffraction
  • the present invention provides the hydrochloride salt of the compound of formula (VI).
  • the hydrochloride salt of the compound of formula (VI) may be in crystalline form, preferably 7.0°, 9.1°, 10.5°, 11.0°, 13.5°, 17.1°, 19.0°, 20.8°, 21.3° , 23.2°, and 25.7° may be in a crystalline form showing an X-ray diffraction (XRD) spectrum comprising characteristic peaks at four or more diffraction angles 2 ⁇ 0.2° selected from the group consisting of, more preferably, FIG. 4 It may be in a crystalline form having an X-ray diffraction (XRD) spectrum as shown in
  • the present invention provides a hydrate of the hydrochloride salt of the compound of formula (VI).
  • the present invention provides solvates of the hydrochloride salts of the compounds of formula (VI).
  • the solvate of the hydrochloride salt of the compound of formula (VI) is acetone, ethanol, methanol, 1-butanol, 2-butanol, 1-propanol, ethyl acetate, diethyl ether, methyltertiarybutyl ether, and heptane. It may be formed by one or more solvents selected from the group consisting of.
  • the present invention provides the anhydride of the hydrochloride salt of the compound of formula (VI).
  • the oxalate salt of a compound of formula (I) of the present invention is prepared by dissolving the compound of formula (I) in a solvent such as acetone, ethanol, methanol, 1-butanol, 2-butanol, 1-propanol, ethyl acetate. , diethyl ether, methyl tertiary butyl ether, and dissolving in one or more solvents selected from the group consisting of heptane to obtain a solution; adding oxalic acid to the solution; and obtaining an oxalate salt of the compound of formula (I).
  • a solvent such as acetone, ethanol, methanol, 1-butanol, 2-butanol, 1-propanol, ethyl acetate.
  • diethyl ether, methyl tertiary butyl ether and dissolving in one or more solvents selected from the group consisting of heptane to obtain a solution; adding ox
  • the acetone solvate of the oxalate of the compound of formula (I) of the present invention is prepared by dissolving the oxalate of the compound of formula (I) in a solvent, for example, a mixture of purified water and acetone to obtain a solution; and obtaining an oxalate acetone solvate of the compound of formula (I).
  • a solvent for example, a mixture of purified water and acetone
  • the hydrate of the oxalate salt of a compound of formula (I) of the present invention is prepared by impregnation with an oxalate solvate of a compound of formula (I), for example acetone solvate; and obtaining a hydrate of the oxalate salt of the compound of formula (I).
  • the anhydride of the oxalate salt of a compound of formula (I) of the present invention is prepared by adding ethanol to the oxalate hydrate of a compound of formula (I); After stirring the mixture, vacuum drying; and obtaining an anhydride of the oxalate salt of the compound of formula (I).
  • the hydrochloride salt of a compound of formula (I) of the present invention is prepared by dissolving the compound of formula (I) in a solvent such as acetone, ethanol, methanol, 1-butanol, 2-butanol, 1-propanol, ethyl acetate, dissolving in one or more solvents selected from the group consisting of diethyl ether, methyl tertiary butyl ether, and heptane to obtain a solution; adding hydrochloric acid to the solution; and obtaining a hydrochloride salt of the compound of formula (I).
  • a solvent such as acetone, ethanol, methanol, 1-butanol, 2-butanol, 1-propanol, ethyl acetate
  • the benzenesulfonate salt of a compound of formula (I) of the present invention is prepared by dissolving the compound of formula (I) in a solvent such as acetone, ethanol, methanol, 1-butanol, 2-butanol, 1-propanol, ethyl dissolving in one or more solvents selected from the group consisting of acetate, diethyl ether, methyl tertbutyl ether, and heptane to obtain a solution; adding benzenesulfonic acid to the solution; and obtaining a benzenesulfonate salt of the compound of formula (I).
  • a solvent such as acetone, ethanol, methanol, 1-butanol, 2-butanol, 1-propanol, ethyl dissolving in one or more solvents selected from the group consisting of acetate, diethyl ether, methyl tertbutyl ether, and heptane
  • the hemifumarate salt of a compound of formula (I) of the present invention is prepared by dissolving the compound of formula (I) in a solvent such as acetone, ethanol, methanol, 1-butanol, 2-butanol, 1-propanol, ethyl dissolving in one or more solvents selected from the group consisting of acetate, diethyl ether, methyl tertbutyl ether, and heptane to obtain a solution; adding fumaric acid to the solution; and obtaining a hemifumarate salt of the compound of formula (I).
  • a solvent such as acetone, ethanol, methanol, 1-butanol, 2-butanol, 1-propanol, ethyl dissolving in one or more solvents selected from the group consisting of acetate, diethyl ether, methyl tertbutyl ether, and heptane
  • the succinate salt of a compound of formula (I) of the present invention is prepared by dissolving the compound of formula (I) in a solvent such as acetone, ethanol, methanol, 1-butanol, 2-butanol, 1-propanol, ethyl acetate. , diethyl ether, methyl tertiary butyl ether, and dissolving in one or more solvents selected from the group consisting of heptane to obtain a solution; adding succinic acid to the solution; and obtaining a succinate salt of the compound of formula (I).
  • a solvent such as acetone, ethanol, methanol, 1-butanol, 2-butanol, 1-propanol, ethyl acetate.
  • diethyl ether, methyl tertiary butyl ether and dissolving in one or more solvents selected from the group consisting of heptane to obtain a solution; adding succinic acid to the solution; and
  • the hemimaleate salt of a compound of formula (I) of the present invention is prepared by dissolving the compound of formula (I) in a solvent such as acetone, ethanol, methanol, 1-butanol, 2-butanol, 1-propanol, ethyl dissolving in one or more solvents selected from the group consisting of acetate, diethyl ether, methyl tertbutyl ether, and heptane to obtain a solution; adding maleic acid to the solution; and obtaining a hemimaleate salt of the compound of formula (I).
  • a solvent such as acetone, ethanol, methanol, 1-butanol, 2-butanol, 1-propanol, ethyl dissolving in one or more solvents selected from the group consisting of acetate, diethyl ether, methyl tertbutyl ether, and heptane
  • the nicotinate salt of a compound of formula (I) of the present invention is prepared by dissolving the compound of formula (I) in a solvent such as acetone, ethanol, methanol, 1-butanol, 2-butanol, 1-propanol, ethyl acetate. , diethyl ether, methyl tertiary butyl ether, and dissolving in one or more solvents selected from the group consisting of heptane to obtain a solution; adding nicotinic acid to the solution; and obtaining a nicotinate salt of the compound of formula (I).
  • a solvent such as acetone, ethanol, methanol, 1-butanol, 2-butanol, 1-propanol, ethyl acetate.
  • diethyl ether, methyl tertiary butyl ether and dissolving in one or more solvents selected from the group consisting of heptane to obtain a solution; adding
  • the glycolate salt of a compound of formula (I) of the present invention is prepared by dissolving the compound of formula (I) in a solvent such as acetone, ethanol, methanol, 1-butanol, 2-butanol, 1-propanol, ethyl acetate. , diethyl ether, methyl tertiary butyl ether, and dissolving in one or more solvents selected from the group consisting of heptane to obtain a solution; adding glycolic acid to the solution; and obtaining a glycolate salt of the compound of formula (I).
  • a solvent such as acetone, ethanol, methanol, 1-butanol, 2-butanol, 1-propanol, ethyl acetate.
  • diethyl ether, methyl tertiary butyl ether and dissolving in one or more solvents selected from the group consisting of heptane to obtain a solution; adding glycolic acid to the solution; and obtaining
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound selected from the group consisting of compounds of formulas (I) to (VIII), a pharmaceutically acceptable salt, hydrate, solvate, hydrate of salt, or solvate of salt, as an active ingredient. to provide.
  • the present invention relates to a CDK7-related disease comprising a compound selected from the group consisting of compounds of formulas (I) to (VIII), a pharmaceutically acceptable salt, hydrate, solvate, salt hydrate, or salt solvate as an active ingredient It provides a pharmaceutical composition for the prevention or treatment of.
  • the CDK7 related disease may be a proliferative disease or an infectious disease.
  • the CDK7-related disease may be cancer, specifically breast cancer, blood cancer, liver cancer, or lung cancer.
  • novel compound according to the present invention exhibits high CDK7 inhibitory activity, it can be usefully used as a pharmaceutical composition for preventing or treating CDK7-related diseases.
  • Example 1 is a graph showing the XRD pattern of Example 8.
  • Example 2 is a graph showing the XRD pattern of Example 9.
  • Example 3 is a graph showing the XRD pattern of Example 10.
  • Example 4 is a graph showing the XRD pattern of Example 11.
  • Example 8 shows a hydrogen nuclear magnetic resonance spectrum analysis diagram of Example 8.
  • Example 6 shows a hydrogen nuclear magnetic resonance spectrum analysis diagram of Example 9.
  • Example 7 shows a hydrogen nuclear magnetic resonance spectrum analysis diagram of Example 10.
  • Example 8 shows a hydrogen nuclear magnetic resonance spectrum analysis diagram of Example 11.
  • Example 9 shows a hydrogen nuclear magnetic resonance spectrum analysis diagram of Example 12.
  • Example 10 shows a hydrogen nuclear magnetic resonance spectrum analysis diagram of Example 13.
  • Example 11 shows a hydrogen nuclear magnetic resonance spectrum analysis diagram of Example 14.
  • Example 12 shows a hydrogen nuclear magnetic resonance spectrum analysis diagram of Example 15
  • FIG. 13 shows a hydrogen nuclear magnetic resonance spectrum analysis diagram of Example 16.
  • Example 14 shows a hydrogen nuclear magnetic resonance spectrum analysis diagram of Example 17
  • alkyl is a hydrocarbon having primary, secondary, tertiary and/or quaternary carbon atoms, substituted or unsubstituted, and saturated, which may be straight-chain, branched, cyclic, or combinations thereof. contains aliphatic groups.
  • an alkyl group has 1 to 20 carbon atoms (ie, C 1 -C 20 alkyl), 1 to 10 carbon atoms (ie, C 1 -C 10 alkyl), or 1 to 6 carbon atoms (ie, C 1 -C 10 alkyl). C 1 -C 6 alkyl).
  • alkyl refers to C 1 -C 6 alkyl.
  • alkyl groups examples include methyl (Me, —CH 3 ), ethyl (Et, —CH 2 CH 3 ), 1-propyl (n-Pr, n-propyl, —CH 2 CH 2 CH 3 ), 2-propyl ( i-Pr, i-propyl, -CH(CH 3 ) 2 ), 1-butyl (n-Bu, n-butyl, -CH 2 CH 2 CH 2 CH 3 ), 2-methyl-1-propyl (i- Bu, i-butyl, -CH 2 CH(CH 3 ) 2 ), 2-butyl (s-Bu, s-butyl, -CH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propyl (t -Bu, t-butyl, -C(CH 3 ) 3 ), 1-pentyl (n-pentyl, -CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH3)CH 2 CH
  • alkyl as used throughout the specification, examples and claims is intended to include both unsubstituted and substituted alkyl groups, the latter of which include haloalkyl groups such as trifluoromethyl, and the like; refers to an alkyl moiety having a substituent replacing a hydrogen on one or more carbons of the hydrocarbon backbone.
  • Cx-y or “Cx-Cy,” when used with alkyl, means containing from x to y carbons in the chain.
  • a C 1 -C 6 alkyl group contains 1 to 6 carbon atoms in the chain.
  • halo or “halogen” includes chloro, fluoro, bromo, and iodo.
  • substituted refers to a particular moiety of a compound of the present invention having one or more substituents.
  • substituted eg, “substituted alkyl,” with respect to alkyl and the like, means that one or more hydrogen atoms of the alkyl are each independently replaced by a non-hydrogen substituent.
  • the term "pharmaceutically acceptable salt” means any acid or base addition salt, which is nontoxic and harmless to the patient and the side effects attributable to the salt do not diminish the beneficial efficacy of the compound of the present invention.
  • Inorganic acids that form suitable salts include hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid, hydrobromic acid, hydroiodic acid, nitrous acid, or phosphorous acid
  • organic acids that form suitable salts include glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, Fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, benzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, nicotinic acid, tosylic acid, camphorsulfonic acid, naphthoic acid, acetic acid, trifluoroacetic acid, oxalic acid, manderic acid
  • solvate refers to a solid in which compound molecules and solvent molecules form a complex
  • hydrate refers to a specific solvate in which the solvent is water
  • the compounds, pharmaceutically acceptable salts, hydrates, solvates, hydrates of salts, and solvates of salts are meant to include both crystalline and amorphous forms, respectively.
  • the compounds of the present invention can be prepared from readily available starting materials using modifications to synthetic protocols known to those skilled in the art.
  • Certain compounds of the present invention may have one or more stereocenters within their structure. Such stereocenters may exist in either the R or S configuration, the R and S designations being described in Pure Appl. Chem. (1976), 45, 11-30].
  • the present invention includes all stereoisomeric forms of a compound or a pharmaceutically acceptable salt thereof, such as enantiomeric and diastereomeric forms, including all possible mixtures of stereoisomers.
  • the pharmaceutical composition of the present invention may be a pharmaceutical composition for preventing or treating a CDK7-related disease, and the CDK7-related disease includes a proliferative disease or an infectious disease.
  • Proliferative disease means, for example, cancer, benign neoplasm, angiogenesis, inflammatory disease, auto-inflammatory disease, or autoimmune disease
  • infectious disease means, for example, bacterial disease or viral disease.
  • Acetonitrile (165 ml) is added to the racemic form of 2-(3-bromophenyl)propanoic acid (33.13 g, 144.63 mmol) followed by addition of (R)-1-phenylethan-1-amine, Stirred at 30-35°C. After stirring at 20-25° C. for 2 hours, the reaction is filtered, washed with 0-5° C. acetonitrile (100 ml) and dried. Acetonitrile (165 ml) was added to the dried compound and the mixture was stirred at 80-85° C. for 1 hour. After that, the mixture was cooled to 30-35° C. and stirred for 1 hour.
  • reaction mixture was diluted with DCM, washed with water, dried (MgSO 4 ), filtered and dried under reduced pressure. Purify the residue by combi-flash column (EA/Hex 0 to 60 % gradient) to (S)-2-(3-bromophenyl)-N-(5-trifluoromethylthiazol-2-yl ) propanamide (3.4 g, 80%) was provided as a white solid.
  • the title compound was prepared in the same manner as in Example 1, except that 5-ethylthiazol-2-amine was used instead of 5-trifluoromethylthiazol-2-amine.
  • CDK7 inhibitory activity was measured using recombinant purified human CDK7 (ThermoFisher, PV3868) and ADP Glo kinase assay kit (Promega, V9102).
  • CDK7 was diluted with IX kinase reaction buffer (40 mM Tris-Cl, pH 7.5, 20 mM MgCl 2 , 0.1 mg/ml BSA and 50 ⁇ M DTT) and added to 96 well plates (CDK7 final concentration per reaction: 50 ng) ).
  • the compound was finally treated to a 1% aqueous DMSO solution, and a substrate cocktail containing ATP (final concentration 90 ⁇ M) and 0.2 ⁇ g/ ⁇ l MBP (myelin basic protein) in a total of 25 ⁇ l reaction mass was added to a 96 well plate.
  • a substrate cocktail containing ATP final concentration 90 ⁇ M
  • MBP myelin basic protein
  • the kinase activity was measured by the chemiluminescence method according to the ADP Glo Kinase Assay Kit instruction manual, and the CDK7 inhibitory activity of the compound according to the present invention was calculated. Results analysis of each compound was performed using Microsoft Excel, and IC 50 values were calculated by Prism software, and the degree of CDK7 inhibition (IC 50 ) is shown in Table 1 below.
  • Example CDK7 inhibition (IC 50 nM) One 7.6 2 4.3 3 5.9 4 8.5 5 4.2 6 6.0 7 4.0
  • the compounds of the present invention have very high CDK7 inhibitory activity.
  • Test Example 2 Antiproliferative effect of the compound of the present invention on cancer cells
  • MDA-MB-468 cells are one of the cells of triple-negative breast cancer (TNBC: negative for estrogen receptor, progesterone receptor and HER2 expression) known as a malignant tumor with a difficult initial diagnosis and high metastatic capacity, and these cells are Used to test inhibition of cell proliferation and survival.
  • TNBC triple-negative breast cancer
  • Compounds of the present invention were tested at different concentrations (from 1000 nM to 1 nM) to assess their ability to inhibit proliferation of MDA-MB-468 cells.
  • Cells were cultured in RPMI 1640 (Wellgene) + 10% FBS (Gibco) + 1% penicillin/streptomycin (Gibco) and incubated at 37° C. in a humidified chamber in the presence of 5% CO 2 .
  • MDA-MB-468 cells cultured in 96-well cell culture plates were treated with the compounds of the present invention and incubated for 72 hours. Then, the antiproliferative effect of the compound was analyzed by the MTT method using a tetrazolium salt, and the degree of inhibition of cell proliferation (IC 50 ) is shown in Table 2 below.
  • Example MDA-MB-468 (IC 50 nM) One 23.0 2 30.0 3 74.0 4 35.0 5 14.0 6 34.0 7 7.0
  • the compound of the present invention has a high inhibitory activity against the proliferation of MDA-MB-468 cells.
  • HepG2 cells a human hepatocellular carcinoma cell
  • MEM Wellgene
  • FBS FBS
  • penicillin/streptomycin Gibco
  • HepG2 cells cultured in 96-well cell culture plates were treated with the compound and incubated for 72 hours.
  • Cell viability was measured by the CCK-8 method using tetrazolium salts and the ability of the compounds according to the invention to inhibit cancer cell proliferation was calculated. Results analysis of each compound was performed using Microsoft Excel, IC 50 values were calculated by Prism software, and the results are shown in Table 3 below.
  • Example HepG2 (IC 50 nM) One 5.0 2 5.0 3 17.4 4 4.2 5 3.0 6 38.0 7 3.8
  • the compound of the present invention has a high inhibitory activity against proliferation of HCC (HepG2) cells.
  • CDK2, CDK5, and CDK7 inhibition was measured using a scanMAX kinase assay panel with a set of 468 kinases including CDK2, CDK5.
  • the compounds of the present invention were screened at 1 ⁇ M, and the results are shown in Table 4 below.
  • Example 5 Comparative Example 1 CDK7 4.0 9.7 Healing cancer MV-4-11 4.2 16.5 Breast Cancer MCF-7 22.1 417.1 Liver Cancer HepG2 3.8 128.1 Liver Cancer Hep3B 22.0 248.7
  • the compound of the present invention contains a "thiazole” ring and has excellent CDK7 inhibitory and cancer cell proliferation inhibitory effects.
  • Example 5 Comparative Example 2 Comparative Example 3 CDK7 (IC 50 nM) 4.2 339 197
  • Example 6 As shown in Table 6, the compound of Example 5 containing a "4-(dimethylamino)but-2-enamide” group exhibited about 80-fold and about 80-fold inhibition of CDK7 compared to the compounds of Comparative Examples 2 and 3, respectively. It was confirmed that it was 45 times superior.
  • the compound of the present invention contains a "4-(dimethylamino)but-2-enamide” group and has an excellent CDK7 inhibitory effect.
  • the compound of Example 5 including a substituted pyridine ring and unsubstituted pyridine
  • the degree of inhibition of CDK7 and the degree of inhibition of cancer cell proliferation were compared between the compound of Comparative Example 4 containing a ring and the compound of Comparative Example 5 without pyridine.
  • Example 5 Comparative Example 4 Comparative Example 5 CDK7 4.0 9.3 96 Blood cancer MV-4-11 4.2 34.4 446 Breast Cancer MCF-7 22.1 55.8 467 Liver Cancer HepG2 3.8 16.7 128 Liver Cancer Hep3B 22.0 51.6 125
  • the compound of the present invention has excellent CDK7 inhibitory and cancer cell proliferation inhibitory effects including the "pyridine” ring, and further increases the inhibitory effect when the pyridine ring is substituted.
  • Example 6 Comparative Example 4 CDK7 (IC 50 nM) 6.0 4.0 11.0
  • the compound of the present invention has excellent CDK7 inhibitory activity when the pyridine ring is substituted with a halogen or cyano group or forms a fused ring with pyrrolidine.
  • the stability of the compound of Example 5 (the compound of formula (VI)) and the compound of Example 9 (the oxalate hydrate of the compound of formula (VI)) of the present invention were compared. Specifically, a stability test was performed according to the ICH guidelines, and analysis was performed using a high-performance liquid chromatography (HPLC) analysis method. After storage for 28 days in a sealed state at a temperature of 25 ⁇ 2 °C and a relative humidity of 60 ⁇ 5 %, the change in purity was measured, and the results are shown in Table 9 below.
  • HPLC high-performance liquid chromatography
  • Example 5 Compound of formula (VI)
  • Example 9 (of the compound of formula (VI) oxalate hydrate) Initial 94.98% 98.14% 7 days 93.98% 98.01% 14 days 93.21% 98.05% 21 days 92.78% 97.73% 28 days 91.91% 97.64%
  • the compound of formula (VI) showed a purity change of at least 3% by day 28, whereas the oxalate hydrate of the compound of formula (VI) showed a purity change of 0.5% by day 28, It was confirmed that the oxalate hydrate of the compound of (VI) has excellent storage stability.
  • Table 10 shows the results of solubility evaluation of the compound of Example 5 (the compound of formula (VI)) and the compound of Example 9 (the oxalate hydrate of the compound of formula (VI)).
  • Example 5 Compound of formula (VI)
  • Example 9 Olalate hydrate of the compound of formula (VI)
  • Solubility (mg/mL) 0.18 238
  • the oxalate hydrate of the compound of formula (VI) of the present invention has very good solubility and is advantageous for drug development by improving absorption and bioavailability of the drug.
  • Test Example 7 X-ray diffraction spectroscopy analysis
  • the salt of the compound of formula (VI), the hydrate of the salt, or the solvate of the salt prepared in Examples 8 to 11 were analyzed using an X-ray diffraction analyzer.
  • the X-ray diffraction analyzer (XRD) measurement conditions are as follows.
  • Hydrogen nuclear magnetic resonance spectral analysis was performed on the salts, hydrates of the salts, or solvates of the salts of the compound of formula (VI) prepared in Examples 8 to 17.
  • the hydrogen nuclear magnetic resonance spectrum measurement conditions were as follows, and the results are shown in FIGS. 5 to 14 .

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Abstract

La présente invention concerne un nouveau composé de formule chimique (I), un sel pharmaceutiquement acceptable, un hydrate et un solvate du composé, et un hydrate ou un solvate du sel. < formule chimique (I) > Le nouveau composé selon la présente invention a une activité inhibitrice de CDK7 élevée, et peut ainsi être utilisé de manière efficace pour le traitement ou la prévention de maladies associées à CDK7.
PCT/KR2021/003100 2020-03-13 2021-03-12 Nouveau composé inhibiteur de cdk7 ou sel pharmaceutiquement acceptable de celui-ci WO2021182914A1 (fr)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003008365A2 (fr) * 2001-07-19 2003-01-30 Pharmacia Italia S.P.A. Derives de phenylacetamido-thiazole, leur procede de preparation et leur utilisation en tant qu'agents antitumoraux
WO2006018188A2 (fr) * 2004-08-17 2006-02-23 F. Hoffmann-La Roche Ag Hydantoines substituees
WO2011079036A1 (fr) * 2009-12-22 2011-06-30 The Translational Genomics Research Institute Dérivés de benzamide
WO2015082357A1 (fr) * 2013-12-02 2015-06-11 Siena Biotech S.P.A. Antagonistes de s1p3
KR20180041112A (ko) * 2015-06-04 2018-04-23 오리진 디스커버리 테크놀로지스 리미티드 Cdk 억제제로서의 치환된 헤테로사이클릴 유도체
KR20200032002A (ko) * 2018-09-17 2020-03-25 영진약품 주식회사 신규한 티아졸 유도체 및 이의 약학적으로 허용가능한 염

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2909194A1 (fr) 2012-10-18 2015-08-26 Dana-Farber Cancer Institute, Inc. Inhibiteurs de cycline-dépendante kinase 7 (cdk7)
EP3057956B1 (fr) 2013-10-18 2021-05-05 Dana-Farber Cancer Institute, Inc. Inhibiteurs polycycliques de la kinase cycline-dépendante 7 (cdk7)

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003008365A2 (fr) * 2001-07-19 2003-01-30 Pharmacia Italia S.P.A. Derives de phenylacetamido-thiazole, leur procede de preparation et leur utilisation en tant qu'agents antitumoraux
WO2006018188A2 (fr) * 2004-08-17 2006-02-23 F. Hoffmann-La Roche Ag Hydantoines substituees
WO2011079036A1 (fr) * 2009-12-22 2011-06-30 The Translational Genomics Research Institute Dérivés de benzamide
WO2015082357A1 (fr) * 2013-12-02 2015-06-11 Siena Biotech S.P.A. Antagonistes de s1p3
KR20180041112A (ko) * 2015-06-04 2018-04-23 오리진 디스커버리 테크놀로지스 리미티드 Cdk 억제제로서의 치환된 헤테로사이클릴 유도체
KR20200032002A (ko) * 2018-09-17 2020-03-25 영진약품 주식회사 신규한 티아졸 유도체 및 이의 약학적으로 허용가능한 염

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