WO2022033552A1 - Inhibiteur de kinase cdk, son procédé de préparation, composition pharmaceutique et application - Google Patents

Inhibiteur de kinase cdk, son procédé de préparation, composition pharmaceutique et application Download PDF

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Publication number
WO2022033552A1
WO2022033552A1 PCT/CN2021/112286 CN2021112286W WO2022033552A1 WO 2022033552 A1 WO2022033552 A1 WO 2022033552A1 CN 2021112286 W CN2021112286 W CN 2021112286W WO 2022033552 A1 WO2022033552 A1 WO 2022033552A1
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alkyl
formula
membered heterocycloalkyl
butyl
substituted
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PCT/CN2021/112286
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Chinese (zh)
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杨磊
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隆泰申医药科技(南京) 有限公司
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Publication of WO2022033552A1 publication Critical patent/WO2022033552A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • 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
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the present invention relates to a CDK kinase inhibitor, its preparation method, pharmaceutical composition and application.
  • Cyclin-dependent kinases are relatively small proteins with a molecular weight between 34 and 40 kilodaltons that contain essentially only the kinase domain. CDKs bind regulatory proteins called cyclins. In the absence of cyclin, CDKs have little kinase activity; only the cyclin-CDK complex is an active kinase. CDKs phosphorylate the serine/threonine residues of their substrates and therefore belong to the class of serine/threonine kinases (David O. Morgan, The Cell Cycle: Principles of Control. London: New Science Press ), 1st edition, (2007)).
  • CDK cyclin-dependent kinase
  • CDK7 exists as a heterotrimeric complex and is thought to function as a CDK1/2-activating kinase (CAK), which is required for fully catalyzed CDK activity and cell cycle progression for CDK1/2 conserveed residues are phosphorylated (Desai et al., Mol. Cell Biol. 15, 345-350 (1995)).
  • CAK CDK1/2-activating kinase
  • CDK7 in the CDK family has been shown to be closely related to the occurrence and development of various malignant tumors.
  • CDK7 inhibitors may be used for the treatment of various malignant tumors.
  • the technical problem to be solved by the present invention is to provide a CDK kinase inhibitor different from the prior art, its preparation method, pharmaceutical composition and application in order to overcome the lack of existing CDK7 kinase inhibitors in the prior art.
  • the compounds of the present invention have better inhibitory activity as CDK kinase inhibitors.
  • the present invention mainly solves the above technical problems through the following technical solutions.
  • the present invention provides a compound shown in formula Ia, its cis-trans isomer, its pharmaceutically acceptable salt, its solvate, its pharmaceutically acceptable salt solvate, its tautomerism a form or a polymorph thereof,
  • R 1 and R 2 are independently C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted by one or more halogens (when there are multiple halogens, the halogens are the same or different), C 3 -C 6 cycloalkyl or -NR 1-1 R 1-2 ;
  • R 1-1 and R 1-2 are independently H or 5-8-membered heterocycloalkyl, and the heteroatom in the 5-8-membered heterocycloalkyl is one or more of N, S and O , the number is 1, 2 or 3 (when the number of heteroatoms is 2 or 3, the types of heteroatoms may be the same or different);
  • X is N or CR 3 , R 3 is hydrogen or halogen
  • Y is N or O
  • R 4 is H or C 1 -C 6 alkyl
  • n 1 or 2;
  • n a is 1 or 2;
  • Z is N or CH
  • L is NH or absent (ie, Z is directly attached to the carbon group);
  • R 5 is H or halogen
  • R 6 and R 7 are independently H, C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted by one or more R 6-1 (when R 6-1 is more than one, the R 6-1 same or different), 5-8-membered heterocycloalkyl or 5-8-membered heterocycloalkyl substituted by one or more R 6-2 (when R 6-2 is more than one, the R 6-2 are the same or different), the heteroatoms in the 5-8-membered heterocycloalkyl, and, one or more R 6-2 -substituted 5-8-membered heterocycloalkyl are independently N, S and one or more of O, the number of which is 1, 2 or 3 (when the number of heteroatoms is 2 or 3, the types of heteroatoms may be the same or different);
  • R 6-1 is -NR 6-1-1 R 6-1-2 ;
  • R 6-1-1 and R 6-1-2 are independently H or C 1 -C 6 alkyl
  • R 6-1-1 and R 6-1-2 together with the N to which they are attached form a 5-8 membered heterocycloalkyl or, one or more C 1 -C 6 alkyl substituted 5-8 membered heterocycle Alkyl; the heteroatoms in the 5-8-membered heterocycloalkyl group and the 5-8-membered heterocycloalkyl group substituted by one or more C 1 -C 6 alkyl groups are independently one of N, S and O One or more, the number is 1, 2 or 3 (when the number of heteroatoms is 2 or 3, the types of heteroatoms may be the same or different);
  • R 6-2 is C 1 -C 6 alkyl
  • the carbon atoms marked with * are chiral carbon in R configuration, chiral carbon in S configuration or achiral carbon.
  • the C 1 -C 6 alkyl group is a C 1 -C 4 alkyl group, preferably methyl, ethyl, n-propyl , isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, further preferably isopropyl or tert-butyl, eg isopropyl.
  • R 1 is C 1 -C 6 alkyl substituted by one or more halogens
  • the halogen is fluorine, chlorine, bromine or iodine
  • the C 1 -C 6 alkyl Preferably it is a C 1 -C 4 alkyl group, more preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
  • R 1 is a C 3 -C 6 cycloalkyl group
  • the C 3 -C 6 cycloalkyl group is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group, such as Cyclopropanyl.
  • the C 1 -C 6 alkyl group is a C 1 -C 4 alkyl group, preferably methyl, ethyl, n-propyl group, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, more preferably methyl.
  • R 2 when R 2 is C 1 -C 6 alkyl substituted by one or more halogens, the halogen is fluorine, chlorine, bromine or iodine;
  • the C 1 -C 6 alkyl Preferably it is a C 1 -C 4 alkyl group, more preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
  • R 1-1 and R 1-2 are independently a 5-8 membered heterocycloalkyl
  • the 5-8 membered heterocycloalkyl is a 5-6 membered heterocycloalkane base
  • the heteroatom is O
  • the number is 1; preferably pyranyl, for example
  • R 2 is -NR 1-1 R 1-2
  • one of R 1-1 and R 1-2 is H, and the other is 5-8 membered heterocycloalkyl.
  • Described-NR 1-1 R 1-2 is preferably
  • the halogen is fluorine, chlorine, bromine or iodine.
  • R 4 when R 4 is a C 1 -C 6 alkyl group, the C 1 -C 6 alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl , isobutyl, sec- or tert-butyl, eg methyl.
  • halogen when R5 is halogen, said halogen is fluorine, chlorine, bromine or iodine, such as fluorine.
  • R 6 and R 7 are independently C 1 -C 6 alkyl, or, one or more R 6-1 substituted C 1 -C 6 alkyl, the C 1 -C 6 alkyl group and one or more R 6-1 substituted C 1 -C 6 alkyl group in which C 1 -C 6 alkyl group is independently methyl, ethyl, n-propyl, isopropyl , n-butyl, isobutyl, sec-butyl or tert-butyl, eg methyl.
  • R 6-1-1 and R 6-1-2 are independently C 1 -C 6 alkyl
  • the C 1 -C 6 alkyl is independently methyl, ethyl , n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, eg methyl.
  • R 6-1-1 and R 6-1-2 together with the N to which they are attached form a 5-8 membered heterocycloalkyl the 5-8 membered heterocycloalkyl is 5-6 membered heterocycloalkyl
  • the heteroatoms are N and/or O, and the number is 2; preferably morpholino, for example
  • R 6-1-1 and R 6-1-2 together with the N to which they are attached form one or more C 1 -C 6 alkyl substituted 5-8 membered heterocycloalkanes
  • the 5-8-membered heterocycloalkyl group is a 5-6-membered heterocycloalkyl group, the heteroatom is N, and the number is 1 or 2; it is preferably a piperazinyl group.
  • the C 1 -C 6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, such as methyl.
  • R 6-1-1 and R 6-1-2 together with the N to which they are attached form one or more C 1 -C 6 alkyl substituted 5-8 membered heterocycloalkyl
  • the one or more C 1 -C 6 alkyl substituted 5-8 membered heterocycloalkyl is methyl substituted piperazinyl, for example
  • R 6 and R 7 are independently one or more R 6-1 substituted C 1 -C 6 alkyl
  • the one or more R 6-1 substituted C 1 -C 6 alkyl is
  • R 6 and R 7 are independently 5-8-membered heterocycloalkyl or 5-8-membered heterocycloalkyl substituted by one or more R 6-2
  • the The 5-8-membered heterocycloalkyl in the 5-8-membered heterocycloalkyl group and the one or more R 6-2 substituted 5-8-membered heterocycloalkyl groups are independently 5-6-membered heterocycloalkyl groups.
  • Cycloalkyl, the heteroatom is N and the number is 2, such as pyrrolidinyl.
  • R 6-2 is a C 1 -C 6 alkyl group
  • the C 1 -C 6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl , isobutyl, sec- or tert-butyl, eg methyl.
  • R 6 and R 7 are independently one or more R 6-2 substituted 5-8-membered heterocycloalkyl
  • said one or more R 6- 2 -substituted 5-8 membered heterocycloalkyl is methyl-substituted pyrrolidinyl, such as
  • R 1 is C 1 -C 6 alkyl.
  • R 1 is C 1 -C 6 alkyl (eg ethyl, isopropyl or tert-butyl) or C 3 -C 6 cycloalkyl (eg cyclopropyl).
  • R 2 is C 1 -C 6 alkyl.
  • R 2 is C 1 -C 6 alkyl (eg methyl) or -NR 1-1 R 1-2 (eg ).
  • R3 is hydrogen
  • na is 1.
  • Y is O.
  • Z is N and L is absent; or, Z is CH and L is NH.
  • R 6 and R 7 are independently H or, one or more R 6-1 substituted C 1 -C 6 alkyl;
  • R 6-1 is -NR 6- 1-1 R 6-1-2 ;
  • R 6-1-1 and R 6-1-2 are independently C 1 -C 6 alkyl, or, R 6-1-1 and R 6-1-2 together with the N to which they are attached Forms a 5-8 membered heterocycloalkyl or a 5-8 membered heterocycloalkyl substituted with one or more C1 - C6 alkyl groups.
  • the compound represented by the formula I-a is the compound represented by the formula I-a1 or I-a2,
  • R 1 and R 2 are independently C 1 -C 6 alkyl
  • Y is O
  • n 2;
  • n a 1;
  • R 6 and R 7 are independently one or more R 6-1 substituted C 1 -C 6 alkyl
  • R 6-1 is -NR 6-1-1 R 6-1-2 ;
  • R 6-1-1 and R 6-1-2 are independently C 1 -C 6 alkyl.
  • R 1 is C 1 -C 6 alkyl
  • R 2 is C 1 -C 6 alkyl or -NR 1-1 R 1-2 ;
  • X is N or CH
  • Y is O
  • R 5 is H
  • R 6 and R 7 are independently H, C 1 -C 6 alkyl, or, one or more R 6-1 substituted C 1 -C 6 alkyl;
  • R 6-1 is -NR 6-1-1 R 6-1-2 ;
  • R 6-1-1 and R 6-1-2 are independently C 1 -C 6 alkyl.
  • the compound represented by formula Ia, its cis-trans isomer, its pharmaceutically acceptable salt, its solvate, its pharmaceutically acceptable salt solvate , its tautomer, or its polymorphic form is a compound shown in formula I, its cis-trans isomer or a pharmaceutically acceptable salt thereof,
  • R 1 and R 2 are independently C 1 -C 6 alkyl, or C 1 -C 6 alkyl substituted with one or more halogens (when there are multiple halogens, the halogens are the same or different);
  • X is N or CR 3 , R 3 is hydrogen or halogen
  • n 1 or 2;
  • the carbon atom marked with * is chiral carbon in R configuration, chiral carbon in S configuration or achiral carbon;
  • the compound shown in formula I is the compound shown in formula I-1,
  • R 1 and R 2 are independently C 1 -C 6 alkyl groups, or C 1 -C 6 alkyl groups substituted with one or more halogens; the carbon atoms marked with * are R-configuration chiral carbon, S-configuration chiral or achiral carbon.
  • the carbon atom marked with * is a chiral carbon of R configuration or a chiral carbon of S configuration.
  • the compound shown in formula I is the compound shown in formula I-2,
  • R 1 and R 2 are independently C 1 -C 6 alkyl, or C 1 -C 6 alkyl substituted by one or more halogens;
  • X is N or CR 3 , and
  • R 3 is hydrogen or halogen.
  • the compound represented by the formula I-a is
  • R 8 is halogen (eg chlorine or bromine) or hydroxy; R 1 , R 2 , X, Y, R 4 , Z, L, n , R 5 , na , R 6 , R 7 and those marked with *
  • the carbon atoms are as described above.
  • the solvent may be a conventional solvent for this type of reaction in the field, and in the present invention, it is particularly preferably a nitrile solvent (eg, acetonitrile).
  • a nitrile solvent eg, acetonitrile
  • the molar concentration of the compound represented by the formula II-a in the solvent can be the conventional molar concentration of this type of reaction in the field, and the present invention is particularly preferably 0.01-0.5 mol/L , more preferably 0.05 to 0.15 mol/L (for example, 0.09 mol/L).
  • the molar ratio of the compound represented by the formula III-a to the compound represented by the formula II-a can be the conventional molar ratio of this type of reaction in the field, and the present invention is particularly Preferably it is 1:1-3:1, More preferably, it is 1.1:1-1.5:1 (for example, 1.3:1).
  • the base can be a conventional base for this type of reaction in the field, and the present invention is particularly preferably an organic base, more preferably N,N-diisopropylethylamine.
  • the molar ratio of the base to the compound shown in formula II-a can be the conventional molar ratio of this type of reaction in the field, and the present invention is particularly preferably 10:1 to 30: 1, more preferably 15:1 to 25:1 (for example, 21:1).
  • the condensing agent may be a conventional condensing agent for this type of reaction in the field, and in the present invention, it is particularly preferably 1-n-propylphosphoric anhydride.
  • the molar ratio of the condensing agent to the compound represented by formula II-a can be the conventional molar ratio of this type of reaction in the field, and is particularly preferably 1:1 to 3 in the present invention. : 1, more preferably 1.2:1 to 2:1 (for example, 1.5:1).
  • the reaction temperature of the condensation reaction can be the conventional reaction temperature of this type of reaction in the art, and is particularly preferably room temperature in the present invention.
  • the reaction time of the condensation reaction can be the conventional reaction time of this type of reaction in the field, and in the present invention, it is particularly preferably 8-20 hours, and more preferably 10-14 hours (for example, 12 hours).
  • a post-processing step may be further included.
  • the post-processing steps can be concentrating the reaction solution, extracting by phase separation, concentrating and purifying the organic phase.
  • the reagents used in the phase separation extraction can be dichloromethane and 10% sodium carbonate aqueous solution.
  • the purification method can be silica gel column purification.
  • the eluent used in the silica gel column purification can be dichloromethane/methanol/triethylamine (volume ratio can be 20:1:0.5).
  • the method for preparing the compound represented by I-a is the method for preparing the compound represented by formula I.
  • the preparation method of the compound shown in the formula I comprises the following steps: in a solvent, the compound shown in the formula II and the compound shown in the formula III are subjected to the following condensation under the action of a base and a condensing agent. reaction to obtain the compound shown in the formula I,
  • the solvent may be a conventional solvent for this type of reaction in the art, and in the present invention, it is particularly preferably a nitrile solvent (eg, acetonitrile).
  • a nitrile solvent eg, acetonitrile
  • the molar concentration of the compound represented by the formula II in the solvent can be the conventional molar concentration of this type of reaction in the field, and is particularly preferably 0.01-0.5 mol/L in the present invention, and further It is preferably 0.05 to 0.15 mol/L (for example, 0.09 mol/L).
  • the mol ratio of the compound shown in the formula III and the compound shown in the formula II can be the conventional mol ratio of this type of reaction in this area, and the present invention is particularly preferably 1: 1 to 3:1, more preferably 1.1:1 to 1.5:1 (for example, 1.3:1).
  • the base can be a conventional base for this type of reaction in the field, and the present invention is particularly preferably an organic base, more preferably N,N-diisopropylethylamine.
  • the molar ratio of the base to the compound shown in formula II can be the conventional molar ratio of this type of reaction in the field, and the present invention is particularly preferably 10:1 to 30:1, More preferably, it is 15:1 to 25:1 (for example, 21:1).
  • the condensing agent may be a conventional condensing agent for this type of reaction in the field, and in the present invention, it is particularly preferably 1-n-propylphosphoric anhydride.
  • the molar ratio of the condensing agent to the compound represented by formula II can be the conventional molar ratio of this type of reaction in the field, and the present invention is particularly preferably 1:1 to 3:1 , and more preferably 1.2:1 to 2:1 (for example, 1.5:1).
  • the reaction temperature of the condensation reaction can be the conventional reaction temperature of this type of reaction in the art, and is particularly preferably room temperature in the present invention.
  • the reaction time of the condensation reaction can be the conventional reaction time of this type of reaction in the field, and in the present invention, it is particularly preferably 8-20 hours, and more preferably 10-14 hours (for example, 12 hours).
  • a post-processing step may be further included.
  • the post-processing steps can be concentrating the reaction solution, extracting by phase separation, concentrating and purifying the organic phase.
  • the reagents used in the phase separation extraction can be dichloromethane and 10% sodium carbonate aqueous solution.
  • the purification method can be silica gel column purification.
  • the eluent used in the silica gel column purification can be dichloromethane/methanol/triethylamine (volume ratio can be 20:1:0.5).
  • the present invention also provides a pharmaceutical composition, which includes the compound shown in formula Ia, its cis-trans isomer, its pharmaceutically acceptable salt, its solvate, its pharmaceutically acceptable Solvates of salts, tautomers thereof, or polymorphs thereof, and pharmaceutically acceptable excipients.
  • the pharmaceutical composition includes the compound shown in formula I, its cis-trans isomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient .
  • the present invention also provides a compound represented by formula Ia, its cis-trans isomer, its pharmaceutically acceptable salt, its solvate, its pharmaceutically acceptable salt solvate, Use of its tautomer, its polymorphic form, or said pharmaceutical composition in the preparation of CDK kinase inhibitor.
  • the CDK kinase inhibitor is a CDK7 kinase inhibitor.
  • the compound shown in formula I its cis-trans isomer or a pharmaceutically acceptable salt thereof, or the application of the pharmaceutical composition in the preparation of a CDK kinase inhibitor .
  • the present invention also provides a compound shown in Ia, its cis-trans isomer, its pharmaceutically acceptable salt, its solvate, the solvate of its pharmaceutically acceptable salt, its mutual Use of the variant, or its polymorphic form, or the described pharmaceutical composition in the preparation of a medicament for preventing and/or treating CDK-related diseases.
  • the compound shown in formula I, its cis-trans isomer or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition is used in the preparation of prevention and/or treatment and CDK The use of medicines for related diseases.
  • the CDK-related disease is a CDK7-related disease, preferably a tumor, such as lung adenocarcinoma, lung cancer or breast cancer.
  • the present invention also provides a compound shown in formula II-a,
  • R 1 , R 2 , X, Y, R 4 , Z, L, n , na and carbon atoms marked with * are as previously described.
  • the compound represented by the formula II-a is the compound represented by the formula II,
  • the compound represented by formula II-a is N-(2-a)-2-a
  • the present invention also provides a compound of formula IV-a1 or IV-a2,
  • R 1 , R 2 , X, Y, R 4 , Z, n , na and carbon atoms marked with * are as previously described.
  • the compound of formula IV-a1 is the compound of formula IV
  • the compound represented by formula IV-a1 or IV-a2 is
  • room temperature refers to 10 to 30°C.
  • a pharmaceutically acceptable salt can be an acid addition salt with a pharmaceutically acceptable acid.
  • pharmaceutically acceptable salt acids include inorganic acids such as nitric acid, boric acid, hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid; and organic acids such as oxalic acid, maleic acid, succinic acid, and citric acid .
  • Non-limiting examples of salts of the compounds of the present invention include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, 2-hydroxyethanesulfonate, phosphate, hydrogen phosphate , acetate, adipate, alginate, aspartate, benzoate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate Salt, Hemisulfate, Heptanoate, Caproate, Formate, Succinate, Fumarate, Maleate, Ascorbate, Isethionate, Salicylic Acid salt, mesylate, mesitylene sulfonate, naphthalene sulfonate, nicotinate, 2-naphthalene sulfonate, oxalate, pamoate, pectate, persulfate, 3 - Phenylpropionate,
  • the choice of pharmaceutically acceptable adjuvants varies with the route of administration and the characteristics of action, and is usually a filler, diluent, binder, wetting agent, disintegrating agent, lubricant, emulsifying agent or suspending agent.
  • Solvate refers to a substance formed by crystallizing a compound with a solvent (including, but not limited to, water, methanol, ethanol, etc.). Solvates are divided into stoichiometric and non-stoichiometric solvates.
  • “Pharmaceutically acceptable salt solvate” refers to a compound with a pharmaceutically acceptable (relatively non-toxic, safe, suitable for patient use) acid or base, solvent (including but not limited to: water, methanol, ethanol, etc.) ) combined to form a substance, wherein the pharmaceutically acceptable salt has the same meaning as the term "pharmaceutically acceptable salt” above and the solvent is either stoichiometric or non-stoichiometric.
  • Solvates of pharmaceutically acceptable salts include, but are not limited to, hydrochloride monohydrate.
  • Tautomer means that different functional group isomers are in dynamic equilibrium at room temperature and can be converted into each other quickly. A chemical equilibrium of tautomers can be achieved if tautomers are possible (eg, in solution).
  • proton tautomers also referred to as proton tautomers
  • proton tautomers include interconversions by migration of protons, such as keto-enol isomerization and imine-enamine isomerization.
  • keto-enol tautomerization is the interconversion between two tautomers, pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • alkyl refers to a straight or branched chain alkyl group having the specified number of carbon atoms (eg, C1 - C6 ).
  • Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl Wait.
  • cycloalkyl refers to a saturated monocyclic cyclic group consisting of only carbon atoms having the specified number of carbon atoms (eg, C3 - C6 ). Cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • heterocycloalkyl refers to a specified number of ring atoms (eg, 5 to 8 members), a specified number of heteroatoms (eg, 1, 2, or 3), a specified heteroatom species (N, O, and S) one or more of), which are monocyclic, bridged, or spirocyclic, and each ring is saturated.
  • Heterocycloalkyl groups include, but are not limited to, azetidinyl, tetrahydropyrrolyl, tetrahydrofuranyl, morpholinyl, piperidinyl, and the like.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the positive improvement effect of the present invention is that the compound of the present invention has better CDK7 inhibitory activity, cell activity and tumor growth inhibitory activity.
  • LDA lithium diisopropylamide
  • rt room temperature
  • DMSO dimethyl sulfoxide
  • HOAc acetic acid
  • EtOH ethanol
  • DCM dichloromethane
  • MTBE methyl tert-butyl ether
  • ACN acetonitrile
  • DIPEA N,N-diisopropylethylamine
  • mCPBA m-chloroperoxybenzoic acid
  • T3P 1 -n-propylphosphoric anhydride
  • Chloroform chloroform
  • MgMeBr methylmagnesium bromide
  • Boc tert-butyloxy carbonyl.
  • Room temperature means 10-30 degreeC.
  • Isovaleronitrile (compound 1, 25 g, 330 mmol) was slowly added dropwise to a solution of LDA in tetrahydrofuran (1.3 M, 300 ml) at -78°C. After the dropwise addition, the solution was continued to stir for 20 minutes, and then slowly added a solution of ethyl formate (compound 2, 30ml, 377mmol) in tetrahydrofuran (100ml) at -78°C, and the total dropwise addition time was controlled at 40 minutes. The reaction solution was at -78°C Stirring was continued for 45 minutes, then slowly warmed to room temperature and stirring was continued for 18 hours.
  • CDK7 Commercially available CDK7 (eurofins, Cat.No, 14-476M, Lot.No.WAE0003), CTD3peptide (GL Biochem, Cat.No.346885, Lot.P160205-SY346885), ATP (Sigma, Cat.No. A7699-1G, CAS No. 987-65-5), DMSO (Sigma, Cat. No. D2650, Lot. No. 474382), EDTA (Sigma, Cat. No. E5134, CAS No. 60-00-4) Other reagents were used to determine the inhibitory rate of compounds on CDK7 at 200nM and 10nM concentrations. The results are shown in Table 1.
  • control compound X is the compound of Example 1 of US20190144456
  • control compound Y is the compound of Example 3 of US20190144456
  • test method of CDK1, 2, 4, 6, 9 inhibitory activity refers to US2019144456A1.
  • CDK1 (Millipore, Cat. No 14-450M, Lot. No 25729U), CDK4 (Carna, Cat. No 04-105, Lot. No 14CBS-0306P), CDK6 (Carna, Cat. No 04- 107, Lot.No 15CBS-0744C), CDK9 (Millipore, Cat.No 14-685M, Lot.NoWAB0200), CDK2 (eurofins, Cat.No 14-448M, Lot.No D7NN039U-G), Peptide FAM-P18 ( GL Biochem, Cat.No.114204, Lot.No.P080319-XY114202), Peptide FAM-P8 (GL Biochem, Cat.No.112396, Lot.No.P080327-XY112396), CTD3 peptide (GL Biochem, Cat.No.
  • control compound X used in the test is the compound in Example 1 of US20190144456.
  • the cells were digested, counted, made into a cell suspension of 1 ⁇ 10 5 cells/ml, seeded in a 96-well plate (100 ⁇ L/well), and placed in a 37°C, 5% CO 2 incubator for 24 hours; each well The test substance containing the corresponding concentration was added, and a negative control group and a blank group were set up at the same time, with 3 duplicate wells in each group; after the plate was incubated in an incubator for 72 hours, the cell morphology of each group was observed under a microscope, and 10 ⁇ L of CCK8 solution was added to each well. Incubate for 4 hours in a cell incubator, measure the absorbance at 450 nm, and calculate the proliferation inhibition rate. The results are shown in Table 3.
  • control compound X used in the test is the compound in Example 1 of US20190144456.
  • Example 4 Effects of Example 4 Compounds on the growth of xenografted tumors in nude mice
  • control compound X used in the test is the compound in Example 1 of US20190144456.
  • tumor inhibition rate (%) (tumor weight in model group - administration Tumor weight in drug group/tumor weight in model group*100%)
  • the three compounds have a certain inhibitory effect on the growth of human lung adenocarcinoma cell NCI-H1299 nude mouse xenograft tumor.
  • the order of antitumor activity against NCI-H1299 xenograft tumor-bearing nude mice from strong to weak is: compound D11>compound F10>control compound X.
  • the three compounds have a certain inhibitory effect on the growth of human lung cancer cell A549 nude mouse xenograft tumor.
  • the order of antitumor activity against human lung cancer cell A549 xenograft tumor-bearing nude mice is: compound D11>compound F10>control compound X.
  • the three compounds have a certain inhibitory effect on the growth of human breast cancer cell MDA-MB-468 nude mouse xenograft tumor.
  • the order of antitumor activity against human breast cancer cells MDA-MB-468 xenograft tumor-bearing nude mice is: compound F10>compound D11>control compound X.

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Abstract

La présente invention concerne un inhibiteur de kinase CDK, son procédé de préparation, une composition pharmaceutique et une application. La présente invention concerne un composé représenté par la formule I-a, un isomère cis-trans de celui-ci, un sel pharmaceutiquement acceptable de celui-ci, un solvate du sel pharmaceutiquement acceptable de celui-ci, un tautomère de celui-ci ou un polymorphe de celui-ci. Le composé de la présente invention présente une bonne activité inhibitrice de CDK7, une bonne activité cellulaire et une bonne activité inhibitrice de la croissance tumorale.
PCT/CN2021/112286 2020-08-12 2021-08-12 Inhibiteur de kinase cdk, son procédé de préparation, composition pharmaceutique et application WO2022033552A1 (fr)

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CN107530329A (zh) * 2015-03-09 2018-01-02 奥瑞基尼探索技术有限公司 用作CDK抑制剂的吡唑并[1,5‑a][1,3,5]三嗪和吡唑并[1,5‑a]嘧啶衍生物
CN111344292A (zh) * 2017-11-16 2020-06-26 伊莱利利公司 用于抑制cdk7的化合物
WO2021087138A1 (fr) * 2019-10-29 2021-05-06 Syros Pharmaceuticals, Inc. Méthodes de traitement du cancer chez des patients identifiés par biomarqueurs avec des inhibiteurs de la kinase 7 dépendante de la cycline (cdk7)
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