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WO2024066986A1 - Composé de 2-aminopyrimidine, utilisation et composition pharmaceutique de celui-ci - Google Patents

Composé de 2-aminopyrimidine, utilisation et composition pharmaceutique de celui-ci Download PDF

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Publication number
WO2024066986A1
WO2024066986A1 PCT/CN2023/117270 CN2023117270W WO2024066986A1 WO 2024066986 A1 WO2024066986 A1 WO 2024066986A1 CN 2023117270 W CN2023117270 W CN 2023117270W WO 2024066986 A1 WO2024066986 A1 WO 2024066986A1
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WO
WIPO (PCT)
Prior art keywords
pharmaceutically acceptable
stereoisomer
acceptable salt
compound
aminopyrimidine
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PCT/CN2023/117270
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English (en)
Chinese (zh)
Inventor
胡璞
陆居权
Original Assignee
楚浦创制（武汉）医药科技有限公司
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Priority to CN202380063760.4A priority Critical patent/CN119790049A/zh
Publication of WO2024066986A1 publication Critical patent/WO2024066986A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • 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

Definitions

  • the present invention relates to the field of medical technology, and in particular to a 2-aminopyrimidine compound and an application thereof and a pharmaceutical composition.
  • Protein kinases are enzymes that catalyze protein phosphorylation. They are widely present in the human body and play an important physiological function. Protein kinases include mitogen-activated protein kinases, cell cycle-dependent kinases, and tyrosine protein kinases. Among them, cell cycle-dependent kinases (CDKs) belong to the serine/threonine kinase family and are involved in physiological processes such as cell proliferation and transcription.
  • CDKs cell cycle-dependent kinases
  • CDKs According to the different functions of CDKs, they can be divided into two categories: one type of CDK is involved in cell cycle regulation, mainly including CDK1, CDK2, CDK4, CDK6, etc.; the other type of CDK is involved in transcriptional regulation, mainly including CDK7, CDK8, CDK9, CDK12, CDK13, etc.
  • cell cycle regulation mainly including CDK1, CDK2, CDK4, CDK6, etc.
  • transcriptional regulation mainly including CDK7, CDK8, CDK9, CDK12, CDK13, etc.
  • protein kinases When protein kinases are abnormally regulated or mutated, they are often prone to hyperproliferative diseases, cardiovascular and cerebrovascular diseases, diabetes, inflammation, and immune system diseases. Therefore, it is of great significance to provide a compound that can inhibit the activity of CDK.
  • the present invention provides a 2-aminopyrimidine compound capable of inhibiting the activity of CDK4 and CDK6, and its application and pharmaceutical composition.
  • R 1 is independently selected from halogen, cyano, trihalomethyl, nitro, carboxyl or acyl, and n 1 is selected from 1 or 2;
  • R 2 , R 4 , and R 5 are independently selected from H, halogen, C1-C4 alkyl, and C1-C4 alkoxy, n 2 is selected from 1 or 2, n 4 is selected from an integer of 1 to 4, and n 5 is selected from an integer of 1 to 3;
  • R3 is selected from H, C1-C4 alkyl, C1-C4 alkoxy, (dialkylamino)methyl, acyl, hydroxy-substituted alkyl;
  • X represents O or NR 6 ;
  • R6 is selected from alkylsulfonyl
  • Y represents N or CR 7 ;
  • R7 is selected from halogen, cyano, trihalomethyl, nitro, carboxyl, and acyl.
  • the general formula (I) is the structure of formula (I-1):
  • R 1 is selected from halogen and cyano.
  • R 1 is selected from Cl, cyano.
  • R 3 is selected from C1-C4 alkyl, (dialkylamino)methyl, acyl, and hydroxy-substituted alkyl.
  • R 3 is selected from methyl, (dimethylamino)methyl, acetyl, and 2-hydroxyisopropyl.
  • R 2 is H.
  • R 4 is H.
  • R 5 is H.
  • X represents O or NR 6 ; and R 6 is methylsulfonyl.
  • Y represents N or CR 7 ; and R 7 is selected from halogen and cyano.
  • the 2-aminopyrimidine compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof In the above, Y represents N or CR 7 ; R 7 is selected from F and cyano.
  • the general formula (I) is selected from any one of the structures of formula (II-1) to (II-9):
  • the present invention provides use of the above-mentioned 2-aminopyrimidine compounds, or pharmaceutically acceptable salts thereof, or stereoisomers thereof in the preparation of protein kinase inhibitors, wherein the protein kinase inhibitors include CDK4 inhibitors and CDK6 inhibitors.
  • the 2-aminopyrimidine compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof is used in the preparation of a protein kinase inhibitor, wherein the protein kinase inhibitor is a CDK4 inhibitor.
  • the present invention provides the use of the above-mentioned 2-aminopyrimidine compounds, or pharmaceutically acceptable salts thereof, or stereoisomers thereof in the preparation of drugs for treating or preventing protein kinase-mediated diseases, wherein the protein kinases include CDK4 and CDK6.
  • 2-aminopyrimidine compounds, or pharmaceutically acceptable salts thereof, or stereoisomers thereof in the preparation of drugs for treating or preventing protein kinase-mediated diseases, wherein the protein kinase is CDK4.
  • the use of 2-aminopyrimidine compounds, or pharmaceutically acceptable salts thereof, or stereoisomers thereof in the preparation of drugs for treating or preventing protein kinase-mediated diseases wherein the protein kinase-mediated disease is cancer, and the cancer includes at least one of breast cancer, non-small cell lung cancer, colon cancer, prostate cancer, thyroid cancer, malignant melanoma, neuroblastoma and mammary secretory carcinoma.
  • the present invention provides a pharmaceutical composition comprising:
  • Active ingredients and pharmaceutically acceptable carriers wherein the active ingredients include the above-mentioned 2-aminopyrimidine compounds, or pharmaceutically acceptable salts thereof, or stereoisomers thereof.
  • the 2-aminopyrimidine compounds of the present invention have the following beneficial effects:
  • the 2-aminopyrimidine compounds of the present invention are a series of new compounds, which can inhibit the activities of CDK4 and CDK6, especially can highly selectively inhibit the activity of CDK4; they can effectively treat or prevent cancer and other transitional proliferative diseases mediated by CDK4 and CDK6, especially treat or prevent cancer and other transitional proliferative diseases mediated by CDK4.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to salts of compounds of the invention, prepared from compounds of the invention having specific substituents with relatively nontoxic acids or bases.
  • base addition salts can be obtained by contacting such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts.
  • acid addition salts can be obtained by contacting such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, and the like; and organic acid salts such as formic acid, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzene
  • the invention also includes salts of amino acids (such as arginine, etc.) and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain basic and acidic functional groups, and thus can be converted into any base or acid addition salt.
  • salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. Generally, the preparation method of such salts is: in water or an organic solvent or a mixture of the two, these compounds in free acid or base form are reacted with a stoichiometric amount of an appropriate base or acid to prepare.
  • the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl. All of these isomers and their mixtures are included within the scope of the present invention.
  • enantiomer or “optical isomer” refers to stereoisomers that are mirror images of one another.
  • cis-trans isomers or “geometric isomers” arises from the inability of a double bond or single bond forming a ring carbon atom to rotate freely.
  • diastereomer refers to stereoisomers that have two or more chiral centers and that are not mirror images of each other.
  • the key is a solid wedge. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond. and straight dashed key To indicate the relative configuration of a stereocenter, use a wavy line Denotes a solid wedge bond or dotted wedge key Or use a wavy line Represents a straight solid bond and straight dashed key
  • a compound contains a double bond structure, such as a carbon-carbon double bond, a carbon-nitrogen double bond, and a nitrogen-nitrogen double bond, and each atom on the double bond is connected to two different substituents (in a double bond containing a nitrogen atom, a lone pair of electrons on the nitrogen atom is regarded as a substituent connected to it), if a wavy line is used between the atom on the double bond and its substituent in the compound, If connected, it means the (Z) isomer, (E) isomer or a mixture of the two isomers of the compound.
  • formula (A) means that the compound exists in the form of a single isomer of formula (A-1) or formula (A-2) or in the form of a mixture of two isomers of formula (A-1) and formula (A-2);
  • formula (B) means that the compound exists in the form of a single isomer of formula (B-1) or formula (B-2) or in the form of a mixture of two isomers of formula (B-1) and formula (B-2).
  • formula (C) means that the compound exists in the form of a single isomer of formula (C-1) or formula (C-2) or in the form of a mixture of two isomers of formula (C-1) and formula (C-2).
  • tautomer or “tautomeric form” refers to isomers of different functional groups that are in dynamic equilibrium at room temperature and can readily interconvert. If tautomerism is possible (such as in solution), chemical equilibrium of the tautomers can be achieved.
  • proton tautomers also called prototropic tautomers
  • Valence tautomers include interconversions via reorganization of some of the bonding electrons.
  • keto-enol tautomerism is the interconversion between pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
  • Optically active (R)- and (S)-isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer.
  • a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are separated by conventional methods known in the art, and then the pure enantiomer is recovered.
  • the separation of enantiomers and diastereomers is usually accomplished by using chromatography, which uses a chiral stationary phase and is optionally combined with a chemical derivatization method (for example, a carbamate is generated from an amine).
  • the compounds of the present invention may contain non-natural proportions of atomic isotopes on one or more atoms constituting the compound.
  • the compound may be labeled with a radioactive isotope, such as tritium ( 3H ), iodine-125 ( 125I ) or C-14 ( 14C ).
  • deuterated drugs may be formed by replacing hydrogen with heavy hydrogen. The bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have the advantages of reducing toxic side effects, increasing drug stability, enhancing therapeutic effects, and extending the biological half-life of drugs. All isotopic composition changes of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention.
  • substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the particular atom is normal and the substituted compound is stable.
  • the type and number of substituents can be any on the basis of chemical achievable.
  • any variable e.g., R 1
  • its definition at each occurrence is independent.
  • the group may be optionally substituted with up to two R 1 s , and each occurrence of R 1 is an independent choice.
  • substituents and/or variants thereof are permitted only if such combinations result in stable compounds.
  • linking group When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
  • substituent When a substituent is vacant, it means that the substituent does not exist. For example, when X in A-X is vacant, it means that the structure is actually A. When the listed substituent does not specify which atom it is connected to the substituted group through, the substituent can be bonded through any atom of it. For example, pyridyl as a substituent can be connected to the substituted group through any carbon atom on the pyridine ring.
  • linking group L When the linking group is listed without specifying its linking direction, its linking direction is arbitrary, for example,
  • the connecting group L is -MW-, in which case -MW- can connect ring A and ring B in the same direction as the reading order from left to right to form You can also connect ring A and ring B in the opposite direction of the reading order from left to right to form Combinations of linkers, substituents, and/or variations thereof are permissible only if such combinations result in stable compounds.
  • any one or more sites of the group can be connected to other groups through chemical bonds.
  • the chemical bond connection mode is non-positional and there are H atoms at the connectable sites, when the chemical bonds are connected, the number of H atoms at the site will decrease accordingly with the number of connected chemical bonds to become a group with a corresponding valence.
  • the chemical bond connecting the site to other groups can be a straight solid bond.
  • the straight solid bond in -OCH 3 indicates that it is connected to other groups through the oxygen atom in the group;
  • the straight dashed bond in the group indicates that the two ends of the nitrogen atom in the group are connected to other groups;
  • the wavy line in the phenyl group indicates that it is connected to other groups through the carbon atoms at positions 1 and 2 in the phenyl group; It means that any connectable site on the piperidine group can be connected to other groups through one chemical bond, including at least These four connection methods, even if the H atom is drawn on -N-, Still includes For groups connected in this way, when one chemical bond is connected, the H at that site will be reduced by one and become the corresponding monovalent piperidine group.
  • the number of atoms in a ring is generally defined as the ring member number, for example, "3-7 membered ring” refers to a “ring” having 3-7 atoms arranged around it.
  • C 1-4 alkyl is used to represent a straight or branched saturated hydrocarbon group consisting of 1 to 4 carbon atoms. It can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine).
  • Examples of C 1-4 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, tert-butyl and sec-butyl).
  • C 1-4 alkoxy refers to those alkyl groups containing 1 to 4 carbon atoms connected to the rest of the molecule through an oxygen atom. Preferably, it is C 1-3 alkoxy. Examples of C 1-3 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
  • alkylsulfonyl means a -SO2R group, where R is alkyl as defined above, for example, methylsulfonyl, ethylsulfonyl, and the like.
  • halo or halogen, by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.
  • 5-membered heteroaromatic ring and “5-membered heteroaryl” are used interchangeably in the present invention.
  • the term “5-membered heteroaryl” refers to a monocyclic group with a conjugated ⁇ electron system consisting of 5 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms.
  • the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) p , p is 1 or 2).
  • the 5-membered heteroaryl can be connected to the rest of the molecule through a heteroatom or a carbon atom.
  • Examples of the 5-membered heteroaryl group include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1,2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazo
  • Cn-n+m or Cn - Cn+m includes any specific case of n to n+m carbon atoms, for example, C1-12 includes C1 , C2 , C3 , C4 , C5 , C6 , C7 , C8 , C9 , C10 , C11 , and C12 , and also includes any range from n to n+m, for example, C1-12 includes C1-3 , C1-6 , C1-9, C3-6 , C3-9 , C3-12 , C6-9 , C6-12 , and C13 .
  • n-membered to n+m-membered means that the number of atoms in the ring is n to n+m
  • 3-12-membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, 9-membered ring, 10-membered ring, 11-membered ring, and 12-membered ring, and also includes any range from n to n+m, for example, 3-12-membered ring includes 3-6-membered ring, 3-9-membered ring, 5-6-membered ring, 5-7-membered ring, 6-7-membered ring, 6-8-membered ring, and 6-10-membered ring, etc.
  • C 3-7 cycloalkyl means a saturated cyclic hydrocarbon group consisting of 3 to 7 carbon atoms, including monocyclic and bicyclic systems, wherein the bicyclic system includes spirocyclic, fused and bridged rings.
  • the C 3-7 cycloalkyl includes C 3-6 , C 4-6 , C 4-5 , C 5-7 or C 5-6 cycloalkyl, etc.; it can be monovalent, divalent or polyvalent.
  • Examples of C 3-7 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.
  • the term "3-7 membered heterocycloalkyl" by itself or in combination with other terms refers to a saturated cyclic group consisting of 3 to 7 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S(O) p , p is 1 or 2). It includes monocyclic and bicyclic ring systems, wherein the bicyclic ring system includes spirocyclic, paracyclic and bridged rings.
  • heteroatoms may occupy the position where the heterocycloalkyl is connected to the rest of the molecule.
  • the 3-7 membered heterocycloalkyl includes 5-7 membered, 3 membered, 4 membered, 5 membered, 6 membered and 7 membered heterocycloalkyl, etc.
  • 3-7 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl
  • 3-7 membered nitrogen-containing heterocycloalkyl refers to a 3-7 membered heterocycloalkyl group containing at least one nitrogen atom.
  • Alicyclic refers to a saturated or partially unsaturated all-carbon ring system. Wherein “partially unsaturated” refers to a ring portion including at least one double bond or triple bond, and “partially unsaturated” is intended to cover rings with multiple unsaturated sites, but is not intended to include aryl or heteroaryl moieties as defined herein.
  • Non-limiting examples include cyclopropyl ring, cyclobutyl ring, cyclopentyl ring, cyclopentenyl ring, cyclohexyl ring, cyclohexenyl ring, cyclohexadienyl ring, cycloheptyl ring, cycloheptatrienyl ring, cyclopentanone ring, cyclopentane-1,3-dione ring, etc.
  • Aryl and “aromatic ring” are used interchangeably and refer to an all-carbon monocyclic or fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group with a conjugated ⁇ electron system, which group can be combined with a cycloalkyl ring, a heterocycloalkyl ring, a cycloalkenyl ring, a heterocycloalkenyl ring, or a cycloalkyl ring.
  • C 6-10 aryl refers to a monocyclic or bicyclic aromatic group having 6 to 10 carbon atoms, and non-limiting examples of the aryl group include phenyl, naphthyl, and the like.
  • Heteroaryl and “heteroaryl ring” are used interchangeably and refer to a monocyclic, bicyclic or polycyclic 4n+2 aromatic ring system (e.g., having 6 or 10 ⁇ electrons shared in a cyclic arrangement) having ring carbon atoms and ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur.
  • heteroaryl also includes a ring system in which the above-mentioned heteroaryl ring is fused with one or more cycloalkyl rings, heterocycloalkyl rings, cycloalkenyl rings, heterocycloalkenyl rings or aromatic rings.
  • the heteroaryl ring may be optionally substituted.
  • “5 to 10 membered heteroaryl” refers to a monocyclic or bicyclic heteroaryl having 5 to 10 ring atoms, wherein 1, 2, 3 or 4 ring atoms are heteroatoms.
  • “5- to 6-membered heteroaryl” refers to a monocyclic heteroaryl group having 5 to 6 ring atoms, wherein 1, 2, 3 or 4 of the ring atoms are heteroatoms, non-limiting examples of which include thienyl, furanyl, thiazolyl, isothiazolyl, imidazolyl, oxazolyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-o
  • 8- to 10-membered heteroaryl refers to a bicyclic heteroaryl group having 8 to 10 ring atoms, wherein 1, 2, 3 or 4 of the ring atoms are heteroatoms, non-limiting examples of which include indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl,
  • heteroatom refers to nitrogen, oxygen or sulfur. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as valence permits. Heteroaryl bicyclic ring systems may include one or more heteroatoms in one or both rings.
  • protecting group includes, but is not limited to, "amino protecting group", “hydroxy protecting group” or “thiol protecting group”.
  • amino protecting group refers to a protecting group suitable for preventing side reactions at the amino nitrogen position.
  • Representative amino protecting groups include, but are not limited to: formyl; acyl, such as alkanoyl (such as acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, such as tert-butyloxycarbonyl (Boc); arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-bis-(4'-methoxyphenyl)methyl; silyl, such as trimethylsilyl (TMS) and tert-butyldi
  • hydroxy protecting group refers to a protecting group suitable for preventing side reactions of the hydroxyl group.
  • Representative hydroxy protecting groups include, but are not limited to, alkyl groups such as methyl, ethyl and tert-butyl; acyl groups such as alkanoyl (e.g., acetyl); arylmethyl groups such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), and the like.
  • alkyl groups such as methyl, ethyl and tert-butyl
  • acyl groups such as alkanoyl (e.g., acetyl)
  • arylmethyl groups such as benzyl (Bn), p-methoxybenzyl (
  • substituted independently selected from
  • substituents independently selected from means when more than one When hydrogen is replaced by a substituent, the substituents may be the same or different in type, and the substituents selected are each independent in type.
  • the compound of the present invention or its pharmaceutically acceptable salt, or its stereoisomer can be used in a suitable dosage form with one or more pharmaceutical carriers.
  • dosage forms are suitable for oral, rectal, topical, oral and other parenteral administration (e.g., subcutaneous, intramuscular, intravenous, etc.).
  • dosage forms suitable for oral administration include capsules, tablets, granules and syrups.
  • the compounds of the present invention contained in these preparations can be solid powders or particles; solutions or suspensions in aqueous or non-aqueous liquids; water-in-oil or water-in-oil emulsions, etc.
  • the above dosage forms can be made from active compounds and one or more carriers or excipients via a common pharmaceutical method.
  • non-toxic carriers include but are not limited to mannitol, lactose, starch, magnesium stearate, cellulose, glucose, sucrose, etc.
  • Carriers for liquid preparations include water, saline, aqueous glucose solution, ethylene glycol and polyethylene glycol, etc.
  • the active compound can form a solution or suspension with the above carriers.
  • compositions of the present invention are formulated, dosed and administered in a manner consistent with medical practice.
  • the "therapeutically effective amount" of the compound administered is determined by factors such as the specific condition to be treated, the individual being treated, the cause of the condition, the target of the drug, and the mode of administration.
  • “Therapeutically effective amount” refers to the amount of the compound of the present invention that will elicit a biological or medical response in a subject, such as reducing or inhibiting enzyme or protein activity or improving symptoms, alleviating symptoms, slowing or delaying disease progression, or preventing disease.
  • the therapeutically effective amount of the compound of the present invention or its pharmaceutically acceptable salt, or its stereoisomer contained in the pharmaceutical composition or the pharmaceutical composition of the present invention is preferably 0.1 mg-5 g/kg (body weight).
  • Treatment means to lessen, slow the progression, attenuate, prevent, or maintain an existing disease or condition (eg, cancer). Treatment also includes curing, preventing the development of, or alleviating to some extent, one or more symptoms of a disease or condition.
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present invention.
  • the structure of the compound of the present invention can be confirmed by conventional methods known to those skilled in the art. If the present invention relates to the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art.
  • single crystal X-ray diffraction (SXRD) is used to collect diffraction intensity data of the cultured single crystal using a Bruker D8 venture diffractometer, the light source is CuK ⁇ radiation, and the scanning mode is: After scanning and collecting relevant data, the crystal structure is further analyzed using the direct method (Shelxs97) to confirm the absolute configuration.
  • SXRD single crystal X-ray diffraction
  • the solvent used in the present invention can be obtained commercially.
  • the present invention uses the following abbreviations: Pd/C represents palladium carbon; H 2 represents hydrogen; N 2 represents nitrogen; mL represents milliliter; NaNO 2 represents sodium nitrite; HCl represents; SnCl 2 .2H 2 O represents dihydrated tin dichloride; H 2 O represents water; AcOH represents acetic acid; B 2 Pin 2 represents bis-pinacol borate; Pd(dppf)Cl 2 represents 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride; KOAc represents potassium acetate; EtOAc represents ethyl acetate; Pd(PPh 3 ) 4 represents tetrakis(triphenylphosphine)palladium; K 2 CO 3 represents potassium carbonate; MeCN represents acetonitrile; DIEA represents N,N-diisopropylethylamine; MeOH represents methanol; NaBH
  • One embodiment of the present invention provides a 2-aminopyrimidine compound having a general formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:
  • R 1 is independently selected from halogen, cyano (-CN), trihalomethyl, nitro, carboxyl or acyl, and n 1 is selected from 1 or 2;
  • R 2 , R 4 , and R 5 are independently selected from H, halogen, C1-C4 alkyl, and C1-C4 alkoxy, n 2 is selected from 1 or 2, n 4 is selected from an integer of 1 to 4, and n 5 is selected from an integer of 1 to 3;
  • R3 is selected from H, C1-C4 alkyl, C1-C4 alkoxy, (dialkylamino)methyl, acyl, hydroxy-substituted alkyl;
  • X represents O or NR 6 ;
  • R6 is selected from alkylsulfonyl
  • Y represents N or CR 7 ;
  • R7 is selected from halogen, cyano, trihalomethyl, nitro, carboxyl, and acyl.
  • connection relationship between Ar 1 and Ar 2 can be any site of the 4th, 5th, and 6th positions of Ar 1 connected to any site of the 1st, 2nd, and 6th positions of Ar 2 ;
  • R 1 can appear at any site of the 4th, 5th, and 6th positions of Ar 1 except the site connected to Ar 2
  • R 2 can appear at any site of the 1st, 2nd, and 6th positions of Ar 2 except the site connected to Ar 1 .
  • halogen includes but is not limited to F, Cl, Br; trihalomethyl includes but is not limited to trifluoromethyl, trichloromethyl, tribromomethyl; acyl includes but is not limited to formyl, acetyl, propionyl; C1-C4 alkyl includes but is not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl; C1-C4 alkoxy includes but is not limited to methoxy, ethoxy, propoxy; (dialkylamino)methyl includes but is not limited to (dimethylamino)methyl, (diethylamino)methyl; hydroxy substituted alkyl includes but Not limited to hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 2-hydroxyisopropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 5-hydroxypent
  • n1 is selected from 1 or 2, which means that one or two R1s may be contained;
  • n2 is selected from 1 or 2, which means that one or two R2s may be contained;
  • n4 is selected from an integer of 1 to 4, and n4 is selected from 1, 2, 3 or 4, which means that 1, 2, 3 or 4 R4s may be contained;
  • n5 is selected from an integer of 1 to 3, and n3 is selected from 1, 2 or 3, which means that 1, 2 or 3 R5s may be contained.
  • CDK4/6 inhibitors include Pfizer's Palbociclib, Novartis' LEE011 and Eli Lilly's Abemaciclib, which are used in combination with endocrine therapy for hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced or metastatic breast cancer.
  • treatment with CDK4/6 inhibitors has been shown to cause adverse reactions in clinical practice, such as gastrointestinal and hematological toxicity.
  • CDK4 is a single oncogenic driver in many breast cancers.
  • 2-aminopyrimidine compounds with the general formula (I) can inhibit the activities of CDK4 and CDK6, especially can highly selectively inhibit the activity of CDK4; can effectively treat or prevent cancer and other transitional proliferative diseases mediated by CDK4 and CDK6, especially treat or prevent cancer and other transitional proliferative diseases mediated by CDK4.
  • the 2-aminopyrimidine compounds of the general formula (I) have a highly selective inhibitory effect on CDK4 activity and can effectively reduce the side effects caused by CDK4/6 inhibitors.
  • the 2-aminopyrimidine compound having the general formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, the general formula (I) is the structure of formula (I-1):
  • R 1 is selected from halogen and cyano.
  • R 1 is selected from Cl and cyano.
  • R 3 is selected from C1-C4 alkyl, (dialkylamino)methyl, acyl, or hydroxy-substituted alkyl.
  • R3 is selected from methyl, (dimethylamino)methyl Acetyl, 2-hydroxyisopropyl
  • R 2 , R 4 , and R 5 are independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl.
  • R 2 is H.
  • R 4 is H.
  • R 5 is H.
  • X represents O or NR 6 ; and R 6 is selected from methylsulfonyl and ethylsulfonyl.
  • R 6 is methylsulfonyl; in this case, NR 6 is
  • Y represents N or CR 7 ; and R 7 is selected from halogen and cyano.
  • R7 is selected from F and cyano.
  • the 2-aminopyrimidine compound having the general formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, the general formula (I) is selected from any one of the structures of formula (II-1) to (II-9):
  • the 2-aminopyrimidine compound having the general formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof is selected from the following compounds:
  • the 2-aminopyrimidine compound having the general formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof is selected from the following compounds:
  • the 2-aminopyrimidine compound having the general formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, the general formula (I) is selected from any one of the structures of formula (II-1), (II-2), (II-5), and (II-7):
  • the pharmaceutically acceptable salt is an alkyl acid salt.
  • the pharmaceutically acceptable salt is formate.
  • One embodiment of the present invention provides the use of the above-mentioned 2-aminopyrimidine compounds, or pharmaceutically acceptable salts thereof, or stereoisomers thereof in the preparation of protein kinase inhibitors, wherein the protein kinase inhibitors include CDK inhibitors.
  • 2-aminopyrimidine compounds, or pharmaceutically acceptable salts thereof, or stereoisomers thereof are used in the preparation of protein kinase inhibitors, and the protein kinase inhibitors include CDK4 inhibitors and CDK6 inhibitors.
  • a 2-aminopyrimidine compound, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof is used in the preparation of a protein kinase inhibitor, wherein the protein kinase inhibitor is a CDK4 inhibitor.
  • One embodiment of the present invention provides the use of the above-mentioned 2-aminopyrimidine compounds, or pharmaceutically acceptable salts thereof, or stereoisomers thereof in the preparation of drugs for treating or preventing protein kinase-mediated diseases, wherein the protein kinase inhibitors include CDK inhibitors.
  • 2-aminopyrimidine compounds, or pharmaceutically acceptable salts thereof, or stereoisomers thereof are used in the preparation of drugs for treating or preventing protein kinase-mediated diseases, wherein the protein kinases include CDK4 and CDK6.
  • the protein kinase in the use of 2-aminopyrimidine compounds, or pharmaceutically acceptable salts thereof, or stereoisomers thereof for preparing a drug for treating or preventing protein kinase-mediated diseases, the protein kinase is CDK4.
  • 2-aminopyrimidine compounds, or pharmaceutically acceptable salts thereof, or stereoisomers thereof are used in the preparation of drugs for treating or preventing protein kinase-mediated diseases, wherein the protein kinase-mediated disease is cancer, and the cancer includes at least one of breast cancer, non-small cell lung cancer, colon cancer, prostate cancer, thyroid cancer, malignant melanoma, neuroblastoma and mammary secretory carcinoma.
  • 2-aminopyrimidine compounds, or pharmaceutically acceptable salts thereof, or stereoisomers thereof are used in the preparation of drugs for treating or preventing protein kinase-mediated diseases, and the drugs for treating or preventing protein kinase-mediated diseases are drugs for inhibiting breast cancer cell proliferation.
  • the breast cancer cells are MCF7 cells or T47D cells.
  • One embodiment of the present invention provides a pharmaceutical composition, comprising:
  • Active ingredients and pharmaceutically acceptable carriers wherein the active ingredients include the above-mentioned 2-aminopyrimidine compounds, or pharmaceutically acceptable salts thereof, or stereoisomers thereof.
  • pharmaceutically acceptable carriers include, but are not limited to, sustained-release agents, excipients, fillers, binders, wetting agents, disintegrants, absorption promoters, adsorption carriers, surfactants and lubricants.
  • the synthetic route is as follows:
  • step 1
  • compound 1-2 (2.00 g, 9.75 mmol, 1.00 eq) and compound 1-3 (1.20 g, 10.7 mmol, 1.10 eq) were added to AcOH (10.0 mL) solution, stirred at 120°C for 5 hours; 10.0 mL H 2 O was added to the reaction system for dilution, extracted three times with 45.0 mL (15.0 mL*3) of ethyl acetate, then washed three times with 45.0 mL (15.0 mL*3) of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product compound 1-4.
  • compound 1-4 500 mg, 1.77 mmol, 1.00 eq
  • B 2 Pin 2 585 mg, 2.30 mmol, 1.30 eq
  • Pd(dppf)Cl 2 144 mg, 177 umol, 0.10 eq
  • KOAc 521 mg, 5.32 mmol, 3.00 eq
  • compound 1-5 400 mg, 1.22 mmol, 1.00 eq
  • compound 1-6 222 mg, 1.22 mmol, 1.00 eq
  • Pd(PPh 3 ) 4 140 mg, 121 umol, 0.100 eq
  • K 2 CO 3 503 mg, 3.65 mmol, 3.00 eq
  • 10.0 mL H 2 O was added to the reaction system for dilution, extracted three times with 15.0 mL (5.00 mL*3) of ethyl acetate, and then washed three times with 15.0 mL (5.00 mL*3) of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain The crude product was obtained.
  • compound 1-7 400 mg, 1.14 mmol, 1.00 eq
  • compound 1-8 (267 mg, 2.28 mmol, 2.00 eq) were dissolved in MeCN (4.00 mL), DIEA (147 mg, 1.14 mmol, 198 uL, 1.00 eq) was added, and the mixture was stirred at 80°C for 12 hours.
  • the synthetic route is as follows:
  • step 1
  • compound 1-2 (5.00 g, 24.3 mmol, 1.00 eq) and compound 2-1 (4.15 g, 24.3 mmol, 1.00 eq) were added to AcOH (10.0 mL) solution and stirred at 120°C for 5 hours.
  • 300 mL H 2 O was added to the reaction system for dilution, extracted three times with EtOAc 300 mL (100 mL*3), then washed three times with saturated sodium chloride solution 300 mL (100 mL*3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product.
  • Boc 2 O (6.38 g, 29.2 mmol, 6.71 mL, 10.0 eq) and DMAP (35.7 mg, 292 umol, 0.100 eq) were added to a solution of compound 2-3 (1.00 g, 2.92 mmol, 1.00 eq) in THF (1.00 mL), and stirred at 25°C for 4 hours.
  • compound 2-4 400 mg, 904 umol, 1.00 eq was added to a solution of THF (4.00 mL) with compound 2-5 (185 mg, 1.90 mmol, 2.10 eq), and then isopropylmagnesium chloride (2.00 M, 2.03 mL, 4.50 eq) was slowly added dropwise, and stirred at -20°C for 1 hour.
  • compound 2-10 23.0 mg, 64.3 umol, 1.00 eq
  • compound 1-6 (11.8 mg, 64.3 umol, 1.0 eq) were dissolved in a mixed solution of dioxane (0.500 mL) and water (0.200 mL), and then Pd(PPh 3 ) 4 (7.44 mg, 6.44 umol, 0.10 eq) and K 2 CO 3 (26.7 mg, 193 umol, 3.00 eq) were added, and stirred at 80°C for 3 hours.
  • the synthetic route is as follows:
  • step 1
  • compound 3-3 (150 mg, 523 umol, 1.00 eq, HCl) was dissolved in ethyl acetate (0.50 mL) and saturated aqueous sodium bicarbonate solution (0.50 mL). After replacing N 2 three times, MsCl (180 mg, 1.57 mmol, 121 uL, 3.00 eq) was added dropwise to the reaction solution at 0°C. After the addition was completed, the mixture was reacted at 0°C for 2 hours. The reaction solution was slowly poured into water (1.00 mL) at 0°C.
  • the synthetic route is as follows:
  • step 1
  • compound 1-5 ((200 mg, 607 umol, 1.00 eq), compound 4-1 (112 mg, 607 umol, 1.00 eq), K 2 CO 3 (251 mg, 1.82 mmol, 3.00 eq) and Pd(Amphos) 2 Cl 2 (43.0mg, 60.7umol, 43.0uL, 0.100eq) was dissolved in dioxane (2.00mL) and water (0.500mL), and replaced with nitrogen 3 times. Reacted for 12 hours under a nitrogen atmosphere at 90°C. Water (2.00mL) was added to the reaction system, and then extracted 3 times with ethyl acetate (5.00mL*3).
  • compound 4-3 (50.0 mg, 146 umol, 1.00 eq), compound 4-4 (27.0 mg, 176 umol, 1.20 eq), DIEA (56.8 mg, 440 umol, 76.6 uL, 3.00 eq) were dissolved in acetonitrile (0.500 mL) and reacted at 80 ° C for 12 hours. Water (1.00 mL) was added to the reaction system, and then extracted with ethyl acetate (2.00 mL*3) for 3 times.
  • CDK4/CyclinD1 was purchased from Invitrogen; Ulight-4E-BP1 peptide, 1X detection buffer, and Eu-anti-phospho-tyrosine antibody were purchased from PerkinElmer; high-purity ATP was purchased from Promega; EDTA was purchased from Sigma; Nivo multi-label analyzer (PerkinElmer).
  • Kinase buffer contained: 50 mM HEPES, 1 mM EDTA, 10 mM MgCl 2 , 0.01% Brij-35, pH 7.4;
  • kinase buffer Add 2.38 g HEPES, 58 mg EDTA, 406 mg MgCl 2 , and 20 mg Brij-35 to 200 mL buffer and adjust the pH to 7.4.
  • kinase buffer to dilute enzyme, Ulight-4E-BP1 peptide, ATP and inhibitor; use detection buffer to dilute Eu-anti-phospho-tyrosine antibody to 8nM/L concentration; dilute the test compound 5 times to the 8th concentration with a gun, that is, from 8 ⁇ M to 0.102nM, the final DMSO concentration is 4%, and set up a double-well experiment.
  • the final concentration gradient of the compound is 2 ⁇ M diluted to 0.0256nM, and the final concentrations of ATP and substrate are 1mM and 25nM.
  • the reaction system is placed at 25°C for 180 minutes. After the reaction, 5 ⁇ L of stop solution was added to each well, and the reaction was continued at 25°C for 5 minutes. After the reaction was completed, 5 uL of Eu-anti-phospho-tyrosine antibody dilution was added to each well, and the reaction was carried out at 25°C for 60 minutes, and the data were collected using the TR-FRET mode of the PerkinElmer Nivo multi-label analyzer (excitation wavelength was 320 nm, and emission wavelengths were 615 nm and 665 nm).
  • CDK6/CyclinD1 was purchased from Carna; Ulight-4E-BP1 peptide, Eu-anti-phospho-tyrosine antibody, and 1X detection buffer were purchased from PerkinElmer; high-purity ATP was purchased from Promega; EDTA was purchased from Sigma; Nivo Multi-label analyzer (PerkinElmer).
  • Kinase buffer contained: 50 mM HEPES, 1 mM EDTA, 10 mM MgCl 2 , 0.01% Brij-35, pH 7.4;
  • kinase buffer Add 2.38 g HEPES, 58 mg EDTA, 406 mg MgCl 2 , and 20 mg Brij-35 to 200 mL buffer and adjust the pH to 7.4.
  • kinase buffer to dilute enzyme, Ulight-4E-BP1 peptide, ATP and inhibitor; use detection buffer to dilute Eu-anti-phospho-tyrosine antibody to 8nM/L concentration; dilute the test compound 5 times to the 8th concentration with a gun, that is, from 8 ⁇ M to 0.102nM, the final DMSO concentration is 4%, and set up a double-well experiment.
  • Add 2.5 ⁇ L of inhibitor concentration gradients, 5 ⁇ L CDK6/CyclinD1 enzyme (2ng), 2.5 ⁇ L of substrate and ATP mixture (4mMATP, 50nM Ulight-4E-BP1 peptide) to the microplate.
  • the final compound concentration gradient is 2 ⁇ M diluted to 0.0256nM, and the final concentrations of ATP and substrate are 1mM and 12.5nM.
  • the reaction system is placed at 25°C for 60 minutes. After the reaction, 5 ⁇ L of stop solution was added to each well, and the reaction was continued at 25°C for 5 minutes. After the reaction was completed, 5 uL of Eu-anti-phospho-tyrosine antibody dilution was added to each well, and the reaction was carried out at 25°C for 60 minutes, and the data were collected using the TR-FRET mode of the PerkinElmer Nivo multi-label analyzer (excitation wavelength was 320 nm, and emission wavelengths were 615 nm and 665 nm).
  • EMEM culture medium was from Vicente; fetal bovine serum was from Biosera; penicillin/streptomycin antibiotics were purchased from Yuanpei; CellTiter-Glo (cell viability chemiluminescence detection reagent) reagent was purchased from Promega; MCF-7 cell line was purchased from Pronose; Envision multi-label analyzer (PerkinElmer).
  • MCF-7 cells were seeded in a white 96-well plate, with 80 ⁇ L of cell suspension per well, containing 2000 MCF-7 cells, and the cell plate was placed in a carbon dioxide incubator for overnight culture.
  • the compound to be tested was diluted 5 times to the 8th concentration, i.e., from 2000 ⁇ M to 0.0256 nM, using a dispenser, and a double-well experiment was set up.
  • 78 ⁇ L of culture medium was added to the middle plate, and then 2 ⁇ L of the gradient dilution compound per well was transferred to the middle plate according to the corresponding position. After mixing, 20 ⁇ L of each well was transferred to the cell plate.
  • the concentration range of the compound transferred to the cell plate was 10 ⁇ M to 0.128 nM, and the cell plate was placed in a carbon dioxide incubator for 7 days. Prepare another cell plate, and read the signal value on the day of drug addition as the maximum value (Max value in the equation below) for data analysis. Add 25 ⁇ L of cell viability chemiluminescent detection reagent to each well of this cell plate, and incubate at room temperature for 10 minutes to stabilize the luminescent signal. Reading was performed using a multi-label analyzer. Add 25 ⁇ L of cell viability chemiluminescent detection reagent to each well of the cell plate and incubate at room temperature for 10 minutes to stabilize the luminescent signal. Read using a multi-label analyzer.
  • 1640 culture medium was from Vivacell; fetal bovine serum was from Biosera; penicillin/streptomycin antibiotics were purchased from Yuanpei; CellTiter-Glo (cell viability chemiluminescence detection reagent) reagent was purchased from Promega; T-47D cell line was purchased from Nanjing Kebai Biotechnology Co., Ltd.; Envision multi-label analyzer (PerkinElmer).
  • T-47D cells were seeded in a white 384-well plate, with 40 ⁇ L of cell suspension per well, containing 300 T-47D cells, and the cell plate was placed in a carbon dioxide incubator for overnight culture.
  • the compound to be tested was diluted 5 times to the 8th concentration, i.e., from 2000 ⁇ M to 0.0256 ⁇ M, using a dispenser, and a double-well experiment was set up.
  • 78 ⁇ L of culture medium was added to the middle plate, and then 2 ⁇ L of the gradient dilution compound per well was transferred to the middle plate according to the corresponding position. After mixing, 10 ⁇ L of each well was transferred to the cell plate.
  • the concentration range of the compound transferred to the cell plate was 10 ⁇ M to 0.128 nM, and the cell plate was placed in a carbon dioxide incubator for 7 days. Prepare another cell plate, and read the signal value on the day of drug addition as the maximum value (Max value in the equation below) for data analysis. Add 10 ⁇ L of cell viability chemiluminescence detection reagent to each well of this cell plate, and incubate at room temperature for 10 minutes to stabilize the luminescence signal. Reading was performed using a multi-label analyzer. Add 10 ⁇ L of cell viability chemiluminescent detection reagent to each well of the cell plate and incubate at room temperature for 10 minutes to stabilize the luminescent signal. Read using a multi-label analyzer.
  • the compounds prepared in Examples 1 to 4 have different degrees of inhibitory effects on CDK4 and CDK6, especially highly selective inhibition of CDK4; and can effectively inhibit the proliferation of MCF7 cells and T47D cells.

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Abstract

La présente invention concerne un composé de 2-aminopyrimidine, et une utilisation et une composition pharmaceutique de celui-ci. Le composé peut inhiber l'activité de CDK4 et de CDK6, en particulier l'activité de CDK4 avec une sélectivité élevée, et traiter ou prévenir des maladies hyperprolifératives telles que des cancers médiés par CDK4 et CDK6, en particulier des maladies hyperprolifératives telles que des cancers médiés par CDK4.
PCT/CN2023/117270 2022-09-30 2023-09-06 Composé de 2-aminopyrimidine, utilisation et composition pharmaceutique de celui-ci WO2024066986A1 (fr)

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WO2023116862A1 (fr) * 2021-12-24 2023-06-29 江苏恒瑞医药股份有限公司 Composé indole hydrogéné, son procédé de préparation et son utilisation médicale

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