WO2021254384A1 - Nouveau dérivé de pyrido[2,3-d]pyrimidine-7(8h)-one - Google Patents

Nouveau dérivé de pyrido[2,3-d]pyrimidine-7(8h)-one Download PDF

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Publication number
WO2021254384A1
WO2021254384A1 PCT/CN2021/100336 CN2021100336W WO2021254384A1 WO 2021254384 A1 WO2021254384 A1 WO 2021254384A1 CN 2021100336 W CN2021100336 W CN 2021100336W WO 2021254384 A1 WO2021254384 A1 WO 2021254384A1
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alkyl
cycloalkyl
independently
membered
heterocycloalkyl
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PCT/CN2021/100336
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English (en)
Chinese (zh)
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谢雨礼
吴应鸣
樊后兴
钱立晖
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微境生物医药科技(上海)有限公司
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Priority to CN202180042700.5A priority Critical patent/CN115702155A/zh
Publication of WO2021254384A1 publication Critical patent/WO2021254384A1/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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with 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
    • 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 invention belongs to the field of medicinal chemistry, and more specifically, to a class of pyrimidine compounds, a preparation method thereof, and the use of this class of compounds as CDK2/4 inhibitors in the preparation of antitumor drugs.
  • Cyclin-dependent kinases are a class of enzymes with important functions in cells that can regulate cell division and proliferation of eukaryotic cells.
  • the catalytic unit of CDKs can be activated by Cyclin or also known as regulatory subunits. So far, at least 16 mammalian cyclins have been identified. Among them, Cyclin A/CDK2, cyclinE/CDK2, cyclinD/CDK4, CyclinD/CDK6 are very important regulators of cell cycle progression.
  • Other physiological functions of the cyclin/CDK complex include regulation of gene transcription, DNA repair, differentiation and apoptosis.
  • CDK inhibitors have been used to treat certain cancers.
  • CDK4/6 inhibitor Palbociclib and ribociclib have been approved for use in combination with aromatase inhibitors to treat estrogen receptor (ER) positive, human epidermal growth factor (HER-2) negative advanced or metastatic postmenopausal Breast cancer patients.
  • Palbociclib can also be used in combination with fulvestrant for patients with disease progression after endocrine therapy.
  • CDK4/6 inhibitors have shown strong efficacy in clinical practice, especially in patients with ER-positive metastatic breast cancer, similar to other kinase inhibitors, over time, primary or acquired resistance will become Reduce the efficacy of CDK4/6 inhibitors.
  • CDK2 The overexpression of CDK2 is related to the abnormal regulation of the cell cycle.
  • CyclinE/CDK2 complex plays a very important role in regulating the G1/S phase transition of the cell cycle, histone biosynthesis and centrosome replication.
  • the phosphorylation of Rb mediated by cyclin D/CDK4/6 and cyclin E/CDK2 will release the G1 transcription factor E2F, thereby promoting the entry of S-phase.
  • E2F the G1 transcription factor
  • the activation of Cyclin A/CDK2 promotes the phosphorylation of endogenous substrates, which leads to DNA replication and E2F inactivation, and promotes the completion of S-phase.
  • Cyclin E of CDK2 The regulatory subunit CyclinE of CDK2 is often overexpressed in cancer.
  • the amplification or overexpression of CyclinE has long been considered to be related to the poor prognosis of breast cancer.
  • the overexpression of Cyclin E2 (CCNE2) is related to the resistance of endocrine therapy in breast cancer. According to reports, inhibiting CDK2 can make tamoxifen resistant and CCNE2 overexpressing cells can regain sensitivity to tamoxifen or CDK4 inhibitors.
  • Cyclin E amplification has also been reported to cause trastuzumab resistance in HER-2 positive breast cancer. Cyclin E overexpression also plays a very important role in triple negative breast cancer (TNBC) and inflammatory breast cancer.
  • TNBC triple negative breast cancer
  • Cyclin E1 (CCNE1) amplification or overexpression is also related to the poor prognosis of ovarian cancer, gastric cancer, endometrial cancer and other cancers.
  • CDK2 and its regulatory subunit Cyclin E play a very important role in the occurrence of cancer, so far no drugs targeting CDK2 have been approved for marketing. Therefore, there is an urgent need for research and discovery of compounds with good CDK2 targeting activity.
  • the present invention aims to provide a compound represented by the general formula (1) or each of its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates:
  • R 1 is -H, -CN, halogen, (C1-C6) alkyl, (C1-C6) haloalkyl, or (C3-C6) cycloalkyl, wherein the alkyl, haloalkyl, and cycloalkyl can each be Independently and optionally substituted by one or more of the following groups: -H, halogen, -OH, -NH 2 , (C1-C6)alkoxy and -NR 8a R 8b ;
  • R 2 is (C3-C8) cycloalkyl or (3-8 membered) heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl may each independently be optionally substituted with one or more of the following groups : -H, halogen, -OH, -NH 2 , (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) alkoxy and -NR 8a R 8b ;
  • X is O or NH
  • R 3 is -H, -CN, halogen, -OH, -(CH 2 ) m NR 8a R 8b , (C1-C6) alkyl or (C1-C6) alkoxy, wherein the alkyl and alkoxy
  • the group may be optionally substituted by one or more of the following groups: -H and halogen;
  • R 4 is or
  • Y is -H, -F or -CH 3 ;
  • R 5a and R 5b are each independently -H, (C1-C6) alkyl, (C3-C6) cycloalkyl, (5-6 membered) heterocycloalkyl, or (5-9 membered) heteroaryl, Wherein the (C1-C6) alkyl, (C3-C6) cycloalkyl, (5-6 membered) heterocycloalkyl and (5-9 membered) heteroaryl groups may each independently be optionally 1 or Multiple substitutions of the following groups: -H, halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl, and -NR 8a R 8b ; or R 5a and R 5b
  • the carbon atoms connected to it can jointly form a (4-8 membered) heterocycloalkyl group, wherein the (4-8 membered) heterocycloalkyl group may each independently be optionally substituted with one or more of the following groups: -H, halogen
  • R 5c and R 5d are each independently -H, (C1-C6) alkyl or (C3-C6) cycloalkyl, or R 5c and R 5d and the carbon atoms to which they are connected can together form one (4-8 member) Heterocycloalkyl, wherein the (C1-C6)alkyl, (C3-C6)cycloalkyl and (4-8 membered)heterocycloalkyl groups may each independently be optionally substituted by one or more of the following groups Substitution: -H, halogen, (C1-C6) alkyl, (C1-C6) alkoxy, (C3-C6) cycloalkyl and -NR 8a R 8b ;
  • R 5e and R 5f are each independently -H or (C1-C6) alkyl, or R 5e and R 5f and the carbon atom to which they are attached can jointly form a (4-8 membered) heterocycloalkyl group, wherein the ( C1-C6) alkyl and (4-8 membered) heterocycloalkyl may each independently be optionally substituted with one or more of the following groups: -H, halogen, (C1-C6) alkyl, (C1- C6) alkoxy, (C3-C6) cycloalkyl and -NR 8a R 8b ;
  • R 6a and R 6b are each independently -H, (C1-C6) alkyl or (C3-C6) cycloalkyl, or R 6a and R 6b and the N atom to which they are connected can together form one (4-8 member) Heterocycloalkyl, this heterocycloalkyl may each independently be optionally substituted with one or more of the following groups: -H, halogen, (C1-C6)alkyl, (C1-C6)alkoxy and ( C3-C6) cycloalkyl;
  • R 7 is -H, (C1-C6) alkyl, (C3-C6) cycloalkyl, (6-10 membered) aryl, (5-10 membered) heteroaryl, or (4-8 membered) heterocyclic ring Alkyl, wherein the alkyl, cycloalkyl, aryl and heteroaryl groups may each independently be optionally substituted with one or more of the following groups: -H, halogen, (C1-C6)alkyl, ( C1-C6) alkoxy or (C3-C6) cycloalkyl;
  • R 7a and R 7b are each independently -H, -CN, -OH, halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl, or -(CH 2 ) m NR 8a R 8b , wherein the alkyl group and cycloalkyl group may each independently be optionally substituted with one or more of the following groups: -H, halogen, (C1-C6) alkyl, (C1-C6 )Alkoxy and (C3-C6)cycloalkyl;
  • R 8a and R 8b are each independently -H, (C1-C6) alkyl or (C3-C6) cycloalkyl, or R 8a and R 8b and the N atom to which they are connected can together form one (4-8 member) Heterocycloalkyl, this heterocycloalkyl may each independently be optionally substituted with one or more of the following groups: -H, halogen, (C1-C6)alkyl, (C1-C6)alkoxy and ( C3-C6) cycloalkyl; and
  • n is an integer of 0, 1, 2 or 3.
  • R 1 is -H, -CN, halogen, (C1-C3)alkyl, (C1-C3)haloalkyl, or (C3-C4) ring Alkyl, wherein the alkyl, haloalkyl and cycloalkyl groups may be optionally substituted by one or more of the following groups: -H, -F, -Cl, -Br, -OH, -OCH 3 , -NH 2. -N(CH 3 ) 2 and -CH 3 .
  • R 1 is:
  • R 2 is (C5-C6) cycloalkyl or (5-6 membered) heterocycloalkyl, wherein said cycloalkyl and heterocycloalkyl
  • the groups may each independently be optionally substituted with one or more of the following groups: -H, -F, -OH, -OCH 3 , -NH 2 , -N(CH 3 ) 2 and -CH 3 .
  • R 2 is:
  • R 3 is -H, -CN, halogen, -OH, -NR 8a R 8b , (C1-C3) alkyl or (C1-C3) Alkoxy, wherein the alkyl group and the alkoxy group may each independently be optionally substituted with one or more of the following groups: -H and -F.
  • R 3 is -H, -CN, -F, -OH, -CH 3 or -OCH 3 .
  • R 5a and R 5b are each independently -H, (C1-C3) alkyl, (C3-C4) cycloalkyl, (5-6 membered) heterocycloalkyl, or (5-6 membered) heteroaromatic Group, wherein the (C1-C3) alkyl group and the (5-6 membered) heterocycloalkyl group may each independently be optionally substituted with one or more of the following groups: -H, -F, -CH 3 , -OCH 3 , -N(CH 3 ) 2 , Or R 5a and R 5b and the carbon atoms to which they are connected can jointly form a (4-6 membered) heterocycloalkyl group, wherein the (4-6 membered) heterocycloalkyl group is oxetane or azetidine Alkane, tetrahydrofuran, pyrrolidine, tetrahydrothiophene, pipe
  • R 4 is:
  • R 5c and R 5d are each independently -H, (C1-C3) alkyl or (C3-C4) cycloalkyl, or R 5c and R 5d and the carbon atoms to which they are connected can form a (4-6 Member) heterocycloalkyl
  • the (4-6 member) heterocycloalkyl group is oxetane, azetidine, tetrahydrofuran, pyrrolidine, tetrahydrothiophene, piperidine, tetrahydropyran
  • the (4-6 membered) heterocycloalkyl group may be independently substituted with one or more of the following groups: -H, -F, -CH 3 , -OCH 3 , And -N(CH 3 ) 2 ;
  • R 5e and R 5f are each independently -H or -CH 3 .
  • R 4 is:
  • R 4 when R 6a and R 6b are each independently -H, (C1-C3) alkyl or (C3-C4) cycloalkyl, or R 6a and R 6b and the N atom to which they are connected can form a (4-6 Member) heterocycloalkyl, the (4-6 membered) heterocycloalkyl group is azetidine, pyrrolidine, piperidine, morpholine or piperazine, and the (4-6 membered) heterocycloalkyl group Each can be independently optionally substituted by one or more of the following groups: -H, -F, -CH 3 , -OCH 3 , And -N(CH 3 ) 2 .
  • R 4 is:
  • R 4 when R 4 is When R 7 is -H, (C1-C3)alkyl, (C3-C4)cycloalkyl, wherein said alkyl and cycloalkyl may each independently be optionally substituted by one or more of the following groups : -H, -F, -CH 3 , -OCH 3 , And -N(CH 3 ) 2 .
  • R 4 is:
  • R 4 when R 4 is When R 7a and R 7b are each independently -H, -CN, -OH, -F, (C1-C3)alkyl, (C1-C3)alkoxy, (C3-C6)cycloalkyl,- NR 8a R 8b or -(CH 2 )NR 8a R 8b , wherein the alkyl group, alkoxy group, and cycloalkyl group may each independently be optionally substituted by one or more of the following groups: -H and -F .
  • R 4 is:
  • the representative compound of the present invention has one of the following structures:
  • Another object of the present invention is to provide a pharmaceutical composition, which contains a pharmacologically acceptable excipient and/or carrier, and the compound of the general formula (1) of the present invention or each isomer, each crystal form, A pharmaceutically acceptable salt, hydrate or solvate.
  • Another object of the present invention is to provide the above-mentioned compound of the present invention or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate or the above-mentioned pharmaceutical composition for preparing treatment and/or prevention Application of CDK protein-related disease drugs.
  • Another object of the present invention is to provide a method for treating CDK protein-related diseases, which comprises administering to a subject a therapeutically effective amount of the above-mentioned compound or each of its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvents.
  • Compound or the above-mentioned pharmaceutical composition comprises administering to a subject a therapeutically effective amount of the above-mentioned compound or each of its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvents.
  • the compound of general formula (1) described above can be synthesized using standard synthesis techniques or well-known techniques and methods combined in the text.
  • the solvent, temperature and other reaction conditions mentioned here can be changed.
  • the starting materials used for the synthesis of the compounds can be synthesized or obtained from commercial sources.
  • the compounds described herein and other related compounds with different substituents can be synthesized using well-known techniques and raw materials, including those found in March, ADVANCED ORGANIC CHEMISTRY 4 th Ed., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4 th Ed., Vols.
  • the compounds described herein are according to methods well known in the art.
  • the conditions of the method such as reactants, solvents, bases, amounts of compounds used, reaction temperature, time required for the reaction, etc. are not limited to the following explanations.
  • the compounds of the present invention can also be conveniently prepared by combining various synthetic methods described in this specification or known in the art, and such combinations can be easily performed by those skilled in the art to which the present invention belongs.
  • the present invention also provides a method for preparing the compound represented by the general formula (1), which is prepared by the following general reaction scheme 1, general reaction scheme 2 or general reaction scheme 3:
  • the embodiment of the compound of general formula (1) can be prepared according to general reaction scheme 1, wherein R 2 , R 3 , R 4 , and X are as defined above, and NH 2 represents an amino group.
  • compound 1-1 reacts with R 2 -NH 2 to form compound 1-2
  • compound 1-2 is formed by oxidation reaction to form compound 1-3
  • compound 1-3 is formed by condensation reaction with ethyl acetate.
  • Compound 1-4, compound 1-4 and CF 2 SO 2 Na react under light conditions to produce compound 1-5
  • compound 1-5 undergo oxidation reaction to produce compound 1-6
  • compound 1-6 and Under basic conditions, the target compound 1-7 is generated by the reaction.
  • the embodiment of the compound of general formula (1) can be prepared according to general reaction scheme 2, wherein R 2 , R 3 , R 4 , and X are as defined above, and NH 2 represents an amino group.
  • compound 2-1 reacts with R 2 -NH 2 to form compound 2-2
  • compound 2-2 is oxidized to form compound 2-3
  • compound 2-3 and Condensation reaction produces compound 2-4
  • compound 2-4 produces compound 2-5 through oxidation reaction
  • the embodiment of the compound of general formula (1) can be prepared according to general reaction scheme 3, wherein R 2 , R 3 , R 4 , and X are as defined above, and NH 2 represents an amino group.
  • compound 3-1 reacts with R 2 -NH 2 to produce compound 3-2
  • compound 3-2 undergoes oxidation reaction to produce compound 3-3
  • compound 3-3 and ethyl acetate undergo condensation reaction to produce Compound 3-4
  • compound 3-4 generate compound 3-5 through oxidation reaction, compound 3-5 and Under alkaline conditions, the target compound 3-6 is generated by the reaction.
  • “Pharmaceutically acceptable” here refers to a substance, such as a carrier or a diluent, that does not make the biological activity or properties of the compound disappear, and is relatively non-toxic, for example, when a substance is administered to an individual, it will not cause unwanted biological effects or Interacts with any components it contains in a harmful way.
  • pharmaceutically acceptable salt refers to a form of a compound that does not cause important irritation to the administered organism and does not cause the biological activity and properties of the compound to disappear.
  • pharmaceutically acceptable salts are obtained by reacting compounds of general formula (1) with acids, such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, phosphoric acid and other inorganic acids, formic acid, acetic acid, etc.
  • organic acids and acidic amino acids such as aspartic acid and glutamic acid.
  • references to pharmaceutically acceptable salts include solvent-added forms or crystalline forms, especially solvates or polymorphs.
  • Solvates contain stoichiometric or non-stoichiometric solvents, and are selectively formed during crystallization with pharmaceutically acceptable solvents such as water, ethanol, etc.
  • a hydrate is formed when the solvent is water, or an alcoholate is formed when the solvent is ethanol.
  • the solvate of the compound of general formula (1) is conveniently prepared or formed according to the method described herein.
  • the hydrate of the compound of general formula (1) is conveniently prepared by recrystallization from a mixed solvent of water/organic solvent.
  • the organic solvent used includes, but is not limited to, tetrahydrofuran, acetone, ethanol or methanol.
  • the compounds mentioned here can exist in unsolvated and solvated forms. In summary, for the purposes of the compounds and methods provided herein, the solvated form is considered equivalent to the unsolvated form.
  • the compound of general formula (1) is prepared in different forms, including, but not limited to, amorphous, pulverized, and nano-particle size forms.
  • the compound of the general formula (1) includes a crystalline form, and may also be a polymorphic form.
  • Polymorphs include different lattice arrangements of the same elemental composition of the compound. Polymorphs usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal form, optical and electrical properties, stability and solubility. Different factors such as recrystallization solvent, crystallization rate and storage temperature may cause a single crystal form to dominate.
  • the compound of general formula (1) may have a chiral center and/or axial chirality, and therefore can be used as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomers.
  • the forms of enantiomers, and cis-trans isomers appear.
  • Each chiral center or axial chirality will independently produce two optical isomers, and all possible optical isomers and diastereomeric mixtures and pure or partially pure compounds are included in the scope of the present invention.
  • the present invention is meant to include all such isomeric forms of these compounds.
  • the compound of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms constituting the compound.
  • compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I), and C-14 ( 14 C).
  • radioisotopes such as tritium ( 3 H), iodine-125 ( 125 I), and C-14 ( 14 C).
  • heavy hydrogen can be used to replace hydrogen atoms to form deuterated compounds.
  • the bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon.
  • deuterated drugs Compared with non-deuterated drugs, deuterated drugs generally have lower toxic and side effects and increase drugs. Stability, enhanced efficacy, and prolonged half-life of drugs in vivo. All changes in the isotopic composition of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention.
  • alkyl refers to saturated aliphatic hydrocarbon groups, including straight and branched chain groups of 1 to 14 carbon atoms. It is preferably a lower alkyl group containing 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl.
  • alkyl includes unsubstituted and substituted alkyl groups, especially alkyl groups substituted with one or more halogens.
  • Preferred alkyl groups are selected from CH 3 , CH 3 CH 2 , CF 3 , CHF 2 , CF 3 CH 2 , CF 3 (CH 3 )CH, i-Pr, n-Pr, i-Bu, n-Bu or t -Bu.
  • alkenyl refers to an unsaturated aliphatic hydrocarbon group containing a carbon-carbon double bond, including straight or branched chain groups of 1 to 14 carbon atoms.
  • a lower alkenyl group containing 1 to 4 carbon atoms such as vinyl, 1-propenyl, 1-butenyl, or 2-methylpropenyl.
  • alkynyl refers to an unsaturated aliphatic hydrocarbon group containing a carbon-carbon triple bond, including straight and branched chain groups of 1 to 14 carbon atoms. Preference is given to lower alkenyl groups containing 1 to 4 carbon atoms, such as ethynyl, 1-propynyl or 1-butynyl.
  • cycloalkyl refers to a 3- to 14-membered all-carbon monocyclic aliphatic hydrocarbon group, in which one or more rings may contain one or more double bonds, but none of the rings have a fully conjugated ⁇ -electron system .
  • cyclopropyl, cyclobutyl, cyclopentyl, cyclohexane, cyclohexadiene and the like are examples of the like.
  • alkoxy refers to an alkyl group bonded to the rest of the molecule through an ether oxygen atom.
  • Representative alkoxy groups are those with 1-6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy And tert-butoxy.
  • alkoxy includes unsubstituted and substituted alkoxy, especially alkoxy substituted with one or more halogens.
  • Preferred alkoxy groups are selected from OCH 3 , OCF 3 , CHF 2 O, CF 3 CH 2 O, i-PrO, n-PrO, i-BuO, n-BuO or t-BuO.
  • aryl refers to a hydrocarbon aromatic group.
  • the aryl group is monocyclic or polycyclic, for example, a monocyclic aryl ring is fused with one or more carbocyclic aromatic groups.
  • Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and phenanthryl.
  • arylene refers to a divalent aryl group as defined above.
  • examples of arylene groups include, but are not limited to, phenylene, naphthylene, and phenanthrylene.
  • heteroaryl refers to an aromatic group containing one or more heteroatoms (O, S, or N), and a heteroaryl group is monocyclic or polycyclic, such as a monocyclic heteroaryl ring and one Or multiple carbocyclic aromatic groups or other monocyclic heterocyclic groups are condensed.
  • heteroaryl groups include, but are not limited to, pyridyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolinyl, isoquinolinyl, furyl, thienyl, Isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, indolyl, benzimidazolyl, benzofuranyl, benzothiazolyl, benzothienyl, benzoxazolyl, benzene Pyridyl and pyrrolopyrimidinyl.
  • heteroarylene refers to a divalent heteroaryl group as defined above.
  • heterocycloalkyl refers to a saturated or partially unsaturated ring system group containing one or more heteroatoms (O, S, or N), wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom Optionally quaternized as ring atoms.
  • heterocycloalkyl ring system can be a monocyclic, bicyclic, spirocyclic or polycyclic ring system.
  • Heterocycloalkyl can be attached to the rest of the molecule through more than one ring carbon or heteroatom.
  • heterocycloalkyl examples include, but are not limited to, pyrrolidine, piperidine, N-methylpiperidine, tetrahydroimidazole, pyrazolidine, butyrolactam, valerolactam, imidazolinone, hydantoin, Dioxolane, phthalimide, piperidine, pyrimidine-2,4(1H,3H)-dione, 1,4-dioxane, morpholine, thiomorpholine, thiomorph Phinoline-S-oxide, thiomorpholine-S, S-oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine, 2-Azaspiro[3.3]heptane and so on.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • halo or halogen substitution
  • appearing in front of the group name means that the group is partially or fully halogenated, that is, substituted by F, Cl, Br or I in any combination, preferably Replaced by F or Cl.
  • the substituent "-O-CH 2 -O-" means that two oxygen atoms in the substituent are connected to two adjacent carbon atoms of a heterocycloalkyl, aryl or heteroaryl group, such as:
  • linking group When the number of a linking group is 0, such as -(CH 2 ) 0 -, it means that the linking group is a single bond.
  • wedge-shaped solid line keys And wedge-shaped dashed key Represents the absolute configuration of a three-dimensional center, with a straight solid line key And straight dashed key Indicates the relative configuration of the three-dimensional center, using wavy lines Represents a wedge-shaped solid line key Or wedge-shaped dashed key Or use wavy lines Represents a straight solid line key Or straight dashed key
  • acceptable refers to a prescription component or active ingredient that does not have unduly harmful effects on the health of the general treatment target.
  • treatment include alleviating, inhibiting, or ameliorating the symptoms or conditions of diseases; inhibiting the occurrence of complications; improving or preventing underlying metabolic syndrome; inhibiting the occurrence of diseases or symptoms, Such as controlling the development of diseases or conditions; reducing diseases or symptoms; reducing diseases or symptoms; reducing complications caused by diseases or symptoms, or preventing or treating signs caused by diseases or symptoms.
  • a certain compound or pharmaceutical composition after administration, can improve a certain disease, symptom or condition, especially its severity, delay the onset, slow the progression of the disease, or reduce the duration of the disease. Regardless of fixed administration or temporary administration, continuous administration or intermittent administration, it can be attributed to or related to the situation of administration.
  • Active ingredient refers to the compound represented by the general formula (1) and the pharmaceutically acceptable inorganic or organic salt of the compound of the general formula (1).
  • the compounds of the present invention may contain one or more asymmetric centers (chiral centers or axial chirality), and are therefore presented as racemates, racemic mixtures, single enantiomers, diastereomeric compounds, and single diastereomers. Appears in the form of enantiomers.
  • the asymmetric centers that can exist depend on the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers, and all possible mixtures of optical isomers and diastereomers and pure or partially pure compounds are included within the scope of the present invention.
  • the present invention is meant to include all such isomeric forms of these compounds.
  • composition refers to when administered to an individual (human or medicament).
  • agent a compound or composition that can induce a desired pharmaceutical and/or physiological response through local and/or systemic effects.
  • administered refers to the direct administration of the compound or composition, or the administration of a prodrug, derivative, or analog of the active compound Wait.
  • the present invention provides methods of using the compounds or pharmaceutical compositions of the present invention to treat diseases, including but not limited to conditions involving CDK protein (such as cancer).
  • a method for cancer treatment comprises administering to an individual in need an effective amount of any of the aforementioned pharmaceutical compositions protecting the compound of general formula (1).
  • cancer is mediated by CDK protein.
  • the cancer is breast cancer, lung cancer, pancreatic cancer, colon cancer, bladder cancer, brain cancer, urothelial cancer, prostate cancer, liver cancer, ovarian cancer, head and neck cancer, stomach cancer, mesothelioma, or all cancers Transfer.
  • the compound of the present invention and its pharmaceutically acceptable salt can be prepared into various preparations, which contain a safe and effective amount of the compound of the present invention or its pharmaceutically acceptable salt and a pharmacologically acceptable excipient or carrier. .
  • the "safe and effective amount” refers to: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the safe and effective amount of the compound is determined according to the age, condition, and course of treatment of the subject to be treated.
  • “Pharmaceutically acceptable excipients or carriers” refer to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use, and must have sufficient purity and sufficiently low toxicity . "Compatibility” here means that each component of the composition can be blended with the compound of the present invention and with each other without significantly reducing the efficacy of the compound.
  • Examples of pharmacologically acceptable excipients or carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • cellulose and its derivatives such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
  • gelatin such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose a
  • the compound of the present invention when administered, it can be administered orally, rectally, parenterally (intravenous, intramuscular, or subcutaneous), or locally.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with the following ingredients: (a) fillers or compatibilizers, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, For example, glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) Absorption accelerators, for example, quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and g
  • Solid dosage forms such as tablets, sugar pills, capsules, pills and granules can be prepared with coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the active compound or the release of the compound in such compositions may be released in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into microcapsules with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • the liquid dosage form may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-Butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.
  • composition may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • composition for parenteral injection may contain physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • the dosage forms of the compound of the present invention for topical administration include ointments, powders, patches, sprays and inhalants.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required if necessary.
  • the compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds.
  • a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage when administered is the effective dosage considered pharmaceutically, for a person with a body weight of 60 kg, a day
  • the dosage is usually 1 to 2000 mg, preferably 50 to 1000 mg.
  • the specific dosage should also consider factors such as the route of administration, the patient's health status, etc., which are all within the skill range of a skilled physician.
  • CDCl 3 stands for deuterated chloroform
  • EtOAc stands for ethyl acetate
  • Hexane stands for n-hexane
  • MeCN stands for acetonitrile
  • DCM stands for dichloromethane
  • DIPEA stands for diisopropylethylamine
  • Dioxane stands for 1 ,4-Dioxane
  • DMF stands for N,N-dimethylformamide
  • DMSO stands for dimethyl sulfoxide
  • h stands for hours
  • IPA stands for isopropanol
  • K 3 PO 4 stands for potassium phosphate
  • LiHMDS stands for bis(tri (Methylsilyl) lithium amide
  • min stands for minutes
  • m-CPBA stands for m-chloroperoxybenzoic acid
  • min stands for minutes
  • MS stands for mass spectrometry
  • NaH stands for sodium hydride
  • NMP stands for 1-methylpyrrolidin-2-one
  • aqueous phase was extracted with EtOAc (30 mL), and the organic phases were combined with saturated sodium chloride solution Washed, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure to about 10mL, and then added dropwise n-hexane (20mL) under stirring at room temperature. The mixture was stirred at room temperature for 30min, then filtered and dried to obtain a white solid product (2.0g, yield Rate: 83.7%).
  • Step 3 Synthesis of 8-cyclopentyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (compound int_5)
  • Step 4 Synthesis of 8-cyclopentyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (compound int_6)
  • Step 5 8-Cyclopentyl-2-(((1-(vinylsulfonyl)piperidin-4-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one (compound 1) Synthesis
  • reaction solution was filtered, the filtrate was taken, the filter cake was washed with DCM (100mL*2), the filtrate was combined, washed with a mixture of saturated sodium bicarbonate (500mL) and saturated sodium thiosulfate (100mL), separated, the organic phase was not It was dried with sodium sulfate in water, filtered, and concentrated at 15°C to obtain a pale yellow liquid (23.5 g, yield: >100%).
  • Second resolution add (S)-2-(3,5-dinitrobenzamide)-2-phenylacetic acid (1.11g, 3.22mmol) and ethanol (15mL) to a 100mL single-neck flask, and heat After reaching 80°C to clear, add dropwise a solution of 2-(benzylamino)-1-methylcyclopentane-1-ol (858mg, 4.18mmol) in ethanol (10mL) preheated to 80°C, a solid precipitated out, dripping After the addition, the mixture was stirred at 80°C for 4 hours, and then stirred at room temperature overnight. The white solid product salt (2.3 g, Y: 85%) was obtained by filtration.
  • Step 5 (1R, 2R)-2-(((5-(hydroxymethyl)-2-(methylthio)pyrimidin-4-yl)amino)-1-methylcyclopentan-1-ol (compound int_3) composition
  • Step 6 Synthesis of 4-((((1R, 2R)-2-hydroxy-2-methylcyclopentyl)amino)-2-(methylthio)pyrimidine-5-carbaldehyde (compound int_4)
  • Step 7 8-((1R, 2R)-2-hydroxy-2-methylcyclopentyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)one (compound int_5) composition
  • Step 8 6-(Difluoromethyl)-8-(((1R,2R)-2-hydroxy-2-methylcyclopentyl)-2-(methylthio)pyrido[2,3-d ] Synthesis of pyrimidine-7(8H)-one (compound int_6)
  • Step 9 6-(Difluoromethyl)-8-(((1R,2R)-2-hydroxy-2-methylcyclopentyl)-2-(methylsulfonyl)pyrido[2,3- d) Synthesis of pyrimidine-7(8H)-one (compound int_7)
  • Step 10 6-(Difluoromethyl)-8-(((1R,2R)-2-hydroxy-2-methylcyclopentyl)-2-(((1-(vinylsulfonyl)piperidine Synthesis of -4-yl)amino]pyridyl[2,3-d]pyrimidin-7(8H)-one (compound 2)
  • Step 3 Synthesis of 8-cyclopentyl-2-(methylthio)-7-oxa-7,8-dihydropyridyl[2,3-d]pyrimidine-6-carbonitrile (compound int_5)
  • Step 4 Synthesis of 8-cyclopentyl-2-(methylsulfonyl)-7-oxa-7,8-dihydropyridyl[2,3-d]pyrimidine-6-carbonitrile (compound int_6)
  • Step 5 8-Cyclopentyl-7-oxa-2-((1-(vinylsulfonyl)piperidin-4-yl)amino)-7,8-dihydropyridyl[2,3-d ] Synthesis of pyrimidine-6-nitrile (compound 3)
  • the target compound 4-245 in Table 1 can be obtained.
  • the ADP-GLO method was used to determine the inhibitory effect of the compound on the activity of CDK2 and CDK4. details as follows.
  • the compound diluted in DMSO was added to a 384-well plate, centrifuged at 1000g for 1 minute and then added with enzyme diluted in kinase buffer, centrifuged at 1000g for 30s, incubated at room temperature for 10 minutes, and then added 2X substrate and ATP. After centrifugation at 1000g for 30s, the reaction was carried out at room temperature for 60 minutes. Add ADP-Glo and incubate at room temperature for 40 minutes, then add detection solution. After incubating for 40 minutes, the luminescence was detected. Compared with the DMSO group, the compound is calculated and the percent inhibition IC 50. The results are shown in Table 3 below.
  • OVCAR-3 cells 1000 OVCAR-3 cells were planted in a 384-well plate, and after one day of growth, serially diluted compounds were added. Seven days after the compound was added, Cell Titer Glow was added to evaluate cell growth, and the percentage and IC 50 value of the compound's inhibition of cell growth were calculated. The results are shown in Table 4 below.
  • the anti-proliferative activity of most of the compounds of the present invention on OVCAR-3 cells is less than 200 nM, and the anti-proliferative activity of PF-06873600 on OVCAR-3 cells is greater than 2000 nM. It can be seen that the compounds of the present invention have strong OVCAR-3 Anti-proliferative activity of cells. Further experiments proved that other compounds of the present invention also have strong anti-proliferative activity of OVCAR-3 cells.

Abstract

La présente invention concerne un composé représenté par la formule générale (1) et un procédé de préparation associé, et l'utilisation du composé représenté par la formule générale (1), des isomères de ceux-ci, des formes cristallines de ceux-ci et des sels pharmaceutiquement acceptables de ceux-ci en tant qu'inhibiteur de CDK2/4 dans la préparation d'un médicament antitumoral.
PCT/CN2021/100336 2020-06-17 2021-06-16 Nouveau dérivé de pyrido[2,3-d]pyrimidine-7(8h)-one WO2021254384A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023051302A1 (fr) * 2021-09-29 2023-04-06 中国医药研究开发中心有限公司 Composé hétérocyclique ayant une activité inhibitrice de kinase cycline-dépendante, son procédé de préparation et son utilisation médicale
WO2023116884A1 (fr) * 2021-12-24 2023-06-29 Qilu Regor Therapeutics Inc. Inhibiteurs de cdk2 et leur utilisation
WO2024067820A1 (fr) * 2022-09-30 2024-04-04 Shenzhen Ionova Life Science Co., Ltd. Composés tricycliques en tant qu'inhibiteurs de cdk et leurs procédés d'utilisation

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US20060142312A1 (en) * 2004-12-23 2006-06-29 Pfizer Inc C6-aryl and heteroaryl substituted pyrido[2,3-D] pyrimidin-7-ones
CN109803968A (zh) * 2016-08-15 2019-05-24 辉瑞公司 吡啶并嘧啶酮cdk2/4/6抑制剂

Patent Citations (2)

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US20060142312A1 (en) * 2004-12-23 2006-06-29 Pfizer Inc C6-aryl and heteroaryl substituted pyrido[2,3-D] pyrimidin-7-ones
CN109803968A (zh) * 2016-08-15 2019-05-24 辉瑞公司 吡啶并嘧啶酮cdk2/4/6抑制剂

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023051302A1 (fr) * 2021-09-29 2023-04-06 中国医药研究开发中心有限公司 Composé hétérocyclique ayant une activité inhibitrice de kinase cycline-dépendante, son procédé de préparation et son utilisation médicale
WO2023116884A1 (fr) * 2021-12-24 2023-06-29 Qilu Regor Therapeutics Inc. Inhibiteurs de cdk2 et leur utilisation
WO2024067820A1 (fr) * 2022-09-30 2024-04-04 Shenzhen Ionova Life Science Co., Ltd. Composés tricycliques en tant qu'inhibiteurs de cdk et leurs procédés d'utilisation

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